Indian Patents. 241890:THROMBIN RECEPTOR ANTAGONISTS

Title of Invention	THROMBIN RECEPTOR ANTAGONISTS
Abstract	A series of compounds represented by the structural formulas and pharmaceutically acceptable isomers, salts, solvates and polymorphs thereof are disclosed. Also disclosed are pharmaceutical compositions containing said compounds and their use as thrombin receptor antagonists and binders to cannabinoid receptors.

Full Text	THROMBIN RECEPTOR ANTAGONISTS BACKGROUND OF THE INVENTION The present invention relates to nor-seco himbacine derivatives useful as thrombin receptor antagonists in the treatment of diseases associated with thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, cerebral ischemia, stroke, neurodegenerative diseases and cancer. Thrombin receptor antagonists are also known as protease activated receptor (PAR) antagonists. The compounds of the invention also bind to cannabinoid (CB2) receptors and are useful in the treatment of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, diabetes, osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia, nephritis, inflammatory disorders of the lungs and gastrointestinal tract, and respiratory tract disorders such as reversible airway obstruction, chronic asthma and bronchitis. The invention also relates to pharmaceutical compositions containing said compounds. Thrombin is known to have a variety of activities in different cell types and thrombin receptors are known to be present in such cell types as human platelets, vascular smooth muscle cells, endothelial cells and fibroblasts. It is therefore expected that thrombin receptor antagonists will be useful in the treatment of thrombotic, inflammatory, atherosclerotic and fibroproliferative disorders, as well as other disorders in which thrombin and its receptor play a pathological role. Thrombin receptor antagonist peptides have been identified based on structure-activity studies involving substitutions of amino acids on thrombin receptors. In Bernatowicz ei ai, J, Med. Chem.. 39 (1996), p. 4879-4887, tetra- and pentapeptides are disclosed as being potent thrombin receptor antagonists, for example N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-NH2 and N-trans-cinnamoyl-pfluoroPhe-p-guan»dinoPhe"Leu-Arg-Arg-NH2. Peptide thrombin receptor antagonists are also disclosed in WO 94/03479, published February 17,1994. Cannabinoid receptors belong to the superfamily of G-protein coupled receptors. They are classified into the predominantly neuronal CBi receptors and the predominantly peripheral CB2 receptors. These receptors exert their biological actions by modulating adenyiate cyclase and Ca2 and K+ currents. While the effects of CB1 receptors are principally associated with the central nervous system, CB2 receptors are believed to have peripheral effects related to bronchial constriction, immunomodulation and inflammation. As such, a selective CB2 receptor binding or a pharmaceutically acceptable isomer, salt, solvate or polymorph thereof. Thrombin receptor antagonist compounds of the present invention can have anti-thrombotic, anti-platelet aggregation, antiatherosclerotic, antirestenotic and anticoagulant activity. Thrombosis-related diseases treated by the compounds of this invention are thrombosis, atherosclerosis, restenosis, hypertension, angina pectons, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic and thromboembolytic stroke, peripheral vascular diseases, other cardiovascular diseases, cerebral ischemia, inflammatory disorders and cancer, as well as other disorders in which thrombin and its receptor play a pathological rote. The compounds of the invention which bind to cannabinoid (C82) receptors can be useful in the treatment of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, diabetes, osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia, nephritis, inflammatory disorders of the lungs and gastrointestinal tract, and respiratory tract disorders such as reversible airway obstruction, chronic asthma and bronchitis. This invention also relates to a method of using at least one compound of formula I in the treatment of thrombosis, platelet aggregation, coagulation, cancer, inflammatory diseases or respiratory diseases, comprising administering a compound of formula I to a mammal in need of such treatment. In particular, the present invention relates to a method of using at least one compound of formula I in the treatment of thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, gJomerutonephritis: thrombotic stroke, thromboembolytic stroke, peripheral vascular diseases, cerebral ischemia, cancer, rheumatoid arthritis, systemic lupus erythematosus. multiple sclerosis, diabetes, osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia, nephritis, inflammatory disorders of the lungs and gastrointestinal tract, reversible airway obstruction, chronic asthma or bronchitis. It is contemplated that a compound of this invention may be useful in treating more than one of the diseases listed. In another aspect, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula I in at least one pharmaceutically acceptable carrier. DETAILED DESCRIPTION: Unless otherwise defined, the term !1alkyl" or "lower alky!" means straight or branched alkyl chains of 1 to 6 carbon atoms and "alkoxy" similarly refers to alkoxy groups having 1 to 6 carbon atoms. FluoroalkyL difluoroalkyl and trifluoroalkyl mean alkyl chains wherein the terminal carbon is substituted by 1, 2 or 3 fluoroatoms, e.g., -CF3, -CH2CF3, -CH2CHF2 or -CH2CH2F. HaloalkyI means an alkyl chain substituted by 1 to 3 halo atoms. "Alkenyl" means straight or branched carbon chains of carbon atoms having one or more double bonds in the chain, conjugated or unconjugated. Similarly, "alkynyl" means straight or branched carbon chains of carbon atoms having one or more triple bonds in the chain. Where an alkyl. alkenyl or alkynyl chain joins two other variables and is therefore bivalent, the terms alkyiene.. alkenylene and alkynylene are used. Unless otherwise defined, alkenyl and alkynyl chains comprise 1 to 6 carbon atoms. Substitution on alkyl. alkenyl and alkynyl chains depends on the length of the chain, and the size and nature of the substituent. Those skilled in the art will appreciate that while longer chains can accommodate multiple substituents, shorter alkyl chains, e.g., methyl or ethyl, can have multiple substitution by halogen, but otherwise are likely to have only one or two substituents other than hydrogen. Shorter unsaturated chains, e.g., ethenyl or ethynyl, are generally unsubstituted or substitution is limited to one or two groups, depending on the number of available carbon bonds. "Cycloalkyl" means a saturated carbon ring of 3 to 7 carbon atoms, while "cycloalkylene11 refers to a corresponding bivalent ring, wherein the points of attachment to other groups include all positional and stereoisomers. "CydoalkenyF refers to a carbon ring of 3 to 7 atoms and having one or more unsaturated bonds, but not having an aromatic nature. "Heterocycloalkyl" means saturated rings of 5 or 6 atoms comprised of 4 to 5 carbon atoms and 1 or 2 heteroatoms selected from the group consisting of -O-, -S-and -NR7- joined to the rest of the molecule through a carbon atom. Examples of heterocycloalkyl groups are 2-pyrroIidinyl, tetrahydrothiophen-2-yl, 1etrahydro-2-furanyl, 4-piperidinyL 2-piperazinyl, tetrahydro-4-pyranyL 2-morpholinyl and 2-thiomorpholinyl. "Halogen" refers to fluorine, chlorine, bromine or iodine radicals. When R4 and R5 join to form a ring with the nitrogen to which they are attached, the rings formed are 1-pyrrolidinyl, 1-piperidiny! and 1-piperazinyI, wherein the piperazinyl ring may also be substituted at the 4-position nitrogen by a group R7. "Dihydroxy(C1-C6)alkyl" refers to an alkyl chain substituted by two hydroxy groups on two different carbon atoms. "Aryl" means phenyl. naphthyl, indenyl, tetrahydronaphthyl or indanyl. "HeteroaryP means a single ring or benzofused heteroaromatic group of 5 to 10 atoms comprised of 2 to 9 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, provided that the rings do not include adjacent oxygen and/or sulfur atoms. N-oxides of the ring nitrogens are also included, as well as compounds wherein a ring nitrogen is substituted by a C1-C4 alkyl group to form a quaternary amine. Examples of single-ring heteroaryl groups are pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazoiyk pyrazolyl, ietrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazinyl, pyrimtdyl, pyridazinyl and triazoiyl. -Examples of benzofused heteroaryl groups are indolyl, quinolyl, isoquinolyl, phthalazinyl. benzothienyl {i.e., thionaphthenyl), benzimidazolyl, benzofuranyl, benzoxazolyl and benzofurazanyl. All positional isomers are contemplated, e.g., 2-pyritiyl, 3-pyridyl and 4-pyridyl. W-substituted heteroaryl refers to such groups wherein substrtutable ring carbon atoms have a substitueni as defined above, or where adjacent carbon atoms form a ring with an alkylene group or a methylenedioxy group, or where a nitrogen in the Het ring can be substituted with R21-aryl or an optionally substituted alkyl substituent as defined in W. The term "Het" is exemplified by the single ring, the ring substituted with another ring (which can be the same or different), benzofused heteroaryl groups as defined immediately above, as well as tricyclic groups such as benzoquinolinyl (e.g., 1,4 or 7,8) or phenanthrolinyl {e.g., 1,7; 1,10; or 4,7). Het groups are joined to group B by a carbon ring member, e.g., Het is 2-pyridyl, 3-pyridyi or 2-quinolyl. Examples of heteroaryl groups wherein adjacent carbon atoms form a ring with an alkylene group are 2,3-cyclopentenopyridine, 2,3-cyctohexenopyridineand 2,3-cydoheptenopyridine. The term "optional double bond" refers to the bond shown by the single dotted line in the middle ring of the structure shown for formula I. The term "optional single bond" refers to the bond shown by the double dotted line between X and the carbon to which Y and R15 are attached in the structure of formula I. The above statements, wherein, for example, R4 and R5 are said to be independently selected from a group of substituents, means that R4 and R5 are independently selected: but also that where an Ft4 or R5 variable occurs more than once in a molecule, those occurrences are independently selected. Those skilled in the art will recognize that the size and nature of the substituent(s) will affect the number of substituents which can be present. It should also be noted that any formula, compound, moiety or chemical illustration with unsatisfied valences in the present specification and/or claims herein is assumed to have sufficient hydrogen atom(s) to satisfy the valences. Compounds of the invention have at least one asymmetrical carbon atom and therefore all isomers, including diastereomers and rotational isomers are contemplated as being part ot this invention. The invention includes (+)- and (-)-isomers in both pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers ot a compound of formula I. "Polymorph" means a crystalline form of a substance that is distinct from another crystalline form but that shares the same chemical formula. Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term "prodrug", as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of formula I or a salt and/or solvate thereof (e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form). A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable oi isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H2O. Compounds of the invention with a carboxylic acid group can form pharmaceutically acceptable esters with an alcohol. Examples of suitable alcohols include methanol and ethanol. Abbreviations which are used in the preparative examples, schemes and examples include the following: DBAD: Di-terf-butyl azodicarboxylate DBU: 1, 8-Diazabicyclo[5.4.0]undec-7-ene DCC: Dicyclohexylcarbodiimide DCM: Dichloromethane DIBAL: Diisobutylaiuminum hydride DMAP: 4-Dimethyl aminopyridine DMF: M/V-Dimethylformamide DMSO: Methyl sulfoxide EDCI: l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HMPA: Hexamethylphosphoramide HOBt: Hydroxybezotriazole LAH: Lithium aluminum hydride LHMDS: Lithium bis NMO: 4-Methylmorphine /V-oxide TBAF: Tetrabutylammonium fluoride TFA: Trifluoroacetic acid THF: Teirahydrofuran TMSI: Trimethylsilyl iodide TRAP: Tetrapropyiammonium perruthenate Typical preferred compounds of the present invention have the following stereochemistry: with compounds having that absolute stereochemistry being more preferred. Those skilled in the art will appreciate that ior some compounds of formula IT one isomer will show greater pharmacological activity than other isomers. Compounds of the invention with a basic group can form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, mettianesulfonic and other mineral and carboxylic acids well known to those in the art. The salt is prepared by contacting the Alternatively, compounds of formula I wherein W is optionally substituted aryl can be prepared from compounds of formula I wherein W is -OH using a trrflate intermediate. For example, 3-hydroxy-6-methylpyridine is treated with triisopropylsilyl chloride, and the resultant hydroxy-protected compound is converted to the phosphonate as described above for preparing intermediate Ilia. The triisopropylsilyl-protected intermediate is then reacted with intermediate II and the protecting group is removed under standard conditions. The resultant compound of formula I wherein W is OH is then treated with triflic anhydride at room temperature in a solvent such as CH2CI2; the triflate is then reacted with an optionally substituted arylboronic acid, e.g., optionally substituted phenylboronic acid, in a solvent such as toluene, in the presence of Pd(PPh3)4 and a base such a K2CO3 at elevated temperatures and under an inert atmosphere. Compounds of formula I wherein W is a substituted hydroxy group (e.g., benzyloxy) can be prepared from compounds of formula I wherein W is hydroxy by refluxing in a suitable solvent such as acetone with a halogen-substituted compound such as optionally substituted benzyl bromide in the presence of a base such as K2CO3. Compounds of formula I wherein Het is substituted by W through a carbon atom {e.g., wherein W is alkyl.. alkenyl or arylalkyl) or a nitrogen atom (i.e., -NR4R5) can be prepared as shown in Scheme 3 using a compound of formula I wherein W is chloroalkyl as an intermediate. Compounds of formula I wherein W is a polar group such as hydroxy alkyl, dihydroxyalkyL -COOH, dirnethylamino and -COH can be prepared as shown in Scheme 4y wherein the starting material is 3 compound of formula I wherein W is alkenyl. The following Schemes 3 and 4 show well-known reaction conditions for preparing various W-substituted compounds wherein X is -O-, Y is =0, R'5 is absent, R1 is methyl, R2: R3; R9, R10 and R11 are each H, B is -CH=CH-; and Het is 2-pyridyl. formulations and pharmaceutical compositions can be prepared using conventional pharmaceutically acceptable excipients and additives and conventional techniques. Such pharmaceutically acceptable excipients and additives include non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, anti-oxidants, lubricants, flavorings, thickeners, coloring agents, emulsifiers and the like. The daily dose of a compound of formula I for treatment of a disease or condition cited above is about 0.001 to about 100 mg/kg of body weight per day, preferably about 0.001 to about 10 mg/kg. For an average body weight of 70 kg, the dosage level is therefore from about 0.1 to about 700 mg of drug per day, given in a single dose or 2-4 divided doses. The exact dose, however, is determined by the attending clinician and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient. Following are examples of preparing starting materials and compounds of formula I. In the procedures, the following abbreviations are used: room temperature (rt), tetrahydrofuran (THF): ethyl ether (Et2O), methyl {Me), ethyl (Et), ethyl acetate (EtOAc): dimethylformamide (DMF), 4-dimethylaminopyridine (DMAP)r 1,8-diazabicyclo[5.4.0jundec-7-ene (DBU), 1r3-dicyclohexylcart>odiimide. Preparation 1 O H H o HT 0 STEP1 See J. Org. Chem.: 59 (17) (1994), p. 4789. Step 2: O To s suspension of 80% NaH (7.42 g, 185.5 mmol, 1.3 eq) in 300 ml THF at 0°C was added dropwise triethylphosphono acetate (37 ml. 186.5 mmoL 1.3 eq) and the mixture was stirred at 0°C for 30 min. The product of Step 1 (14.0 g, 142.7 mmol) was added and the mixture was stirred atO°C for 30 min. The reaction was quenched by the addition of aq. NH4CI (500 ml), the THF was evaporated and the aqueous phase was extracted with 3x200 ml of Et2O, the combined organic layer was washed with brine (300 ml)r dried over MgSO4s filtered and evaporated to give the crude mixture which was chromatographed was shaken in a Parr vessel at 50 Psi H2 for 2 days. The mixture was filtered through celite™ and evaporated to give 980 mg (99%) of the acid as foam. 'H NMR (400 MHz, CDCI3) 4.73-4.66 (m, 1H), 2.71 (dd, J = 11.8, 5.4, 1H), 2.68-2.62 (m, 1H), 2.53 (dt, J = 10.0, 6.4, 1H), 1.92, ddd, J = 13.4, 6.0, 2.6, 1H), 1.63-1.57 (m, 1H), 1.52-1.20 (unresolved m, 3H), 1.30(d, J = 5.9, 3H), 0.96 (d, J = 6.6, 3H), 0.93- 0.89 (m, 1H), 0.80 (t, J = 7.5, 3H). MS: 319.1 (MhT.DMSO). Step B: To a solution of the product of Step 7 (490 mg, 2.04 mmo!) in CH2CI2 (20 ml) was added oxaly! chloride (360 u.l, 4.13 mmol, 2 eq.) followed by 1 drop of DMF. The solution was stirred at rt for 1 hour and the solvent was removed to provide the crude acid chloride, which was dissolved in toluene (20 ml) and cooled to 0°C. To this was added Pd(PPh3)a (236 mg, 0.20 mmol, 0.1 eq.) followed by Bu3SnH (825 \i\, 3.07 mmol, 1.5 eq.). The mixture was stirred for 3 hours at 0°C, concentrated and chromatographed with 25% EtOAc-hexane to provide the title compound 220 mg (48%) as a resin. nH NMR (400 MHz, CDCI3) 9.72 (d, J = 3.6,1H), 4.70 (dq, J = 5.7, 9.5, 1H), 2.71-2.64 (m, 2H), 2.56-2.51 (m, 1H), 1.98 (ddd, J = 13.5, 6.1, 2.9, 1H), 1.68-1.59 (m, 3H), 1.52-1.37 (m, 1H), 1.35 (d, J = 5.9, 3H), 1.32-1.20 (m, 1H), 1.00 (d, J = 6.2, 3H): 0.80 (d, J = 7.3, 3H). Step 1: The thiopyran enal was prepared according to the procedure of McGinnis and Robinson, J. Chem. Soc, 404 (1941), 407. Step 2: To a suspension of 60% NaH (6.3 g, 158 mmol, 1.3 eq.) in THF (200 ml) at 0°C was added methyl diethylphosphonoacetate (29 ml, 158 mmol, 1.3 eq.) and the The reaction was quenched with aq. NH4CI (50 ml) and extracted with EtOAc (3x20 ml). The combined organic layer was washed with brine (50 ml), dried over MgSO4 and concentrated to provide the crude alcohol. A solution of the alcohol in MeOH-THF (6 ml; 1:1 v/v) was added to a flask containing excess Raney nickel which was washed with dioxane and THF. The suspension was heated at reflux for 3 h, cooled, filtered, concentrated and chromatographed with 25% EtOAc-hex to provide 54 mg (67%) of title compound as a resin. 1H NMR (400 MHz, CDCI3) 4.70 (dq, J = 9.7, 5.9 Hz, 1H)t 3.73 (dd, J = 10.5, 3.4 Hz, 1H), 3.62 (dd: J = 10.5, 7.6 Hz, 1H), 2.60-2.53 (m, 1H), 2.46 (ddd, J = 9.6, 7.2, 5.2 Hz, 1H), 1.90 (ddd, J = 13.5, 6.1, 3.1 Hz, 1H), 1.87-1.81 (m, 1H), 1.77 (br s, 1H): 1.66-1.59 (m, 1H), 1.50 (d, J = 6.0 Hz, 3H), 1.48-1.36 (m, 2H): 1.25-1.14 Step1 Prepared according to the procedure described in Wang et a/., Tet Lett, 41, (2000), p. 4335-4338. Step 2: To a solution of the product of Step 1 (20 g, 106 mmol) and E13N (17.8 ml, 128 mmol, 1.2 eq.) in CH2CI2 (300 ml) kepi -30cC was slowly added CH3SO2CI {9.1 ml, 118 mmol, 1.1 eq.). The slurry was stirred for 1 hour while it warmed up to 0 °C. The reaction mixture was diluted with aq. NaHCO3 (500 ml) and the organic layer was separated. The aqueous layer was extracted with Et2O (2x200 ml) and the combined organic layers were washed with aq. NaHCO3 (2x300 ml) and brine (300 ml). The solution was dried over MgSO, filtered and evaporated to give the crude mesylate, which was used as such for the next step. 1H NMR: 8.67 (d, J = 2.0 Hz: 1H), 7.89 (dd, J = 8.4, 2.4 Hz; 1H), 7.33 (d, J = 8.4 Hz, 1H), 5.28 (s,2H), 3.10 (s,3H). Step 3: To a suspension of 60% NaH (8.5 g, 212 mmol 2.0 eq.) in THF (500 ml) at rt was added diethylphosphite (27.4 ml, 213 mmol, 2 eq,) drop by drop and the mixture was stirred for 1 h. To this cloudy solution was added a solution of the product of Step 2 in THF (125 ml) and the mixture was stirred at rt for 1 h. The reaction was quenched by the addition of H2O (500 ml), the THF was evaporated and the aq. layer was extracted with EtOAc (4x150 ml). The combined organic layers were washed with aq. K2CO3 (2x300 ml), brine {300 ml), dried over MgSO4; filtered, evaporated and the crude product was chromatographed with 5:95 CH3OH-CH2CI2 to give 31.7 g (97%) of oil. 1H NMR: 8.59 (d, J = 2.0 Hz, 1H), 7.76 (dd, J = 8.2, 2.1 Hz, 1H), 7.29 (ddf J = 6.2, 2.2 Hz, 1H), 4.12-4.05 (m, 4 H), 3.36 (d, J = 22.0 Hz, 2H), 1.27 (t? J = 7.0 Hz, 6H). To a solution of the product of Preparation 3 (15 g, 49 mmol. 1.5 eq.) in THF (100 ml) at 0 °C was added 1M LHMDS in THF (49 ml, 49 mmol, 1.5 eq.) and the solution was stirred for 30 min. To this was added TKO'Pr) (14.4 rnL 49 mmol. 1.5 eq.) followed by a solution of the product of Preparation 1 (7.3 g, 32 mmol) in THF stirred for 15 min at -78°C, 1 hour at rt, then quenched with the addition of aq. NH4CI (500 ml). The THF was evaporated and the aqueous layer was extracted with EtOAc (3x200 ml). The combined organic layers were washed with H2O (2x300 ml) and brine (300 ml), dried over MgSO4, filtered, evaporated and the crude was chromatographed with 10% EtOAc-hex to provide 16,5 g (71%) of resin. 1H NMR: 7.77-7.74 (m, 2H), 7.71-7.68 (m, 2H), 7.46-7.36 (mf 6H), 4,53 (tq, J = 1.8, 6.5 Hz, 1H), 4.08 (dd, J = 6.2,1.8 Hz), 2.82 (d, J = 6.4 Hz, 3H), 1.07 Preparation 1 To a solution of the phosphonate {850 mg, 2.01 mmol, 2 eq.) in THF (8 ml) at 0cC was added BuLi in hexanes (790 µI of 2.5M solution, 2.0 mmol, 2 eq.), the mixture was stirred for 10 min, then Ti(OPr)* (590 µl, 2.0 mmol, 2 eq.) was added and the solution was stirred at rt for 10 min. To this was added a solution of the product of Preparation 1 (220 rr.g, 0.98 mmo!) in THF (3 ml) and ihe mixture was stirred at rt for 1.5 h. To the solution was added aq. Rochelles's salt (100 ml) and THF was evaporated. The aqueous phase was extracted with EtOAc (3x30 ml) and the combined organic layer was washed with brine (50 ml). The solution was dried over MgSO, concentrated and the resultant residue was chromatographed with 20% EtOAc-hexane to provide the title compound (240 mg, 62%) as a resin. 'H NMR (400 MHz, CDCfe) 8.78 (d, J = 2.0, 1H), 7.82 (dd, J = 2.4, 8.0, 1H), 7.44 Anal, calc'd for C25H2BFNO2.HCI: C, 69.84; Ht 6.80; N, 3.26. Found: C, 71.00, H, 6.96; N, 3.19. Using a similar procedure with the appropriate phosphonate, the following compound 1A was prepared: 1H NMR: 8.7B (d, J = 2.4 Hz, 1H), 7.82 (dd, J = 8.2, 2.6 Hz, 1H), 7.44 (dt, J = 6.0,8.0 Hz, 1H), 7.37-7.35 (m, 1H), 7.29-7.25 (m, 2H), 7.09 (ddt, J = 1.0, 2.4, 8.3 Hz, 1H), 6.67-6.58 (m, 2H), 4.67-4.60 (m, 1H), 2.85-2.79 (m, 2H), 2.32 The Suzuki coupling procedure is exemplified by heating a solution of a bromide of Preparation 4 or 5 with boronic acid {1.0 to 2.0 eq.), K2CO3 (4 eq.) and Pd(PPh3)4 (5 to 10 mol%) in toluene:EtOH:H2O (4:2:1, v/v/v) at 100°C until the reaction is complete. The reaction mixture is diluted with H2O, extracted with EtOAc, and the organic layer is washed with brine, dried over MgSO4, filtered, concentrated and purified by chromatography to provide the desired compounds. Using the Suzuki coupling procedure described above, the following compounds were prepared: 1H NMR: 6.54 (00, J = 2.2, 0.6 Hz: 1H), 7.62 (dd, J = 8.0, 2.2 Hz.. 1H), 7.31-7.25 (m, 4H), 7.22-7.20 (m, 1H), 6.65-6.56 (m, 1H), 4.67-4.80 (m, 1H), 3.20 (br s, 1H), 2.89-2.80 (m, 1H), 2.34 (ddd, J = 10.1, 5.7, 1.5 Hz, 1H), 2.30 (s, 3H), 1.91-1.77 (m, 2H); 1.70-1.64 (m, 1H), 1.55-1.43 (m, 2H), 1.45 (d, J = 6.0 Hz, 3H), 1.39-1.25 (m, 1H), 0.98 (d, J = 6.50, 3H), 0.79 1H NMR: 8.80 (d: J = 2.0 Hz, 1H), 7.84 h. It was diluted with aq. NH4CI (150 ml), the THF was evaporated and the aq. layer was extracted with EtOAc (3x60 ml). The combined organic layers were washed with H2O (50 ml), brine (50 ml), dried over MgSO4, filtered, evaporated and the residue was chromatographed with 30% EtOAc-hex to provide 2.0 g (94%) of resin. 1H NMR: 8.80 (d, J = 2.0 Hz: 1H), 7.81 (dd, J = 8.0, 2.4 Hz, 1H), 7.64 (ddd, J = 15.1, 11.5, 1.1 Hz, 1H), 7.44 (dt, J = 5.6, 7.9 Hz, 1H), 7-38-7.33 (m, 2H), 7.30-7.26 (m, 1H), 7.09 (ddt, J = 1.0, 2.5, 8.3 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 6.24 (t, J = 11.2 Hz, 1H), 5.70-5.65 (m, 1H), 5.07-5.00 (m, 1H), 1.35 (d, J = 6.4 Hz, 3H). To a solution of the alcohol oi Step 4 (110 mg, 0.41 mmol) and the acid (85 mg; 0.61 mmol, 1.5 eq.) in CH2CI2 (2 ml) was added DCC (130 mg, 0.63 mmol, 1.5 eq.) and DMAP (10 mg, 0.08 mmol, 0.2 eq.) and stirred at 0 °C until the reaction was complete. The mixture was diluted with Et2O (50 ml), washed with aq. NaHCOs (2x20 ml) and brine (20 ml), dried over MgSO4, filtered, concentrated and the residue was chromatographed with 10% EtOAc-hex to provide 135 mg (84%) of resin. 'H NMR: 8.79 (d, J = 2.4 Hz, 1H), 7.81 (dd, J = 8.0, 2.4 Hz, 1H), 7.67 (ddd, J = 15.3, 11.5, 1.2 Hz, 1H),7.47-7.27(m,5H),7.15(ddt,J = 2.0! 1.0, 8.3 Hz, 1H), 6.71 (d, J = 15.6 Hz: 1H), 6.29 (dt, J = 0.8, 11.4 Hz, 1H), 6.11-6.00 (m, 1H), 5.88 (t, J = 7.6 Hz, 1H), 5.63 (t: J = 10.0 Hz, 1H), 2.24-2.16 (m, 2H), 7.76 (d, J = 0.8 Hz, 3H), 1.43 (d, J = 6.4 Hz, 3H), 1.00 (t, J = 7.6 Hz, 3H). Step 6: A solution of the tetraene of Step 5 (130 mg) in toluene (10 ml) was stirred in a sealed tube at 185 °C for 7 h, cooled to rt and stirred with 10 \iL of DBU for 3 hr. The solution was concentrated and purified by preparative chromatography to afford 63 mg (49%) of resin. nH NMR: 8.72 (d, J= 2.0 Hz, 1H), 7.77 (dd, J = 8.4, 2.4 Hz: 1H), 7.41 (dt, J = 6.0, 8.0 Hz, 1 H), 7.36-7.31 (m, 2H): 7.26-7.22 (m, 1H), 7.06 (ddt, J = 1.0, 2.7, 8.3 Hz, 1H), 6.66 (d, J = 16.0 Hz, 1H), 6.47 (dd, J = 15.8, 9.8 Hz, 1H), 5.62-561 (m, 1H), 4.55 (dq, J = 4.0, 6.4 Hz, 1H): 3.27-3.24 (m, 1H), 2.80-2.75 (m, 1H), 2.56-2.52 (m, 1H), 2.02- Step 1: To a solution of oxazole (75 pi, 1.1 mmol) in THF (2 ml) at -78 °C was added a solution of 2.5 M BuLi in hexanes (465 JAL 1.2 mmol, 2.2 eq.) and the mixture was stirred for 30 min. To this was added 0.5 M 2nCI2 in Et2O (4.3 ml, 2.2 mmol, 4 eq.) and the mixture stirred for 30 min at -78 °C and 30 min. at 0 °C. Step 2: Separately, to a suspension of PcKPPh3)^Cl2 {37 mg, 0.05 mmol) in THF at 0 °C was added 2.5 M BuLi in hexanes (43 jxl, 0.11 mmol) and the suspension was stirred for 20 min. This solution was added to zincate of Step 1, followed by the product of Preparation 4 (200 mg? 0.5 mmol) and the mixture was refluxed overnight. It was cooled, diluted with aq. NH4CI (60 ml) and extracted with EtOAc (3x20 ml). The combined organic layer was washed with brine Step 1: A solution of Preparation 5 {60 mg, 0.15 mmol), Et3N (26 pJ, 0.19 mmol, 1.2 eq.), bis(diphenylphosphino)propane (3 mg, 7 \|imol, 5 mol%), Pd{OAc)2 (1.7 mg, 7.6 nmo!, 5 mol%) and vinyl n-propyl ether (85 jxl, 0.76 mmol, 5 eq.) in DMF (1.5 ml) in a sealed tube was heated at 1O0 °C for 2 h, cooled to rt and stirred with 2N HC1 3: extracted with EtOAc, dried over MgSO, filtered, concentrated and the residue was purified by preparative TLC to provide 25 mg of ketone. Step 2: A solution of the product of Step 1 (13 mg, 36 jxmol) and hydroxyiamine hydrochloride (8 mg, 0.12 mmol) in pyridine (0.5 ml) was stirred overnight at rt. The To 0.15 g of compound 7 in 10 mL of dry dichloromethane at 0 °C was added 77 µL of triethylamine (1.5 eq.) and 34µL of methanesulfonylchtoride To this product in 10 mL of DMSO was added 0.290 g of sodium azide (15 eq.) and the mixture heated to 65 °C while stirring under N2for 3 days. The reaction mixture was poured onto H2O and extracted three times with ethyiacetate. The combined extracts were washed with brine, dried with MgSO4? filtered and evaporated to dryness yielding 65 mg of azide. To a solution of this aride in 5 ml of ethyiacetate and 50 µL of H2O at 0 °C was added 300 µL of 1 M THF solution of trimethylphosphine (2 eq.) and the mixture allowed to warm to room temperature while stirring under argon. After 24 hours, the reaction was evaporated to dryness and purified by flash chromatography yielding 0.053 g of amine 8. MS(ESI)mfc409 Example 20: 7a-Amination Chemistry diluted with EtOAc, washed twice with aq. K2CO3, and twice with H20 and brine. It was dried over MgSO4, filtered, concentrated and chromatographed with 20% EtOAc in hexanes to provide 260 mg of 12. HRMS: 380.2032 (MH+), calculated 380.2026. Using a similar procedure, the following compound was prepared: EX.21B HRMS: 394.2188 (MH4), calculated 394.218. Further embodiments of the invention encompass the administration of compounds of Formula I along with at least one additional cardiovascular agent. The contemplated additional cardiovascular agent is one that differs in either atomic make up or arrangement from the compounds of Formula I. Additional cardiovascular agents that can be used in combination with the novel compounds of this invention include drugs which have anti-thrombotic, anti-platelet aggregation, antiatherosclerotic. antirestenotic and/or anti-coagulant activity. Such drugs are useful in treating thrombosis-related diseases including thrombosis, atherosclerosis, restenosis.. hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, giomerulonephritis, thrombotic and thromboembolic stroke, peripheral vascular diseases, other cardiovascular diseases, cerebral ischemia, inflammatory disorders and cancer, as well as other disorders in which thrombin and its receptor play a pathological role. Suitable cardiovascular agents are selected from the group consisting of thromboxane A2 biosynthesis inhibitors such as aspirin; thromboxane antagonists such as seratrodast, picotamide and ramatroban; adenosine diphosphate (ADP) inhibitors such as clopidogrel; cyclooxygenase inhibitors such as aspirin, rneloxicam, rofecoxib and ceiecoxib; angiotensin antagonists such as valsartan. telmisartan, candesartran, irbesartran, losartan and eprosartan; endothelin antagonists such as tezosenten; phosphodiesterase inhibitors such as milrinoone and enoximone; angiotensin converting enzyme (ACE) inhibitors such as captopril, enalapril, enaliprilat, spirapril, quinapril, perindopril, ramipril, fosinopril, trandolaprii, lisinopril, moexipril and benazapri!; neutral endopeptidase inhibitors such as candoxatril and ecadotri!; anticoagulants such as ximelagatran, fondaparin and enoxaparin; diuretics such as chlorothiazide, hydrochlorothiazide, ethacrynic acid, furosemide and amiioride; platelet aggregation inhibitors such as abciximab and eptifibatide; and GP Ilb/lila antagonists. Preferred types of drugs for use in combination with the novel compounds of this invention are thromboxane A2 biosynthesis inhibitors, cydooxygenase inhibitors and ADP antagonists. Especially preferred for use in the combinations are aspirin and clopidogre! bisulfate. When the invention comprises a combination of a compound of Formula I and another cardiovascular agent, the two active components may be co-administered simultaneously or sequentially, or a single pharmaceutical composition comprising a compound of Formula I and another cardiovascular agent in a pharrnaceutically acceptable carrier can be administered. The components of the combination can be administered individually or together in any conventional dosage form such as capsule, tablet, powder, cachet, suspension, solution, suppository, nesal spray, etc. The dosage of the cardiovascular agent can be determined from published material, and may range from 1 to 1000 mg per dose. in ihis specification, the term "at least one compound of Formula I" means that one to three different compounds of Formula I may be used in a pharmaceutical composition or method of treatment. Preferably one compound of Formula I is used. Similarly, the term "one or more additional cardiovascular agents" means that one to three additional drugs may be administered in combination with a compound of Formula I; preferably, one additional compound is administered in combination with a compound of Formula I. The additional cardiovascular agents can be administered sequentially or simultaneously with reference to the compound of Formula I. When separate compounds of Formula I and the other cardiovascular agents are to be administered as separate compositions, they can be provided in a kit comprising in a single package, one container comprising a compound of Formula I in a pharmaceutically acceptable carrier, and a separate container comprising another cardiovascular ageni in a pharmaceutically acceptable carrier, with the compound of Formula I and the other cardiovascular agent being present in amounts such that the combination is therapeutically effective. A kit is advantageous tor administering a mCi) was then added to the flask, which was stirred at room temperature for 2 hours. At the completion of the reaction, the excess tritium was removed and the reacted peptide solution was diluted with DMF (0.5 ml) and filtered to remove the catalyst. The collected DMF solution of the crude peptide was diluted with water and freeze dried to remove the labile tritium. The solid peptide was redissolved in water and the freeze drying process repeated. The tritiated peptide ([3H]haTRAP) was dissolved in 0.5 ml of 0.1 % aqueous TFA and purified by HPLC using the following conditions: column, Vydac™ C1 Bs 25 cm x 9.4 mm I.D.; mobile phase, (A) 0.1 % TFA in water, (B) 0.1% TFA in CH3CN; gradient, (A/B) from 100/0 to 40/60 over 30 min; flow rate; 5 ml /min; detection, UV at 215 nm. The radiochemical purity of [3H]haTRAP was 99% as analyzed by HPLC. A batch of 14.9 mCi at a specific activity of 18.4 Ci/mmol was obtained. Preparation of platelet membranes Platelet membranes were prepared using a modification of the method of Natarajan ei a/. (Natarajan et a/; Int. J. Peptide Protein Res. 45:145-151 (1995)) from 20 units of platelet concentrates obtained from the North Jersey Blood Center (6ast Orange, NJ) within 48 hours of collection. Ail steps were carried out at 4° C under approved biohazard safety conditions. Platelets were centrifuged at 100 x g for 20 minutes at 4° C to remove red cells. The supernatants were decanted and centrifuged at 3000 x g for 15 minutes to pellet platelets. Platelets were resuspended in 10 mM Tris-HCI, pH 7.5, 150 mM NaCI, 5 mM EDTA, to a total volume of 200 ml and centrifuged at 4400 x g for 10 minutes. This step was repeated two additional times. Platelets were resuspended in 5 mM Tris-HCL pH 7.5, 5 rnM EDTA to a final volume of approximately 30 ml and were homogenized with 20 strokes in a DounceTW homogenizer. Membranes were pelleted at 41,000 x g, resuspended in 40-50 ml 20 mM Tris-HCI, pH 7.5, 1 mM EDTA, 0.1 mM dithiothreitol, and 10 ml aliquots were frozen in liquid N2 and stored at -80* C. To complete membrane preparation, aliquots were thawed, pooled, and homogenized with 5 strokes of a Dounce homogenizer. Membranes were pelleted and washed 3 times in 10 mM triethanolamine-HCI, pH 7.4, 5 mM EDTA, and resuspended in 20-25 ml 50 mM Tris-HCI, pH 7.5, 10 mM MgCfe, 1 mM EGTA, and 1% DMSO. Aliquots of membranes were frozen in liquid N2 and stored at -80c C. Membranes were stable for at least 3 months. 20 units of platelet concentrates typically yielded 250 mg o1 membrane protein. Protein concentration was determined by a Lowry assay (Lowry etai, J. Biol. Chem.. 193:265-275 (1951)). High Throughput Thrombin Receptor Radioliqand Binding Assay Thrombin receptor antagonists were screened using a modification of the thrombin receptor radioligand binding assay of Ahn et al (Ahn ei. al., Mol. Pharmacol., 51:350-356 (1987)). The assay was performed in 96 well Nunc plates (Cat. No. 269620) at a final assay volume of 200 //I. Platelet membranes and [3H]haTRAP were diluted to 0.4 mg/ml and 22.2 nM, respectively, in binding buffer (50 mM Tris-HCI, pH 7.5,10 mM MgCfc, 1 mM EGTA, 0.1% BSA). Stock solutions (10 mM in 100% DMSO) of test compounds were further diluted in 100% DMSO. Unless otherwise indicated, 10 µl of diluted compound solutions and 90 p\ of radioligand (a final concentration of 10 nM in 5% DMSO) were added to each well, and the reaction was started by the addition of 100µl of membranes (40 µg protein/well). The binding was not significantly inhibited by 5% DMSO. Compounds were tested at three concentrations (0.1, 1 and 10//M). The plates were covered and vortex-mixed gently on a Lab-Line™ Titer Plate Shaker for 1 hour at room temperature. Packard UniFifter™ GF/C filter plates were soaked for at least 1 hour in 0.1 % polyethyleneimine. The incubated membranes were harvested using a Packard FilterMate™ Universal Harvester and were rapidly washed four times with 300 fj\ ice cold 50 mM Tris-HCI, pH 7.5,10 mM MgCI2, 1 mM EGTA. MicroScint™ 20 scintillation cocktail (25 //I) wss added to each well, and the plates were counted in a Packard TopCount™ Microplaie Scintillation Counter. The specific binding was defined as the total binding minus the nonspecific binding observed in the presence of excess (50 pM) unlabeled haTRAP. The % inhibition by a compound of [3H]haTRAP binding to thrombin receptors was calculated from the following relationship: % Inhibition = Total bindino-Bindino in the presence of a test compound x 100 Total binding-Nonspecific binding Materials A(pF-F)R(ChA)(hR)Y-NH2 and A(pF-F)R(ChA)(hR)(l2-Y)-NH2, were custom synthesized by AnaSpec Inc. (San Jose, CA). The purity of these peptides was >95%. Tritium gas (97%) was purchased from EG&G Mound, Miarnisburg, Ohio. The gas was subsequently loaded and stored on an IN/US Systems Inc. Trisorber. MicroScint™ 20 scintillation cocktail was obtained from Packard Instrument Co. Protocol For Ex-Vivo Platelet Aggregation In Cvnomolaus Whole Blood Drug Administration and Blood Collection: Conscious chaired cynomolgus monkeys are allowed to equilibrate for 30 min. A needle catheter is inserted into a brachial vein for infusion of test drugs. Another needle catheter is inserted into the other brachial or saphenous vein and used for blood sampling. In those experiments where the compound is administered orally only one catheter is used. A baseline blood sample (1-2 ml) is collected in vacutainer tubes containing a thrombin inhibitor CVS 2139 (100µg/0.1 ml saline) as an anticoagulant. The drug is then infused intravenously over a period of 30 min. Blood samples (1 ml) are collected at 5,10,20, 30 min during and 30, 60, 90 min after termination of the drug infusion. In PO experiments the animals are dosed with the drug using a gavage cannula. Blood samples are collected at 0, 30,60, 90; 120,180, 240,300, 360 min after dosing. 0.5 ml of the blood is used for whole blood aggregation and the other 0.5 ml is used for determining the plasma concentration of the drug or its metabolites. Aggregation is performed immediately after collection of the blood sample as described below. Whole Blood Aggregation: A 0.5 ml blood sample is added to 0.5 ml of saline and warmed to 37°C in a Chronolog whole blood aggregometer. Simultaneously, the impedance electrode is warmed in saline to 37°C. The blood sample with a stir bar is placed in the heating block well, the impedance electrode is placed in the blood sample and the collection software is started. The software is allowed to run until the baseline is stabilized and then a 20 Q calibration check is performed. 20 £2 is equal to 4 blocks on the graphic produced by the computer software. The agonist In vitro Platelet Aggregation Procedure: Platelet aggregation studies were performed according to the method of Bednar el al {Bednar, B., Condra, CM Gould, R.J.. and Connolly, T.M., Throm. Res., 77:453-463 (1995)). Blood was obtained from healthy human subjects who were aspirin free for at least 7 days by venipuncture using ACD as anticoagulant, Piateiet rich plasma was prepared by centrifugation at lOOxg for 15 minutes at 15 deg C. Platelets were pelleted at 3000xg and washed twice in buffered saline containing 1 rnM EGTA and 20//g/ml apyrase to inhibit aggregation. Aggregation was performed at room temperature in buffered saline supplemented with 0.2 mg/ml human fibrinogen. Test compound and platelets were preincubated in 96-well flat-bottom plates for 50 minutes. Aggregation was initiated by adding 0.3 ^M haTRAP or 0.1 U/ml thrombin and rapidly vortexing the mixture using a Lab LineTW Titer Plate Shaker (speed 7). Percent aggregation was monitored as increasing light transmiftance at 405 nm in a Spectromax™ Plate Reader. In vivo Antitumor Procedure: Tests in the human breast carcinoma model in nude mouse are conducted according to the procedure reported in S. Even-Ram ei a/., Nature Medicine, 4, 8 (1988)r p. 909-914. Cannabinoid GB? fteceptor Binding Assay Binding to the human cannabinoid CB2 receptor was carried out using the procedure of Showalter, eiaL (1996, J. Pharmacol EXD Ther. 278(3), 989-99), with minor modifications. All assays were carried out in a final volume of 100 ul. Test compounds were resuspended to 10 mM in DMSO, then serially diluted in 50 mM Tris, pH 7.1, 3 mM MgCI2, 1 mM EDTA, 50% DMSO. Aliquots (10 ul) of each diluted sample were then transferred into individual wells of a 96-well microtiter plate. Membranes from human CB2 transfected CHO/Ki cells (Receptor Biology, Inc) were resuspended in binding buffer {50 mM Tris, pH 7.1, 3 mM MgCI2, 1 mM EDTA, 0.1 % fatty acid free bovine serum albumin), then added to the binding reaction (-15 ug in 50 ul per assay). The reactions were initiated with the addition of [3H] CP-55, 940 diluted in binding buffer (specific activity = 180 Ci/mmol; New England Nuclear, Boston, Mass.). The final ligand concentration in the binding reaction was 0,48 nM. Following incubation at room temperature for 2 hours. membranes were harvested by filtration through pretreated (0.5% polyethylenimine; Sigma P-3143) GF-C filler plates (Unifilter-96, Packard) using a TomTec™ Mach 3U 96-well cell harvester (Hamden, Ct). Plates were washed 10 times in 100 ul binding buffer, and the membranes allowed to air dry. Radioactivity on membranes was quanfrtated following addition of Packard Omniscint™ 20 scintillation fluid using aTopCount™ NXT Microplate Scintillation and Luminescence Counter (Packard, Meriden, Ct). Non-linear regression analysis was performed using Prism™ 20b. (GraphPad Software, San Diego, Ca). Using the test procedures described above, representative compounds of formula I were found to have thrombin receptor IC50 values (i.e., the concentration at which a 50% inhibition of thrombin receptor was observed) of 1 to 1000 nM, preferably 1-100 nM, more preferably 1-20 nM. CB2 Ki values range from 1 to 1000 nM, preferably 1-200 nM, more preferably 1-100 nM. For example, IC50 values of Example Nos. 8BU; 8CAf BCB, 8CL, 17H, 20Er 20F, 20G and 20H range from 1-100 nM. or a pharmaceutically acceptable isomer, salt, solvate or poiymorph thereof. 2. A pharmaceutical composition comprising an effective amount of at least one • compound of Claim 1 and at least one pharmaceutically acceptable carrier. 3. A method of inhibiting thrombin receptors comprising administering to a mammal in need of such treatment an effective amount of at least one compound of Claim 1. 4. A method of inhibiting cannabinoid receptors comprising administering to a mammal in need of such treatment an effective amount of at least one compound of Claim 1. 5. A method of treating thrombosis, platelet aggregation, coagulation, cancer, inflammatory diseases or respiratory diseases comprising administering to a mammal in need of such treatment an effective amount of at least one compound of Claim 1. 6. A method of treating atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolytic stroke, peripheral vascular diseases, cerebral ischemia, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, diabetes, osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia, nephritis, inflammatory disorders of the lungs and gastrointestinal tract., reversible airway obstruction, chronic asthma or bronchitis comprising administering to a mammal in need of such treatment an effective amount of at least one compound of Claim 1.

Full Text

THROMBIN RECEPTOR ANTAGONISTS
BACKGROUND OF THE INVENTION
The present invention relates to nor-seco himbacine derivatives useful as thrombin receptor antagonists in the treatment of diseases associated with thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, cerebral ischemia, stroke, neurodegenerative diseases and cancer. Thrombin receptor antagonists are also known as protease activated receptor (PAR) antagonists. The compounds of the invention also bind to cannabinoid (CB2) receptors and are useful in the treatment of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, diabetes, osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia, nephritis, inflammatory disorders of the lungs and gastrointestinal tract, and respiratory tract disorders such as reversible airway obstruction, chronic asthma and bronchitis. The invention also relates to pharmaceutical compositions containing said compounds.
Thrombin is known to have a variety of activities in different cell types and thrombin receptors are known to be present in such cell types as human platelets, vascular smooth muscle cells, endothelial cells and fibroblasts. It is therefore expected that thrombin receptor antagonists will be useful in the treatment of thrombotic, inflammatory, atherosclerotic and fibroproliferative disorders, as well as other disorders in which thrombin and its receptor play a pathological role.
Thrombin receptor antagonist peptides have been identified based on structure-activity studies involving substitutions of amino acids on thrombin receptors. In Bernatowicz ei ai, J, Med. Chem.. 39 (1996), p. 4879-4887, tetra- and pentapeptides are disclosed as being potent thrombin receptor antagonists, for example N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-NH2 and N-trans-cinnamoyl-p*fluoroPhe-p-guan»dinoPhe"Leu-Arg-Arg-NH2. Peptide thrombin receptor antagonists are also disclosed in WO 94/03479, published February 17,1994.
Cannabinoid receptors belong to the superfamily of G-protein coupled receptors. They are classified into the predominantly neuronal CBi receptors and the predominantly peripheral CB2 receptors. These receptors exert their biological actions by modulating adenyiate cyclase and Ca*2 and K+ currents. While the effects of CB1 receptors are principally associated with the central nervous system, CB2 receptors are believed to have peripheral effects related to bronchial constriction, immunomodulation and inflammation. As such, a selective CB2 receptor binding

or a pharmaceutically acceptable isomer, salt, solvate or polymorph thereof.
Thrombin receptor antagonist compounds of the present invention can have anti-thrombotic, anti-platelet aggregation, antiatherosclerotic, antirestenotic and anticoagulant activity. Thrombosis-related diseases treated by the compounds of this invention are thrombosis, atherosclerosis, restenosis, hypertension, angina pectons, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic and thromboembolytic stroke, peripheral vascular diseases, other cardiovascular diseases, cerebral ischemia, inflammatory disorders and cancer, as well as other disorders in which thrombin and its receptor play a pathological rote.
The compounds of the invention which bind to cannabinoid (C82) receptors can be useful in the treatment of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, diabetes, osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia, nephritis, inflammatory disorders of the lungs and gastrointestinal tract, and respiratory tract disorders such as reversible airway obstruction, chronic asthma and bronchitis.
This invention also relates to a method of using at least one compound of formula I in the treatment of thrombosis, platelet aggregation, coagulation, cancer, inflammatory diseases or respiratory diseases, comprising administering a compound of formula I to a mammal in need of such treatment. In particular, the present invention relates to a method of using at least one compound of formula I in the treatment of thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, gJomerutonephritis: thrombotic stroke, thromboembolytic stroke, peripheral vascular diseases, cerebral ischemia, cancer, rheumatoid arthritis, systemic lupus erythematosus. multiple sclerosis, diabetes, osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia, nephritis, inflammatory disorders of the lungs and gastrointestinal tract, reversible airway obstruction, chronic asthma or bronchitis. It is contemplated that a compound of this invention may be useful in treating more than one of the diseases listed.

In another aspect, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula I in at least one pharmaceutically acceptable carrier.
DETAILED DESCRIPTION:
Unless otherwise defined, the term !1alkyl" or "lower alky!" means straight or branched alkyl chains of 1 to 6 carbon atoms and "alkoxy" similarly refers to alkoxy groups having 1 to 6 carbon atoms.
FluoroalkyL difluoroalkyl and trifluoroalkyl mean alkyl chains wherein the terminal carbon is substituted by 1, 2 or 3 fluoroatoms, e.g., -CF3, -CH2CF3, -CH2CHF2 or -CH2CH2F. HaloalkyI means an alkyl chain substituted by 1 to 3 halo
atoms.
"Alkenyl" means straight or branched carbon chains of carbon atoms having one or more double bonds in the chain, conjugated or unconjugated. Similarly, "alkynyl" means straight or branched carbon chains of carbon atoms having one or more triple bonds in the chain. Where an alkyl. alkenyl or alkynyl chain joins two other variables and is therefore bivalent, the terms alkyiene.. alkenylene and alkynylene are used. Unless otherwise defined, alkenyl and alkynyl chains comprise 1 to 6 carbon atoms.
Substitution on alkyl. alkenyl and alkynyl chains depends on the length of the chain, and the size and nature of the substituent. Those skilled in the art will appreciate that while longer chains can accommodate multiple substituents, shorter alkyl chains, e.g., methyl or ethyl, can have multiple substitution by halogen, but otherwise are likely to have only one or two substituents other than hydrogen. Shorter unsaturated chains, e.g., ethenyl or ethynyl, are generally unsubstituted or substitution is limited to one or two groups, depending on the number of available carbon bonds.
"Cycloalkyl" means a saturated carbon ring of 3 to 7 carbon atoms, while "cycloalkylene11 refers to a corresponding bivalent ring, wherein the points of attachment to other groups include all positional and stereoisomers. "CydoalkenyF refers to a carbon ring of 3 to 7 atoms and having one or more unsaturated bonds, but not having an aromatic nature.
"Heterocycloalkyl" means saturated rings of 5 or 6 atoms comprised of 4 to 5 carbon atoms and 1 or 2 heteroatoms selected from the group consisting of -O-, -S-and -NR7- joined to the rest of the molecule through a carbon atom. Examples of heterocycloalkyl groups are 2-pyrroIidinyl, tetrahydrothiophen-2-yl, 1etrahydro-2-furanyl, 4-piperidinyL 2-piperazinyl, tetrahydro-4-pyranyL 2-morpholinyl and 2-thiomorpholinyl.
"Halogen" refers to fluorine, chlorine, bromine or iodine radicals.

When R4 and R5 join to form a ring with the nitrogen to which they are attached, the rings formed are 1-pyrrolidinyl, 1-piperidiny! and 1-piperazinyI, wherein the piperazinyl ring may also be substituted at the 4-position nitrogen by a group R7.
"Dihydroxy(C1-C6)alkyl" refers to an alkyl chain substituted by two hydroxy groups on two different carbon atoms.
"Aryl" means phenyl. naphthyl, indenyl, tetrahydronaphthyl or indanyl.
"HeteroaryP means a single ring or benzofused heteroaromatic group of 5 to 10 atoms comprised of 2 to 9 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, provided that the rings do not include adjacent oxygen and/or sulfur atoms. N-oxides of the ring nitrogens are also included, as well as compounds wherein a ring nitrogen is substituted by a C1-C4
alkyl group to form a quaternary amine. Examples of single-ring heteroaryl groups are pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazoiyk pyrazolyl, ietrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazinyl, pyrimtdyl, pyridazinyl and triazoiyl. -Examples of benzofused heteroaryl groups are indolyl, quinolyl, isoquinolyl, phthalazinyl. benzothienyl {i.e., thionaphthenyl), benzimidazolyl, benzofuranyl, benzoxazolyl and benzofurazanyl. All positional isomers are contemplated, e.g., 2-pyritiyl, 3-pyridyl and 4-pyridyl. W-substituted heteroaryl refers to such groups wherein substrtutable ring carbon atoms have a substitueni as defined above, or where adjacent carbon atoms form a ring with an alkylene group or a methylenedioxy group, or where a nitrogen in the Het ring can be substituted with R21-aryl or an optionally substituted alkyl substituent as defined in W.
The term "Het" is exemplified by the single ring, the ring substituted with another ring (which can be the same or different), benzofused heteroaryl groups as defined immediately above, as well as tricyclic groups such as benzoquinolinyl (e.g., 1,4 or 7,8) or phenanthrolinyl {e.g., 1,7; 1,10; or 4,7). Het groups are joined to group B by a carbon ring member, e.g., Het is 2-pyridyl, 3-pyridyi or 2-quinolyl.
Examples of heteroaryl groups wherein adjacent carbon atoms form a ring with an alkylene group are 2,3-cyclopentenopyridine, 2,3-cyctohexenopyridineand 2,3-cydoheptenopyridine.
The term "optional double bond" refers to the bond shown by the single dotted line in the middle ring of the structure shown for formula I. The term "optional single bond" refers to the bond shown by the double dotted line between X and the carbon to which Y and R15 are attached in the structure of formula I.
The above statements, wherein, for example, R4 and R5 are said to be independently selected from a group of substituents, means that R4 and R5 are independently selected: but also that where an Ft4 or R5 variable occurs more than once in a molecule, those occurrences are independently selected. Those skilled in

the art will recognize that the size and nature of the substituent(s) will affect the
number of substituents which can be present.
It should also be noted that any formula, compound, moiety or chemical
illustration with unsatisfied valences in the present specification and/or claims herein is assumed to have sufficient hydrogen atom(s) to satisfy the valences.
Compounds of the invention have at least one asymmetrical carbon atom and therefore all isomers, including diastereomers and rotational isomers are contemplated as being part ot this invention. The invention includes (+)- and (-)-isomers in both pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers ot a compound of formula I.
"Polymorph" means a crystalline form of a substance that is distinct from another crystalline form but that shares the same chemical formula.
Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term "prodrug", as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of formula I or a salt and/or solvate thereof (e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form). A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto.
"Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable oi isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H2O.
Compounds of the invention with a carboxylic acid group can form pharmaceutically acceptable esters with an alcohol. Examples of suitable alcohols include methanol and ethanol.

Abbreviations which are used in the preparative examples, schemes and examples include the following:
DBAD: Di-terf-butyl azodicarboxylate
DBU: 1, 8-Diazabicyclo[5.4.0]undec-7-ene
DCC: Dicyclohexylcarbodiimide
DCM: Dichloromethane
DIBAL: Diisobutylaiuminum hydride
DMAP: 4-Dimethyl aminopyridine
DMF: M/V-Dimethylformamide
DMSO: Methyl sulfoxide
EDCI: l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
HMPA: Hexamethylphosphoramide
HOBt: Hydroxybezotriazole
LAH: Lithium aluminum hydride
LHMDS: Lithium bis NMO: 4-Methylmorphine /V-oxide
TBAF: Tetrabutylammonium fluoride
TFA: Trifluoroacetic acid
THF: Teirahydrofuran
TMSI: Trimethylsilyl iodide
TRAP: Tetrapropyiammonium perruthenate
Typical preferred compounds of the present invention have the following stereochemistry:
with compounds having that absolute stereochemistry being more preferred.
Those skilled in the art will appreciate that ior some compounds of formula IT one isomer will show greater pharmacological activity than other isomers.
Compounds of the invention with a basic group can form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, mettianesulfonic and other mineral and carboxylic acids well known to those in the art. The salt is prepared by contacting the

Alternatively, compounds of formula I wherein W is optionally substituted aryl can be prepared from compounds of formula I wherein W is -OH using a trrflate intermediate. For example, 3-hydroxy-6-methylpyridine is treated with triisopropylsilyl chloride, and the resultant hydroxy-protected compound is converted to the phosphonate as described above for preparing intermediate Ilia. The triisopropylsilyl-protected intermediate is then reacted with intermediate II and the protecting group is removed under standard conditions. The resultant compound of formula I wherein W is OH is then treated with triflic anhydride at room temperature in a solvent such as CH2CI2; the triflate is then reacted with an optionally substituted arylboronic acid, e.g.,
optionally substituted phenylboronic acid, in a solvent such as toluene, in the presence of Pd(PPh3)4 and a base such a K2CO3 at elevated temperatures and
under an inert atmosphere.
Compounds of formula I wherein W is a substituted hydroxy group (e.g., benzyloxy) can be prepared from compounds of formula I wherein W is hydroxy by refluxing in a suitable solvent such as acetone with a halogen-substituted compound such as optionally substituted benzyl bromide in the presence of a base such as K2CO3.
Compounds of formula I wherein Het is substituted by W through a carbon atom {e.g., wherein W is alkyl.. alkenyl or arylalkyl) or a nitrogen atom (i.e., -NR4R5) can be prepared as shown in Scheme 3 using a compound of formula I wherein W is chloroalkyl as an intermediate. Compounds of formula I wherein W is a polar group such as hydroxy alkyl, dihydroxyalkyL -COOH, dirnethylamino and -COH can be prepared as shown in Scheme 4y wherein the starting material is 3 compound of formula I wherein W is alkenyl. The following Schemes 3 and 4 show well-known reaction conditions for preparing various W-substituted compounds wherein X is -O-, Y is =0, R'5 is absent, R1 is methyl, R2: R3; R9, R10 and R11 are each H, B is -CH=CH-; and Het is 2-pyridyl.

formulations and pharmaceutical compositions can be prepared using conventional pharmaceutically acceptable excipients and additives and conventional techniques. Such pharmaceutically acceptable excipients and additives include non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, anti-oxidants, lubricants, flavorings, thickeners, coloring agents, emulsifiers and the like.
The daily dose of a compound of formula I for treatment of a disease or condition cited above is about 0.001 to about 100 mg/kg of body weight per day, preferably about 0.001 to about 10 mg/kg. For an average body weight of 70 kg, the dosage level is therefore from about 0.1 to about 700 mg of drug per day, given in a single dose or 2-4 divided doses. The exact dose, however, is determined by the attending clinician and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient.
Following are examples of preparing starting materials and compounds of formula I. In the procedures, the following abbreviations are used: room temperature (rt), tetrahydrofuran (THF): ethyl ether (Et2O), methyl {Me), ethyl (Et), ethyl acetate (EtOAc): dimethylformamide (DMF), 4-dimethylaminopyridine (DMAP)r 1,8-diazabicyclo[5.4.0jundec-7-ene (DBU), 1r3-dicyclohexylcart>odiimide.
Preparation 1
O H H
o HT
0
STEP1
See J. Org. Chem.: 59 (17) (1994), p. 4789.
Step 2:
O
To s suspension of 80% NaH (7.42 g, 185.5 mmol, 1.3 eq) in 300 ml THF at 0°C was added dropwise triethylphosphono acetate (37 ml. 186.5 mmoL 1.3 eq) and the mixture was stirred at 0°C for 30 min. The product of Step 1 (14.0 g, 142.7 mmol) was added and the mixture was stirred atO°C for 30 min. The reaction was quenched by the addition of aq. NH4CI (500 ml), the THF was evaporated and the aqueous phase was extracted with 3x200 ml of Et2O, the combined organic layer was washed with brine (300 ml)r dried over MgSO4s filtered and evaporated to give the crude mixture which was chromatographed

was shaken in a Parr vessel at 50 Psi H2 for 2 days. The mixture was filtered through
celite™ and evaporated to give 980 mg (99%) of the acid as foam.
'H NMR (400 MHz, CDCI3) 4.73-4.66 (m, 1H), 2.71 (dd, J = 11.8, 5.4, 1H), 2.68-2.62
(m, 1H), 2.53 (dt, J = 10.0, 6.4, 1H), 1.92, ddd, J = 13.4, 6.0, 2.6, 1H), 1.63-1.57 (m,
1H), 1.52-1.20 (unresolved m, 3H), 1.30(d, J = 5.9, 3H), 0.96 (d, J = 6.6, 3H), 0.93-
0.89 (m, 1H), 0.80 (t, J = 7.5, 3H).
MS: 319.1 (MhT.DMSO).
Step B:
To a solution of the product of Step 7 (490 mg, 2.04 mmo!) in CH2CI2 (20 ml) was added oxaly! chloride (360 u.l, 4.13 mmol, 2 eq.) followed by 1 drop of DMF. The solution was stirred at rt for 1 hour and the solvent was removed to provide the crude acid chloride, which was dissolved in toluene (20 ml) and cooled to 0°C. To this was added Pd(PPh3)a (236 mg, 0.20 mmol, 0.1 eq.) followed by Bu3SnH (825 \i\, 3.07 mmol, 1.5 eq.). The mixture was stirred for 3 hours at 0°C, concentrated and chromatographed with 25% EtOAc-hexane to provide the title compound 220 mg (48%) as a resin.
nH NMR (400 MHz, CDCI3) 9.72 (d, J = 3.6,1H), 4.70 (dq, J = 5.7, 9.5, 1H), 2.71-2.64 (m, 2H), 2.56-2.51 (m, 1H), 1.98 (ddd, J = 13.5, 6.1, 2.9, 1H), 1.68-1.59 (m, 3H), 1.52-1.37 (m, 1H), 1.35 (d, J = 5.9, 3H), 1.32-1.20 (m, 1H), 1.00 (d, J = 6.2, 3H): 0.80 (d, J = 7.3, 3H).
Step 1:
The thiopyran enal was prepared according to the procedure of McGinnis and Robinson, J. Chem. Soc, 404 (1941), 407.
Step 2:
To a suspension of 60% NaH (6.3 g, 158 mmol, 1.3 eq.) in THF (200 ml) at 0°C was added methyl diethylphosphonoacetate (29 ml, 158 mmol, 1.3 eq.) and the

The reaction was quenched with aq. NH4CI (50 ml) and extracted with EtOAc (3x20 ml). The combined organic layer was washed with brine (50 ml), dried over MgSO4 and concentrated to provide the crude alcohol. A solution of the alcohol in MeOH-THF (6 ml; 1:1 v/v) was added to a flask containing excess Raney nickel which was washed with dioxane and THF. The suspension was heated at reflux for 3 h, cooled, filtered, concentrated and chromatographed with 25% EtOAc-hex to provide 54 mg (67%) of title compound as a resin. 1H NMR (400 MHz, CDCI3) 4.70 (dq, J = 9.7, 5.9 Hz, 1H)t 3.73 (dd, J = 10.5, 3.4 Hz, 1H), 3.62 (dd: J = 10.5, 7.6 Hz, 1H), 2.60-2.53 (m, 1H), 2.46 (ddd, J = 9.6, 7.2, 5.2 Hz, 1H), 1.90 (ddd, J = 13.5, 6.1, 3.1 Hz, 1H), 1.87-1.81 (m, 1H), 1.77 (br s, 1H): 1.66-1.59 (m, 1H), 1.50 (d, J = 6.0 Hz, 3H), 1.48-1.36 (m, 2H): 1.25-1.14 Step1
Prepared according to the procedure described in Wang et a/., Tet Lett, 41, (2000), p. 4335-4338.
Step 2:
To a solution of the product of Step 1 (20 g, 106 mmol) and E13N (17.8 ml, 128 mmol, 1.2 eq.) in CH2CI2 (300 ml) kepi -30cC was slowly added CH3SO2CI {9.1 ml, 118 mmol, 1.1 eq.). The slurry was stirred for 1 hour while it warmed up to 0 °C. The reaction mixture was diluted with aq. NaHCO3 (500 ml) and the organic layer was separated. The aqueous layer was extracted with Et2O (2x200 ml) and the combined organic layers were washed with aq. NaHCO3 (2x300 ml) and brine (300 ml). The solution was dried over MgSO*, filtered and evaporated to give the crude mesylate, which was used as such for the next step.
1H NMR: 8.67 (d, J = 2.0 Hz: 1H), 7.89 (dd, J = 8.4, 2.4 Hz; 1H), 7.33 (d, J = 8.4 Hz, 1H), 5.28 (s,2H), 3.10 (s,3H).

Step 3:
To a suspension of 60% NaH (8.5 g, 212 mmol 2.0 eq.) in THF (500 ml) at rt was added diethylphosphite (27.4 ml, 213 mmol, 2 eq,) drop by drop and the mixture was stirred for 1 h. To this cloudy solution was added a solution of the product of Step 2 in THF (125 ml) and the mixture was stirred at rt for 1 h. The reaction was quenched by the addition of H2O (500 ml), the THF was evaporated and the aq. layer was extracted with EtOAc (4x150 ml). The combined organic layers were washed with aq. K2CO3 (2x300 ml), brine {300 ml), dried over MgSO4; filtered, evaporated and the crude product was chromatographed with 5:95 CH3OH-CH2CI2 to give 31.7 g (97%) of oil.
1H NMR: 8.59 (d, J = 2.0 Hz, 1H), 7.76 (dd, J = 8.2, 2.1 Hz, 1H), 7.29 (ddf J = 6.2, 2.2 Hz, 1H), 4.12-4.05 (m, 4 H), 3.36 (d, J = 22.0 Hz, 2H), 1.27 (t? J = 7.0 Hz, 6H).

To a solution of the product of Preparation 3 (15 g, 49 mmol. 1.5 eq.) in THF (100 ml) at 0 °C was added 1M LHMDS in THF (49 ml, 49 mmol, 1.5 eq.) and the solution was stirred for 30 min. To this was added TKO'Pr)* (14.4 rnL 49 mmol. 1.5 eq.) followed by a solution of the product of Preparation 1 (7.3 g, 32 mmol) in THF

stirred for 15 min at -78°C, 1 hour at rt, then quenched with the addition of aq. NH4CI (500 ml). The THF was evaporated and the aqueous layer was extracted with EtOAc (3x200 ml). The combined organic layers were washed with H2O (2x300 ml) and brine (300 ml), dried over MgSO4, filtered, evaporated and the crude was chromatographed with 10% EtOAc-hex to provide 16,5 g (71%) of resin.
1H NMR: 7.77-7.74 (m, 2H), 7.71-7.68 (m, 2H), 7.46-7.36 (mf 6H), 4,53 (tq, J = 1.8, 6.5 Hz, 1H), 4.08 (dd, J = 6.2,1.8 Hz), 2.82 (d, J = 6.4 Hz, 3H), 1.07 Preparation 1
To a solution of the phosphonate {850 mg, 2.01 mmol, 2 eq.) in THF (8 ml) at 0cC was added BuLi in hexanes (790 µI of 2.5M solution, 2.0 mmol, 2 eq.), the mixture was stirred for 10 min, then Ti(OPr)* (590 µl, 2.0 mmol, 2 eq.) was added and the solution was stirred at rt for 10 min. To this was added a solution of the product of Preparation 1 (220 rr.g, 0.98 mmo!) in THF (3 ml) and ihe mixture was stirred at rt for 1.5 h. To the solution was added aq. Rochelles's salt (100 ml) and THF was evaporated. The aqueous phase was extracted with EtOAc (3x30 ml) and the combined organic layer was washed with brine (50 ml). The solution was dried over MgSO*, concentrated and the resultant residue was chromatographed with 20% EtOAc-hexane to provide the title compound (240 mg, 62%) as a resin. 'H NMR (400 MHz, CDCfe) 8.78 (d, J = 2.0, 1H), 7.82 (dd, J = 2.4, 8.0, 1H), 7.44

Anal, calc'd for C25H2BFNO2.HCI: C, 69.84; Ht 6.80; N, 3.26. Found: C, 71.00, H, 6.96; N, 3.19.
Using a similar procedure with the appropriate phosphonate, the following compound 1A was prepared:

1H NMR: 8.7B (d, J = 2.4 Hz, 1H), 7.82 (dd, J = 8.2, 2.6 Hz, 1H), 7.44 (dt, J = 6.0,8.0 Hz, 1H), 7.37-7.35 (m, 1H), 7.29-7.25 (m, 2H), 7.09 (ddt, J = 1.0, 2.4, 8.3 Hz, 1H), 6.67-6.58 (m, 2H), 4.67-4.60 (m, 1H), 2.85-2.79 (m, 2H), 2.32 The Suzuki coupling procedure is exemplified by heating a solution of a bromide of Preparation 4 or 5 with boronic acid {1.0 to 2.0 eq.), K2CO3 (4 eq.) and Pd(PPh3)4 (5 to 10 mol%) in toluene:EtOH:H2O (4:2:1, v/v/v) at 100°C until the reaction is complete. The reaction mixture is diluted with H2O, extracted with EtOAc, and the organic layer is washed with brine, dried over MgSO4, filtered, concentrated and purified by chromatography to provide the desired compounds.
Using the Suzuki coupling procedure described above, the following compounds were prepared:

1H NMR: 6.54 (00, J = 2.2, 0.6 Hz: 1H), 7.62 (dd, J = 8.0, 2.2 Hz.. 1H), 7.31-7.25 (m, 4H), 7.22-7.20 (m, 1H), 6.65-6.56 (m, 1H), 4.67-4.80 (m, 1H), 3.20 (br s, 1H), 2.89-2.80 (m, 1H), 2.34 (ddd, J = 10.1, 5.7, 1.5 Hz, 1H), 2.30 (s, 3H), 1.91-1.77 (m, 2H); 1.70-1.64 (m, 1H), 1.55-1.43 (m, 2H), 1.45 (d, J = 6.0 Hz, 3H), 1.39-1.25 (m, 1H), 0.98 (d, J = 6.50, 3H), 0.79
1H NMR: 8.80 (d: J = 2.0 Hz, 1H), 7.84

h. It was diluted with aq. NH4CI (150 ml), the THF was evaporated and the aq. layer was extracted with EtOAc (3x60 ml). The combined organic layers were washed with H2O (50 ml), brine (50 ml), dried over MgSO4, filtered, evaporated and the residue was chromatographed with 30% EtOAc-hex to provide 2.0 g (94%) of resin. 1H NMR: 8.80 (d, J = 2.0 Hz: 1H), 7.81 (dd, J = 8.0, 2.4 Hz, 1H), 7.64 (ddd, J = 15.1, 11.5, 1.1 Hz, 1H), 7.44 (dt, J = 5.6, 7.9 Hz, 1H), 7-38-7.33 (m, 2H), 7.30-7.26 (m, 1H), 7.09 (ddt, J = 1.0, 2.5, 8.3 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 6.24 (t, J = 11.2 Hz, 1H), 5.70-5.65 (m, 1H), 5.07-5.00 (m, 1H), 1.35 (d, J = 6.4 Hz, 3H).

To a solution of the alcohol oi Step 4 (110 mg, 0.41 mmol) and the acid (85 mg; 0.61 mmol, 1.5 eq.) in CH2CI2 (2 ml) was added DCC (130 mg, 0.63 mmol, 1.5 eq.) and DMAP (10 mg, 0.08 mmol, 0.2 eq.) and stirred at 0 °C until the reaction was complete. The mixture was diluted with Et2O (50 ml), washed with aq. NaHCOs (2x20 ml) and brine (20 ml), dried over MgSO4, filtered, concentrated and the residue was chromatographed with 10% EtOAc-hex to provide 135 mg (84%) of resin. 'H NMR: 8.79 (d, J = 2.4 Hz, 1H), 7.81 (dd, J = 8.0, 2.4 Hz, 1H), 7.67 (ddd, J = 15.3, 11.5, 1.2 Hz, 1H),7.47-7.27(m,5H),7.15(ddt,J = 2.0! 1.0, 8.3 Hz, 1H), 6.71 (d, J = 15.6 Hz: 1H), 6.29 (dt, J = 0.8, 11.4 Hz, 1H), 6.11-6.00 (m, 1H), 5.88 (t, J = 7.6 Hz, 1H), 5.63 (t: J = 10.0 Hz, 1H), 2.24-2.16 (m, 2H), 7.76 (d, J = 0.8 Hz, 3H), 1.43 (d, J = 6.4 Hz, 3H), 1.00 (t, J = 7.6 Hz, 3H).
Step 6:
A solution of the tetraene of Step 5 (130 mg) in toluene (10 ml) was stirred in a sealed tube at 185 °C for 7 h, cooled to rt and stirred with 10 \iL of DBU for 3 hr. The solution was concentrated and purified by preparative chromatography to afford 63 mg (49%) of resin.
nH NMR: 8.72 (d, J= 2.0 Hz, 1H), 7.77 (dd, J = 8.4, 2.4 Hz: 1H), 7.41 (dt, J = 6.0, 8.0 Hz, 1 H), 7.36-7.31 (m, 2H): 7.26-7.22 (m, 1H), 7.06 (ddt, J = 1.0, 2.7, 8.3 Hz, 1H), 6.66 (d, J = 16.0 Hz, 1H), 6.47 (dd, J = 15.8, 9.8 Hz, 1H), 5.62-561 (m, 1H), 4.55 (dq, J = 4.0, 6.4 Hz, 1H): 3.27-3.24 (m, 1H), 2.80-2.75 (m, 1H), 2.56-2.52 (m, 1H), 2.02-

Step 1: To a solution of oxazole (75 pi, 1.1 mmol) in THF (2 ml) at -78 °C was added a solution of 2.5 M BuLi in hexanes (465 JAL 1.2 mmol, 2.2 eq.) and the mixture was stirred for 30 min. To this was added 0.5 M 2nCI2 in Et2O (4.3 ml, 2.2 mmol, 4 eq.) and the mixture stirred for 30 min at -78 °C and 30 min. at 0 °C. Step 2: Separately, to a suspension of PcKPPh3)^Cl2 {37 mg, 0.05 mmol) in THF at 0 °C was added 2.5 M BuLi in hexanes (43 jxl, 0.11 mmol) and the suspension was stirred for 20 min. This solution was added to zincate of Step 1, followed by the product of Preparation 4 (200 mg? 0.5 mmol) and the mixture was refluxed overnight. It was cooled, diluted with aq. NH4CI (60 ml) and extracted with EtOAc (3x20 ml). The combined organic layer was washed with brine
Step 1: A solution of Preparation 5 {60 mg, 0.15 mmol), Et3N (26 pJ, 0.19 mmol, 1.2 eq.), bis(diphenylphosphino)propane (3 mg, 7 |imol, 5 mol%), Pd{OAc)2 (1.7 mg, 7.6 nmo!, 5 mol%) and vinyl n-propyl ether (85 jxl, 0.76 mmol, 5 eq.) in DMF (1.5 ml) in a sealed tube was heated at 1O0 °C for 2 h, cooled to rt and stirred with 2N HC1 3: extracted with EtOAc, dried over MgSO*, filtered, concentrated and the residue was purified by preparative TLC to provide 25 mg of ketone.
Step 2: A solution of the product of Step 1 (13 mg, 36 jxmol) and hydroxyiamine hydrochloride (8 mg, 0.12 mmol) in pyridine (0.5 ml) was stirred overnight at rt. The

To 0.15 g of compound 7 in 10 mL of dry dichloromethane at 0 °C was added 77 µL of triethylamine (1.5 eq.) and 34µL of methanesulfonylchtoride To this product in 10 mL of DMSO was added 0.290 g of sodium azide (15 eq.) and the mixture heated to 65 °C while stirring under N2for 3 days. The reaction mixture was poured onto H2O and extracted three times with ethyiacetate. The combined extracts were washed with brine, dried with MgSO4? filtered and evaporated to dryness yielding 65 mg of azide.
To a solution of this aride in 5 ml of ethyiacetate and 50 µL of H2O at 0 °C was added 300 µL of 1 M THF solution of trimethylphosphine (2 eq.) and the mixture allowed to warm to room temperature while stirring under argon. After 24 hours, the reaction was evaporated to dryness and purified by flash chromatography yielding 0.053 g of amine 8. MS(ESI)mfc409 Example 20: 7a-Amination Chemistry

diluted with EtOAc, washed twice with aq. K2CO3, and twice with H20 and brine. It was dried over MgSO4, filtered, concentrated and chromatographed with 20% EtOAc in hexanes to provide 260 mg of 12. HRMS: 380.2032 (MH+), calculated 380.2026.
Using a similar procedure, the following compound was prepared:

EX.21B HRMS: 394.2188 (MH4), calculated 394.218.
Further embodiments of the invention encompass the administration of compounds of Formula I along with at least one additional cardiovascular agent. The contemplated additional cardiovascular agent is one that differs in either atomic make up or arrangement from the compounds of Formula I. Additional cardiovascular agents that can be used in combination with the novel compounds of this invention include drugs which have anti-thrombotic, anti-platelet aggregation, antiatherosclerotic. antirestenotic and/or anti-coagulant activity. Such drugs are useful in treating thrombosis-related diseases including thrombosis, atherosclerosis, restenosis.. hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, giomerulonephritis, thrombotic and thromboembolic stroke, peripheral vascular diseases, other cardiovascular diseases, cerebral ischemia, inflammatory disorders and cancer, as well as other disorders in which thrombin and its receptor play a pathological role. Suitable cardiovascular agents are selected from the group consisting of thromboxane A2 biosynthesis inhibitors such as aspirin; thromboxane antagonists such as seratrodast, picotamide and ramatroban; adenosine diphosphate (ADP) inhibitors such as clopidogrel; cyclooxygenase inhibitors such as aspirin, rneloxicam, rofecoxib and ceiecoxib; angiotensin antagonists such as valsartan. telmisartan, candesartran, irbesartran, losartan and eprosartan; endothelin antagonists such as tezosenten; phosphodiesterase inhibitors such as milrinoone and

enoximone; angiotensin converting enzyme (ACE) inhibitors such as captopril, enalapril, enaliprilat, spirapril, quinapril, perindopril, ramipril, fosinopril, trandolaprii, lisinopril, moexipril and benazapri!; neutral endopeptidase inhibitors such as candoxatril and ecadotri!; anticoagulants such as ximelagatran, fondaparin and enoxaparin; diuretics such as chlorothiazide, hydrochlorothiazide, ethacrynic acid, furosemide and amiioride; platelet aggregation inhibitors such as abciximab and eptifibatide; and GP Ilb/lila antagonists.
Preferred types of drugs for use in combination with the novel compounds of this invention are thromboxane A2 biosynthesis inhibitors, cydooxygenase inhibitors and ADP antagonists. Especially preferred for use in the combinations are aspirin and clopidogre! bisulfate.
When the invention comprises a combination of a compound of Formula I and another cardiovascular agent, the two active components may be co-administered simultaneously or sequentially, or a single pharmaceutical composition comprising a compound of Formula I and another cardiovascular agent in a pharrnaceutically acceptable carrier can be administered. The components of the combination can be administered individually or together in any conventional dosage form such as capsule, tablet, powder, cachet, suspension, solution, suppository, nesal spray, etc. The dosage of the cardiovascular agent can be determined from published material, and may range from 1 to 1000 mg per dose.
in ihis specification, the term "at least one compound of Formula I" means that one to three different compounds of Formula I may be used in a pharmaceutical composition or method of treatment. Preferably one compound of Formula I is used. Similarly, the term "one or more additional cardiovascular agents" means that one to three additional drugs may be administered in combination with a compound of Formula I; preferably, one additional compound is administered in combination with a compound of Formula I. The additional cardiovascular agents can be administered sequentially or simultaneously with reference to the compound of Formula I.
When separate compounds of Formula I and the other cardiovascular agents are to be administered as separate compositions, they can be provided in a kit comprising in a single package, one container comprising a compound of Formula I in a pharmaceutically acceptable carrier, and a separate container comprising another cardiovascular ageni in a pharmaceutically acceptable carrier, with the compound of Formula I and the other cardiovascular agent being present in amounts such that the combination is therapeutically effective. A kit is advantageous tor administering a

mCi) was then added to the flask, which was stirred at room temperature for 2 hours. At the completion of the reaction, the excess tritium was removed and the reacted peptide solution was diluted with DMF (0.5 ml) and filtered to remove the catalyst. The collected DMF solution of the crude peptide was diluted with water and freeze dried to remove the labile tritium. The solid peptide was redissolved in water and the freeze drying process repeated. The tritiated peptide ([3H]haTRAP) was dissolved in 0.5 ml of 0.1 % aqueous TFA and purified by HPLC using the following conditions: column, Vydac™ C1 Bs 25 cm x 9.4 mm I.D.; mobile phase, (A) 0.1 % TFA in water, (B) 0.1% TFA in CH3CN; gradient, (A/B) from 100/0 to 40/60 over 30 min; flow rate; 5 ml
/min; detection, UV at 215 nm. The radiochemical purity of [3H]haTRAP was 99% as
analyzed by HPLC. A batch of 14.9 mCi at a specific activity of 18.4 Ci/mmol was
obtained.
Preparation of platelet membranes
Platelet membranes were prepared using a modification of the method of Natarajan ei a/. (Natarajan et a/; Int. J. Peptide Protein Res. 45:145-151 (1995)) from 20 units of platelet concentrates obtained from the North Jersey Blood Center (6ast Orange, NJ) within 48 hours of collection. Ail steps were carried out at 4° C under approved biohazard safety conditions. Platelets were centrifuged at 100 x g for 20 minutes at 4° C to remove red cells. The supernatants were decanted and centrifuged at 3000 x g for 15 minutes to pellet platelets. Platelets were resuspended in 10 mM Tris-HCI, pH 7.5, 150 mM NaCI, 5 mM EDTA, to a total volume of 200 ml and centrifuged at 4400 x g for 10 minutes. This step was repeated two additional times. Platelets were resuspended in 5 mM Tris-HCL pH 7.5, 5 rnM EDTA to a final volume of approximately 30 ml and were homogenized with 20 strokes in a DounceTW homogenizer. Membranes were pelleted at 41,000 x g, resuspended in 40-50 ml 20 mM Tris-HCI, pH 7.5, 1 mM EDTA, 0.1 mM dithiothreitol, and 10 ml aliquots were frozen in liquid N2 and stored at -80* C. To complete membrane preparation, aliquots
were thawed, pooled, and homogenized with 5 strokes of a Dounce homogenizer. Membranes were pelleted and washed 3 times in 10 mM triethanolamine-HCI, pH 7.4, 5 mM EDTA, and resuspended in 20-25 ml 50 mM Tris-HCI, pH 7.5, 10 mM MgCfe, 1 mM EGTA, and 1% DMSO. Aliquots of membranes were frozen in liquid N2 and stored at -80c C. Membranes were stable for at least 3 months. 20 units of platelet concentrates typically yielded 250 mg o1 membrane protein. Protein concentration was determined by a Lowry assay (Lowry etai, J. Biol. Chem.. 193:265-275 (1951)).
High Throughput Thrombin Receptor Radioliqand Binding Assay
Thrombin receptor antagonists were screened using a modification of the thrombin receptor radioligand binding assay of Ahn et al (Ahn ei. al., Mol. Pharmacol., 51:350-356 (1987)). The assay was performed in 96 well Nunc plates (Cat. No.

269620) at a final assay volume of 200 //I. Platelet membranes and [3H]haTRAP were diluted to 0.4 mg/ml and 22.2 nM, respectively, in binding buffer (50 mM Tris-HCI, pH 7.5,10 mM MgCfc, 1 mM EGTA, 0.1% BSA). Stock solutions (10 mM in 100%
DMSO) of test compounds were further diluted in 100% DMSO. Unless otherwise indicated, 10 µl of diluted compound solutions and 90 p\ of radioligand (a final concentration of 10 nM in 5% DMSO) were added to each well, and the reaction was started by the addition of 100µl of membranes (40 µg protein/well). The binding was not significantly inhibited by 5% DMSO. Compounds were tested at three concentrations (0.1, 1 and 10//M). The plates were covered and vortex-mixed gently on a Lab-Line™ Titer Plate Shaker for 1 hour at room temperature. Packard UniFifter™ GF/C filter plates were soaked for at least 1 hour in 0.1 % polyethyleneimine. The incubated membranes were harvested using a Packard FilterMate™ Universal Harvester and were rapidly washed four times with 300 fj\ ice cold 50 mM Tris-HCI, pH 7.5,10 mM MgCI2, 1 mM EGTA. MicroScint™ 20
scintillation cocktail (25 //I) wss added to each well, and the plates were counted in a Packard TopCount™ Microplaie Scintillation Counter. The specific binding was defined as the total binding minus the nonspecific binding observed in the presence of excess (50 pM) unlabeled haTRAP. The % inhibition by a compound of [3H]haTRAP binding to thrombin receptors was calculated from the following relationship:
% Inhibition = Total bindino-Bindino in the presence of a test compound x 100
Total binding-Nonspecific binding
Materials
A(pF-F)R(ChA)(hR)Y-NH2 and A(pF-F)R(ChA)(hR)(l2-Y)-NH2, were custom
synthesized by AnaSpec Inc. (San Jose, CA). The purity of these peptides was >95%. Tritium gas (97%) was purchased from EG&G Mound, Miarnisburg, Ohio. The gas was subsequently loaded and stored on an IN/US Systems Inc. Trisorber. MicroScint™ 20 scintillation cocktail was obtained from Packard Instrument Co.
Protocol For Ex-Vivo Platelet Aggregation In Cvnomolaus Whole Blood Drug Administration and Blood Collection:
Conscious chaired cynomolgus monkeys are allowed to equilibrate for 30 min. A needle catheter is inserted into a brachial vein for infusion of test drugs. Another needle catheter is inserted into the other brachial or saphenous vein and used for blood sampling. In those experiments where the compound is administered orally only one catheter is used. A baseline blood sample (1-2 ml) is collected in vacutainer tubes containing a thrombin inhibitor CVS 2139 (100µg/0.1 ml saline) as an anticoagulant. The drug is then infused intravenously over a period of 30 min. Blood

samples (1 ml) are collected at 5,10,20, 30 min during and 30, 60, 90 min after termination of the drug infusion. In PO experiments the animals are dosed with the drug using a gavage cannula. Blood samples are collected at 0, 30,60, 90; 120,180, 240,300, 360 min after dosing. 0.5 ml of the blood is used for whole blood aggregation and the other 0.5 ml is used for determining the plasma concentration of the drug or its metabolites. Aggregation is performed immediately after collection of the blood sample as described below. Whole Blood Aggregation:
A 0.5 ml blood sample is added to 0.5 ml of saline and warmed to 37°C in a Chronolog whole blood aggregometer. Simultaneously, the impedance electrode is warmed in saline to 37°C. The blood sample with a stir bar is placed in the heating block well, the impedance electrode is placed in the blood sample and the collection software is started. The software is allowed to run until the baseline is stabilized and then a 20 Q calibration check is performed. 20 £2 is equal to 4 blocks on the graphic produced by the computer software. The agonist In vitro Platelet Aggregation Procedure:
Platelet aggregation studies were performed according to the method of Bednar el al {Bednar, B., Condra, CM Gould, R.J.. and Connolly, T.M., Throm. Res., 77:453-463 (1995)). Blood was obtained from healthy human subjects who were aspirin free for at least 7 days by venipuncture using ACD as anticoagulant, Piateiet rich plasma was prepared by centrifugation at lOOxg for 15 minutes at 15 deg C. Platelets were pelleted at 3000xg and washed twice in buffered saline containing 1 rnM EGTA and 20//g/ml apyrase to inhibit aggregation. Aggregation was performed at room temperature in buffered saline supplemented with 0.2 mg/ml human fibrinogen. Test compound and platelets were preincubated in 96-well flat-bottom plates for 50 minutes. Aggregation was initiated by adding 0.3 ^M haTRAP or 0.1 U/ml thrombin and rapidly vortexing the mixture using a Lab LineTW Titer Plate Shaker (speed 7). Percent aggregation was monitored as increasing light transmiftance at 405 nm in a Spectromax™ Plate Reader.
In vivo Antitumor Procedure:
Tests in the human breast carcinoma model in nude mouse are conducted according to the procedure reported in S. Even-Ram ei a/., Nature Medicine, 4, 8 (1988)r p. 909-914.
Cannabinoid GB? fteceptor Binding Assay

Binding to the human cannabinoid CB2 receptor was carried out using the procedure of Showalter, eiaL (1996, J. Pharmacol EXD Ther. 278(3), 989-99), with minor modifications. All assays were carried out in a final volume of 100 ul. Test compounds were resuspended to 10 mM in DMSO, then serially diluted in 50 mM Tris, pH 7.1, 3 mM MgCI2, 1 mM EDTA, 50% DMSO. Aliquots (10 ul) of each diluted sample were then transferred into individual wells of a 96-well microtiter plate. Membranes from human CB2 transfected CHO/Ki cells (Receptor Biology, Inc) were resuspended in binding buffer {50 mM Tris, pH 7.1, 3 mM MgCI2, 1 mM EDTA, 0.1 % fatty acid free bovine serum albumin), then added to the binding reaction (-15 ug in 50 ul per assay). The reactions were initiated with the addition of [3H] CP-55, 940 diluted in binding buffer (specific activity = 180 Ci/mmol; New England Nuclear, Boston, Mass.). The final ligand concentration in the binding reaction was 0,48 nM. Following incubation at room temperature for 2 hours. membranes were harvested by filtration through pretreated (0.5% polyethylenimine; Sigma P-3143) GF-C filler plates (Unifilter-96, Packard) using a TomTec™ Mach 3U 96-well cell harvester (Hamden, Ct). Plates were washed 10 times in 100 ul binding buffer, and the membranes allowed to air dry. Radioactivity on membranes was quanfrtated following addition of Packard Omniscint™ 20 scintillation fluid using aTopCount™ NXT Microplate Scintillation and Luminescence Counter (Packard, Meriden, Ct). Non-linear regression analysis was performed using Prism™ 20b. (GraphPad Software, San Diego, Ca).
Using the test procedures described above, representative compounds of formula I were found to have thrombin receptor IC50 values (i.e., the concentration at
which a 50% inhibition of thrombin receptor was observed) of 1 to 1000 nM, preferably 1-100 nM, more preferably 1-20 nM. CB2 Ki values range from 1 to 1000 nM, preferably 1-200 nM, more preferably 1-100 nM. For example, IC50 values of
Example Nos. 8BU; 8CAf BCB, 8CL, 17H, 20Er 20F, 20G and 20H range from 1-100 nM.

or a pharmaceutically acceptable isomer, salt, solvate or poiymorph thereof.
2. A pharmaceutical composition comprising an effective amount of at least one
• compound of Claim 1 and at least one pharmaceutically acceptable carrier.
3. A method of inhibiting thrombin receptors comprising administering to a
mammal in need of such treatment an effective amount of at least one compound of
Claim 1.
4. A method of inhibiting cannabinoid receptors comprising administering to a
mammal in need of such treatment an effective amount of at least one compound of
Claim 1.
5. A method of treating thrombosis, platelet aggregation, coagulation, cancer,
inflammatory diseases or respiratory diseases comprising administering to a mammal
in need of such treatment an effective amount of at least one compound of Claim 1.
6. A method of treating atherosclerosis, restenosis, hypertension, angina
pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis,
thrombotic stroke, thromboembolytic stroke, peripheral vascular diseases, cerebral
ischemia, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis,
diabetes, osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia, nephritis,
inflammatory disorders of the lungs and gastrointestinal tract., reversible airway
obstruction, chronic asthma or bronchitis comprising administering to a mammal in
need of such treatment an effective amount of at least one compound of Claim 1.

Documents:

1002-CHENP-2006 CORRESPONDENCE OTHERS.pdf

1002-CHENP-2006 CORRESPONDENCE PO.pdf

1002-CHENP-2006 OTHER PATENT DOCUMENT 19-08-2009.pdf

1002-chenp-2006-abstract.pdf

1002-chenp-2006-assignement.pdf

1002-chenp-2006-claims.pdf

1002-chenp-2006-correspondnece-others.pdf

1002-chenp-2006-description(complete).pdf

1002-chenp-2006-form 1.pdf

1002-chenp-2006-form 26.pdf

1002-chenp-2006-form 3.pdf

1002-chenp-2006-form 5.pdf

1002-chenp-2006-pct.pdf

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Patent Number

241890

Indian Patent Application Number

1002/CHENP/2006

PG Journal Number

32/2010

Publication Date

06-Aug-2010

Grant Date

29-Jul-2010

Date of Filing

24-Mar-2006

Name of Patentee

SCHERING CORPORATION

Applicant Address

2000 Galloping Hill Road, Kenilworth, NJ 07033-0530.

Inventors:

#	Inventor's Name	Inventor's Address
1	CHACKALAMANNIL, Samuel	17 Windy Heights Road, Califon, NJ 07830
2	CHELLIAH, Mariappan, V.	56 Portland Street, Edison, NJ 08820
3	XIA, Yan	66 Tower Road, Edison, NJ 08820

PCT International Classification Number

C07D

PCT International Application Number

PCT/US2004/031495

PCT International Filing date

2004-09-23

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	10/671,216	2003-09-25	U.S.A.