WO1994022444A1 - Composes tricycliques utilises pour inhiber l'agregation plaquettaire - Google Patents

Composes tricycliques utilises pour inhiber l'agregation plaquettaire Download PDF

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WO1994022444A1
WO1994022444A1 PCT/US1994/003383 US9403383W WO9422444A1 WO 1994022444 A1 WO1994022444 A1 WO 1994022444A1 US 9403383 W US9403383 W US 9403383W WO 9422444 A1 WO9422444 A1 WO 9422444A1
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compound according
group
independently
chr6
compounds
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PCT/US1994/003383
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English (en)
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James Francis Callahan
William F. Huffman
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Smithkline Beecham Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention relates to novel compounds which inhibit platelet aggregation, pharmaceutical compositions containing the compounds and methods of using the compounds.
  • GPIIb-IIIa platelet receptor complex which is a member of a family of adhesion receptors referred to as integrins. It has been found that frequently the natural ligands of integrin receptors are proteins which contain an Arg-Gly-Asp sequence. Von Willebrand factor and fibrinogen, which are considered to be natural ligands for the GP ⁇ b-iria receptor, possess an Arg-Gly-Asp (RGD in single letter ami no acid code) sequence in their primary structure. Functionally, these proteins are able to bind and crosslink GPIIb-IIIa receptors on adjacent platelets and thereby effect aggregation of platelets.
  • Fibronectin, vitronectin and thrombospondin are RGD-containing proteins which have also been demonstrated to bind to GP ⁇ b-IIIa.
  • Fibronectin is found in plasma and as a structural protein in the intracellular matrix. Binding between the structural proteins and GPIIb-IIIa may function to cause platelets to adhere to damaged vessel walls.
  • Linear and cyclic peptides which bind to vitronectin and contain an RGD sequence are disclosed in WO 89/05150 (PCT US88/04403).
  • EP 0 275 748 discloses linear tetra- to hexapeptides and cyclic hexa- to octapeptides which bind to the GPIIb-IIIa receptor and inhibit platelet aggregation.
  • Other linear and cyclic peptides are reported in EP-A 0 341 915.
  • the peptide like structures of such inhibitors often pose problems, such as in drug delivery, metabolic stability and selectivity.
  • SUBST ⁇ UTC SHEET fibrinogen receptor antagonists which mimic a conformational ⁇ -turn in the RGD sequence by forming a monocyclic seven-membered ring structure.
  • novel fibrinogen receptor antagonists e.g. inhibitors of the GPIIb-IIIa protein
  • the present invention discloses novel bicyclic compounds including benzazepines and benzodiazepines, which are inhibitors of the GPIIb-IIIa receptor and inhibit platelet aggregation.
  • Certain 5-phenyl- 1,4-benzodiazepines are known as a class of drugs which affect the central nervous system, and have been used as anxiolytics. See Sternbach, L.H., J. Med. Chem., 22, 2 (1979). It has also been disclosed that certain 5-phenyl-l,4-benzodiazepines antagonize the effects of cholecystokinin. See Friedinger, Med. Res. Rev., 9, 271 (1989). However, no such bicyclic compounds have been reported to have anti-platelet activity.
  • this invention is a tricyclic compound comprising a substituted six-membered ring which is fused to both a substituted seven-membered ring and a substituted eight-membered ring as described hereinafter in formula (I).
  • This invention is also a pharmaceutical composition for inhibiting platelet aggregation or clot formation, which comprises a compound of formula (I) and a pharmaceutically acceptable carrier.
  • This invention is further a method for inhibiting platelet aggregation in a mammal in need thereof, which comprises internally administering an effective amount of a compound of formula (I).
  • this invention provides a method for inhibiting reocclusion of an artery or vein in a mammal following fibrinolytic therapy, which comprises internally administering an effective amount of a fibrinolytic agent and a compound of formula (I).
  • This invention is also a method for treating stroke, transient ischemia attacks, and myocardial infarction.
  • novel tricyclic compounds which inhibit platelet aggregation.
  • the novel tricyclic compounds comprise a seven- membered ring fused to an aromatic six-membered ring which is also fused to a nitrogen-containing eight-membered ring.
  • An aliphatic substituent containing an acidic moiety is present on the seven- membered ring.
  • the seven-membered ring may contain heteroatoms, such as nitrogen, oxygen and sulfur, and the six-membered ring may be carbocyclic or contain up to two nitrogen atoms.
  • the fused 8-6-7 ring system is believed to interact favorably with the GPIIb-IIIa receptor and to orient the substituent sidechains on the eight- and seven-membered rings so that they may also interact favorably with the receptor.
  • these compounds are believed to inhibit the binding of fibrinogen to the platelet-bound fibrinogen receptor GPIIb-IIIa, and may interact with other adhesion proteins via antagonism of a putative RGD binding site.
  • the compounds of this invention are compounds of formula (I):
  • a 1 to A 5 form an accessible substituted seven-membered ring, which may be saturated or unsaturated, optionally containing up to two heteroatoms chosen from the group of O, S and N wherein S and N may be optionally oxidized;
  • D 1 , D 2 , D-3 and D 4 independently are CH or N, with the proviso that at least one of D-3 or D ⁇ is N;
  • R * is H, Q-Ci- ⁇ alkyl, Q-Ci- ⁇ oxoalkyl, Q-C 2 - 6 alkenyl, Q-C 3 ⁇ oxoalkenyl, Q-C 3 - 4 ⁇ xoalkynyl, Q-C 2 - alkynyl, C 3 - 6 cycloalkyl, Ar, or Het, optionally substituted by one or more of R 11 ; each Q is H, C3.6cycloal.kyl, Het or Ar;
  • E and L independently are O or (H,H);
  • G is (CHR6)f Y, (CHR6) p -Het-(CH 2 ) p -Y, (CHR6) p -C 3 .7cycloalkyl-(CH2)p-Y or
  • Y is R'R'N-, R'R"NR , N-, R , R M NR'NCO-, R ⁇ NR'NC ⁇ NR')-
  • R is H, Ci ⁇ alkyl, C3_7cycloalkyl-Co-4alkyl, or Ar-Co-4alkyl;
  • R" is R, -C(O)R or -C(O)ORl5 R M, is R" or AA2:
  • AA2 is an amino acid attached through its carboxyl group, and having its amino group optionally protected;
  • R** is V-M, wherein V is H, R 1 ", RlO-J-CO or Rl0-J-S(O) m , in which J is O, NH, S or a covalent bond, and M is -NH(CHR 1 6)CO- or a covalent bond;
  • R6 is H or C * ⁇ _4alkyl; ' R 7 is -COR 8 , -COCR2R 9 , -C(S)R 8 , -S(O) m OR, -S(O) m NR'R",
  • R8 is -OR', -NR * R", -NR'SO2R', -NROR, -OCR' 2 CO(O)R', -OCR' 2 OC(0)R', -OCR , 2C(O)NR' 2 , CF3 or AA1;
  • R9 is -OR 1 , -CN, -S(O) r R, -S(O) m NR , 2) -C(O)R, C(O)NR' 2 , or -CO2R;
  • SUBS ⁇ TUTE SHEET RIO is (CHR6) r -H, (CHR6) r -C 3 . 6 cycloalkyl ) (CHR6) r -Ar or (CHR 6 ) r -Het;
  • RU is H, halo, -OR 12 , -CN, -NR'R l 2, -N0 2 , -CF 3 , CF 3 S(O) r - ( -CO2R', -CONR'2, Q-C 0 -6alkyl-, Q-C ⁇ . 6 oxoalkyl-, Q-C 2 -6alkenyl-, -C2-6alkynyl-, Q-Co-ealkyloxy-, Q-Co-6alkyla ⁇ ino- or Q-Co-6alkyl-S(O) r -;
  • R12 is R, -C(O)R ⁇ -C(O)NR'2, -C(O)OR, -S(O) m R', or -S(O) m NR' 2 ;
  • R!3 is R', -CF 3 , -SR, or OR';
  • R 14 is R, C(O)R, CN, NO 2 , SO 2 R, or C(O)ORl5; each Rl5 independently is Ci. ⁇ alkyl or Ar-Co-4alkyl;
  • Rl6 i s H, C ⁇ _ 6 alkyl, C 3 . 6 cycloalkyl, (CH 2 ) n -Het or (CH 2 ) q Z, wherein Z is C3_6cycloalkyl, OH, NH 2 , SH, SC ⁇ . alkyl, CO 2 R 6 , CONH 2 or NHC( NH)NH 2 ;
  • AA1 is an amino acid attached through its amino group and having its carboxyl group optionally protected; each m independently is 1 or 2; each n independently is 0 to 2; each p independently is 0 to 2; q is 1 to 4; each r independently is 0 to 4; and t is 2 to 5; or a pharmaceutically acceptable salt thereof.
  • Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo.
  • this invention includes each unique nonracemic compound which may be synthesized and resolved by conventional techniques.
  • compounds may have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention.
  • compounds may have one or more chiral centers, unless specified, this invention includes each unique nonracemic compound which may be synthesized and resolved by conventional techniques.
  • compounds may have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention.
  • keto-enol tautomers such as
  • Al is CRiR 1' , CR 1 , NR 1 , N, O, or S(O) x ;
  • A is CR 2 R 2' , CR 2 , or NR ;
  • A3 is CR 3 R 3' , CR 3 , NR 3 , N, O, or S(O) x ;
  • a 4 is CR 4 R 4* , CR 4 , NR 4 , or N;
  • a ⁇ is CR 5 R 5' , CR 5 , NR 5 , N, 0, or S(0) x;
  • D 1 and D 2 are CH;
  • R 2 and R 2' are R * .
  • R or O
  • R3 and R 3' are R * .
  • R or O
  • a 1 is CR i R 1' , CR 1 , NR 1 , N, O, or S;
  • a 2 is CR 2 R 2' , NR 2 or CR 2 ;
  • A3 is CR3R3 '
  • a 4 is CR R 4' , CR 4 , NR 4 , or N;
  • a 5 is CR 5 R 5' , CR 5 NR 5 , N or O;
  • D 1 and D 2 are CH;
  • R 2 or R 4 are R;
  • L is O and E is O or (H,H);
  • R** is methyl, acetyl or benzoyl
  • R 1 is H, C- ⁇ alkyl, or C(O)R';
  • SUBSTTTUTE SHEET R2 is CH 2 CO 2 H
  • R3,R3 ' O or H,H
  • R 4 is H, Ci.galkyl or C ⁇ _4alkyl-Ar.
  • G is
  • a preferred compound of this invention is:
  • Y represents a nitrogen-containing group which is capable of making a hydrogen bond.
  • Y is a basic nitrogen moiety.
  • R 7 represents a group with a non-bonding pair of electrons which is capable of forming a hydrogen bond or chelating with a metal.
  • R 7 is acidic. It is also preferred that 10-15 intervening covalent bonds via the shortest intramolecular path will exist between the group R 7 and Y for optimal spacing between these groups.
  • Arg refers to arginine
  • MeArg refers to N ⁇ -methyl-arginine
  • HArg refers to homoarginine
  • NArg refers to norarginine
  • (Me 2 )Arg refers to N',N"-dimethyl arginine
  • (Et 2 )Arg refers to N',N"-diethyl arginine
  • Orn refers to ornithine.
  • These radicals are suitable components of the substituent R 6 .
  • N ⁇ -Substituted derivatives of these amino acid are also useful in this invention. Representative methods for preparing ⁇ - substituted derivatives are disclosed in U.S. Patent No. 4,687,758; Cheung et al, Can. J.
  • Ci-4alkyl as applied herein is meant to include methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl and t-butyl.
  • Ci- ⁇ alkyl additionally includes pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof.
  • Co-4alkyl and Co- ⁇ alkyl additionally indicates that no alkyl group need be present ⁇ e.g., that a covalent bond is present).
  • C2-6 alkenyl as applied herein means an alkyl group of 2 to 6 carbons wherein a carbon-carbon single bond is replaced by a carbon- carbon double bond.
  • C2- ⁇ alkenyl includes ethylene, 1-propene, 2- propene, 1-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included.
  • C2-6 alkynyl means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond.
  • C2-6 alkynyl includes acetylene, 1-propyne, 2-propyne, 1-butyne, 2- butyne, 3-butyne and the simple isomers of pentyne and hexyne.
  • C ⁇ _4 ⁇ xoalkyl refers to an alkyl group of up to four carbons wherein a CH2 group is replaced by a C(O), or carbonyl, group. Substituted formyl, acetyl, 1-propanal, 2-propanone, 3-propanal, 2-butanone, 3- butanone, 1- and 4-butanal groups are representative. Ci- ⁇ oxoalkyl includes additionally the higher analogues and isomers of five and six
  • C 3 - 6 ⁇ xoalkenyl and C 3 .
  • ⁇ oxoalkynyl refers to a C 3 - 6 alkenyl or C 3 - 6 alkynyl group wherein a CH 2 group is replaced by C(O) group.
  • C 3 - 4 ⁇ xoalkenyl includes l-oxo-2- propenyl, 3-oxo-l-propenyl, 2-oxo-3-butenyl and the like.
  • a substituent on a Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or Ci-6 oxoalkyl group, such as R 11 may be on any carbon atom which results in a stable structure, and is available by conventional synthetic techniques.
  • Q-Ci-6 alkyl refers to a Ci- 6 alkyl group wherein in any position a carbon-hydrogen bond is replaced by a carbon-Q bond.
  • Q-C2- 6 alkenyl and Q-C2-6 alkynyl have a similar menaing with respect to C2-6 alkenyl and C2-6 alkynyl.
  • R 11 means phenyl or naphthyl, or phenyl or naphthyl substituted by one to three moieties R 11 .
  • R 11 may be Ci ⁇ alkyl, Ci ⁇ alkoxy, Ci ⁇ alkthio, trifluoroalkyl, OH, F, Cl, Br or I.
  • Het, or heterocycle indicates an optionally substituted five or six membered monocyclic ring, or a nine or ten-membered bicyclic ring containing one to three heteroatoms chosen from the group of nitrogen, oxygen and sulfur, which are stable and available by conventional chemical synthesis.
  • Illustrative heterocycles are benzofuryl, benzimidazole, benzopyran, benzothiophene, furan, imidazole, indoline, morpholine, piperidine, piperazine, pyrrole, pyrrolidine, pyridine, thiazole, thiophene, quinoline, isoquinoline, and tetra- and perhydro- quinoline and isoquinoline. . Any accessible combination of up to three substituents, such as chosen from R 11 , on the Het ring that is available by chemical synthesis and is stable is within the scope of this invention.
  • C3-7cycloalkyl refers to an optionally substituted carbocyclic system of three to seven carbon atoms, which may contain up to two unsaturated carbon-carbon bonds.
  • Typical of Cs. cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and cycloheptyl. Any combination of up to three substituents, such as chosen from R 11 , on the cycloalkyl ring that is available by conventional chemical synthesis and is stable, is within the scope of this invention.
  • An accessible substituted seven-membered ring as referred to herein is any saturated or unsaturated seven-membered ring which (i)
  • SUBST ⁇ JTE SHEET has up to five substituents, such as R or R*, wherein the substituents may be present on any atom or heteroatom that results in a stable structure, and (ii) contains up to two heteroatoms selected from the group of N, O and S, wherein S and N may optionally be oxidized, and (iii) is stable and may be synthesized by one skilled in the chemical arts in a form fused via two adjacent ring carbon atoms to a phenyl, pyridyl, or pyrazinyl ring.
  • substituents such as R or R*, wherein the substituents may be present on any atom or heteroatom that results in a stable structure, and (ii) contains up to two heteroatoms selected from the group of N, O and S, wherein S and N may optionally be oxidized, and (iii) is stable and may be synthesized by one skilled in the chemical arts in a form fused via two adjacent ring carbon atoms to
  • Typical of accessible seven-membered rings are the common saturated and unsaturated rings of cycloheptane, thiepin, oxapin, azepine, diazepine, thiazepin, oxazepin, dioxepin, oxathiepin and dithiepin.
  • An accessible substituted six-membered ring as referred to herein is an unsaturated (e.g. aromatic) six-membered ring which (i) has one to three substituents, such as chosen from R 6 and R 11 , (ii) optionally contains up to two nitrogens, (iii) is fused via two adjacent carbon atoms to an accessible substituted seven-membered ring, and (iv) is stable and may be prepared by one skilled in the chemical arts.
  • Typical of accessible six-membered rings are phenyl, pyridyl or pyrazinyl ring. Phenyl is a preferred accessible six-membered ring, and di- or tetrahydroazepine, diazepine, thiazepine and oxazepine are preferred accessible seven-membered rings.
  • Any accessible substituted eight-membered ring as referred to herein is a saturated eight-membered ring which (i) has up to two substituents, such as G and R**, (ii) contains one or two nitrogen atoms, and (iii) is stable and may be synthesized by one skilled in the chemical arts in a form fused via two adjacent ring carbon atoms to a phenyl, pyridyl, or pyrazinyl ring.
  • Typical of accessible eight-membered rings are diazocine and azocine.
  • CR 1 R 1 -CR 5 R 5 may also represent an sp 2 carbon atom.
  • CR-'-CR 5 and N represent an unsaturated sp 2 carbon or nitrogen atom, which may be connected by an endocyclic double bond to an adjacent atom in the ring, provided such arrangement results in the creation of a stable compound.
  • SUBST ⁇ UTE SHEET indicates a nitrogen heterocycle, which may be a saturated or unsaturated stable five-, six- or seven-membered monocyclic ring, or a seven- to ten-membered bicyclic ring containing up to three nitrogen atoms or containing one nitrogen atom and a heteroatom chosen from oxygen and sulfur, and which may be substituted on any atom that results in a stable structure.
  • the nitrogen atom in such ring may be substituted so as to result in a quaternary nitrogen.
  • the nitrogen heterocycle may be substituted in any stable position by Ci ⁇ talkoxy, Ci ⁇ alkylthio, F, Cl, Br, I, NO2, NR'2, OH, CO2R', CONHR' or Ci-4alkyl, optionally substituted by any of the aforementioned sustituents.
  • pyrrolidine imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, piperidine, piperazine, morpholine, pyridine, pyridinium, tetrahydropyridine, tetrahydro- and hexahydro-azepine, quinuclidine, quinuclidinium, quinoline, isoquinohne, and tetra- and perhydro- quinoline and isoquinoline.
  • ( ) tetrahydropyridinyl. _ is preferably 4-piperidinyl, 4-pyridyl or 4- piperazinyl.
  • AA1 as referred to herein is an amino acid with its carboxyl group optionally protected, wherein the amino acid may be any of the natural amino acids or penicillamine.
  • the unprotected carboxyl group is a free carboxylic acid group.
  • Protecting groups for the carboxyl are esters or amides which are formed, for instance, when the OH of the carboxy group is replaced by R 8 .
  • AA2 is an amino acid, as above, with its amino group optionally protected. Amino protecting groups are well known in the art, for instance, when the amino group is substituted by R 12 . .An unprotected amino group is a free NH2 group.
  • C(O) indicates a carbon doubly bonded to oxygen (eg. carbonyl)
  • C(S) indicates a carbon doubly bonded to sulfur (eg. thiocarbonyl).
  • t-Bu refers to the tertiary butyl radical
  • Boc refers to the t- butyloxycarbonyl radical
  • Fmoc refers to the fluorenylmethoxycarbonyl radical
  • Ph refers to the phenyl radical
  • Cbz refers to the benzyloxycarbonyl radical
  • BrZ refers to the o-bromobenzyloxycarbonyl radical
  • CIZ refers to the o-chlorobenzyloxycarbonyl radical
  • Bzl refers to
  • DCC refers to dicyclohexylcarbodiimide
  • DMAP refers to dimethylanainopyridine
  • DIEA refers to diisopropylethyl amine
  • EDC refers to N-ethyl-NXdimethylaminopropyl)-carbodiimide.
  • HOBt refers to 1-hydroxybenzotriazole
  • THF tetrahydrofuran
  • DIEA diisopropylethylamine
  • DMF dimethyl formamide
  • NBS N-bromo-succinimide
  • Pd/C a palladium on carbon catalyst
  • PPA 1-propanephosphonic acid cyclic anhydride
  • DPPA diphenylphosphoryl azide
  • BOP refers to benzotriazol- l-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate
  • HF refers to hydrofluoric acid
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • PCC pyridinium chlorochromate.
  • the compounds of formula (I) are generally prepared by cyclizing a compound of the formula (X):
  • D 1 , D 2 , D 3 , A-J-A 5 , R, R*, R**, R 6 , E, and G are as defined in formula (I), except any reactive functional groups are protected, and thereafter removing any protecting groups, and optionally forming a pharmaceutically acceptable salt.
  • the compounds of formula (I) are prepared starting from commercially available reagents, such as substituted tetralones, using conventional synthetic techniques.
  • the scheme disclosed herein is illustrative of the methods of this invention.
  • suBs ⁇ ruTE SHEET Scheme 1 provides a method of preparing compounds wherein one of A* - A-5 is nitrogen (a benzazepine), the six-membered ring is a phenyl and the eight-membered ring is a diazocine. Generally, the synthesis is begun with a 3-halo-l-tetralone. Protection of the ketone with, for example, a dithioacetal using 1,3-dithiapropane, in the presence of a Lewis Acid, such as boron trifluoride etherate, followed by formylation, using, for example, dichloromethyl methyl ether in the presence of a Lewis Acid, such as aluminum chloride, yields compounds of formula (3).
  • a Lewis Acid such as boron trifluoride etherate
  • Reductive amination using an appropriately substituted R ⁇ -substituted a ine, such as l-amino-2-phenyl ethane, in the presence of sodium cyanoborohydride yields formula (4) compounds. Protection of the amine using standard techniques, for example, conversion to the Boc- protected amine, followed by palladium-catalyzed coupling of the aromatic halide of formula (5) with dimethyl itaconate gives formula (6) compounds. Deprotection of the ketone and subsequent reduction of the double bond using, for example, hydrogen in the presence of a catalyst, such as palladium on carbon, gives formula (8) compounds.
  • Scheme 1 presents a representative R ⁇ group, namely, a 2- phenylethyl group, and a representative G group, namely, a 4-amino- methylbenzyl group. This scheme is illustrative of the methods of this invention.
  • benzodiazepines and benzazepines of formula (X) are prepared by the general methods detailed in PCT Publication No.
  • Coupling reagents as used herein denote reagents which may be used to form peptide bonds.
  • Typical coupling methods employ carbodiimides, activated anhydrides and esters and acyl halides.
  • Reagents such as EDC, DCC, DPPA, PPA, BOP reagent, HOBt, N- hydroxysuccinimide and oxalyl chloride are typical.
  • Coupling methods to form peptide bonds are generally well known to the art. The methods of peptide synthesis generally set forth by Bodansky et al., THE PRACTICE OF PEPTIDE SYNTHESIS, Springer-Nerlag, Berlin, 1984, Ali et al. in J. Med. Chem., 29, 984 (1986) and J. Med. Chem., 30, 2291 (1987) are generally illustrative of the technique and are incorporated herein by reference.
  • Solution synthesis for the formation of amide or peptide bonds is accomplished using conventional methods used to form amide bonds.
  • the amine or aniline is coupled via its free amino group to an appropriate carboxylic acis substrate using a suitable carbodiimide coupling agent, such as ⁇ , ⁇ ' dicyclohexyl carbodiimide (DCC), optionally in the presence of catalysts such as 1-hydroxybenzotriazole (HOBt) and dimethylamino pyridine (DMAP).
  • DCC ⁇ , ⁇ ' dicyclohexyl carbodiimide
  • catalysts such as 1-hydroxybenzotriazole (HOBt) and dimethylamino pyridine (DMAP).
  • Other methods such as the formation of activated esters, anhydrides or acid halides, of the free carboxyl of a suitably protected acid substrate, and subsequent reaction with the free amine of a suitably protected amine, optionally in the presence of a base, are also suitable.
  • a protected Boc-amino acid or Cbz- amidino benzoic acid is treated in an anhydrous solvent, such as methylene chloride or tetrahydrofuran(THF), in the presence of a base, such as N-methyl morpholine, DMAP or a trialkylamine, with isobutyl chloroformate to form the "activated anhydride", which is subsequently reacted with the free amine of a second protected amino acid or aniline.
  • anhydrous solvent such as methylene chloride or tetrahydrofuran(THF)
  • a base such as N-methyl morpholine, DMAP or a trialkylamine
  • SUBSTTTUTE SHEET Compounds of formula (X) are prepared by conventional methods known in the art from commercially available materials.
  • Y is generally a basic functional group, such as amino, guanidino, amidino ro heterocyclic group, and is protected during the synthesis of Formula (I) compounds.
  • X-, and X is C(O), are prepared, inter ⁇ li ⁇ , by methods disclosed in United States Patent 3,714,253 and Can. J. Chem., 43, 3103 (1965).
  • SUBST ⁇ JTE SHEET The reactive functional groups of the sidechains of each synthetic fragment are suitably protected as known in the art. Suitable protective groups are disclosed in Greene, PROTECTIVE GROUPS IN ORGANIC CHEMISTRY, John Wiley and Sons, New York, 1981.
  • the Boc, Cbz, phthaloyl or Fmoc group may be used for protection of an amino or amidino group.
  • the Boc group is generally preferred for protection of an ⁇ -amino group.
  • a t-Bu, cHex or benzyl ester may be used for the protection of the side chain carboxyl.
  • a benzyl group or suitably substituted benzyl group eg.
  • 4-methoxy-benzyl or 2,4- dimethoxy-benzyl) is used to protect the mercapto group or the hydroxyl group.
  • the tosyl group may be used for protection of the imidazolyl group and tosyl or nitro group for protection of the guanidino group.
  • a suitably substituted carbobenzyloxy group or benzyl group may be also be used for the hydroxyl group or amino group.
  • Suitable substitution of the carbobenzyloxy or benzyl protecting groups is ortho and/or para substitution with chloro, bromo, nitro or methyl, and is used to modify the reactivity of the protective group.
  • the protective groups for the amino moiety are, most conveniently, those which are not removed by mild acid treatment. These protective groups are removed by such methods as catalytic hydrogenation, sodium in liquid ammonia or HF treatment, as known in the art.
  • Modification of amino groups especially on the six-membered ring of the tricyclic system may be accomplished by alkylation, sulfonylation, cyanation or acylation as is generally known in the art.
  • Acid addition salts of the peptides are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic or methanesulfonic.
  • the acetate salt form is especially useful. Certain of the compounds form inner salts or zwitterions which may be acceptable.
  • Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine.
  • alkaline reagent such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine.
  • Cations such as Li+, Na+, K+, Ca++, Mg++ and NH4+ are specific examples of cations present in pharmaceutically acceptable salts.
  • This invention provides a pharmaceutical composition which comprises a compound according to formula (I) and a pharmaceutically
  • the compounds of formula (I) may be used in the manufacture of a medicament.
  • Pharmaceutical compositions of the compounds of formula (I) prepared as hereinbefore described may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
  • the liquid formulation may be a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
  • Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • the compounds of formula (I) may be encapsulated, tableted or prepared in a emulsion or syrup for oral administration.
  • Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
  • Liquid carriers include syrup, peanut oil, olive oil, saline and water.
  • the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit.
  • the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
  • a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non- aqueous suspension.
  • Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
  • formula (I) compounds may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
  • the compounds of this invention may be used in vitro to inhibit the aggregation of platelets in blood and blood products, e.g., for storage, or for ex vivo manipulations such as in diagnostic or research use.
  • This invention also provides a method of inhibiting platelet aggregation and clot formation in a mammal, especially a human, which comprises the internal administration of a compound of formula (I) and a pharmaceutically acceptable carrier.
  • Indications for such therapy include acute myocardial infarction (AMI), deep vein thrombosis, pulmonary embolism, dissecting anurysm, transient ischemia attack (TLA), stroke and other infarct-related disorders, and unstable angina.
  • DIC disseminated intravascular coagulation
  • septicemia surgical or infectious shock
  • post-operative and post-partum trauma cardiopulmonary bypass surgery
  • incompatible blood transfusion abruptio placenta
  • thrombotic thrombocytopenic purpura TTP
  • snake venom immune diseases
  • the compounds of this invention may be useful in a method for the prevention of metastatic conditions, the prevention or treatment of fungal or bacterial infection, inducing immunostimulation, treatment of sickle cell disease, and the prevention or treatment of diseases in which bone resorption is a factor.
  • the formula (I) compound is administered either orally or parenterally to the patient, in a manner such that the concentration of drug in the plasma is sufficient to inhibit platelet aggregation, or other such indication.
  • the pharmaceutical composition containing the compound of this invention is administered at a dose between about 0.2 to about 50 mg kg in a manner consistent with the condition of the patient.
  • parenteral administration is preferred.
  • an intravenous infusion of the formula (I) compound in 5% dextrose in water or normal saline is most effective, although an intramuscular bolus injection may be sufficient.
  • oral administration of a capsule or tablet, or a bolus intramuscular injection is suitable.
  • the compound of formula (I) is administered one to four times daily at a level of about 0.4 to about 50 mg kg to achieve a total daily dose of about 0.4 to about 200 mg/kg/day.
  • SUBSTITUTE SHEET This invention further provides a method for inhibiting the reocclusion of an artery or vein following fibrinolytic therapy, which comprises internal administration of a compound of formula (I) and a fibrinolytic agent. It has been found that administration of a formula (I) compound in fibrinolytic therapy either prevents reocclusion completely or prolongs the time to reocclusion.
  • fibrinolytic agent is intended to mean any compound, whether a natural or synthetic product, which directly or indirectly causes the lysis of a fibrin clot.
  • Plasminogen activators are a well known group of fibrinolytic agents.
  • Useful plasminogen activators include, for example, anistreplase, urokinase (UK), pro-urokinase (pUK), streptokinase (SK), tissue plasminogen activator (tPA) and mutants, or variants, thereof, which retain plasminogen activator activity, such as variants which have been chemically modified or in which one or more amino acids have been added, deleted or substituted or in which one or more or functional domains have been added, deleted or altered such as by combining the active site of one plasminogen activator with the fibrin binding domain of another plasminogen activator or fibrin binding molecule.
  • Other illustrative variants include tPA molecules in which one or more glycosylation sites have been altered.
  • plasminogen activators are variants of tPA in which the primary amino acid sequence has been altered in the growth factor domain so as to increase the serum half-life of the plasminogen activator.
  • tPA Growth factor variants are disclosed, e.g., by Robinson et al., EP-A 0 297 589 and Browne et al., EP- A 0 240 334.
  • Other variants include hybrid proteins, such as those disclosed in EP 0 028 489, EP 0 155 387 and EP 0 297 882, all of which are incorporated herein by reference.
  • Anistreplase is a preferred hybrid protein for use in this invention.
  • Fibrinolytic agents may be isolated from natural sources, but are commonly produced by traditional methods of genetic engineering.
  • fibrinolytic agent may be formulated in an aqueous, buffered, isotonic solution, such as sodium or ammonium acetate or adipate buffered at pH 3.5 to 5.5. Additional excipients such as polyvinyl pyrrolidone, gelatin,
  • SUBST ⁇ TUTE SHEET hydroxy cellulose, acacia, polyethylene, glycol, mannitol and sodium chloride may also be added. Such a composition can be lyophilized.
  • the pharmaceutical composition may be formulated with both the compound of formula (I) and fibrinolytic in the same container, but formulation in different containers is preferred.
  • both agents are provided in solution form they can be contained in an infusion/injection system for simultaneous administration or in a tandem arrangement.
  • Indications for such therapy include myocardial infarction, deep vein thrombosis, pulmonary embolism, stroke and other infarct-related disorders.
  • the compound of formula (I) is administered just prior to, at the same time as, or just after parenteral administration of tPA or other fibrinolytic agent. It may prove desirable to continue treatment with the formula (I) compound for a period of time well after reperfusion has been established to maximally inhibit post-therapy reocclusion.
  • the effective dose of tPA, SK, UK or pUK may be from 0.5 to 5 mg/kg and the effective dose of the peptide may be from about 0.1 to 25 mg kg.
  • a kit for convenient administration of the inhibitor and the fibrinolytic agent at the same or different times, comprising, in a single container, such as a box, carton or other container, individual bottles, bags, vials or other containers each having an effective amount of the inhibitor for parenteral administration, as described above, and an effective amount of tPA, or other fibrinolytic agent, for parenteral administration, as described above.
  • kit can comprise, for example, both pharmaceutical agents in separate containers or the same container, optionally as lyophilized plugs, and containers of solutions for reconstitution.
  • a variation of this is to include the solution for reconstitution and the lyophilized plug in two chambers of a single container, which can be caused to admix prior to use.
  • the fibrinolytic and the peptide may be packaged separately, as in two containers, or lyophilized together as a powder and provided in a single container.
  • both agents When both agents are provided in solution form, they can be contained in an infusion/injection system for simultaneous administration or in a tandem arrangement.
  • the platelet aggregation inhibitor may be in an i.v. injectable form, or infusion bag linked in series, via tubing, to the fibrinolytic agent in a second infusion bag.
  • a patient can receive an initial bolus-type
  • the pharmacological activity of the compounds of this invention is assessed by their ability to inhibit the binding of 3 H-SK&F 107260, a known RGD-fibrinogen antagonist, to the GPIIb ⁇ la receptor; their ability to inhibit platelet aggregation, in vitro, and their ability to inhibit thrombus formation in vivo.
  • the column was washed with 50 mL cold buffer A.
  • the lectin-retained GPIIb-IIIa was eluted with buffer A containing 10% dextrose. All procedures were performed at 4°C.
  • the GPIIb-IIIa obtained was >95% pure as shown by SDS polyacrylamide gel electrophoresis.
  • a mixture of phosphatidylserine (70%) and phosphatidylcholine (30%) (Avanti Polar Lipids) were dried to the walls of a glass tube under a stream of nitrogen.
  • Purified GPIIb-IIIa was diluted to a final concentration of 0.5 mg/mL and mixed with the phospholipids in a protein ⁇ hospholipid ratio of 1:3 (w:w). The mixture was resuspended and sonicated in a bath sonicator for 5 min.
  • the mixture was then dialyzed overnight using 12,000-14,000 molecular weight cutoff dialysis tubing against a 1000-fold excess of 50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 2 mM CaC12 (with 2 changes).
  • the GPIIb-IIIa-containing liposomes wee centrifuged at 12,000g for 15 min and resuspended in the dialysis buffer at a final protein concentration of approximately 1 mg mL. The liposomes were stored at -70C until needed.
  • the binding to the fibrinogen receptor (GPIIb-IIIa) was assayed by an indirect competitive binding method using [ 3 H]-SK&F- 107260 as an RGD-type ligand.
  • the binding assay was performed in a 96- well filtration plate assembly (Millipore Corporation, Bedford, MA) using 0.22 urn hydrophilic durapore membranes.
  • the wells were precoated with 0.2 mL of 10 ⁇ g/mL polylysine (Sigma Chemical Co., St. Louis, MO.) at room temperature for 1 h to block nonspecific binding.
  • Various concentrations of unlabeled benzadiazapines were added to the wells in quadruplicate.
  • [ 3 H]-SK&F- 107260 was applied to each well at a final concentration of 4.5 nM, followed by the addition of 1 ⁇ g of the purified platelet GPIIb- IHa-containing liposomes. The mixtures were incubated for 1 h at room temperature. The GPIIb-IIIa-bound [3H1-SK&F-107260 was seperated from the unbound by filtration using a Millipore filtration manifold, followed by washing with ice-cold buffer (2 times, each 0.2 mL).
  • % aggregation [(90-CR) ⁇ (90-10)] x 100, where CR is the chart reading, 90 is the baseline, and 10 is the PRP blank reading.
  • IC ⁇ O's were determined by plotting [% inhibition of aggregation] vs. [concentration of peptide]. Peptides were assayed at 200 mM and diluted sequentially by a factor of 2 to establish a suitable dose response curve.
  • the compounds were incubated for 3 h (rather than 3 min) in the PRP prior to addition of the agonist.
  • Compound 2 is formylated using the method of Lewin, et al. (Org. Prep. Proced. Int. 1978, 10, 201) with dichloromethyl methyl ether and .AICI3 to give a mixture of 6- and 8- formyl products which are separated by chromatography to give the desired 3.
  • suBs ⁇ ruTE SHEET vigorously at room temperature for 4 d.
  • the layers were separated and the organic layer was dried over anhydrous MgSO. 4 and evaporated.
  • the residue was purified by flash chromatography (silica gel, 6x20 cm, 30% ethyl acetate in hexane) to give 2.59 g (9.62 mmol, 65%) of 15d.
  • the methyl eater in 16 is selectively hydrolyzed, using the method of L.M. Weinstock (Tetrahedron Lett 1975, 3979), with NaCN and HMPA at 75 °C for 24 h.
  • the crude acid after workup is dissolved in CH3CN with triethylamine and this solution is added dropwise to a refluxing solution of 2-chloro-l-methylpyridinium iodide. After the addition is completed, the reaction is continued at reflux for 4 d.
  • the reaction mixture is evaporated at reduced pressure and the residue is taken into CHCI3, washed with 5% Na2CO3 (aqueous) and IN HCl (aqueous), dried over anhydrous MgSO.4 and evaporated at reduced pressure.
  • the residue is purified by flash chromatography to give 17.
  • SUBST ⁇ TUTE SHEET Example 2 Parenteral Dosage Unit Composition
  • a preparation which contains 20 mg of the compound of Example 1 as a sterile dry powder is prepared as follows: 20 mg of the compound is dissolved in 15 ml of distilled water. The solution is filtered under sterile conditions into a 25 ml multi-dose ampoule and lyophilized. The powder is reconstituted by addition of 20 ml of 5% dextrose in water (D5W) for intravenous or intramuscular injection. The dosage is thereby determined by the injection volume.
  • D5W dextrose in water
  • Subsequent dilution may be made by addition of a metered volume of this dosage unit to another volume of D5W for injection, or a metered dose may be added to another mechanism for dispensing the drug, as in a bottle or bag for IV drip infusion or other injection-infusion system.
  • Oral Dosage Unit Com osition A capsule for oral administration is prepared by mixing and milling 50 mg of the compound of Example 1 with 75 mg of lactose and 5 mg of magnesium stearate. The resulting powder is screened and filled into a hard gelatin capsule.
  • Example 4 Oral Dosage Unit Composition A tablet for oral administration is prepared by mixing and granulating 20 mg of sucrose, 150 mg of calcium sulfate dihydrate and 50 mg of the compound of Example 1 with a 10% gelatin solution. The wet granules are screened, dried, mixed with 10 mg starch, 5 mg talc and 3 mg stearic acid; and compressed into a tablet.

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Abstract

L'invention concerne des composés de la formule (I) ou leurs sels acceptables sur le plan pharmaceutique. Ces composés sont efficaces pour inhiber l'agrégation plaquettaire. L'invention concerne également des compositions pharmaceutiques manifestant une telle activité et un procédé pour inhiber l'agrégation plaquettaire.
PCT/US1994/003383 1993-03-29 1994-03-29 Composes tricycliques utilises pour inhiber l'agregation plaquettaire WO1994022444A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BG64902B1 (bg) * 1996-07-25 2006-08-31 Biogen, Inc. IIb/IIIa ИНХИБИТОРИ НА КЛЕТЪЧНА АДХЕЗИЯ, МЕТОД ЗАПОЛУЧАВАНЕ, ФАРМАЦЕВТИЧЕН СЪСТАВ И ИЗПОЛЗВАНЕ
WO2017012966A1 (fr) * 2015-07-17 2017-01-26 Bayer Cropscience Aktiengesellschaft Hydrazides substitués d'acide arylcarboxylique et hétéroarylcarboxylique ou leurs sels, et leur utilisation pour accroître la tolérance au stress chez les végétaux

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4957911A (en) * 1986-01-23 1990-09-18 Hoffmann-La Roche Inc. Benzazecine derivatives for cognitive and memory functions

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4957911A (en) * 1986-01-23 1990-09-18 Hoffmann-La Roche Inc. Benzazecine derivatives for cognitive and memory functions

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BG64902B1 (bg) * 1996-07-25 2006-08-31 Biogen, Inc. IIb/IIIa ИНХИБИТОРИ НА КЛЕТЪЧНА АДХЕЗИЯ, МЕТОД ЗАПОЛУЧАВАНЕ, ФАРМАЦЕВТИЧЕН СЪСТАВ И ИЗПОЛЗВАНЕ
WO2017012966A1 (fr) * 2015-07-17 2017-01-26 Bayer Cropscience Aktiengesellschaft Hydrazides substitués d'acide arylcarboxylique et hétéroarylcarboxylique ou leurs sels, et leur utilisation pour accroître la tolérance au stress chez les végétaux
CN107848977A (zh) * 2015-07-17 2018-03-27 拜耳农作物科学股份公司 取代的芳基‑和杂芳基甲酸酰肼或其盐及其用于提高植物的胁迫耐受性的用途

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