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WO1998030551A1 - INHIBITEURS MACROCYCLIQUES DE METALLOPROTEINASES MATRICIELLES ET DE SECRETION DE FNT$g(a) - Google Patents

INHIBITEURS MACROCYCLIQUES DE METALLOPROTEINASES MATRICIELLES ET DE SECRETION DE FNT$g(a) Download PDF

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WO1998030551A1
WO1998030551A1 PCT/US1998/000144 US9800144W WO9830551A1 WO 1998030551 A1 WO1998030551 A1 WO 1998030551A1 US 9800144 W US9800144 W US 9800144W WO 9830551 A1 WO9830551 A1 WO 9830551A1
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Prior art keywords
carbon atoms
alkyl
group
substituted
haloalkyl
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PCT/US1998/000144
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English (en)
Inventor
Steven K. Davidsen
Douglas H. Steinman
George S. Sheppard
Lianhong Xu
James H. Holms
Yan Guo
Alan Scott Florjancic
James B. Siummers
Michael R. Michaelides
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Abbott Laboratories
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Priority to CA002277121A priority Critical patent/CA2277121A1/fr
Priority to AU58155/98A priority patent/AU5815598A/en
Priority to JP53103198A priority patent/JP2001509151A/ja
Priority to EP98901696A priority patent/EP1021423A1/fr
Publication of WO1998030551A1 publication Critical patent/WO1998030551A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D225/06—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
    • C07D245/02—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
    • C07D245/04—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D245/06—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic

Definitions

  • This invention relates to compounds having activity to inhibit matrix metalloproteinases and TNF ⁇ secretion, to pharmaceutical compositions comprising these compounds, and to a medical method of treatment. More particularly, this invention concerns macrocyclic compounds which inhibit matrix metalloproteinases and TNF ⁇ secretion, to pharmaceutical compositions comprising these compounds and to a method of inhibiting matrix metalloproteinases and TNF ⁇ secretion.
  • MMP's matrix metalloproteinases
  • collagenase stromelysin
  • gelatinase which are believed to be involved in the tissue destruction which accompanies a large number of disease states varying from arthritis to cancer.
  • Typical connective tissue cells are embedded within an extracellular matrix of high molecular weight proteins and glycoproteins.
  • healthy tissue there is a continual and delicately- balanced series of processes which include cell division, matrix synthesis, and matrix degradation.
  • an imbalance of these three processes can lead to improper tissue restructuring.
  • joint mobility can be lost when there is improper remodelling of load-bearing joint cartilage.
  • lack of coordination of cell division and the two processes of matrix synthesis and degradation can lead to conversion of transformed cells to invasive phenotypes in which increased matrix turnover permits tumor cells to penetrate basement membranes surrounding capillaries leading to subsequent metastasis.
  • Tumor Necrosis Factor ⁇ is a potent proinflammatory mediator which has been implicated in inflammatory conditions including arthritis, asthma, septic shock, non-insulin dependent diabetes mellitus and inflammatory bowel disease.
  • TNF ⁇ is originally expressed as a membrane- bound protein of about 26 kD, which is proteolytically cleaved to release a soluble 17 kD fragment (TNF ⁇ processing) which combines with two other secreted TNF ⁇ molecules to form a circulating 51 kD homotrimer.
  • TNF ⁇ processing a soluble 17 kD fragment
  • MMP inhibitors were found to inhibit TNF ⁇ processing (see Mohler, et al., Nature, 1994, 370, 218; Gearing, et al.
  • TGF ⁇ Transfoirning growth factor alpha
  • EGF epidermal growth factor
  • the present invention provides a novel class of macrocyclic inhibitors of matrix metalloproteinases and/or TNF ⁇ secretion.
  • the present invention provides a macrocyclic compound of formula I
  • W is NHOH or OH.
  • R 1 and R 3 are independently selected from hydrogen or alkyl of one to four carbon atoms.
  • R 2 is selected from the group consisting of (a) alkyl of one to ten carbon atoms, (b) alkenyl of two to ten carbon atoms,
  • phenyl (h) phenyl substituted with 1, 2, or 3 substutuents independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CO2R 4 wherein R 4 is independently selected at each occurrence from hydrogen and alkyl of one to four carbon atoms, and -CONR R 5 wherein R 4 is defined above and and R 5 is independently selected at each occurrence from hydrogen and alkyl of one to four carbon atoms,
  • phenylalkyl wherein the alkylene portion is of one to six carbon atoms
  • phenylalkyl wherein the alkylene portion is of one to six carbon atoms and the phenyl ring is substituted with 1 , 2, or 3 substituents independently selected from alkoxyalkyloxy, alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CO2R 4 , -CONR R 5 , phenyl, and phenyl substituted with 1, 2, or 3 substutuents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, - CO R 4 , and -CONR 4 R 5
  • fluorenylalkyl wherein the alkylene portion is of one to four carbon atoms.
  • Y is absent or -O-.
  • L 1 is alkylene of two to six carbon atoms.
  • L 2 is selected from the group consisting of
  • D is CH or N
  • L 3 is absent or is alkylene of one to four carbon atoms
  • R a , R b and R c are independently selected from hydrogen, alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, -SO2R 6 wherein R 6 is alkyl of one to four carbon atoms, -SO2NH2, - CO2R 4 , 2-tetrazolyl, and -CONR 7 R 8 wherein R 7 and R 8 are independently selected at each occurrence from hydrogen and alkyl of one to four carbon atoms, or R 7 and R 8 together with the N atom to which they are attached define a a 5-or 6-membered heterocychc ring selected from the group consisting of morpholinyl, thiomorpholinyl. thiomorpholinyl sulfone, pyrrolidinyl, piperaz
  • A is absent or is selected from the group consisting of (a) -O-, (b) -NR 9 - wherein R 9 is selected from the group consisting of
  • R 10 is independently selected at each occurrence from the group consisting of alkyl of one to four carbon atoms, haloalkyl of one to four carbon atoms, phenyl, phenyl substituted with 1, 2, or 3 substituents independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, nitro, cyano, cyanoalkyl, -SO2NH2, -CO2R 4 , and -CONR R 5 , phenylalkyl wherein the alkylene portion is of one to four carbon atoms, phenylalkyl wherein the alkylene portion is of one to four carbon atoms, and the phenyl ring is substituted with 1, 2, or 3 substituents independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, halogen, haloal
  • V wherein V is O or NOR 4 ,
  • J is O or NR 4 ,
  • J K wherein J is defined above and K is selected from O and NR 4 , provided that J and K are not simultaneously O,
  • L 4 is alkylene of two to six carbon atoms
  • L 5 is alkylene of one to three carbon atoms
  • R 4 is defined above and R 12 is selected from hydrogen, alkyl of one to four carbon atoms, -COR 10 , -CO2R 10 , and -SO2R 10 ,
  • T and V are independently selected from O and S and R a is defined above, (bb) RC wherein R a , R b , and R c are defined above,
  • R e wherein R d and R e are independently selected from hydrogen and alkyl of one to four carbon atoms, and (ff)
  • R e provided that when A is selected from (aa), (bb), (cc), (dd) and (ff) above, L 2 is alkylene, and further provided that when both Y and A are absent, LI is alkylene of three to six carbon atoms.
  • Z is absent or is selected from the group consisting of (a) -CO 2 H, (b) -CO 2 R 10 ,
  • R 13 is hydrogen or alkyl of one to six carbon atoms
  • R 14 is selected from the group consisting of (1) hydrogen, (2) alkyl of one to six carbon atoms
  • aryl wherein the aryl group is selected from (a) phenyl, (b) phenyl substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, cyano, -C(O)R 4 , -NR R 5 , -CO2R 4 , - SO2R 4 , -SO2NR 4 R 5 , (c) naphthyl, (d) naphthyl substituted with 1, 2 or 3 substituents independently selected from alkyl of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, cyano, -C(O)R 4 , -NR R 5 , -CO2R 4 , - SO 2 R 4 , -SO 2 NR 4
  • heteroarylalkyl wherein the alkylene portion is of one to four carbon atoms and the heteroaryl group is defined above,
  • R 15 is selected from hydrogen, hydroxy, alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and alkoxyalkyl of one to four carbon atoms, and
  • R x is the side chain of a naturally occurring amino acid
  • R 13 and R 14 together with the N atom to which they are attached define a 5-or 6-membered heterocychc ring selected the group consisting of
  • R 16 is hydrogen or benzyl
  • R 17 is selected from the group consisting of
  • phenyl (4) phenyl substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, hydroxy, hydroxyalkyl of one to four carbon atoms, haloalkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, amino. cyano, -NR 4 R 5 , -SO2NR 4 R 5 . -SO2R 4 , -CH2NR 7 R 8 , -CONR 7 R 8 .
  • phenyl wherein the phenyl ring may be substituted with 1 , 2, or 3 substituents independently selected from alkyl of one to four carbon atoms, halogen, and haloalkyl of one to four carbon atoms,
  • R 18 and R 19 are independently selected from the group consisting of
  • alkoxyalkyl wherein the alkoxy and alkylene portions are independently of one to six carbon atoms
  • the present invention provides pharmaceutical compositions which comprise a therapeutically effective amount of compound of formula I in combination with a pharmaceutically acceptable carrier.
  • the present invention provides a method of inhibiting matrix metalloproteinases and/or TNF ⁇ secretion in a host mammal in need of such treatment comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I.
  • alkyl refers to a monovalent group derived from a straight or branched chain saturated hydrocarbon by the removal of a single hydrogen atom.
  • Alkyl groups are exemplified by methyl, ethyl, n- and wo-propyl, n-. sec-, iso- and tert-butyl, and the like.
  • alkanoyl represents an alkyl group, as defined above, attached to the parent molecular moiety through a carbonyl group. Alkanoyl groups are exemplified by formyl, acetyl, propionyl, butanoyl and the like.
  • alkoxy and alkoxyl denote an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom.
  • Representative alkoxy groups include methoxy, ethoxy, propoxy, butoxy, and the like.
  • alkoxycarbonyl represents an ester group; i.e. an alkoxy group, attached to the parent molecular moiety through a carbonyl group such as methoxycarbonyl, ethoxycarbonyl, and the like.
  • alkenyl refers to monovalent straight or branched chain groups of 2 to 6 carbon atoms containing a carbon-carbon double bond, derived from an alkene by the removal of one hydrogen atom and include, but are not limited to groups such as ethenyl, 1-propenyl, 2- propenyl, 2-methyl- 1-propenyl, 1-butenyl, 2-butenyl and the like.
  • alkylene denotes a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon containing by the removal of two hydrogen atoms, for example -CH2-, -CH2CH2-. -CH(CH3)CH2- and the like.
  • alkenylene denotes a divalent group derived from a straight or branched chain hydrocarbon containing at least one carbon-carbon double bond.
  • alkynylene refers to a divalent group derived by the removal of two hydrogen atoms from a straight or branched chain acychc hydrocarbon group containing at least one carbon- carbon triple bond.
  • alkynylene include -CH ⁇ CH-, -CH ⁇ C-CH 2 -, -CH ⁇ CH- CH(CH 3 )- and the like.
  • (cycloalkyl)alkyl and "(cycloalkenylene)alkyl” refer, respectively, to a cycloalkyl group or cycloalkenylene group as defined above attached to the parent molecular moiety through an alkylene group.
  • cyanoalkyl denotes an alkyl group, as defined above, substituted by a cyano group and includes, for example, cyanomethyl, cyanoethyl, cyanopropyl and the like.
  • haloalkyl denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluorornethyl, and the like.
  • hydroxy alkyl represents an alkyl group, as defined above, substituted by one to three hydroxyl groups with the proviso that no more than one hydroxy group may be attached to a single carbon atom of the alkyl group.
  • phenoxy refers to a phenyl group attached to the parent molecular moiety through an oxygen atom.
  • salt By pharmaceutically acceptable salt is meant those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art . For example, S. M Berge, et al. describe pharmaceutically acceptable salts in detail in J.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesuLfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate,
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • ester refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • Examples of particular esters includes formates, acetates, propionates, butyates. acrylates and ethyl succinates.
  • prodrugs refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • Asymmetric centers may exist in the compounds of the present invention.
  • the present invention contemplates the various stereoisomers and mixtures thereof.
  • Individual stereoisomers of compounds of the present invention are made by synthesis from starting materials containing the chiral centers or by preparation of mixtures of enantiomeric products followed by separation as, for example, by conversion to a mixture of diastereomers followed by separation by recrystallization or chromatographic techniques, or by direct separation of the optical enantiomers on chiral chromatographic columns.
  • Starting compounds of particular stereochemistry are either commercially available or are made by the methods detailed below and resolved by techniques well known in the organic chemical arts.
  • W and L 2 are defined above, Y is absent or -O-; R 1 and R 3 are H;
  • L 1 is alkylene of two to six carbon atoms;
  • A is selected from the group consisting of (a) -O-, (b) -NR 9 - wherein R 9 is selected from the group consisting of
  • R 10 is independently selected at each occurrence from the group consisting of alkyl of one to four carbon atoms, phenyl, phenyl substituted with 1, 2, or 3 substituents independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, nitro, cyano, cyanoalkyl, -SO2NH2, - CO2R 4 , and -CONR 4 R 5 , phenylalkyl wherein the alkylene portion is of one to four carbon atoms, phenylalkyl wherein the alkylene portion is of one to four carbon atoms, and the phenyl ring is substituted with 1, 2, or 3 substituents independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano
  • R wherein R d and R e are independently selected from hydrogen and alkyl of one to four carbon atoms, provided that when A is (f) above, L 2 is alkylene; R 2 is selected from the group consisting of isobutyl, cyclohexyl, cyclopentylmethyl, phenyl, 3-(4-tolyl)propyl, 3-(4-chlorophenyl)propyl, 2-(4-propylphenyl)ethyl, 3- benzyloxypropyl, 4-phenoxybutyl, 4-(4-butylphenoxy)butyl, 4-biphenyloxy, and 2-(4-(4'cyano)biphenyloxy)ethyl; and
  • Z is absent or is selected from the group consisting of
  • R 13 is hydrogen or alkyl of one to six carbon atoms
  • R 14 is selected from the group consisting of
  • R 15 is hydrogen
  • CH 3 or R 13 and R 14 together with the N atom to which they are attached define a 5-or 6-membered heterocyclic ring selected the group consisting of morpholinyl, pyrroUdinyl, piperidinyl, and wherein R 16 is hydrogen or benzyl,
  • R 17 is selected from the group consisting of (1) phenyl, (2) phenyl substituted with alkyl of one to four carbon atoms, methanesulfonyl or dimethylaminomethyl,
  • More preferred compounds of the present invention have formula II wherein W is -NHOH.
  • Still more preferred compounds have formula ⁇ wherein Y, R 1 , R 3 , L 1 and A are defined above; R 2 is selected from isobutyl, 3-(4-tolyl)propyl, 2-(4-propylphenyl)ethyl; and Z is absent or is selected from the group consisting of -CO2H, -CO2CH3, -CO2benzyl, -CONHCH3, - CON(CH 3 ) 2 ,
  • Still yet more preferred compounds have the formula ⁇ wherein W is -NHOH and Z is
  • W is NHOH
  • L 1 is alkylene of two to six carbon atoms
  • L 3 is absent or methylene
  • A is selected from the group consisting of
  • R 2 is selected from isobutyl, 3-(4-tolyl)propyl, 2-(4-propylphenyl)ethyl;
  • Z is is selected from the group consisting of -CONHCH3, -CON(CH3)2,
  • the efficacy of the compounds of this invention as matrix metalloproteinase inhibitors was determined by measuring the inhibition of stromelysin.
  • the inhibition of stromelysin by the compounds of this invention was determined as follows: Recombinant truncated stromelysin (human sequence) produced in E. coli was prepared by expression and purification of the protein as described by Ye et al., Biochemistry , 1992, 37, 11231-11235.
  • the enzyme was assayed by its cleavage of the thiopeptide ester substrate Ac-Pro-Leu-Gly-[2-mercapto-4-methyl-pentanoyl]- Leu-Gly-OEt described by Weingarten and Feder, Anal. Biochem. , 1985, 747, 437-440 (1985), as a substrate of vertebrate collagenase.
  • the reported conditions were modified to allow assays to be carried out in a microtiter plate.
  • DTNB 5,5'-dithio-bis(2-nitrobenzoic acid)
  • the rates of cleavage of the substrate by stromelysin in the presence or absence of inhibitors are measured in a 30 min assay at ambient temperature. Solutions of the compounds in DMSO are prepared, and these are diluted at various concentrations into the assay buffer (50 mM MES/NaOH pH 6.5 with 10 mM CaCl2 and 0.2% Pluronic F-68), which is also used for dilution of the enzyme and substrate.
  • the potency of the compounds [IC50] are calculated from the inhibition/inhibitor concentration data.
  • the compounds of this invention inhibit stromelysin as shown by the data for representative examples in Table 1.
  • the present invention also provides pharmaceutical compositions which comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers.
  • the pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally , intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally. or as an oral or nasal spray.
  • parenteral administration refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
  • Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • aqueous and nonaqueous carriers, diluents, solvents or vehicles examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like, Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents.
  • the absorption of the drug in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalhne form. Alternatively, delayed absorption of a parenteraUy administered drug form is accompUshed by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • biodegradable polymers such as polylactide-polyglycolide.
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterUe soUd compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, piUs, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and sUicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain sUicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaoUn and
  • SoUd compositions of a simUar type may also be employed as fillers in soft and hard-fiUed gelatin capsules using such excipients as lactose or milk sugar as weU as high molecular weight polyethylene glycols and the like.
  • soUd dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings weU known in the pharmaceutical formulating art They may optionaUy contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • coatings and shells such as enteric coatings and other coatings weU known in the pharmaceutical formulating art
  • They may optionaUy contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceuticaUy acceptable emulsions, solutions, suspensions, syrups and eUxirs.
  • the liquid dosage forms may contain inert dUuents commonly used in the art such as, for example, water or other solvents, solubihzing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert dUuents commonly used in the art such as, for example, water or other solvents, solubihzing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystaUine cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • hposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated hquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabiUzers, preservatives, excipients, and the like.
  • the preferred lipids are the phosphohpids and the phosphatidyl choUnes (lecithins), both natural and synthetic.
  • Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceuticaUy acceptable carrier and any needed preservatives, buffers, or propellants which may be required.
  • Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration.
  • the selected dosage level wUl depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to graduaUy increase the dosage until the desired effect is achieved.
  • dosage levels of about 1 to about 50, more preferably of about 5 to about 20 mg of active compound per kilogram of body weight per day are administered orally to a mammahan patient.
  • the effective daily dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.
  • the compounds of this invention may be prepared by a variety of synthetic routes.
  • CycUzation of 4 can be achieved using Mitsunobu conditions (Mitsunobu et al., J. Am. Chem. Soc, 1972, 94. 679).
  • Mitsunobu et al. J. Am. Chem. Soc, 1972, 94. 679.
  • addition of 4 to a solution of triphenylphosphine and diethylazodicarboxylate gives macrocycle 5.
  • Conversion of 5 to the corresponding carboxylic acid 6 is accomplished by acidic removal of the tert-butyl ester with, for example, trifluoroacetic acid or hydrogen chloride in dioxane.
  • Preparation of intermediate 2 is accomptished by treating commercially avaUable acid K) with the requisite amine of general formula HNR 13 R 14 using, for example, EDCI»HC1, HOBt, and 7V-methylmorpholine as shown in Scheme 2.
  • the resulting amide ⁇ is subjected to acidic removal of the /V-t-butoxycarbonyl nitrogen protecting group using trifluoroacetic acid or hydrogen chloride in dioaxane giving amide 2.
  • Amino ketones of the general formula 15_ are prepared by treating acid 12 with ethereal diazomethane to produce methyl ester 13.
  • This compound is subsequently reacted with a anion such as R 17 MgX wherein X is Br, Cl or I, or R 17 Li to generate ketone .14.
  • a anion such as R 17 MgX wherein X is Br, Cl or I, or R 17 Li to generate ketone .14.
  • Acidic removal of the te/ -butyl protecting groups gives amino ketone 15.
  • carboxyUc acid 12 can be treated with a carbon anion such as phenylUthium which gives J4 directly.
  • Benzimidazole-containing macrocycles are prepared according to Scheme 5.
  • o-Amino amide 25 prepared as described in Scheme 1 wherein HNR 13 R 14 is 1 ,2-phenylenediamine, is heated with an acid such as camphor sulfonic acid to generate benzimidazole 26.
  • Conversion of this compound to the corresponding carboxyUc acid 27 and hydroxamate 28 is accomphshed by analogy with the sequence shown in Scheme 1.
  • Macrocyclic olefins such as 30 are prepared by treating aryl iodide 29 with a suitable palladium catalyst, for instance tetrakis(triphenylphosphine)pallaium (0), and an amine base such as triethylamine and heating in a solvent such as acetonitrile. Olefin 30 is converted to the corresponding acid 31 and hydroxamate 32 according to the sequence outhned in Scheme 1.
  • a suitable palladium catalyst for instance tetrakis(triphenylphosphine)pallaium (0)
  • an amine base such as triethylamine
  • Tryptophan-derived macrocycles are prepared according to Scheme 7.
  • Alcohol 3_3_ is converted to a suitable leaving group, for example by reaction with p-toluenesulfonyl chloride in the presence of a tertiary base such as pyridine to give tosylate 24.
  • This compound is subjected to phase-transfer alkylation conditions using, for example, potassium hydroxide and benzyltrimethyl ammonium chloride in a mixture of water and methylene chloride.
  • the resulting macrocyclic ester 35 is converted to the corresponding acid 3_6 and hydroxamate 37 according to the sequence outhned in Scheme 1.
  • /7-Aminophenylalanine-derived compounds of this invention are prepared as outlined in Scheme 8.
  • Alcohol 38 . is first converted to its mesylate using methanesulfonyl chloride and a tertiary amine base such as triethylamine. Hydrogenation of this material using 10% palladium on carbon and triethylamine in a solvent such as wo-propanol generates macrocycUc ester 39 directly. Conversion to acid 40 and hydroxamate 41 is accompUshed by the reaction sequence shown in Scheme 1.
  • Alcohol 3_8 can also be oxidized to acid 42 using, for example, chromic acid in sulfuric acid. Hydrogenation of the aromatic nitro group is achieved using hydrogen over a paUadium catalyst.
  • Lactam formation is completed by treatment with a coupling agent such as bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOP-C1) in the presence of a tertiary amine base such as triethylamine giving 43 which is converted to the corresponding acid 44 and hydroxamate 45 as outlined in Scheme 1.
  • a coupling agent such as bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOP-C1) in the presence of a tertiary amine base such as triethylamine giving 43 which is converted to the corresponding acid 44 and hydroxamate 45 as outlined in Scheme 1.
  • Carbamate and urea-derived macrocycles can be prepared according to Scheme 9.
  • Alcohol 46 is treated with bromoacetyl bromide in the presence of sodium carbonate.
  • the resulting ester 47 is subjected to hydrogenation conditions using, for example 10% paUadium on carbon in the presence of a tertiary amine base such as triethylamine which gives macrocycle 48.
  • the tert-butyl ester group of 48 can be converted to acid 49 and to hydroxamate 50 under the conditions illustrated in Scheme 1.
  • Alcohol 46 is converted to the corresponding methanesulfonate 5 . by reaction with methanesulfonyl chloride in the presence of triethylamine.
  • Mesylate 5 is converted to the corresponding methanesulfonate 5 .
  • the desired compound was prepared according to the method used to prepare succinate ester 1, except substituting allyl bromide for 4-bromo-l-butene.
  • the desired compound was prepared according to the method used to prepare succinate ester 1, except substituting 5-bromo-l-pentene for 4-bromo-l-butene.
  • the filtrate was concentrated to a small volume and the residue was partitioned between aqueous 1 M sodium carbonate and ether.
  • the aqueous phase was extracted with ether.
  • the combined ether layers were extracted with aqueous 1 M sodium carbonate.
  • the basic solution was treated with charcoal and filtered.
  • the filtrate was acidified with 3 M hydrochloric acid. After cooling in an ice bath, the soft sohd was filtered, washed with ice water, and dried over sodium hydroxide to give yji (45 g) as a mixture of isomers which was used without further purification.
  • the mixtureof isomers yji was hydrogenated in 600 mL THF over 9 g of 10% paUadium on carbon at 4 atmospheres of hydrogen for 18 hours. After filtration and concentration of the solution, the residue was crystalUzed from hexane to yield 5-(4-tolyl)pentanoic acid (vi ⁇ . 33 g, mp 77-78 °C).
  • the desired compound was prepared using Steps 4, 5 and 6 of the preparation of succinate ester 1 , except substituting x for iii and substituting 5-bromo- 1 -pentene for 4-bromo- 1 -butene.
  • the desired compound was prepared using step 5 of the procedure for the preparation of succinate ester 4, except substituting TBDMS0(CH2) (10.8g, 34.5mmol), prepared as described by Helquist et al., Tetrahedron Lett., 1985, 26, 5393, for 5-bromo- 1 -pentene.
  • the desired compound was prepared by hydroysis of ester xtij, foUowed by conversion of the carboxyUc acid to succinate ester 6 according to steps 3, 4 and 5 of the preparation of succinate ester 4, substituting TBDMS0(CH2)4l, for 5-bromo- 1 -pentene.
  • the desired compound was prepared according to the procedure used to prepare succinate ester 1, except substituting TBDMS0(CH2)4l, for 4-bromo-l-butene.
  • the desired compound was prepared in the same manner as succinate ester 5, except replacing acid viii with 6-benzyloxy hexanoic acid.
  • the desired compound was prepared according to the method of Examples 1E-G, except substituting cyclopropylamine for 4-(2-aminoethyl)benzenesulphonamide. mp > 270 °C. *H
  • the desired compound was prepared using the procedure described for example IE, except substituting 1,2-phenylenediamine for 4-(2-aminoethyl)benzenesulphonamide.
  • Step 1 To a -78 °C solution in THF (8 mL) of diisopropylamine (541 mg, 5.35 mmol) was added butylUthium (2 ml, 5 mmol, 2.5M in hexanes) dropwise and the solution was stirred for 15 minutes. A mixture of (R)-wo-butylsuccinic acid tert-butylester (0.5g, 2.17 mmol) in DMPU (1 mL) and THF (3 mL) was added dropwise.
  • Step 2 To a -78 °C solution in THF (7 mL) of diisopropylamine (523 mg, 5.17 mmol) was added butylUthium (1.93 ml, 4.83 mmol, 2.5M in hexanes) dropwise and the solution was stirred for 15 minutes. A solution of Sb (611 mg, 2.15 mmol) in THF (8 mL) was added dropwise. The reaction mixture was warmed to -20°C and stirred for 15 minutes before being cooled to -78C and quenched with a solution of methanol(356 mg, 11 mmol) in 2 ml THF.
  • the desired compound 8d was prepared from 8c by hydroboration/oxidation according to the method of Example IC.
  • Example 8E
  • the desired compound ⁇ £ was prepared by saponification of 8e using trifluoroacetic acid in dichloromethane according to the method of Example IF.
  • the desired compound was prepared according to the method of Examples 8C-F, except substituting aUyl bromide for 4-bromo-l-butene in Example 8B.
  • the desired compound 12a was prepared according to the method of Example 8B, except substituting 6-bromo-l-hexene for 4-bromo-l-butene.
  • the crude material was triturated in 5:1 ether/methanol and the sohd coUected by filtration to give 109mg of the (9-benzylhydroxamate.
  • This material was dissolved in 75ml of 70:30 THF/MeOH and treated with lOmg of 10% Pd/C under 1 arm of H2 for 2hours.
  • the catalyst was filtered off and the solution concentrated to give the desired anti isomer (35mg) as a white solid.
  • the desired compound 3a was prepared by coupling of 12a and p-iodo-phenylalanine-N- methylamide hydrochloride using the described above for the preparation of ja.
  • reaction mixture was extracted with CH2CI2 (3x), dried over Na2SO4, filtered and the solvent was evaporated.
  • the crude product was purified by flash chromatography (30% ethyl acetate-hexanes) to give the desired compound 15a (2.46 g, 56%) as a light brown foam.
  • Example 16C The desired compound was prepared by deprotection of 16j
  • Example 16C
  • the desired compound was prepared according to the method of Examples 1 A-C, F and G, except substituting commerciaUy succinate ester 3. for succinate ester 1, and substituting commerciaUy-available O-benzyl-(L)-proline hydrochloride for 4-(2- aminoethyl)benzenesulphonamide. mp > 250 °C.
  • the desired compound was prepared as an off-white solid according to the method of Examples 1 A-E, except substituting succinate ester 3 for succinate ester 1 and omitting 4-(2- aminoethyl)benzenesulphonamide and substituting methanol for DMF in Example IE. mp > 250°C.
  • the desired compound was prepared as a white sohd according to the method of Example 1 , except substituting succinate ester 3. for succinate ester 1 and substituting dimethylamine hydrochloride for 4-(2-aminoethyl)benzenesulphonamide. mp > 250 °C.
  • Example 29A l-tert-butyldimethylsUyl-3-bromoindole
  • indole 4.0g, 34mmol
  • THF 120mL
  • nBuLi 2.5M/Hexanes
  • TBDMS-Cl 5.8g, 38mmol
  • the desired compound was prepared according to the method of Examples IA, B, C and F, except substituting succinate ester 4 for succinate ester 1, and substituting L-tyrosine N- methylamide hydrochloride for benzyltyrosine tosylate salt, mp >270°C.
  • Example 32B The desired compound was prepared according to the method of Example IA, except substituting succinate ester 5 for succinate ester 1.
  • Example 32B Example 32B
  • the desired compound was prepared from 32c by ring closure, hydrolysis of the tert-butyl ester, conversion to the hydroxamic acid and debenzylation according to the method of Examples IC, F, G and D.
  • the desired compound was prepared according to the method of Example IA, except substituting succinate ester 6 for succinate ester 1, and substituting L-tyrosine N-methylamide hydrochloride for benzyltyrosine tosylate salt.
  • the desired compound was prepared from 33e by desUylation according to the method of
  • Example 32D followed by ring closure and saponification of the tert-butyl ester according to the method of Examples IC and F. mp 193-195°C.
  • the desired compound was prepared according to the method of Examples 8A, C and D except substituting N- ⁇ -t-BOC-N- ⁇ -Cbz-L-lysine for BOC-L-tyrosine in Example 8A and substituting succinate ester 2 for 8b.
  • the desired compound was prepared by catalytic hydrogenation of 35b (methanol, palladium hydroxide on carbon, 1 atm. H2) for 3 days.
  • the desired compound was prepared according to the method of Example 18, except substituting 35c for the compound of Example 17.
  • the desired compound was prepared according to the method of Example 19, except substituting the compound of Example 35 for the compound of Example 18.
  • the desired compound was prepared by hydrogenation of 37a (methanol, 10% paUadium on carbon, 1 atm H2) for 3 days.
  • reaction mixture was dUuted with 40ml water and extracted 1 X 400ml with ether.
  • the organic layer was dried over MgSO4, filtered and the filtrate concenttated to a yeUow solid which was purified using flash chromatography eluting with 30% EtOAc/CH2Cl2 to give a white sohd (166mg, 33% yield).
  • the desired compound was prepared according to the method of Examples IE, F and G, except substituting 38b for If and substituting N,N-dimethylethylenediamine for 4-(2- aminoethyDbenzenesulphonamide. mp >250 °C.
  • the desired compound was prepared according to the method of Example IE, except substituting methylamine hydrochloride for 4-(2-aminoethyl)benzenesulphonamide.
  • the desired compound was prepared according to the method of Example 1 A, except substituting succinate ester 3 for succintate ester 1, and substituting 41c for benzyltyrosine tosylate salt.
  • the desired compound was prepared according to the method of Examples 1 A-C, F and G, except substituting tyramine for benzyltyrosine tosylate salt, mp > 270 °C.
  • the desired compound was prepared according to the method of Example 40 A, except substituting 4-bromo-tert-butyl benzene for 4-bromothioanisole.
  • the desired compound is prepared by coupUng of 43a and 7, and deprotection using tettabutylammonium fluoride according to the method of Examples 32B and C.
  • the desired compound was prepared by ring closure according to the method of Example 8E, foUowed by saponification of the tert-butyl ester and conversion to the hydroxamate according to the method of Examples IF and G, except substituting 43c for lc. mp 220-221°C.
  • the desired compound was prepared as a white foam according to the method of Examples IE and F, except substituting piperidine for 4-(2-aminoethyl)benzenesulphonamide, substituting 32a for le and substituting methanol for DMF in Example IE.
  • the desired compound was prepared according to the method of Examples IE and F, except subsituting 38b for le, and substituting 2-aminothiazole for 4-(2- aminoethyDbenzenesulphonamide.
  • l H NMR 300 MHz, DMSO-d6) ⁇ -0.34-(-0.20) (m, IH), 0.60-0.74 (m, IH), 0.81-0.97 (m, 2H), 1.13-1.25 (m, 2H), 1.36-1.45 (m, 2H), 1.55-1.67 (m, 2H), 1.90-2.01 (m.
  • the desired compound was prepared as a white sohd according to the method of Examples IF and G, except substituting 48a for If. mp 242-244 °C (dec). l H NMR (DMSO-D6) ⁇ -0.118
  • the desired compound was prepared according to the method of Example 48, except substituting p-toluenesuifonyl chloride for methanesulfonyl chloride, mp: 235-237 °C (dec).
  • Example 50E The desired compound was prepared according to the method of Example IB, except substituting 50c for _lb.
  • Example 50E
  • the desired compound was prepared by following the procedures described in Examples 1A-C and IF starting with succinate ester 7 and ketone 14b.
  • the desired compound was prepared by according to the method of Example IG, except substituting acid 52_for la. *H NMR (300MHz, DMSO-d 6 ) ⁇ 10.1 (s, IH), 8.50 (s, IH), 7.92- 7.85 (m, 3H), 7.52-7.47 (m, IH), 7.39-7.34 (m, 2H), 7.27-7.24 (m, IH), 7.09-7.06 (m, IH), 6.82-6.74 (m, IH), 3.95-3.90 (m, IH), 3.00-2.92 (m, IH), 2.72-2.64 (m, IH), 1.88-1.80 (m, IH), 1.59-1.52 (m, 3H), 0.94-0.47 (bm, 5H), 0.46-0.23 (mm, 6H), (-)0.55-(-)0.57 (m, IH).
  • the desired compound was prepared according to the method of Example 40A except substituting 4-bromo- l,2-(methylenedioxy)benzene for 4-bromothioanisole.
  • the desired compound was prepared according to the method of Example 40A, except substituting 4-bromofluorobenze for 4-bromothioanisole.
  • the desired compound was prepared according to the method of example 40A except substituting
  • the desired compound was prepared according to the method of Example 40A, except substituting 4-benzyloxymethyl bromobenzene for 4-bromothioanisole.
  • the desired compound was prepared according to the methods of Examples IA, couphng succinate 5 with ketone 60 A, followed by deprotection of the silyl ether as in Example 32B and subsequent cyclization as in Example IC. MS (DCI/NH3) m/e 720 (M+H).
  • ester 60b (0.050 g, 7.0 x IO- 2 mmol) in 4: 1 CH3CN/H2O (5 mL) was treated with eerie ammonium nitrate (0.19 g, 3.5 x 10" 1 mmol) and stirred and 1.5 h. The solution was partitioned between ethyl acetate and water, the organic layer was dried (MgSO4) and concenttated to a soUd. The solid was purified on sUica gel with 25% ethyl acetate/hexane ramped to 60% to provide 0.01 g(26%) of 60c.
  • the desired compound was prepared according to the methods of Examples IF, except substituting 60c for If.
  • the desired compound was prepared according to the methods of Examples 1A-C, coupling succinate 1 with ketone 60A, followed by deprotection of the benzyl ether as in Example 60C.
  • the desired compound was prepared according to the methods of Examples IF-G, substituting ester 6Q_c for If.
  • Example 62B The desired compound was prepared according to the methods of Examples 1 A, coupUng succinate 9 with ketone 14b, followed by deprotection of the silyl ether as in Example 32B and subsequent cychzation as in Example IC.
  • Example 62B
  • Example IG The desired compound was prepared by according to the method of Example IG, except substituting Example 62 62 for fa.
  • the desired compound was prepared according to the method of Examples 62-63, except substituting 3,5-dimethoxy-bromobenzene for 3,4,5-ttimethoxy-bromobenzene in Example 62B.
  • Example 67c (1.67 g, 3.65 mmole) in THF (40 mL) at -78 °C was treated with phenyllithium (1.8 M in Et2 ⁇ and cyclohexane, 7.0 mL, 36.6 g, 1.08 mole). The mixture was warmed to -15 °C, stirred for 2 hours, and then quenched with saturated ammonium chloride. The mixture was partitioned between EtOAc and brine, the aqueous layer was separated and exttacted three times with EtOAc. The combined organic exttacts (100 mL) were dried (MgSO4), and concenttated to an oil.
  • the desired compound 67e was prepared according to the methods of Examples 1 A, coupling succinate 9 with ketone 67d.
  • Example 67e A mixture of Example 67e (0.46 g, 0.608 mmol), P(o-tol)3 (37.0 mg, 0.122 mmol),
  • the desired compound was prepared according to the previous methods. Deprotecion of the sUyl ether as in Example 32B and subsequent cyclization as in Example 17 A-B.
  • Example 67g (65.3 mg, 0.099 mole) hi CH2CI2 (4 mL) at 0 °C was treated with pyridine (0.032 mL, 0.39 mmol) followed by (0.018 mL, 0.24 mol), warmed to room temperature for 7 hours. The mixture was poured into CH2CI2 and washed with brine and saturated aqueous NaHCO3. The organic layer was dried (MgSO4) and concentrated to give 73 mg of 67h as an oU.

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Abstract

Cette invention concerne des composés macrocycliques qui correspondent à la formule (I). Ces composés consistent en de puissants inhibiteurs de métalloprotéinase matricielle, et peuvent être utilisés dans le traitement de maladies où la métalloprotéinase matricielle joue un rôle. Cette invention concerne également des compositions inhibant la métalloprotéinase matricielle, ainsi qu'un procédé d'inhibition de métalloprotéinase matricielle chez un mammifère.
PCT/US1998/000144 1997-01-07 1998-01-07 INHIBITEURS MACROCYCLIQUES DE METALLOPROTEINASES MATRICIELLES ET DE SECRETION DE FNT$g(a) WO1998030551A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002277121A CA2277121A1 (fr) 1997-01-07 1998-01-07 Inhibiteurs macrocycliques de metalloproteinases matricielles et de secretion de fnt.alpha.
AU58155/98A AU5815598A (en) 1997-01-07 1998-01-07 Macrocyclic inhibitors of matrix metalloproteinases and tnfalpha secretion
JP53103198A JP2001509151A (ja) 1997-01-07 1998-01-07 マトリックス金属プロテイナーゼおよびＴＮＦα分泌の大環状阻害剤
EP98901696A EP1021423A1 (fr) 1997-01-07 1998-01-07 INHIBITEURS MACROCYCLIQUES DE METALLOPROTEINASES MATRICIELLES ET DE SECRETION DE FNT$g(a)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US78206197A 1997-01-07 1997-01-07
US08/782,061 1997-01-07

Publications (1)

Publication Number Publication Date
WO1998030551A1 true WO1998030551A1 (fr) 1998-07-16

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Country Status (6)

Country Link
EP (1) EP1021423A1 (fr)
JP (1) JP2001509151A (fr)
AU (1) AU5815598A (fr)
CO (1) CO4920228A1 (fr)
WO (1) WO1998030551A1 (fr)
ZA (1) ZA9820B (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001022952A3 (fr) * 1999-09-25 2003-02-20 Smithkline Beecham Plc Utilisation medicale
US6838466B2 (en) 2001-12-20 2005-01-04 Schering Corporation Compounds for the treatment of inflammatory disorders
WO2020070239A1 (fr) 2018-10-04 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de l'egfr pour traiter les kératodermies

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060148839A1 (en) * 2003-02-11 2006-07-06 Boehringer Ingelheim International Gmbh New pharmaceutical compositions based on anticholinergics and tace-inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992013831A1 (fr) * 1991-02-07 1992-08-20 British Bio-Technology Limited Derives d'acide hydroxamique, procede pour leur preparation, et utilisation
WO1997018207A2 (fr) * 1995-11-14 1997-05-22 The Du Pont Merck Pharmaceutical Company Nouveaux composes macrocycliques tenant lieu d'inhibiteurs de la metalloprotease

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992013831A1 (fr) * 1991-02-07 1992-08-20 British Bio-Technology Limited Derives d'acide hydroxamique, procede pour leur preparation, et utilisation
WO1997018207A2 (fr) * 1995-11-14 1997-05-22 The Du Pont Merck Pharmaceutical Company Nouveaux composes macrocycliques tenant lieu d'inhibiteurs de la metalloprotease

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001022952A3 (fr) * 1999-09-25 2003-02-20 Smithkline Beecham Plc Utilisation medicale
US6838466B2 (en) 2001-12-20 2005-01-04 Schering Corporation Compounds for the treatment of inflammatory disorders
US7034057B2 (en) 2001-12-20 2006-04-25 Schering Corporation Compounds for the treatment of inflammatory disorders
US7598242B2 (en) 2001-12-20 2009-10-06 Schering Corporation Compounds for the treatment of inflammatory disorders
WO2020070239A1 (fr) 2018-10-04 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de l'egfr pour traiter les kératodermies

Also Published As

Publication number Publication date
EP1021423A1 (fr) 2000-07-26
AU5815598A (en) 1998-08-03
ZA9820B (en) 1998-07-02
JP2001509151A (ja) 2001-07-10
CO4920228A1 (es) 2000-05-29

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