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WO2000078725A1 - Synthese d'amidines substituees - Google Patents

Synthese d'amidines substituees Download PDF

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Publication number
WO2000078725A1
WO2000078725A1 PCT/US2000/011880 US0011880W WO0078725A1 WO 2000078725 A1 WO2000078725 A1 WO 2000078725A1 US 0011880 W US0011880 W US 0011880W WO 0078725 A1 WO0078725 A1 WO 0078725A1
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Prior art keywords
optionally substituted
alkyl
group
halo
hydrogen
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PCT/US2000/011880
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English (en)
Inventor
Daniele Choueiry
Daniel Lionel Giraud
Theo Schotten
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Eli Lilly And Company
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Priority to EP00941119A priority Critical patent/EP1204644A1/fr
Priority to AU55872/00A priority patent/AU5587200A/en
Publication of WO2000078725A1 publication Critical patent/WO2000078725A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/06—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/04—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures

Definitions

  • the present invention relates to a novel process for the preparation of substituted amidine compounds.
  • the process provided by this invention provides a method for making useful amidine compounds.
  • certain imidazoline-type compounds and analogues thereof can be useful in the treatment of diabetes, diabetic complications, metabolic disorders, or related diseases where impaired glucose disposal is present. These compounds can also be useful for the treatment of cardiovascular disease where above normal glucose levels are present or initial insulin resistance has occurred.
  • the compounds which can be prepared using the process of this invention can be used for a broad range of pharmaceutical indications as well as for other utilities such as in the area of photographic developers and pesticides.
  • the process of this invention can fulfil a long felt need for a more efficient and broadly applicable process to prepare amidines.
  • the present invention provides a process for preparing amidines starting from carboxylic acid derivatives, in which the carboxylic acid containing moiety is attached to a sp 3 -, or sp 2 - or sp 1 -hybridized carbon atom.
  • the sp 2 -hypridized carbon atom, to which the carboxylic acid containing moiety is attached to may be part of an aromatic or heteroaromatic or olefinic system.
  • the present invention provides a process for preparing a compound of Formula ⁇ ,
  • R is independently selected from the group consisting of hydrogen, optionally substituted C MS alkyl, optionally substituted C 3 . 10 cycloalkyl, optionally substituted
  • R is hydrogen or optionally substituted C ⁇ - 18 alkyl, optionally substituted C 3 - 10 cycloalkyl, optionally substituted C 3 - 10 cycloalkenyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;
  • X is selected from the group consisting of a bond and a linker element -X ⁇ X ⁇ X 3 -; and when X and Y are each -X'-X 2 -X 3 - and each of X 1 , X 2 , and X 3 are (CR 12 R 13 ) Z or
  • X and Y optionally together combine and along with the nitrogen and carbon to which they are each respectively attached optionally form a fused C 4 - 18 heterocyclic ring;
  • X 1 is attached to the amidine forming moiety and is independently selected from the group consisting of
  • X 2 andX 3 - are each independently selected from the group consisting of - (CR 12 R 13 ) Z >,
  • R u ,R 12 , andR 13 are each independently selected from the group consisting of hydrogen, optionally substituted C S alkyl, optionally substituted C 3 . 10 cycloalkyl, optionally substituted C 3 _ 10 cycloalkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl;
  • E is selected from the group consisting of a bond, an optionally substituted aromatic and a heteroaromatic ring;
  • n, n", n'" and n" are each independently 0, 1, 2, 3, or 4 provided that one selected from the group consisting of n, n", n'" and n"" is 1,2,3, or 4 and further provided that the sum of n, n", n '"and n"" is less than seven, if E represents a bond; or n, n", n'" and n"" are each independently 0, 1, 2, 3, or 4, provided that the sum of n, n", n'"and n"" is greater than 1 and less than five, if E represents an optionally substituted aromatic or optionally substituted heteroaromatic ring;
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of hydrogen, optionally substituted C MO alkyl, optionally substituted C 2 - ! o alkenyl, optionally substituted C ⁇ -io aryl, optionally substituted C 3 - 10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted bicyclic; or
  • R , R , R 6 , and R 8 together with the carbon atoms to which they are attached combine to form an optionally substituted 3 to 7 membered carbocyclic or form a bridging ring if the two selected from R 2 , R 4 , R 6 , and R 8 were not substituents on adjacent carbon atoms, and each of the remaining R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are hydrogen or one of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 combines with another of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 which is a substituent on an adjacent carbon atom, to optionally form a bond; or
  • R 2 and R 3 , R 4 and R 5 , R 6 and R 7 , and R 8 and R 9 substituents which are attached to the same carbon atom are selected from the group consisting of R 2 and R 3 , R 4 and R 5 , R 6 and R 7 , and R 8 and R 9 , together with the carbon atom to which they are both attached combine to form a spirocarbocyclic ring, and each of the remaining R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are hydrogen or one of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 combines with another of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 which is a substituent on an adjacent carbon atom, to optionally form a bond;
  • R 10 is hydrogen or an amino protecting group; provided that when Formula ⁇ is a group of the formula: ,wherein R 19 , R 20 , R 21 , and R 22 are each independently selected from the group consisting of hydrogen and -s alkyl; or;
  • Rl9 and R21 optionally together form a bond and R20 and R22 are each independently hydrogen or C ⁇ .g alkyl; or
  • Rl9 and R 1 optionally combine together with the carbon atoms to which they are attached form a C3-.7 carbocyclic ring and R20 and R22 are each independently hydrogen or C _g alkyl; or
  • Rl9 and R20 together with the carbon atom to which they are attached optionally combine to form a C3-.7 spirocarbocyclic ring and R21 and R 2 are independently hydrogen or C ⁇ .g alkyl; or
  • R21 and R22 together with the carbon atom to which they are attached optionally combine to form a C3.7 spirocarbocyclic and Rl9 and R20 are independently hydrogen or Q.
  • R6* and R ⁇ * are independently hydrogen, Cj.g alkyl, 03.7 cycloalkyl, C j .g alkoxy, Cj.g alkylthio, halo C ⁇ .g alkylthio, Cj.g alkylsulfinyl, C ⁇ .g alkylsulfonyl, C3.7 cycloalkoxy, aryl-C ⁇ _g alkoxy, halo, halo-Cj.g alkyl, halo- C ⁇ .g alkoxy, nitro,
  • R 8 * is hydrogen, Cj.g alkyl, halo-Cj.g alkyl, optionally substituted phenyl, optionally substituted heterocyclyl, COO Cj.g alkyl, optionally substituted COaryl, COC ⁇ .g alkyl, SO2Cj-. alkyl, optionally substituted SO aryl, optionally substituted phenyl-Cj.g alkyl, CH 3 (CH2)p-O-(CH 2 ) q -O-;
  • R9 is hydrogen, halo, Cj.g alkyl, halo Cj.g alkyl, Cj.g alkylthio, halo C _ g alkylthio, C3.7 cycloalkylthio, optionally substituted arylthio or heteroarylthio, C _ g alkoxy, C3.7 cycloalkoxy, optionally substituted aryloxy , optionally substituted heteroaryloxy, or optionally substituted aryl or heteroaryl, C3.7 cycloalkyl, halo C3-.7 cycloalkyl, C3.7 cycloalkenyl, cyano, COOR 10 *, CONR 10 *RU* or NR 10 *RU*, C2-.6 alkenyl, optionally substituted heterocyclyl, optionally substituted aryl C ⁇ .
  • alkyl optionally substituted heteroaryl C ⁇ .g alkyl in which the alkyl group can be substituted by hydroxy, or Cj.g alkyl substituted by hydroxy
  • RIO and R ⁇ * are independently hydrogen, C ⁇ .g alkyl, optionally substituted aryl C ⁇ . alkyl, optionally substituted phenyl, or R ⁇ and RU* together with the nitrogen atom to which they are attached may combine to form a ring with up to six carbon atoms which optionally may be substituted with up to two Cj.g alkyl groups or one carbon atom may be replaced by oxygen or sulfur;
  • Rl4 and RI" are independently hydrogen, halo, Cj.g alkyl, C3-.7 cycloalkyl, C3-.7 cycloalkoxy, C3-.7 cycloalkylC ⁇ .g alkoxy, halo-C ⁇ .g alkyl, halo-C ⁇ _g alkoxy, Cj. alkoxy, carbo(C 1 _s)alkoxy, optionally substituted aryl, or optionally substituted heteroaryl;
  • Rl5 and R ⁇ are independently hydrogen, halo, Cj.g alkoxy, C3-.7- cycloalkyl, C3.7 cycloalkylCj.g alkoxy, C ⁇ .g alkyl, C3-.7 cycloalkoxy, hydroxy, halo
  • C MO alkyl can be an alkyl group which is branched or unbranched, containing up to 10 carbon atoms.
  • C 1-n" alkyl is a branched or unbranched alkyl containing up to n" carbon atoms whereing n" is an integer. Examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl.
  • Preferred values of C ⁇ _ ⁇ o alkyl are C _ alkyl.
  • the C ⁇ _ ⁇ o alkyl group may preferably be methyl or ethyl.
  • alkyl group may optionally be substituted at any available carbon atom with from one to three substituents selected from the group consisting of OH, -NH 2 , C 2-4 alkenyl, cyano, - NO 2 , halo, halo Ci _g alkyl, and -CONH 2 .
  • C ⁇ .g alkylthio has the meaning known to the artisan. That is that one of the carbon atoms is replaced with a sulfur atom.
  • C 2 . n* alkenyl wherein n* can be from 3 through 18, as used herein, represents an olefinically unsaturated branched or linear group having from 2 to the specified number of carbon atoms and at least one double bond.
  • n* alkenyl means that the alkenyl substituent may optionally be substituted at any available carbon atom with from one to three substituents selected from the group consisting of OH, -NH 2 , C 2 . 4 alkenyl, cyano, -NO 2 , halo, halo Cj_g alkyl, and -CONH 2 .
  • C 3 - n** cycloalkenyl wherein n** is 3 to 10, is an olefinically unsaturated ring having from three to 10 carbon atoms.
  • groups include, but are not limited to, cyclohexa-l,3-dienyl, cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, cyclohexa-l,4-dienyl, cyclohepta-l,4-dienyl, cycloocta-l,3,5-trienyl and the like.
  • cycloalkenyl means that the alkenyl substituent may optionally be substituted at any available carbon atom with from one to three substituents each independently selected from the group consisting of OH, - NH 2 , C 2 - alkenyl, cyano, -NO 2 , halo, halo C g alkyl, and -CONH 2 .
  • base when referring to a process reactant, has the meaning known to the skilled artisan.
  • the term means both soluble and insoluble base.
  • the soluble or insoluble base may be, for example but not limited to, triethyl amine or dimethylaminomethyl polystyrene.
  • a “C3-.7 cycloalkyl” group is a cycyloalkyl group including but not limited to cyclopropyl, cyclobutyl, cycloheptyl, cyclohexyl or cyclopentyl.
  • a “C ⁇ _g alkoxy” group is one of the above-mentioned Cj.g alkyl groups attached through oxygen to the base molecule, and preferred examples are methoxy and ethoxy.
  • a "C3..7 cycloalkoxy” group is a C3.7 cycloalkyl group as mentioned above linked through an oxygen atom to the cycloalkyl as, for example, cyclopropyloxy, cyclopentyloxy and cyclohexyloxy.
  • a "C3.7 cycloalkylCi.g alkoxy” group is a C3.7 cycoalkyl-Cj.g alkyl as mentioned above linked through an oxygen atom to the base molecule as, for example, cyclohexylmethoxy.
  • a "carbo(C 1 -s)alkoxy” group is a 1"8 group, for example a carbomethoxy or carboethoxy group.
  • aryl is a mononuclear or polynuclear aromatic hydrocarbon group, for example phenyl, aryl-C ⁇ .g alkoxy, aryl- -s alkyl-
  • An "optionally substituted phenyl” group is a phenyl which is optionally substituted with from one to three substituents each independently selected from the group consisting of C ⁇ . alkyl, C ⁇ .g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, amino, and phenyl which is optionally substituted by from one to three substituents each independently selected from the group consisting of Cj.g alkyl, C ⁇ .g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, and amino.
  • An "optionally substituted naphthyl” group is a naphthyl which is optionally substituted with from one to three substituents each independently selected from, the group consisting of C ⁇ .g alkyl, Cj. alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, amino, and phenyl which is optionally substituted by from one to three each independently selected from the group consisting of C ⁇ .g alkyl, C ⁇ _g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, and amino.
  • An “optionally substituted COaryl” group is an optionally substituted aryl
  • a “optionally substituted aryl-Cj-s alkyl-S(O) m " " group is an optionally substituted aryl which is bound to the base molecule through an alkyl-S(O) m " group, wherein the S- bonds to the base molecule and m" is 0, 1 or 2.
  • the optionally substituted aryl group is as defined herein above.
  • An “optionally substituted bicyclic” means a 5 to 10 membered fused bicyclic ring, which ring may be saturated or partially unsaturated to include from 0 to 4 double bonds in the bicyclic ring.
  • the bicyclic ring is optionally substituted with from 0 to three substituents selected from the group consisting of of Cj.g alkyl, Cj.g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4- methylenedioxy, and amino.
  • optionally substituted aromatic means a mono- or bicyclic 5 to 10- membered aromatic ring which is attached to the cyclic amidine forming atoms, by the two adjacent carbon atoms of the optionally substituted aromatic ring.
  • the resulting group is a group of the general formula:
  • the optionally substituted aromatic or heteroaromatic ring is optionally substituted with from 0 to 3 each independently selected from the group consisting of C j i .g alkyl, Cj.g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, and amino.
  • optionally substituted heteroaromatic means a mono- or bicyclic 5 to 10-membered aromatic ring in which from one to three carbon atoms of the aromatic ring, defined above, are replaced with an atom each independently selected from group consisting of N, O, and S, and which heteroaromatic ring is attached to the cyclic amidine forming atoms, by the two adjacent carbon atoms of the optionally substituted heteroaromatic ring.
  • Such group is as illustrated above for optionally substituted aromatic; however, the aromatic ring contains up to three heteroatoms as described herein.
  • the optionally substituted heteroaromatic ring is optionally substituted with from 0 to 3 each independently selected from the group consisting of C ⁇ .g alkyl, C ⁇ . alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4- methylenedioxy, and amino.
  • Heteroaryl means a four to a ten membered aromatic mononuclear or binuclear ring system in which from one to three atoms of the ring system are each independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • heteroaryl groups include, but are not limited to, indolyl, imidazolyl, furanyl, thienyl, isoquinolinyl, benzofuranyl, benzothienyl, pyridyl, quinolinyl, oxazolyl, pyrrolyl, isoxazolyl, pyrimidyl, thiazolyl, and benzimidazolyl.
  • An “optionally substituted heteroaryl” group is a heteroaryl group which is optionally substituted with from one to three substituents each independently selected from the group consisting of Cj_g alkyl, C ⁇ .g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, amino, and phenyl which is optionally substituted by from one to three substituents each independently selected from the group consisting of C ⁇ . alkyl, Cj.g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, and amino.
  • Optionally substituted heterocyclyl means a four to 10 membered mononuclear or binuclear saturated or partially unsaturated ring system in which from one to three atoms of the ring system are each independently selected from the group consisting of nitrogen, oxygen, and sulfur, and which ring system is optionally substituted with from one to three substituents each independently selected from the group consisting of Cj.
  • alkyl C ⁇ .g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, amino, and phenyl which is optionally substituted by from one to three substituents each independently selected from the group consisting of C _g alkyl, C ⁇ .g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, and amino.
  • heterocyclyl groups include, but are not limited to, piperidinyl, piperazinyl, imidazolidinyl, tetrahydrofuranyl, morpholinyl, homopiperidinyl, tetrahydroquinolinyl, dioxanyl, and tetrahydropyranyl.
  • aryl-C ⁇ .g alkyl can be, for example, optionally substituted phenyl-
  • Cj.g alkyl or optionally substituted naphthyl-C ⁇ .g alkyl such optionally substituted phenyl or naphthyl groups being optionally substituted with one or more, preferably one to three, substituents selected from, Cj.g alkyl, Cj.g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro and amino.
  • a preferred aryl-Cj-.g alkyl group is optionally substituted phenyl-(CH2) - where x is 1 or 2, most preferably optionally substituted benzyl.
  • the alkyl group serves as the link between the phenyl or naphtyl and the base molecule.
  • An "optionally substituted phenyloxy” is a group wherein the phenyl group is attached to the base molecule through an oxygen, and such phenyl group is optionally substituted with one or more, preferably one to three, substituents selected from, C ⁇ _ alkyl, C ⁇ -. alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro and amino.
  • An "optionally substituted phenyl -s alkoxy” is a group wherein the phenyl group is attached to the base molecule through an alkoxy group, and such phenyl group is optionally substituted with one or more, preferably one to three, substituents selected from, C ⁇ .g alkyl, C ⁇ _g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro and amino.
  • An "aryl-Cj.g alkoxy” group can be, for example, optionally substituted phenyl-Ci _g alkoxy or optionally substituted naphthyl-C ⁇ .g alkoxy, such optionally substituted groups being optionally substituted with one or more, preferably one to three, substituents selected from, for example, C ⁇ _g alkyl, Cj. alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro and amino.
  • a preferred aryl-C j .g alkyl group is optionally substituted phenyl-(CH2) x - where x " is 1 or 2.
  • the aryl is linked to the base molecule through the alkoxy group.
  • a halo group is fluoro, chloro, bromo or iodo, preferably fluoro, chloro, or bromo.
  • halo Ci _g alkyl or "halo C g alkoxy” or "halo Ci _g alkylthio” is a substituent in which one or more, preferably one to three, hydrogen atoms on the C j .g alkyl moiety is replaced by a halo atom, preferably chloro, bromo or fluoro. Trifluoromethyl is one preferred haloalkyl group.
  • alkoxyalkoxy is of the formula CH3(CH2)p-O-(CH2)q-O-, where p is 0-4 and q is 1-5, preferred examples being those in which p is 0 or 1 and q is 1-3, especially methoxyethoxy, ethoxyethoxy, ethoxypropoxy, or methoxypropoxy.
  • a "C ⁇ _g acylamino" substituent is preferably of the formula RCONH- where
  • RCO is any appropriate acid residue, RCO containing from 1-8 carbon atoms.
  • R include Ci _g alkyl, in particular methyl or ethyl, acetyl being the most preferred acyl group.
  • R can also be aryl Ci _g alkyl, especially benzyl, or R can be halo- Cj_g alkyl, especially trifluoromethyl.
  • a "haloCi.g acylamino" substituent is an acylamino group substituted with from one to three halo. It is preferable that acylamino is substituted with one halo.
  • spirocarbocyclic means a ring which is fused to the base molecule through one shared tetravalent carbon atom to form two rings which are annelated by a single carbon atom.
  • Ci _g alkylsulfinyl has the meaning known to the artisan. That is ⁇ s ⁇ alkyl
  • halo C ⁇ _g alkylsulfinyl means that one of the alkyl groups is substituted with a halo. It is most preferred that the halo group is F or CI.
  • Ci _g alkylsulfonyl has the meaning known to the artisan. That is
  • halo Cj.g alkylsulfonyl means that one of the alkyl groups is substituted with a halo. It is preferred that the haloalkylsuflonyl group is CF SO -.
  • sulfoximino has the meaning known to the artisan. That is, a
  • acyl moiety, alone or in combination, is derived from an alkanoic acid containing from one to eight carbon atoms.
  • acyl also includes moieties derived from an aryl carboxylic acid.
  • base molecule means the moiety to which the named substituent is bound.
  • amino protecting group means any of the conventional amino protecting groups, see, for instance, T. W. Greene, Protective Groups in Organic Synthesis, chapter 7, John Wiley and Sons, New York, 1981, and by J. W. Barton, Protective Groups in Organic Chemistry, chapter 2, J. F. W. McOmie, ed., Plenum Press, New York, 1973.
  • Such groups include but are not intended to be limited to benzyl and substituted benzyl such as 3,4-dimethoxybenzyl, o-nitrobenzyl, and triphenylmethyl; those of the formula -COOR where R includes such groups as methyl, ethyl, propyl, isopropyl, 2,2,2-trichloroethyl, 1 -methyl- 1-phenylethyl, isobutyl, t-butyl, t-amyl, vinyl, allyl, phenyl, benzyl, rj-nitrobenzyl, o-nitrobenzyl, and 2,4-dichlorobenzyl; acyl groups and substituted acyl such as formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, benzoyl, and p_-methoxybenzoyl; and other groups such as me
  • Preferred nitrogen protecting groups are benzyl, acyl, like benzyloxycarbonyl or t-butyloxycarbonyl, or silyl or acetyl phenyloxycarbonyl. It is most preferred that the amino protecting group is a silyl.
  • silyl amino protecting group means an amino protecting group, known to the artisan, which contains a silyl functionality.
  • the term includes, but is not limited to, trimethylsilyl;
  • protected amino means that the amino group is substituted with an amino protecting group, as defined herein.
  • protected hydroxy means that the hydroxyl group is substituted with any of the conventional hydroxyl protecting groups, see, for instance, T. W. Greene, Protective Groups in Organic Synthesis, chapter 2, John Wiley and Sons, New York, 1981, and by J. W. Barton, Protective Groups in Organic Chemistry, J. F. W. McOmie, ed., Plenum Press, New York, 1973.
  • Such groups include but are not intended to be limited to acetals, ethers such as silyl ethers and the like; esters such as formate, benzoylformate, acetate, phenoxyacetate and the like; carbonates such as methyl carbonate, ethyl carbonate, isobutylcarbonate, benzyl, nitrobenzyl, and the like; and others such as nitrate, borate, phenylcarbamate, tetrahydropyranyl (THP), trityloxy and the like.
  • THP tetrahydropyranyl
  • protected SH means that the thiol group is substituted with any of the conventional thiol protecting groups, see, for instance, T. W. Greene, Protective Groups in Organic Synthesis, chapter 6, John Wiley and Sons, New York, 1981, and by J. W. Barton, Protective Groups in Organic Chemistry. J. F. W. McOmie, ed., Plenum Press, New York, 1973.
  • Examples of such groups include but are not intended to be limited to thioethers like benzylthioether, 4- methylbenzylthioether, p-nitrobenzylthioether, diphenylmethylthioether, substituted methyl derivatives such as methoxymethyl (MOM), isobutoxymethyl, 2- tetrahydropyranyl, thioesters like, acetyl, benzoyl, thiocarbonates like t- butoxycarbonyl, and the like.
  • thioethers like benzylthioether, 4- methylbenzylthioether, p-nitrobenzylthioether, diphenylmethylthioether, substituted methyl derivatives such as methoxymethyl (MOM), isobutoxymethyl, 2- tetrahydropyranyl, thioesters like, acetyl, benzoyl, thiocarbonates like t- butoxycarbonyl, and the like.
  • the two-stage process herein described, is very general, employs very mild reaction conditions, is compatible with a very broad range of functionalities, delivers comparably high yields and pure products, thus providing significant advantages over the methods known to the artisan.
  • the process described herein is compatible to many functionalities present in an organic molecule.
  • the process is appropriate for unprotected hydroxy, unprotected primary or secondary amino, olefinic double bond, cyano, nitro, aromatic halogeno, carboxamido, formyl and carbonyland can be successfully applied, when conventional methods have failed (Chem. Pharm. Bull. 1980, 25, 1394-1402).
  • the process is highly suitable for the synthesis of combinatorial cyclic amidine libraries utilizing all kinds of polymerbound esters.
  • This process may also be suitable for the synthesis of substituted imidazolines, e.g. 4-alkyl-, 4,4'-dialkyl-, 4,5 dialkyl-, 4,4'spirocycloalkyl-, 4,5-cycloalkylsubsituted 2-imidazolines or 1 ,2-substituted imidazolines.
  • substituted imidazolines e.g. 4-alkyl-, 4,4'-dialkyl-, 4,5 dialkyl-, 4,4'spirocycloalkyl-, 4,5-cycloalkylsubsituted 2-imidazolines or 1 ,2-substituted imidazolines.
  • substituted imidazolines e.g. 4-alkyl-, 4,4'-dialkyl-, 4,5 dialkyl-, 4,4'spirocycloalkyl-, 4,5-cycloalkylsubsituted 2-imidazolines or 1 ,2-substituted imidazolines.
  • This process may also be suitable for the synthesis of substituted imidazoles annelated to an optionally substituted aromatic or heteroaromatic ring system, e.g. benzimidazoles, imidazo-[4,5-b]-pyridines, imidazo-[4,5-c]-pyridines, or purines
  • This process may also be suitable for the synthesis of substituted or unsubstituted tetrahydropyrimi dines, optionally annelated to an optionally substituted aromatic or heteroaromatic ring system.
  • This process may also be suitable for the synthesis of substituted or unsubstituted hexahydro-l,3-diazepines, optionally annelated to an optionally substituted aromatic or heteroaromatic ring system.
  • the following scheme illustrates different ring systems,but is by no way limited to these:
  • each independently represents N or C-R', provided that not more than two nitrogens are present in the annelated ring and t is 2,3, or 4 depending on the number of carbon atoms in the annelated ring accessible for substitution by R'.
  • R' represents a substituent each independently selected from the group consisting of C ⁇ _ alkyl, Cj.g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro,
  • the process may, in some instances, be improved or accelerated by the addition of Lewis-acids, (e.g. trimethylsilyl trifluoromethane sulfonate, rare earth trifluoromethane sulfonates, A1C1 3 , BC1 3 , SnCl 4 , TiCl 4 , ZnCl 2 ), metals(e.g. Cu, rare earth metals) or metal salts (e.g. Cul, or rare earth metal salts) catalysis, e.g. rare earth metals and their salts to the reaction mixture.
  • Lewis acid catalysis e.g. Sc(HI) trifluoromethane sulfonate
  • the carboxylic acid moiety is esterified by a lower alkanol (e.g. methanol, ethanol) or with alcohols, which may also be residues of polymers.
  • the residues of polymers are those known in to the artisan.
  • the residues of polymers are for example, polystyrene based resins, like Merrifield-, Wang- , Tentagel-resins and the like, or polyethylene glycol or monoethers of polyethylene glycol.
  • the esterified carboxylic acid moiety is contacted with about an equimolar amount or an excess of diamine. If an excess of diamine is used, the excess may be up to about 100 fold molar excess. It is preferable that the diamine excess is about 2 to about twenty fold molar excess.
  • the product of this process is an carboxamide of Formula I or a carboxamide of Formula I.
  • This stage of the process includes the use of solvents or mixtures of solvents, like water, alcohols, ethers, halogenated hydrocarbons, dimethyl formamide, dimethyl sulphoxide, hexamethyl phosphoric acid triamide, dimethyl propylene urea, dimethyl ethylene urea, acetonitrile, aliphatic, cycloaliphatic or aromatic hydrocarbons, and the like.
  • ethers means for example, but not limited to ethers such as t-butyl methyl ether, tetrahydrofuran, dioxane, and the like.
  • halogenated hydrocarbons means, for example, but not limited to, chloroform, dichloromethane, trichloroethene and the like.
  • aromatic hydrocarbons means, for example, but not limited to benzene, toluene, xylene and the like.
  • aliphatic hydrocarbons means, for example, but not limited to pentane, hexane, iso-hexane, octane, petroleum ether and the like.
  • cycloaliphatic hydrocarbons means, for example, but not limited to cyclopentane, cyclohexane, decaline and the like.
  • the process may be advantageously run in diamine/water mixtures, containing up to about 100 equivalents of water, which is calculated in respect to the starting ester. It is preferable that the diamine/water mixture contains about 10 equivalents of water. It is especially preferred that the diamine/water mixture contains from about 1 to 1.5 equivalents of water.
  • the process may be advantageously run also without any solvents in neat diamine.
  • reaction temperature may range from about -10°C to about 250°C or at the reflux temperature of the reaction mixture.
  • a preferable reaction temperature is from about ambient temperature to about 120°C.
  • An especially preferred reaction temperature is from about 50 to about 70°C.
  • An advantage of using neat diamine reaction conditions for the claimed process is that no practical amount of dimerisation product is detectable.
  • amino alkyl carboxamides are also accessible by other methods known in the art.
  • amino alkyl carboxamides can be prepared using the reaction of an activated carboxylic acid derivative, like an acid chloride or an activated imidazolide with an appropriate diamine.
  • an activated carboxylic acid derivative like an acid chloride or an activated imidazolide
  • a disadvantage of these reaction conditions using an activated carboxylic acid derivative, an acid chloride or an activated imidazolide is the potential for extended dimerisation even at low temperatures (J. Org. Chem. 1987,52,2592- 2594). In these cases monoprotection of the diamine prior to aminolysis of the activated carboxylic acid derivative may be advantageous.
  • the product of this process is an aminoalkyl carboxamide of Formula I or a carboxamide of Formula I' in which R 10 is an amino protecting group.
  • Deprotection of the amino group prior to the cyclisation step producing an amidine of Formula II or of Formula II' may be not required, if the so said amino protecting group is a silyl amino protecting group, e.g. trimethyl silyl.
  • the amino alkyl carboxamides thus obtained and serve as the starting materials for the process claimed herein.
  • the carboxamides are cyclized, with or without purification. Cyclisation is induced by a silylating agent or a mixture of silylating agents, optionally in the presence of an soluble or insoluble organic or inorganic base.
  • the soluble or insoluble base may be, for example but not limited to, triethyl amine,pyridine, collidine,lutidine, DBN, DBU or basic polymer resins like dimethylaminomethyl polystyrene or piperidinylmethyl polystyrene or the like and a solvent.
  • Useful silylating reagents are available to the artisan as described in FLUKA Chemika "Silylating Agents" (1995) ISBN 3-905617-08-0 and the literature cited therein.
  • the silylating agents which are especially preferred are trimethyl silyl halogenides, TMS-X (wherein TMS-X means trimethyl silyl chloride, trimethyl silyl bromide or trimethyl silyl iodide) or hexamethyl disilazane, HMDS or trimethyl silyl diethylamine, TMS-DEA or N,O -bis trimethylsilyl acetamide, or N,O -bis trimethylsilyl trifluoroacetamide, or trimethylsilyl imidazole or mixtures of them.
  • TMS-X trimethyl silyl chloride, trimethyl silyl bromide or trimethyl silyl iodide
  • HMDS trimethyl silyl diethylamine
  • TMS-DEA N,O -bis trimethylsilyl acetamide
  • N,O -bis trimethylsilyl trifluoroacetamide or trimethylsilyl imidazole or mixtures of them.
  • Suitable silylating reagents may advantageously generated in situ, for example but not limited to, by contacting TMS-C1 with an inorganic iodide or bromide salt or an organic compound like imidazole.
  • the silylation reaction is carried out either in neat HMDS or a mixtures of HMDS and other silylating agents as cited above.
  • especially preferred HMDS mixtures include but are not limited to, HMDS/TMS-Cl 99/1 or HMDS/TMS-Cl 98/2. It is especially preferred that the HMDS is used without additional base and solvent.
  • a preferred reaction temperature for HMDS is about 50°C to reflux of the mixture. It is especially preferred that the temperature is 70°C to 90°C.
  • the silylation is done in methylene chloride with excess TMS-C1 or TMS-I. It is especially preferred that the silylation is done in TMS-I in presence of triethyl amine or dimethylaminomethyl polystyrene. When the silylation is done in TMS-I in the in presence of triethyl amine or dimethylaminomethyl polystyrene the reaction is most preferably run at about ambient temperature.
  • TMS-I can be obtained commercially or may be generated in situ. It is particularly preferred that the TMS-I is generated in situ by addition of sodium iodide to TMS-CL
  • TMS-X is used as the cyclizing reagent
  • an excess of TMS-X reagent has to be added in several portions within a period of time to ensure complete conversion.
  • the period of time for making such additions of TMS-X may be up to about 2 weeks. It is most preferred that the reaction time is less than one day.
  • TMS-X silylating agent
  • TMS-I silylating agent
  • Y 1 represents halogen, N-imidazole
  • the R 1 ⁇ substituent is selected from the group consisting of CH 3 , CH 2 CH 3 , and an alcoholic hydroxy groups containing polymer resin.
  • HMDS HMDS
  • the silylating agent is TMS-I
  • iii) the silylating agent is TMS-I and is generated in situ
  • R 10 is hydrogen
  • the product of the claimed process is a compound of Formula II
  • R is selected from the group consisting of optionally substituted C S alkyl, optionally substituted C 3 . 10 cycloalkyl, optionally substituted C 3 .
  • n, n", n'" and n"" are each 1; viii) n and n'" are each 1; ix) n and n" are each 0, n'" is 1; x) n and n" are each 0, n'" and n"" are each 1, R 2 , R 3 , R 8 , R 9 are each hydrogen O ⁇ C HO alkyl; xi) R 1 is hydrogen; xii) n is 0, n", n'", and n"" are each 1; R 2 and R 6 along with the carbon to which they are bound combine to form an aromatic benzofused ring, R 8 and
  • R 9 are each hydrogen
  • some of the compounds of Formula II include the pharmaceutically acceptable base addition salts thereof.
  • Such salts may be prepared following the amidine formation process described herein.
  • Such salts include those derived from inorganic bases such as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, as well as salts derived from basic organic amines such as aliphatic and aromatic amines, aliphatic diamines, hydroxy alkamines, and the like.
  • Such bases useful in preparing the salts of this invention thus include ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, methylamine, diethylamine, ethylenediamine, cyclohexylamine, ethanolamine and the like.
  • the compounds of Formula II can also exist as pharmaceutically acceptable acid addition salts.
  • the salt may optionally be prepared following the amidine formation process described herein.
  • Acids commonly employed to form such salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para- bromophenylsulfonic, carbonic, succinic, citric, benzoic, acetic acid, and related inorganic and organic acids.
  • Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, mono-hydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, heptanoate, propiolate, oxalate, malonate, succmate, suberate, sebacate, fumarate, maleate, 2-butyne-l,4 dioate, 3- hexyne-2, 5-d ⁇ oate, benzoate, chlorobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hippurate, ⁇ -hydroxybutyrate, glyco
  • desired isome ⁇ c forms may be obtained using separation methods which are generally known.
  • ⁇ -amino alkyl amide was dissolved in neat hexamethylene disilazane (HMDS) containing 2% of trimethyl chlorosilane (TMS-C1) (approx. 1,5ml of silylating agent/1 mMol of amide).
  • TMS-C1 trimethyl chlorosilane
  • the mixture was stirred at 100 °C, until TLC check (methylene chloride/ethanolic ammonia 9:1) showed nearly complete conversion (16 to 48 h). After cooling the mixture was diluted with ethanol and evaporated. The residue was dissolved in methylene chloride, coated on silica gel, and purified via flash chromatography on silica gel using a methylene chloride/ethanolic ammonia gradient 99:1 to 80:20. Yields and physical data as indicated in table 1 :
  • ⁇ -amino alkyl amide (1 mMol) was dissolved in 20 ml of dry methylene and lg (3 mequiv.) of dimethylaminomethyl polystyrene together with 3 mMol of trimethyl iodo silane (TMS-I) were added. The mixture was stirred at ambient temperature, until TLC check (methylene chloride/ethanolic ammonia 9:1) showed nearly complete conversion (2 to 18 d). If conversion was incomplete after 3 d the same amount of basic resin and TMS-I was added. The slurry was filtered off, the remaining resin was thoroughly rinsed with methylene chloride and ethanol, and the collected filtrates were evaporated.
  • TMS-I trimethyl iodo silane
  • Step A 2-Aminoethyl 3-(4-Methylphenyl)-5,6,7,8-tetrahydronaphthalene-
  • Step A 2-Aminoethyl 3-(4-Methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-
  • Step A 2-Aminoethyl 3-(2-(Morpholin-4-yl)ethoxy)-5,6,7,8- tetrahydronaphthalene-2-carboxamide

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Abstract

La présente invention concerne un procédé de préparation d'amidines à partir de dérivés d'acide carboxylique, dans lequel la fraction contenant l'acide carboxylique est liée à un atome de carbone hybridé à sp?3, sp2 ou sp1¿. L'atome de carbone hybridé à sp2 auquel est liée la fraction contenant l'acide carboxylique peut faire partie d'un système aromatique, hétéroaromatique ou oléfinique.
PCT/US2000/011880 1999-06-18 2000-06-19 Synthese d'amidines substituees WO2000078725A1 (fr)

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WO2003051360A1 (fr) * 2001-12-18 2003-06-26 F. Hoffmann-La Roche Ag Cis-imidazolines inhibiteurs de mdm2
US7132421B2 (en) 2003-06-17 2006-11-07 Hoffmann-La Roche Inc. CIS-imidazoles
US7425638B2 (en) 2003-06-17 2008-09-16 Hoffmann-La Roche Inc. Cis-imidazolines
CN100562316C (zh) * 2003-06-17 2009-11-25 霍夫曼-拉罗奇有限公司 作为mdm2抑制剂的顺式咪唑啉
US7625895B2 (en) 2007-04-12 2009-12-01 Hoffmann-Le Roche Inc. Diphenyl-dihydro-imidazopyridinones
EP2130822A1 (fr) 2005-12-01 2009-12-09 F. Hoffmann-La Roche AG Dérivés de 2,4,5-triphényl imidazoline en tant qu'inhibiteurs de l'interaction entre les proteines p53 et mdm2, utilisés en tant qu'agents anticancereux
US7705007B2 (en) 2006-01-18 2010-04-27 Hoffmann-La Roche Inc. Cis-imidazolines
US7893278B2 (en) 2004-06-17 2011-02-22 Hoffman-La Roche Inc. CIS-imidazolines
EP2325180A1 (fr) 2007-10-09 2011-05-25 F. Hoffmann-La Roche AG CIS-imidazolines chiraux
US7964724B2 (en) 2004-05-18 2011-06-21 Hoffmann-La Roche Inc. Chiral cis-imidazolines
WO2022139593A1 (fr) 2020-12-23 2022-06-30 Klingelberg Products As Amidines et procédé pour les fabriquer sans faire appel à des solvants

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Cited By (17)

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Publication number Priority date Publication date Assignee Title
US6617346B1 (en) 2001-12-18 2003-09-09 Hoffmann-La Roche Inc. Cis-imidazolines
RU2312101C2 (ru) * 2001-12-18 2007-12-10 Ф.Хоффманн-Ля Рош Аг Цис-имидазолины в качестве ингибиторов mdm2
WO2003051360A1 (fr) * 2001-12-18 2003-06-26 F. Hoffmann-La Roche Ag Cis-imidazolines inhibiteurs de mdm2
US7132421B2 (en) 2003-06-17 2006-11-07 Hoffmann-La Roche Inc. CIS-imidazoles
US7425638B2 (en) 2003-06-17 2008-09-16 Hoffmann-La Roche Inc. Cis-imidazolines
CN100562316C (zh) * 2003-06-17 2009-11-25 霍夫曼-拉罗奇有限公司 作为mdm2抑制剂的顺式咪唑啉
US7964724B2 (en) 2004-05-18 2011-06-21 Hoffmann-La Roche Inc. Chiral cis-imidazolines
US7893278B2 (en) 2004-06-17 2011-02-22 Hoffman-La Roche Inc. CIS-imidazolines
EP2311814A1 (fr) 2005-12-01 2011-04-20 F. Hoffmann-La Roche AG Dérivés de 2,4,5-triphenyl imidazoline en tant qu'inhibiteurs de l'interaction entre les protéines P53 et MDM2, utilises en tant qu'agents anticancereux
EP2130822A1 (fr) 2005-12-01 2009-12-09 F. Hoffmann-La Roche AG Dérivés de 2,4,5-triphényl imidazoline en tant qu'inhibiteurs de l'interaction entre les proteines p53 et mdm2, utilisés en tant qu'agents anticancereux
US7851626B2 (en) 2005-12-01 2010-12-14 Hoffmann-La Roche Inc. 4,4,5,5, tetrasubstituted imidazolines
US7705007B2 (en) 2006-01-18 2010-04-27 Hoffmann-La Roche Inc. Cis-imidazolines
US7625895B2 (en) 2007-04-12 2009-12-01 Hoffmann-Le Roche Inc. Diphenyl-dihydro-imidazopyridinones
EP2325180A1 (fr) 2007-10-09 2011-05-25 F. Hoffmann-La Roche AG CIS-imidazolines chiraux
US8513239B2 (en) 2007-10-09 2013-08-20 Hoffmann-La Roche Inc. Chiral cis-imidazolines
WO2022139593A1 (fr) 2020-12-23 2022-06-30 Klingelberg Products As Amidines et procédé pour les fabriquer sans faire appel à des solvants
WO2022139594A1 (fr) 2020-12-23 2022-06-30 Klingelberg Products As Amides et leur procédé de fabrication sans solvant

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