WO1998057934A1 - Agents aromatiques a six membres amidino utiles en tant qu'inhibiteurs du facteur xa - Google Patents

Agents aromatiques a six membres amidino utiles en tant qu'inhibiteurs du facteur xa Download PDF

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Publication number
WO1998057934A1
WO1998057934A1 PCT/US1998/012682 US9812682W WO9857934A1 WO 1998057934 A1 WO1998057934 A1 WO 1998057934A1 US 9812682 W US9812682 W US 9812682W WO 9857934 A1 WO9857934 A1 WO 9857934A1
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Prior art keywords
phenyl
methyl
pyridyl
pyrimidyl
sch
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PCT/US1998/012682
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English (en)
Inventor
James Russell Pruitt
Donald Joseph Phillip Pinto
Mimi Lifen Quan
Ruth Richmond Wexler
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The Du Pont Merck Pharmaceutical Company
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Priority to CA002293824A priority Critical patent/CA2293824A1/fr
Priority to AU79769/98A priority patent/AU7976998A/en
Priority to EP98930362A priority patent/EP0993448A1/fr
Publication of WO1998057934A1 publication Critical patent/WO1998057934A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3

Definitions

  • This invention relates generally to novel 6-membered aromatics which are inhibitors of trypsin-like serine protease enzymes, especially factor Xa, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.
  • Z 1 and Z 2 are O, N(R) , S or OCH 2 and the central ring may be phenyl or a variety of heterocycles .
  • the presently claimed compounds do not contain the Z 1 linker or the substitution pattern of the above compounds.
  • WO 95/18111 addresses fibrinogen receptor antagonists, containing basic and acidic termini, of the formula:
  • R 1 represents the basic termini
  • U is an alkylene or heteroatom linker
  • V may be a heterocycle
  • the right hand portion of the molecule represents the acidic termini .
  • the presently claimed compounds do not contain the acidic termini of WO 95/18111.
  • Activated factor Xa whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation.
  • thrombin the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca 2+ and phospholipid) . Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K. : Optimization of condi tions for the catalytic effect of the factor IXa- factor VIII Complex: Probable role of the complex in the amplification of blood coagulation . Thromb. Res . 1979, 15, 617-629), inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.
  • one object of the present invention is to provide novel 6-membered aromatics which are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof .
  • I or pharmaceutically acceptable salt or prodrug forms thereof wherein A, B, D, E, M, R la , R lb , and Z are defined below, are effective factor Xa inhibitors.
  • the present invention provides novel compounds of formula I :
  • ring M contains from 0-4 N atoms
  • E is selected from phenyl, 2-pyridyl, 4-pyridyl, pyrimidyl, and piperidinyl substituted with 1 R;
  • R is selected from H, F, Cl, Br, I, OR 3 , SR 3 , CO 2 R 3 , NO 2 , and CH 2 OR 3 , and (CR 8 R 9 ) t NR 8 R 9 ;
  • E and R combine to form methylenedioxy or ethylenedioxy;
  • Z is selected from a bond, C ⁇ _ 4 alkylene, (CH 2 ) r O (CH 2 ) r ( CH 2 ) rNR 3( CH 2 )r, ( CH 2 ) r C ( 0 ) (CH 2 ) r , ( CH 2 ) r C ( 0 ) 0 ( CH 2 ) r , (CH 2 ) r 0C(0) (CH 2 )r/ (CH 2 ) r C (0) NR 3 (CH 2 ) r , (CH 2 ) r NR 3 C(0) (CH 2 ) r , (CH 2 ) r 0C (0) 0 (CH 2 ) r , (CH 2 )rOC(0)NR 3 (CH 2 )r, (CH 2 ) r NR 3 C (0) 0 ( CH 2 ) r , ( CH 2 )rNR 3 C(0)NR 3 (CH 2
  • R la and R lb when attached to adjacent carbon atoms, together with the atoms to which they are attached form a 5-8 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R 4 and which contains from 0-2 heteroatoms selected from the group consisting of N, 0, and S;
  • R la is a C(0) which replaces the amide hydrogen of Z to form a cyclic imide
  • R 1 " is selected from H, CH(CH 2 OR 2 ) , C(0)R 2c , C(0)NR 2 R 2a , S(0)R 2b , S(0) R 2b , and S0NR 2 R 2a ;
  • R 2 at each occurrence, is selected from H, CF 3 , C ⁇ _ 6 alkyl, benzyl, C 3 _ 6 carbocyclic residue substituted with 0-2 R 4b , and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with ⁇ -2 R 4b ;
  • R 2a is selected from H, CF 3 , C ⁇ _ 6 alkyl, benzyl, phenethyl, C 3 - 6 carbocyclic residue substituted with 0-2 R b , and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R b ;
  • R 2b is selected from CF , C 1 -. 4 alkoxy, C ⁇ - 6 alkyl, benzyl, C 3 _ 6 carbocyclic residue substituted with 0-2 R 4b , and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R 4b ;
  • R c at each occurrence, is selected from CF 3 , OH, C 1 - 4 alkoxy, C ⁇ _ 6 alkyl, benzyl, C 3 _ 6 carbocyclic residue substituted with 0-2 R b , and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R b ;
  • R 2 and R a together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R b and containing from 0-1 additional heteroatoms selected from the group consisting of N, 0, and S;
  • R 3 at each occurrence, is selected from H, C 1 - 4 alkyl, and phenyl ;
  • R 3a at each occurrence, is selected from H, C 1 - 4 alkyl, and phenyl
  • R 3b at each occurrence, is selected from H, C ⁇ _ 4 alkyl, and phenyl ;
  • R 3c at each occurrence, is selected from C 1 - 4 alkyl, and phenyl ,-
  • A is selected from:
  • B is selected from: H, Y, and X-Y;
  • Y is selected from:
  • one R 4 is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S;
  • one R a is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S and substituted with 0-1 R 5 ;
  • R 5 at each occurrence, is selected from CF 3 , C ⁇ _ 6 alkyl, phenyl substituted with 0-2 R 6 , and benzyl substituted with 0-2 R 6 ;
  • R 7 is selected from H, OH, C ⁇ - ⁇ alkyl, C ⁇ - 6 alkylcarbonyl , C 1 - 6 alkoxy, C ⁇ _ 4 alkoxycarbonyl , (CH 2 ) n -phenyl, C 6 - ⁇ o aryloxy, C 6 - ⁇ o aryloxycarbonyl, C 6 - ⁇ o aryl ethylcarbonyl , C ⁇ _ 4 alkylcarbonyloxy C _ 4 alkoxycarbonyl , C ⁇ -io arylcarbonyloxy C 1 - 4 alkoxycarbonyl , C ⁇ - 6 alkylaminocarbonyl , phenylaminocarbonyl , and phenyl-C ⁇ - 4 alkoxycarbonyl;
  • R 8 at each occurrence, is selected from H, C ⁇ _ 6 alkyl and (CH 2 ) n-pheny1 ;
  • R 7 and R 8 combine to form a 5 or 6 membered saturated, ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, 0, and S;
  • R 9 at each occurrence, is selected from H, C 1 - 6 alkyl and (CH 2 ) n -phenyl;
  • n is selected from 0, 1, 2, and 3;
  • n 0, 1, and 2;
  • p is selected from 0, 1, and 2 ,-
  • r is selected from 0, 1, 2, and 3;
  • s is selected from 0, 1, and 2;
  • t is selected from 0 and 1.
  • Z is selected from a bond, CH 2 0, OCH 2 , CH 2 NH, NHCH 2 , CH 2 C(0) ,
  • B is selected from: Y, X-Y, and NR 2 R 2a ;
  • Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R 4a ; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1, 2 , 3-oxadiazole, 1,2,4- oxadiazole, 1, 2 , 5-oxadiazole, 1, 3 , 4-oxadiazole, 1,2,3- thiadiazole, 1, 2 , 4-thiadiazole, 1, 2, 5-thiadiazole, 1,3,4- thiadiazole, 1, 2, 3-triazole, 1, 2 , 4-triazole, 1,2,5- triazole
  • Y may also be selected from the following bicyclic heteroaryl ring systems :
  • K is selected from 0, S, NH, and N.
  • R is selected from H, F, Cl, OR 3 , CH 2 OR 3 , CH 2 NH 2 ;
  • A is selected from: piperidinyl , piperazinyl, 5 - 6 carbocyclic residue substituted with 0-2 R 4 , and
  • Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R 4a ; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl , oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, benzimidazolyl, oxadiazole, thiadiazole, triazole, 1, 2 , 3 -oxadiazole, 1, 2 , 4-oxadiazole, 1, 2 , 5-oxadiazole, 1 , 3 , 4-oxadiazole, 1, 2 , 3 -thiadiazole
  • the present invention provides novel compounds wherein:
  • E is phenyl
  • R is selected from H, F, Cl, and Br;
  • A is selected from:
  • C 5 _ 6 carbocyclic residue substituted with 0-2 R 4 , and 5-6 membered heteroaryl containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R 4 ;
  • Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R a ; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, benzimidazolyl, oxadiazole, thiadiazole, triazole, 1, 2 , 3 -oxadiazole, 1, 2 , 4-oxadiazole, 1, 2 , 5-oxadiazole, 1, 3 , 4-oxadiazole, 1,2 , 3 -thiadiazole, 1, 2 , 4-thiadiazole, 1, 2 , 5-thiadiazole, 1, 3 , 4-thiadiazole, 1, 2 , 3-triazole,
  • R at each occurrence, is selected from H, CF 3 , C ⁇ _ 6 alkyl, benzyl, C 5 - 6 carbocyclic residue substituted with 0-2
  • R b and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R 4b ;
  • R 2a is selected from H, CF 3 , C ⁇ _ 6 alkyl, benzyl, phenethyl, C 5 - 6 carbocyclic residue substituted with 0-2 R b , and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R b ;
  • R 2b at each occurrence, is selected from CF 3 , C _ 4 alkoxy,
  • R 2c is selected from CF 3 , OH, C ⁇ _ 4 alkoxy, C ⁇ _ 6 alkyl, benzyl, Cs_ 6 carbocyclic residue substituted with 0-2 R 4b , and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R b ;
  • R 2 and R 2a together with the atom to which they are attached, combine to form a ring selected from imidazolyl, morpholino, piperazinyl, pyridyl, and pyrrolidinyl, substituted with 0-2 R 4b ;
  • the present invention provides novel compounds selected from:
  • the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof .
  • the present invention provides a novel method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof .
  • the compounds herein described may have asymmetric centers.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • 2 hydrogens on the atom are replaced.
  • Keto substituents are not present on aromatic moieties.
  • the present invention is intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • Isotopes of carbon include C-13 and C-14.
  • substituents and/or variables are permissible only if such combinations result in stable compounds.
  • a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring.
  • a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent.
  • Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds .
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms .
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.
  • haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl .
  • Alkoxy represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge.
  • alkoxy examples include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy.
  • Cycloalkyl is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl.
  • Alkenyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like.
  • Alkynyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.
  • Halo or "halogen” as used herein refers to fluoro, chloro, bromo, and iodo; and "counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
  • carbocycle or “carbocyclic residue” is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13 -membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic.
  • carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3. OJbicyclooctane, [4.3.0]bicyclononane, [4.4.
  • OJbicyclodecane [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl .
  • heterocycle or “heterocyclic system” is intended to mean a stable 5-to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic) , and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized.
  • the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
  • heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and 0 atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and 0 atoms in the heterocycle is not more than 1.
  • aromatic heterocyclic system is intended to mean a stable 5-to 7- membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, 0 and S. It is preferred that the total number of S and 0 atoms in the aromatic heterocycle is not more than 1.
  • heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl , benzothiophenyl, benzoxazolyl , benzthiazolyl, benztriazolyl, benztetrazolyl , benzisoxazolyl, benzisothiazolyl, benzimidazolinyl , carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1 , 5 , 2-dithiazinyl , dihydrofuro [2 , 3 -b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl , imidazolyl, lJ-indazolyl,
  • Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, lH-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl . Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic,
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington ' s Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
  • Prodrugs are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively.
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like.
  • “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent .
  • “Substituted” is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group (s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • “Therapeutically effective amount” is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host.
  • the combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul . 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components .
  • the compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis .
  • the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.
  • the reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will sometimes require a judgment to modify the order of synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.
  • W is defined as a suitable protected nitrogen, such as N0 2 or NHBOC; a protected sulfur, such as S-tBu or SMOM; or a methyl ester.
  • a suitable protected nitrogen such as N0 2 or NHBOC
  • a protected sulfur such as S-tBu or SMOM
  • a methyl ester e.g., a protected boronic acid, B-B(OH) 2 .
  • the W-A-Br subunit may be already linked to ring M before the Suzuki coupling reaction. Deprotection provides the complete subunit.
  • Scheme 2 describes a typical example of how the A-B subunit is prepared for attachment to ring M.
  • 4-Bromoaniline is protected as Boc-derivative and the coupled to 2-(t- butylamino) sulfonylphenylboronic acid under Suzuki conditions.
  • 2- (t-Butylamino) sulfonylphenylboronic acid is prepared by the method described by Rivero (Bioorg. Med. Chem . Lett . 1994, 189) .
  • Deprotection with TFA can provide the aminobiphenyl compound.
  • the aminobiphenyl is then coupled to the core ring structures as described below.
  • A-C(0)C1 a secondary NH as A-C(0)-Y part of a ring or chain
  • the chemistry of Table A can be carried out in aprotic solvents such as a chlorocarbon, pyridine, benzene or toluene, at temperatures ranging from -20°C to the reflux point of the solvent and with or without a trialkylamine base.
  • aprotic solvents such as a chlorocarbon, pyridine, benzene or toluene
  • the coupling chemistry of table B can be carried out by a variety of methods.
  • the Grignard reagent required for Y is prepared from a halogen analog of Y in dry ether, dimethoxyethane or tetrahydrofuran at 0°C to the reflux point of the solvent. This Grignard reagent can reacted directly under very controlled conditions, that is low temperature (-20°C or lower) and with a large excess of acid chloride or with catalytic or stoichiometric copper bromide*dimethyl sulfide complex in dimethyl sulfide as a solvent or with a variant thereof.
  • the ether and thioether linkages of Table C can be prepared by reacting the two components in a polar aprotic solvent such as acetone, dimethylformamide or dimethylsulfoxide in the presence of a base such as potassium carbonate, sodium hydride or potassium t-butoxide at a temperature ranging from ambient to the reflux point of the solvent used.
  • a polar aprotic solvent such as acetone, dimethylformamide or dimethylsulfoxide
  • a base such as potassium carbonate, sodium hydride or potassium t-butoxide
  • Table D Preparation of -SO- and -S0- linkages from thioether of Table C.
  • Alumina/Oxone to chloroperbenzoic acid give: to give :
  • the thioethers of Table C serve as a convenient starting material for the preparation of the sulfoxide and sulfone analogs of Table D.
  • a combination of wet alumina and Oxone can provide a reliable reagents for the oxidation of the thioether to the sulfoxide as shown by Greenhalgh ( Syn . Lett . 1992, 235) .
  • the sulfone can be prepared according to the method of Satoh ( Chem . Lett . 1992, 381) using m- chloroperbenzoic acid.
  • Scheme 3 describes the synthesis of compounds wherein M is a benzene ring and Q is a protected precursor of group D of Formula I and V is a nitro, protected sulfonamide or ester group and precursor of group Z of Formula I.
  • the V group is placed on an appropriately substituted phenol either via nitration as shown by Poirier et al . ( Tetrahedron 1989, 45 (5) , 1415) , sulfonylation as shown by Kuznetsov (Akad. Nauk SSSR Ser . Khim 1990, 8, 1888) or carboxylation by Sartori et al . (Synthesis 1988, 10, 763) . Bromination with triphenylphosphine and bromine (J " . Am . Chem . Soc . 1964, 86, 964) gives the desired bromide. Suzuki coupling with the appropriate boronic acid provides the desired substituted pyridine .
  • Schemes 4, 5, 6, and 7 describe the synthesis of compounds wherein M is pyridine and Q is a protected precursor of group D of Formula I. Each scheme represents a different substitution pattern for the pyridine ring.
  • a suitably protected aldehyde is subjected to base-catalyzed condensation with an activated ester to give after deprotection the desired aldehyde.
  • Refluxing with ammonium chloride as shown by Dornow and Ische Chem . Ber. 1956, 89, 876) provides the pyridinol which is brominated with POBr 3 (Tjeenk et al . Rec . Trav. Chi . 1948, 67, 380) to give the desired 2-bromopyridine.
  • Suzuki coupling with the appropriate boronic acid provides the desired substituted pyridine.
  • Scheme 6 describes a synthesis of a third substitution pattern on a pyridine ring.
  • the appropriate tricarbonyl compound which can be prepared by methods described in Scheme 4 is treated with ammonium chloride to form the pyridinol which is subsequently brominated. Palladium-catalyzed coupling provides the desired substituted pyridine.
  • Scheme 7 takes a suitably substituted dicarbonyl compound and by chemistry illustrated in Schemes 4 and 6, reacts it with ammonium chloride. Bromination gives the 3 -bromopyridine which upon palladium-catalyzed coupling provides the desired substituted pyridine.
  • Schemes 8, 9, and 10 describe the synthesis of compounds wherein M is pyridazine and Q is a protected precursor of group D of Formula I. Each scheme represents a different substitution pattern for the pyridine ring.
  • an activated ester is reacted with an appropriately substituted ⁇ -keto aldehyde and hydrazine as shown by Schmidt and Druey (Helv. Chim. Acta 1954, 37, 134 and 1467) .
  • Conversion of the pyridazinone to the bromide using POBr 3 and palladium- catalyzed coupling provides the desired substituted pyridazine.
  • glyoxal can react under basic conditions with an activated ketone and subsequently brominated/dehydro- brominated to give the desired ketoaldehyde .
  • a protected ketone can react with an activated aldehyde, undergo bromination/dehydrobromination, be deprotected and oxidized to give the regioisomeric ketoaldehyde.
  • Cyclization as shown by Sprio and Madonia (Ann. Chim . 1958, 48, 1316) with hydrazine followed by palladium-catalyzed coupling provides the desired substituted pyridazine.
  • a aldehyde can be reacted with an activated ketone, brominated, de ydro- brominated and deprotected to give the desired diketone.
  • a regioisomeric ketone can be placed through the same reaction sequence to produce an isomeric keto aldehyde. Reaction with hydrazine followed by palladium- catalyzed coupling provides the desired substituted pyridazine .
  • Schemes 11, and 12 describe the synthesis of compounds wherein M is pyrimidine and Q is a protected precursor of group D of Formula I. Each scheme represents a different substitution pattern for the pyrimidine ring.
  • a condensation with an appropriately substituted acid chloride and an activated ester followed by conjugate reduction by tin hydride gives the desired 1,4 dicarbonyl compound.
  • Cyclization with formamidine or a substituted amidine followed by bromination gives the desired regioisomeric pyrimidine.
  • Palladium-catalyzed coupling provides the desired substituted pyrimidine.
  • Scheme 12 shows how an amidine can be condensed with a 1, 3-dicarbonyl compound and subsequently brominated in the 5-position (J " . Het. Chem . 1973, 10, 153) to give a specific regioisomeric bromopyrimidine .
  • Palladium-catalyzed coupling provides the desired substituted pyrimidine.
  • Schemes 14 and 15 describe the synthesis of compounds wherein M is a 1, 2 , 3-triazine and Q is a protected precursor of group D of Formula I.
  • a vinyl bromide is palladium coupled to a molecule containing the substituent R . Allylic bromination followed by azide displacement provide the cyclization precursor.
  • Triphenylphosphine- mediated cyclization J. Org. Chem . 1990, 55, 4724
  • Lead tetraacetate mediated rearrangement as shown by Neunhoeffer et al . (Ann . 1985, 1732) provides the desired regioisomeric 1, 2 , 3-triazine.
  • Palladium-catalyzed coupling provides the substituted triazine.
  • Schemes 16 and 17 describe the synthesis of compounds wherein M is a 1, 2 , 4-triazine and Q is a protected precursor of group D of Formula I.
  • a nitrile is converted using hydrazine to give the amidrazone which is condensed with a ⁇ -ketoester to give the triazinone as shown by Paudler and Lee ( M Org. Chem . 1971, 36, 3921) .
  • Bromination as shown by Rykowski and van der Plas ( J. Org. Chem . 1987, 52, 71) followed by palladium-catalyzed coupling provides the desired 1, 2, 4-triazine.
  • Scheme 18 describes the synthesis of compounds wherein M is a 1, 2 , 3 , 4-tetrazine and Q is a protected precursor of group D of Formula I.
  • Lithiation of a vinyl bromide, transmetallation with tin, palladium catalyzed carbonylation and hydrazone formation provides a diene for a subsequent Diels-Alder reaction as shown by Carboni and Lindsey ( J. Am. Chem. Soc . 1959, 81 , 4342) .
  • Reaction with dibenzyl azodicarboxylate followed by catalytic hydrogenation to debenzylate and decarboxylate should give after bromination the desired 1, 2 , 3 , 4-tetrazine .
  • Palladium-catalyzed coupling provides the desired substitution.
  • Potassium permanganate (18.4 g, 116 mmol) was dissolved in water (400 mL) and added to 2-bromo-3-methylpyridine (10.0 g, 58 mmol) and refluxed for 16 hours. After cooling to room temperature, the slurry was filtered through a celite plug and rinsed with water and chloroform. The entire filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted again with CHC1 3 and acidified with 6N HCl to pH 1. A white solid was obtained on standing (2.08 g of product) . The pH of the remaining aqueous was adjusted to pH 4 with 2M NaOH and 2M HCl, then concentrated to ⁇ 100mL.
  • Methyl 2-bromonicotinate (2.0 g, 9.3 mmol) and 3- cyanophenylboronic acid (2.7 g, 18.4 mmol) were combined in 190 mL benzene.
  • bis (triphenylphosphine) palladium (II) chloride 325 mg, 0.5 mmol
  • Methyl 2- (3 ' -cyanophenyl) nicotinate (300 mg, 1.3 mmol) was combined with of 4-amino-2 ' -t-butylaminosulfonyl- [1 , 1 ' ] biphenyl (383 mg, 1.3 mmol) in 12 mL dry CH 2 C1 2 .
  • a solution of trimethylaluminum (3.8 mL, 2.0 M in heptane) was added, and an exothermic reaction immediately occurred and the mixture darkened.
  • the resulting solution was stirred at room temperature under argon for 3 days and then quenched carefully with a few drops of 1 M HCl. An emulsion was obtained on dilution with EtOAc and water.
  • Methyl 2- (3 ' -cyanophenyl) nicotinate (1.21 g, 5.1 mmol) was partially dissolved in MeOH (40 mL) , and lithium hydroxide monohydrate (234 mg dissolved in 6 mL H0, 5.6 mmol) was added. After 20 hours, the resulting solution was diluted with water and extracted with CHC1 3 . The aqueous was acidified to pK 4 with 1 M HCl and extracted several times with CHC1 3 . Solid sodium chloride was added to the aqueous solution and the solution was extracted with 5-10% MeOH/CHCl 3 .
  • N- [5- (2-t-butylaminosulfonyl)phenylpyrid-2-yl] -2- (3 ' - cyanophenyl) nicotinamide (410 mg, 1.03) was dissolved in a mixture of dry MeOH (5mL) and dry CHC1 3 (15mL) and cooled to 0°C .
  • HCl(g) was generated by the addition of concentrated H 2 S0 4 (45 mL) to NaCl (220 g) over 55 min and was bubbled into the reaction mixture. The HCl generator and ice bath were removed, and the reaction was stirred under argon for 16 hours and evaporated.
  • the following table contains representative examples of the present invention. Each entry in the table is intended to be paired with each formulae at the start of the table. For example, example 1 in Table 2 is intended to be paired with each of formulae ⁇ ss 4 .

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Abstract

Cette invention concerne des composés aromatiques à six éléments de formule (I) ou des formes de sel pharmaceutiquement acceptable de ces derniers. Dans la formule, D peut représenter CH2NH2 ou C(=NH)NH2. Ces composés sont utiles en tant qu'inhibiteurs du facteur Xa.
PCT/US1998/012682 1997-06-19 1998-06-18 Agents aromatiques a six membres amidino utiles en tant qu'inhibiteurs du facteur xa WO1998057934A1 (fr)

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AU79769/98A AU7976998A (en) 1997-06-19 1998-06-18 (amidino)6-membered aromatics as factor xa inhibitors
EP98930362A EP0993448A1 (fr) 1997-06-19 1998-06-18 Agents aromatiques a six membres amidino utiles en tant qu'inhibiteurs du facteur xa

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Cited By (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999050255A2 (fr) * 1998-03-27 1999-10-07 Du Pont Pharmaceuticals Company Pyrazolines et triazolines disubstituees, utilisees en tant qu'inhibiteurs du facteur xa
WO2000047554A2 (fr) * 1999-02-11 2000-08-17 Cor Therapeutics Inc. INHIBITEURS DU FACTEUR Xa
WO2000071508A2 (fr) * 1999-05-24 2000-11-30 Cor Therapeutics, Inc. Inhibiteurs du facteur xa
WO2001019788A2 (fr) * 1999-09-17 2001-03-22 Cor Therapeutics, Inc. BENZAMIDES ET INHIBITEURS CORRESPONDANTS DU FACTEUR Xa
WO2001019798A2 (fr) * 1999-09-17 2001-03-22 Cor Therapeutics Inc. INHIBITEURS DU FACTEUR Xa
WO2001064643A2 (fr) * 2000-02-29 2001-09-07 Cor Therapeutics, Inc. Benzamides et inhibiteurs associes du facteur xa
EP1135131A1 (fr) * 1998-12-04 2001-09-26 Berlex Laboratories, Inc. Derives de pyrimidine a substitution aryle et heterocyclyle en tant qu'anticoagulants
WO2002010145A1 (fr) * 2000-07-28 2002-02-07 Merck Patent Gmbh Derives d'urethane
US6358960B1 (en) 1998-02-17 2002-03-19 Ono Pharmaceutical Co., Ltd. Amidino derivatives and drugs containing the same as the active ingredient
US6369227B1 (en) 1998-12-23 2002-04-09 Bristol-Myers Squibb Pharma Company Thrombin or factor Xa inhibitors
WO2002076945A1 (fr) * 2001-03-09 2002-10-03 Ortho-Mcneil Pharmaceutical, Inc. Aminopyrrolidine-sulfonamides utilises comme inhibiteurs de serine protease
EP1254136A1 (fr) * 2000-01-29 2002-11-06 LG Chem Investment, Ltd. INHIBITEURS DU FACTEUR Xa CONTENANT DES ARYLAMIDINES ET DES DERIVES, ET PROMEDICAMENTS OBTENUS A PARTIR DESDITS INHIBITEURS
US6506771B2 (en) 2000-06-23 2003-01-14 Bristol-Myers Squibb Pharma Company Heteroaryl-phenyl heterobicyclic factor Xa inhibitors
US6599926B2 (en) 2000-06-23 2003-07-29 Bristol-Myers Squibb Company Heteroaryl-phenyl substituted factor Xa inhibitors
US6632815B2 (en) 1999-09-17 2003-10-14 Millennium Pharmaceuticals, Inc. Inhibitors of factor Xa
US6670362B2 (en) 2000-09-20 2003-12-30 Pfizer Inc. Pyridazine endothelin antagonists
US6686368B1 (en) 1999-09-17 2004-02-03 Millennium Pahrmaceuticals, Inc. Inhibitors of factor Xa
US6710061B2 (en) 2001-03-09 2004-03-23 Ortho-Mcneil Pharamceutical, Inc. Aminopyrrolidine sulfonamides as serine protease inhibitors
US6716834B2 (en) 2000-05-16 2004-04-06 Astrazeneca Ab Thiochromane derivatives and their use as thrombin inhibitors
US6844367B1 (en) 1999-09-17 2005-01-18 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US6949550B2 (en) 2001-12-04 2005-09-27 Bristol-Myers Squibb Company Substituted amino methyl factor Xa inhibitors
US6967208B2 (en) 2001-09-21 2005-11-22 Bristol-Myers Squibb Pharma Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
US7115627B2 (en) 2001-12-04 2006-10-03 Bristol-Myers Squibb Company Glycinamides as factor Xa inhibitors
US7122557B2 (en) 2003-03-18 2006-10-17 Bristol-Myers Squibb Company Sulfonyl-amidino-containing and tetrahydropyrimidino-containing compounds as factor Xa inhibitors
US7125898B2 (en) 2002-02-12 2006-10-24 Smithkline Beecham Corporation Nicotinamide derivatives useful as p38 inhibitors.
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US7338963B2 (en) 2001-09-21 2008-03-04 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
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US7396843B2 (en) 2001-10-17 2008-07-08 Glaxo Group Limited 5′-carbamoyl-1,1′-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors
US7432289B2 (en) 2001-10-17 2008-10-07 Glaxo Group Limited 5-Acylamino-1,1′-biphenyl-4-carboxamide derivatives and their use as P38 kinase inhibitors
US7615651B2 (en) 2006-11-13 2009-11-10 Pfizer Inc. Diaryl, dipyridinyl and aryl-pyridinyl derivatives and uses thereof
EP2319516A1 (fr) * 2003-07-23 2011-05-11 Synta Pharmaceuticals Corp. Composés pour le traitement de troubles inflammatoires et de maladie autoimmunes
US8202999B2 (en) 2005-01-07 2012-06-19 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
US8524907B2 (en) 2006-11-02 2013-09-03 Millennium Pharmaceuticals, Inc. Methods of synthesizing pharmaceutical salts of a factor Xa inhibitor
EP2982668A2 (fr) 2002-12-03 2016-02-10 Pharmacyclics LLC Dérivés de 2-(2-hydroxybiphényl-3-yl)-1h-benzoimidazole-5-carboxamidine en tant qu'inhibiteurs du facteur viia inhibitors pour le traitement de maladies thromboemboliques

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995018111A1 (fr) * 1993-12-28 1995-07-06 The Du Pont Merck Pharmaceutical Company Composes contenant des terminaisons basiques et acides utiles en tant qu'antagonistes des recepteurs de fibrinogene
WO1996016940A1 (fr) * 1994-12-02 1996-06-06 Yamanouchi Pharmaceutical Co., Ltd. Nouveau derive d'amidinonaphtyle ou sel de celui-ci
WO1996028427A1 (fr) * 1995-03-10 1996-09-19 Berlex Laboratories, Inc. Derives de benzamidine et utilisation de ces derives en tant qu'anticoagulants
WO1997023212A1 (fr) * 1995-12-21 1997-07-03 The Du Pont Merck Pharmaceutical Company ISOXAZOLINE, ISOTHIAZOLINE ET PYRAZOLINE INHIBITEURS DU FACTEUR Xa
WO1997038984A1 (fr) * 1996-04-17 1997-10-23 Du Pont Pharmaceuticals Company DERIVES DE N-(AMIDINOPHENYL)-N'-(SUBST.)-3H-2,4-BENZODIAZEPINE-3-ONE EN TANT QU'INHIBITEURS DU FACTEUR Xa
WO1998006694A1 (fr) * 1996-08-16 1998-02-19 Du Pont Pharmaceuticals Company Amidinophenyl-pyrrolidines, -pyrrolines et -isoxazolidines et leurs derives
WO1998011094A1 (fr) * 1996-09-12 1998-03-19 Schering Aktiengesellschaft Derives benzamidine, substitues par des derives d'acides amines cycliques ou d'hydroxyacides cycliques, et leur utilisation en tant qu'anticoagulants
WO1998028269A1 (fr) * 1996-12-23 1998-07-02 Du Pont Pharmaceuticals Company COMPOSES HETEROAROMATIQUES CONTENANT DE L'AZOTE, UTILISES EN TANT QU'INHIBITEURS DU FACTEUR Xa
WO1998028282A2 (fr) * 1996-12-23 1998-07-02 Du Pont Pharmaceuticals Company OXYGENE OU SOUFRE CONTANANT DES HETERO-AROMATIQUES UTILISES COMME INHIBITEURS DU FACTEUR Xa

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995018111A1 (fr) * 1993-12-28 1995-07-06 The Du Pont Merck Pharmaceutical Company Composes contenant des terminaisons basiques et acides utiles en tant qu'antagonistes des recepteurs de fibrinogene
WO1996016940A1 (fr) * 1994-12-02 1996-06-06 Yamanouchi Pharmaceutical Co., Ltd. Nouveau derive d'amidinonaphtyle ou sel de celui-ci
EP0798295A1 (fr) * 1994-12-02 1997-10-01 Yamanouchi Pharmaceutical Co. Ltd. Nouveau derive d'amidinonaphtyle ou sel de celui-ci
WO1996028427A1 (fr) * 1995-03-10 1996-09-19 Berlex Laboratories, Inc. Derives de benzamidine et utilisation de ces derives en tant qu'anticoagulants
WO1997023212A1 (fr) * 1995-12-21 1997-07-03 The Du Pont Merck Pharmaceutical Company ISOXAZOLINE, ISOTHIAZOLINE ET PYRAZOLINE INHIBITEURS DU FACTEUR Xa
WO1997038984A1 (fr) * 1996-04-17 1997-10-23 Du Pont Pharmaceuticals Company DERIVES DE N-(AMIDINOPHENYL)-N'-(SUBST.)-3H-2,4-BENZODIAZEPINE-3-ONE EN TANT QU'INHIBITEURS DU FACTEUR Xa
WO1998006694A1 (fr) * 1996-08-16 1998-02-19 Du Pont Pharmaceuticals Company Amidinophenyl-pyrrolidines, -pyrrolines et -isoxazolidines et leurs derives
WO1998011094A1 (fr) * 1996-09-12 1998-03-19 Schering Aktiengesellschaft Derives benzamidine, substitues par des derives d'acides amines cycliques ou d'hydroxyacides cycliques, et leur utilisation en tant qu'anticoagulants
WO1998028269A1 (fr) * 1996-12-23 1998-07-02 Du Pont Pharmaceuticals Company COMPOSES HETEROAROMATIQUES CONTENANT DE L'AZOTE, UTILISES EN TANT QU'INHIBITEURS DU FACTEUR Xa
WO1998028282A2 (fr) * 1996-12-23 1998-07-02 Du Pont Pharmaceuticals Company OXYGENE OU SOUFRE CONTANANT DES HETERO-AROMATIQUES UTILISES COMME INHIBITEURS DU FACTEUR Xa

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
EDMUNDS J J ET AL: "THROMBIN AND FACTOR XA INHIBITION", ANNUAL REPORTS IN MEDICINAL CHEMISTRY, vol. 31, 1996, pages 51 - 60, XP000653962 *
KUNITADA S ET AL: "FACTOR XA INHIBITORS", CURRENT PHARMACEUTICAL DESIGN, vol. 2, no. 5, October 1996 (1996-10-01), pages 531 - 542, XP002057653 *
MAO S -S: "FACTOR XA INHIBITORS", PERSPECTIVES IN DRUG DISCOVERY AND DESIGN, vol. 1, no. 3, 1993, pages 423 - 430, XP000654087 *
STUERZEBECHER J ET AL: "SYNTHETIC INHIBITORS OF SERINE PROTEINASES XXIII. INHIBITION OF FACTOR XA BY DIAMIDINES", THROMBOSIS RESEARCH, vol. 17, no. 3/04, 1980, pages 545 - 548, XP000602215 *
TIDWELL R R ET AL: "STRATEGIES FOR ANTICOAGULATION WITH SYNTHETIC PROTEASE INHIBITORS XA INHIBITORS VERSUS THROMBIN INHIBITORS", THROMBOSIS RESEARCH, vol. 19, no. 3, 1 August 1980 (1980-08-01), pages 339 - 349, XP000574196 *

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WO1999050255A3 (fr) * 1998-03-27 1999-11-18 Du Pont Pharm Co Pyrazolines et triazolines disubstituees, utilisees en tant qu'inhibiteurs du facteur xa
WO1999050255A2 (fr) * 1998-03-27 1999-10-07 Du Pont Pharmaceuticals Company Pyrazolines et triazolines disubstituees, utilisees en tant qu'inhibiteurs du facteur xa
US6191159B1 (en) 1998-03-27 2001-02-20 Dupont Pharmaceuticals Company Disubstituted pyrazolines and triazolines as factor Xa inhibitors
US6630468B2 (en) 1998-03-27 2003-10-07 Donald J. P. Pinto Disubstituted pyrazolines and triazolines as factor Xa inhibitors
US6436985B2 (en) 1998-03-27 2002-08-20 Bristol-Myers Squibb Pharma Company Disubstituted pyrazolines and triazolines as factor Xa inhibitors
EP1135131A4 (fr) * 1998-12-04 2002-01-02 Berlex Lab Derives de pyrimidine a substitution aryle et heterocyclyle en tant qu'anticoagulants
EP1135131A1 (fr) * 1998-12-04 2001-09-26 Berlex Laboratories, Inc. Derives de pyrimidine a substitution aryle et heterocyclyle en tant qu'anticoagulants
US6369227B1 (en) 1998-12-23 2002-04-09 Bristol-Myers Squibb Pharma Company Thrombin or factor Xa inhibitors
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US6545054B1 (en) 1999-02-11 2003-04-08 Millennium Pharmaceuticals, Inc. Alkenyl and alkynyl compounds as inhibitors of factor Xa
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US6638980B1 (en) 1999-05-24 2003-10-28 Millennium Pharmaceuticals, Inc. Inhibitors of factor Xa
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WO2000071508A2 (fr) * 1999-05-24 2000-11-30 Cor Therapeutics, Inc. Inhibiteurs du facteur xa
WO2001019788A2 (fr) * 1999-09-17 2001-03-22 Cor Therapeutics, Inc. BENZAMIDES ET INHIBITEURS CORRESPONDANTS DU FACTEUR Xa
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US7285565B2 (en) 1999-09-17 2007-10-23 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US6844367B1 (en) 1999-09-17 2005-01-18 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US6720317B1 (en) 1999-09-17 2004-04-13 Millennium Pharmaceuticals, Inc. Inhibitors of factor Xa
US6686368B1 (en) 1999-09-17 2004-02-03 Millennium Pahrmaceuticals, Inc. Inhibitors of factor Xa
WO2001019788A3 (fr) * 1999-09-17 2001-08-09 Cor Therapeutics Inc BENZAMIDES ET INHIBITEURS CORRESPONDANTS DU FACTEUR Xa
WO2001019798A2 (fr) * 1999-09-17 2001-03-22 Cor Therapeutics Inc. INHIBITEURS DU FACTEUR Xa
US6632815B2 (en) 1999-09-17 2003-10-14 Millennium Pharmaceuticals, Inc. Inhibitors of factor Xa
EP1254136A4 (fr) * 2000-01-29 2005-06-01 Lg Chem Investment Ltd INHIBITEURS DU FACTEUR Xa CONTENANT DES ARYLAMIDINES ET DES DERIVES, ET PROMEDICAMENTS OBTENUS A PARTIR DESDITS INHIBITEURS
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US10179124B2 (en) 2000-02-29 2019-01-15 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US9629831B2 (en) 2000-02-29 2017-04-25 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor XA
US6716834B2 (en) 2000-05-16 2004-04-06 Astrazeneca Ab Thiochromane derivatives and their use as thrombin inhibitors
US6599926B2 (en) 2000-06-23 2003-07-29 Bristol-Myers Squibb Company Heteroaryl-phenyl substituted factor Xa inhibitors
US6506771B2 (en) 2000-06-23 2003-01-14 Bristol-Myers Squibb Pharma Company Heteroaryl-phenyl heterobicyclic factor Xa inhibitors
WO2002010145A1 (fr) * 2000-07-28 2002-02-07 Merck Patent Gmbh Derives d'urethane
US6670362B2 (en) 2000-09-20 2003-12-30 Pfizer Inc. Pyridazine endothelin antagonists
US6890939B2 (en) 2001-03-09 2005-05-10 Ortho-Mcneil Pharmaceutical, Inc. Aminopyrrolidine sulfonamides as serine protease inhibitors
US6538017B2 (en) 2001-03-09 2003-03-25 Ortho-Mcneil Pharmaceutical, Inc. Aminopyrrolidine sulfonamides as serine protease inhibitors
US6630505B2 (en) 2001-03-09 2003-10-07 Ortho-Mcneil Pharmaceutical, Inc. Aminopyrrolidine sulfonamides as serine protease inhibitors
WO2002076945A1 (fr) * 2001-03-09 2002-10-03 Ortho-Mcneil Pharmaceutical, Inc. Aminopyrrolidine-sulfonamides utilises comme inhibiteurs de serine protease
US6710061B2 (en) 2001-03-09 2004-03-23 Ortho-Mcneil Pharamceutical, Inc. Aminopyrrolidine sulfonamides as serine protease inhibitors
US6989391B2 (en) 2001-09-21 2006-01-24 Bristol-Myers-Squibb Pharma Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
US7531535B2 (en) 2001-09-21 2009-05-12 Bristol-Meyers Squibb Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
US9975891B2 (en) 2001-09-21 2018-05-22 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
US6967208B2 (en) 2001-09-21 2005-11-22 Bristol-Myers Squibb Pharma Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
US6995172B2 (en) 2001-09-21 2006-02-07 Bristol-Myers Squibb Pharma Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
US7005435B2 (en) 2001-09-21 2006-02-28 Bristol-Myers Squibb Pharma Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
US7338963B2 (en) 2001-09-21 2008-03-04 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
US8470854B2 (en) 2001-09-21 2013-06-25 Bristol-Meyers Squibb Company Lactam-containing compounds and derivatives thereof as factor XA inhibitors
US7371761B2 (en) 2001-09-21 2008-05-13 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
US8188120B2 (en) 2001-09-21 2012-05-29 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
US7960411B2 (en) 2001-09-21 2011-06-14 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
US7691846B2 (en) 2001-09-21 2010-04-06 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
EP2105436A1 (fr) 2001-09-21 2009-09-30 Bristol-Myers Squibb Company Composés comprenant un lactame et leurs dérivés en tant qu'inhibiteurs du facteur Xa
US7384963B2 (en) 2001-10-17 2008-06-10 Glaxo Group Limited 2′-Methyl-5-(1,3,4-oxadiazol-2-yl)1, 1′-biphenyl-4-carboxaide derivatives and their use as p38 kinase
US7166623B2 (en) 2001-10-17 2007-01-23 Glaxo Group Limited 2′-Methyl-5′-(1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors
US7432289B2 (en) 2001-10-17 2008-10-07 Glaxo Group Limited 5-Acylamino-1,1′-biphenyl-4-carboxamide derivatives and their use as P38 kinase inhibitors
US7208629B2 (en) 2001-10-17 2007-04-24 Glaxo Group Limited 5′-Carbamoyl-1,1-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors
US7151118B2 (en) 2001-10-17 2006-12-19 Glaxo Group Limited Biphenylcarboxylic amide derivatives as p38-kinase inhibitors
US7309800B2 (en) 2001-10-17 2007-12-18 Glaxo Group Limited Biphenylcarboxylic amide derivatives as p38 kinase inhibitors
US7183297B2 (en) 2001-10-17 2007-02-27 Glaxo Group Limited Biphenyl-derivatives as p38-kinase inhibitors
US7396843B2 (en) 2001-10-17 2008-07-08 Glaxo Group Limited 5′-carbamoyl-1,1′-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors
US6949550B2 (en) 2001-12-04 2005-09-27 Bristol-Myers Squibb Company Substituted amino methyl factor Xa inhibitors
US7115627B2 (en) 2001-12-04 2006-10-03 Bristol-Myers Squibb Company Glycinamides as factor Xa inhibitors
US7125898B2 (en) 2002-02-12 2006-10-24 Smithkline Beecham Corporation Nicotinamide derivatives useful as p38 inhibitors.
US7514456B2 (en) 2002-02-12 2009-04-07 Smithkline Beecham Corporation Nicotinamide derivatives useful as p38 inhibitors
US7709506B2 (en) 2002-02-12 2010-05-04 Glaxosmithkline Llc Nicotinamide derivatives useful as p38 inhibitors
US7312214B2 (en) 2002-05-10 2007-12-25 Bristol-Myers Squibb Company 1, 1-disubstituted cycloalkyl derivatives as factor Xa inhibitors
EP2982668A2 (fr) 2002-12-03 2016-02-10 Pharmacyclics LLC Dérivés de 2-(2-hydroxybiphényl-3-yl)-1h-benzoimidazole-5-carboxamidine en tant qu'inhibiteurs du facteur viia inhibitors pour le traitement de maladies thromboemboliques
US7122557B2 (en) 2003-03-18 2006-10-17 Bristol-Myers Squibb Company Sulfonyl-amidino-containing and tetrahydropyrimidino-containing compounds as factor Xa inhibitors
US7271289B2 (en) 2003-04-09 2007-09-18 Smithkline Beecham Corporation Biphenylcarboxylic amide derivatives as p38 kinase inhibitors
EP2319516A1 (fr) * 2003-07-23 2011-05-11 Synta Pharmaceuticals Corp. Composés pour le traitement de troubles inflammatoires et de maladie autoimmunes
US8202999B2 (en) 2005-01-07 2012-06-19 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
US8592486B2 (en) 2005-01-07 2013-11-26 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
US8524907B2 (en) 2006-11-02 2013-09-03 Millennium Pharmaceuticals, Inc. Methods of synthesizing pharmaceutical salts of a factor Xa inhibitor
US9221758B2 (en) 2006-11-02 2015-12-29 Millennium Pharmaceuticals, Inc. Methods of synthesizing pharmaceutical salts of a factor Xa inhibitor
US7615651B2 (en) 2006-11-13 2009-11-10 Pfizer Inc. Diaryl, dipyridinyl and aryl-pyridinyl derivatives and uses thereof

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