EP0677041A1 - Chemische verbindungen - Google Patents

Chemische verbindungen

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Publication number
EP0677041A1
EP0677041A1 EP94905503A EP94905503A EP0677041A1 EP 0677041 A1 EP0677041 A1 EP 0677041A1 EP 94905503 A EP94905503 A EP 94905503A EP 94905503 A EP94905503 A EP 94905503A EP 0677041 A1 EP0677041 A1 EP 0677041A1
Authority
EP
European Patent Office
Prior art keywords
compound according
benzoyl
4alkyl
phenoxy
pyrrolidinyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP94905503A
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English (en)
French (fr)
Other versions
EP0677041A4 (de
Inventor
James Samanen
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP0677041A4 publication Critical patent/EP0677041A4/de
Publication of EP0677041A1 publication Critical patent/EP0677041A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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 (RGD in single letter amino acid code). Von Willebrand factor and fibrinogen, which are considered to be natural ligands for the GPIIb-IIIa receptor, possess an RGD 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.
  • RGD Arg-Gly-Asp sequence
  • Fibronectin, vitronectin and thrombospondin are RGD-containing proteins which have also been demonstrated to bind to GPIIb-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.
  • Inhibitors of the fibrinogen receptor which are not constructed of natural amino acid sequences are disclosed in EP-A 0372,486, EP-A 0 381 033 and EP-A 0478 363.
  • WO 92/07568 discloses 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 compounds that inhibit binding to the GPIIb-IIIa receptor and inhibit platelet aggregation.
  • this invention is a compound comprising a five- or six- 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, myocardial infarction, or atherosclerosis.
  • This invention discloses novel compounds which inhibit platelet aggregation.
  • the novel compounds comprise a five- or six-membered ring.
  • the five- or six- membered ring may contain heteroatoms, such as nitrogen, oxygen and sulfur.
  • the five- or six-membered ring system is believed to interact favorably with the GPIIb- IIIa receptor and to orient the substituent sidechains on the five- or six-membered rings so that they may also interact favorably with the receptor.
  • the compounds of this invention are compounds of formula (I):
  • A is -(CH2)r > Het, Ar, or C3_7cycloalkyl
  • Qi to Q" form any accessible substituted five- or six-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;
  • Y is -CO-, -CR'(OH)-, -SO 2 -, -CR'2-, -CONR'-, -NR'CO-, SO 2 NR', or -NR'SO 2 -;
  • M is Het, Ar, or C3_7cycloalkyl, each of which is unsubstituted or substituted by R 3 ;
  • each R' independently is hydrogen, C ⁇ _4alkyl, C3.7cycloalkyl-C ⁇ -4alkyl, or
  • each R" independently is R', -C(O)R', or -C(O)OR 15 ;
  • R 2 is absent or present as C ⁇ alkyl, CO2 ', Z-CO2R', C ⁇ alkoxy, hydroxy, C ⁇ alkylthio, CONR'R', CN, CF 3 , halo, or NR'R';
  • R 3 is C ⁇ _4al yl, C ⁇ alkoxy, Cj ⁇ alkylthio, hydroxy, halo, CO2R', Z-CO 2 R', NR'R', CN CONR'R', CF3, or Ar-Co-4alkyl;
  • each R*5 independently is Cj.galkyl, C3.7cycloalkyl-C ⁇ -4alkyl, or Ar-Co-4alkyl;
  • J is absent or present as S or O;
  • n 1 or 2;
  • each n independently is 0 or 1;
  • each t independently is 0 to 2;
  • 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 exist in tautomeric forms, such as keto-enol tautomers, such as and tautomers of guanidine-type groups, such as NR" NR' 2
  • R-R'N I NR'-X- and R . R . N NR'-X-, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or locked in one form by appropriate substitution with R'.
  • the meaning of any substituent at any one occurrence is independent of its meaning, or any other substituent's meaning, at any other occurrence, unless specified otherwise.
  • Q ⁇ to Q" optionally substituted by R 2 are any accessible combination of the following:
  • Q 1 is CH, C, or N
  • Q 2 is CH, C, or N
  • Q3 is CH 2 , CHR 2 , C(R 2 ) 2 , CH, CR 2 , NH, NR 2 , N, O, or S;
  • Q 4 is CH 2 , CHR 2 , C(R 2 ) 2 , CH, CR 2 , NH, NR 2 , N, O, or S;
  • Q 5 is absent or present as CH2, CHR 2 , C(R 2 )2, CH, CR 2 , NH, NR 2 , N, O, or S;
  • Q 6 is CH 2 , CHR 2 , C(R 2 ) 2 , CH, CR 2 , NH, NR 2 , N, O, or S.
  • Q 1 to Q ⁇ optionally substituted by R 2 is
  • A is phenyl;
  • X is -CO-, -CH(OH)-, -SO 2 -, -CONR'- or -NR'CO-;
  • Y is -CO-, -CH(OH)-, -SO2-, -CONR'- or -NR'CO-;
  • M is phenyl;
  • R 2 is absent; t is O to 1; each n independently is 0; and Q 1 to Q 6 is
  • Particular compounds of the invention include, but are not limited to, the following:
  • the most prefered compound of this invention is N-[4- aminoiminomethyl)benzoyl]-4-oxyacetic acid-(R)-prolylbenzene or a pharmaceutically acceptable salt thereof.
  • C ⁇ _4alkyl as applied herein means carbon chains which are branched or unbranched and includes 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 additionally indicates that no alkyl group need be present (e.g. that a covalent bond is present).
  • Ar, or aryl as applied herein, means phenyl or naphthyl, or phenyl or naphthyl substituted by one to three moieties R 2 .
  • R 2 may be Ci ⁇ alkyl, Ci ⁇ alkoxy, C ⁇ alkythio, CF3, OH, CI, Br, I, F, C ⁇ 2R', or Z-CO2R', wherein Z and R' are as defined in formula (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 imidazole, benzimidazole, pyrrole, indole, pyridine, pyrimidine, pyrazine, quinoline, benzofuran, furan, benzopyran, benzothiophene, thiophene, thiazole, benzothiazole, indoline, moipholine, piperidine, piperazine, pyrrolidine, isoquinoline, and tetra- and perhydro- quinoline and isoquinoline. Any accessible combination of up to three substituents, such as chosen from R 2 , 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 C3-7cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and cycloheptyl. Any combination of up to three substituents, such as chosen from R 2 , on the cycloalkyl ring that is available by conventional chemical synthesis and is stable, is within the scope of this invention.
  • Any accessible substituted five- or six-membered ring as referred to herein is any saturated or unsaturated five- or six-membered ring which (i) is optionally substituted by R 2 , 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.
  • Typical of accessible five-membered rings are the common saturated and unsaturated rings of cyclopentane, cyclopentene, furan, thiophene, imidazole, pyrrole, thiazole, oxazole, pyrrolidine, pyrroline, and pyrazole.
  • Typical of accessible six-membered rings are the common saturated and unsaturated rings of cyclohexane, cyclohexene, benzene, pyridine, pyrimidine, pyridazine, pyrazine, piperidine, piperazine, morpholine, and dihydropyridine. ⁇ .
  • a nitrogen heterocycle which may be a saturated or an 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, and wherein the nitrogen heteroatom may be optionally quaternized.
  • _ are pyrroline, pyrrolidine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, piperidine, piperazine, morpholine, pyridine, tetrahydropyridine, tetrahydro- and hexahydro-azepine.
  • _ may be pyrolidinyl, piperidinyl, tetrahydropyridinyl, or piperidinyl.
  • 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
  • C1Z refers to the o-chlorobenzyloxycarbonyl radical
  • Bzl refers to the benzyl radical
  • 4-MBzl refers to the 4-methyl benzyl radical
  • Me refers to methyl
  • Et refers to ethyl
  • Ac refers to acetyl
  • Alk refers to C ⁇ _4alkyl
  • Nph refers to 1- or 2-naphthyl
  • cHex refers to cyclohexyl.
  • DCC refers to dicyclohexylcarbodiimide
  • DMAP refers to dimethylaminopyridine
  • DIEA refers to diisopropylethyl amine
  • EDC refers to N- ethyl-N'(dimethylaminopropyl)carbodiimide.
  • HOBt refers to
  • THF tetrahydrofuran
  • DIEA diisopropylethylamine
  • DMF dimethyl formamide
  • NBS N- bromosuccinimide
  • 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 hydrofluoric acid
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • PCC pyridinium chlorochromate.
  • the compounds of formula (I) are generally prepared by reacting a compound :
  • L 1 and L 2 are groups which are capable of reacting to form the linkage -X-, wherein X is as defined in formula (I); or L* is hydrogen, Ql is nitrogen, and L 2 is a functional group which is capable of reacting with the Q* nitrogen to from certain X linkages; and thereafter removing any protecting groups, and optionally forming a pharmaceutically acceptable salt. It will be apparent that the precise identity of L 1 and L 2 will be dependent upon the site of the linkage being formed. For instance, if X is CONH, L 1 may be -NH2 L 2 and may be COOH or COC1. When L 2 is COOH, a coupling agent is used. Similarly, if X is NHCO, L 1 may be -CO2H or COC1 and L 2 may be -NH2.
  • L 1 may be H and Q 1 is nitrogen and L 2 may be COOH or COC1.
  • L 1 may be SO2CI and L 2 may be -NH2.
  • L 1 may be -NH2 and L 2 may be SO2CI.
  • 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- Verlag, 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 acids substrate using a suitable carbodiimide coupling agent, such as N,N' dicyclohexyl carbodiimide (DCC), optionally in the presence of catalysts such as 1- hydroxybenzotriazole (HOBt) and dimethylaminopyridine (DMAP).
  • DCC N,N' dicyclohexyl carbodiimide
  • catalysts such as 1- hydroxybenzotriazole (HOBt) and dimethylaminopyridine (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-methylmorpholine, 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-methylmorpholine, DMAP or a trialkylamine
  • D is generally a basic functional group attached to A, optionally via an alkyl chain, and is protected during the synthesis, where necessary.
  • 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 orFmoc 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 may be accomplished by alkylation, sulfonylation, cyanation or acylation as is generally known in the art.
  • Scheme I provides a method of preparing compounds wherein Q ⁇ is absent, trogen, Q 2 is CH, Q 3 , OA and Q ⁇ are CH2, and A and M are each phenyl.
  • me I, R 2 ' and R 3 ', D', and R* indicate R 2 , R 3 , D, and R, respectively, or a suitable precursor thereof, wherein any functional groups are protected as known in the art.
  • Y' represents -CH(OH)- and -CO- groups.
  • a suitably protected prolylhalide of formula (I), such as N-trifluoroacetyl-D-prolylchloride is reacted with an aromatic compound of formula (2), such as anisole, in the presence of a Lewis acid catalyst, such as aluminum chloride, aluminum bromide, titanium tetrachloride or boron trifluoride, particularly aluminum chloride, in a suitable solvent, such as methylene chloride.
  • a Lewis acid catalyst such as aluminum chloride, aluminum bromide, titanium tetrachloride or boron trifluoride, particularly aluminum chloride
  • a suitable solvent such as methylene chloride
  • prolyl compounds are coupled with an appropriately substituted D'-(CH2)t-A-carboxylic acid compound, such as 4-N-Cbz- amidinobenzoic acid, in the presence of a suitable amide coupling agent, such as N- ethyl-N'(dimethylaminopropyl)carbodiimide, and optionally in the presence of a catalyst, such as 1-hydroxybenzotriazole, in a suitable solvent, such as dimethylfor amide.
  • a suitable amide coupling agent such as N- ethyl-N'(dimethylaminopropyl)carbodiimide
  • a catalyst such as 1-hydroxybenzotriazole
  • the formula (5) compounds may then be deprotected using conventional chemical techniques, for example, using hydrogen in the presence of a suitable catalyst, such as palladium on carbon, when a Cbz-protecting group is present, or using trifluoroacetic acid in a suitable solvent, such as methylene chloride, when a t-butyl ester is present.
  • a suitable catalyst such as palladium on carbon
  • trifluoroacetic acid in a suitable solvent, such as methylene chloride, when a t-butyl ester is present.
  • Acid addition salts of the compounds of formula (I) 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.
  • 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 acceptable carrier. Accordingly, 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.
  • 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. Alternately, these compounds may be encapsulated, tableted or prepared in a emulsion or syrup for oral administration.
  • 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.
  • the compounds of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
  • 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 peptide of formula (I) and a pharmaceutically acceptable carrier.
  • Indications for such therapy include acute myocardial infarction (AMI), deep vein thrombosis, pulmonary embolism, dissecting aneurysm, transient ischemia attack (TIA), 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 and 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, and the prevention or treatment of diseases in which bone resorption is a factor.
  • the compounds of mis invention are 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 compositions containing the compounds of this invention are 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 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 compounds of this invention are 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.
  • 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 certain compounds 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.
  • tPA molecules in which one or more glycosylation sites have been altered.
  • Preferred among 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. Useful formulations of tPA, SK, UK and pUK are disclosed, for example, in EP-A 0 211 592, EP-A 0092 182 and U.S. Patent 4,568,543, all of which are incorporated herein by reference.
  • the 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, 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 this invention 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 claimed compounds 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.
  • kits 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 compound of this invention may be packaged separately, as in two containers, or lyophilized together as a powder and provided in a single container.
  • 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 injection or infusion of the inhibitor followed by an infusion of the fibrinolytic agent.
  • the pharmacological activity of the compounds of this invention is assessed by their ability to inhibit the binding of H-SK&F 107260, a known RGD- fibrinogen antagonist, to the GPIIbllla receptor; their ability to inhibit platelet aggregation, in vitro, and their ability to inhibit thrombus formation in vivo.
  • GPIIb-IIIa Ten units of outdated, washed human platelets (obtained from Red Cross) were lyzed by gentle stirring in 3% octylglucoside, 20 mM Tris-HCl, pH 7.4, 140 mM NaCI, 2 mM CaC at 4°C for 2 h. The lysate was centrifuged at 100,000g for 1 h. The supernatant obtained was applied to a 5 mL lentil lectin sepharose 4B column (E.Y. Labs) preequilibrated with 20 mM Tris-HCl, pH 7.4, 100 mM NaCI, 2 mM CaCl2, 1% octylglucoside (buffer A).
  • 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 NaCI, 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.
  • GPIIb-IIIa 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 um 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-IIIa-containing liposomes. The mixtures were incubated for 1 h at room temperature. The GPIIb-IIIa-bound [3H]- 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) O (90-10)] x 100, where CR is the chart reading, 90 is the baseline, and 10 is the PRP blank reading.
  • IC50's were determined by plotting [% inhibition of aggregation] vs. [concentration of compound]. Compounds were assayed at 200 mM and diluted sequentially by a factor of 2 to establish a suitable dose response curve.
  • the compounds of this invention inhibit the aggregation of human platelets stimulated with ADP with IC50 of about 0.1 to about 40 ⁇ M.
  • the compounds were incubated for 3 h (rather than 3 min) in the PRP prior to addition of the agonist.
  • Example 2 N-r4-(Aminoiminomethyl benzoyll-4-oxyacetic acid-CRV ⁇ -ffR.SV hvdroxymethvDproIylbenzene
  • a solution consisting of N-carbobenzoxy-[4-(aminoiminomethyl) benzoyl]- 4-[oxy(t-butyl)acetate]-(R)- ⁇ -((R,S)-hydroxymethyl)prolylbenzene (150mg, 0.26 mmol), 10% palladium on carbon (25mg), and 1M hydrochloric acid solution in diethyl ether (0.3 mL, 0.3 mmol) and ethanol (10 mL) was hydrogenated at 50 psi for 1 hour.
  • Example 3 fRVr4-f ri-r4-rAminoiminomethyl benzoyll-2- pyrrolidinylcarbonv ⁇ - 2-('2- phenylethyDphenoxyl acetic acid.
  • 2-(2-phenylethyl)anisole A 500-mL flask was charged with ortho-anisaldehyde (lOg, 74 mmol), benzyltriphenylphosphonium chloride (28.7g, 74 mmol) and methylene chloride (100 mL). To this was added dropwise at room temperature. 50% sodium hydroxide solution (38.7 mL, 740 mmol) over a 20 minutes period (exothermic).
  • N-Carl_>obenzoxy-[4-(aminoiminomethyl)benzoyl]-4-prolyl-(R)- ⁇ -((R,S)- hydroxymethyl)-2-(2-phenylethyl)phenoxy(t-butyl)acetate was oxidized according to the procedure of Example 1(f) to give a slighlty impure product. Purification by chromatography (silica gel, 3%methanol/chloroform) and rotary evaporation of the desired fractions afforded the title compound as a white wax (62% yield),
  • N-Carbobenzoxy-(R)[4-(aminoiminomethyl)benzoyl]-4-prolyl-2-(2- phenylethyl)phenoxy(t-butyl)acetate was deprotected according to the procedure of Example 1(g) to give the desired compound as an impure wax.
  • 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. 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.
  • D5W dextrose in water
  • Example 8 Oral Dosage Unit Composition 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 9 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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