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Definitions

• 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.
• thromboin receptor antagonists are also known as protease activated receptor (PAR) antagonists.
• the compounds of the invention also bind to cannabinoid (CB 2 ) 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.
• CBD 2 cannabinoid receptors
• 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 Bematowicz et al., J. Med. Chem.. 39 (1996), p.
• 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-guanidinoPhe-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 CB 2 receptors.
• CBi receptors exert their biological actions by modulating adenylate cyclase and Ca +2 and K + currents. While the effects of CBi receptors are principally associated with the central nervous system, CB 2 receptors are believed to have peripheral effects related to bronchial constriction, immunomodulation and inflammation.
• a selective CB 2 receptor binding agent is expected to have therapeutic utility in the control of diseases associated with 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 (R. G. Pertwee, Curr. Med. Chem. 6(8), (1999), 635).
• Himbacine a piperidine alkaloid of the formula
• Z is -(CH 2 ) n -; , when R 1 l 0 ⁇ is absent; or
• R 1 and R 2 are independently selected from the group consisting of H, C-i-C ⁇ alkyl, fluoro(C ⁇ -C6)alkyl, difluoro(C ⁇ -C 6 )alkyl, trifluoro-(C ⁇ -C6)alkyl, C3-C7 cycloalkyl, C 2 -C 6 alkenyl, aryl(CrC6)alkyl, aryl(C 2 -C 6 )alkenyl, heteroaryl(C ⁇ -C 6 )alkyl, heteroaryl(C2-C6)alkenyl, hydroxy-(C-
• R 4 and R 5 are independently selected from the group consisting of H, Ci-C ⁇ alkyl, phenyl, benzyl and C3-C7 cycloalkyl, or R 4 and R 5 together are -(CH2)4-, "(CH2)5- or -(CH2)2 R 7 -(CH2)2- and form a ring with the nitrogen to which they are attached;
• R 6 is independently selected from the group consisting of H, C-i-Ce alkyl, phenyl, (C3-C 7 )cycloalkyl, (C3-C )cycloalkyl(C ⁇ -C6)alkyl, (C ⁇ -C 6 )alkoxy
• R 15 is H or C C 6 alkyl
• R 16 is C1-C6 lower alkyl, phenyl or benzyl
• R 17 , R 18 and R 19 are independently selected from the group consisting of H, C-I-C ⁇ alkyl, phenyl, benzyl
• R 2 ° is H, C-1-C-6 alkyl, phenyl, benzyl, -C(O)R6 or -SO 2 R 6
• R 21 is 1 to 3 substutuents independently selected from the group consisting of hydrogen, CN, -CF 3 , -OCF3, halogen, -NO2, Ci-C ⁇ alkyl, C ⁇ -C6alkoxy, (C-
• C6)alkylamino di-((C ⁇ -C6)alkyl)amino, amino(C ⁇ -C6)alkyl, (C-
• -C6)-alkylamino(C ⁇ - C 6 )alkyl, di-((C ⁇ -C 6 )alkyl)-amino(C ⁇ -C 6 )alkyl, hydroxy-(C ⁇ -C 6 )alkyl, -COOR 17 , - COR 17 -NHCOR 1 6, -NHSO 2 R 16 , -NHSO2CH2CF 3 , heteroaryl or -C( NOR 17 )R 18 ; R 22 and R 23 are independently selected from the group consisting of hydrogen,
• R 26 is 1 , 2, or 3 substituents independently selected from the group consisting of hydrogen, halogen and (CrC 5 )alkoxy;
• R 27 is 1 , 2 or 3 substituents independently selected from the group consisting of hydrogen, R 28 -(C C 10 )alkyl, R 28 -(C 2 -C ⁇ 0 )alkenyl, R 28 -(C 2 -C ⁇ 0 )alkynyl, R >2 ⁇ 8° is hydrogen, -OH or (C C
• R 9 is preferably H, OH or alkoxy.
• R is preferably Ci-C ⁇ alkyl, more preferably methyl.
• the double dotted line preferably represents a single bond;
• Het is preferably pyridyl, substituted pyridyl, quinolyl or substituted quinolyl.
• Preferred substituents (W) on Het are R 21 -aryl, R 41 -heteroaryl or alkyl.
• Het is 2- pyridyl substituted in the 5-position by R 21 -aryl, R 41 -heteroaryl or alkyl, or 2-pyridyl substituted in the 6-position by alkyl.
• R 34 is preferably (H,H) or (H,OH).
• R 22 and R 23 are preferably selected from OH, (d-C ⁇ o)alkyl, (C 2 -C ⁇ 0 )-alkenyl, (C 2 -C ⁇ o)-alkynyl, trifluoro(C ⁇ -C ⁇ o)alkyl, trifluoro(C 2 -C 10 )-alkenyl, trifluoro(C 2 -do)alkynyl, (C 3 -C 7 )-cycloalkyl, R 25 -aryl, R 25 -aryl(d-C 6 )alkyl, R 25 -arylhydroxy(d-C 6 )alkyl, R 25 -aryl- alkoxy-(d-C 6 )alkyl, (C 3 -C 7 )cycloalkyl-(d-C 6 )alkyl, (C r C ⁇ 0 )alkoxy, (C 3 - C 7 )cycloalkyloxy, (CrC 6 )al
• thrombin receptor antagonists represented by any of the following structural formulas:
• Thrombin receptor antagonist compounds of the present invention can have anti-thrombotic, anti-platelet aggregation, antiatherosclerotic, antirestenotic and anti- coagulant activity.
• Thrombosis-related diseases treated by the compounds of this invention are thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, 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 role.
• the compounds of the invention which bind to cannabinoid (CB 2 ) 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.
• 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, glomerulonephritis, 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.
• a compound of this invention may be useful in treating more than one of the diseases listed.
• 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.
• alkyl or “lower alkyl” 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., -CF 3 , -CH 2 CF3, -
• Haloalkyl 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.
• alkynyl means straight or branched carbon chains of carbon atoms having one or more triple bonds in the chain.
• alkylene, alkenylene and alkynylene are used. Unless otherwise defined, alkenyl and alkynyl chains comprise
• alkyl 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
• cycloalkylene refers to a corresponding bivalent ring, wherein the points of attachment to other groups include all positional and stereoisomers.
• Cycloalkenyl 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 -NR 7 - joined to the rest of the molecule through a carbon atom.
• heterocycloalkyl groups examples include 2-pyrrolidinyl, tetrahydrothiophen-2-yl, tetrahydro-2- furanyl, 4-piperidinyl, 2-piperazinyl, tetrahydro-4-pyranyl, 2-morpholinyl and 2- thiomorpholinyl.
• "Halogen” refers to fluorine, chlorine, bromine or iodine radicals.
• Dihydroxy(C ⁇ -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.
• Heteroaryl 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.
• single-ring heteroaryl groups are pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl and triazolyl.
• 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-pyridyl, 3-pyridyl and 4-pyridyl.
• W-substituted heteroaryl refers to such groups wherein substitutable ring carbon atoms have a substituent 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 R 21 -aryl or an optionally substituted alkyl substituent as defined in W.
• 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-pyridyl or 2-quinolyI.
• heteroaryl groups wherein adjacent carbon atoms form a ring with an alkylene group are 2,3-cyclopentenopyridine, 2,3-cyclohexenopyridine and 2,3- cycloheptenopyridine.
• optional double bond refers to the bond shown by the single dotted line in the middle ring of the structure shown for formula I.
• optional single bond refers to the bond shown by the double dotted line between X and the carbon to which Y and R 15 are attached in the structure of formula I.
• R 4 and R 5 are said to be independently selected from a group of substituents, means that R 4 and R 5 are independently selected, but also that where an R 4 or R 5 variable occurs more than once in a molecule, those occurrences are independently selected.
• R 4 and R 5 are independently selected, but also that where an R 4 or R 5 variable occurs more than once in a molecule, those occurrences are independently selected.
• the size and nature of the substituent(s) will affect the number of substituents which can be present.
• 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 of 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 of 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.
• prodrug 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 of 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 H 2 O. 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.
• Typical preferred compounds of the present invention have the following stereochemistry:
• Compounds of the invention with a basic group can form pharmaceutically acceptable salts with organic and inorganic acids.
• suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art.
• the salt is prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt.
• the free base form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium bicarbonate.
• a suitable dilute aqueous base solution such as dilute aqueous sodium bicarbonate.
• the free base form differs from its respective salt form somewhat in certain physical properties, such as solubility in polar solvents, but the salt is otherwise equivalent to its respective free base forms for purposes of the invention.
• Certain compounds of the invention are acidic (e.g., those compounds which possess a carboxyl group). These compounds form pharmaceutically acceptable salts with inorganic and organic bases. Examples of such salts are the sodium, potassium, calcium, aluminum, lithium, gold and silver salts. Also included are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
• Bisulfate salts of the compounds of the invention are preferred embodiments.
• Compounds of the present invention are generally prepared by processes known in the art, for example by the processes described below.
• the alkyne of formula 4 is esterified with the dienoic acid of formula 3 using standard conditions to yield the ester 5.
• Selective reduction of the triple bond of 5 using Lindlar catalyst under hydrogen gives the intermediate 6, which upon thermal cyclization at about 185°C, followed by base treatment, gives the intermediate 7.
• the ester 7 is subjected to hydrogenation in the presence of platinum oxide to generate the intermediate saturated carboxylic acid, treatment of which with oxalyl chloride gives the corresponding acid chloride which is converted to the aldehyde Ma by reduction using tributyltin hydride in the presence of Palladium catalyst.
• Dienoic acids of formula 3 are commercially available or are readily prepared.
• Aldehydes of formula II also can be prepared by a thiopyran ring opening, for example compounds of formula Ma as defined above can be prepared according to the following reaction scheme.
• the alkyne of formula 4 is reduced to the alkene 13 using Lindlar catalyst under hydrogen.
• the alkene 13 is esterified with the dienoic acid of formula 12 using standard conditions to yield the ester 14.
• the ester 15 is converted to the intermediate carboxylic acid, and the double bond is reduced by hydrogenation in the presence of a platinum catalyst.
• the acid is then treated with oxalyl chloride to obtain the corresponding acid chloride, which is converted to the aldehyde 18 by reduction using tributyltin hydride in the presence of Palladium catalyst.
• the aldehyde moiety on 18 is treated with a reducing agent such as NaBH 4 , and the sulfur-containing ring is then opened by treatment with a reagent such as Raney nickel to obtain the alcohol 19.
• the alcohol is then oxidized to the aldehyde, lla, using tetrapropylammonium perruthenate (TPAP) in the presence of 4- methylmorpholine N-oxide (NMO).
• TPAP tetrapropylammonium perruthenate
• NMO 4- methylmorpholine N-oxide
• Phosphonates of formula III wherein W is aryl or R 1 -aryl can be prepared by a process similar to that described immediately below for preparing the trifluoromethy- phenyl-substituted compound, Ilia.
• hydroxypyridine derivative is converted to the corresponding triflate using triflic anhydride, which is then coupled with commercially available boronic acid in the presence of Pd(0) under Suzuki conditions.
• the resulting product is converted to the phosphonate by treatment with n-butyllithium followed by quenching with diethylchiorophosphonate.
• compounds of formula I wherein W is optionally substituted aryl can be prepared from compounds of formula I wherein W is -OH using a triflate intermediate.
• 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 CH 2 CI 2 ; 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(PPh3J4 and a base such a K2CO3 at elevated temperatures and under an inert atmosphere.
• Y O
• R 15 is absent
• R is methyl
• R 2 , R3, R9, Rio and R 1 are each H
• B is
• the resultant compounds wherein Y is (H, OH) can be converted to the corresponding compounds wherein Y is (H, alkoxy) by reacting the hydroxy compound with an appropriate alkanol in the presence of a reagent such as BF3»OEt2-
• a compound wherein Y is (H, OH) can also be converted to the corresponding compound wherein
• Y is (H, H) by treating the hydroxy compound with BF3»OEt 2 and Et3SiH in an inert solvent such as CH 2 CI2 at low temperatures.
• Compounds of formula I wherein R 9 is hydrogen can be converted to the corresponding compound wherein R 9 is hydroxy by heating with an oxidizing agent such as Se ⁇ 2.
• Compounds of formula IB, wherein R 2 is H, R 3 is H or OH, and W 1 is R 21 -aryl, R 41 -heteroaryl, amino or hydroxylamino derivatives, are prepared from compounds of formula 1 A wherein W is 5-bromo (compounds of formula 23 or 24) using a variety of standard chemical transformations, e.g. the Suzuki reaction, Stille coupling, and Buchwald amination.
• Reaction Scheme 5 shows the process from the 2,5- dibromopyridine:
• the phosphonate 22 is prepared from the known alcohol 21 by a two step transformation: the alcohol is treated with CH 3 SO 2 CI to provide the mesylate, which is then displaced with sodium diethylphosphite to provide 22.
• Intermediate 23 can also be -hydroxylated using Davis reagent to provide alcohol 24. Both 23 and 24 can be converted into diverse analogs as shown in Scheme 6: Scheme 6: W 1
• the bromide (23 or 24) can be coupled with boronic acids under palladium catalysis condition (method 1). If the boronic acid possesses a functional group, it can be subsequently transformed. Similarly, aryl-tin compounds (method 2), aryl-zinc compounds (method 3) and amines (method 4) can be coupled. Heck reaction with vinyl ethers can introduce a keto-group, which can be subsequently functionalized (method 5). Imidazoles can be coupled using Copper(l) triflate as catalyst (method 6). The bromide can also be converted to a cyanide which can be subsequently transformed, for example to a tetrazole (method 7).
• Alcohol 25 is prepared from the readily available (R)-(+)-3-butyn-2-ol 27.
• the alcohol is protected as its TBDPS ether, the alkyne is deprotonated and quenched with paraformaldehyde to provide alcohol 29.
• the alkyne is reduced to s-alkene using Lindlar catalyst in presence of quinoline and the allylic alcohol was oxidized to provide the aldehyde 30, which is converted to the alcohol 25.
• Compounds of formula ID wherein R 22 is -CH 2 OC(O)CH 3 or a derivative thereof, R 23 is ethyl, R 2 is H and the remaining variables are as defined for IA can be prepared from the corresponding tetrahydropyran analog by opening the ring.
• the compounds of formula ID can be converted to other compounds of formula I, e.g. compounds of formula IE wherein R 22 is -CH 2 OH, by well known methods.
• the reaction is shown in Scheme 8:
• Tetrahydropyran analog 31 can be prepared starting from 3-formyl-5,6-dihydro-
• the present invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula I of this invention and a pharmaceutically acceptable carrier.
• the compounds of formula I can be administered in any conventional oral dosage form such as capsules, tablets, powders, cachets, suspensions or solutions.
• the 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.
• 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 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.
• Step 1 See J. Org. Chem., 59 (17) (1994), p. 4789.
• Step 2 To a suspension of 60% NaH (7.42 g, 185.5 mmol, 1.3 eq) in 300 ml THF at
• Step 3 To a solution of the product of Step 2 (6.4 g, 38 mmol) in THF and MeOH (40 ml each) was added a solution of KOH (6.4 g, 114 mmol, 3 eq) in H 2 O (40 ml). The mixture was stirred at rt for 2 h, cooled to 0°C and H 2 O (100 ml) and 1 N HCI (150 ml) were added. The mixture was extracted with EtOAc (3x100 ml), the combined organic layer was washed with H 2 O (150 ml) and brine (150 ml), dried over MgSO , filtered and evaporated to give 5.26 g (99% yield) of crystalline solid.
• Step 8 To a solution of the product of Step 7 (490 mg, 2.04 mmol) in CH 2 CI 2 (20 ml) was added oxalyl chloride (360 ⁇ 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(PPh 3 ) (236 mg, 0.20 mmol, 0.1 eq.) followed by Bu 3 SnH (825 ⁇ l, 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.
• oxalyl chloride 360 ⁇ l, 4.13 mmol, 2 eq.
• 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 mixture was stirred at 0°C for 30 min. The solution was then transferred to a solution of the product of Step 1 (15.6 g, 122 mmol) in THF (100 ml) and stirred at 0°C for 1 h. The reaction was quenched by the addition of aq. NH 4 CI (500 ml) and the THF was evaporated.
• Step 4 4 To a solution of 4 (5.2 g) in EtOAc (120 ml) was added Lindlar catalyst (520 mg) and the suspension was stirred under 1 atm. H 2 . Another portion of catalyst (500 mg) was added after 45 min. and the mixture stirred for further 30 min. The mixture was filtered through a celiteTM pad and evaporated to provide 5.2 g (99%) of the desired alkene.
• the solution was diluted with 350 mlof Et 2 O and washed with 2x200 ml of aq. citric acid, 200 ml of aq. NaHCO 3 and 200 ml of brine.
• the solution was dried over MgSO , filtered, concentrated and the resultant residue was chromatographed with 6% EtOAc-hex to provide 2.1 g (41 %) of resin.
• Step 10 To a solution of the product of Step 9 (90 mg, 0.35 mmol) in MeOH (10 ml) (4:1 v/v) at 0 °C, excess NaBH 4 was added and the mixture stirred for 15 min at 0°C. The reaction was quenched with aq. NH 4 CI (50 ml) and extracted with EtOAc (3x20 ml). The combined organic layer was washed with brine (50 ml), dried over MgSO 4 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.
• Step 1
• Step 2 To a solution of the product of Step 1 (20 g, 106 mmol) and Et 3 N (17.8 ml, 128 mmol, 1.2 eq.) in CH 2 CI 2 (300 ml) kept ⁇ -30°C was slowly added CH 3 SO 2 CI (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. NaHCO 3 (500 ml) and the organic layer was separated. The aqueous layer was extracted with Et 2 O (2x200 ml) and the combined organic layers were washed with aq.
• 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 H 2 O (500 ml), the THF was evaporated and the aq. layer was extracted with EtOAc (4x150 ml). The combined organic layers were washed with aq.
• Step 2 To a solution of the product of Step 1 in THF (200 ml) at -78°C was added 2.5M BuLi in hexanes (30.4 ml, 76 mmol, 1.1 eq.), the solution was stirred for 1 hour and solid paraformaldehyde (4.15 g, 138 mmol, 2.0 eq.) was added. The mixture was stirred for 15 min at -78°C, 1 hour at rt, then quenched with the addition of aq. NH 4 CI (500 ml). The THF was evaporated and the aqueous layer was extracted with EtOAc (3x200 ml).
• 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.), K 2 CO 3 (4 eq.) and Pd(PPh 3 ) 4 (5 to 10 mol%) in toluene:EtOH:H 2 O (4:2:1 , v/v/v) at 100°C until the reaction is complete.
• the reaction mixture is diluted with H 2 O, extracted with EtOAc, and the organic layer is washed with brine, dried over MgSO 4 , filtered, concentrated and purified by chromatography to provide the desired compounds.
• the Suzuki coupling procedure described above the following compounds were prepared:
• R 3 , R 22 , R 23 and W are as defined in the following table (Me is methyl, Et is ethyl and Ph is phenyl):
• Step 1 A suspension of the alkyne of Preparation 6 (3.1 g, 9.2 mmol), quinoline (215 ⁇ l, 1.8 mmol, 0.2 eq.), and Lindlar catalyst (310 mg, 10 wt%) in EtOAc (50 ml) was stirred under 1 atm. H 2 (balloon) and the reaction was monitored by NMR. After the reaction was completed, it was filtered through a celiteTM pad, washed with 1 N HCI and brine, dried over MgSO , filtered and evaporated to give -3.4 g of resin which was used as such for the next step.
• Step 2 Dess-Martin reagent (4.28 g, 10.1 mmol, 1.1 eq.) was added to a mixture of the product of Step 1 and NaHCO 3 (1.54 g, 18.3 mmol, 2 eq.) in CH 2 CI 2 (30 ml) at rt and stirred for 1 hr. The mixture was diluted with Et 2 O (60 ml) and a solution of
• 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 ⁇ L of DBU for 3 hr. The solution was concentrated and purified by preparative chromatography to afford 63 mg (49%) of resin.
• R >11 , R ⁇ >22 , R 5 23 and W are as defined in the table (Me is methyl, Et is ethyl, Bn is benzyl):
• Step 1 To a solution of oxazole (75 ⁇ l, 1.1 mmol) in THF (2 ml) at -78 °C was added a solution of 2.5 M BuLi in hexanes (465 ⁇ l, 1.2 mmol, 2.2 eq.) and the mixture was stirred for 30 min. To this was added 0.5 M ZnCI 2 in Et 2 O (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 Pd(PPh 3 ) 2 CI 2 (37 mg, 0.05 mmol) in THF at 0 °C was added 2.5 M BuLi in hexanes (43 ⁇ l, 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. NH 4 CI (60 ml) and extracted with EtOAc (3x20 ml). The combined organic layer was washed with brine (20 ml), dried over MgSO , filtered, evaporated and purified by preparative TLC to provide 29 mg of resin. HRMS: 367.2025 (MH 4 ), calculated 367.2022.
• Step 1 A solution of Preparation 5 (60 mg, 0.15 mmol), Et 3 N (26 ⁇ l, 0.19 mmol, 1.2 eq.), bis(diphenylphosphino)propane (3 mg, 7 ⁇ mol, 5 mol%), Pd(OAc) 2 (1.7 mg, 7.6 ⁇ mol, 5 mol%) and vinyl n-propyl ether (85 ⁇ l, 0.76 mmol, 5 eq.) in DMF (1.5 ml) in a sealed tube was heated at 100 °C for 2 h, cooled to rt and stirred with 2N HCI (2 ml) for 2 h. The mixture was diluted with aq. NaHCO 3 , extracted with EtOAc, dried over MgS0 , 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 ⁇ mol) and hydroxylamine hydrochloride (8 mg, 0.12 mmol) in pyridine (0.5 ml) was stirred overnight at rt. The mixture was diluted with aq. NH 4 CI (30 ml) and extracted with EtOAc (2x10 ml), the combined organic layer was washed with brine (10 ml), dried over MgSO 4 , filtered, concentrated and the residue was purified by preparative TLC to provide 13 mg of the title compound as a resin.
• HRMS 373.2113 (MH 4 ), calculated 373.2127. imilar procedure the following compound is prepared:
• Step 1 To a solution of compound 31a (wherein W is 3-fluorophenyl) (480 mg, 1.2 mmol) in CH 2 CI 2 was added 1 M solution of BBr 3 in CH 2 CI 2 (11.7 ml, 11.7 mmol, 10 eq.), and the mixture refluxed for 2.5 h, then diluted with aq. NaHCO 3 (100 ml). After stirring for about 30 min. the organic layer was isolated and the aqueous layer was extracted with CH 2 CI 2 (2x40 ml). The combined organic layer was washed with aq. NaHCO 3 (100 ml), brine (100 ml), dried over MgSO 4 , filtered and evaporated to give the crude alcohol.
• W 3-fluorophenyl
• R , R 5 22 , D R23 and W are as defined in the table (Me is methyl, Et is ethyl):
• the crude product was stirred with 5 ml DCM and 10 ml trifluoroacetic acid at 0 °C for 1 hour. It was concentrated and suspended in 100 ml of aq. K 2 CO 3 . The aqueous phase was extracted with DCM to provide the crude hydrazide. This crude material was dissolved in 10 ml glacial acetic acid and 2 ml acetone. To this was added 2 g of Zn dust in portions. The suspension was stirred vigorously for 2 hours and filtered through a celiteTM pad and washed with plenty of DCM. The DCM layer was washed with water followed by aq. NaHCO 3 and brine. It was dried over MgSO 4 , concentrated and purified by chromatography to give 500 mg of 10. MS: 409.2 (MH + ). The following compounds were prepared using a similar procedure:
• 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, glomerulonephritis, 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.
• thrombosis-related diseases including thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, 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, meloxicam, rofecoxib and celecoxib; angiotensin antagonists such as valsartan, telmisartan, candesartran, irbesartran, losartan and eprosartan; endothelin antagonists such as tezosentan; phosphodiesterase inhibitors such as milrinoone and enoximone; angiotensin converting enzyme (ACE) inhibitors such as captopril, enalapril, enaliprilat, spirapril, quinapril, perindopril, rami
• Preferred types of drugs for use in combination with the novel compounds of this invention are thromboxane A2 biosynthesis inhibitors, cyclooxygenase inhibitors and ADP antagonists. Especially preferred for use in the combinations are aspirin and clopidogrel bisulfate.
• 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 pharmaceutically 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, nasal spray, etc.
• the dosage of the cardiovascular agent can be determined from published material, and may range from 1 to 1000 mg per dose.
• 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.
• 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.
• 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 agent 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 for administering a combination when, for example, the components must be administered at different time intervals or when they are in different dosage forms.
• the following formulations exemplify some of the dosage forms of this invention.
• the term "active compound" designates a compound of formula I.
• EXAMPLE A - Tablets No. Ingredient m ⁇ /tablet mg/tablet 1 Active Compound 100 500 2 Lactose USP 122 113 3 Corn Starch, Food Grade, as a 10% 30 40 paste in Purified Water 4 Corn Starch, Food Grade 45 40 5 Magnesium Stearate 3 7 Total 300 700
• Active Compound 100 500 2 Lactose USP 106 123 3 Corn Starch, Food Grade 40 70 4 Magnesium Stearate NF 4 7 Total 250 700 Method of Manufacture Mix Item Nos. 1 , 2 and 3 in a suitable blender for 10-15 minutes. Add Item No. 4 and mix for 1 -3 minutes. Fill the mixture into suitable two-piece hard gelatin capsules on a suitable encapsulating machine.
• the activity of the compounds of formula I can be determined by the fol lowing procedures.
• 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 [ 3 H]haTRAP) was dissolved in 0.5 ml of 0.1% aqueous TFA and purified by HPLC using the following conditions: column, VydacTM C18, 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 [ 3 H]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 et al. (Natarajan et al, Int. J. Peptide Protein Res. 45: 145-151 (1995)) from 20 units of platelet concentrates obtained from the North Jersey Blood Center (East Orange, NJ) within 48 hours of collection. All 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 supematants 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-HCI, pH 7.5, 5 mM EDTA to a final volume of approximately 30 ml and were homogenized with 20 strokes in a DounceTM 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 2 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 MgCl2, 1 mM EGTA, and 1% DMSO. Aliquots of membranes were frozen in liquid N2 and stored at -80° C. Membranes were stable for at least 3 months. 20 units of platelet concentrates typically yielded 250 mg of membrane protein. Protein concentration was determined by a Lowry assay (Lowry et al., J. Biol. Chem., 193:265-275 (1951)).
• Thrombin receptor antagonists were screened using a modification of the thrombin receptor radioligand binding assay of Ahn et al. (Ahn et al., Mol. Pharmacol.. 51:350-356 (1997)). The assay was performed in 96 well Nunc plates (Cat. No. 269620) at a final assay volume of 200 ⁇ l. Platelet membranes and [ 3 H]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 MgCl2, 1 mM EGTA, 0.1% BSA).
• the incubated membranes were harvested using a Packard FilterMateTM Universal Harvester and were rapidly washed four times with 300 ⁇ l ice cold 50 mM Tris-HCI, pH 7.5, 10 mM MgCI 2 , 1 mM EGTA.
• MicroScintTM 20 scintillation cocktail 25 ⁇ l was added to each well, and the plates were counted in a Packard TopCountTM Microplate Scintillation Counter.
• the specific binding was defined as the total binding minus the nonspecific binding observed in the presence of excess (50 ⁇ M) unlabeled haTRAP.
• the % inhibition by a compound of [ 3 H]haTRAP binding to thrombin receptors was calculated from the following relationship:
• A(pF-F)R(ChA)(hR)Y-NH 2 and A(pF-F)R(ChA)(hR)(l 2 -Y)-NH 2 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, Miamisburg, Ohio. The gas was subsequently loaded and stored on an IN/US Systems Inc. Trisorber. MicroScintTM 20 scintillation cocktail was obtained from Packard Instrument Co.
• 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.
• 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 ⁇ calibration check is performed. 20 ⁇ is equal to 4 blocks on the graphic produced by the computer software.
• the agonist (haTRAP) is added by an adjustable volume pipette (5-25 ⁇ l) and the aggregation curve is recorded for 10 minutes. Maximum aggregation in 6 minutes following agonist is the value recorded.
• 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 60 minutes. Aggregation was initiated by adding 0.3 ⁇ M haTRAP or 0.1 U/ml thrombin and rapidly vortexing the mixture using a Lab LineTM Titer Plate Shaker (speed 7). Percent aggregation was monitored as increasing light transmittance at 405 nm in a SpectromaxTM Plate Reader.
• membranes were harvested by filtration through pretreated (0.5% polyethylenimine; Sigma P-3143) GF-C filter plates (Unifilter-96, Packard) using a TomTecTM 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 quantitated following addition of Packard OmniscintTM 20 scintillation fluid using a TopCountTM NXT Microplate Scintillation and Luminescence Counter (Packard, Meriden, Ct). Non-linear regression analysis was performed using PrismTM 20b. (GraphPad Software, San Diego, Ca).
• thrombin receptor IC50 values i.e., the concentration at which a 50% inhibition of thrombin receptor was observed
• CB 2 Ki values range from 1 to 1000 nM, preferably 1-200 nM, more preferably 1-100 nM.
• IC50 values of Example Nos. 8BU, 8CA, 8CB, 8CL, 17H, 20E, 20F, 20G and 20H range from 1-100 nM.

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• 2006
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  • 2006-03-23 CO CO06029040A patent/CO5680428A2/es not_active Application Discontinuation
  • 2006-03-24 ZA ZA200602448A patent/ZA200602448B/en unknown
  • 2006-03-24 EC EC2006006455A patent/ECSP066455A/es unknown
  • 2006-04-24 NO NO20061797A patent/NO20061797L/no not_active Application Discontinuation
• 2008
  • 2008-10-30 US US12/261,514 patent/US20090076088A1/en not_active Abandoned
  • 2008-10-30 US US12/261,545 patent/US20090069383A1/en not_active Abandoned

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