EP1115702A1 - Composes alicycliques substitues a base d'azote et de soufre et methodes de synthese desdits composes - Google Patents

Composes alicycliques substitues a base d'azote et de soufre et methodes de synthese desdits composes

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Publication number
EP1115702A1
EP1115702A1 EP99932200A EP99932200A EP1115702A1 EP 1115702 A1 EP1115702 A1 EP 1115702A1 EP 99932200 A EP99932200 A EP 99932200A EP 99932200 A EP99932200 A EP 99932200A EP 1115702 A1 EP1115702 A1 EP 1115702A1
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EP
European Patent Office
Prior art keywords
substituted
optionally substituted
compound
alkyl
alkynyl
Prior art date
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EP99932200A
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German (de)
English (en)
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EP1115702A4 (fr
Inventor
Mukund Shankar Chorghade
Mukund Keshao Quarter D-II/5 GURJAR
Radha Krishna Palakodety
Sista Venkata Sai Lalitha
Kashinath Sadalapure
Susanta Sekhar Adhikari
Andappan Murugaiah Subbaiah Murugaiah
Batchu Venkateswara S/O BS Prakasa Rao RAO
Arindam Talukdar
Aminul Islam
Chittineni Hariprasad
Alla Venkata Rana Aura Laboratories RAO
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Millennium Pharmaceuticals Inc
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Millennium Pharmaceuticals Inc
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Publication of EP1115702A1 publication Critical patent/EP1115702A1/fr
Publication of EP1115702A4 publication Critical patent/EP1115702A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/32—Oxygen atoms

Definitions

  • the present invention provides new methods for preparation of various heterocyclic ring compounds (sulfur or nitrogen as alicyclic ring members) including 2,5- disubstituted tetrahydrothiophenes, 2,5-disubstituted pyrrolidines, 2,6-disubstituted thianes, 2,6-disubstituted hexahydropyridines, 2,7-disubstituted thiepanes, 2,7- disubstituted hexahydroazepines, 2,8-disubstituted thiocanes and 2,8-disubstituted octahydroazocines.
  • the invention further provides novel compounds and pharmaceutical compositions and therapeutic methods that comprise such compounds.
  • Leukotrienes are recognized potent local mediators, playing a significant role in inflammatory and allegeric responses, including arthritis, asthma, psoriasis and thrombotic disease.
  • Leukotrienes are produced by the oxidation of arachidonic acid by lipoxygenase. More particularly, arachidonic acid is oxidized by 5-lipooxygenase to the hydroperoxide, 5-hydroperoxy-eicosatetraenoic acid (5-HPETE), that is converted to leukotriene A 4 , that in turn can be converted to leukotriene B 4 , C 4 , or D 4 .
  • the slow- reacting substance of anaphylaxis is now known to be a mixture of leukotrienes C , D 4 and E 4 , all of which are potent bronchoconstrictors.
  • cyclic nitrogen or sulfur-containing compounds i.e., alicyclic compounds having a nitrogen or sulfur ring member
  • compounds of the following Formula I including compounds of the following Formula I:
  • X is S, S(O), S(O) , N or substituted N (including N-alkyl and N-oxide);
  • Ar is optionally substituted carbocychc aryl or optionally substituted heteroaryl; each R 1 , Y and Y' is independently hydrogen or a non-hydrogen substituent such as halogen, hydroxyl, optionally substituted alkyl preferably having from 1 to about 20 carbon atoms, optionally substituted alkenyl preferably having from 2 to about 20 carbon atoms, optionally substituted alkynyl preferably having from 2 to about 20 carbon atoms, optionally substituted alkoxy preferably having from 1 to about 20 carbon atoms, optionally substituted alkylthio preferably having from 1 to about 20 carbon atoms, optionally substituted alkylsulfinyl preferably having from 1 to about 20 carbon atoms, optionally substituted alkylsulfonyl preferably having from 1 to about 20 carbon atoms, optionally substituted aminoalkyl preferably having from 1 to about 20 carbon atoms, optionally substituted alkanoyl preferably having from 1 to about 20 carbon atoms
  • Z is a chemical bond, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, or a hetero atom such as O, S, S(O), S(O) , or NR 1 wherein R 1 is the same as defined immediately above; n is an integer from 1 to 11, and preferably is 1 to 9, more preferably 1 to 7; p is an integer from 0 (where the ⁇ and ⁇ ring positions are fully hydrogen- substituted) to 4; and pharmaceutically acceptable salts thereof.
  • 5-membered ring heterocycles including compounds of the following Formula II:
  • Ar and X are each the same as defined in Formula I above; m is O or 1; n is 1-6; W is -AN(OM)C(O)N(R 3 )R 4 , -N(OM)C(O)N(R 3 )R 4 , -AN(R 3 )C(O)N(OM)R 4 ,
  • A is lower alkyl, lower alkenyl, lower alkynyl, alkylaryl or arylalkyl, wherein one or more carbons optionally can be replaced by N, O or S, however -Y-A-, -A-, or -AW- should not include two adjacent heteroatoms;
  • M is hydrogen, a pharmaceutically acceptable cation or a metabolically cleavable leaving group;
  • Y is O, S, S(O), S(O) 2 , NR 3 or CHR 5 ;
  • Z is O, S, S(O), S(O) 2 , or NR 3 ;
  • R 1 and R 2 are each independently hydrogen, lower alkyl, C 3-8 cycloalkyl, halolower alkyl, halo or -COOH;
  • R 3 and R 4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, C ⁇ _ 6 alkoxy-C ⁇ - ⁇ oalkyl, C ⁇ -6 alkylthio-C 1-10 alkyl, heteroaryl, or heteroarylalkyl;
  • R 5 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, arylalkyl, alkaryl, -AN(OM)C(O)N(R 3 )R 4 , -AN(R 3 )C(O)N(OM)R 4 , -AN(OM)C(O)R 4 , -AC(O)N(OM)R 4 , -AS(O) x R 3 , -AS(O) x CH 2 C(O)R 3 , -AS(O) x CH 2 CH(OH)R 3 , or -AC(O)NHR 3 , wherein x is 0-2; and pharmaceutically acceptable of such compounds.
  • Preferred compounds of Formula II include compounds where Ar is substituted by halo (including but not limited to fluoro), lower alkoxy (including methoxy), lower aryloxy (including phenoxy), W (as defined above in Formula II), cyano, or R 3 (as defined above in Formula II). Those substituents are also preferred Ar group substituents for compounds of other formulae disclosed herein.
  • Ar groups for the above Formula II as well as the other formulae disclosed herein include phenyl, trimethoxyphenyl, dimethoxyphenyl, fluorophenyl (specifically 4-fluorophenyl), difiuorophenyl, pyridyl, dimethoxypyridyl, quinolinyl, furyl, imidazolyl, and thienyl.
  • W suitably is lower alkyl, such as a branched alkyl group, e.g.
  • n 1-5, and specifically -(CH 2 ) 2 C(CH 3 )H-, or lower alkynyl such as of the formula -C ⁇ C-CH(alkyl)-, including -C ⁇ C-CH(CH 3 )-.
  • methods of the invention include preparation of enantiomerically enriched compounds of Formula I.
  • synthetic methods of the invention provide thio ring compounds and comprise reaction of an epoxyether substituted aryl compound with a thiolating reagent to form a thioepoxy ether.
  • aryl refers to both carbocychc aryl and hetoaromatic or heteroaryl groups, which terms in turn are further discussed below.
  • That thioepoxy ether is then reacted with an active methylene compound to form a thiolactone, preferably a ⁇ -thiolactone.
  • the active methylene compound can be a variety of agents.
  • Diethyl and dimethyl malonate are generally preferred, which provide an ethyl or methyl ester as a thiolactone ring substituent. That ester group is then removed (particularly by hydrolysis and decarboxylation), and the lactone suitably reduced to a hydroxy(thioalicyclic)-aryl ether compound, particularly a hydroxy(tetrahydrothiophene)-aryl ether.
  • the hydroxy(tetrahydrothiophene)-aryl ether compound can be further functionalized as desired, particularly by activating the hydroxyl substituent of the tetrahydrothiophene followed by substitution of the corresponding position of the thioalicyclic ring such as by a 1 -alkyne reagent. Also, rather than directly activating the hydroxyl moiety, that group can be replaced with a halide, and the halide-substituted tetrahydrothiophene reacted with a benzylsulfonic acid reagent.
  • synthetic methods of the invention provide nitrogen ring compounds and preferably comprise reaction of a sulfonyl substituted hydroxyalkylaryl ether compound, in which the sulfonyl group is enantiomerically enhanced, either in the R or S configuration, with a reagent that will displace the sulfonyl with an azido group with inversion of configuration to form an azidohydroxyaryl ether. That azidohydroxy aryl ether is then oxidized to a 2,3-epoxide, preferably an optically active epoxide such as a (2S,3S) epoxide.
  • a 2,3-epoxide preferably an optically active epoxide such as a (2S,3S) epoxide.
  • That azidohydroxyaryl ether is further reacted with base and then triphenylphosphine to form a pyrrolidine compound which is further reacted to achieve carbon chain extension to yield an alkynylhydroxy arylether substituted pyrrolidine.
  • the hydroxy pyrrolidine can be further functionalized as desired.
  • larger ring alkynyl-substituted compounds are readily provided through corresponding chain homologation of the epoxy reagent, i.e. by interposing additional "spacing" or alkylene chain members between the reagent's activated positions.
  • a reagent is employed that has at least a seven-carbon alkyl or alkylene chain that is activated at the 1- and 7- carbon positions e.g. by substitution by suitable leaving groups (such as those mentioned above), and the 2- and 3- positions of the chain form an epoxide ring. That compound is reacted with base to provide an alkynyl-substituted tetrahydropyridene.
  • a reagent is employed that has at least a seven-carbon alkyl or alkylene chain activated (particularly by leaving groups) at the 1- and 8-carbon positions, and the 2- and 3-postion of the chain form an epoxide ring.
  • a reagent is employed that has at least eight-carbon alkyl of alkylene chain activated at the 1- and 9-carbon positions, with the 2- and 3 -positions of the chain forming an epoxide ring. Treatment of those respective reagents with appropriate base provides alkynyl- substituted hexahydroazepine and octahydroazocines compound.
  • preparative methods include multiple reactions that surprisingly can proceed as a single step without isolation of intermediates to provide sulfur ring compounds that have varying ring size as desired. These methods are suitable for preparation of sulfur ring compounds having from 5 to 12 or more ring members, and are particularly useful for synthesis of sulfur ring compounds having from 5 to 8 or 9 ring members. 00/01670
  • the one step procedure is enantioselective.
  • the starting reagent a 2,3-thioepoxide
  • the resulting substituted thio-ring compound also will be optically active.
  • the methods include formation, in a single step, of an alkynyl-substituted thio-ring compound.
  • a compound is reacted that has at least a six-carbon alkyl or alklyene chain that is activated at the 1- and 6-carbon positions such as by substitution by suitable leaving groups, and 2- and 3-carbon positions of the chain form a thioepoxide ring.
  • the leaving groups of the 1- and 6-positions may be e.g. halo, such as chloro or bromo, or an ester, such as an alkyl or aryl sulfonic ester.
  • the 1 -position is halo-substituted, particularly bromo-, iodo- or chloro-substituted, and the 6-position is substituted by an ester such as by a benzylsulfonyl group. That compound is reacted with a molar excess of a strong base such as an alkyllithium reagent that affords an alkynyl- substituted tetrahydrothiophene in a single step.
  • a strong base such as an alkyllithium reagent that affords an alkynyl- substituted tetrahydrothiophene in a single step.
  • a reagent is employed that has at least a seven-carbon alkyl or alkylene chain that is activated at the 1- and 7- carbon positions e.g. by substitution by suitable leaving groups (such as those mentioned above), and the 2- and 3- positions of the chain form a thioepoxide ring. That compound is reacted with base to provide an alkynyl-substituted thiane.
  • a reagent is employed that has at least a seven-carbon alkyl or alkylene chain activated (particularly by leaving groups) at the 1- and 8-carbon positions, and the 2- and 3-postion of the chain form a 00/01670
  • thioepoxide ring To prepare an alkynyl-substituted thiocane compound, a reagent is employed that has at least eight-carbon alkyl of alkylene chain activated at the 1- and 9- carbon positions, with the 2- and 3-positions of the chain forming a thioepoxide ring. Treatment of those respective reagents with appropriate base provides alkynyl-substituted thiane and thiocane compounds.
  • the invention further provides additional methods for synthesis of nitrogen ring compounds, which do not require use of an azide reagent. These methods include cyclization to provide a nitrogen ring compound, preferably having one or more activated positions in the ring to facilitate functionalization of the formed heterocycle.
  • a ring carbon can have a carbonyl group as a direct ring member, or as a pendant group (e.g. pyrrolidinone, and/or pyrrolidinone with an acyl or other alkanoyl ring substituent), hydroxyl, haloalkyl as a pendant group, and the like.
  • these routes include reaction of a protected hydroxyurea (e.g., a compound of the formula NH C(O)NHOR, where R is a hydroxy protecting group such as para- methoxybenzyl-) with a substituted alcohol, preferably in the presence of suitable dehydrating agent(s) to provide an amino ester, which is treated with ammonia and a Lewis acid to provide a hydroxy urea.
  • a protected hydroxyurea e.g., a compound of the formula NH C(O)NHOR, where R is a hydroxy protecting group such as para- methoxybenzyl-
  • suitable dehydrating agent(s) to provide an amino ester, which is treated with ammonia and a Lewis acid to provide a hydroxy urea.
  • compounds produced by the methods of the invention will be useful as pharmaceutical agents, including to treat disorders or diseases mediated by 5- lipoxygenase such as immune, allegeric and cardiovascular disorders and diseases, e.g. general inflammation, hypertension, skeletal-muscular disorders, osteoarthritis, gout, asthma, lung edema, adult respiratory distress syndrome, pain, aggregation of platelets, shock, rheumatoid arthritis, psoriatic arthritis, psoriasis, autoimmune uveitis, allergic encephalomyelitis, systemic lupus erythematosis, acute necrotizing hemmorrhagic encephalopathy, idiopathic thrombocytopenia, polychondritis, chronic active hepatitis, O 00/01670
  • disorders or diseases mediated by 5- lipoxygenase such as immune, allegeric and cardiovascular disorders and diseases, e.g. general inflammation, hypertension, skeletal-muscular disorders, osteoarthritis, g
  • the invention provides new compounds as well as pharmaceutical compositions that comprise one or more of such compounds preferably with a pharmaceutically acceptable carrier.
  • compounds of the invention include those of Formula I above, where n is 2 or greater (i.e. compounds with alicyclic rings that have 6 or more ring members), which includes compounds of Formulae III, Ilia, IV, IVa, V, Va, as those formulae are defined below.
  • the invention further provides methods for treatment and/or prophylaxis of various disorders and diseases including those disclosed above such as immune, allegeric and cardiovascular disorders and diseases , the methods in general comprising administering an effective amount of one or more compounds of Formula I above, where n is 2 or greater, to a subject, such as a mammal particularly a primate such as a human, that is suffering from or susceptible to such a disorder or disease.
  • preferred compounds that can be produced by the methods of the invention include substituted tetrahydrothiophenes, pyrrolidines, thianes, hexahydropyridines, thiepanes, hexahydroazepines, thiocanes and octahydroazocines.
  • preferred compounds produced by the methods of the invention include substituted thianes and hexahydropyridines including substituted thianes and hexahydropyridines of the following Formula III:
  • Ar, X, Z and R 1 are each the same as defined above for Formula I, and q is an integer of from 0 to 9, and preferably q is 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
  • 2,6-disubstituted thianes and hexahydropyridines such as compounds of the following Formula Ilia;
  • Ar, X, Z, Y, W, R 1 and m are each the same as defined for Formula II above, and q' is an integer of from 0 to 6 , and preferably q' is 0, 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
  • Ar, X, Z and R 1 are each the same as defined above for Formula I, and r is an integer of from 0 to 11, and preferable r is 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
  • 2,7-disubstituted thiepanes and hexahydroazepines such as compounds of the following Formula TVa:
  • Ar, X, Z and R' are each the same as defined above for Formula I, and s is an integer of from 0 to 13, and preferable s is 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
  • 2,8-disubstituted thiocanes and octahydroazocines such as compounds of the following Formula Va:
  • Ar, X, Z, Y, W, R and m are each the same as defined for Formula II above, and s is an integer of from 0 to 10, and preferably s is 0, 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
  • alkyl refers to a saturated straight, branched, or cyclic hydrocarbon preferably of to do, and specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.
  • the alkyl group can be optionally substituted with any appropriate group, including but not limited to R or one or more moieties selected from the group consisting of halo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as disclosed in Greene et al., "Protective Groups in Organic Synthesis", John Wiley and Sons, Second Edition, 1991.
  • halo refers to chloro, fluoro, iodo, or bromo.
  • lower alkyl refers to a Ci to C 6 saturated straight, branched, or cyclic (in the case of C 5-6 ) hydrocarbon, and specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2- dimethylbutyl, and 2,3-dimethylbutyl, optionally substituted as described above for the alkyl groups.
  • alkenyl refers to a straight, branched, or cyclic (in the case of C 5-6 ) hydrocarbon preferably of C 2 to C 10 with at least one double bond, optionally substituted as described above.
  • lower alkenyl refers to an alkenyl group of C 2 to C 6 , and specifically includes vinyl and allyl.
  • lower alkylamino refers to an amino group that has one or two lower alkyl substituents.
  • alkynyl refers to preferably C 2 to Cio straight or branched hydrocarbon with at least one triple bond, optionally substituted as described above.
  • lower alkynyl refers to a C 2 to C 6 alkynyl group, specifically including acetylenyl, propynyl, and -C ⁇ C-CH(alkyl)-, including -C ⁇ C-CH(CH 3 )-.
  • carbocychc aryl refers to non-hetero aromatic groups that have 1 to 3 separate or fused rings and 6 to about 18 carbon ring atoms and include e.g. phenyl, napthyl, biphenyl, phenanthryl, anthracyl, and the like.
  • the carbocychc aryl group can be optionally substituted with any suitable group, including but not limited to one or moieties selected from the group consisting of halo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene et al., "Protective Groups in Organic Synthesis", John Wiley and Sons, Second Edition, 1991, and preferably with halo (including but not limited to fluoro), lower alkoxy (including methoxy), lower aryloxy (including phenoxy), W, cyano, or R 3 .
  • any suitable group including but not limited to one or moieties selected from the group consisting of halo, hydroxyl, amino, alkylamino, arylamino, al
  • haloalkyl, haloalkenyl, or haloalkynyl refers to alkyl, alkenyl, or alkynyl group in which at least one of the hydrogens in the group has been replaced with a halogen atom.
  • heteroaryl, heterocycle or heteroaromatic refers to an aromatic moiety that includes at least one sulfur, oxygen, or nitrogen in the aromatic ring, which can optionally be substituted as described above for the aryl groups.
  • Non-limiting examples are pyrryl, furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuran, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl.
  • Suitable heteroaromatic or heteroaryl groups will have 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms (N, O or S).
  • arylalkyl refers to a carbocychc aryl group with an alkyl substituent.
  • alkylaryl refers to an alkyl group that has a carbocyclic aryl substituent.
  • organic or inorganic anion refers to an organic or inorganic moiety that carries a negative charge and can be used as the negative portion of a salt.
  • pharmaceutically acceptable cation refers to an organic or inorganic moiety that carries a positive charge and that can be administered in association with a pharmaceutical agent, for example, as a counter cation in a salt.
  • Pharmaceutically acceptable cations are known to those of skill in the art, and include but are not limited to sodium, potassium, and quaternary amine.
  • metabolically cleavable leaving group refers to a moiety that can be cleaved in vivo from the molecule to which it is attached, and includes but it not limited to an organic or inorganic anion, a pharmaceutically acceptable cation, acryl (for example (alkyl)C(O), including acetyl, propionyl, and butyryl), alkyl, phosphate, sulfate and sulfonate.
  • Alkylene and heteroalkylene groups typically will have about 1 to about 8 atoms in the chain, more typically 1 to about 6 atoms in the linkage.
  • Alkenylene, heteroalkenylene, alkynylene and heteroalkynylene groups typically will have about 2 to about 8 atoms in the chain, more typically 2 to about 6 atoms in the linkage, and one or more unsaturated carbon-carbon bonds, typically one or two unsaturated carbon-carbon bonds.
  • a heteroalkylene, heteroalkenylene or heteroalkynylene group will have at least one hetero atom (N, O or S) as a divalent chain member.
  • alkylthio generally refers to moieties having one or more thioether linkages and preferably from 1 to about 12 carbon atoms, more preferably from 1 to about 6 carbon atoms.
  • alkylsulfinyl generally refers to moieties having one or more sulfinyl (S(O)) linkages and preferably from 1 to about 12 carbon atoms, more preferably from 1 to about 6 carbon atoms.
  • alkylsulfonyl generally refers to moieties having one or more sulfonyl (S(O) 2 ) linkages and preferably from 1 to about 12 carbon atoms, more preferably from 1 to about 6 carbon atoms.
  • aminoalkyl generally refers to groups having one or more N atoms and from 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms.
  • substituent groups of the above formulae may be optionally substituted.
  • Suitable groups that may be present on such a "substituted” group include e.g. halogen such as fluoro, chloro, bromo and iodo; cyano; hydroxyl; nitro; azido; sulfhydryl; alkanoyl e.g.
  • C ⁇ -6 alkanoyl group such as acetyl and the like; carboxamido; alkyl groups including those groups having 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon atoms, preferably from 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen linkages and from 1 to about 12 carbon atoms, preferably 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those moieties having one or more thioether linkages and from 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms; alkylsulfinyl groups including those moieties having one or more sulfinyl linkages and from 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms; alkylsulfonyl groups including those moieties
  • a "substituted" group of a compound of the invention prepared by a method of the invention may be substituted at one or more available positions, typically 1 to about 3 positions, by one or more suitable groups such as those listed immediately above.
  • references to "aryl" with respect to the Schemes includes those groups specified for the substituent Ar in Formula I above and thus encompasses carbocychc aryl such as phenyl and the like as well as heteroaryl groups.
  • compounds in the below Scheme generally depict substitution at the ring carbons to the ring hetero atom, other ring positions can be readily substituted e.g. by using appropriately substituted starting reagents.
  • various stereoisomers are depicted in the below Schemes, corresponding other stereoisomers can be readily obtained by use of the corresponding optically active reagents or enantiomertic selective reactions or separations.
  • Scheme I exemplifies a preferred preparative method of the invention wherein the enantiomerically pure epoxide 1 and thiourea react to form the cyclic sulfide (thiirane) 2 maintaining the R configuration.
  • Preferred epoxides are those that are enantiomerically enriched with R stereochemistry at the C2 carbon, such as the (R) glycidyl fluorophenyl 1 shown above.
  • the preferred epoxide I and thiourea are reacted in a suitable solvent such as methanol for a time and temperature sufficient for reaction completion to provide thioaryl ether 2. See Example 1, Part 1 below for exemplary reaction conditions.
  • the compound 1 and thiourea typically react in a suitable solvent, e.g. methanol, ethanol and the like.
  • a suitable solvent e.g. methanol, ethanol and the like.
  • Enantiomerically enriched epoxides suitable for conversion to a suitable (R) thioglycidyl ether are commercially available or can be readily prepared by known procedures. See, for instance, U.S. Patents Nos. 4,946,974 and 5,332,843 to Sharpless et al. for preparation of optically active derivatives of glycidol. 00/01670
  • the thioepoxyaryl ether 2 then is reacted with an active methylene group, such as a diethyl or dimethyl malonate to provide thiobutyrolactone 3.
  • the exocyclic ester of 3 is then suitably cleaved, e.g. with reaction with magnesium chloride hexahydrate, to provide the corresponding carbonyl thiolactone ether 4.
  • the thiolactone 4 is then reduced to the hydroxy-tetrahydrothiophene 5.
  • Suitable reducing agents include e.g. DIBAL-H and the like. See Example 1, Part 4, which follows.
  • tetrahydrothiophene 5 is preferably activated, e.g. as an ether, tosyl, mesyl or benzene sulfinic acid derivative.
  • the hydroxy moiety of 5 can be reacted with a suitable sulfinic or silyl reagent, e.g. to form the benzenesulfonyl derivative 6, or with reagents for silylation, e.g. a silyl chloride such as TMSC1. See Example 1, Part 5 and Example 2, Part 1 for suitable reaction conditions. 00/01670
  • the activated aryltetrahydrothiophene ether 6 can then react to provide the alkynyl-substituted tetrahydrothiophene 7 by treatment with a 1 -alkyne in the presence of a strong base such an alkyllithium.
  • the alkyne reagent contains a protected hydroxy moiety such as an ether, e.g. a mefhoxyethoxymefhyl, methoxymethyl or tetrahydropyranyl ether 7 as depicted in the above Scheme.
  • the hydroxy group can be readily deprotected after coupling of the alkynyl reagent to the tetrahydrothiophene ring, e.g. by treatment with dilute acid to yield the corresponding alcohol 8.
  • the alkyne reagent will contain a primary or secondary hydroxy moiety. See Example 1, Part 7 for suitable reaction conditions.
  • the enantiomerically enriched hydroxy- tetrahydrothiophene 9 can be obtained by purification by crystallization of the isomeric mixture 8.
  • the hydroxy tetrahydrothiophene 9 can be further functionalized as desired by amidation using a N,O-substituted hydroxylamine such as N-phenoxycarbonyl-O-p- methoxybenzyl-hydroxylamine in the presence of dehydrating reagents such as, triphenylphosphine and diethylazodicarboxylate, followed by treatment of the resulting O 00/01670
  • Schemes IV- VI below exemplify a further aspect of the invention that provides methods for synthesis of larger sulfur heterocyclic compounds such as thianes, thiepanes and thiocanes and an alternative method of obtaining substituted tetrahydrothiophenes. This is accomplished by utilizing analogs of compound 15 which have an extended alkyl chain of the appropriate length.
  • intermediate 15 is suitably obtained by reaction of arylepoxy ether 1 and the appropriate haloalkene utilizing Grignard conditions to obtain the alkene 12.
  • the arylepoxy ether and a haloalkene such as 4-bromo-l-butene, react in the presence of magnesium and a suitable catalyst system such as iodine and cuprous cyanide to provide the arylalkene ether 12.
  • the secondary hydroxyl group of 12 is suitably protected, e.g. preferably as a sulfonic ester to provide the terminal alkene 13.
  • Alkene 13 is further extended and fuctionalized by condensation to form the ⁇ , ⁇ -unsaturated ester 14.
  • the ester 14 is then reduced to an alcohol, typically by treatment with a strong base such as DIBAL-H to obtain intermediate homo allylic alcohol 15.
  • the homoallylic alcohol 5 is then enantioselectively oxidized to provide the epoxy group of 16.
  • Scheme V shows the Sharpless asymmetric epoxidation of 15 to give the corresponding (2S,3S, 6S) arylether epoxide 16.
  • Other procedures may be used where in an optically active ligand or catalyst is used to promote enanteoselectivity of the oxidation of 15.
  • the racemic epoxides may also be resolved, e.g. by chromatography using an optically active packing material.
  • the arylether epoxide 16 is then converted to the corresponding thiirane 17 by reaction with thiourea or phosphorous pentoxide.
  • the Cl alcohol of compound 17 is then halogenated to provide the (2S,3S,6S) thiirane 18 where suitable halogens include chlorine and bromine.
  • Scheme V illustrates halogenation by in situ activation of the hydroxyl group to a mesylate e.g. methane sulfonyl chloride with a nitrogen base such as pyridine or triethyl amine and can include catalysis by dimethylaminopyridine. Subsequent substitution may be accomplished using the appropriate lithium salt e.g. lithium chloride or lithium bromide, dissolved in an appropriate solvent such as dimethylformamide or THF.
  • the arylether thiirane 17 could also be directly halogenated using an appropriate reagent.
  • Dehalogenation with concomitant rearrangement of compound 18 to the (3R) hydroxy alkyne ⁇ 9 is accomplished by reaction with an appropriate lithium base, such as lithium diisopropyl amine, in a suitable solvent e.g. THF.
  • an appropriate lithium base such as lithium diisopropyl amine
  • THF a suitable solvent
  • the alkyne 19 is extended by two carbons units by treatment with butylhthium in the presence of boron trifluoride diethyl etherate followed by ethylene oxide to yield the trans-tetrahydrothiophine 8.
  • This methodology may be used to synthesize tetrahydrothiophenes by reacting 1 and an appropriate alkene such as 4-bromo-l-butyene to obtain the necessary terminal alkene 12 for synthesis of tetrahydrothiophenes.
  • an appropriate alkene such as 4-bromo-l-butyene
  • preparation of key intermediates of thianes are obtained by reaction of 1 and an appropriate alkene such as 5-bromo-l-pentene, thiepanes by reaction of 1 and an appropriate alkene such as 6- bromo-1-hexene and thiocanes by reaction of 1 and an appropriate alkene such as 7- bromo-1-heptene.
  • routes to substituted hydroxy ureas are provided. More particularly, a protected hydroxy urea (e.g., a compound of the formula NH C(O)NHOR, where R is a hydroxy protecting group such as an alkyl, aryl or preferably aryalkyl ether such as an ether of an optionally substituted (phenyl)OCH -) is reacted with a substituted alcohol compound, such as analogues of 9 of Scheme III, preferably in the presence of suitable dehydrating agent(s) such as triphenyl phosphine and diethylazodicarboxylate (DEAD), to provide an amino ester, i.e.
  • a protected hydroxy urea e.g., a compound of the formula NH C(O)NHOR, where R is a hydroxy protecting group such as an alkyl, aryl or preferably aryalkyl ether such as an ether of an optionally substituted (phenyl)OCH -
  • R is as defined immediately above and R 1 is a non-hydrogen group such as aryl, particularly phenyl, alkyl, e.g. Ci-io alkyl, etc. That amino ester is then treated with ammonia and a Lewis acid such as boron trifluoride etherate and the like to provide a hydroxy urea.
  • a Lewis acid such as boron trifluoride etherate and the like.
  • para-methoxybenzyl- is utilized as the hydroxy protection group R.
  • synthetic methods of the invention include preparation of compounds useful as intermediates to prepare pyrrolidine compounds of the above Formula II (X being nitrogen in Formula II).
  • Scheme VII exemplifies a preferred preparative method of the invention wherein the enantiomerically enriched (6R) sufonic ester of the homo allylic alcohol 15 is transformed to an azide 25 with inversion to the S configuration at the C6 carbon.
  • sulfonic ester 15 and a suitable reagent such as lithium azide react in a solvent such as dimethyl formamide to yield the (6S) azide 25
  • the (6S) azido alcohol 25 is then enantioselectively oxidized to provide the epoxy group of 26.
  • Scheme VII shows the Sharpless asymmetric epoxidation of 25 to give the corresponding (2S,3S, 6S) epoxyazide 26.
  • Dehalogenation with concomitant rearrangement of compound 27 to the (3R) hydroxy alkyne 28 is accomplished by reaction with an appropriate lithium base, such as lithium diisopropyl amine, in a suitable solvent e.g. THF.
  • the alkyne 28 is reacted with triphenylphosphine in an appropriate manner to yield the trans-alkynyl-pyrrolidine 29.
  • the alkyne 29 is extended by two carbons units by treatment with butylhthium in the presence of boron trifluoride diethyl etherate followed by ethylene oxide to yield the trans-hydroxypyrrolidine 30.
  • the invention provides methods for synthesis of larger nitrogen heterocyclic compounds such as hexahydropyridines, hexahydroazepines, and octahydroazocines. This is accomplished by utilizing reagents akin to compound 15 (Scheme VII) which have an extended alkyl chain of the appropriate length as previously described above and shown in Scheme VIII.
  • Scheme VII reagents akin to compound 15 which have an extended alkyl chain of the appropriate length as previously described above and shown in Scheme VIII.
  • the synthesis of hexahydropyridine by way of this method is outlined immediately above in Scheme VIII.
  • the arylepoxy ether 1 and and an appropriate haloalkene such as 5-bromo-l-pentene react in the presence of magnesium and a suitable catalyst system such as iodine and cuprous cyanide to provide the arylalkene ether 25.
  • the secondary hydroxy group is suitably protected, e.g. as an ester, preferrably a sulfonic ester and reacted as described for Scheme VII to obtain homo allylic alcohol 26.
  • This methodology may be used to synthesize pyrrolidines by reacting 1 and an appropriate haloalkene such as 4-bromo-l-butyene to obtain the necessary terminal alkene 12 necessary for synthesis of pyrrolidines.
  • an appropriate haloalkene such as 4-bromo-l-butyene
  • hexahydropyridines are obtained by reaction of 1 and an appropriate haloalkene such as 5-bromo-l-pentene, hexahydroazepines by reaction of 1 and 6-bromo- 1-hexene and octahydroazocines by reaction of 1 and an appropriate haloalkene such as 7-bromo-l-heptene.
  • the resulting terminal alkenes of each of the above reaction products are converted to the appropriate homo allylic alcohol analogs of 15 and 25.
  • the homo allylic alcohol can then be processed by methodologies described for Scheme VII to obtain the desired disubstituted nitrogen ring heterocycle.
  • the invention includes methods to prepare nitrogen ring compounds of the invention without employing an azide intermediate.
  • an amino acid reagent is cyclized to provide a nitrogen ring compound (pyrrolidinone 1), which can be functionalized to provide a desired aryl ring substituent (fluorophenyl as exemplified in Scheme IX).
  • the pyrrolidinone can be reduced, and functionalized as desired, e.g.
  • aryl nucleophile in the presence of a hydride reagent (base), such as potassium hydride or more preferably sodium hydride to yield the alcicylic compound having an arylalkyl substituent, particularly an aryalkoxy substituent as depicted in the Scheme below.
  • base such as potassium hydride or more preferably sodium hydride
  • Preferred aryl nucelophiles include aryl compounds having one or more hydroxy ring substituents (i.e. an aryl hydroxy compound), preferably a carboxylic aromatic compound such as an optionally substituted phenol, e.g. phenol optionally substituted by halo, C ⁇ - 6 alkyl, C ⁇ -6 alkoxy, cyano and the like.
  • the aryl nucelophile is preferably reacted with a nitrogen alicyclic compound having an alkyl ring substituent, typically a C 1-8 or C ⁇ -6 alkyl such as methyl and the like that preferably has an activated carbon, e.g. a carbon substituted by a sulfonic ester (e.g. tosylate, mesylate, etc.), where the aryl nucleophile reacts.
  • a nitrogen alicyclic compound having an alkyl ring substituent typically a C 1-8 or C ⁇ -6 alkyl such as methyl and the like that preferably has an activated carbon, e.g. a carbon substituted by a sulfonic ester (e.g. tosylate, mesylate, etc.), where the aryl nucleophile reacts.
  • a nitrogen alicyclic compound having an alkyl ring substituent typically a C 1-8 or C ⁇ -6 alkyl such as methyl and the like that
  • the conversion of alicyclic compound having a hydroxy ring substituent to the corresponding sulfinic ester can proceed via an alkoxy intermediate (e.g. C ⁇ -8 alkoxy, more preferably C1- 3 alkoxy, more preferably methoxy) intermediate by esterfication of the hydroxy ring moiety e.g. by reaction of the corresponding alcohol such as methanol and the like followed by reaction of alkoxy ring substituent with a sulfinic acid reagent, preferably an aryl reagent such as optionally substituted phenyl sulfinic acid.
  • the phenyl sulfinic acid reagent may be optionally substituted on the phenyl ring by C ⁇ -8 alkyl preferably methyl, C 1-8 alkoxy, cyano, halo and the like.
  • Scheme X depicts another route to nitrogen ring compounds of the invention without an azide intermediate compound.
  • an alcohol which may be optically active to provide a resolved final product, can be provided by ring- opening of an epoxide (which may be optically active).
  • the alcohol can be substituted be a variety of groups, including aryl groups, as exemplified in the below Scheme X. That alcohol (compound 3 below) then can be functionalized as desired to provide a nitrogen that can be cyclized to provide a nitrogen ring member.
  • the alcohol intermediate can be reacted with a phthalimide, followed by hydrazine to provide an amine which can be cyclized to provide a nitrogen ring, e.g. by ozonolysis of the terminal alkene to an aldehyde which then cyclizes to 7.
  • the amine group and alkene group can be spaced by additional carbons to provide nitrogen ring groups with additional carbon ring members.
  • the invention provides new routes to substituted hydroxy ureas. More particularly, a protected hydroxy urea (e.g., a compound of the formula NH 2 C(O)NHOR, where R is a hydroxy protecting group such as an alkyl, aryl or preferably aryalkyl ether such as an ether of an optionally substituted (phenyl)OCH -) is reacted with a substituted alcohol compound such as 21 of Scheme IV in the presence of suitable dehydrating agent(s) such as triphenyl phosphine and diethylazodicarboxylate (DEAD) to provide an amino ester, i.e.
  • a protected hydroxy urea e.g., a compound of the formula NH 2 C(O)NHOR, where R is a hydroxy protecting group such as an alkyl, aryl or preferably aryalkyl ether such as an ether of an optionally substituted (phenyl)OCH -
  • a substituted alcohol compound
  • R is as defined immediately above and R is a non-hydrogen group such as aryl, particularly phenyl, alkyl, e.g. C MO alkyl, etc. That amino ester is then treated with ammonia and a Lewis acid such as boron trifluoride etherate and the like to provide a hydroxy urea.
  • a Lewis acid such as boron trifluoride etherate and the like.
  • para-methoxybenzyl- is utilized as the hydroxy protection group R.
  • Compounds of the invention that have substituted nitrogen or sulfur alicyclic ring members e.g. compounds of Formulae I through V wherein X is -S(O)-, -S(O) -, substituted N include -N(O)- can be readily prepared.
  • the prepared thio or nitrogen alicyclic group can be oxidized to provide a ring member of -S(O)-, -S(O) 2 -, or -N(O)- by known techniques such as with H O 2 and/or sodium periodate.
  • the nitrogen ring member is otherwise substituted, e.g. by an optionally substituted alkyl group
  • the preformed ring member can be reacted with an alkyl halide to provide the substituted nitrogen ring member.
  • the compounds can be administered to a subject, particularly a mammal such as human, in need of treatment, by a variety of routes.
  • the compound can be administered orally, parenterally, intravenously, intradermally, subcutaneously, or topically.
  • parenteral application particularly suitable are solutions, preferably oily or aqueous solutions as well as suspensions, emulsions, or implants, including suppositories.
  • Ampules are n ⁇ Mschreib ⁇ O 00/01670
  • tablets, dragees or capsules e.g. having talc and/or carbohydrate carrier binder or the like, the carrier suitably being lactose and/or corn starch and/or potato starch.
  • an optically active or enantiomerically enriched mixture of a chiral compound of the invention typically refers to a compound mixture that is at least approximately 70 mole%, 80 mole%, 85 mole% or 90 mole% of a single stereoisomer, and preferably a compound mixture that contains approximately at least about 92 mole%, 95 mole%, 97 mole%, 98 mole%, 99 mole% or 100% of a single enantiomer of the compound.
  • the active compound may be administered to a subject as a pharmaceutically active salt, e.g. salts formed by addition of an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc., or an organic acid such as acetic acid, oxalic acid, tartaric acid, succinic acid, etc.
  • Base addition salts also can be formulated if an appropriate acidic group is present on the compound.
  • suitable base addition salts include those formed by addition of metal cations such as zinc, calcium, etc., or salts formed by addition of ammonium, tetraethylammonium, etc.
  • Suitable dosages for a given therapy can be readily determined by the medical practitioner such as by standard dosing protocols. See also U.S. Patent 5,703,093.
  • Benzenesulfinic acid (2.34 g, 16.4 mmol.) CaCl 2 (1.82 g, 16.4 mmol.) and 25 ml of CH C1 were added to a 50 ml round bottom flask. The solution was cooled to 0 °C and (25)(5R,5)-2-(4-Fluorophenoxymethy ⁇ )-5-hydroxy tetrahydrothiophene 5, 2.5 g, 0.011 mol., dissolved in dry CH 2 C1 was added. The reaction mixture was stirred and after 6 hours, filtered through celite and washed with CH 2 C1 2 .
  • Grignard grade magnesium 0.81 g, 33.7 mmol
  • Dry THF, 70 ml, and 1,2-dibromoethane (cat.) were added sequentially to the activated magnesium.
  • isopropyl bromide (2.07 g, 16.8 mol.) dissolved in THF was added dropwise over 10 minutes and the reaction was stirred for 1 hour.
  • the resulting isopropyl magnesium bromide was cannulated into a 100 ml flame dried round bottom flask.
  • reaction mixture was refluxed till completion of reaction with monitoring by TCL (ethyl acetate:light petroleum 1 :4). At the end of 16 hours, the reaction was cooled to 0 °C and quenched with saturated aqueous NH CI. THF was removed in vacuo and the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with water, brine, dried (Na 2 SO 4 ) and concentrated to yield 3 g of the crude tetrahydropyranoyl derivative 7.
  • TCL ethyl acetate:light petroleum 1 :4
  • Lithium chloride (8.17g, 190mmol) and sodium borohydride (7.2g, 190 mmol) were taken in a solvent mixture of ethanol (100 ml) and THF (60 ml) at 0°C.
  • a solution of (S)-5-Methoxycarbonyl-l- (4-methoxybenzyl)-2-pyrrolidinone (20g, 76 mmol) (prepared as in Part 1 above) in 40 ml of THF was added at 0°C.
  • the reaction mixture was stirred at room temperature for 6 hours.
  • the solid was filtered off.
  • the filtrate was neutralised to pH approximately 7 by dropwise addition of saturated aqueous NH 4 C1 solution at O°C.
  • reaction mixture was stirred for 10 hours.
  • the reaction mixture was quenched with aqueous NH 4 C1 solution (3ml) and partitioned between ether (300ml) and water (100ml). The organic part was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated to afford the crude product which was dissolved in methanol (15ml).
  • PPTS (66mg, 0.26mmol) was added and the reaction mixture was stirred at room temperature overnight.
  • the residue after the removal of methanol was purified by column chromatography (60-120mesh, 30%) ethyl acetate in hexane) to afford the pure product as colorless oil (1.0g, 86%).
  • Trifluoroacetic acid (0.5ml, 5.49mmol) was added to a solution of substrate (0.8g, 1.83mmol) in 10ml of DCM at 0°C. The reaction mixture was stirred for 3 hours at room temperature. Aqueous saturated NaHCO 3 was added at 0°C. After being stirred for 10 min. the organic layer was separated, washed with brine, dried over anhydrous Na SO 4 and concentrated to afford the brown residue which was purified by column chromatography (10%methanol in ethyl acetate) to afford the colorless semi-solid (0.55g, 86%).
  • reaction mixture was stirred for 10 hours.
  • the reaction mixture was quenched with aqueous NH 4 C1 solution (0.3ml) and partitioned between ether (30ml) and water (10ml). The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated to afford the crude product which was dissolved in methanol (1.5ml).
  • PPTS (7mg, 0.026mmol) was added and the reaction mixture was stirred at room temperature overnight.
  • test compound Heparinized human whole blood was pre-incubated with selected concentrations of the test compound for 15 minutes at 37°C and stimulated with 50 ⁇ M calcium ionphor for 30 minutes at 37°C. The reaction was stopped by placing samples on ice and cold centrifugation at 4°C for 10 minutes at 1100 x g. Test sample plasma was diluted in buffer and assayed for LTB 4 content. Test compound activity was determined as per Cayman LTD EIA and evaluated as IC 50 [nM]. The compound had an IC 50 of 256 nM.

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Abstract

L'invention concerne de nouvelles méthodes de préparation de différents composés qui comprennent des groupes alicycliques ayant l'azote et le soufre comme éléments du noyau. Ces composés comprennent des tétrahydrothiophènes 2,5-disubstituées, des pyrrolidines 2,5-disubstituées, des thianes 2,6-disubstituées, des hexahydropyridines 2,6-disubstituées, des thiépanes 2,7-disubstituées, des hexahydroazépines 2,7-disubstituées, des thiocanes 2,8-disubstituées et des octahydroazocines 2,8-disubstituées. L'invention concerne également de nouveaux composés, des compositions pharmaceutiques ainsi que des méthodes thérapeutiques qui comprennent ces composés et compositions.
EP99932200A 1998-07-03 1999-07-02 Composes alicycliques substitues a base d'azote et de soufre et methodes de synthese desdits composes Withdrawn EP1115702A4 (fr)

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WO1994001430A1 (fr) * 1992-07-13 1994-01-20 Cytomed, Inc. 2,5-diaryle tetrahydro-thiophenes, -furanes et analogues utilises dans le traitement de troubles inflammatoires et immuns
US5358938A (en) * 1992-07-13 1994-10-25 Cytomed, Inc. Compounds and methods for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase
US5434151A (en) * 1992-08-24 1995-07-18 Cytomed, Inc. Compounds and methods for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase
US5681966A (en) * 1994-06-27 1997-10-28 Cytomed, Inc. Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US5703093A (en) * 1995-05-31 1997-12-30 Cytomed, Inc. Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders

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US5543531A (en) * 1987-06-16 1996-08-06 Sandoz Ltd. Thiophen compounds and their preparation
JP3777408B2 (ja) * 1994-12-28 2006-05-24 株式会社カネカ カルボン酸誘導体の製造法

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WO1994001430A1 (fr) * 1992-07-13 1994-01-20 Cytomed, Inc. 2,5-diaryle tetrahydro-thiophenes, -furanes et analogues utilises dans le traitement de troubles inflammatoires et immuns
US5358938A (en) * 1992-07-13 1994-10-25 Cytomed, Inc. Compounds and methods for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase
US5434151A (en) * 1992-08-24 1995-07-18 Cytomed, Inc. Compounds and methods for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase
US5681966A (en) * 1994-06-27 1997-10-28 Cytomed, Inc. Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US5703093A (en) * 1995-05-31 1997-12-30 Cytomed, Inc. Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders

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See also references of WO0001670A1 *

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