JP2006519250A - Use of EP2 selective receptor agonists in medical procedures - Google Patents

Abstract

The present invention uses EP ₂ selective receptor agonists to treat pulmonary hypertension, promote joint fusion, promote tendon and ligament repair, reduce the occurrence of secondary fractures, and avascular necrosis Promote cartilage repair, promote bone healing after limb transplantation, promote liver regeneration, promote wound healing, reduce gastric ulcer development, treat hypertension, dental enamel or The present invention relates to a method for promoting nail growth of toes and toes, treating glaucoma, treating ocular hypertension, or repairing damage caused by metastatic bone disease.

Description

FIELD OF THE INVENTION The present invention uses EP ₂ selective receptor agonists to treat pulmonary hypertension, promote joint fusion, promote tendon and ligament repair, reduce the occurrence of secondary fractures, Treat vascular necrosis, promote cartilage repair, promote bone healing after limb transplantation, promote liver regeneration, promote wound healing, reduce gastric ulcer development, treat hypertension, treat dental It relates to a method of promoting enamel or toenail growth, treating glaucoma, treating ocular hypertension, or repairing damage caused by metastatic bone disease.

BACKGROUND OF THE INVENTION Compounds that are prostaglandin receptor ligands are known to be useful for treating various diseases such as osteoporosis. A variety of natural prostaglandins such as PGE, PGD and PGF are involved in skeletal metabolism. PGE2 has been reported to stimulate bone formation and increase bone mass and strength in animal models of osteoporosis when administered systemically or locally. However, there are serious side effects associated with PGE2, such as diarrhea, gastrointestinal bleeding, decreased food intake, dehydration, weight loss and decreased physical activity. Therefore, PGE2 is not widely used in humans due to these side effects. Recently, four different subtypes of PGE2 receptors have been cloned. These four subtypes are named EP ₁ , EP ₂ , EP ₃ and EP ₄ and studies are currently underway to better understand the pharmacological effects of these receptor subtypes.

The present invention uses EP ₂ selective receptor agonists to treat pulmonary hypertension, promote joint fusion, promote tendon and ligament repair, reduce the occurrence of secondary fractures, and avascular necrosis Promote cartilage repair, promote bone healing after limb transplantation, promote liver regeneration, promote wound healing, reduce gastric ulcer development, treat hypertension, dental enamel or Methods for promoting nail growth on toes, toes, treating glaucoma, treating ocular hypertension, or repairing damage caused by metastatic bone disease are provided. Certain EP ₂ selective receptor agonists are known in the art. See for example USP 6,498,172.

SUMMARY OF THE INVENTION The present invention treats pulmonary hypertension, promotes joint fusion, promotes tendon and ligament repair, reduces secondary fracture development, treats avascular necrosis, promotes cartilage repair Promotes bone healing after limb transplantation, promotes liver regeneration, promotes wound healing, reduces gastric ulcer development, treats hypertension, promotes tooth enamel or finger and toe nail growth A method of treating glaucoma, treating ocular hypertension, or repairing damage caused by metastatic bone disease, wherein a therapeutically effective amount of an EP ₂ selective receptor agonist is administered to a patient in need thereof A method comprising:

The invention relates to compounds wherein the EP ₂ selective receptor agonist is of formula I

Or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
In the formula:
A is SO ₂ or CO;
G is Ar, Ar ¹ -V-Ar ² , Ar- (C ₁ -C ₆ ) alkylene, Ar-CONH- (C ₁ -C ₆ ) alkylene, R ¹ R ² -amino, oxy (C ₁ -C ₆ ) alkylene, amino substituted with Ar, or amino substituted with Ar (C ₁ -C ₄ ) alkylene, and R ¹¹ , where R ¹¹ is H or (C ₁ -C ₈ ) alkyl R ¹ and R ² are separate and independently selected from H and (C ₁ -C ₈ ) alkyl, or R ¹ and R ² together with the nitrogen atom of the amino group are 5-membered or 6 Form a membered azacycloalkyl, which may contain an oxygen atom and is independently up to two oxo, hydroxy, (C ₁ -C ₄ ) alkyl, fluoro or chloro mono-, di- Or may be tri-substituted;
B is N or CH;
Q is the following:
-(C ₂ -C ₆ ) alkylene-W- (C ₁ -C ₃ ) alkylene-: each alkylene is independently up to 4 substituents selected from fluoro or (C ₁ -C ₄ ) alkyl May be substituted,
-(C ₄ -C ₈ ) alkylene-: alkylene may be optionally substituted with up to 4 substituents selected from fluoro or (C ₁ -C ₄ ) alkyl;
-X- (C ₁ -C ₅ ) alkylene-: alkylene may be optionally substituted with up to 4 substituents selected from fluoro or (C ₁ -C ₄ ) alkyl;
-(C ₁ -C ₅ ) alkylene-X-: alkylene may be substituted with up to 4 substituents independently selected from fluoro or (C ₁ -C ₄ ) alkyl,
-(C ₁ -C ₃ ) alkylene-X- (C ₁ -C ₃ ) alkylene-: each alkylene is independently up to 4 substituents selected from fluoro or (C ₁ -C ₄ ) alkyl May be substituted,
-(C ₂ -C ₄ ) alkylene-WX- (C ₀ -C ₃ ) alkylene-: each alkylene is independently at most 4 substituents selected from fluoro or (C ₁ -C ₄ ) alkyl Optionally substituted with
-(C ₀ -C ₄ ) alkylene-XW- (C ₁ -C ₃ ) alkylene-: each alkylene is independently at most 4 substituents selected from fluoro or (C ₁ -C ₄ ) alkyl Optionally substituted with
-(C ₂ -C ₅ ) alkylene-WXW- (C ₁ -C ₃ ) alkylene-: the two Ws are independent of each other and each alkylene is independently fluoro or (C ₁ -C ₄ ) Optionally substituted with up to 4 substituents selected from alkyl,
-(C ₁ -C ₄ ) alkylene-ethenylene- (C ₁ -C ₄ ) alkylene-: each alkylene and ethenylene is each independently up to ₄ selected from fluoro or (C ₁ -C ₄ ) alkyl Optionally substituted with a substituent,
-(C ₁ -C ₄ ) alkylene-ethenylene- (C ₀ -C ₂ ) alkylene-X- (C ₀ -C ₅ ) alkylene-: each alkylene and ethenylene are each independently fluoro or (C ₁ -C ₄ ) optionally substituted with up to 4 substituents selected from alkyl,
-(C ₁ -C ₄ ) alkylene-ethenylene- (C ₀ -C ₂ ) alkylene-XW- (C ₁ -C ₃ ) alkylene-: each alkylene and ethenylene are each independently fluoro or (C ₁ -C ₄ ) optionally substituted with up to 4 substituents selected from alkyl,
-(C ₁ -C ₄ ) alkylene-ethynylene- (C ₁ -C ₄ ) alkylene-: each alkylene and ethynylene is each independently up to ₄ selected from fluoro or (C ₁ -C ₄ ) alkyl Optionally substituted with a substituent, or
-(C ₁ -C ₄ ) alkylene-ethynylene-X- (C ₀ -C ₃ ) alkylene-: each alkylene and ethynylene is each independently selected from fluoro or (C ₁ -C ₄ ) alkyl up to 4 Optionally substituted with 1 substituent;
Z is carboxyl, (C ₁ -C ₆ ) alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, ( C ₁ -C ₄₎ be alkylsulfonylcarbamoyl or phenyl sulfonylcarbamoyl;
K is a bond, (C ₁ -C ₉ ) alkylene, thio (C ₁ -C ₄ ) alkylene, (C ₁ -C ₄ ) alkylenethio (C ₁ -C ₄ ) alkylene, (C ₁ -C ₄ ) alkylene Oxy (C ₁ -C ₄ ) alkylene or oxy (C ₁ -C ₄ ) alkylene, where (C ₁ -C ₉ ) alkylene may be mono-unsaturated, and when K is not a bond, K is independent Optionally mono-, di- or tri-substituted with chloro, fluoro, hydroxy or methyl;
M ^{is, -Ar 3, -Ar 4 -V 1} -Ar 5, -Ar 4 -S-Ar 5, -Ar 4 -SO-Ar 5, -Ar 4 -SO 2 -Ar 5 or -Ar ^4, - O-Ar ⁵ ;
Ar is a partially saturated or fully unsaturated 5- to 8-membered ring and may contain 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or two fused An independently partially saturated, fully saturated or fully unsaturated 5- or 6-membered bicyclic ring, independently containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen Or three condensed, independently partially saturated, fully saturated or fully unsaturated 5- or 6-membered tricyclic rings independently from nitrogen, sulfur and oxygen May contain 1 to 4 heteroatoms selected, and these partially saturated or fully saturated rings, bicyclic rings or tricyclic rings are substituted with 1 or 2 oxo groups at the carbon atom Or one or two oxo groups substituted at the sulfur atom At best; or Ar is a fully saturated 5 to 7 membered ring, containing oxygen, 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen independently;
Ar ¹ and Ar ² are each independently a partially saturated, fully saturated or fully unsaturated 5- to 8-membered ring and independently selected from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen Or two fused, independently partially saturated, fully saturated or fully unsaturated bicyclic rings consisting of 5 or 6 members, independently nitrogen, sulfur and oxygen 1 to 4 heteroatoms selected from: or three condensed, independently tricyclic rings consisting of a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring And may contain 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen, and these partially saturated or fully saturated rings, bicyclic rings or tricyclic rings are: In one or two oxo groups or sulfur atoms substituted at the carbon atom It may include substituted one or two oxo groups;
Ar, Ar ¹ and Ar ² moieties are one ring when the moiety is monocyclic, one or both rings when the moiety is bicyclic, or the moiety is tricyclic. In some cases, at one, two or three ring carbons or nitrogens, each moiety may be substituted with up to ^three independently selected substituents selected from R ³ , R ⁴ and R ⁵ , where R ³ , R ⁴ and R ⁵ are independently: hydroxy, nitro, halo, carboxy, (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₄ ) alkoxy (C ₁ -C ₄ ) Alkyl, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₇ ) alkyl, (C ₂ -C ₇ ) alkenyl, (C ₂ -C ₇ ) alkynyl, (C ₃ -C ₇ ) cycloalkyl, ( C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₄ ) alkyl, (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₄ ) alkanoyl, formyl, (C ₁ -C ₈ ) alkanoyl, (C _1- C ₆ ) Alkanoyl (C ₁ -C ₆₎ alkyl, (C ₁ -C ₄₎ alkanoylamino, (C ₁ -C ₄₎ alkoxycarbonylamino, hydroxysulfonyl, aminocarbonylamino or mono -N-, di -N, N-, di -N, N'- or tri-N, N, N '-(C ₁ -C ₄ ) alkyl substituted aminocarbonylamino, sulfonamide, (C ₁ -C ₄ ) alkylsulfonamide, amino, mono-N- or di-N , N- (C ₁ -C ₄ ) alkylamino, carbamoyl, mono-N- or di-N, N- (C ₁ -C ₄ ) alkylcarbamoyl, cyano, thiol, (C ₁ -C ₆ ) alkylthio, ( C ₁ -C ₆₎ alkylsulfinyl, (C ₁ -C ₄₎ alkylsulfonyl or mono -N- or di _{-N,, N- (C 1 -C} 4) alkylamino sulfinyl;
Ar ³ , Ar ⁴ and Ar ⁵ are each independently a partially saturated, fully saturated or fully unsaturated 5- to 8-membered ring and independently selected from oxygen, sulfur and nitrogen Or two fused, independently partially saturated, fully saturated or fully unsaturated bi- or 5-membered bicyclic rings, independently nitrogen, May contain 1 to 4 heteroatoms selected from sulfur and oxygen, or three fused, independently, partially saturated, fully saturated or fully unsaturated 5- or 6-membered tricycles Cyclic rings, which may contain 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen, and these partially saturated or fully saturated rings, bicyclic rings or tricyclic rings The ring is attached to one or two oxo groups or sulfur atoms substituted at the carbon atom. Optionally containing 1 or 2 oxo groups substituted; the Ar ³ , Ar ⁴ and Ar ⁵ moieties are of one ring if the moiety is monocyclic and the moiety is bicyclic Up to 3 independently for each moiety R ³¹ , R ^{41 on} one or both rings, or if the moiety is tricyclic, on 1, 2 or 3 ring carbons or nitrogens. and it may be substituted with a substituent selected from R ^51, wherein R ^31, R ⁴¹ and R ⁵¹ are those of the following independently: hydroxy, nitro, halo, carboxy, (C ₁ -C ₇₎ alkoxy, (C ₁ -C ₄₎ alkoxy (C ₁ -C ₄₎ alkyl, (C ₁ -C ₄₎ alkoxycarbonyl, (C ₁ -C ₇₎ alkyl, (C ₂ -C ₇₎ alkenyl, ( C ₂ -C ₇₎ alkynyl, (C ₃ -C ₇₎ cycloalkyl, (C ₃ -C ₇₎ cycloalkyl (C ₁ -C ₄₎ alkyl, (C ₃ -C ₇₎ cycloalkyl (C ₁ -C ₄₎ Al Noil, formyl, (C ₁ -C ₈₎ alkanoyl, (C ₁ -C ₆₎ alkanoyl (C ₁ -C ₆₎ alkyl, (C ₁ -C ₄₎ alkanoylamino, (C ₁ -C ₄₎ alkoxycarbonylamino Hydroxysulfonyl, aminocarbonylamino or mono-N-, di-N, N-, di-N, N′- or tri-N, N, N ′-(C ₁ -C ₄ ) alkyl-substituted aminocarbonylamino, Sulfonamide, (C ₁ -C ₄ ) alkylsulfonamide, amino, mono-N- or di-N, N- (C ₁ -C ₄ ) alkylamino, carbamoyl, mono-N- or di-N, N- (C ₁ -C ₄ ) alkylcarbamoyl, cyano, thiol, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylsulfinyl, (C ₁ -C ₄ ) alkylsulfonyl, or mono-N- or di- _{-N, N- (C 1 -C 4} ) alkylamino sulfinyl;
W is oxy, thio, sulfino, sulfonyl, aminosulfonyl -, - mono -N- (C ₁ -C ₄₎ alkylene aminosulfonyl -, sulfonylamino, N- (C ₁ -C ₄₎ alkylene sulfonylamino, carboxamido, N- (C ₁ -C ₄₎ alkylene-carboxamide, carboxamide oxy, N- (C ₁ -C ₄₎ alkylene carboxamide oxy, carbamoyl, - mono -N- (C ₁ -C ₄₎ alkylene carbamoyl, carbamoyloxy, or - Mono-N- (C ₁ -C ₄ ) alkylenecarbamoyloxy, the alkyl group of W may be substituted with 1 to 3 fluorines at the carbon;
X is a 5- or 6-membered aromatic ring and may contain 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur; the ring is independently halo, ( C ₁ -C ₃ ) alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C ₁ -C ₄ ) alkoxy, or carbamoyl may be mono-, di- or tri-substituted;
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹¹ , R ³¹ , R ⁴¹ and R ⁵¹ are independently halo or hydroxy mono on the carbon when containing an alkyl, alkylene, alkenylene or alkynylene moiety. May be-, di- or tri-substituted;
V and V ¹ are each independently a bond, thio (C ₁ -C ₄ ) alkylene, (C ₁ -C ₄ ) alkylenethio, (C ₁ -C ₄ ) alkyleneoxy, oxy (C ₁ -C ₄ ) Alkylene or (C ₁ -C ₃ ) alkylene, which may independently be mono- or di-substituted with hydroxy or fluoro;
However:
a. When K is (C ₂ -C ₄ ) alkylene, M is Ar ³ and Ar ³ is cyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cyclooct-1-yl, These (C ₅ -C ₈ ) cycloalkyl substituents are not substituted with hydroxy at the 1-position;
b. When K is a bond; G is phenyl, phenylmethyl, substituted phenyl or substituted phenylmethyl; Q is (C ₃ -C ₈ ) alkylene; and M is Ar ³ or Ar ⁴ -Ar ⁵ Is sulfonyl.

  The present invention treats pulmonary hypertension, promotes joint fusion, promotes tendon and ligament repair, reduces the occurrence of secondary fractures, treats avascular necrosis, promotes cartilage repair, Promotes bone healing after transplantation, promotes liver regeneration, promotes wound healing, reduces gastric ulcer development, treats hypertension, promotes tooth enamel or toenails growth and promotes glaucoma , Treating ocular hypertension, or repairing damage caused by metastatic bone disease, wherein a therapeutically effective amount of (3-(((4-t-butyl-benzyl Also provided is a method comprising administering)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid or a pharmaceutically acceptable salt thereof.

Detailed description of the invention
EP ₂ selective receptor agonists are shown in USP 6,498,172. Preferred EP ₂ selective receptor agonists that can be used in the present invention are compounds of formula I as defined above.

A preferred group of compounds labeled Group A includes the following compounds having Formula I above, prodrugs thereof, and pharmaceutically acceptable salts of those compounds and prodrugs: B is N; Carboxyl, (C ₁ -C ₆ ) alkoxycarbonyl or tetrazolyl; Ar is phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 2H-pyrrolyl 3H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, 1,2,3-oxadiazolyl, 1,2 , 4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxa Diazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 2H-pyranyl, 4H-pyranyl, pyridyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, 1, 3,5-triazinyl, 1,2,4-triazinyl, azepinyl, oxepinyl, thiepinyl, cyclopentenyl, cyclohexenyl, benzo (b) thienyl, benzoxazolyl, benzoimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl , Naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl and 1,4-benzodioxane; the Ar ¹ , Ar ² , Ar ³ , Ar ⁴ and Ar ⁵ moieties are each independently cyclopentyl, cyclohexyl, cycloheptyl, Cyclooctyl, phenyl, furyl, thienyl, pyrrole Oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, 2H- Imidazolyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2, 3-triazolyl, 1,2,4-triazolyl, 2H-pyranyl, 4H-pyranyl, pyridyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, azepinyl, oxepinyl, thiepinyl, 1,2,4-diazepinyl, cyclope Tenenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclooctadienyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, 1H-isoindolyl, indolinyl, cyclopenta (b) pyridinyl, pyrano (3,4-b) pyrrolyl, benzofuryl, isobenzo Furyl, benzo (b) thienyl, benzo (c) thienyl, 1H-indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl, benzothiazolyl, purinyl, 4H-quinolidinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinazolinyl, quinazolinyl, 1 , 8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, 1,4-benzodioxan, pyrido (3,4-b) -pyridinyl , Pyrido (3,2-b) -pyridinyl, pyrido (4,3-b) -pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 1H-2,3 -Benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1,2-benzoxazinyl and 4H-1,4-benzoxazinyl; X is tetrahydrofuranyl, phenyl, thiazolyl , Thienyl, pyridyl, pyrazolyl, furanyl or pyrimidyl, and X is independently mono-, di- or tri-substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl. Each of the Ar, Ar ¹ and Ar ² groups may be substituted on carbon or nitrogen with up to three independently selected substituents selected from R ³ , R ⁴ and R ⁵ , Ar, each Ar ¹ and Ar ² groups, 1 at a carbon or sulfur and independently Others may be substituted by two oxo groups; Ar ^3, Ar ⁴ and Ar ⁵ groups respectively, on carbon or nitrogen, independently substituted with up to three R ^31, R ⁴¹ and R ⁵¹ groups Ar ³ , Ar ⁴ and Ar ⁵ groups may each independently be substituted with 1 or 2 oxo groups at carbon or sulfur.

One group of compounds within Group A (designated Group B) includes the following compounds, their prodrugs, and pharmaceutically acceptable salts of those compounds and prodrugs: A is CO; G is oxy (C ₁ -C ₆ ) alkylene; Q is:
-(C ₂ -C ₆ ) alkylene-O- (C ₁ -C ₃ ) alkylene-,
-(C ₄ -C ₈ ) alkylene-: The-(C ₄ -C ₈ ) alkylene- is substituted with up to 4 substituents independently selected from fluoro or (C ₁ -C ₄ ) alkyl. May be,
-X- (C ₂ -C ₅ ) alkylene-,
-(C ₁ -C ₅ ) alkylene-X-,
-(C ₁ -C ₃ ) alkylene-X- (C ₁ -C ₃ ) alkylene-,
-(C ₂ -C ₄ ) alkylene-OX- (C ₀ -C ₃ ) alkylene-, or
-(C ₀ -C ₄ ) alkylene-XO- (C ₁ -C ₃ ) alkylene-;
X is phenyl, thienyl, furanyl or thiazolyl, and X may be mono-, di- or tri-substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl.

Another preferred group of compounds within Group A (designated Group C) includes the following compounds, their prodrugs, and pharmaceutically acceptable salts of those compounds and prodrugs: A is CO; Is Ar; Q is:
-(C ₂ -C ₆ ) alkylene-O- (C ₁ -C ₃ ) alkylene-,
-(C ₄ -C ₈ ) alkylene-: The-(C ₄ -C ₈ ) alkylene- is substituted with up to 4 substituents independently selected from fluoro or (C ₁ -C ₄ ) alkyl. May be,
-X- (C ₂ -C ₅ ) alkylene-,
-(C ₁ -C ₅ ) alkylene-X-,
-(C ₁ -C ₃ ) alkylene-X- (C ₁ -C ₃ ) alkylene-,
-(C ₂ -C ₄ ) alkylene-OX- (C ₀ -C ₃ ) alkylene-, or
-(C ₀ -C ₄ ) alkylene-XO- (C ₁ -C ₃ ) alkylene-;
X is phenyl, thienyl, furanyl or thiazolyl, and X may be mono-, di- or tri-substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl.

Another preferred group of compounds within Group A (designated Group D) includes the following compounds, their prodrugs, and pharmaceutically acceptable salts of those compounds and prodrugs: A is CO; Is R ¹ R ² -amino or amino substituted with Ar, or amino substituted with Ar (C ₁ -C ₄ ) alkylene, and R ¹¹ , where R ¹¹ is H; Q is Is:
-(C ₂ -C ₆ ) alkylene-O- (C ₁ -C ₃ ) alkylene-,
-(C ₄ -C ₈ ) alkylene-: The-(C ₄ -C ₈ ) alkylene- is substituted with up to 4 substituents independently selected from fluoro or (C ₁ -C ₄ ) alkyl. May be,
-X- (C ₂ -C ₅ ) alkylene-,
-(C ₁ -C ₅ ) alkylene-X-,
-(C ₁ -C ₃ ) alkylene-X- (C ₁ -C ₃ ) alkylene-,
-(C ₂ -C ₄ ) alkylene-OX- (C ₀ -C ₃ ) alkylene-, or
-(C ₀ -C ₄ ) alkylene-XO- (C ₁ -C ₃ ) alkylene-;
X is phenyl, thienyl, furanyl or thiazolyl and X may be mono-, di- or tri-substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl;
R ¹ and R ² are separate and independently selected from H and (C ₁ -C ₈ ) alkyl, or R ¹ and R ² together form a 5- or 6-membered azacycloalkyl. The azacycloalkyl may contain an oxygen atom.

Another preferred group of compounds within Group G (designated Group E) includes the following compounds, their prodrugs, and pharmaceutically acceptable salts of those compounds and prodrugs: A is SO ₂ ; G is R ¹ R ² -amino, or amino substituted with Ar and R ¹¹ ; Q is:
-(C ₂ -C ₆ ) alkylene-O- (C ₁ -C ₃ ) alkylene-,
-(C ₄ -C ₈ ) alkylene-: The-(C ₄ -C ₈ ) alkylene- is substituted with up to 4 substituents independently selected from fluoro or (C ₁ -C ₄ ) alkyl. May be,
-X- (C ₂ -C ₅ ) alkylene-,
-(C ₁ -C ₅ ) alkylene-X-,
-(C ₁ -C ₃ ) alkylene-X- (C ₁ -C ₃ ) alkylene-,
-(C ₂ -C ₄ ) alkylene-OX- (C ₀ -C ₃ ) alkylene-, or
-(C ₀ -C ₄ ) alkylene-XO- (C ₁ -C ₃ ) alkylene-;
X is phenyl, thienyl, furanyl or thiazolyl and X may be mono-, di- or tri-substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl;
R ¹ and R ² are separate and independently selected from H and (C ₁ -C ₈ ) alkyl, or R ¹ and R ² together form a 5- or 6-membered azacycloalkyl. The azacycloalkyl may contain an oxygen atom.

Another preferred group of compounds within Group A (designated as Group F) includes the following compounds, their prodrugs, and pharmaceutically acceptable salts of those compounds and prodrugs: A is SO ₂ ; G is Ar, Ar (C ₁ -C ₂ ) alkylene or Ar ¹ -V-Ar ² ; Q is:
-(C ₂ -C ₆ ) alkylene-O- (C ₁ -C ₃ ) alkylene-,
-(C ₄ -C ₈ ) alkylene-: The-(C ₄ -C ₈ ) alkylene- is substituted with up to 4 substituents independently selected from fluoro or (C ₁ -C ₄ ) alkyl. May be,
-X- (C ₂ -C ₅ ) alkylene-,
-(C ₁ -C ₅ ) alkylene-X-,
-(C ₁ -C ₃ ) alkylene-X- (C ₁ -C ₃ ) alkylene-,
-(C ₂ -C ₄ ) alkylene-OX- (C ₀ -C ₃ ) alkylene-, or
-(C ₀ -C ₄ ) alkylene-XO- (C ₁ -C ₃ ) alkylene-;
X is phenyl, pyrimidyl, pyridyl, thienyl, tetrahydrofuranyl, furanyl or thiazolyl, X is chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl mono-, di- or tri- May be substituted.

A particularly preferred group of compounds within group F (designated FA group) includes the following compounds, their prodrugs, and pharmaceutically acceptable salts of those compounds and prodrugs: G is Ar or Ar- (C ₁ -C ₂ ) alkylene; A is phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, isothiazolyl, 1,2,3-triazolyl, 1,2 , 4-triazolyl or 1,3,4-thiadiazolyl; the Ar group may be substituted at each carbon or nitrogen with R ¹ , R ² and R ³ ; Ar ⁴ is cyclopentyl, cyclohexyl, cyclo Heptyl, cyclooctyl, phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazol Ril, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, thiomorpholinyl, piperazinyl, 1,3,5-triazinyl, 1,2, 4-triazinyl, 1,2,3-triazinyl, azepinyl, oxepinyl or thiepinyl, the Ar ⁴ group being mono-, di- or tri-substituted with R ³¹ , R ⁴¹ or R ⁵¹ on carbon or nitrogen, respectively Ar ⁵ may be cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, 1, 2,3-triazolyl, 1,2,4-to Azolyl, pyranyl, 1,4-dioxanyl, thiomorpholinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, azepinyl, a oxepinyl or thiepinyl, Ar ⁵ groups are Each may be mono-, di- or tri-substituted at R ³¹ , R ⁴¹ and R ⁵¹ on carbon or nitrogen; Q is — (C ₅ -C ₇ ) -alkylene-, — (C _1- C ₂ ) -alkylene-X- (C ₁ -C ₂ ) alkylene-,-(C ₁ -C ₂ ) -XO- (C ₁ -C ₂ ) alkylene-,-(C ₂ -C ₄ ) -alkylene- Thienyl-,-(C ₂ -C ₄ ) -alkylene-furanyl- or-(C ₂ -C ₄ ) -alkylene-thiazolyl-; X is phenyl, pyridyl, pyrimidyl or thienyl, and the X group is Mono-, di- or tri-substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl At best ;-( C ₂ -C ₄₎ - alkylene - furanyl - and - (C ₂ -C ₄₎ - alkylene - thienyl -, for example

With a 2,5-substitution pattern of
A particularly preferred group of compounds within the FA group (designated FB group) includes the following compounds, their prodrugs, and pharmaceutically acceptable salts of those compounds and prodrugs: K is methylene and M is Ar ⁴ -Ar ⁵ , Ar ⁴ -O-Ar ⁵ or Ar ⁴ -S-Ar ⁵ , Ar is phenyl, pyridyl, pyrazolyl, imidazolyl, pyrimidyl, thienyl or thiazolyl, Ar is carbon or nitrogen In which R ³ , R ⁴ and R ⁵ may be mono-, di- or tri-substituted.

A particularly preferred group of compounds within the FB group (designated as the FC group) includes the following compounds, their prodrugs, and pharmaceutically acceptable salts of these compounds and prodrugs: M is Ar ⁴ -Ar ⁵ Yes; Ar is phenyl, pyridyl or imidazolyl; Ar ⁴ is phenyl, furanyl or pyridyl; Ar ⁵ is cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, imidazolyl, pyrimidyl, thienyl, pyridazinyl, pyrazinyl, Imidazolyl, pyrazolyl or thiazolyl, Ar, Ar ⁴ and Ar ⁵ groups are independently mono-, di-, chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethyl or trifluoromethoxy in carbon or nitrogen Or it may be tri-substituted.

A particularly preferred group of compounds within the FC group (denoted as FD group) are compounds wherein Q is — (C ₅ -C ₇ ) -alkylene-, their prodrugs, and pharmaceutically acceptable of those compounds and prodrugs Contains possible salt.

Another particularly preferred group of compounds within the FC group (denoted as FE group) is that Q is CH ₂ —X—CH ₂ — and X is chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl. Or methyl, mono-, di- or tri-substituted metaphenylene, prodrugs thereof, and pharmaceutically acceptable salts of the compounds and prodrugs.

  A particularly preferred group of compounds within the FE group includes compounds selected from the following, prodrugs thereof, and pharmaceutically acceptable salts of those compounds and prodrugs: (3-(((pyridine-3- (Sulfonyl)-(4-pyrimidin-5-yl-benzyl) -amino) -methyl) -phenyl) -acetic acid; (3-(((5-phenyl-furan-2-ylmethyl)-(pyridine-3-sulfonyl) -Amino) -methyl) -phenyl) -acetic acid; (3-(((pyridin-3-sulfonyl)-(4-pyrimidin-2-yl-benzyl) -amino) -methyl) -phenyl) -acetic acid; -((((Pyridin-3-sulfonyl)-(4-thiazol-2-yl-benzyl) -amino) -methyl) -phenyl) -acetic acid; and (3-(((4-pyrazin-2-yl-benzyl) )-(Pyridin-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid.

Particularly preferred compounds within the FE group are: Ar is pyrid-3-yl; Z is carboxy; M is Ar ⁴ -Ar ⁵ , Ar ⁴ is a furanyl ring, Ar ⁵ is phenyl; A compound in which the phenyl moiety is substituted at the 5-position of the furanyl ring; Q is —CH ₂ —X—CH ₂ — and X is metaphenylene.

Other particularly preferred compounds within the FE group are: Ar is pyrid-3-yl; Z is carboxy; M is Ar ⁴ -Ar ⁵ , Ar ⁴ is phenyl, Ar ⁵ is pyrimido-2 A compound in which the pyrimido-2-yl moiety is substituted at the 4-position of the phenyl ring; Q is —CH ₂ —X—CH ₂ — and X is metaphenylene.

Still other particularly preferred compounds within the FE group are: Ar is pyrid-3-yl; Z is carboxy; M is Ar ⁴ -Ar ⁵ , Ar ⁴ is phenyl, and Ar ⁵ is thiazole- A compound in which the thiazol-2-yl moiety is substituted at the 4-position of the phenyl ring; Q is —CH ₂ —X—CH ₂ — and X is metaphenylene.

Still other particularly preferred compounds within the FE group are: Ar is pyrid-3-yl; Z is carboxy; M is Ar ⁴ -Ar ⁵ , Ar ⁴ is phenyl, and Ar ⁵ is pyrimido- A compound in which the pyrimido-5-yl moiety is substituted at the 4-position of the phenyl ring; Q is —CH ₂ —X—CH ₂ — and X is metaphenylene.

Other particularly preferred compounds within the FE group are: Ar is pyrid-3-yl; Z is carboxy; M is Ar ⁴ -Ar ⁵ , Ar ⁴ is phenyl, Ar ⁵ is pyrazine-2 A compound in which the pyrazin-2-yl is substituted at the 4-position of the phenyl ring; Q is —CH ₂ —X—CH ₂ — and X is metaphenylene.

Preferred compound groups within the FC group (designated as G group) are those in which Q is — (C ₂ -C ₄ ) -alkylene-thienyl-, — (C ₂ -C ₄ ) -alkylene-furanyl- or — (C ₂ -C ₄₎ - include those compounds, prodrugs thereof, and pharmaceutically acceptable salts of the compounds and prodrugs thereof - alkylene - thiazolyl.

A particularly preferred compound within group G is 5- (3-((pyridin-3-sulfonyl)-(4-thiazol-2-yl-benzyl) -amino) -propyl) -thiophene-2-carboxylic acid.
Particularly preferred compounds within Group G are: Q is n-propylenyl; X is thienyl; Z is carboxy; Ar is 3-pyridyl; Ar ⁴ is phenyl; Ar ⁵ is 2-thiazolyl Wherein 2-thiazolyl is substituted at the 4-position of the phenyl ring, prodrugs thereof, and pharmaceutically acceptable salts of these compounds and prodrugs.

A preferred group of compounds within the FC group (designated as group H) are: Q is —CH ₂ —XO—CH ₂ —; Ar ⁴ is phenyl or pyridyl; these phenyl and pyridyl are chloro, fluoro, methoxy , Difluoromethoxy, trifluoromethoxy, trifluoromethyl and methyl; including compounds where X is metaphenylene, prodrugs thereof, and pharmaceutically acceptable salts of these compounds and prodrugs.

  A preferred group of compounds within group H is (3-(((4-cyclohexyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid; (3-(((pyridine-3 -Sulfonyl)-(4-pyridin-2-yl-benzyl) -amino) -methyl) -phenoxy) -acetic acid; (3-(((pyridin-3-sulfonyl)-(4-pyridin-3-yl-benzyl) ) -Amino) -methyl) -phenoxy) -acetic acid; (3-(((pyridin-3-sulfonyl)-(4-pyridin-4-yl-benzyl) -amino) -methyl) -phenoxy) -acetic acid; (3-(((Pyridin-3-sulfonyl)-(4-thiazol-2-yl-benzyl) -amino) -methyl) -phenoxy) -acetic acid.

Particularly preferred compounds within Group H are Ar is pyrid-3-yl; Z is carboxy; Ar ⁴ is phenyl; Ar ⁵ is cyclohexyl; the cyclohexyl moiety is the 4-position of the phenyl ring And the prodrugs thereof, and pharmaceutically acceptable salts of those compounds and prodrugs.

Other particularly preferred compounds within Group H are: Ar is pyrid-3-yl; Z is carboxy; Ar ⁴ is phenyl; Ar ⁵ is thiazol-2-yl; In this compound, the yl moiety is substituted at the 4-position of the phenyl ring.

Still other particularly preferred compounds within Group H are: Ar is pyrid-3-yl; Z is carboxy; Ar ⁴ is phenyl; Ar ⁵ is 2-pyridyl; A compound substituted at the 4-position of the phenyl ring.

Still other particularly preferred compounds within Group H are: Ar is pyrid-3-yl; Z is carboxy; Ar ⁴ is phenyl; Ar ⁵ is 3-pyridyl; A compound substituted at the 4-position of the phenyl ring.

Still other particularly preferred compounds within Group H are: Ar is pyrid-3-yl; Z is carboxy; Ar ⁴ is phenyl; Ar ⁵ is 4-pyridyl; the 4-pyridyl moiety is A compound substituted at the 4-position of the phenyl ring.

A preferred group of compounds within the FA group (designated as Group I) include the following compounds, their prodrugs, and pharmaceutically acceptable salts of those compounds and prodrugs: K is methylene, G is Ar Ar is phenyl, pyridazinyl, pyrazolyl, pyrazinyl, pyridyl, imidazolyl, pyrimidyl, thienyl or thiazolyl and Ar may be mono-, di- or tri-substituted with R ³ , R ⁴ and R ⁵ , M is Ar ³ and Ar ³ is cyclopentyl, cyclohexyl, phenyl, thienyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuryl, benzo (b) thienyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, naphthyl, tetralinyl a 2H-1-benzopyranyl or 1,4-benzodioxan, R ^31, click B, fluoro, methyl, methoxy, mono difluoromethoxy, trifluoromethyl or trifluoromethoxy, - di - or tri - may be substituted.

  A particularly preferred group of compounds within group I is (3-(((2,3-dihydro-benzo [1,4] dioxin-6-ylmethyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl ) -Acetic acid; and (3-((benzofuran-2-ylmethyl- (pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid.

Particularly preferred compounds within Group I are: Ar is pyrid-3-yl; Z is carboxy; M is 6- (1,4-benzodioxane); Q is —CH ₂ —X—CH ₂ -, Wherein X is metaphenylene, prodrugs thereof, and pharmaceutically acceptable salts of these compounds and prodrugs.

Other particularly preferred compounds within Group I are: Ar is pyrid-3-yl; Z is carboxy; M is 2-benzofuryl; Q is —CH ₂ —X—CH ₂ —; Is a compound that is metaphenylene.

Another particularly preferred group of compounds within Group I (designated Group J) includes the following compounds, their prodrugs, and pharmaceutically acceptable salts of those compounds and prodrugs: Ar is phenyl, pyridyl or Imidazolyl, these phenyl, pyridyl and imidazolyl may be independently substituted with chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethyl or trifluoromethoxy; Ar ³ is substituted with R ³¹ R ³¹ is (C ₁ -C ₇ ) alkyl, mono-N- or di-N, N- (C ₁ -C ₄ ) alkylamine, or (C ₁ -C ₅ ) alkoxy, These (C ₁ -C ₇ ) alkyl or (C ₁ -C ₅ ) alkoxy may independently be mono-, di- or tri-substituted with hydroxy or fluoro; Ar ³ may further be chloro, full B, methyl, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl mono- - or di - may be substituted.

Preferred groups of compounds within Group J (designated as Group K) are compounds wherein Q is — (C ₅ -C ₇ ) alkylene-, prodrugs thereof, and pharmaceutically acceptable salts of these compounds and prodrugs including.

Another preferred group of compounds within Group J (denoted as Group L) is that Q is —CH ₂ —X—CH ₂ — and X is chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl. Or methyl, which may be mono-, di- or tri-substituted phenyl, prodrugs thereof, and pharmaceutically acceptable salts of the compounds and prodrugs.

  A particularly preferred group of compounds within group L are (3-(((4-butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid; (3-((benzenesulfonyl- (4-Butyl-benzyl) -amino) -methyl) -phenyl) -acetic acid; (3-(((4-butyl-benzyl)-(1-methyl-1H-imidazol-4-sulfonyl) -amino) -methyl ) -Phenyl) -acetic acid; and (3-(((4-dimethylamino-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid.

Particularly preferred compounds within Group L are: Ar is pyrid-3-yl; Z is carboxy; M is phenyl substituted with n-butyl in the 4-position; Q is —CH ₂ —X— Compounds in which CH ₂ — and X is metaphenylene, prodrugs thereof, and pharmaceutically acceptable salts of these compounds and prodrugs.

Other particularly preferred compounds within Group L are: Ar is phenyl; Z is carboxy; M is phenyl substituted with n-butyl in the 4-position; Q is —CH ₂ —X—CH ₂ -, Wherein X is metaphenylene, prodrugs thereof, and pharmaceutically acceptable salts of these compounds and prodrugs.

Still other particularly preferred compounds within Group L are Ar is 4- (1-methyl-imidazolyl); Z is carboxy; M is phenyl substituted with n-butyl in the 4-position; Are —CH ₂ —X—CH ₂ —, wherein X is metaphenylene, prodrugs thereof, and pharmaceutically acceptable salts of these compounds and prodrugs.

Still other particularly preferred compounds within Group L are: Ar is pyrid-3-yl; Z is carboxy; M is phenyl substituted with dimethylamino in the 4-position; and Q is —CH ₂ —. Compounds in which X—CH ₂ — and X is metaphenylene, prodrugs thereof, and pharmaceutically acceptable salts of these compounds and prodrugs.

Another preferred group of compounds in group J is, Q is - (C ₂ -C ₄₎ - alkylene - _{thienyl, - (C 2 -C 4)} - alkylene - furanyl or - (C ₂ -C ₄₎ - alkylene - Compounds that are thiazolyl, prodrugs thereof, and pharmaceutically acceptable salts of those compounds and prodrugs.

A preferred group of compounds within Group J (denoted as Group M) is that Q is — (C ₁ -C ₂ ) —XO— (C ₁ -C ₂ ) alkylene-, X is metaphenylene, and X is Compounds that may be mono-, di- or tri-substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl, prodrugs thereof, and pharmaceuticals of these compounds and prodrugs Contains acceptable salts.

  Particularly preferred compounds within group M are (3-(((4-dimethylamino-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid and (3-(((4 -t-butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid.

Particularly preferred compounds within group M are: Ar is pyrid-3-yl; Z is carboxy; M is phenyl substituted with dimethylamino in the 4-position; Q is —CH ₂ —X—CH _2- compounds in which X is metaphenylene, prodrugs thereof, and pharmaceutically acceptable salts of these compounds and prodrugs.

Still other particularly preferred compounds within Group M are: Ar is pyrid-3-yl; Z is carboxy; M is phenyl substituted with t-butyl in the 4-position; Q is —CH ₂ -X-CH ₂ - and is, compounds wherein X is metaphenylene, its prodrug, and pharmaceutically acceptable salts of the compounds and prodrugs thereof.

Preferred compound groups within the FA group (designated N group) are: G is Ar; K is (C ₂ -C ₄ ) alkylene or n-propenylene; Ar is phenyl, pyrazolyl, pyridazinyl, pyrazinyl, pyridyl , Imidazolyl, pyrimidyl, thienyl or thiazolyl, Ar may be mono-, di- or tri-substituted with R ³ , R ⁴ and R ⁵ ; M is Ar ³ , chloro, fluoro, methyl, Includes compounds that may be mono-, di- or tri-substituted with methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl, prodrugs thereof, and pharmaceutically acceptable salts of those compounds and prodrugs.

Particularly preferred compounds within group N are trans- (3-(((3- (3,5-dichloro-phenyl) -allyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid. It is.
A particularly preferred compound within the N group is where K is trans-n-propenylene; the M group is attached to the 1-position of the n-propenylene and the N atom is attached to the 3-position of the n-propenylene; Ar is pyrid-3-yl; M is phenyl 3,5-disubstituted with chloro; Z is carboxy; Q is —CH ₂ —X—CH ₂ — and X is metaphenylene And their prodrugs, and pharmaceutically acceptable salts of those compounds and prodrugs.

A preferred group of compounds within Group N (designated as Group O) are compounds wherein Ar ³ is phenyl optionally substituted with chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl, The prodrugs, and pharmaceutically acceptable salts of those compounds and prodrugs are included.

Preferred compounds within the group O (denoted as group P) are compounds wherein Q is — (C ₅ -C ₇ ) alkylene-, prodrugs thereof, and pharmaceutically acceptable salts of these compounds and prodrugs including.

The other group of compounds in group O (denoted as group Q) are compounds wherein Q is —CH ₂ —X—CH ₂ — and X is metaphenylene, prodrugs thereof, and compounds and prodrugs thereof A pharmaceutically acceptable salt of

Yet another group of compounds within group O (denoted as group R) is a compound wherein Q is — (C ₂ -C ₄ ) alkylene-X— and X is furanyl, thienyl or thiazolyl, a prodrug thereof, And pharmaceutically acceptable salts of these compounds and prodrugs.

Still another preferred group of compounds within the group O (denoted as group S), Q is — (C ₁ -C ₂ ) —XO— (C ₁ -C ₂ ) alkylene-, and X is metaphenylene. Compounds, their prodrugs, and pharmaceutically acceptable salts of those compounds and prodrugs.

Other preferred compound groups within the FA group (designated T group) are: G is Ar; K is thioethylene or oxyethylene; Ar is phenyl, pyrazolyl, pyridazinyl, pyrazinyl, pyridyl, imidazolyl, pyrimidyl, thienyl Or thiazolyl, Ar may be substituted with up to ³ R ³ , R ⁴ and R ⁵ ; M is Ar ³ and is chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl And mono-, di- or tri-substituted compounds, prodrugs thereof, and pharmaceutically acceptable salts of these compounds and prodrugs.

A preferred group of compounds within Group T (designated as Group U) include compounds wherein Ar ³ is phenyl, prodrugs thereof, and pharmaceutically acceptable salts of these compounds and prodrugs.

Preferred groups of compounds within Group U (designated as Group V) are compounds wherein Q is — (C ₅ -C ₇ ) alkylene-, prodrugs thereof, and pharmaceutically acceptable salts of these compounds and prodrugs including.

The other compound groups in the U group (denoted as the W group) are compounds in which Q is —CH ₂ —X—CH ₂ — and X is metaphenylene, prodrugs thereof, and those compounds and prodrugs A pharmaceutically acceptable salt of

Yet another group of compounds within Group U (designated as Group X) is a compound wherein Q is — (C ₂ -C ₄ ) alkylene-X— and X is furanyl, thienyl or thiazolyl, a prodrug thereof, And pharmaceutically acceptable salts of those compounds and prodrugs.

Still another preferred group of compounds within the U group (designated as the Y group) is Q is — (C ₁ -C ₂ ) —XO— (C ₁ -C ₂ ) alkylene- and X is metaphenylene. Compounds, their prodrugs, and pharmaceutically acceptable salts of those compounds and prodrugs.

A particularly preferred compound within group Y is (3-(((2- (3,5-dichloro-phenoxy) -ethyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid. .
A particularly preferred compound within group Y is that K is ethylenyloxy; the M group is bonded to the oxygen atom of the ethylenyloxy group and the N atom is bonded to the 2-position of the ethylenyloxy group; Ar is pyrid-3-yl M is phenyl 3,5-disubstituted with chloro; Z is carboxy; Q is —CH ₂ —XO—CH ₂ —, X is a second phenyl ring, and CH Compounds in which ₂ and OCH ₂ substituents are located in this second phenyl ring in a meta-substituted manner, their prodrugs, and pharmaceutically acceptable salts of these compounds and prodrugs.

Another preferred group of compounds (designated as group Z) includes compounds of formula I wherein B is CH, prodrugs thereof, and pharmaceutically acceptable salts of these compounds and prodrugs.
Preferred compounds within Group Z include the following compounds, their prodrugs, and pharmaceutically acceptable salts of those compounds and prodrugs: A is CO; G is Ar, K is methylenyl, Propyrenyl, propenylenyl, or oxyethylenyl; M is Ar ³ or Ar ⁴ -Ar ⁵ ; Ar ³ is phenyl or pyridyl; Ar ⁴ is phenyl, thienyl, pyridyl, or furanyl; Ar ⁵ is ( C ₅ -C ₇ ) cycloalkyl, phenyl, pyridyl, imidazolyl, pyrimidyl, thienyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl or thiazolyl; Ar is phenyl, pyrazolyl, pyridazinyl, pyrazinyl, pyridyl, imidazolyl, pyrimidyl, thienyl or thiazolyl; Ar, Ar ^3, Ar ⁴ and Ar ^5, up to three independently Chloro, fluoro, methyl, difluoromethoxy, may be substituted by trifluoromethoxy or trifluoromethyl.

Another particularly preferred group of compounds within group Z includes the following compounds, their prodrugs, and pharmaceutically acceptable salts of those compounds and prodrugs: A is CO; G is Ar, K Is methylenyl, propylenyl, propenylenyl or oxyethylenyl; M is Ar ³ or Ar ⁴ -Ar ⁵ ; Ar ³ is phenyl or pyridyl; Ar ⁴ is phenyl, thienyl, pyridyl or furanyl; Ar ⁵ Is (C ₅ -C ₇ ) cycloalkyl, phenyl, pyridyl, imidazolyl, pyrimidyl, thienyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl or thiazolyl; Ar is phenyl, pyrazolyl, pyridazinyl, pyrazinyl, pyridyl, imidazolyl, pyrimidyl , thienyl or thiazolyl; Ar, Ar ^3, Ar ⁴ and Ar ⁵ independently Up to three chloro, fluoro, methyl, difluoromethoxy, may be substituted by trifluoromethoxy or trifluoromethyl.

  Examples of 5- to 6-membered aromatic rings which may contain 1 to 2 heteroatoms independently selected from oxygen, nitrogen and sulfur (ie X ring) are phenyl, furyl, Thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrdiazinyl, pyrimidinyl and pyrazinyl.

Partially saturated, fully saturated or fully unsaturated 5- to 8-membered ring which may contain 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen (ie Ar, Ar Examples of ¹ and Ar ² ) are cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl. Examples of other 5-membered rings are furyl, thienyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H-imidazolyl, 2 -Imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 3H-1,2-oxathiolyl, 1,2,3-oxadiazolyl, 1,2,4 -Oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, 1,2,3,4 -Oxatriazolyl, 1,2,3,5-oxatriazolyl, 3H-1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4 -Dioxazolyl, 5H-1,2,5-oxathiazolyl and 1,3-oxathioli It is.

  Examples of other 6-membered rings are 2H-pyranyl, 4H-pyranyl, pyridyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyridazinyl , Pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-trithianyl, 4H-1,2-oxazinyl, 2H-1 , 3-oxazinyl, 6H-1,3-oxazinyl, 6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl, 1,2,5-oxa Thiazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl, 1,4,2-oxathiazinyl and 1,3,5,2 -Oxadiazinyl.

Examples of other 7-membered rings are azepinyl, oxepinyl, thiepinyl and 1,2,4-diazepinyl.
Examples of other 8-membered rings are cyclooctyl, cyclooctenyl and cyclooctadienyl.

  Two fused, independently partially saturated, fully saturated or fully unsaturated bicyclic rings consisting of 5 and / or 6 membered rings, independently selected from nitrogen, sulfur and oxygen Examples of what may contain 4 heteroatoms are indolizinyl, indolyl, isoindolyl, 3H-indolyl, 1H-isoindolyl, indolinyl, cyclopenta (b) pyridinyl, pyrano (3,4-b) pyrrolyl, benzofuryl, iso Benzofuryl, benzo (b) thienyl, benzo (c) thienyl, 1H-indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzoimidazolyl, benzothiazolyl, purinyl, 4H-quinolidinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinazolinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, iso Indenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, 1,4-benzodioxane, pyrido (3,4-b) -pyridinyl, pyrido (3,2-b) -pyridinyl, pyrido (4,3-b ) -Pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 1H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H- 1,2-benzoxazinyl and 4H-1,4-benzoxazinyl.

  3 fused, independently partially saturated, fully saturated or fully unsaturated bicyclic rings consisting of 5 and / or 6 membered rings, independently selected from nitrogen, sulfur and oxygen Examples of what may contain 4 heteroatoms are indacenyl, biphenylenyl, acenaphthylenyl, fluorenyl, phenalenyl, phenanthrenyl, anthracenyl, naphthothienyl, thianthenyl, xanthenyl, phenoxathiinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl Perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl and phenoxazinyl. It will be understood that these fully saturated and all partially unsaturated rings are within the scope of the present invention. Further, it will be understood that the nitrogen can be substituted as a heteroatom in the heterocyclic ring at any position including the bridgehead position. It will further be appreciated that sulfur and oxygen can be substituted as heteroatoms in the heterocyclic ring at any position that is not a bridgehead position.

  Alkylene means a saturated hydrocarbon (straight chain or branched chain) in which a hydrogen atom is removed from each terminal carbon. Examples of such groups (assuming the indicated lengths include specific examples) are methylene, ethylene, propylene, butylene, pentylene, hexylene and heptylene.

  Alkenylene means hydrocarbons containing monounsaturation in the form of one double bond (hydrocarbons are straight or branched) with hydrogen atoms removed from each terminal carbon. Examples of such groups (assuming the indicated lengths encompass specific examples) are ethenylene (or vinylene), propenylene, butenylene, pentenylene, hexenylene and heptenylene.

  Alkynylene means a hydrocarbon containing diunsaturation in the form of one triple bond, where the hydrocarbon is straight or branched, with hydrogen atoms removed from each terminal carbon. Examples of such groups (assuming the indicated lengths include specific examples) are ethynylene, propynylene, butynylene, pentynylene, hexynylene and heptynylene.

Halo means chloro, bromo, iodo or fluoro.
Alkyl means a straight chain saturated hydrocarbon or a branched chain saturated hydrocarbon. Examples of such alkyl groups (assuming the indicated length includes specific examples) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, t- Pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl.

  Alkoxy means linear saturated alkyl or branched saturated alkyl linked by oxy. Examples of such alkoxy groups (assuming the indicated length includes specific examples) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, isopentoxy, neopentoxy, t-pentoxy , Hexoxy, isohexoxy, heptoxy and octoxy.

As used herein, the term mono-N- or di-N, N- (C ₁ -C _x ) alkyl ..... is a di-N, N- (C ₁ -C _x ) alkyl. .... independently represents a (C ₁ -C _x ) alkyl moiety (where x represents an integer and when two (C ₁ -C _x ) alkyl groups are present independently, for example methyl Ethylamino is included in the range of di-N, N- (C ₁ -C _x ) alkyl).

Unless stated otherwise, the "M" moiety defined above may be optionally substituted (eg, a mere list of substituents such as R ¹ in the dependent claims is where M is substituted with the R ¹ moiety ). Does not imply that M is always substituted with the R ¹ moiety unless otherwise specified). However, in the compound of formula I, when K is a bond and M is phenyl, the phenyl group is substituted with 1 to 3 substituents. Furthermore, when Ar or Ar ¹ is a fully saturated 5- to 8-membered ring in the compound of formula I, the ring is not substituted.

  When a carbocyclic or heterocyclic moiety is attached to the indicated substituent by various ring atoms, or otherwise linked, without designation of a specific point of attachment, either by a carbon atom or, for example, a trivalent nitrogen atom It should be understood that all possible attachment points are included. For example, the term “pyridyl” means 2-, 3- or 4-pyridyl, the term “thienyl” means 2- or 3-thienyl, and so forth.

  A particularly preferred compound of formula I is (3-(((4-t-butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid, or a pharmaceutically acceptable salt thereof. Or it is a prodrug or a salt of a prodrug. A particularly preferred salt is the sodium salt.

Other EP ₂ selective receptor agonists that can be used in the present invention include the prostaglandin receptor agonists disclosed in USP 6,288,120; and 6,124,314; and PCT published patent application WO 98/58911 (PCT / IB98 / 00866). included. A preferred EP ₂ compound disclosed in USP 6,288,120 is 7-[(4-butyl-benzyl) -methanesulfonyl-amino] -heptanoic acid, or a pharmaceutically acceptable salt or prodrug thereof, or a salt of a prodrug. is there. A preferred salt of 7-[(4-butyl-benzyl) -methanesulfonyl-amino] -heptanoic acid is the monosodium salt.

Other EP ₂ selective receptor agonists that can be used in the present invention include the compounds described below: Burk, Robert M .; Holoboski, Mark; Posner, Mari F., as an EP2-receptor agonist Production of prostaglandin E2 analogues-US Patent Application 2002187961; Burk, Robert M .; Holoboski, Mark; Posner, Mari F., Production of prostaglandin E2 analogues as EP2-receptor agonists-USP 6,376,533; Duckworth Marshall, K .; Clayton, JK, Prostaglandin EP2 receptor agonist butaprost on human myometrium isolated from pregnant and non-pregnant women, Journal of Endocrinology (2002) ), 172 (2), 263-269; Tani, Kousuke; Naganawa, Atsushi; Ishida, Akiharu; Egashira, Hiromu; Odagaki, Yoshihiko; Miyazaki, Toru; Hasegawa, Tomoyuki; Kawanaka, Yasufumi; Nakai, Hisao; Ohuchida, Shuichi ; Toda, Masaaki, Synthesis of highly selective EP2-receptor agonists, Synlett (2002), (2), 239-242; Tani, Kousuke; Naganawa, Atsushi; Ishida, Akiharu; Egashira, Hiromu; Sagawa, Kenji; Harada, Hiroyuki; Ogawa, Mikio; Maruyama, Takayuki; Ohuchida, Shuichi; Nakai, Hisao; Kondo, Kigen; Toda, Masaaki, Development of highly selective EP2-receptor agonists, Part 2. Identification of 16-hydroxy-17,17-trimethylene 9b-chloro PGF derivatives, Bioorganic & Medicinal Chemistry (2002), 10 (4), 1107-1114; Tani, Kousuke; Naganawa, Atsushi; Ishida, Akiharu; Sagawa, Kenji; Harada, Hiroyuki; Ogawa, Mikio; Maruyama, Takayuki; Ohuchida, Shuichi; Nakai, Hisao; Kondo, Kigen; Toda, Masaaki, Development of highly selective EP2-receptor agonists, Part 1. Identification of 16-hydroxy-17,17-trimethylene PGE2 derivatives, Bioorganic & Medicinal Chemistry (2002), 10 (4), 1093-1106; Michelet, Jean -Francois; Mahe, Yann; Bernard, Bruno, non-pross of EP-2 and / or EP-4 prostaglandin receptors as cosmetic agents to reduce or stop hair loss -European Patent Application EP 1175891 A1; Tani, K .; Naganawa, A .; Ishida, A .; Egashira, H .; Sagawa, K .; Harada, H .; Ogawa, M .; Maruyama, T .; Ohuchida, S .; Nakai, H .; Kondo, K .; Toda, M., Design and synthesis of highly selective EP2-receptor agonists, Bioorganic & Medicinal Chemistry Letters (2001), 11 (15), 2025-2028; Crider, JY; Sharif, NA, Functional pharmacological evidence of EP2 and EP4 prostanoid receptors in immortalized human trabecular meshwork and uncolored ciliated epithelial cells, International Journal of Environmental Studies (2000 ), 58 (1), 35-46; Crider, JY; Sharif, NA, functional pharmacological evidence for EP2 and EP4 prostanoid receptors in immortalized human trabecular meshwork and uncolored ciliated epithelial cells, Journal of Ocular Pharmacology and Therapeutics (2001), 17 (1), 35-46; Klimko, Peter G .; Sharif, Najam A .; Griffin, Brenda W., prostaglandin E agonist-WO for the treatment of glaucoma 0038 667 A2; Woodward, David F., EP2 receptor agonist as an eye neuroprotectant-US 5877211; Regan, John W .; Gil, Daniel W .; Woodward, David F., pharmacologically determined EP2 sub Cloning of a novel human prostaglandin receptor with type characteristics-US 5716835; Woodward, David F., EP2-receptor agonist as a drug to reduce intraocular pressure-US 5698598; Woodward, David F., EP2-receptor agonists as agents for lowering intraocular pressure-WO 9519964; Woodward, DF; Bogardus, AM; Donello, JE; Fairbairn, CE; Gil, DW; Kadzie, KM; Burke, JA; Kharlamb, A .; Runde, E .; et al., Molecular characterization and intraocular pressure-lowering properties of prostanoid EP2 receptor, Journal of Ocular Pharmacology and Therapeutics (1995), 11 (3), 447-54; Nials, Anthony T. ; Vardey, Christopher J .; Denyer, Lois H .; Thomas, Malcolm; Sparrow, Susan J .; Shepherd, Gillian D .; Coleman, Robert A., AH13205, selective prostanoid EP2- Toxic agonist, Cardiovascular Drug Reviews (1993), 11 (2), 165-79; and Woodward, DF, Protzman, CE; Krauss, AHP; Williams, LS, 19 (R as a selective prostanoid EP2-receptor agonist ) -OH Prostaglandin E2 identification, Prostaglandins (1993), 46 (4), 371-83.

  The method of the invention can be used to treat pulmonary hypertension. Pulmonary hypertension, also known as primary pulmonary hypertension, is an unknown cause of disease associated with the middle and small arteries of the lung, generally leading to right ventricular failure or fatal syncope after 2-5 years of detection. Intimal hyperplasia and the resulting vascular lumen stenosis are always seen. In more advanced cases, inner thickening and hyperplasia, irreversible plexiform lesions, and areas of necrotic arteries (multifactorial arteropathy) occur. Those skilled in the art are familiar with the perception of patients with pulmonary hypertension.

  The present invention can also be used to promote joint fusion. Examples of joint fusion include bone fusion of the wrist or ankle or other joints. During joint fusion, two or more bones fuse together.

  The present invention can also be used to facilitate tendon and / or ligament repair. This repair can include tendon or ligament strengthening, or can include reconstruction of the damaged portion of the tendon and / or ligament. Another aspect of tendon and ligament repair is to strengthen or repair tendon or ligament attachment to bone.

  The method of the present invention can also be used to reduce the occurrence of secondary fractures. A secondary fracture is a fracture that occurs following a primary fracture. After a fracture has occurred, the method of the present invention can be used to prevent other fractures from occurring or to reduce the degree and complexity of secondary fractures. For example, when a patient has a hip fracture, the method of the present invention can be used to help avoid or reduce the degree of secondary fractures on the same hip joint as the primary fracture or on the other hip joint. Prevention or reduction of damage caused by secondary fractures is also important when the risk of secondary fractures is high, for example due to chemotherapy. Prevention of secondary fractures of the spine and stabilization of the spine are also important.

  The present invention also provides a method of treating avascular necrosis. Avascular necrosis is characterized by bone cell death caused by impaired blood supply. Hip, femur and shoulder joints are the affected bones in general. Avascular necrosis is associated with a variety of conditions, including femoral neck fracture, femoral dislocation, decompression sickle, sickle cell disease, radiation therapy, Gaucher disease, and corticosteroid high dose therapy. Other conditions associated with avascular necrosis include systemic lupus erythematosus, renal transplantation, erythrocytosis, Cushing syndrome, diabetes, atherosclerosis, cytotoxic chemotherapy, alcohol addiction, fatty liver, psoriasis, pancreatitis Includes pancreatic cancer and gout. Thus, the presence of symptoms associated with avascular necrosis can be an indicator for applying the method of the invention to prevent or reduce the onset of avascular necrosis in a patient.

  The present invention promotes cartilage repair, promotes bone healing after limb transplantation, promotes liver regeneration, promotes wound healing, reduces gastric ulcer development, treats hypertension, dental enamel or It can also be used to promote fingernail growth, treat glaucoma, treat ocular hypertension, or repair damage caused by metastatic bone disease. These symptoms are well known to those skilled in the art. Patients with such symptoms can be easily recognized by those skilled in the art.

The terms “promoting”, “promoting”, etc. with respect to the method of the present invention means making the treatment easier or improving the speed of the treatment. For example means that to promote bone healing is to easier achievement of treatment in the presence of EP ₂ selective receptor agonist than the absence of EP ₂ selective receptor agonist, or to perform a treatment more quickly To do.

A preferred dose is about 0.001 to 100 mg / kg / day of an EP ₂ selective receptor agonist, such as a compound of formula I. A particularly preferred dose is about 0.01-10 mg / kg / day of an EP ₂ selective receptor agonist, such as a compound of formula I.

The present invention also relates to pharmaceutical compositions comprising an EP ₂ selective receptor agonist, such as a compound of formula I, and a carrier, solvent, diluent, and the like.
Another aspect of the invention relates to the combination of an EP ₂ selective receptor agonist, such as a compound of formula I, with other therapeutically useful compounds.

In one embodiment, the combination of the present invention comprises: a therapeutically effective amount of a first compound, an EP ₂ selective receptor agonist, eg, a first compound that is a compound of formula I; and a therapeutically effective amount Wherein the second compound is an anti-resorptive agent, such as an estrogen agonist / antagonist or bisphosphonate. An estrogen agonist / antagonist is also called a selective estrogen receptor modulator (SERM).

  When referring to compounds herein, it is pointed out that the compounds can be administered to patients as therapeutically acceptable salts, prodrugs, or salts of prodrugs. Such other forms are intended to be included in the present invention.

Another embodiment of the present invention is a kit comprising:
a. An amount of an EP ₂ selective receptor agonist, such as a compound of formula I, and a pharmaceutically acceptable carrier or diluent in a first unit dosage form;
b. An amount of an absorption inhibitor and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and c. container.

Yet another aspect of the invention is an EP ₂ selective receptor agonist, such as a compound of formula I, and other bone anabolic agents (wherein other bone anabolic agents are other EP ₂ selective receptor agonists such as Pharmaceutical composition or kit, which may be different from the compound of formula I Such compositions include: a therapeutically effective amount of a first compound, an EP ₂ selective receptor agonist, eg, a first compound that is a compound of formula I; and a therapeutically effective amount of a second compound A second compound that is another bone anabolic agent.

The first compound can be administered concurrently with the second compound in the same dosage form or in a different dosage form. Alternatively, the first compound and the second compound can be administered at different times. Furthermore, the combinations of the present invention can contain more than two compounds. For example, two EP ₂ selective receptor agonists and resorption inhibitors or bone anabolic agents can be administered to the patient.

Another embodiment of the present invention is a kit comprising:
a. An amount of an EP ₂ selective receptor agonist, such as a compound of formula I, in a first unit dosage form;
b. An amount of a second compound in a second unit dosage form that is another bone anabolic agent; and c. container.

  Preferred bone anabolic agents include IGF-1, prostaglandins, prostaglandin agonists / antagonists, sodium fluoride, parathyroid hormone (PTH), active fragments of parathyroid hormone, parathyroid hormone related peptides and parathyroid hormone related Active fragments and analogs of peptides, growth hormone or growth hormone secretagogues, and pharmaceutically acceptable salts or prodrugs thereof, or salts of prodrugs are included.

Since the present invention has aspects relating to combinations of active ingredients that may be administered separately, the present invention also relates to combining separate pharmaceutical compositions into kit form. The kit comprises two separate pharmaceutical compositions: an EP ₂ selective receptor agonist, such as a compound of formula I, and a second compound as described above. The kit includes a container member for containing a separate composition, such as a partitioned bottle or a partitioned foil packet, although the separate composition can be contained in a single undivided container. Generally, the kit includes instructions for administering the separate components. When it is preferable to administer separate components in different dosage forms (eg, oral and parenteral), when administered at different dosing intervals, or when it is desirable for the prescribing physician to determine the potency of each component of the combination, The kit form is particularly advantageous.

  An example of such a kit is the so-called PTP packaging (blister pack). PTP packaging is well known in the packaging industry and is widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). PTP packaging generally consists of a sheet of relatively rigid material, preferably covered with a foil of transparent plastic material. A dimple is formed in the plastic foil during the packaging process. The depression has the size and shape of the tablet or capsule to be packaged. The tablets or capsules are then placed in the recesses and the relatively rigid sheet of material is sealed to the plastic foil surface opposite the one where the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablet or capsule can be removed from the PTP packaging by manually applying pressure to the depression to form an opening at the location of the sheet depression. Thus, the tablet or capsule can be removed from the opening.

  It may be desirable to have a number associated with the specified date on which such a dosage form is to be taken, for example by applying a memory aid in the form of a number, for example adjacent to the tablet or capsule. Another example of such a memory aid is a calendar printed on a card, for example: "1st week, month, fire, ....... 2nd week, month, fire, ...."Such. Other forms of memory aid are self-evident. A “daily dose” may be a single tablet or capsule to be taken that day, or several tablets or capsules. The daily dose of the compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of those compounds or prodrugs consists of one tablet or capsule, while several daily doses of the second compound Or tablets or capsules, and vice versa. This should be reflected in the memory aid.

  In another embodiment of the present invention, a dispenser is provided that is designed to dispense a daily dose at a time depending on the intended use. Preferably, the dispenser is equipped with a memory aid to further facilitate compliance with the regulatory system. An example of such a memory aid is a counter that indicates the number of daily doses that have been dispensed. Other examples of such memory aids include battery-powered microchip memory in conjunction with a liquid crystal readout, or read out the date when the last daily dose was taken and / or reminded when the next dose should be taken An audible reminder signal.

  Preferred estrogen agonist / antagonists of the present invention include the compounds described in U.S.P. 5,552,412. These compounds are described by the formulas shown herein as formula (I) below:

In the formula:
A is selected from CH ₂ and NR;
B, D and E are independently selected from CH and N;
Y is:
(A) phenyl: optionally substituted with 1 to 3 substituents independently selected from R ⁴ ;
(B) naphthyl: optionally substituted by 1 to 3 substituents independently selected from R ⁴ ;
(C) C ₃ -C ₈ cycloalkyl: optionally substituted with 1 to 2 substituents independently selected from R ⁴ ;
(D) C ₃ -C ₈ cycloalkenyl: optionally substituted by 1 to 2 substituents independently selected from R ⁴ ;
(E) a 5-membered heterocyclic ring: containing up to two heteroatoms selected from the group consisting of —O—, —NR ² — and —S (O) _n —, and independently selected from R ⁴ Optionally substituted with ~ 3 substituents;
(F) a 6-membered heterocyclic ring: containing up to 2 heteroatoms selected from the group consisting of —O—, —NR ² — and —S (O) _n —, and independently selected from R ⁴ Optionally substituted with ~ 3 substituents; or (g) a bicyclic ring system consisting of a 5- or 6-membered heterocycle fused to a phenyl ring: the heterocycle is —O—, —NR ² — and Containing up to 2 heteroatoms selected from the group consisting of —S (O) _n — and optionally substituted with 1 to 3 substituents independently selected from R ⁴ ;
Z ¹ is:

  G is:

Where n is 0, 1 or 2; m is 1, 2 or 3; Z ² is —NH—, —O—, —S— or —CH ₂ —; Or may be fused with two phenyl rings, optionally substituted with 1 to 3 substituents independently on carbon, and chemically appropriate selected from R ⁴ independently on nitrogen. Optionally substituted with a substituent;
(C) a bridged or fused bicyclic amine containing 5 to 12 carbon atoms: optionally substituted with 1 to 3 substituents independently selected from R ⁴ ;
Z ¹ and G together may be:

  W is:

R is hydrogen or C ₁ -C ₆ alkyl;
R ² and R ³ are independently:
(A) hydrogen; or (b) C ₁ -C ₄ alkyl;
R ⁴ is:
(A) hydrogen;
(B) halogen;
(C) C ₁ -C ₆ alkyl;
(D) C ₁ -C ₄ alkoxy;
(E) C ₁ -C ₄ acyloxy;
(F) C ₁ -C ₄ alkylthio;
(G) C ₁ -C ₄ alkylsulfinyl;
(H) C ₁ -C ₄ alkylsulfonyl;
(I) hydroxy (C ₁ -C ₄ ) alkyl;
(J) aryl (C ₁ -C ₄ ) alkyl;
(K) -CO ₂ H;
(L) -CN;
(M) -CONHOR;
(N) -SO ₂ NHR;
(O) -NH ₂ ;
(P) C ₁ -C ₄ alkylamino;
(Q) C ₁ -C ₄ dialkylamino;
(R) -NHSO ₂ R;
(S) -NO ₂ ;
(T) aryl; or (u) -OH;
R ⁵ and R ⁶ are independently C ₁ -C ₈ alkyl, or together form a C ₃ -C ₁₀ carbocyclic ring:
R ⁷ and R ⁸ are independently:
(A) phenyl;
(B) a saturated or unsaturated C ₃ -C ₁₀ carbocyclic ring;
(C) -O -, - N- and C ₃ -C ₁₀ heterocyclic ring containing up to two heteroatoms selected from -S-;
(D) H;
(E) C ₁ -C ₆ alkyl; or (f) together with R ⁵ or R ⁶ form a nitrogen containing 3-8 membered ring;
R ⁷ and R ⁸ may be substituted with up to 3 substituents independently selected from C ₁ -C ₆ alkyl, halogen, alkoxy, hydroxy and carboxy, whether linear or cyclic. ;
The ring formed by R ⁷ and R ⁸ may be fused to a phenyl ring;
e is 0, 1 or 2;
m is 1, 2 or 3;
n is 0, 1 or 2;
p is 0, 1, 2 or 3;
q is 0, 1, 2 or 3;
And optical and geometric isomers thereof; and pharmaceutically acceptable non-toxic acid addition salts, N-oxides, esters, quaternary ammonium salts and prodrugs thereof.

  Other preferred estrogen agonist / antagonists are disclosed in U.S.P. 5,552,412 and are described herein by the formula designated as formula (IA):

In the formula:
G is:

R ⁴ is H, OH, F or Cl; B and E are independently selected from CH and N;
And optical and geometric isomers thereof; and pharmaceutically acceptable non-toxic acid addition salts, N-oxides, esters, quaternary ammonium salts and prodrugs thereof.

Particularly preferred estrogen agonist / antagonists for the method of the invention are:
cis-6- (4-fluoro-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalen-2-ol;
(-)-cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalen-2-ol;
cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalen-2-ol;
cis-1- [6'-pyrrolidinoethoxy-3'-pyridyl] -2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;
1- (4'-pyrrolidinoethoxyphenyl) -2- (4 "-fluorophenyl) -6-hydroxy-1,2,3,4-tetrahydroisoquinoline;
cis-6- (4-hydroxyphenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalen-2-ol;
1- (4′-pyrrolidinoethoxyphenyl) -2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;
As well as pharmaceutically acceptable salts thereof.

A particularly preferred salt of (-)-cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalen-2-ol is , D-tartrate.
Other preferred estrogen agonist / antagonists are disclosed in USP 5,047,431. The structures of these compounds are described by the following formula, designated herein as formula (II):

In the formula:
R ^1A and R ^2A may be the same or different and are H, methyl, ethyl or benzyl groups;
As well as optical or geometric isomers thereof; and pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts and prodrugs thereof.

Other preferred estrogen agonist / antagonists are: compounds disclosed in USP 4,536,516; 4-hydroxy tamoxifen (ie, tamoxifen having a hydroxy group at the 4-position of the 2-phenyl moiety) and Other compounds: disclosed in USP 4,623,660; raloxifene ([6-hydroxy-2- (4-hydroxyphenyl) benzo [b] thien-3-yl] [4- [2- (1-piperidinyl) ethoxy] Phenyl] -methanone hydrochloride) and other compounds: disclosed in USP 4,418,068; 5,393,763; 5,457,117; 5,478,847 and 5,641,790; toremifene (2- [4- (4-chloro-1,2-diphenyl-1-butenyl) Phenoxy] -N, N-dimethyl-ethanamine, (Z)-, 2-hydroxy-1,2,3-propanetricarboxylate (1: 1) and other compounds: disclosed in USP 4,696,949 and 4,996,225; centchroman 1- [2-[[4-(-Methoxy-2,2-dimethyl-3-phenyl-chroman-4-yl) -phenoxy] -ethyl] -pyrrolidine] and other compounds: disclosed in USP 3,822,287; idoxifene (Idoxifene): 1-[-[4-[[1- (4-iodophenyl) -2-phenyl-1-butenyl] phenoxy] ethyl] pyrrolidine and other compounds: disclosed in USP 4,839,155; 6- (4- Hydroxy-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -naphthalen-2-ol and other compounds: disclosed in USP 5,484,795; and {4- [2- (2- Aza-bicyclo [2.2.1] hept-2-yl) -ethoxy] -phenyl}-[6-hydroxy-2- (4-hydroxy-phenyl) -benzo [b] thiophen-3-yl] -methanone and others Compounds: disclosed in published international patent application WO 95/10513. Other preferred compounds include GW 5638 and GW 7604, the synthesis of which is Willson et al., J. Med. Chem. , 1994; 37: 1550- 1552.

Other preferred estrogen agonist / antagonists include EM-652 (denoted herein by the formula denoted as formula (III)) and EM-800 (denoted herein by the formula denoted as formula (IV)). included. The synthesis of EM-652 and EM-800 and the activity of various enantiomers is described in Gauthier et al., J. Med. Chem. , 1997; 40: 2117-2122.

  Other preferred estrogen agonist / antagonists include TSE 424, as well as other compounds described in USP 5,998,402, USP 5,985,910, USP 5,780,497, USP 5,880,137, and European Patent Application EP 0802183 A1, herein. Included are compounds described by the following formulas denoted as V and VI in:

In the formula:
R _1B is H, OH or its C ₁ -C ₁₂ ester (straight or branched) or C ₁ -C ₁₂ (straight or branched or cyclic) alkyl ether, or halogen; or C _1- Selected from C ₄ halogenated ethers (including trifluoromethyl ether and trichloromethyl ether);
R _2B , R _3B , R _4B , R _5B , and R _6B are independently H, OH, or a C ₁ -C ₁₂ ester (linear or branched) or C ₁ -C ₁₂ alkyl ether (linear) Or branched or cyclic), halogen, or C ₁ -C ₄ halogenated ethers (including trifluoromethyl ether and trichloromethyl ether), cyano, C ₁ -C ₆ alkyl (straight or branched), Or selected from trifluoromethyl;
X _A is selected from H, C ₁ -C ₆ alkyl, cyano, nitro, trifluoromethyl and halogen;
s is 2 or 3;
Y _A is selected from:
a) The following parts:

R _7B and R _8B are independently selected from the following group: H, C ₁ -C ₆ alkyl, or phenyl optionally substituted with: CN, C ₁ -C ₆ alkyl (linear) Or branched), C ₁ -C ₆ alkoxy (straight or branched), halogen, —OH, —CF ₃ , or —OCF ₃ ;
b) 5-membered saturated, unsaturated or partially unsaturated heterocycle: —O—, —NH—, —N (C ₁ -C ₄ alkyl)-, —N =, and —S (O) _u — (u is Containing up to 2 heteroatoms selected from the group consisting of (which is an integer from 0 to 2) and optionally substituted with 1 to 3 substituents independently selected from: hydrogen , hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ acyloxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ - C ₄ alkylsulfonyl, hydroxy (C ₁ -C _{4) alkyl, -CO 2 H, -CN, -CONHR} 1B, -NH 2, C 1 -C 4 alkylamino, di (C ₁ -C ₄₎ alkylamino, —NHSO ₂ R _1B , —NHCOR _1B , —NO ₂ , and phenyl optionally substituted with _{1 to} 3 (C ₁ -C ₄ ) alkyl;
c) 6-membered saturated, unsaturated or partially unsaturated heterocycles: —O—, —NH—, —N (C ₁ -C ₄ alkyl)-, —N =, and —S (O) _u — (u is Containing up to 2 heteroatoms selected from the group consisting of (which is an integer from 0 to 2) and optionally substituted with 1 to 3 substituents independently selected from: hydrogen , hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ acyloxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ - C ₄ alkylsulfonyl, hydroxy (C ₁ -C _{4) alkyl, -CO 2 H, -CN, -CONHR} 1, -NH 2, C 1 -C 4 alkylamino, di (C ₁ -C ₄₎ alkylamino, —NHSO ₂ R _1B , —NHCOR _1B , —NO ₂ , and phenyl optionally substituted with _{1 to} 3 (C ₁ -C ₄ ) alkyl;
d) 7-membered saturated, unsaturated or partially unsaturated heterocycles: —O—, —NH—, —N (C ₁ -C ₄ alkyl)-, —N =, and —S (O) _u — (u is Containing up to 2 heteroatoms selected from the group consisting of (which is an integer from 0 to 2) and optionally substituted with 1 to 3 substituents independently selected from: hydrogen , hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ acyloxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ - C ₄ alkylsulfonyl, hydroxy (C ₁ -C _{4) alkyl, -CO 2 H, -CN, -CONHR} 1B, -NH 2, C 1 -C 4 alkylamino, di (C ₁ -C ₄₎ alkylamino, —NHSO ₂ R _1B , —NHCOR _1B , —NO ₂ , and phenyl optionally substituted with _{1 to} 3 (C ₁ -C ₄ ) alkyl; or e) a bridge containing 6 to 12 carbon atoms Or a fused bicyclic ring system: —O—, —NH—, Containing up to two heteroatoms selected from the group consisting of —N (C ₁ -C ₄ alkyl)-, and —S (O) _u — (u is an integer from 0 to 2), independently with 1-3 substituents selected from the following ones may be substituted: hydrogen, hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ acyloxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, hydroxy (C ₁ -C _{4) alkyl, -CO 2 H, -CN, -CONHR} 1B, _{-NH 2, -N =, C 1} -C 4 alkylamino, di (C ₁ -C _{4) alkylamino, -NHSO 2 R 1B, -NHCOR 1B} , -NO 2, and 1-3 (C ₁ -C ₄₎ phenyl optionally substituted by alkyl;
And optical and geometric isomers thereof; and pharmaceutically acceptable non-toxic acid addition salts, N-oxides, esters, quaternary ammonium salts and prodrugs thereof.

Preferred compounds of the invention are the following compounds having the general structural formula V or VI above:
R _1B is selected from H, OH, or a C ₁ -C ₁₂ ester or alkyl ether thereof, and halogen;
R _2B , R _3B , R _4B , R _5B , and R _6B are independently H, OH, or a C ₁ -C ₁₂ ester or alkyl ether thereof, halogen, cyano, C ₁ -C ₆ alkyl, or trihalomethyl , Preferably selected from trifluoromethyl, provided that when R _1B is H, R _2B is not OH;
X _A is selected from H, C ₁ -C ₆ alkyl, cyano, nitro, trifluoromethyl and halogen;
Y _A is the following part:

R _7B and R _8B are independently selected from H, C ₁ -C ₆ alkyl, or joined by — (CH ₂ ) _w — (w is an integer from 2 to 6) to form a ring; The ring may be substituted with up to 3 substituents selected from: hydrogen, hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, hydroxy (C ₁ -C ₄ ) alkyl, -CO ₂ H, -CN, -CONH (C ₁ -C ₄ alkyl ), —NH ₂ , C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino, —NHSO ₂ (C ₁ -C ₄ alkyl), —CO (C ₁ -C ₄ alkyl), and —NO ₂ ;
And optical and geometric isomers thereof; and pharmaceutically acceptable non-toxic acid addition salts, N-oxides, esters, quaternary ammonium salts and prodrugs thereof.

Such rings formed by linked R _7B and R _8B include, but are not limited to, aziridine, azetidine, pyrrolidine, piperidine, hexamethyleneamine or heptamethyleneamine rings.

Preferred compounds of structural formulas V and VI are: R _1B is OH; R _{2B to} R _6B are as defined above; X _A is Cl, NO ₂ , CN, CF ₃ , Or selected from the group of CH ₃ ; Y _A is the following moiety:

R _7B and R _8B are joined together as — (CH ₂ ) _t — (t is an integer from 4 to 6) to form a ring, the ring comprising at most 3 selected from Optionally substituted with hydrogen: hydroxyl, halo, C ₁ -C ₄ alkyl, trihalomethyl, C ₁ -C ₄ alkoxy, trihalomethoxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl , C ₁ -C ₄ alkylsulfonyl, hydroxy (C ₁ -C ₄ ) alkyl, -CO ₂ H, -CN, -CONH (C ₁ -C ₄ alkyl), -NH ₂ , C ₁ -C ₄ alkylamino, Di (C ₁ -C ₄ ) alkylamino, —NHSO ₂ (C ₁ -C ₄ alkyl), —NHCO (C ₁ -C ₄ alkyl), and —NO ₂ ;
And optical and geometric isomers thereof; and pharmaceutically acceptable non-toxic acid addition salts, N-oxides, esters, quaternary ammonium salts and prodrugs thereof.

  Another preferred compound is TSE-424, described by the following formula, denoted as formula (Va):

Another estrogen agonist / antagonist that can be used in the combination aspect of this invention is arzoxifene, which is disclosed in USP 5,723,474.
A particularly preferred combination of an EP ₂ selective receptor agonist and an estrogen agonist / antagonist is (3-(((4-t-butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -Acetic acid and (-)-cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalen-2-ol . In a more preferred combination, (3-(((4-t-butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid is in the form of the sodium salt and (-) -cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalen-2-ol is in the form of D-tartrate is there.

  Preferred bisphosphonates include tiludronic acid, alendronic acid, zoledronic acid, ibandronic acid, risedronic acid, etidronic acid, Included are clodronic acid, and pamidronic acid, and their pharmaceutically acceptable salts or prodrugs, or salts of prodrugs.

  It will be appreciated that prodrugs and pharmaceutically acceptable salts can be formed from the compounds of the present invention. Such prodrugs and pharmaceutically acceptable salts thus formed are within the scope of the present invention. Particularly preferred salt forms of estrogen agonist / antagonists include raloxifene hydrochloride, tamoxifen citrate, toremifene citrate, and lazofoxifene tartrate.

Absorption inhibitors such as progestins, polyphosphonates, bisphosphonate (s), estrogen agonists / antagonists, estrogens, estrogen / progestin combinations, Premarin® (conjugated estrogens), estrone, estriol Alternatively, it will be appreciated by those skilled in the art that 17α- or 17β-ethynylestradiol can be used in combination with an EP ₂ selective receptor agonist in the methods of the invention.

  Examples of progestins are commercially available and include the following: algestone acetophenide, altrenogest, amadinone acetate, anagestone acetate, chlormadinone acetate, Singgestol, Clogestone acetate, Clogegestone acetate, Delmadinone acetate, Desogestrel, Dimethisterone, Didrogesterone, Ethynerone, Ethinodiol diacetate ethynodiol, etonogestrel, flurogestone acetate, gestaclone, gestodene, gestonolone caproate, gestrinone, haloprogesterone sterone, hydroxyprogesterone caproate (hydroxyprogesterone), levonogestrel, lynestenol, medrogestone, medroxyprogesterone acetate, melengeprolol acetate, methinodiol acetate, methynodiol Norethindrone, norethindrone acetate, norethynodrel, norgestimate, norgestomet, norgestrel, fengepropionate oxogestone, progesterone, quinanol gestanol, gestanolone Quingestrone, and tigestol.

Preferred progestins are medroxyprogesterone, norethindrone and norethinodrel.
Examples of polyphosphonates include polyphosphonates of the type disclosed in USP 3,683,080. A preferred polyphosphonate is gem-diphosphonate (also called bis-phosphonate). Tiludronate disodium is a particularly preferred polyphosphonate. Ibandronic acid is a particularly preferred polyphosphonate. Alendronate is a particularly preferred polyphosphonate. Zoledronic acid is a particularly preferred polyphosphonate. Other preferred polyphosphonates are 6-amino-1-hydroxy-hexylidene-bisphosphonic acid and 1-hydroxy-3- (methylpentylamino) -propylidene-bisphosphonic acid. The polyphosphonate can be administered in acid form or in the form of a soluble alkali metal salt or alkaline earth metal salt. Also included are hydrolysable esters of polyphosphonates. Specific examples include: ethane-1-hydroxy-1,1-diphosphonic acid, methanediphosphonic acid, pentane-1-hydroxy-1,1-diphosphonic acid, methanedichlorodiphosphonic acid, methane Hydroxydiphosphonic acid, ethane-1-amino-1,1-diphosphonic acid, ethane-2-amino-1,1-diphosphonic acid, propane-3-amino-1-hydroxy-1,1-diphosphonic acid, propane- N, N-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid, propane-3,3-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid, phenylaminomethane diphosphonic acid N, N-dimethylaminomethane diphosphonic acid, N- (2-hydroxyethyl) aminomethane diphosphonic acid, butane-4-amino-1-hydroxy-1,1-diphosphonic acid, pentane-5-amino-1 -Hydroxy-1,1-diphosphonic acid, hexane-6-amino-1-hydroxy-1,1-diphosphonic acid, and Pharmaceutically acceptable esters and salts of

Any prostaglandin can be used in combination with the EP ₂ selective receptor agonist in the methods of the invention. The term prostaglandin refers to compounds that are analogs of the natural prostaglandins PGD ₁ , PGD ₂ , PGE ₂ , PGE ₁ and PGF ₂ . These compounds bind to the prostaglandin receptor. Such binding can be readily determined by those skilled in the art by standard assays (eg, An S. et al., Cloning and expression of the human prostaglandin E ₂ receptor of the EP ₂ subtype, Biochemical and Biophysical Research Communications , 1993, 197 (1): 263-270).

Prostaglandins are alicyclic compounds related to the basic compound prostanoic acid. The basic prostaglandin carbon atoms are numbered sequentially from the carboxyl carbon atom through the cyclopentyl ring to the terminal carbon atom on the adjacent side chain. Usually the adjacent side chains are in the trans orientation. The presence of an oxo group at the C-9 position of the cyclopentyl moiety is an indicator of an E class prostaglandin, while PGE ₂ is a trans unsaturated double bond at C ₁₃ -C ₁₄ and cis at the C ₅ -C ₆ position. Includes double bonds.

  A variety of prostaglandins are described and referenced below, but other prostaglandins will be known to those skilled in the art. Examples of prostaglandins are disclosed in U.S.P. 4,171,331 and 3,927,197.

Norrdin et al, the role of prostaglandins in bone in vivo , Prostaglandins Leukotriene Essential Fatty Acids 41, 139-150, 1990 is a review of bone catabolic prostaglandins.

Any prostaglandin agonist / antagonist can be used as the second compound in certain embodiments of the invention. The term prostaglandin agonist / antagonist binds to the prostaglandin receptor (eg, An S. et al., Cloning and expression of the human prostaglandin E ₂ receptor of the EP ₂ subtype, Biochemical and Biophysical Research Communications , 1993, 197 (1): 263-270), representing compounds that mimic the action of prostaglandins in vivo. Their effects can be readily determined by those skilled in the art according to standard assays. Eriksen EF et al., Bone Histomorphometry , Raven Press, New York, 1994, p.1-74; Grier SJ et al., Use of dual energy X-ray absorptiometry in animals, Inv. Radiol. , 1996, 31 ( 1): 50-62; Wahner HW and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice., Martin Dunitz Ltd., London, 1994, p.1-296. These various compounds are described and referenced below, but other prostaglandin agonists / antagonists will be known to those skilled in the art. Examples of prostaglandin agonists / antagonists are disclosed below: USP 3,932,389 2-descarboxy-2- (tetrazol-5-yl) -11-desoxy-15-substituted-ω-pentanol prostaglandins USP 4,018,892 discloses 16-aryl-13,14-dihydro-PGE ₂ p-biphenyl esters; USP 4,219,483 and 4,132,847 disclose 2,3,6-substituted-4-pyrones USP 4,000,309 and 3,982,016 disclose 16-aryl-13,14-dihydro-PGE ₂ p-biphenyl esters; USP 4,621,100 discloses substituted cyclopentanes; USP 5,216,183 discloses cyclopentanones It is disclosed.

In some embodiments of the invention, sodium fluoride can be used as the second compound. The term sodium fluoride refers to all forms of sodium fluoride (eg sustained release sodium fluoride, sustained release sodium fluoride). Sustained release sodium fluoride is disclosed in USP 4,904,478. The activity of sodium fluoride can be easily measured by experts in biological protocols (eg Eriksen EF et al., Bone Histomorphometry , Raven Press, New York, 1994, p.1-74; Grier SJ et al., Animals Use of dual energy X-ray absorptiometry, Inv. Radiol. , 1996, 31 (1): 50-62; Wahner HW and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice. , Martin Dunitz Ltd., London, 1994, p.1-296).

In some embodiments of the invention, parathyroid hormone (PTH) can be used as the second compound. The term parathyroid hormone refers to parathyroid hormone, fragments or metabolites thereof, and structural analogs thereof that can stimulate bone formation and increase bone mass. Also included are parathyroid hormone related peptides, and active fragments and analogs of parathyroid related peptides (see PCT Publication WO 94/01460). These various compounds are described and referenced below, although other parathyroid hormones will be known to those skilled in the art. Examples of parathyroid hormone are disclosed in the following references:
"Treatment of vertebral osteoporosis with human parathyroid peptides", Osteoporosis Int., 3, (Supp 1): 199-203;
“Treatment of osteoporosis with PTH 1-34 plus hormone replacement therapy: biochemical, kinetic and histological response”, Osteoporosis Int., 1: 162-170.

  In one embodiment of the present invention, growth hormone or a growth hormone secretagogue can be used as the second compound. The term growth hormone secretagogue refers to a compound that stimulates the release of growth hormone or mimics the action of growth hormone (eg, enhances bone formation and increases bone mass). Such effects can be readily determined by those skilled in the art by standard assay methods well known in the art. These various compounds are disclosed in the following published international patent applications: WO 95/14666; WO 95/13069; WO 94/19367; WO 94/13696; and WO 95/34311. However, other growth hormones or growth hormone secretagogues will be known to those skilled in the art.

  A particularly preferred growth hormone secretagogue is N- [1 (R)-[1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl]- 2- (Phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide: MK-677.

Other preferred growth hormone secretagogues include the following:
2-Amino-N- (2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo- [4,3-c] pyridine -5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl) -isobutyramide or its L-tartrate salt;
2-Amino-N- (1- (R) -benzyloxymethyl-2- (3a- (R)-(4-fluoro-benzyl) -2-methyl-3-oxo-2,3,3a, 4, 6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -2-oxo-ethyl) isobutyramide;
2-Amino-N- (2- (3a- (R) -benzyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl) isobutyramide; and
2-Amino-N- (1- (2,4-difluoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3a-pyridin-2-ylmethyl-2- (2,2,2-tri Fluoro-ethyl) -2,3,3a, 4,6,7-hexahydro-pyrazolo- [4,3-c] pyridin-5-yl) -ethyl) -2-methyl-propionamide.

  As used herein, the term “treating, treat” or “treatment” includes preventative, prophylactic (eg, prevention), palliative and therapeutic treatment.

  “Pharmaceutically acceptable” means that the carrier, diluent, excipient, and / or salt or prodrug is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Means.

The term “prodrug” means a compound that is converted in vivo to yield a compound of the invention. Transformation can occur by a variety of mechanisms, for example by hydrolysis in blood. For a discussion of the use of prodrugs, see T. Higuchi and W. Stella, “Prodrugs as Novel Delivery Systems,” ACSSymposium Series , Vol. 14, and Bioreversible Carriers in Drug Design , Editor Edward B. Roche, American Pharmaceutical. Provided by Association and Pergamon Press, 1987.

For example, if the compound of the present invention contains a carboxylic acid functional group, the prodrug may include an ester formed by exchanging the hydrogen atom of the acid group with, for example, the following group: (C ₁ -C ₈ ) Alkyl, (C ₂ -C ₁₂ ) alkanoyloxymethyl, 1- (alkanoyloxy) ethyl having 4 to 9 carbon atoms, 1-methyl-1- (alkanoyloxy)-having 5 to 10 carbon atoms Ethyl, alkoxycarbonyloxymethyl with 3-6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl with 4-7 carbon atoms, 1-methyl-1- (5 with 8-8 carbon atoms) Alkoxycarbonyloxy) ethyl, N- (alkoxycarbonyl) aminomethyl having 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, γ-butyrolac Down-4-yl, di _{-N, N- (C 1 -C 2} ) alkylamino (C ₂ -C ₃₎ alkyl (e.g. β- dimethylaminoethyl) carbamoyl - (C ₁ -C ₂₎ alkyl, N , N-di (C ₁ -C ₂ ) alkylcarbamoyl- (C ₁ -C ₂ ) alkyl, and piperidino-, pyrrolidino- or morpholino (C ₂ -C ₃ ) alkyl.

Similarly, when a compound of the invention contains an alcohol functional group, a prodrug can be formed by exchanging the hydrogen atom of the alcohol group with, for example, the following group: (C ₁ -C ₆ ) alkanoyloxymethyl 1-((C ₁ -C ₆ ) alkanoyloxy) ethyl, 1-methyl-1-((C ₁ -C ₆ ) alkanoyloxy) -ethyl, (C ₁ -C ₆ ) alkoxycarbonyloxymethyl, N- (C ₁ -C ₆ ) alkoxycarbonylaminomethyl, succinoyl, (C ₁ -C ₆ ) alkanoyl, α-amino (C ₁ -C ₄ ) alkanoyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl Each α-aminoacyl group is independently a natural L-amino acid, P (O) (OH) ₂ , —P (O) (O (C ₁ -C ₆ ) alkyl) ₂ or glycosyl (hemiacetal form of carbohydrate); Selected from the group obtained by removing the hydroxyl group of That.

If the compounds of the invention contain an amine function, prodrugs can be formed by exchanging the hydrogen atoms of the amine group with, for example, the following groups: R ^X -carbonyl, R ^X O-carbonyl, NR ^X R ^{X ′} -carbonyl [R ^X and R ^{X ′} are each independently (C ₁ -C ₁₀ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, benzyl, or R ^X -carbonyl is a natural α-aminoacyl Or natural α-aminoacyl-natural α-aminoacyl], —C (OH) C (O) OY ^X [Y ^X is H, (C ₁ -C ₆ ) alkyl or benzyl], —C (OY ^X0 ) Y ^X1 (Y ^X0 is (C ₁ -C ₄ ) alkyl, Y ^X1 is (C ₁ -C ₆ ) alkyl, carboxy (C ₁ -C ₆ ) alkyl, amino (C ₁ -C ₄ ) alkyl, Or is mono-N- or di-N, N- (C ₁ -C ₆ ) alkylaminoalkyl], -C (Y ^X2 ) Y ^X3 [Y ^X2 is H or methyl, Y ^X3 is mono-N -Or Di-N, N- (C _1- C ₆ ) alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl].

  The expression “pharmaceutically acceptable salts” refers to non-toxic anionic salts including, but not limited to, for example, the following anions: chloride, bromide, iodide, sulfate, hydrogen sulfate, phosphate, acetic acid Salt, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, methanesulfonate and 4-toluenesulfonate. This representation also represents, for example, but not limited to, salts of the following non-toxic cations: sodium, potassium, calcium, magnesium, ammonium or protonated benzathine (N, N'-dibenzylethylenediamine), choline, ethanolamine , Diethanolamine, ethylenediamine, megramin (N-methyl-glucamine), venetamine (N-benzylphenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol).

  As used herein, the terms “reactive inert solvent” and “inert solvent” interact with starting materials, reagents, intermediates or products in a manner that adversely affects the yield of the desired product. It represents a solvent without any problems.

It will be appreciated that the compounds of the invention may be in a radiolabeled form. That is, the compound of the present invention can contain one or more atoms having an atomic mass or mass number different from that of the atomic mass or mass number normally found in nature. Radioisotopes of hydrogen, carbon, phosphorus, fluorine and chlorine include ³ H, ¹⁴ C, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl, respectively. Compounds of the present invention that contain these radioisotopes and / or other radioisotopes of other atoms are within the scope of the invention. Tritiated, ie, ³ H, and carbon-14, ie, ¹⁴ C, radioisotopes are particularly preferred for ease of manufacture and detectability. The radiolabeled compounds of the present invention can generally be prepared by methods well known to those skilled in the art. Such a radiolabeled compound can be conveniently produced by replacing the non-radioactive reagent with a readily available radiolabeled reagent and carrying out the methods described in the above reaction pathways and / or examples and production methods below. .

  One skilled in the art will recognize that certain compounds of the present invention have at least one asymmetric carbon atom and are therefore enantiomers or diastereomers. Diastereomeric mixtures can be separated into their respective diastereomers on the basis of their physicochemical differences by methods known per se, for example by chromatography and / or fractional crystallization. Enantiomers convert enantiomer mixtures into diastereomeric mixtures by reaction with appropriate optically active compounds (eg, alcohols), separate diastereomers, and convert each diastereomer to the corresponding pure enantiomer. Can be separated by transformation into the body (eg hydrolyzing: including chemical hydrolysis methods and microbiological lipase hydrolysis methods such as enzyme-catalyzed hydrolysis). All such isomers, including diastereomers, enantiomers and mixtures thereof are considered as part of this invention. Similarly, certain compounds of the present invention are atropisomers (eg, substituted biaryls) and are considered as part of this invention.

  In addition, compounds of the present invention, including compounds of formula I, resorption inhibitors, bone anabolic agents, prostaglandin agonists / antagonists, parathyroid hormone, growth hormone and growth hormone secretagogue form hydrates or solvates If so, they are also included in the scope of the present invention.

  Administration of the compounds of the present invention may be by any method that delivers the compounds of the present invention systemically and / or locally. These methods include oral routes, parenteral routes, duodenal routes and the like. In general, the compounds of the present invention can be administered orally, but for example, when oral administration is inappropriate for the target, or when the patient cannot take the drug orally, parenteral administration (eg, intravenous, intramuscular, transdermal, subcutaneous, rectal) Or intramedullary).

  The compounds of the present invention can also be applied topically to the patient's site in a suitable carrier or diluent, optionally in combination with one or more of the above anabolic or absorption inhibitors.

  The dosage and timing of compound administration will of course depend on the subject being treated, the severity of the disease, the mode of administration and the judgment of the prescribing physician. Thus, the dosages shown herein are guidelines because of patient diversity, and the physician can determine the drug dosage to achieve the treatment that the physician deems appropriate for the patient. In considering the degree of treatment desired, the physician must balance a variety of factors such as the patient's age, the presence of pre-existing conditions, and the presence of other diseases (eg, cardiovascular disease).

In general, the effective amount of the anabolic agent used in the present invention is 0.001 to 100 mg / kg / day, preferably 0.01 to 50 mg / kg / day.
The following sections show preferred dosage ranges for various absorption inhibitors.

In general, an effective amount of an absorption inhibitor is from about 0.001 to about 20 mg / kg / day.
In general, an effective amount of progestin is about 0.1-10 mg / day; a preferred amount is about 0.25-5 mg / day.

In general, the effective amount of polyphosphonate is determined by the potency of the standard assay as a bone resorption inhibitor.
The daily dosage range for certain polyphosphonates is about 0.001 to about 20 mg / kg / day.

  In general, an effective amount for the treatment of the present invention, eg, the bone resorption treatment of the present invention, is 0.01 to 200 mg / kg / day, preferably 0.5 to 100 mg / kg / day for the estrogen agonist / antagonist of the present invention. .

In particular, the effective amount of raloxifene is 0.1-100 mg / kg / day, preferably 0.1-10 mg / kg / day.
In particular, the effective amount of tamoxifen is 0.1-100 mg / kg / day, preferably 0.1-5 mg / kg / day.

In particular, the effective amount of 2- (4-methoxy-phenyl) -3- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -benzo [b] thiophen-6-ol is 0.001-1 mg / kg / day.
In particular,
cis-6- (4-fluoro-phenyl) -5- (4- (2-piperidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalen-2-ol;
(-)-cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalen-2-ol;
cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalen-2-ol;
cis-1- (6′-pyrrolidinoethoxy-3′-pyridyl) -2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;
1- (4'-pyrrolidinoethoxyphenyl) -2- (4 "-fluorophenyl) -6-hydroxy-1,2,3,4-tetrahydroisoquinoline;
cis-6- (4-hydroxyphenyl) -5- (4- (2-piperidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalen-2-ol; or
The effective amount of 1- (4′-pyrrolidinoethoxyphenyl) -2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline is 0.0001-100 mg / kg / day, preferably 0.001-10 mg / kg / day.

  The compounds of the invention are generally administered in the form of a pharmaceutical composition comprising at least one compound of the invention together with a pharmaceutically acceptable vehicle or diluent. Thus, the compounds of the present invention can be administered individually or together in any common oral, parenteral, rectal or transdermal dosage form.

  For oral administration, the pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like. Various excipients such as sodium citrate, calcium carbonate and calcium phosphate, various disintegrants such as starch, preferably potato or tapioca starch, and certain complex silicates, and binders such as polyvinylpyrrolidone, Tablets containing with sucrose, gelatin and gum arabic can be used. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tablet manufacture. Similar types of solid compositions can also be used as fillers in soft and hard gelatin capsules; preferred materials in this regard also include lactose, milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the compounds of the present invention may be combined with various sweetening, flavoring, coloring, emulsifying and / or suspending agents, and diluents such as water, ethanol , Propylene glycol, glycerin and various combinations thereof.

  For parenteral administration, solutions in sesame or peanut oil or aqueous propylene glycol solutions and sterile aqueous solutions of the corresponding water-soluble salts can be used. Such aqueous solutions can be appropriately buffered if necessary, and the liquid diluent can first be made isotonic with sufficient saline or glucose. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection. All sterile aqueous media used in this regard can be readily obtained by standard methods well known to those skilled in the art.

For transdermal (eg, topical) administration, a low concentration, sterile aqueous solution or partial aqueous solution (usually about 0.1-5% concentration) is prepared that is otherwise similar to the parenteral solutions described above.
Methods for preparing various pharmaceutical compositions containing specific amounts of active ingredients are known or will be apparent to those skilled in the art in view of the disclosure herein. For examples of methods for preparing pharmaceutical compositions, see Remington's Pharmaceutical Sciences , Mack Publishing Company, Easton, PA, 19th Edition (1995).

  The pharmaceutical composition of the present invention may contain 0.1 to 95%, preferably 1 to 70% of the compound (one or more) of the present invention. In any event, the composition or formulation to be administered will contain an amount of the compound (s) of the invention effective to treat the disease / condition of the subject being treated.

The present invention may also be administered using an injectable fluid composition that provides sustained release at the infused local site by forming a solid or gel depot, matrix or implant that is biodegradable. it can. Examples of such delivery systems are EP ₂ selective receptor agonist compound biodegradable polymer in the sustained release delivery system in which a base material.

The polymer-based delivery system includes an EP ₂ selective receptor agonist compound, and optionally an additional therapeutically useful compound, dissolved or dispersed in a solution or dispersion of a biodegradable thermoplastic polymer in an organic solvent. . When the flowable composition is injected, the organic solvent diffuses from the injection site and the polymer precipitates or gels; this traps the compound in a sustained release depot. The compound is then released from the polymer matrix by diffusion and erosion. The polymer matrix is gradually eroded by hydrolysis and eventually disappears from the site of administration. The molecular weight and concentration of the polymer can control the in vivo release of the compound and the degradation rate of the matrix.

Delivery systems the polymer and substrate, the EP ₂ selective receptor agonist compound sustained release over an extended period of time in vivo in a patient in need thereof, massive release is minimized or reduced. When a compound is released in large quantities, local tolerability of the compound will decrease due to local action (eg, irritation) and the amount of compound that is effectively utilized will decrease. The advantage of this method of administration is that it minimizes or reduces the initial mass release and delivers an effective level of the compound over a long period of time with a single local injection.

The polymer system is prepared by contacting the flowable composition with a gelling medium to solidify or gel the composition into a solid microporous polymer gel or gel polymer matrix. The flowable composition contains a thermoplastic polymer or copolymer with a suitable solvent. The polymer or copolymer that forms the body of the matrix is substantially insoluble in water and body fluids, preferably essentially completely insoluble. Since the matrix body is insoluble, it can serve as the sole site for controlled release of the EP ₂ selective receptor agonist compound. The polymer or copolymer is also biocompatible and biodegradable and / or bioerodible in the body of an animal, such as a mammal. Being biodegradable, the patient can metabolize the polymer matrix so it is excreted from the patient without the need for further surgery to remove it. Because the flowable composition and the polymer system are biocompatible, the process of insertion and the presence of the polymer system in the body does not cause substantial tissue irritation or necrosis at the implantation site. The compositions of the present invention are administered directly to body tissue as a flowable composition.

  Thermoplastic polymers suitable for incorporation into a controlled release polymer-based solid matrix are solids that are pharmaceutically compatible and biodegradable by the action of cells and / or the action of body fluids. Examples of suitable thermoplastic polymers include diol and dicarboxylic acid or hydroxycarboxylic acid polyesters such as polylactide, polyglycolide and copolymers thereof. More preferably, the polymer is a copolymer, poly-lactic acid-co-glycolic acid (PLGH for short), which produces lactic acid and glycolic acid when hydrolyzed. By adding polyethylene glycol (PEG) to form PEG end-capped PLGH, mass release of this copolymer can be further minimized.

Preferred materials for use in the present invention are polylactide, polyglycolide and copolymers thereof. Part of the reason these polymers can be used advantageously in polymer systems is because they exhibit excellent biocompatibility. They rarely cause tissue irritation, inflammation, necrosis or toxicity (if any). In the presence of water, these polymers produce lactic acid and glycolic acid, respectively, which are readily metabolized by the body. The polylactide may contain glycolide monomers to facilitate degradation of the product polymer. The reason these polymers are used is that they effectively control the release rate of the EP ₂ selective receptor agonist compound from the polymer system and that they localize the EP ₂ selective receptor agonist compound at the site of administration. It is also to hold.

The solubility or miscibility of the thermoplastic polymer in the organic solvent of the composition will vary according to factors such as the crystallinity, hydrophilicity, hydrogen bonding capacity and molecular weight of the polymer. Accordingly, the molecular weight of the polymer and the concentration in the solvent are adjusted to achieve the desired miscibility and the desired release rate of the incorporated EP ₂ selective receptor agonist compound.

The flowable composition of thermoplastic polymer, solvent and EP ₂ selective receptor agonist compound is a stable flowable material. Preferably, a homogeneous solution of the EP ₂ selective receptor agonist compound in an organic solvent is produced. The thermoplastic polymer is substantially soluble in organic solvents. When the flowable composition is placed in the body, the solvent will dissipate and the polymer will solidify or gel, forming a polymer system containing the EP ₂ selective receptor agonist compound within a solid or gel-like polymer matrix. .

When using a flowable composition as a vehicle, it has been found that the molecular weight of the polymer used significantly affects the release rate of the EP ₂ selective receptor agonist compound from the site of use and the degradation rate of the polymer.

For certain preferred polymers used in the present invention, the molecular weight of the polymer or copolymer is adjusted to about 0.2 to about 0.4 inherent viscosity (IV, dl / g) for effective sustained release of the bone growth promoting compound. Typical release rates of incorporated bone growth promoting compounds occur at IV of about 0.2 (molecular weight of about 8,000 to about 16,000) or IV of about 0.3 (molecular weight of about 23,000 to about 45,000). May vary depending on specific ingredients. For effective sustained release of EP ₂ selective receptor agonist compounds, it is preferred to adjust the molecular weight of the polymer to an IV of about 0.2 for most systems. The unit of measure for molecular weight is Dalton.

  For poly (DL-lactide) or lactide-co-glycolide polymer systems, the desired molecular weight range is from about 0.2 to about 0.4 I.V., with about 0.2 I.V. being most preferred. The molecular weight of the polymer can be varied by any of a variety of methods. The choice of method is generally determined by the type of polymer composition. Preferred polymers for use are commercially available.

  A highly preferred thermoplastic polymer for use in the present invention is the following: PLGH copolymer (copolymer RESOMER from Boehringer Ingelheim, registered with a 1: 1 ratio of lactic acid to glycolic acid and an inherent viscosity of about 0.2 dl / g) (Trademark) RG 502 H commercially available (molecular weight of about 12,000); PLGH copolymer (copolymer RESOMER® RG 503 from Boehringer Ingelheim) with a 1: 1 ratio of lactic acid to glycolic acid and an inherent viscosity of about 0.3 dl / g (Commercially available as H) (molecular weight of about 37,000); PLGH copolymer (commercially available from Boehringer Ingelheim as copolymer RESOMER® RG 504 H) with a 1: 1 ratio of lactic acid to glycolic acid and an inherent viscosity of about 0.4 dl / g (Molecular weight of about 47,000); and a ratio of lactic acid to glycolic acid 1: 1, an inherent viscosity of about 0.79 dl / g, a polyethylene glycol (PEG) end-capped PLGH copolymer -(Commercially available as PLG-PEG from Boehringer Ingelheim) (approximately 52,000 molecular weight).

By appropriately selecting the molecular weight and viscosity of the polymer, the rate and extent of release of the EP ₂ selective receptor agonist compound from the polymer system can be varied from very fast to very slow. For example, according to the present invention, the rate of release of (3-(((4-t-butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid sodium salt is reduced, The complete release of the compound can be substantially within about 7 days. Using a higher viscosity polymer in accordance with the present invention, this period can be extended to about 15 days. The target release rate of the EP ₂ selective receptor agonist compound will depend on several factors, including the species of animal being treated and the particular condition being treated.

The concentration of polymer in the system can also be varied to adjust the release rate of the incorporated EP ₂ selective receptor agonist compound. It has been found that the thinner the polymer concentration, the more rapidly the EP ₂ selective receptor agonist compound is released. This effect can be combined with other methods to more effectively control the release of incorporated EP ₂ selective receptor agonist compounds according to purpose. For example, a wide range of release rates can be obtained by adjusting the concentration of polymer and EP ₂ selective receptor agonist compound as desired.

The solvent used in the thermoplastic composition of the present invention is preferably pharmaceutically acceptable biocompatible and diffuses into the body fluids in situ, thus having a water solubility ranging from high solubility to insolubility. Could be classified as having. Preferably, they are relatively unlikely (if any) to cause tissue irritation or necrosis at the site of injection and implantation. Preferably, the solvent will have at least minimal water solubility. If the organic solvent is water insoluble or minimally water soluble, the solvent will gradually disperse from the flowable polymer composition. As a result, an embedding agent will be obtained in which the amount of residual solvent contained varies over the course of its lifetime. Particularly preferably, the organic solvent has a moderate to high water solubility and will thus disperse rapidly from the polymer composition into the body fluid. More preferably, the solvent is rapidly dispersed from the polymer composition so that a solid embedding agent is rapidly formed. Simultaneously with the dispersion of the solvent, the thermoplastic polymer solidifies or gels into a solid polymer system. Preferably, pores are formed in the polymer system by solvent dispersion as the thermoplastic polymer solidifies. As a result, a flowable composition containing a thermoplastic polymer, a solvent, and an EP ₂ selective receptor agonist compound will form a porous solid polymer system. Similarly, if the solvent is slightly water soluble or water insoluble, a solid porous embedment is formed when the solvent is dispersed, or some solvent remains with the embedment, resulting in little pores, Alternatively, a gel-like embedding agent may be formed.

  Suitable solvents include liquid organic compounds that meet the above criteria. A preferred solvent for use in the present invention is N-methyl-2-pyrrolidone (NMP). At least part of the reason is its solvating ability and its biocompatibility.

  The solvent for the flowable thermoplastic polymer composition is selected to provide polymer and solvent compatibility and appropriate solubility. A low molecular weight thermoplastic polymer will usually more readily dissolve in a solvent than a high molecular weight polymer. Accordingly, the concentration of the thermoplastic polymer dissolved in various solvents varies depending on the type of polymer and its molecular weight. Conversely, high molecular weight thermoplastic polymers will tend to coagulate, gel or solidify more rapidly than very low molecular weight thermoplastic polymers. Furthermore, higher molecular weight polymers tend to produce higher solution viscosities than low molecular weight materials. Therefore, in order to obtain an advantageous injection efficiency, the molecular weight and the polymer concentration in the solvent as well as the advantageous release rate are controlled.

As the polymer system is formed from the flowable composition, the EP ₂ selective receptor agonist compound becomes incorporated into the polymer matrix. After the flowable composition is injected and the polymer system is formed in situ, the EP ₂ selective receptor agonist compound is released from the matrix into the adjacent tissue or fluid by a mechanism of diffusion and polymer degradation. These mechanisms can also be manipulated to affect the controlled rate release of the EP ₂ selective receptor agonist compound to the environment. For example, the polymer matrix can be formulated such that an effective and / or substantial amount of the EP ₂ selective receptor agonist compound degrades after it is released from the matrix. Thus, the release of the EP ₂ selective receptor agonist compound from the matrix depends on, among other factors, the solubility of the EP ₂ selective receptor agonist compound in water, the distribution of bone growth promoting compounds in the matrix, or the polymer It can vary depending on the size, shape, porosity, solubility and biodegradability of the matrix. Release of the EP ₂ selective receptor agonist compound from the matrix is controlled in its intrinsic rate by altering the polymer molecular weight to obtain the desired residence time and release rate.

For example, a preferred dosage form of EP ₂ selective receptor agonist compound (3-(((4-t-butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid is The dry sodium salt is reconstituted with PLGH solution in NMP before administration. A dosage form consisting of a lyophilized compound in one syringe (syringe A) and a PLGH solution in NMP in a second syringe (syringe B) is known as an A / B reconstitution system. The contents of both syringes are mixed immediately prior to delivery at or near the site of application. After reconstitution, the contents are transferred to a graduated dose syringe for delivery. The dosage form to be administered is a solution in which the compound is dispersed in a PLGH solution in NMP at the desired concentration, eg 5 and 50 mgA / ml (mgA / ml represents the free acid equivalent of the sodium salt form of the compound). There will be. The dosage form is a parenteral (eg, subcutaneous, intramuscular or intramedullary) sustained release injectable for topical administration. This compound (depot infusate) in a sustained release polymer matrix is designed for administration at or near the site of application and not for intravenous administration. In order to impart adequate storage stability to this dosage form, the two syringe system (A / B) described above, preferably using a compound in the sodium salt form, can be employed. A single phase formulation, preferably using the free acid form of the compound, is a preferred alternative form of formulation. Based on the stability of the compound and polymer, sterile filtration of the compound and irradiation of the polymer solution may be preferred to produce a stable sterile formulation. In one embodiment, a dosage form may be prepared and delivered as a separate aluminum pouch with one pouch filled with a lyophilized form of the compound and the other pouch filled with a polymer solution filled syringe. it can. A delivery container, delivery system and lyophilization method of the bone growth promoting formulation of the present invention for preparing pharmaceutical compositions and kits are described in published international patent application WO 01/73363.

Example A
The following combinations A) and B) for lyophilized syringes and polymer syringes, respectively, were used to obtain dosage forms of concentrations 5 and 50 mgA / ml:
A) (3-(((4-t-butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid sodium salt formulation with 5 mgA / ml (at the time of reconstitution) object:
Drug Syringe A contained 4 mgA sodium salt lyophilized in a 1.25 ml graduated male syringe;
Vehicle Syringe B contained 0.8 ml of 50% RG502H / 50% NMP solution in a 1.25 ml graduated female syringe;
B) (3-(((4-t-butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid sodium salt formulation at 50 mgA / ml (at the time of reconstitution) object:
Drug Syringe A contained 40 mgA sodium salt lyophilized in a 1.25 ml unscaled male (thick) BD syringe;
Vehicle Syringe B contained 0.8 ml of 50% RG502H / 50% NMP solution in a 1.25 ml unscaled female (thin) syringe;
mgA represents the free acid equivalent of the sodium salt form compound;
The% used in these examples is based on the weight of the indicated ingredient;
RG502H is a PLGH copolymer with a 1: 1 ratio of lactic acid to glycolic acid and an inherent viscosity of about 0.2 dl / g, and is commercially available, for example, as the copolymer RESOMER® RG 502 H from Boehringer Ingelheim.

Example 1
50% RG502H / 50% NMP containing 5 mgA / ml (3-(((4-t-butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid sodium salt, Mixed A / B (polymer solution autoclaved, compound lyophilized).

Example 2
50% RG502H / 50% NMP, containing 10 mgA / ml (3-(((4-t-butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid sodium salt, Mixed A / B (polymer solution irradiated, compound lyophilized).

Example 3
50% RG502H / 50% NMP with 50 mgA / ml (3-(((4-t-butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid sodium salt, Mixed A / B (polymer solution irradiated, compound lyophilized).

Example 4
47% RG502H / 3% PLG- containing 50 mgA / ml (3-(((4-t-butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid sodium salt PEG / 50% NMP, single phase.

Example 5
47% RG503H / 3% PLG- containing 50 mgA / ml (3-(((4-t-butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid sodium salt PEG / 50% NMP, single phase.

Example 6
45% RG504H / 55% NMP containing 50 mgA / ml (3-(((4-t-butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid sodium salt, Single-phase.

Example 7
37% RG503H / 63% NMP, containing 50 mgA / ml (3-(((4-t-butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid sodium salt, Mixed A / B (polymer solution autoclaved, compound lyophilized).

Example 8
37% RG503H / 63% NMP, containing 50 mgA / ml (3-(((4-t-butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid sodium salt, Mixed A / B (polymer solution irradiated, compound lyophilized).

Example 9
50% RG502H / 50% NMP, single phase with 5 mgA / ml (3-(((4-t-butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid .

Other examples of such polymer matrix delivery systems can be found in US Provisional Patent Application 60 / 337,255 (filed Nov. 30, 2001).
In a preferred administration system, syringe A is a lyophilized product of (3-(((4-t-butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid sodium salt, Store at 4 mg per syringe or 40 mg per syringe. Syringe B contains Resormer 502H, 50:50 poly (D, L lactide-co-glycolide) (50,50 PLGH) and N-methyl-2-pyrrolidone (NMP).

  The dose used for the A / B syringe system can vary widely and is determined by, among other factors, the disease being treated. A preferred dose range includes 0.5 to about 100 mgA. For syringes containing 50 mgA / ml, preferred doses include 0.1 ml, 0.2 ml, 0.6 ml and 2 ml. For syringes containing 5 mgA / ml, preferred doses include 0.1 ml, 0.2 ml, 0.3 ml, 0.6 ml and 2 ml.

Other methods for administering EP ₂ selective receptor agonists include local administration by injection to a specific site, or site delivery by a catheter. Another example can be found in US Provisional Patent Application 60 / 335,156 (filed Nov. 30, 2001).

General Experimental Methods In general, the compounds of the present invention can be prepared by methods including those known in the chemical art, particularly in light of the description contained herein. One method for preparing the compounds of the present invention is provided as another aspect of the present invention and is illustrated by the following reaction pathways. Other methods are described in the experimental section.

  Certain substituents (eg, carboxyls) are best prepared by conversion of other functional groups at a later point in the synthetic pathway (eg, carboxyl substituents can be prepared, for example, by conversion of hydroxyl or carboxaldehyde).

  Compounds of formula I where B is nitrogen can be prepared using the methods described in Reaction Routes 1-5. These methods include: (a) Sequential alkylation of sulfonamides or amides with two suitable alkylating agents, generally alkyl halides or alkyl sulfonates; (b) alkyl halides or sulfones. Alkylation of sulfonamides or amides with alkyl acids; or (c) reductive amination of aldehydes followed by reaction with acylating agents such as acyl chlorides, chloroformates, isocyanates or chlorocarbonyl amides; or sulfonylating agents For example, reaction with sulfonyl chloride. When performing sequential alkylation, one of the alkylating agents includes a QZ moiety (if necessary, the Z moiety is appropriately protected), while the other alkylating agent is a KM moiety (the functional group requiring protection is Either will be adequately protected). The order of alkylation, ie whether the alkylating agent containing the QZ moiety is added first or second, will depend on the reactivity of the electrophilic side chain. When performing reductive amination, the Q-Z moiety can be linked to either an amine reagent or an aldehyde reagent, depending on the ease of reagent manufacture and the reactivity of the reagent in the reductive amination reaction. Reductive amination is followed by acylation or sulfonylation with a suitable acylating agent or sulfonyl chloride, and the product is hydrolyzed if desired. Starting materials including amines, aldehydes and alkylating agents are prepared by methods well known to those skilled in the art. Certain preferred methods for making them are described herein.

  For example, compounds of formula I wherein B is N are prepared using the methods described in Reaction Routes 1 and 2 below. In general, these reaction pathways involve sequential alkylation of an appropriate sulfonamide of formula 1 or an amide of formula 1 with two appropriate alkyl halides or alkyl sulfonates. Reaction routes 1 and 2 differ only in the order of addition of the two alkylating agents. The order of alkylation is generally selected according to the reactivity of the electrophilic side chain. In general, it is preferred to react the less reactive electrophilic side chain first. This reduces the amount of dialkylation that occurs in the first alkylation step, thereby increasing the yield of monoalkylated material that is transferred to the next alkylation. In reaction pathways 1 and 2, one alkylating agent comprises a carboxylic acid or carboxylic acid isostere protected with an appropriate protecting group if necessary. Further in Reaction Paths 1 and 2, the carboxylic acid precursor of formula 3 is a carboxylic acid ester and R is a suitable carboxylic acid protecting group. Generally the protecting group is a straight chain lower alkyl, preferably methyl or ethyl, or t-butyl, or phenyl. Other acid homologs well known to those skilled in the art can be used by appropriately modifying the methods of Reaction Routes 1 and 2 (see, for example, Reaction Route 6 describing the preparation of tetrazole). Common alkylating agents are primary-, secondary-, benzyl- or allyl-halides and -sulfonates, preferably alkyl bromides or alkyl iodides.

  The sulfonamide or amide of Formula 1 can be reacted with a strong base such as sodium hydride, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, potassium t-butoxide and the like with an aprotic solvent such as dimethylformamide, Convert to its anion in tetrahydrofuran or N, N-dimethylformamide / benzene at a temperature of about -78 to about 100 ° C. The resulting anion is converted to about 0 to about 100 ° C. with a suitable alkyl halide of formula 2 or 3, or a suitable alkyl sulfonate of formula 2 or 3, wherein X ′ is a halide or sulfonate moiety of an alkylating agent. Alkylation at the temperature gives the corresponding monoalkylated compounds of formula 4 or 5. Optionally, varying amounts of by-products resulting from dialkylation of amides or sulfonamides are obtained, which can be removed by chromatographic methods, preferably flash chromatography (WCStill, M. Kahn, A. Mitra, J Org. Chem. 43, 2923, 1978). After the initial alkylation is complete, the compound of formula 4 or 5 is converted to a suitable base such as sodium hydride, lithium bis (trimethylsilyl) amide, lithium diisopropylamide, potassium bis (trimethylsilyl) amide, potassium t-butoxide, or Conversion to an anion in an aprotic solvent such as N, N-dimethylformamide, tetrahydrofuran, N, N-dimethylformamide / benzene, or acetone at a temperature of about −78 to about 100 ° C., such as with potassium carbonate. Alkylation of the anion with an appropriate second alkyl halide of formula 3 or 2 or an alkyl sulfonate of formula 3 or 2 gives the corresponding dialkylated compound of formula 6. When R is methyl or ethyl, the ester of formula 6 is hydrolyzed with dilute aqueous base to the corresponding carboxylic acid of formula I. This hydrolysis is preferably carried out using sodium or potassium hydroxide in aqueous methanol or ethanol, lithium hydroxide in aqueous alcoholic solvent or aqueous tetrahydrofuran at a temperature of about 0 to about 80 ° C. Alternatively, this hydrolysis can be carried out using methods well known to those skilled in the art, such as those described in “Protecting Groups in Organic Synthesis”, 2nd edition, TWGreene and PGMWuts, John Wiley and Sons, Inc., 1991. .

  Compounds of formula I wherein B is N can also be prepared from amines as described in Reaction Routes 3-4. In general, suitable amine starting materials of formulas 9 and 10 are commercially available or can be prepared by methods well known to those skilled in the art (see: “The Chemistry of Amino, Nitroso and Nitro Compounds and their Derivatives”, editor S. Patai). , J. Wiley, New York, 1982). For example, amine starting materials are prepared from the corresponding nitriles of formula 7 or 8. These nitrites are either commercially available or can be prepared by methods well known to those skilled in the art (see: Rappaport, “The Chemistry of the Cyano Group”, Interscience, New York, 1970, or Patai and Rappaport, “The Chemistry of Functional Groups”. ", Pt.2, Wiley, New York, 1983). The nitrile of formula 7 or 8 is converted to about -78 to about 60 in a non-protic solvent such as tetrahydrofuran or diethyl ether with a reducing agent such as borane-tetrahydrofuran complex, borane-methyl sulfide complex, or lithium aluminum hydride. Reduce at a temperature of ° C. Alternatively, the nitrile is hydrogenated in a proton solvent such as methanol or ethanol at a temperature of about 0 to about 50 ° C. in the presence of Raney nickel or a platinum or palladium catalyst, generally under a hydrogen atmosphere of 0 to 50 psi. It may be desirable to add an equivalent amount of acid, such as hydrogen chloride, to complete the reduction. The amine of formula 9 or 10 thus obtained is converted to the sulfonamide of formula 11 or 12 by sulfonylation with sulfonyl chloride, or the amine of formula 11 or 12 is acylated with an appropriate acyl chloride. Convert to amide. Both sulfonylation and acylation reactions are generally carried out at about −20 to about 50 ° C. in an aprotic solvent such as methylene chloride or diethyl ether in the presence of a weak base such as triethylamine, pyridine or 4-methylmorpholine. Done at temperature. Alternatively, the reaction of an amine of formula 9 or 10 with a carboxylic acid can be carried out in an inert solvent such as dichloromethane or N, N-dimethylformamide with a binder such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride Conveniently carried out in the presence of 1-hydroxybenzotriazole hydrate (HOBT) with a salt (EDC) or 1,3-dicyclohexylcarbodiimide (DCC) to produce a compound of formula 11 or 12. When the amine is present as a hydrochloride salt or other salt, it is preferred to add 1 equivalent of a suitable base, such as triethylamine, to the reaction mixture. Alternatively, this conjugation can be carried out in an inert solvent such as methanol with a conjugating reagent such as benzotriazol-1-yloxy-tris (dimethylamino) -phosphonium hexafluorophosphate (BOP). Such a coupling reaction is generally carried out at a temperature of about -30 to about 80 ° C, preferably 0 to about 25 ° C. For a discussion of other conditions used for peptide binding, see Houben-Weyl, Vol. XV, part II, E. Wunsch, George Thieme Verlag, 1974, Stuttgart. Alkylation of compounds of formula 11 or 12 as described in Reaction Routes 1 and 2, and optionally deprotection, provides the corresponding acid compounds of formulas 13 and 14. The compound of formula 11 or 12 is alkylated similarly to the alkylation of the compounds of formulas 1, 4 and 5 of reaction pathways 1 and 2 above. Deprotection of the alkylated product, if necessary, provides compounds of formulas 13 and 14.

  Amines of formulas 9 and 10 are also prepared by reduction of the appropriate amides of formulas 15 and 16. This reduction is accomplished with reagents such as borane-tetrahydrofuran complex, borane-methyl sulfide complex, or diisobutylaluminum hydride in an aprotic solvent such as tetrahydrofuran or diethyl ether at a temperature of about -78 to about 60 ° C. Is done.

  Amines of formulas 9 and 10 are also prepared from the corresponding nitro precursors by reduction of the nitro group with a reducing agent such as zinc / HCl, hydrogenation in the presence of Raney nickel, palladium or platinum catalysts, and other reagents. PNRylander “Hydrogenation Methods”, Academic Press, New York, 1985.

The amines and alkylating agents useful in the synthesis described above are described in the section below titled Manufacturing Methods and are prepared accordingly.
Alternatively, compounds of formula I wherein B is N are prepared by reductive amination of an aldehyde containing a suitably protected appropriate acidic functional group with an amine. This route is shown in Reaction Route 5. Alternatively, the amine may contain appropriate acidic functional groups that are appropriately protected.

This reductive amination is generally carried out at pH 6-8 with a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride. This reaction is usually carried out in a protic solvent such as methanol or ethanol at a temperature of about −78 to about 40 ° C. (eg A. Abdel-Magrid, C. Maryanoff, K. Carson, Tetrahedron Lett. 39 , 31 , 5595-5598, 1990). This reductive amination reaction can be carried out using titanium isopropoxide and sodium cyanoborohydride (RJ Mattson et al., J. Org. Chem. 1990, 55, 2552-4), or by pre-forming an imine under dehydrating conditions. Subsequent reduction may be carried out. The resulting amines of formulas 42 and 42A are converted to the desired amides or sulfonamides by coupling with acid chlorides, sulfonyl chlorides or carboxylic acids as shown in reaction pathways 3 and 4. If desired, the amine intermediate of formula 42 or 42A can be converted to urethane by treatment with chloroformate or to tetra-substituted urea by treatment with chlorocarbonylamide. These reactions are carried out in the presence of a weak base such as triethylamine, pyridine or 4-methylmorpholine in an aprotic solvent such as methylene chloride or diethyl ether at a temperature of about -20 to about 50 ° C. Conversion of an amine of formula 42 or 42A to a trisubstituted urea is accomplished by treatment with an isocyanate in an aprotic solvent such as methylene chloride or diethyl ether at a temperature of -20-50 ° C (eg reaction (See path 5A). If the amine is present as a hydrochloride salt, it is preferred to add an equivalent amount of a suitable base, such as triethylamine, to the reaction. If desired, hydrolysis of the resulting sulfonamide or amide provides the corresponding acid.

Aldehydes useful for the above reaction pathway 5 are described in the section entitled Manufacturing Methods below and are prepared accordingly.
Compounds of formula I wherein B is N and Z is tetrazolyl are prepared as described in Reaction Scheme 6. A sulfonamide or amide of formula 4 with a suitable alkyl halide or sulfonate containing nitrile (X ′ is a halide or sulfonate), preferably primary-, secondary-, benzyl- or allyl-bromide, -iodide Alkylation with, or -sulfonate provides the nitrile of formula 59. This alkylation can be accomplished by reacting a sulfonamide or amide of Formula 59 with an aprotic solvent such as sodium hydride, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, potassium t-butoxide, or potassium carbonate, such as This is accomplished by treatment in dimethylformamide, dimethylformamide / benzene, or acetone, followed by reaction of the resulting anion with a suitable alkylating agent. The alkylation is performed at a temperature of about -78 to about 100 ° C. A preferred method for converting the resulting nitrile of formula 59 to tetrazole of formula 60 is to treat the alkylated nitrile with dibutyltin oxide and trimethylsilyl azide in refluxing toluene (SJWittenberger and BGDonner, J. Org Chem. 1993, 58, 4139-4141, 1993). For an overview of alternative methods of tetrazole production, see RNButler, Tetrazoles, In Comprehensive Heterocyclic Chemistry; edited by Potts, KT; Pergamon Press: Oxford, 1984, Vol. 5, pp. 791-838.

  Alternatively, certain Formula I compounds where B is N are prepared as described in Reaction Route 7. For example, the ester of formula 46 is prepared using the methods described in Reaction Routes 1 and 2 above. This intermediate Heck linkage to an aryl halide (preferably aryl bromide or aryl iodide), aryl triflate, or ring system containing vinyl bromide, iodide or triflate is then coupled to a palladium catalyst such as palladium acetate or tetrakis ( Triphenylphosphine) palladium (0) is achieved in the presence of a trialkylamine, such as triethylamine. Optionally, additives such as triarylphosphine or triarylarsenic may be added to the reaction. This reaction is generally carried out in an aprotic solvent such as dimethylformamide or acetonitrile at a temperature of about 0 to about 150 ° C. (see RFHeck, Comp. Org. Syn. Vol. 4, Ch. 4.3, p. 833). Or Daves and Hallberg, Chem. Rev. 1989, 89, 1433). If desired, the compound of formula 47 can be hydrolyzed to the corresponding acid. Alternatively, the compound of formula 47 can be hydrogenated and optionally further hydrolyzed to the corresponding acid of formula 49. Hydrogenation is accomplished at a temperature of about 0 to about 50 ° C. in an alcoholic solvent such as ethanol or methanol, preferably in the presence of a palladium or platinum catalyst, generally under a hydrogen atmosphere of 0 to 50 psi. If M is a partially saturated ring system, hydrogenation will give a fully saturated ring system.

  Alternatively, certain compounds of formula I wherein B is N are prepared as described in Reaction Scheme 8. A compound of formula 51 is prepared by alkylating a compound of formula 5 with an electrophile of formula 2 containing an appropriate functional group on the M ring, as described in Reaction Routes 1 and 2 above. At least one substituent on the M ring must be suitable for subsequent conversion to an aldehyde. For example, an electrophilic compound of formula 2 containing a protected alcohol on the M ring can be alkylated with reagents well known to those skilled in the art and then deprotected and oxidized to an aldehyde to form the compound of formula 51. An alternative is to alkylate with an electrophile of formula 2 where M contains a vinyl group. Following alkylation, oxidative cleavage of the double bond yields the desired aldehyde of formula 51. This oxidative cleavage is accomplished by converting the double bond to 1,2-diol with the catalysts osmium tetroxide and N-methylmorpholine, followed by oxidative cleavage with sodium periodate to an aldehyde. The Alternatively, oxidative cleavage by ozonolysis followed by reduction with reagents such as methyl sulfide, triphenylphosphine, zinc / acetic acid, or thiourea provides the desired formula 51 aldehyde. LMetal (LMetal is an organometallic reagent such as organolithium or Grignard reagent) in an aprotic solvent such as diethyl ether or tetrahydrofuran is added at a temperature of about -78 to about 80 ° C., followed by hydrolysis of the ester as described above. Upon decomposition, the desired compound of formula 50 is obtained.

Alternatively, certain compounds of formula I wherein B is N are prepared as described in Reaction Scheme 9. The appropriate sulfonamide or amide of formula 5 is alkylated under the conditions described in Reaction Routes 1 and 2. Alkylating agents are electrophiles [including aromatic bromides or iodides or ring systems (Ar ¹ ) containing vinyl bromides or iodides] that give compounds of formula 53. When the thus obtained compound of formula 53 is subjected to a Suzuki type bond with arylboronic acid (Ar ² ), a compound of 53a is obtained. For a review of the Suzuki reaction, see ARMartin and Y. Yang, Acta Chem. Scand. 1993, 47, 221. This conjugation reaction is carried out using about 2 equivalents of a base, such as sodium carbonate, potassium carbonate, sodium hydroxide, thallium hydroxide or potassium phosphate, using a palladium catalyst such as tetrakis (triphenylphosphine) palladium (0), palladium acetate. , Palladium chloride, tris (dibenzylideneacetone) dipalladium (0) or [1,4-bis (diphenylphosphine) butane] palladium (0). This reaction can be carried out in a hydroalcoholic solvent such as methanol or ethanol; or in another aqueous solvent such as aqueous tetrahydrofuran, aqueous acetone, aqueous glycol dimethyl ether or aqueous benzene at a temperature of about 0 to about 120 ° C. If Ar ¹ is a partially saturated ring, at this point, if desired, the reaction can be performed to reduce the ring to obtain a saturated ring system. This conversion is accomplished by hydrogenating the partially saturated ring in the presence of a catalyst such as palladium or platinum in an alcoholic solvent (ethanol or methanol) and / or ethyl acetate. If desired, ester hydrolysis of the compound of formula 53 or 53a provides the corresponding acid. The resulting acid may contain functional groups on either ring system (Ar ¹ or Ar ² ), which can be modified by methods well known to those skilled in the art. An example of such modification is shown in Reaction Path 10.

  Compounds of formula 54 containing aldehyde functionality are prepared using the methods described in Reaction Routes 8 and 9. For Reaction Pathway 10, the compound of formula 54 is treated with a suitable organometallic reagent (LMetal) such as organolithium or Grignard reagent in an aprotic solvent such as diethyl ether or tetrahydrofuran at a temperature of about −78 to about 80 ° C. Subsequent hydrolysis of the ester provides the compound of formula 56. Alternatively, reduction of the aldehyde followed by hydrolysis yields the compound of formula 55.

  Alternatively, certain compounds of formula I where B is N are prepared as described in Reaction Scheme 11. The starting alcohol of formula 58 is prepared by methods well known to those skilled in the art, for example using the methods described in Reaction Routes 1 and 2. One skilled in the art will recognize that protecting groups are required for the synthesis of certain of these alcohols. Intermediate 58 is coupled with a variety of aryl alcohols (M is as defined above) under Mitsunobu coupling conditions (for review see O. Mitsonobu, Synthesis, 1, 1981). Generally, this linkage is achieved at a temperature of about 0 to about 80 ° C. in an inert solvent such as methylene chloride or tetrahydrofuran by addition of a binder such as triphenylphosphine and diethyl azodicarboxylate or diisopropyl azodicarboxylate. . Subsequent hydrolysis, if desired, gives the corresponding acid.

  Alternatively, certain compounds of formula I where B is N are prepared as described in Reaction Route 12. The compound of formula 102 is added to the compound of formula 105 (where X is as defined above for the compound of formula I) in the presence of a Lewis acid, such as titanium tetrachloride, or a mineral acid, such as hydrochloric acid. If desired, the ester of formula 106 can be converted to the corresponding acid by hydrolysis or deprotection.

  Alternatively, certain compounds of formula I where B is N are prepared as described in Reaction Route 13. A chloromethyl compound of formula 104 is converted to an aprotic solvent such as chloroform in the presence of a Lewis acid such as titanium tetrachloride, or a mineral acid such as hydrochloric acid, with an appropriately substituted aromatic ring system M such as 4-ethoxybenzene or thiophene. In the treatment at a temperature of about 0 to about 80 ° C., a compound of formula 107 is obtained. This is then hydrolyzed or deprotected as described above to give the corresponding carboxylic acid. Alternatively, treatment of a chloromethyl compound of formula 104 with a Lewis acid such as titanium tetrachloride and an optionally substituted vinylsilane in an aprotic solvent such as methylene chloride at a temperature of about -50 to about 50 ° C. Is obtained. If desired, hydrolysis or deprotection of the compound of formula 108 as described above provides the corresponding acid. If desired, double bond reduction can be achieved using the conditions described in Reaction Route 7.

  Alternatively, certain compounds of formula I wherein B is N are prepared as described in Reaction Route 14. Treatment of a chloromethyl compound of formula 104 with a Lewis acid, such as titanium tetrachloride, and an optionally substituted allylsilane in an aprotic solvent such as chloroform at a temperature of about 0 to about 80 ° C. yields a compound of formula 109 can get. This is then hydrolyzed or deprotected as described above to give the corresponding carboxylic acid.

  Alternatively, certain compounds of formula I wherein B is N are prepared as described in Reaction Route 15. Treatment of a chloromethyl compound of formula 104 with a sulfinic acid of formula 111 in the presence of a base, such as triethylamine, in an aprotic solvent, such as chloroform, at a temperature of about -30 to about 50 ° C yields the compound of formula 112 can get. This is then hydrolyzed or deprotected as described above to give the corresponding acid.

  Compounds of formula I, wherein B is C (H) and Q, G, M and K are as described in the Summary of the Invention above, are prepared as described in Reaction Route 16. The β-ketoester of formula 113 is in turn alkylated with the compound of formula 114 to form the compound of formula 115, followed by alkylation with the compound of formula 116 to give the compound of formula 117 (J. Med. Chem. 26, 1993, p 335-41). Alkylation can be carried out in a suitable solvent such as DMF, THF, ether or benzene with a suitable base such as sodium hydride, LDA or potassium carbonate at a temperature of about −78 to about 80 ° C. Hydrolysis and decarboxylation of the resulting disubstituted ketoester of formula 117 provides the corresponding compound of formula 118: hydrolysis of the ester with an aqueous base, such as sodium hydroxide, followed by, for example, aqueous hydrochloric acid, etc. The reaction is stopped with acid to perform decarboxylation.

  Alternatively, compounds of formula I wherein B is C (H) and Q, G, M and K are as described in the Summary of the Invention above can be prepared as described in Reaction Route 17. Sequential alkylation of the malonic acid derivative of formula 119 provides the dialkylated compound of formula 121. Deprotection of the ester group by treatment with a strong acid such as TFA or HCl (in ethanol) at a temperature of about −20 to about 50 ° C. provides the decarboxylated product of formula 122. Convert the acid to the acid chloride using thionyl chloride or oxalyl chloride in an aprotic solvent at a temperature of about −78 to about 50 ° C., or use methoxymethylamine to form a suitable binder such as DCC or DEC. Conversion to Weinreb amide in the presence of an aprotic solvent at a temperature of about −30 to about 50 ° C. yields a compound of formula 123. The compound of formula 123 is a suitable substrate for the addition of various organometallic species such as Grignard reagents and organocadmium reagents, and the keto acid compound of formula 118 is obtained after hydrolysis of the terminal ester.

  Alternatively, the keto acid compound of formula 118 can be prepared using the methods previously described in Reaction Routes 7-11. In this case, one or both side chains are further functionalized after attachment to the alkanoyl fragment.

Preparation Amine, Amides and Sulfonamides Specific amides or sulfonamides described by formulas 21, 22 and 23, wherein W and Z are as described in the Summary of the Invention above, X and M are aromatic ring systems Or a saturated ring system) is prepared as described in Reaction Route 18. Alkynyl amides or sulfonamides of formulas 25, 26 and 27 are alkynyl sulfonamides or alkynyl amides of formula 24, aromatic halides or vinyl halides, preferably aromatic or vinyl bromides or iodides (W and Z are as defined above Wherein X and M are aromatic or partially saturated ring systems). This bond is generally in the presence of copper iodide, a palladium catalyst such as palladium chloride, bis (triphenylphosphine) palladium dichloride or tetrakis (triphenylphosphine) palladium (0), and an amine such as triethylamine, diisopropylamine or butylamine. In an aprotic solvent such as acetonitrile at a temperature of about 0 to about 100 ° C. Hydrogenation of an alkyne of formula 25, 26 and 27 in the presence of a palladium or platinum catalyst in a solvent such as methanol, ethanol and / or ethyl acetate at a temperature of about 0 to about 50 ° C. Convert to 23 corresponding alkanes. If M represents a partially saturated ring system, hydrogenation will convert M to a fully saturated ring system. Alternatively, the alkyne is converted to a cis-alkene with a Lindlar catalyst (Pd—CaCO ₃ —PbO) or other suitable catalyst. Alkylation and deprotection as described in Reaction Routes 1 and 2 gives the corresponding compound of formula I.

  The compound of formula 33 is prepared from a suitable amine of formula 32 (eg, methoxyarylalkylamine). Amines of formula 32 are commercially available or are prepared by methods well known to those skilled in the art (see, for example, Reaction Route 4). The amine of formula 32 is converted to the sulfonamide or amide of formula 31 by the method described in Reaction Routes 3 and 4, for example. The resulting aromatic methyl ester of formula 31 can be converted to reagents such as boron tribromide, pyridinium hydrochloride, hydrogen bromide / acetic acid, or “Protecting Groups in Organic Synthesis”, 2nd edition, TWGreene and PGM Wuts, John Deprotect with other reagents as described in Wiley and Sons, Inc., 1991. Alkylation with a bromoalkyl ester using a mild base such as potassium carbonate in an aprotic solvent such as dimethylformamide or acetone at a temperature of about 0 to about 100 ° C. produces an amide or sulfonamide of formula 33 .

Alkylating agents There are a number of methods for synthesizing the desired alkylating agents for use in the above-described methods and are known to those skilled in the art (see: Rappaport, “The Chemistry of the Carbon-Halogen Bond”, Editor S. Patai, J. Wiley, New York, 1973 and “The Chemistry of the Halides, Pseudo-Halides, and Azides”, editor S. Patai and Z. Rappaport, J. Wiley, New York, 1983). Some examples are shown in Reaction Routes 20-24. As shown in Reaction Route 20, a tolyl or allyl substrate can be converted to benzyl or allyl bromide by halogenation (M, X, W and Z are as described in the Summary of the Invention above). This reaction is generally carried out with N-bromosuccinimide (NBS) in the presence of a radical initiator such as 2,2′-azobisisobutyronitrile (AIBN), or a peroxide, preferably benzoyl peroxide. . Alternatively, the reaction can be initiated by light. This reaction is carried out in an inert solvent such as carbon tetrachloride or chloroform at a temperature of about 50 to about 100 ° C.

Reaction route 21 illustrates the synthesis of an alkylating agent useful in the preparation of compounds of formula I where M represents a biaryl or aryl ring group. Using the conditions described in Reaction Scheme 9, a compound of formula 34 is formed by a Suzuki-type bond of a ring system containing aryl iodide or -bromide or vinyl bromide or -iodide (Ar ² ) and methylaryl boronic acid (Ar ¹ ). can get. When using vinyl bromide or -iodide, the compound of formula 34 can be reduced to produce a fully saturated ring. This reduction is accomplished by hydrogenation in the presence of a palladium or platinum catalyst, generally in a protic solvent such as methanol or ethanol, or tetrahydrofuran or ethyl acetate. Halogenation of the methyl group using the reagents and conditions described in reaction pathway 20 provides the alkylating agent of formula 35.

  Another common method for obtaining alkyl halides is by halogenation of alcohols or alcohol derivatives. Alcohols are commercially available or can be prepared by methods well known to those skilled in the art. For example, the corresponding alcohols from a carboxylic acid or ester using a reagent such as, but not limited to, sodium borohydride, lithium aluminum hydride, borane-tetrahydrofuran complex, borane-methyl sulfide complex in reaction path 22 Indicates reduction to Corresponding alkyl chlorides are generally prepared from alcohols using reagents such as hydrogen chloride, thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, or triphenylphosphine / carbon tetrachloride. For the production of alkyl bromides, alcohols are generally treated with reagents such as hydrogen bromide, phosphorus tribromide, triphenylphosphine / bromine, or carbonyldiimidazole / alkyl bromide (Kamijo, T., Harada H., Iizuka, K. Chem. Pharm. Bull. 1983, 38, 4189). To obtain alkyl iodides, suitable alcohols are generally reacted with reagents such as triphenylphosphine / iodine / imidazole or hydrogen iodide. Alternatively, a more reactive alkyl bromide or iodide by reacting the alkyl chloride with an inorganic salt such as sodium bromide, lithium bromide, sodium iodide or potassium iodide in a solvent such as acetone or methyl ethyl ketone. Can be converted to alkyl. Alkyl sulfonates can also be used as electrophiles or can be converted to alkyl halides. Alkyl sulfonates are prepared from the corresponding alcohols using a mild base such as triethylamine or pyridine and sulfonyl chloride in an inert solvent such as methylene chloride or diethyl ether. If desired, conversion to the halide can be accomplished by treating the alkyl sulfonate with an inorganic halide (sodium iodide, sodium bromide, potassium iodide, potassium bromide, lithium chloride, lithium bromide, etc.) or tetrabutylammonium halide. Is achieved.

  Cinnamic acid or esters are generally available from commercial sources and can be converted to alkylating agents of formula 37 or 38 according to the following (see reaction pathway 23). Cinnamic acid or ester derivatives are reduced by hydrogenation in the presence of a palladium or platinum catalyst, generally in a protic solvent (eg methanol or ethanol), tetrahydrofuran or ethyl acetate. Reduction and conversion to alkyl halides or sulfonates as described in Reaction Route 22 provides compounds of Formula 38. If appropriate, the cinnamic acid or ester can be converted directly to the alcohols of formula 39 by treating the cinnamic acid or ester with a reagent such as lithium ammonium hydride in an inert solvent such as tetrahydrofuran and diethyl ether. Alternatively, the cinnamic acid or ester can be reduced to an allyl alcohol of formula 40 with a reagent such as lithium aluminum hydride / aluminum chloride, diisobutylaluminum hydride or lithium borohydride. Conversion to allyl halide or allyl sulfonate described in Reaction Route 22 gives the compound of formula 37.

  The preparation of the alkylating agent of formula 41 (W and M are as described in the Summary of the Invention above) is shown in Reaction Path 24. Compounds of formula 42 can be alkylated with a variety of bases. The choice of base depends on the nature of W and M. Some preferred bases include, but are not limited to, sodium hydroxide, sodium hydride, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, and potassium t-butoxide. Treatment of the resulting anion with a variety of dialkyl halides yields the desired alkylating agent of formula 41. For the preparation of compounds wherein W is oxygen and M is an aromatic ring, it is preferred to form an alkoxide anion with sodium hydroxide followed by the addition of a dihaloalkane, such as a dibromoalkane. This reaction is usually carried out in water at a temperature of about 75 to about 125 ° C.

  Aldehydes useful for the process described in Reaction Scheme 5 are available from commercial sources or can be obtained from commercially available intermediates by methods well known to those skilled in the art (for general reference "The Chemistry of Carbonyl Group", editor S. Patai, Interscience, New York (1966-70)). Reaction pathway 25 exemplifies the method used to prepare the hydroxy aldehyde of formula 43 wherein M of reaction pathway 5 contains a hydroxy substituted alkyl group. A dialdehyde of formula 44 in which one aldehyde is protected as an acetal (OR group is a common substituent commonly used for an acetal protecting group) with an organometallic reagent (LMetal), preferably an organolithium or Grignard reagent, Treatment in an inert solvent such as tetrahydrofuran or diethyl ether provides the compound of formula 45. Subsequent mild acidic conditions such as dilute hydrogen chloride, Amberlyst-15® resin, silica gel, or “Protecting Groups in Organic Synthesis”, 2nd edition, TWGreene and PGMWuts, John Wiley and Sons, Inc. , 1991 to obtain the desired hydroxy aldehyde of formula 43.

  Aldehydes useful for the method described in Reaction Route 5 can be produced by the methods described in Reaction Routes 26-28. For example, as shown in Reaction Pathway 26, an arylboronic acid containing an aldehyde is coupled to an aryl bromide, aryl iodide, or a ring system containing vinyl bromide or -iodide via the Suzuki protocol described in Reaction Pathway 9 to form the formula 60 The aldehyde is obtained.

  Reaction path 27 describes the preparation of an aldehyde of formula 62 that contains an appropriately protected acid moiety and can be used to prepare the compound of formula 42A described in reaction path 5. Selective reduction of a nitrile of formula 61 (see Reaction Paths 3-4 for preparation) provides an aldehyde of formula 62. A preferred method for this reduction involves heating the nitrile with an aluminum-nickel (Raney) alloy in the presence of an acid, such as formic acid. The aldehydes of formula 64 (reaction pathway 5) useful for the preparation of compounds of formula 42 are derived from starting nitriles of formula 63 from various reducing agents such as diisobutylaluminum hydride, tin (II) chloride / hydrogen chloride, or lithium. It can be produced by a treatment using triethoxyalanine.

  A process for the preparation of propionaldehyde of formula 65 is described in reaction route 28, according to Kang (J. Org. Chem. 1996, 61, 2604) and Jeffery (J. Chem. Soc. Chem. Commun. 1984, 19, 1287). It is according to the method. The aryl iodide or aryl bromide is coupled to allyl alcohol in the presence of a suitable palladium catalyst, preferably palladium acetate. This reaction is carried out in a suitable polar aprotic solvent, preferably dimethylformamide, with the addition of a base, such as sodium bicarbonate, and an ammonium salt, such as tetrabutylammonium chloride, to give the propionaldehyde of formula 65.

Chloromethyl Intermediate The intermediate chloromethyl compound can be prepared as described in Reaction Routes 29 and 30. In general, the appropriate sulfonamide or carboxamide of formula 66 or 68 is transformed with a suitable catalyst such as HCl, zinc chloride or trimethylsilyl chloride in an inert organic solvent such as methylene chloride or chloroform with a formaldehyde equivalent such as paraformaldehyde. When used and treated at temperatures from about 0 to about 60 ° C., chloromethyl derivatives of formula 67 and 69 are obtained, respectively.

  Reaction pathway 31 shows the synthesis of a biaryl aldehyde of formula 60. Heating the fluorobenzonitrile of formula 70 with a nucleophilic group such as pyrazole or imidazole in a suitable solvent such as DMF to displace the fluoro group provides the intermediate of formula 71. The target biaryl aldehyde of formula 60 is obtained by reducing the nitrile by hydrogenation using a Raney alloy or by reduction with a hydride source, such as diisobutylaluminum hydride.

  The examples and synthesis methods provided herein are for the purpose of illustrating particular embodiments of the invention and are not intended to limit the scope of the specification or the claims. All documents cited herein are hereby incorporated by reference.

Example 1
7-((4-Butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -heptanoic acid
Step A: Reductive amination
7- (4-Butyl-benzylamino) -heptanoic acid methyl ester . 7-Aminoheptanoic acid methyl ester hydrochloride (1.12 g. 5.9 mmol), 4-butyl-benzaldehyde (0.915 g. 5.65 mmol) and triethylamine (0.83 mL, 5.98 mmol) prepared in Preparation Example 1 in 20 mL of MeOH The solution was stirred at room temperature for 3 hours. After cooling to 0 ° C., NaBH ₄ (0.342 g. 9.04 mmol) was added and the reaction was stirred at room temperature for 15 minutes. The mixture was quenched with 1: 1 NaHCO ₃ : H ₂ O and MeOH was removed in vacuo. The resulting residue was diluted with CH ₂ Cl ₂ and the organic solution was washed with water and brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound of Step A (1.4 g).

Step B: Formation of amide
7-((4-Butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -heptanoic acid methyl ester . 7- (4-Butyl-benzylamino) -heptanoic acid methyl ester (0.10 g. 0.33 mmol), N, N-diisopropylethylamine (0.85 g. 0.66 mmol) prepared in Step A of Example 1, and Preparation Example 2 A solution of pyridine-3-sulfonyl chloride hydrochloride prepared in (0.070 g. 0.33 mmol) in 3 mL of CH ₂ Cl ₂ was stirred overnight at room temperature. The mixture was diluted with CH ₂ Cl ₂ and the organic solution was washed with water and brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (10% EtOAc / hexanes to 30% EtOAc / hexanes) to give the title compound of Step B.

Step C: Ester hydrolysis
7-((4-Butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -heptanoic acid . 7-((4-Butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -heptanoic acid methyl ester (0.040 g. 0.158 mmol) prepared in Step B of Example 1 was added to 2 mL of MeOH and 0.5 N of 2N NaOH. The solution in mL was stirred overnight at room temperature. The mixture was quenched with 2N HCl and diluted with CH ₂ Cl ₂ . The organic layer was washed with 1N HCl and water, dried over MgSO ₄ , filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (2% MeOH / CH ₂ Cl ₂ to 5% MeOH / CH ₂ Cl ₂ ) to give the title compound (42 mg).

Examples 1a-1an
Examples 1a-1an were prepared from the appropriate starting materials in a manner similar to that of Example 1 with the reaction time, temperature and reagents changed as indicated.

Example 1a
7- (Benzenesulfonyl- (4-butyl-benzyl) -amino) -heptanoic acid

Example 1b
(3-(((1-Methyl-1H-indol-3-ylmethyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid

Example 1c
(3-(((5-Phenyl-furan-2-ylmethyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid

Example 1d
(3-(((5-Benzyl-pyridin-2-ylmethyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid Step A: Reaction time 3.5 hours at room temperature.

Example 1e
(3-(((4-Phenethylsulfanyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid Step A: Reaction time 4 hours at room temperature.

Example 1f
(3-(((3-Hydroxy-4-propoxy-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid Step A: Reaction time 3.5 hours at room temperature.

Example 1g
(3-(((4-Pentyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid Step A: Reaction time 3.5 hours at room temperature.

Example 1h
(3-(((4-Methylsulfamoyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid Step A: Reaction time 3.5 hours at room temperature.

Example 1i
(3-(((4-Isopropoxy-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid Step A: Reaction time 3.5 hours at room temperature.

Example 1j
(3-(((4-Chloro-thiophen-2-ylmethyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid Step A: Reaction time 3.5 hours at room temperature.

Example 1k
(3-(((4-Butyl-benzyl)-(4-nitro-benzenesulfonyl) -amino) -methyl) -phenyl) -acetic acid

Example 1l
(3-(((4-Butyl-benzyl)-(4-cyano-benzenesulfonyl) -amino) -methyl) -phenyl) -acetic acid

Example 1m
(3-(((4-Butyl-benzyl)-(3-fluoro-benzenesulfonyl) -amino) -methyl) -phenyl) -acetic acid

Example 1n
(3-(((4-Butyl-benzyl)-(5-pyridin-2-yl-thiophen-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid Step B: Instead of N, N-diisopropylethylamine Triethylamine was used.

Example 1o
(3-(((4-Butyl-benzyl)-(toluene-4-sulfonyl) -amino) -methyl) -phenyl) -acetic acid Step B: Triethylamine was used instead of N, N-diisopropylethylamine.

Example 1p
(3-(((2,3-Dihydro-benzo [1,4] dioxin-6-ylmethyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid

Example 1q
(3-((Benzofuran-2-ylmethyl- (pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid

Example 1r
(3-(((4-Butyl-benzyl)-(1-methyl-1H-imidazol-4-sulfonyl) -amino) -methyl) -phenyl) -acetic acid

Example 1s
(3-(((4-Imidazol-1-yl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid

Example 1t
(3-((((Pyridin-3-sulfonyl)-(4-pyrimidin-2-yl-benzyl) -amino) -methyl) -phenyl) -acetic acid

Example 1u
(3-((((Pyridin-3-sulfonyl)-(4-thiazol-2-yl-benzyl) -amino) -methyl) -phenyl) -acetic acid

Example 1v
(3-(((1-Methyl-1H-imidazol-4-sulfonyl)-(4-thiazol-2-yl-benzyl) -amino) -methyl) -phenyl) -acetic acid Step B: N, N-diisopropylethylamine Instead of, triethylamine was used.

Example 1w
(3-(((4-Dimethylamino-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid Step A: Reaction time 4 hours at room temperature. Step B: Triethylamine was used in place of N, N-diisopropylethylamine.

Example 1x
(3-(((4-Cyclohexyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid Step B: Triethylamine was used instead of N, N-diisopropylethylamine.

Example 1y
(3-(((2- (3,5-Dichloro-phenoxy) -ethyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid Step B: Instead of N, N-diisopropylethylamine Triethylamine was used.

Example 1z
(3-(((4-Dimethylamino-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid Step B: Triethylamine was used instead of N, N-diisopropylethylamine.

Example 1aa
(3-(((4-t-Butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid Step B: Triethylamine was used instead of N, N-diisopropylethylamine.

Example 1ab
(3-(((3- (3-Chloro-phenyl) -propyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid Step B: Triethylamine instead of N, N-diisopropylethylamine Was used.

Example 1ac
(3-(((4-t-Butyl-benzyl)-(1-methyl-1H-imidazol-4-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid step B: instead of N, N-diisopropylethylamine Triethylamine was used.

Example 1ad
(3-(((4-Cyclohexyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid Step B: Triethylamine was used in place of N, N-diisopropylethylamine.

Example 1ae
(3-(((1-Methyl-1H-imidazol-4-sulfonyl)-(4-phenoxy-benzyl) -amino) -methyl) -phenyl) -acetic acid Step B: Triethylamine instead of N, N-diisopropylethylamine Was used.

Example 1af
(3-(((4-Phenoxy-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid

Example 1ag
(3-(((4- (2-Oxo-pyrrolidin-1-yl) -benzyl)-(pyridin-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid Step B: N, N-diisopropylethylamine Instead of, triethylamine was used.

Example 1ah
(3-((Benzo [1,3] dioxol-5-ylmethyl- (pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid

Example 1 ai
(3-(((1-Methyl-1H-imidazol-4-sulfonyl)-(4-pyrimidin-5-yl-benzyl) -amino) -methyl) -phenyl) -acetic acid Step B: N, N-diisopropylethylamine Instead of, triethylamine was used.

Example 1aj
(3-((((Pyridin-3-sulfonyl)-(4-pyrimidin-5-yl-benzyl) -amino) -methyl) -phenyl) -acetic acid

Example 1ak
(3-(((4-Pyrazin-2-yl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid

Example 1al
(3-(((1-Methyl-1H-imidazol-4-sulfonyl)-(4-pyrimidin-2-yl-benzyl) -amino) -methyl) -phenyl) -acetic acid

Example 1am
(3-(((4-Butyl-benzyl) -phenylmethanesulfonyl-amino) -methyl) -phenyl) -acetic acid

Example 1an
5- (3-((Pyridin-3-sulfonyl)-(4-thiazol-2-yl-benzyl) -amino) -propyl) -thiophene-2-carboxylic acid Step A: N, N-diisopropyl instead of triethylamine Ethylamine was used.

Example 2
(3-(((2- (3-Chloro-phenoxy) -ethyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid
Step A: Alkylation
(3-(((2- (3-Chloro-phenoxy) -ethyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid methyl ester . To a solution of sodium hydride (60% in mineral oil, 0.016 g. 0.3996 mmol) in 2 mL of DMF was added (3-((pyridine-3-sulfonylamino) -methyl) -phenyl) -acetic acid methyl ester (Preparation Example 14). From 0.096 g. 0.333 mmol) was added at 0 ° C. and the reaction was stirred at room temperature for 30 min. After cooling to 0 ° C., 1- (2-bromo-ethoxy) -3-chloro-benzene (from Preparation 29, 0.094 g. 0.399 mmol) was added and the reaction was stirred at room temperature overnight. DMF was removed in vacuo. The residue was diluted with EtOAc and the organic solution was washed with water and brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (0.5% MeOH / CH ₂ Cl ₂ to 2% MeOH / CH ₂ Cl ₂ ) to give the title compound of Step A (0.025 g). MS 475 (M + 1).

Step B: Hydrolysis of ester
(3-(((2- (3-Chloro-phenoxy) -ethyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid . A solution of the compound of Example 2, Step A (0.025 g. 0.053 mmol) in 2 mL of MeOH and 0.5 mL of 2N NaOH was stirred overnight at room temperature. The mixture was quenched with 2N HCl and diluted with CH ₂ Cl ₂ . The organic layer was washed with 1N HCl and water, dried over MgSO ₄ , filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (2% MeOH / CH ₂ Cl ₂ to 5% MeOH / CH ₂ Cl ₂ ) to give the title compound (20 mg).

Examples 2a-2c
Examples 2a-2c were prepared in a manner similar to that of Example 2 from the appropriate starting materials.
Example 2a
trans- (3-(((3- (3,5-dichloro-phenyl) -allyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid

Example 2b
(3-(((2- (3,5-Dichloro-phenoxy) -ethyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid

Example 2c
(3-(((4- (1-hydroxy-hexyl) -benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid

Example 3
5- (3-((2-Benzylsulfanyl-ethyl)-(pyridine-3-sulfonyl) -amino) -propyl) -thiophene-2-carboxylic acid
Step A: Reductive amination
5- (3- (2-Benzylsulfanyl-ethylamino) -propyl) -thiophene-2-carboxylic acid t-butyl ester . Step A was performed in the same manner as in Step A of Example 1.

Step B: Formation of amide
5- (3-((2-Benzylsulfanyl-ethyl)-(pyridine-3-sulfonyl) -amino) -propyl) -thiophene-2-carboxylic acid t-butyl ester . Step B was carried out in the same manner as in Step B of Example 1. However, triethylamine was used in place of N, N-diisopropylethylamine.

Step C: Ester hydrolysis
5- (3-((2-Benzylsulfanyl-ethyl)-(pyridine-3-sulfonyl) -amino) -propyl) -thiophene-2-carboxylic acid TFA . 5- (3-((2-Benzylsulfanyl-ethyl)-(pyridine-3-sulfonyl) -amino) -propyl) -thiophene-2-carboxylic acid t-butyl ester prepared in Step B of Example 3 (0.038 A solution of g) in 1 mL of CH ₂ Cl ₂ was cooled to 0 ° C. and 1 mL of TFA was added. The mixture was raised to room temperature and stirred for 1 hour. CH ₂ Cl ₂ and TFA were removed by evaporation azeotroping with added CH ₂ Cl ₂ to give the title compound (46.3 mg) MS 475 (M−1).

Examples 3a-3i were prepared from the appropriate starting materials in a manner similar to that of Example 3 with the modifications as indicated.
Example 3a
5- (3-((2- (3-Chloro-phenylsulfanyl) -ethyl)-(pyridine-3-sulfonyl) -amino) -propyl) -thiophene-2-carboxylic acid

Example 3b
(3-((((Pyridin-3-sulfonyl)-(4-thiazol-2-yl-benzyl) -amino) -methyl) -phenoxy) -acetic acid 2 TFA

Example 3c
(3-((((Pyridin-3-sulfonyl)-(4-pyrimidin-2-yl-benzyl) -amino) -methyl) -phenoxy) -acetic acid ・ 2 HCl
The TFA salt was converted to the HCl salt by stirring in 2 equivalents of 1N HCl followed by removal of water and vacuum drying.

Example 3d
(3-(((1-Methyl-1H-imidazol-4-sulfonyl)-(4-thiazol-2-yl-benzyl) -amino) -methyl) -phenoxy) -acetic acid 2 TFA

Example 3e
(3-((((Pyridin-3-sulfonyl)-(4-pyridin-2-yl-benzyl) -amino) -methyl) -phenoxy) -acetic acid / HCl
No triethylamine was used in step A. The TFA salt was converted to the HCl salt by stirring in 2 equivalents of 1N HCl followed by removal of water and vacuum drying. MS 490 (M + 1), 488 (M-1).

Example 3f
(3-(((1-Methyl-1H-imidazol-4-sulfonyl)-(4-pyridin-2-yl-benzyl) -amino) -methyl) -phenoxy) -acetic acid / HCl
No triethylamine was used in step A. The TFA salt was converted to the HCl salt by stirring in 2 equivalents of 1N HCl followed by removal of water and vacuum drying. MS 493 (M + 1), 491 (M-1).

Example 3g
(3-((((Pyridin-3-sulfonyl)-(4-pyridin-3-yl-benzyl) -amino) -methyl) -phenoxy) -acetic acid / HCl
No triethylamine was used in step A. The TFA salt was converted to the HCl salt by stirring in 2 equivalents of 1N HCl followed by removal of water and vacuum drying. MS 490 (M + 1), 488 (M-1).

Example 3h
(3-(((1-Methyl-1H-imidazol-4-sulfonyl)-(4-pyridin-3-yl-benzyl) -amino) -methyl) -phenoxy) -acetic acid / HCl
No triethylamine was used in step A. The TFA salt was converted to the HCl salt by stirring in 2 equivalents of 1N HCl followed by removal of water and vacuum drying. MS 493 (M + 1), 491 (M-1).

Example 3i
(3-((((Pyridin-3-sulfonyl)-(4-pyridin-4-yl-benzyl) -amino) -methyl) -phenoxy) -acetic acid / HCl
No triethylamine was used in step A. The TFA salt was converted to the HCl salt by stirring in 2 equivalents of 1N HCl followed by removal of water and vacuum drying. MS 490 (M + 1), 488 (M-1).

Example 4
5- (3-((3- (3-Chloro-phenyl) -propyl)-(pyridine-3-sulfonyl) -amino) -propyl) -thiophene-2-carboxylic acid
Step A: Formation of sulfonamide
5- (3-((3- (3-Chloro-phenyl) -propyl)-(pyridine-3-sulfonyl) -amino) -propyl) -thiophene-2-carboxylic acid methyl ester . 5- (3- (3- (3-Chloro-phenyl) -propylamino) -propyl) -thiophene-2-carboxylic acid methyl ester (from Preparation Example 8, 0.0855 g. 0.243 mmol), triethylamine (0.0541 g. 0.534 mmol), and pyridine-3-sulfonyl chloride hydrochloride (from Preparation Example 2, 0.0572 g. 0.267 mmol) in 10 mL of CH ₂ Cl ₂ (mixed at 0 ° C.) were stirred overnight at room temperature. The organic solution was washed with water, saturated NaHCO ₃ and brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound of Step A as an oil. MS 494 (M + 1).

Step B: Hydrolysis of ester
5- (3-((3- (3-Chloro-phenyl) -propyl)-(pyridine-3-sulfonyl) -amino) -propyl) -thiophene-2-carboxylic acid . Methyl 5- (3-((3- (3-chloro-phenyl) -propyl)-(pyridine-3-sulfonyl) -amino) -propyl) -thiophene-2-carboxylate prepared in Step A of Example 4 A solution of the ester (0.119 g. 0.241 mmol) in 5 mL EtOH and 0.72 mL 1N NaOH was stirred overnight at room temperature. The reaction mixture was adjusted to pH 6.2 and the layers were separated. The organic solution was washed with water, dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound (16 mg).

Examples 4a-4h
Examples 4a-4h were prepared in a manner similar to that of Example 4 from the appropriate starting materials.
Example 4a
5- (3-((3- (3-Chloro-phenyl) -propyl)-(4-methoxy-benzenesulfonyl) -amino) -propyl) -thiophene-2-carboxylic acid

Example 4b
5- (3-((Benzo [1,2,5] thiadiazole-4-sulfonyl)-(3- (3-chloro-phenyl) -propyl) -amino) -propyl) -thiophene-2-carboxylic acid

Example 4c
5- (3- (Benzenesulfonyl- (3- (3-chloro-phenyl) -propyl) -amino) -propyl) -thiophene-2-carboxylic acid

Example 4d
5- (3-((3- (3-Chloro-phenyl) -propyl) -phenylmethanesulfonyl-amino) -propyl) -thiophene-2-carboxylic acid

Example 4e
5- (3-((3- (3-Chloro-phenyl) -propyl)-(pyridine-3-sulfonyl) -amino) -propyl) -furan-2-carboxylic acid

Example 4f
5- (3-((3- (3-Chloro-phenyl) -propyl)-(naphthalene-2-sulfonyl) -amino) -propyl) -thiophene-2-carboxylic acid

Example 4g
5- (3-((3- (3-Chloro-phenyl) -propyl)-(naphthalene-1-sulfonyl) -amino) -propyl) -thiophene-2-carboxylic acid

Example 4h
5- (3-((2-acetylamino-4-methyl-thiazole-5-sulfonyl)-(3- (3-chloro-phenyl) -propyl) -amino) -propyl) -thiophene-2-carboxylic acid

Example 5
5- (3-((3- (3-Chloro-phenyl) -propyl)-(pyridine-3-carbonyl) -amino) -propyl) -thiophene-2-carboxylic acid
Step A: Formation of amide
5- (3-((3- (3-Chloro-phenyl) -propyl)-(pyridine-3-carbonyl) -amino) -propyl) -thiophene-2-carboxylic acid methyl ester . 5- (3- (3- (3-Chloro-phenyl) -propylamino) -propyl) -thiophene-2-carboxylic acid methyl ester (from Preparation Example 8, 0.075 g. 0.213 mmol), DCC (0.0483 g. 0.234 mmol) and nicotinic acid (0.0289 g. 0.234 mmol) in 10 mL CH ₂ Cl ₂ were stirred overnight at room temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in 15 mL of EtOAc, and the insoluble matter was removed by filtration. The organic solution was washed with water followed by brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound of Step A as an oil (113 mg). MS 457 (M +).

Step B: was performed similarly to the method of Step B of the ester hydrolysis step B of Example 4.

Examples 5a-5b
Examples 5a-5b were prepared in a manner similar to that of Example 5 from the appropriate starting materials.
Example 5a
5- (3-((3- (3-Chloro-phenyl) -propyl)-(pyridin-2-yl-acetyl) -amino) -propyl) -thiophene-2-carboxylic acid

Example 5b
5- (3-((3- (3-Chloro-phenyl) -propyl)-(pyridin-3-yl-acetyl) -amino) -propyl) -thiophene-2-carboxylic acid

Example 6
5- (3-((2-Chloro-benzenesulfonyl)-(3- (3-chloro-phenyl) -propyl) -amino) -propyl) -thiophene-2-carboxylic acid
Step A: Formation of amide
5- (3-((2-Chloro-benzenesulfonyl)-(3- (3-chloro-phenyl) -propyl) -amino) -propyl) -thiophene-2-carboxylic acid t-butyl ester . 5- (3- (3- (3-Chloro-phenyl) -propylamino) -propyl) -thiophene-2-carboxylic acid t-butyl ester (from Preparation Example 9, 0.10 g. 0.254 mmol) of CH ₂ Cl ₂ A stock solution in 10 mL was prepared and 1 mL (0.010 g. 0.0254 mmol) of this solution was added to a 1-dram vial. To this was added triethylamine (0.78 mL, 0.056 mmol) and 2-chloro-benzenesulfonyl chloride (0.0059 g. 0.028 mmol). The reaction was stirred at room temperature overnight and diluted with ₂ mL CH ₂ Cl ₂ . The organic solution was washed with 3 mL of 5.5% aqueous HCl (2 times) and 3 mL of saturated bicarbonate solution (2 times). The organic layer was dried over MgSO ₄ and concentrated to give the title compound of Step A (10 mg).

Step B: Hydrolysis of ester
5- (3-((2-Chloro-benzenesulfonyl)-(3- (3-chloro-phenyl) -propyl) -amino) -propyl) -thiophene-2-carboxylic acid . 5- (3-((2-Chloro-benzenesulfonyl)-(3- (3-chloro-phenyl) -propyl) -amino) -propyl) -thiophene-2-carboxylic acid prepared in Step A of Example 6 A solution of t-butyl ester (0.010 g. 0.010 mmol) in 4N HCl in 1,4-dioxane (3 mL) was prepared and the reaction was stirred at room temperature overnight. HCl (gas) was bubbled in until the reaction was confirmed by thin layer chromatography. The reaction mixture was concentrated in vacuo. The resulting organic residue was azeotroped with CCl ₄ to give a powder (5 mg).

Examples 6a-6j
Examples 6a-6j were prepared in a manner similar to that of Example 6 from the appropriate starting materials.
Example 6a
5- (3-((3- (3-Chloro-phenyl) -propyl)-(2,5-dimethyl-benzenesulfonyl) -amino) -propyl) -thiophene-2-carboxylic acid

Example 6b
5- (3-((3- (3-Chloro-phenyl) -propyl)-(2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-sulfonyl) -amino) -propyl)- Thiophene-2-carboxylic acid

Example 6c
5- (3-((4- (2-carboxy-benzoylamino) -butane-1-sulfonyl)-(3- (3-chloro-phenyl) -propyl) -amino) -propyl) -thiophene-2-carbon acid

Example 6d
5- (3-((3- (3-Chloro-phenyl) -propyl)-(4- (3,5-dioxo-4,5-dihydro-3H- [1,2,4] triazin-2-yl ) -Benzenesulfonyl) -amino) -propyl) -thiophene-2-carboxylic acid

Example 6e
5- (3-((3- (3-Chloro-phenyl) -propyl)-(2-methoxycarbonyl-benzenesulfonyl) -amino) -propyl) -thiophene-2-carboxylic acid

Example 6f
5- (3-((4-Bromo-benzenesulfonyl)-(3- (3-chloro-phenyl) -propyl) -amino) -propyl) -thiophene-2-carboxylic acid

Example 6g
5- (3-((3- (3-Chloro-phenyl) -propyl)-(4- (1,1-dimethyl-propyl) -benzenesulfonyl) -amino) -propyl) -thiophene-2-carboxylic acid

Example 6h
5- (3-((3- (3-Chloro-phenyl) -propyl)-(3,5-dimethyl-isoxazole-4-sulfonyl) -amino) -propyl) -thiophene-2-carboxylic acid

Example 6i
5- (3-((3- (3-Chloro-phenyl) -propyl)-(2,5-dimethoxy-benzenesulfonyl) -amino) -propyl) -thiophene-2-carboxylic acid

Example 6j
5- (3-((3- (3-Chloro-phenyl) -propyl)-(2-fluoro-benzenesulfonyl) -amino) -propyl) -thiophene-2-carboxylic acid

Example 7
5- (3- (1- (3- (3-Chloro-phenyl) -propyl) -3-ethyl-ureido) -propyl) -thiophene-2-carboxylic acid
Step A: Addition of isocyanate
5- (3- (1- (3- (3-Chloro-phenyl) -propyl) -3-ethyl-ureido) -propyl) -thiophene-2-carboxylic acid t-butyl ester . 5- (3- (3- (3-Chloro-phenyl) -propylamino) -propyl) -thiophene-2-carboxylic acid t-butyl ester (from Preparation Example 9, 0.10 g. 0.254 mmol) of CH ₂ Cl ₂ A stock solution in 10 mL was prepared and 1 mL (0.010 g. 0.0254 mmol) was added to a 1-dram vial. Triethylamine (0.7 mL, 0.051 mmol) and ethyl isocyanate (0.004 g. 0.051 mmol) were added and the mixture was stirred at room temperature overnight. This solution was diluted with ₂ mL of CH ₂ Cl ₂ . The organic solution was washed with 3 mL of 5.5% aqueous HCl (2 times) followed by 3 mL of saturated bicarbonate solution (2 times). The organic layer was dried over MgSO ₄ and concentrated to give the title compound of Step A (10 mg).

Step B: Ester hydrolysis Step B was carried out in the same manner as in Step B of Example 6.

Examples 7a-7j
Examples 7a-7j were prepared in a manner similar to that of Example 7 from the appropriate starting materials.
Example 7a
5- (3- (1- (3- (3-Chloro-phenyl) -propyl) -3-isopropyl-ureido) -propyl) -thiophene-2-carboxylic acid

Example 7b
5- (3- (1- (3- (3-Chloro-phenyl) -propyl) -3-phenyl-ureido) -propyl) -thiophene-2-carboxylic acid

Example 7c
5- (3- (1- (3- (3-Chloro-phenyl) -propyl) -3- (3,4-dichloro-phenyl) -ureido) -propyl) -thiophene-2-carboxylic acid

Example 7d
5- (3- (1- (3- (3-Chloro-phenyl) -propyl) -3-propyl-ureido) -propyl) -thiophene-2-carboxylic acid

Example 7e
5- (3- (3- (4-Chloro-phenyl) -1- (3- (3-chloro-phenyl) -propyl) -ureido) -propyl) -thiophene-2-carboxylic acid

Example 7f
5- (3- (1- (3- (3-Chloro-phenyl) -propyl) -3- (2,3-dichloro-phenyl) -ureido) -propyl) -thiophene-2-carboxylic acid

Example 7g
5- (3- (1- (3- (3-Chloro-phenyl) -propyl) -3- (3,5-dichloro-phenyl) -ureido) -propyl) -thiophene-2-carboxylic acid

Example 7h
5- (3- (1- (3- (3-Chloro-phenyl) -propyl) -3- (2,6-difluoro-phenyl) -ureido) -propyl) -thiophene-2-carboxylic acid

Example 7i
5- (3- (1- (3- (3-Chloro-phenyl) -propyl) -3- (4-fluoro-phenyl) -ureido) -propyl) -thiophene-2-carboxylic acid

Example 7j
5- (3- (3-Butyl-1- (3- (3-chloro-phenyl) -propyl) -ureido) -propyl) -thiophene-2-carboxylic acid

Example 8
5- (3-((3- (3-Chloro-phenyl) -propyl)-(pyrrolidine-1-carbonyl) -amino) -propyl) -thiophene-2-carboxylic acid
Step A: Formation of amide
5- (3- (1- (3- (3-Chloro-phenyl) -propyl) -3-ethyl-ureido) -propyl) -thiophene-2-carboxylic acid t-butyl ester . 5- (3- (3- (3-Chloro-phenyl) -propylamino) -propyl) -thiophene-2-carboxylic acid t-butyl ester (from Preparation Example 9, 0.10 g. 0.254 mmol) of CH ₂ Cl ₂ A stock solution in 10 mL was prepared and 1 mL (0.010 g. 0.0254 mmol) was added to a 1-dram vial. Triethylamine (0.7 mL, 0.051 mmol) and ethyl isocyanate (0.004 g. 0.051 mmol) were added and the reaction was stirred at room temperature overnight. The reaction was diluted with ₂ mL CH ₂ Cl ₂ and the organic solution was washed with 3 mL 5.5% aqueous HCl (2 ×) followed by 3 mL saturated bicarbonate solution (2 ×). The organic layer was dried over MgSO ₄ and concentrated to give the title compound of Step A (10 mg).

Step B: Ester hydrolysis Step B was carried out in the same manner as in Step B of Example 6.

Examples 8a-8c
Examples 8a-8c were prepared in a manner similar to that of Example 8 from the appropriate starting materials.
Example 8a
5- (3-((3- (3-Chloro-phenyl) -propyl)-(morpholine-4-carbonyl) -amino) -propyl) -thiophene-2-carboxylic acid

Example 8b
5- (3-((3- (3-Chloro-phenyl) -propyl) -isopropoxycarbonyl-amino) -propyl) -thiophene-2-carboxylic acid

Example 8c
5- (3-((3- (3-Chloro-phenyl) -propyl) -propoxycarbonyl-amino) -propyl) -thiophene-2-carboxylic acid

Example 9
(3-(((4-Butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid
Step A: Reductive amination
(3-((4-Butyl-benzylamino) -methyl) -phenyl) -acetic acid methyl ester . A solution of 4-butyl-benzylamine (from Preparation 15, 0.918 g. 6 mmol) in MeOH is added to 4N HCl in dioxane (0.75 mL, 3 mmol) followed by (3-formyl-phenyl) -acetic acid. Methyl ester (from Production Example 13, 0.534 g. 3.0 mmol) was added. NaCNBH ₃ (0.194 mL, 3 mmol) was added and the reaction was stirred at room temperature overnight. The mixture was diluted with EtOAc and 2N NaOH was added. The organic solution was dried over MgSO ₄ , filtered and concentrated in vacuo. The product was purified by flash chromatography (50% hexane, 50% EtOAc, 0.1% Et ₃ N) to give the title compound of Step A.

Step B: Formation of amide
(3-(((4-Butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid methyl ester . Step B was performed in the same manner as in Step B of Example 1 to give the title compound.

Step C: Ester hydrolysis
(3-(((4-Butyl-benzyl)-(pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid . Step C was performed in the same manner as in Step C of Example 1 to obtain the title compound.

Examples 9a-9d
Examples 9a-9d were prepared in a manner similar to that of Example 9 from the appropriate starting materials.
Example 9a
(3-((Benzenesulfonyl- (4-butyl-benzyl) -amino) -methyl) -phenyl) -acetic acid

Example 9b
(3-(((4-Butyl-benzyl)-(thiophen-2-sulfonyl) -amino) -methyl) -phenyl) -acetic acid

Example 9c
(3-(((4-Acetylamino-benzenesulfonyl)-(4-butyl-benzyl) -amino) -methyl) -phenyl) -acetic acid

Example 9d
(3-(((Benzo [1,2,5] oxadiazol-4-sulfonyl)-(4-butyl-benzyl) -amino) -methyl) -phenyl) -acetic acid

Example 10
(3-(((1-Methyl-1H-imidazol-4-sulfonyl)-(4-pyrimidin-2-yl-benzyl) -amino) -methyl) -phenoxy) -acetic acid / HCl
Step A: Reductive amination
(3-((4-Pyrimidin-2-yl-benzylamino) -methyl) -phenoxy) -acetic acid t-butyl ester . Step A was performed in the same manner as in Step A of Example 1.

Step B: Formation of amide
(3-(((1-Methyl-1H-imidazol-4-sulfonyl)-(4-pyrimidin-2-yl-benzyl) -amino) -methyl) -phenoxy) -acetic acid t-butyl ester . Step B was carried out in the same manner as in Step B of Example 1. However, triethylamine was used as the base instead of N, N-diisopropylethylamine.

Step C: Ester hydrolysis
(3-(((1-Methyl-1H-imidazol-4-sulfonyl)-(4-pyrimidin-2-yl-benzyl) -amino) -methyl) -phenoxy) -acetic acid.HCl . (3-(((1-Methyl-1H-imidazol-4-sulfonyl)-(4-pyrimidin-2-yl-benzyl) -amino) -methyl) -phenoxy) -acetic acid prepared in Step B of Example 10 A solution of t-butyl ester (0.094 g. 0.17 mmol) (in 1N HCl) in diethyl ether was stirred for 20 minutes as precipitate formed. To the mixture was added 1 mL water and 1 mL dioxane and the reaction was stirred for 3 hours. The solvent was removed by azeotroping with ethanol in vacuo to give the title compound as a solid (54 mg).

Production Example 1
7-aminoheptanoic acid methyl ester hydrochloride . A solution of 7-aminoheptanoic acid (3.0 g. 21.0 mmol) in 25 mL MeOH and 2.4 mL concentrated HCl was heated to reflux for 4 hours and stirred at room temperature for 60 hours. The mixture was concentrated in vacuo to give the title compound (3.3 g).

Production Example 2
Pyridine-3-sulfonyl chloride hydrochloride . The title compound was prepared by the method described in Karaman, R. et al., J. Am. Chem. Soc. 114, 12, 1992, 4889-4898.

Production Example 3
3- (3-Chloro-phenyl) -propionaldehyde . 1-chloro-3-iodobenzene (9.63 g. 40.38 mmol), allyl alcohol (5.86 g. 100.96 mmol), sodium bicarbonate (8.48 g. 100.96 mmol), tetrabutylammonium chloride (11.22 g. 40.38 mmol) and Pd A solution of (OAc) ₂ (317 mg. 1.413 mmol) in 25 mL of DMF was stirred at 50 ° C. for 16 hours. The mixture was cooled to room temperature, diluted with water, and the aqueous solution was washed with EtOAc. The organic solution was washed with water followed by brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (9: 1 hexane: EtOAc) to give the title compound as an oil (5.04 g).

Production Example 4
5- (3-Oxo-propyl) -thiophene-2-carboxylic acid t-butyl ester
Step A: Formation of ester
5-Bromo-thiophene-2-carboxylic acid t-butyl ester . To a solution of anhydrous MgSO ₄ (11.60 g. 96.4 mmol) in 100 mL CH ₂ Cl ₂ was added concentrated H ₂ SO ₄ (1.45 mL, 24.1 mmol) and the mixture was stirred for 15 min, followed by 5-bromo -Thiophene-2-carboxylic acid (5.0 g. 24.1 mmol) was added. After stirring for 1 minute, t-butanol (11.6 g. 20 mmol) was added and the reaction was stirred at room temperature for 16 hours. The reaction was quenched with saturated NaHCO ₃ . The layers were separated, the aqueous layer was extracted with CH ₂ Cl ₂ and the combined organic layers were dried over MgSO ₄ . Concentration of the organic solution gave a clear oil that was purified by medium pressure chromatography (3% EtOAc in hexanes) to give the title compound of Step A (4.97 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45 (d, 1H), 7.02 (d, 1H), 1.54 (s, 9H).

Step B: Formation of aldehyde
5- (3-Oxo-propyl) -thiophene-2-carboxylic acid t-butyl ester . To a solution of 5-bromo-thiophene-2-carboxylic acid t-butyl ester (0.50 g. 1.89 mmol) prepared in Step A of Preparation Example 4 in 5 mL of DMF, allyl alcohol (0.51 mL, 7.57 mmol), followed by NaHCO ₃ (0.397 g. 4.72 mmol), tetrabutylammonium chloride (0.525 g. 1.89 mmol) and palladium acetate (0.021 g. 0.094 mmol) were added. The reaction was placed in an oil bath heated to 65 ° C. and heated to 90 ° C. for 2 hours. The mixture was diluted with EtOAc and 25 mL water and the solid was removed by filtration through Celite®. The layers were separated and the organic solution was washed with water (4 times), dried over MgSO ₄ and concentrated to give a dark yellow oil which was purified by medium pressure chromatography (7: 1 hexane: EtOAc). To give the title compound (0.190 g).

Production Example 5
5- (3-Amino-propyl) -thiophene-2-carboxylic acid methyl ester
Process A
5- (3-t-Butoxycarbonylamino-prop-1-ynyl) -thiophene-2-carboxylic acid methyl ester . Prop-2-ynyl-carbamic acid t-butyl ester (from Production Example 41, 1.67 g. 0.011 mmol), 5-bromo-thiophene-2-carboxylic acid methyl ester (2.50 g. 0.011 mmol), tetrakistriphenylphosphine palladium A mixture of (0) (0.622 g. 0.0538 mmol), CuI (0.102 g. 0.538 mmol) and triethylamine (1.57 mL, 0.011 mmol) in 50 mL of acetonitrile was heated to reflux for 16 hours. The reaction was cooled to room temperature, diluted with 75 mL EtOAc, washed with 5.5% HCl, water and brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give an oil. The product was purified by flash chromatography (9: 1 to 4: 1 hexanes: EtOAc) to give the title compound of Step A as an oil (2.06 g). MS 313 (M + 18).

Process B
5- (3-t-Butoxycarbonylamino-propyl) -thiophene-2-carboxylic acid methyl ester . Of 5- (3-t-butoxycarbonylamino-prop-1-ynyl) -thiophene-2-carboxylic acid methyl ester (2.06 g) and 10% Pd / C (1.03 g) prepared in Step A of Preparation Example 5. The solution in 50 mL of MeOH was hydrogenated on a Parr shaker with 50 psi H ₂ for 16 hours. The reaction was filtered through Celite® with the aid of MeOH and the filtrate was concentrated in vacuo to give the title compound of Step B as a solid (1.93 g). MS 317 (M + 18).

Process C
5- (3-Amino-propyl) -thiophene-2-carboxylic acid methyl ester . A solution of 5- (3-t-butoxycarbonylamino-propyl) -thiophene-2-carboxylic acid methyl ester (0.118 g. 0.5 mmol) prepared in Step B of Preparation Example 5 in 50 mL of MeOH was heated to 0 ° C. Cooled and saturated with HCl (gas). The reaction was stirred at room temperature for 90 minutes. The solution was concentrated to a solid and partitioned between EtOAc and saturated NaHCO ₃ . The layers were separated and the combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound as an oil (399 mg). MS 200 (M + 1).

Production Example 6
5- (3-Amino-propyl) -furan-2-carboxylic acid methyl ester hydrochloride . The compound of Preparation Example 6 was prepared from an appropriate starting material by the same method as that of Preparation Example 5 except for the following points: (1) The hydrogenation performed in Step B was performed for 5.5 hours; 2) In Step C, the reaction was stirred at room temperature for 16 hours and concentrated in vacuo to give the title compound as the hydrochloride salt.

Production Example 7
5- (3-Amino-propyl) -thiophene-2-carboxylic acid t-butyl ester
Process A
Prop-2-ynyl-carbamic acid benzyl ester . To a solution of propargylamine (6.4 g. 71.2 mmol) in pyridine (100 mL) was added benzyl chloroformate (13.37 g. 78.2 mmol) in 100 mL of CH ₂ Cl ₂ over 0.5 h. The reaction was stirred for 16 hours and volatile components were removed in vacuo. The residue was dissolved in EtOAc and the organic solution was washed with water (2 times). The organic solution was washed with dilute aqueous HCl followed by saturated NaHCO ₃ . The organic solution was dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound of Step A (4.43 g).

Process B
5- (3-Benzyloxycarbonylamino-prop-1-ynyl) -thiophene-2-carboxylic acid t-butyl ester . The title compound of Step B was prepared from the appropriate starting material in the same manner as in Step A of Preparation Example 5.

Process C
5- (3-Amino-propyl) -thiophene-2-carboxylic acid t-butyl ester . 5- (3-Benzyloxycarbonylamino-prop-1-ynyl) -thiophene-2-carboxylic acid t-butyl ester (1.0 g. 2.69 mmol) prepared in Step B of Preparation Example 7 was added to 15 mL of MeOH and 1N HCl. (Aqueous solution) Pd (OH) ₂ was added to the solution in 2.69 mL. The mixture was hydrogenated on a Pal shaker at 45 psi H ₂ for 16 hours. The mixture was filtered through Celite®, the catalyst was exchanged, and the reaction was shaken for an additional 6 hours. The mixture was filtered through Celite® and concentrated in vacuo. The residue was further treated with CCl ₄ and triturated with Et ₂ O. The product was isolated as a solid (360 mg).

Production Example 8
5- (3- (3- (3-Chloro-phenyl) -propylamino) -propyl) -thiophene-2-carboxylic acid methyl ester . 5- (3-amino-propyl) -thiophene-2-carboxylic acid methyl ester (from Preparation C, step C, 0.118 g. 0.5 mmol) and N, N-diisopropylethylamine (0.071 g. 0.55 mmol) in MeOH The solution in 10 mL was stirred at room temperature for 30 minutes and 3- (3-chloro-phenyl) -propionaldehyde (from Preparation 3, 0.093 g. 0.55 mmol) was added. The mixture was stirred for 90 minutes. The reaction was cooled to 0 ° C., NaBH ₄ (30.3 g. 0.801 mmol) was added and the mixture was stirred for 30 minutes. The reaction was quenched with 1: 1 NaHCO ₃ : H ₂ O and washed with CH ₂ Cl ₂ . The CH ₂ Cl ₂ extract was washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound as an oil (171 mg). MS 352 (M + 1).

Production Examples 9 to 10
The compounds of Production Examples 9 and 10 were produced in the same manner as in Production Example 8 from appropriate starting materials.

Production Example 9
5- (3- (3- (3-Chloro-phenyl) -propylamino) -propyl) -thiophene-2-carboxylic acid t-butyl ester
Production Example 10
5- (3- (3- (3-Chloro-phenyl) -propylamino) -propyl) -furan-2-carboxylic acid methyl ester
MS 336 (M + 1).

Production Example 11
(3-Formyl-phenoxy) -acetic acid methyl ester . A mixture of (3-formyl-phenoxy) -acetic acid (3.6 g. 20.0 mmol), potassium carbonate (3.30 g. 23.9 mmol) and methyl iodide (1.86 g. 30.0 mmol) in 25 mL of DMF Heated for hours and stirred at room temperature for 16 hours. The mixture was diluted with water and the aqueous solution was extracted with EtOAc. The organic solution was washed with water, dried over MgSO ₄ , filtered and concentrated in vacuo. The product was purified by silica gel chromatography (4: 1 hexane: EtOAc) to give the title compound as a pale yellow oil (3.4 g).

Production Example 12
3- (3-Chloro-phenyl) -propylamine
Process A
3- (3-Chloro-phenyl) -acrylamide . A solution of 3- (3-chloro-phenyl) -acrylic acid (Aldrich, 15.0 g. 82.15 mmol) in 50 mL thionyl chloride was heated to reflux for 30 minutes. Excess thionyl chloride was removed by atmospheric distillation. The residue was azeotroped with benzene in vacuo to yield 17.288 g of an orange oil. This oil was dissolved in 25 mL CH ₂ Cl ₂ and this solution was slowly added to liquid NH ₃ (20 mL, 80.07 mmol) in CHCl ₃ (50 mL) at −78 ° C. The resulting suspension was allowed to warm to room temperature and concentrated in vacuo to give the title compound of Step A as a gray solid (19.38 g).

Process B
3- (3-Chloro-phenyl) -propylamine . A 1.0 M LiAlH ₄ solution in THF (6.0 mL) was added at 0 ° C. in 30 mL of THF of 3- (3-chloro-phenyl) -acrylamide (1.0 g. 5.51 mmol) prepared in Preparation 12, Step A. Added dropwise to the suspension. The reaction was warmed to room temperature and stirred for 5 hours. An additional 4 mL of 1M LiAlH ₄ was added and the reaction was stirred for 18 hours. An additional 2 mL of 1M LiAlH ₄ was added and the reaction was stirred for 24 hours. The reaction mixture was quenched by the dropwise addition of water. The mixture was concentrated in vacuo to remove THF and diluted with water. This aqueous solution was extracted with EtOAc. The organic solution was washed with water, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was dissolved in CHCl ₃ and the organic solution was washed with 1M HCl. The aqueous solution was basified to pH 11 with 1M NaOH and the product was extracted into CHCl ₃ . The organic solution was dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound as a yellow oil (0.134 g).

Production Example 13
(3-Formyl-phenyl) -acetic acid methyl ester
Process A
(3-Cyano-phenyl) -acetic acid methyl ester . Nitrogen was bubbled through the mixture of (3-bromo-phenyl) -acetic acid methyl ester (22.85 g. 99.78 mmol), Zn (CN) ₂ (7.25 g. 61.75 mmol) and DMF (100 mL), followed by tetrakis Triphenylphosphine palladium (0) (4.60 g. 3.98 mmol) was added. The mixture was heated at 80 ° C. for 3 hours and cooled to room temperature. 2N NH ₄ OH aqueous solution was added and the product was extracted into EtOAc (3 times). The organic solution was washed with 2N NH ₄ OH (2 times) followed by brine (2 times). The organic solution was dried (MgSO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography (6: 1 hexane: EtOAc) gave the title compound of Step A as an oil (15.19 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57-7.41 (m, 4H), 3.706 (s, 3H), 3.703 (s, 2H).

Process B
(3-Formyl-phenyl) -acetic acid methyl ester . A mixture of (3-cyano-phenyl) -acetic acid methyl ester (1.56 g. 8.91 mmol), aluminum-nickel alloy (1.63 g) and 75% formic acid (25 mL) prepared in Step A of Preparation Example 13 was added for 1.75 hours. Heated to reflux. The mixture was cooled to room temperature and the solid separated by filtration through Celite® with the aid of boiling EtOH. Water was added and the aqueous solution was washed with CH ₂ Cl ₂ (3 times). Saturated aqueous NaHCO ₃ was carefully added to the organic solution until the pH was about 8-9. The organic solution was washed with brine, dried over MgSO ₄ and concentrated. Purification by flash chromatography (5: 1 hexane: EtOAc) afforded the title compound as a clear colorless oil (870 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.98 (s, 1H), 7.77 (m, 2H), 7.55-7.46 (m, 2H), 3.68 (s, 5H).

Production Example 14
(3-((Pyridin-3-sulfonylamino) -methyl) -phenyl) -acetic acid methyl ester . To a solution of (3-aminomethyl-phenyl) -acetic acid methyl ester hydrochloride (from Preparation Example 18, 0.56 g) and diisopropylamine (2.2 mL) in 10 mL of dichloromethane was added pyridine-3-sulfonyl chloride (from Preparation Example 2). 0.601 g. 2.83 mmol) was added and the reaction was stirred at room temperature for 16 h. 1N aqueous HCl was added and the solution was washed with CH ₂ Cl ₂ . The organic solution was washed with saturated NaHCO ₃ , dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound. Purification by flash chromatography on silica gel (2: 1 hexane: EtOAc) gave the title compound as a white solid.

Production Example 15
Method A
4-Butylbenzylamine . A solution of 4-butylbenzonitrile (3.63 g. 22.8 mmol) in THF (10 mL) was placed in a three neck round bottom flask equipped with a Vigreux column and a short pass distillation head. The solution was heated to reflux and BH ₃ -methyl sulfide complex (2.0 M in THF, 15 mL, 30 mmol) was added dropwise over 15 minutes. Methyl sulfide was distilled from the reaction mixture over 1 hour and the solution was cooled to room temperature. Aqueous HCl (6N, 25 mL) was added slowly with a dropping funnel and the mixture was heated to reflux for 30 min. The reaction was cooled to 0 ° C. and NaOH (7.0 g) was added in small portions. The aqueous solution was washed with EtOAc (3 times) and the organic solution was dried (MgSO ₄ ), filtered and concentrated to give the title compound of Method A (4.01 g).

Method B
4-Butylbenzylamine hydrochloride . A solution of 4-butylbenzonitrile (30.09 g) in EtOH (380 mL) and HCl (4N in dioxane, 50 mL, 200 mmol) was placed on a Pal shaker in the presence of 10% palladium on carbon (6.09 g). Hydrogenated at 50 psi. The catalyst was removed by filtration through Celite® and the solution was concentrated in vacuo. The residue was suspended in Et ₂ O and filtered to give 4-butylbenzylamine hydrochloride as an off-white solid (32.47 g).

The compounds of Production Examples 16 to 18 were produced in the same manner as in Production Example 15 using appropriate starting materials.
Production Example 16
2- (3,5-dichloro-phenoxy) -ethylamine . The title compound was prepared according to Method 15 of Preparation 15.

Production Example 17
2- (3-Chloro-phenoxy) -ethylamine . The title compound was prepared according to Method 15 of Preparation 15.

Production Example 18
(3-Aminomethyl-phenyl) -acetic acid methyl ester hydrochloride . The title compound was prepared by (3-cyano-phenyl) -acetic acid methyl ester (Preparation Example 13, from Step A), using the method described in Method B of Preparation Example 15, except that the hydrogenation was carried out in MeOH. . The catalyst was removed by filtration and the organic solution was concentrated in vacuo. The resulting solid was stirred in EtOAc and filtered to give the title compound as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) □ 7.42-7.32 (m, 4H), 4.09 (s, 2H), 3.69 (s, 2H), 3.67 (s, 3H); MS 180 (M + 1).

Production Example 19
trans-1- (3-Bromo-propenyl) -3,5-dichloro-benzene
Process A
1- (3,5-dichloro-phenyl) -prop-2-en-1-ol . A solution of 3,5-dichlorobenzaldehyde (7.5 g. 43 mmol) in THF (75 mL) was cooled to 0 ° C. and vinylmagnesium bromide (1M in THF, 48 mL, 48 mmol) was added dropwise. The reaction was warmed to room temperature and stirred for 16 hours. Aqueous HCl (1N) and EtOAc were added. The aqueous solution was washed with EtOAc and the organic solution was dried (MgSO ₄ ), filtered and concentrated. The residue was used in the next step without further purification.

Process B
The residue produced in Step A was dissolved in Et ₂ O and HBr gas was slowly bubbled into the solution for about 15 minutes. The reaction was stirred at room temperature for 24 hours and water and EtOAc were added. The aqueous solution was extracted with EtOAc and the organic solution was dried (MgSO ₄ ), filtered and concentrated. Purification by flash chromatography (hexane) gave the title compound of Preparation 19 (6.91 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.24 (s, 3H), 6.53 (d, 1H), 6.40 (m, 1H), 4.10 (m, 2H).

Production Example 20
(3-Aminomethyl-phenoxy) -acetic acid t-butyl ester
Process A
(3-Formyl-phenoxy) -acetic acid t-butyl ester . To a solution of 3-hydroxybenzaldehyde (5.00 g. 40.9 mmol) in DMF (40 mL) was added 1M potassium t-butoxide (40.9 mL, 40.9 mmol) in t-butanol. The reaction was stirred for 2 minutes and t-butyl bromoacetate (6.61 mL, 40.9 mmol) was added. The reaction was stirred for 1 hour and quenched with 200 mL of water. The product was extracted into EtOAc and the organic solution was washed with water, dried over MgSO ₄ , filtered and concentrated in vacuo. Purification by flash chromatography on silica gel (9: 1 hexane: EtOAc) afforded the title compound of Step A as a clear oil (3,53 g).

Process B
(3- (Hydroxyimino-methyl) -phenoxy) -acetic acid t-butyl ester . To a solution of (3-formyl-phenoxy) -acetic acid t-butyl ester (2.05 g. 8.68 mmol) prepared in Step A of Preparation Example 20 in MeOH (30 mL) was added NH ₂ OH · HCl (0.66 g. 9.54). mmol) and pyridine (3.5 mL, 43.4 mmol) were added and the reaction was stirred for 2 h. MeOH was removed in vacuo and the residue was diluted with EtOAc and 1N HCl. The layers were separated and the aqueous solution was washed with EtOAc. The combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound of Step B (1.99 g).

Process C
(3-Aminomethyl-phenoxy) -acetic acid t-butyl ester . To a solution of (3- (hydroxyimino-methyl) -phenoxy) -acetic acid t-butyl ester (2.25 g. 5.96 mmol) prepared in Step B of Preparation 20 in EtOH (10 mL) was added Raney nickel in 100 mL EtOH. (About 1 g, water followed by EtOH) was added. Additional EtOH (90 mL) was required to transfer. Ammonium hydroxide (10 mL) was added and the mixture was shaken under 45 psi H ₂ for 4 hours. The catalyst was removed by filtration through Celite® and the solution was concentrated to a clear oil. Purification by flash chromatography on silica gel (96.5 / 3.5 / 0.1 to 9/1 / 0.1 CH ₂ Cl ₂ / MeOH / NH ₄ OH) gave the title compound as a yellow oil.

Production Example 21
4-pyrimidin-2-yl-benzaldehyde
A solution of 2-bromopyrimidine (1.00 g. 6.3 mmol) and tetrakistriphenylphosphine palladium (0) (0.218 g. 0.189 mmol) in ethylene glycol dimethyl ether (30 mL) was stirred at room temperature for 10 minutes. A solution of 4-formylbenzeneboronic acid (1.14 g. 7.61 mmol) and sodium bicarbonate (1.58 g. 18.9 mmol) in 15 mL of water was added and the reaction was heated to reflux for 16 hours. The mixture was diluted with water and CH ₂ Cl ₂ . The layers were separated and the aqueous solution was washed with CH ₂ Cl ₂ . The organic layers were combined, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (10% to 30%, hexane in EtOAc) to give the title compound (0.979 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ, 10.11 (s, 1H), 8.83 (s, 2H), 8.82 (s, 1H), 7.98 (s, 2H), 7.23 (s, 2H).

Production Examples 22 to 27
Production Examples 22 to 27 were produced from appropriate starting materials in the same manner as in Production Example 21.

Production Example 22
4-Pyridin-2-yl-benzaldehyde

Production Example 23
4-Pyridin-3-yl-benzaldehyde

Production Example 24
4-Pyridin-4-yl-benzaldehyde

Production Example 25
4-thiazol-2-yl-benzaldehyde
MS 189 (M +).

Production Example 26
4-pyrimidin-5-yl-benzaldehyde

Production Example 27
4-pyrazin-2-yl-benzaldehyde

Production Example 28
1- (2-Bromo-ethoxy) -3,5-dichloro-benzene . To a solution of NaOH (2.45 g. 61.3 mmol) in water (20 mL) was added 3,5-dichlorophenol (5 g. 30.7 mmol). The solution was heated to reflux for 1 hour and cooled to room temperature. 1,2-Dibromoethane (11.52 g. 61.3 mmol) was added and the reaction was heated to reflux for 24 hours. The cooled solution was diluted with EtOAc and the organic solution was washed sequentially with HCl (1N, 1 ×), water (1 ×) and brine (1 ×). The organic solution was dried (MgSO ₄ ), filtered and concentrated. Purification by flash chromatography (hexane to 5% EtOAc in hexane) afforded the title compound (3.79 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.98 (m, 1H), 6.82 (m, 2H), 4.25 (t, 2H), 3.61 (t, 2H).

Production Example 29
1- (2-Bromo-ethoxy) -3-chlorobenzene . The compound of Production Example 29 was produced in the same manner as in Production Example 28 from an appropriate starting material.

Production Example 30
4-[(1-Acetyloxy) -hexyl] -benzyl bromide
Step A: Grignard reaction and protection
4-[(1-Acetyloxy) -hexyl] -toluene . Pentylmagnesium bromide (2.0 M in Et ₂ O, 25 mL, 50 mmol) was slowly added to p-tolylbenzaldehyde (5.0 mL, 42.4 mmol) in THF (50 mL) at 0 ° C. The reaction was warmed to room temperature and stirred for 3 hours. 1N aqueous HCl was added and the aqueous solution was extracted with EtOAc. The organic solution was washed with brine, dried over MgSO ₄ , filtered and concentrated. The residue was dissolved in pyridine (35 mL) and Ac ₂ O (10 mL) was added. The reaction was stirred for 24 hours and diluted with water. The product was extracted into EtOAc (3 times) and the organic solution was washed with 1N HCl followed by brine, dried over MgSO ₄ , filtered and concentrated. The product was purified by flash chromatography (10% EtOAc / hexane) to give 4-((1-acetyloxy) -hexyl) -toluene (2.082 g).

Step B: Bromination of benzyl 4-[(1-acetyloxy) -hexyl] -toluene (2.082 g. 8.89 mmol), N-bromosuccinimide (1.58 g. 8.89 mmol) prepared in Step A of Preparation Example 30 And a mixture of catalyst 2,2′-azobisisobutyronitrile (30 mL) in carbon tetrachloride was heated to reflux for 2 hours. The reaction was cooled, washed with aqueous NaHCO ₃ (saturated), dried over MgSO ₄ , filtered and concentrated. The product was purified by flash chromatography (5% EtOAc / hexanes) to give the title compound of Preparation 30 (2.67 g).

Production Example 31
1-methyl-1H-indole-2-carbaldehyde . The title compound can be prepared by the method described in Comins et al., J. Org. Chem. 52, 1, 104-9, 1987.

Production Example 32
5-Phenyl-furan-2-carbaldehyde . The title compound can be prepared by the method described in D'Auria et al., Heterocycles, 24, 6, 1575-1578, 1986.

Production Example 33
4-phenethylsulfanyl-benzaldehyde . The title compound can be prepared by the method described in Clark et al., EP 332331.

Production Example 34
3-hydroxy-4-propoxy-benzaldehyde . The title compound can be produced by the method described in Beke, Acta Chim. Acad. Sci. Hung., 14,325-8, 1958.

Production Example 35
4-Formyl-N-methyl-benzenesulfonamide . The title compound can be prepared by the method described in Koetschet, Helv. Chim. Acta, 12, 682, 1929.

Production Example 36
4-Chloro-thiophene-2-carbaldehyde . The title compound can be prepared by the method described in Raggon et al., Org. Prep. Proced. Int .; EN, 27,2, 233-6, 1995.

Production Example 37
4-cyclohexyl-benzylamine . The title compound can be prepared by the method described in Meglio et al., Farmaco Ed. Sci .; IT; 35, 3, 191-202, 1980.

Production Example 38
4-imidazol-1-yl-benzaldehyde . The title compound can be prepared by the method described in Sircar et al., J. Med. Chem. 30, 6, 1023-9, 1987.

Production Example 39
4- (2-Oxo-pyrrolidin-1-yl) -benzaldehyde . The title compound can be produced by the method described in Kukalenko et al., Chem. Heterocycl. Compd. (Engl. Transl.), 8, 43, 1972.

Production Example 40
2- (3-Chloro-phenylsulfanyl) -ethylamine . The title compound can be prepared by the method described in Elz et al., Fed. Rep. Ger. Sci. Pharm., 56, 4, 229-234, 1988.

Production Example 41
Prop-2-ynyl-carbamic acid t-butyl ester . The title compound can be produced by the method described in J. Chem. Soc. Perkin Trans. I, 1985, 2201-2208.

Unless otherwise stated, all reactions were performed under an inert atmosphere such as nitrogen (N ₂ ).
NMR spectra were measured at about 23 ° C. and about 300 or 400 for protons with a Varian XL-300 (Varian Co., Palo Alto, Calif.), Bruker AM-300 spectrometer (Bruker Co., Billerica, Mass.) Or Varian Unity 400. It was recorded at MHz and 75.4 MHz for carbon nuclei. Chemical shifts are expressed in ppm down from trimethylsilane. The peak shape is expressed as follows: s, singlet; d, doublet; t, triplet; q, quadruple; m, multiplet; bs, broad singlet. In another NMR experiment in which the sample was shaken with a few drops of D ₂ O in the same solvent, no resonance appeared to be exchangeable. Atmospheric pressure chemical ionization (APCI) mass spectra were obtained on a Fisons Platform II spectrometer. Chemical ionization mass spectra were obtained with a Hewlett-Packard 5989 instrument (Hewlett-Packard Co., Palo Alto, CA) (ammonia ionization, PBMS). When describing the intensity of ions containing chlorine or bromine, the expected intensity ratio is observed (about 3: 1 for ³⁵ Cl / ³⁷ Cl-containing ions, about 1: 1 for ⁷⁹ Br / ⁸¹ Br-containing ions). ), Showing only the intensity of low mass ions.

  Column chromatography was performed under low nitrogen pressure using Baker silica gel (40 μm) (J.T. Baker, Phillipsburg, NJ) or silica gel 60 (EM Sciences, Gibbstown, NJ) in a glass column. Radial chromatography was performed using a Chromatoron® (model 7924T, Harrison Research). Medium pressure chromatography was performed with the Flash 40 Biotage System (Biotage Inc., Dyax Corp., Charlottesville, VA). Unless otherwise stated, reagents were used as received from commercial suppliers. When dimethylformamide, 2-propanol, acetonitrile, methanol, tetrahydrofuran and dichloromethane were used as reaction solvents, these were anhydrous grades supplied by Aldrich Chemical Company (Milwaukee, Wis.). The terms “concentration” and “co-evaporation” refer to removal of the solvent at a water aspirator pressure at a bath temperature lower than 45 ° C. by a rotary evaporator. Reactions carried out at “0-20 ° C.” or “0-25 ° C.” were performed by first cooling the vessel in an insulated ice bath and allowing it to rise to room temperature over several hours. The abbreviations “min” and “h” represent “minute” and “hour”, respectively. DTT means dithiothreitol. DMSO means dimethyl sulfoxide. EDTA means ethylenediaminetetraacetic acid.

Certain manufacturing methods useful for the preparation of the compounds described herein require protecting unrelated functional groups (eg, primary amines, secondary amines, carboxyls of the precursors of Formula I). The need for such protection will depend on the nature of the unrelated functional groups and the conditions of the preparation methods. The need for such protection can be readily determined by one skilled in the art. The use of such protection / deprotection methods can also be easily made by those skilled in the art. For a general description of protecting groups and their use, see TW Greene, Protective Groups in Organic Synthesis , John Wiley and Sons, New York, 1991.

Biological assay
CDNA representing the complete open reading frame of the measuring person EP ₂ and EP ₄ receptors cAMP increase in 293-S cell line stably overexpressing recombinant human EP ₂ and EP ₄ receptors, published sequence (1 2) and an oligonucleotide primer based on 2), and primary human kidney cell-derived (EP ₂ ) or primary human lung cell-derived (EP ₄ ) RNA as a template. The cDNA is cloned into the multiple cloning site of pcDNA3 (Invitrogen Corporation, 3985B Sorrento Valley Blvd., San Diego, CA 92121) and used to transfect 293-S human embryonic kidney cells by the calcium phosphate coprecipitation method. G418 resistant colonies are grown and tested for specific [ ³ H] PGE ₂ binding. Transfectants exhibiting high levels of specific [ ³ H] PGE ₂ binding are further characterized by Scatchard analysis to determine Bmax and Kd for PGE ₂ . Compound screening selected system for, for about 338,400 pieces PGE ₂ (EP ₂₎ / cell receptor and Kd = 12 nM, a receptor and Kd = 2.9 nM to about 256,400 / cell for PGE ₂ (EP ₄₎ Have. Constitutive expression of both receptors in parental 293-S cells is negligible. Cells are maintained in RPMI supplemented with fetal calf serum (final 10%) and G418 (final 700 ug / ml).

CAMP responses in the 293-S / EP ₂ and 293-S / EP ₄ systems are measured as follows: vigorous striking, addition of serum-free RPMI to a final cell concentration of 1 × 10 ⁶ cells / ml, and a final concentration of 1 mM. Cells are detached from the culture flask into 1 ml Ca ⁺⁺ and Mg ⁺⁺ deficient PBS by addition of the resulting 3-isobutyl-1-methylxanthine (IBMX). Immediately dispense 1 ml of cell suspension into each 2 ml microcentrifuge tube with screw cap and incubate for 10 minutes at 37 ° C., 5% CO ₂ , 95% relative humidity with the lid removed. The test compound is then added to the cells at a dilution of 1: 100 so that the final concentration of DMSO or ethanol is 1%. Immediately after adding the compound, the tube is capped, mixed by two inversions, and incubated at 37 ° C. for 12 minutes. The sample is then lysed by incubation at 100 ° C. for 10 minutes and immediately cooled on ice for 5 minutes. Cell debris is precipitated by centrifugation at 1000 × g for 5 minutes and the clear lysate is transferred to a new tube. The clear lysate was diluted 1:10 in cAMP RIA assay buffer (included in the kit) and then commercially available cAMP radioimmunoassay kit RIA (NEK-033, DuPont / NEN Research Products, 549 Albany St., Boston , MA 02118) to measure the cAMP concentration. In general, cells are treated with 6-8 different concentrations of test compound increasing in 1 log increments. For the linear portion of the dose response curve, the EC50 is calculated by a computer using linear regression analysis.

Reference 1. Regan, JW, Bailey, TJ, Pepperl, DJ, Pierce, KL, Bogardus, AM, Donello, JE, Fairbairn, CE, Kedzie, KM, Woodward, DF and Gil, DW 1994, pharmacologically determined EP ₂ sub Cloning of a novel human prostaglandin receptor with type characteristics, Mol. Pharmacology 46: 213-220;
2. Bastien, L., Sawyer, N., Grygorczyk, R., Metters, K., and Adam, M. 1994, Cloning, functional expression and characterization of the human prostaglandin E2 receptor EP2 subtype, J. Biol Chem. Vol 269, 16: 11873-11877.

Binding assays to prostaglandin E ₂ receptor
Membrane preparation :
All manipulations were performed at 4 ° C. Harvest transfected cells that express prostaglandin E ₂ type 1 receptor (EP ₁ ), type 2 receptor (EP ₂ ), type 3 receptor (EP ₃ ) or type 4 receptor (EP ₄ ) Buffer A [50 mM Tris-HCl (pH 7.4), 10 mM MgCl ₂ , 1 mM EDTA, 1 mM Pefabloc peptide (Boehringer Mannheim Corp., Indianapolis, IN), 10 uM phosphoramidon peptide to 2 million cells / ml (Sigma, St. Louis, MO), 1 uM pepstatin A peptide (Sigma, St. Louis, MO), 10 uM elastatin peptide (Sigma, St. Louis, MO), 100 uM antipine peptide (Sigma, St. Louis, MO)]. Cells are lysed using a Branson Sonifier (# 250, Branson Ultrasonics Corporation, Danbury, Conn.) By sonicating in two bursts for 15 seconds each. Unlysed cells and cell debris are removed by centrifugation at 100 xg for 10 minutes. The membrane is then harvested by centrifugation at 45,000 xg for 30 minutes. The pelleted membrane is resuspended to 3-10 mg / ml and the protein concentration is determined by the Bradford method [Bradford, M., Anal. Biochem., 72, 248 (1976)]. The resuspended membrane is then stored frozen at −80 ° C. until use.

Binding assay :
A frozen membrane is prepared as above, thawed and diluted in buffer A as described above to 1 mg / ml protein. Mix 1 volume of membrane preparation with 0.05 volume of test compound or buffer and 1 volume of 3 nM ³ H-prostaglandin E ₂ (#TRK 431, Amersham, Arlington Heights, Ill.) In Buffer A. . This mixture (205 μL total volume) is incubated at 25 ° C. for 1 hour. The membrane was then filtered using a Tomtec harvester (Mach II / 96, Tomtec, Orange, CT) with a GF / C glass fiber filter (# 1205-401, Wallac, Geysersburg, MD). to recover. ^The membrane to which ³ H-prostaglandin E ₂ is bound is captured by the filter, but the buffer and unbound ³ H-prostaglandin E ₂ pass through the filter and enter the waste solution. Each sample is then washed 3 times with 3 ml [50 mM Tris-HCl (pH 7.4), 10 mM MgCl ₂ , 1 mM EDTA]. The filter is then dried by heating in a microwave. To determine the amount of ³ H-prostaglandin bound to the membrane, place a dry filter in a plastic bag containing scintillation fluid and count with an LKB 1205 Betaplate reader (Wallac, Geysersburg, MD). . From the test compound concentration required to displace 50% of the specifically bound ³ H- prostaglandin E _2, determining the IC50.

The full length EP ₁ receptor is prepared as described in Funk et al., Journal of Biological Chemistry, 1993, 268, 26767-26772. Full length EP ₂ receptor is prepared as described in Regan et al., Molecular Pharmacology, 1994, 46, 213-220. The full length EP ₃ receptor is prepared as described in Regan et al., British Journal of Pharmacology, 1994, 112, 377-385. The full length EP ₄ receptor is prepared as described in Bastien, Journal of Biological Chemistry, 1994, 269, 11873-11877. These full length receptors are used to make 293-S cells that express EP ₁ , EP ₂ , EP ₃ and EP ₄ receptors.

293S cells expressing either EP ₁ , EP ₂ , EP ₃ or EP ₄ prostaglandin E ₂ receptors are made according to methods known to those skilled in the art. In general, PCR (polymerase chain reaction) primers corresponding to the 5 ′ and 3 ′ ends of the published full-length receptor are prepared according to the well-known methods described above, derived from human kidney (for EP ₁ ), Used for RT-PCR reactions using total RNA from human lung (for EP ₂ ), human lung (for EP ₃ ) or human lymphocytes (for EP ₄ ). The PCR product is cloned into pCR2.1 (Invitrogen, Carlsbad, Calif.) By the TA overhang method, and the identity of the cloned receptor is confirmed by DNA sequencing.

  The receptor cloned in pcDNA3 is transfected into 293S cells (Mayo, Dep. of Biochemistry, Northwest Univ.) by electroporation. By selecting the transfected cells with G418, a stable cell line expressing the receptor is established.

A clonal cell line expressing the maximum number of receptors is selected by a whole cell ³ H-PGE ₂ binding assay using unlabeled PGE ₂ as a competitor.

Claims (15)

Treat pulmonary hypertension, promote joint fusion, promote tendon and ligament repair, reduce secondary fracture occurrence, treat avascular necrosis, promote cartilage repair, bone after limb transplantation Promote healing, promote liver regeneration, promote wound healing, reduce gastric ulcer development, treat hypertension, promote tooth enamel or toenails growth, treat glaucoma, A method of treating ocular hypertension or repairing damage caused by metastatic bone disease, comprising administering to a patient in need thereof a therapeutically effective amount of an EP ₂ selective receptor agonist. Treat pulmonary hypertension, promote joint fusion, promote tendon and ligament repair, reduce secondary fracture occurrence, treat avascular necrosis, promote cartilage repair, bone after limb transplantation Promote healing, promote liver regeneration, promote wound healing, reduce gastric ulcer development, treat hypertension, promote tooth enamel or toenails growth, treat glaucoma, A method of treating ocular hypertension or repairing damage caused by metastatic bone disease, wherein a therapeutically effective amount of a compound of formula I for patients in need thereof

Or a method comprising administering a prodrug thereof, or a pharmaceutically acceptable salt thereof:
In the formula:
A is SO ₂ or CO;
G is Ar, Ar ¹ -V-Ar ² , Ar- (C ₁ -C ₆ ) alkylene, Ar-CONH- (C ₁ -C ₆ ) alkylene, R ¹ R ² -amino, oxy (C ₁ -C ₆ ) alkylene, amino substituted with Ar, or amino substituted with Ar (C ₁ -C ₄ ) alkylene, and R ¹¹ , where R ¹¹ is H or (C ₁ -C ₈ ) alkyl R ¹ and R ² are separate and independently selected from H and (C ₁ -C ₈ ) alkyl, or R ¹ and R ² together with the nitrogen atom of the amino group are 5-membered or 6 Form a membered azacycloalkyl, which may contain an oxygen atom and is independently up to two oxo, hydroxy, (C ₁ -C ₄ ) alkyl, fluoro or chloro mono-, di- Or may be tri-substituted;
B is N or CH;
Q is the following:
-(C ₂ -C ₆ ) alkylene-W- (C ₁ -C ₃ ) alkylene-: each alkylene is independently up to 4 substituents selected from fluoro or (C ₁ -C ₄ ) alkyl May be substituted,
-(C ₄ -C ₈ ) alkylene-: alkylene may be optionally substituted with up to 4 substituents selected from fluoro or (C ₁ -C ₄ ) alkyl;
-X- (C ₁ -C ₅ ) alkylene-: alkylene may be optionally substituted with up to 4 substituents selected from fluoro or (C ₁ -C ₄ ) alkyl;
-(C ₁ -C ₅ ) alkylene-X-: alkylene may be substituted with up to 4 substituents independently selected from fluoro or (C ₁ -C ₄ ) alkyl,
-(C ₁ -C ₃ ) alkylene-X- (C ₁ -C ₃ ) alkylene-: each alkylene is independently at most 4 substituents selected from fluoro or (C ₁ -C ₄ ) alkyl Optionally substituted with
-(C ₂ -C ₄ ) alkylene-WX- (C ₀ -C ₃ ) alkylene-: each alkylene is independently at most 4 substituents selected from fluoro or (C ₁ -C ₄ ) alkyl Optionally substituted with
-(C ₀ -C ₄ ) alkylene-XW- (C ₁ -C ₃ ) alkylene-: each alkylene is independently at most 4 substituents selected from fluoro or (C ₁ -C ₄ ) alkyl Optionally substituted with
-(C ₂ -C ₅ ) alkylene-WXW- (C ₁ -C ₃ ) alkylene-: the two Ws are independent of each other and each alkylene is independently fluoro or (C ₁ -C ₄ ) Optionally substituted with up to 4 substituents selected from alkyl,
-(C ₁ -C ₄ ) alkylene-ethenylene- (C ₁ -C ₄ ) alkylene-: each alkylene and ethenylene is each independently up to ₄ selected from fluoro or (C ₁ -C ₄ ) alkyl Optionally substituted with a substituent,
-(C ₁ -C ₄ ) alkylene-ethenylene- (C ₀ -C ₂ ) alkylene-X- (C ₀ -C ₅ ) alkylene-: each alkylene and ethenylene are each independently fluoro or (C ₁ -C ₄ ) optionally substituted with up to 4 substituents selected from alkyl,
-(C ₁ -C ₄ ) alkylene-ethenylene- (C ₀ -C ₂ ) alkylene-XW- (C ₁ -C ₃ ) alkylene-: each alkylene and ethenylene are each independently fluoro or (C ₁ -C ₄ ) optionally substituted with up to 4 substituents selected from alkyl,
-(C ₁ -C ₄ ) alkylene-ethynylene- (C ₁ -C ₄ ) alkylene-: each alkylene and ethynylene is each independently up to ₄ selected from fluoro or (C ₁ -C ₄ ) alkyl Optionally substituted with a substituent, or
-(C ₁ -C ₄ ) alkylene-ethynylene-X- (C ₀ -C ₃ ) alkylene-: each alkylene and ethynylene is each independently selected from fluoro or (C ₁ -C ₄ ) alkyl up to 4 Optionally substituted with 1 substituent;
Z is carboxyl, (C ₁ -C ₆ ) alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, ( C ₁ -C ₄₎ be alkylsulfonylcarbamoyl or phenyl sulfonylcarbamoyl;
K is a bond, (C ₁ -C ₉ ) alkylene, thio (C ₁ -C ₄ ) alkylene, (C ₁ -C ₄ ) alkylenethio (C ₁ -C ₄ ) alkylene, (C ₁ -C ₄ ) alkylene Oxy (C ₁ -C ₄ ) alkylene or oxy (C ₁ -C ₄ ) alkylene, where (C ₁ -C ₉ ) alkylene may be mono-unsaturated, and when K is not a bond, K is independent Optionally mono-, di- or tri-substituted with chloro, fluoro, hydroxy or methyl;
M ^{is, -Ar 3, -Ar 4 -V 1} -Ar 5, -Ar 4 -S-Ar 5, -Ar 4 -SO-Ar 5, -Ar 4 -SO 2 -Ar 5 or -Ar ^4, - O-Ar ⁵ ;
Ar is a partially saturated or fully unsaturated 5- to 8-membered ring and may contain 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or two fused An independently partially saturated, fully saturated or fully unsaturated 5- or 6-membered bicyclic ring containing 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen Or three fused, independently partially saturated, fully saturated or fully unsaturated, 5- or 6-membered tricyclic rings, independently selected from nitrogen, sulfur and oxygen 1 to 4 heteroatoms may be included, and these partially saturated or fully saturated rings, bicyclic rings or tricyclic rings may be substituted with 1 or 2 oxo groups substituted at carbon atoms or Contains 1 or 2 oxo groups substituted at the sulfur atom At best; or Ar is a fully saturated 5 to 7 membered ring, containing oxygen, 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen independently;
Ar ¹ and Ar ² are each independently a partially saturated, fully saturated or fully unsaturated 5- to 8-membered ring and independently selected from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen Or two fused, independently partially saturated, fully saturated or fully unsaturated bicyclic rings consisting of 5 or 6 members, independently nitrogen, sulfur and oxygen 1 to 4 heteroatoms selected from: or three condensed, independently tricyclic rings consisting of a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring And may contain 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen, and these partially saturated or fully saturated rings, bicyclic rings or tricyclic rings are: In one or two oxo groups or sulfur atoms substituted at the carbon atom It may include substituted one or two oxo groups;
Ar, Ar ¹ and Ar ² moieties are one ring when the moiety is monocyclic, one or both rings when the moiety is bicyclic, or the moiety is tricyclic. In some cases, at one, two or three ring carbons or nitrogens, each moiety may be substituted with up to ^three independently selected substituents selected from R ³ , R ⁴ and R ⁵ , where R ³ , R ⁴ and R ⁵ are independently: hydroxy, nitro, halo, carboxy, (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₄ ) alkoxy (C ₁ -C ₄ ) Alkyl, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₇ ) alkyl, (C ₂ -C ₇ ) alkenyl, (C ₂ -C ₇ ) alkynyl, (C ₃ -C ₇ ) cycloalkyl, ( C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₄ ) alkyl, (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₄ ) alkanoyl, formyl, (C ₁ -C ₈ ) alkanoyl, (C _1- C ₆ ) Alkanoyl (C ₁ -C ₆₎ alkyl, (C ₁ -C ₄₎ alkanoylamino, (C ₁ -C ₄₎ alkoxycarbonylamino, hydroxysulfonyl, aminocarbonylamino or mono -N-, di -N, N-, di -N, N'- or tri-N, N, N '-(C ₁ -C ₄ ) alkyl substituted aminocarbonylamino, sulfonamide, (C ₁ -C ₄ ) alkylsulfonamide, amino, mono-N- or di-N , N- (C ₁ -C ₄ ) alkylamino, carbamoyl, mono-N- or di-N, N- (C ₁ -C ₄ ) alkylcarbamoyl, cyano, thiol, (C ₁ -C ₆ ) alkylthio, ( C ₁ -C ₆₎ alkylsulfinyl, (C ₁ -C ₄₎ alkylsulfonyl or mono -N- or di _{-N,, N- (C 1 -C} 4) alkylamino sulfinyl;
Ar ³ , Ar ⁴ and Ar ⁵ are each independently a partially saturated, fully saturated or fully unsaturated 5- to 8-membered ring and independently selected from oxygen, sulfur and nitrogen Or two fused, independently partially saturated, fully saturated or fully unsaturated bi- or 5-membered bicyclic rings, independently nitrogen, May contain 1 to 4 heteroatoms selected from sulfur and oxygen, or three fused, independently, partially saturated, fully saturated or fully unsaturated 5- or 6-membered tricycles Cyclic rings, which may contain 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen, and these partially saturated or fully saturated rings, bicyclic rings or tricyclic rings The ring is attached to one or two oxo groups or sulfur atoms substituted at the carbon atom. Optionally containing 1 or 2 oxo groups substituted; the Ar ³ , Ar ⁴ and Ar ⁵ moieties are of one ring if the moiety is monocyclic and the moiety is bicyclic Up to 3 independently for each moiety R ³¹ , R ^{41 on} one or both rings, or if the moiety is tricyclic, on 1, 2 or 3 ring carbons or nitrogens. and it may be substituted with a substituent selected from R ^51, wherein R ^31, R ⁴¹ and R ⁵¹ are those of the following independently: hydroxy, nitro, halo, carboxy, (C ₁ -C ₇₎ alkoxy, (C ₁ -C ₄₎ alkoxy (C ₁ -C ₄₎ alkyl, (C ₁ -C ₄₎ alkoxycarbonyl, (C ₁ -C ₇₎ alkyl, (C ₂ -C ₇₎ alkenyl, ( C ₂ -C ₇₎ alkynyl, (C ₃ -C ₇₎ cycloalkyl, (C ₃ -C ₇₎ cycloalkyl (C ₁ -C ₄₎ alkyl, (C ₃ -C ₇₎ cycloalkyl (C ₁ -C ₄₎ Al Noil, formyl, (C ₁ -C ₈₎ alkanoyl, (C ₁ -C ₆₎ alkanoyl (C ₁ -C ₆₎ alkyl, (C ₁ -C ₄₎ alkanoylamino, (C ₁ -C ₄₎ alkoxycarbonylamino Hydroxysulfonyl, aminocarbonylamino or mono-N-, di-N, N-, di-N, N′- or tri-N, N, N ′-(C ₁ -C ₄ ) alkyl-substituted aminocarbonylamino, Sulfonamide, (C ₁ -C ₄ ) alkylsulfonamide, amino, mono-N- or di-N, N- (C ₁ -C ₄ ) alkylamino, carbamoyl, mono-N- or di-N, N- (C ₁ -C ₄ ) alkylcarbamoyl, cyano, thiol, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylsulfinyl, (C ₁ -C ₄ ) alkylsulfonyl, or mono-N- or di- _{-N, N- (C 1 -C 4} ) alkylamino sulfinyl;
W is oxy, thio, sulfino, sulfonyl, aminosulfonyl -, - mono -N- (C ₁ -C ₄₎ alkylene aminosulfonyl -, sulfonylamino, N- (C ₁ -C ₄₎ alkylene sulfonylamino, carboxamido, N- (C ₁ -C ₄₎ alkylene-carboxamide, carboxamide oxy, N- (C ₁ -C ₄₎ alkylene carboxamide oxy, carbamoyl, - mono -N- (C ₁ -C ₄₎ alkylene carbamoyl, carbamoyloxy, or - Mono-N- (C ₁ -C ₄ ) alkylenecarbamoyloxy, the alkyl group of W may be substituted with 1 to 3 fluorines at the carbon;
X is a 5- or 6-membered aromatic ring and may contain 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur; the ring is independently halo, ( C ₁ -C ₃ ) alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C ₁ -C ₄ ) alkoxy, or carbamoyl may be mono-, di- or tri-substituted;
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹¹ , R ³¹ , R ⁴¹ and R ⁵¹ are independently halo or hydroxy mono on the carbon when containing an alkyl, alkylene, alkenylene or alkynylene moiety. May be-, di- or tri-substituted;
V and V ¹ are each independently a bond, thio (C ₁ -C ₄ ) alkylene, (C ₁ -C ₄ ) alkylenethio, (C ₁ -C ₄ ) alkyleneoxy, oxy (C ₁ -C ₄ ) Alkylene or (C ₁ -C ₃ ) alkylene, which may independently be mono- or di-substituted with hydroxy or fluoro;
However:
a. When K is (C ₂ -C ₄ ) alkylene, M is Ar ³ and Ar ³ is cyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cyclooct-1-yl, These (C ₅ -C ₈ ) cycloalkyl substituents are not substituted with hydroxy at the 1-position;
b. When K is a bond; G is phenyl, phenylmethyl, substituted phenyl or substituted phenylmethyl; Q is (C ₃ -C ₈ ) alkylene; and M is Ar ³ or Ar ⁴ -Ar ⁵ Is sulfonyl.   Treat pulmonary hypertension, promote joint fusion, promote tendon and ligament repair, reduce secondary fracture occurrence, treat avascular necrosis, promote cartilage repair, bone after limb transplantation Promote healing, promote liver regeneration, promote wound healing, reduce gastric ulcer development, treat hypertension, promote tooth enamel or toenail growth, treat glaucoma, A method of treating ocular hypertension or repairing damage caused by metastatic bone disease, wherein a therapeutically effective amount of (3-(((4-t-butyl-benzyl)-(pyridine -3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid or a pharmaceutically acceptable salt thereof.   The method according to any one of claims 1 to 3, which is a method for treating hypertension or treating pulmonary hypertension.   The method according to any one of claims 1 to 3, which is a method of promoting joint fusion.   The method according to any one of claims 1 to 3, which is a method of promoting tendon and ligament repair or cartilage repair.   The method of any one of Claims 1-3 which is a method of reducing generation | occurrence | production of a secondary fracture.   4. The method according to any one of claims 1 to 3, which is a method for treating avascular necrosis.   The method according to any one of claims 1 to 3, which is a method of promoting bone healing after limb transplantation.   The method according to any one of claims 1 to 3, which is a method of promoting liver regeneration.   The method according to any one of claims 1 to 3, which is a method of promoting wound healing.   The method according to any one of claims 1 to 3, which is a method for reducing the onset of gastric ulcer.   The method according to any one of claims 1 to 3, which is a method for promoting the growth of tooth enamel, fingernails or toenails.   The method according to any one of claims 1 to 3, which is a method for treating glaucoma or treating ocular hypertension.   The method according to any one of claims 1 to 3, which is a method for repairing damage caused by metastatic bone disease.