Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
  • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
  • C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala

Definitions

• the invention relates generally to modulating cell adhesion and to inhibiting the binding of fibrinogen and other proteins to blood platelets, and inhibiting the aggregation of blood platelets specifically to the gp Ilb/ ⁇ ia fibrinogen receptor site.
• Fibrinogen is a glycoprotein present in blood plasma that participates in platelet aggregation and in fibrin formation. Platelets are cell-like anucleated fragments, found in the blood of all mammals, that also participate in blood coagulation. Interaction of fibrinogen with the Ilb/IIIa receptor site is known to be essential for normal platelet function.
• platelets When a blood vessel is damaged by an injury or other causative factor, platelets adhere to the disrupted subendothethial surface. The adherent platelets subsequently release biologically active constituents and aggregate. Aggregation is initiated by the binding of agonists, such as thrombin, epinephrine, or ADP to specific platelet membrane receptors. Stimulation by agonists results in exposure of latent fibrinogen receptors on the platelet surface, and binding of fibrinogen to the glycoprotein Ilb/IIIa receptor complex.
• agonists such as thrombin, epinephrine, or ADP
• arginine- glycine-aspartic acid containing tripeptides are recognized by at least one member of a family of structurally related receptors, integrins, which are heterodimeric proteins with two membrane-spanning subunits.
• integrins which are heterodimeric proteins with two membrane-spanning subunits. The authors state that the conformation of the tripeptide sequence in the individual proteins may be critical to recognition specificity.
• Ruggeri et al. Proc. Nat'l Acad. Sci. U.S.A., 83, 5708- 5712 (1986) explore a series of synthetic peptides designed in lengths to 16 residues, that contain RGD and a valine attached to the aspartic acid residue of RGD that inhibit fibrinogen binding to platelets. See also Koczewiak et al., Biochem. 23, 1767-1774 ( 1984); Ginsberg et al, J. Biol. Chem. 260(7), 3931-3936 (1985); and Haverstick et al., Blood 66(4), 946-952 (1985). Other inhibitors are disclosed in Eur. Pat. App. Nos. 275,748 and 298,820.
• Ilb IIIa complex This polypeptide contains 49 amino acids and has the RGD subunit and various disulfide bridges.
• Gan et al. J. Biol. Chem., 263, 19827-19832 (1988).
• Dennis et al Proc. Nat'l Acad. Sci. USA, 87, 2471 -2475 (1989).
• these snake venom factors also have high affinity for other members of the adhesive protein receptor family including the vitronectin and fibronectin receptors so are not selective for the gp Ilb/IIIa complex.
• 5,037,808 discloses the use of indolyl platelet-aggregation inhibitors which are believed to act by antagonizing interactions between fibrinogen and/or extracellular matrix proteins and the platelet gp Ilb/IIIa receptor.
• U.S. Patent No. 5,037,808 discloses guanidino peptide mimetic compounds that retain an Asp residue which inhibit platelet aggregation.
• WO9014103 describes the use of antibody-poly-peptide conjugates wherein said polypeptides contain the Arg-Gly-Asp (RGD) sequence.
• W091 1 1458 discloses the use of large cyclic peptides containing RGD flanked by proline residues which are platelet aggregation inhibitors.
• WO9101331 discloses small cyclic platelet aggregation inhibitors which are synthetic cyclic pentapeptides containing the tripeptide sequence Arg-Gly-Asp and a thioether linkage in the cycle.
• U.S. Patent No. 5,051 ,405 also discloses the use of peptides and pseudopeptides such as N-amidino-piperidine-3- carboxylglycyl-L-aspartyl-L-valine that inhibit platelet aggregation and thrombus formation in mammalian blood.
• EP 445 796 discloses linear compounds which can include internal piperazinyl or piperidinyl derivatives.
• EP437 367 discloses linear polypeptide fibrinogen receptor antagonists.
• U.S. Patent No. 5,256,812 discloses compounds of the Rl- A-(W) a -X-(CH2)b-(Y)c-B-Z-COOR wherein Rl is a guandidino or amidino moiety and A and B are chosen from specific monosubstituted aryl or heterocyclic moieties.
• a number of very serious diseases and disorders involve hyperthrombotic complications which lead to intravascular thrombi and emboli.
• Myocardial infarction, stroke, phlebitis and a number of other serious conditions create the need for novel and effective fibrinogen receptor antagonists.
• Compounds of the invention are useful for inhibiting the binding of fibrinogen to blood platelets and for inhibiting the aggregation of blood platelets.
• the above-mentioned compounds can be used in a method of acting upon a fibrinogen receptor which comprises administering a therapeutically effective but non-toxic amount of such compound to a mammal, preferably a human.
• a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, dispersed therein, an effective but non-toxic amount of such compound is another feature of this invention.
• the invention also includes the use of a compound of Claim 1 , or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the aggregation of blood platelets, preventing platelet thrombosis, preventing thromboembolism or preventing reocclusion, in a mammal.
• Fibrinogen receptor antagonist compounds of Formula I are useful in a method of inhibiting the binding of fibrinogen to blood platelets and for inhibiting the aggregation of blood platelets.
• Fibrinogen receptor antagonists of this invention have the formula:
• X is a 5 or 6-membered monocyclic aromatic ring system containing
• Rl, R ⁇ , R3 and R ⁇ are independently selected from the group consisting of hydrogen, halogen, Cl-io alkyl, C3-8 cycloalkyl, aryl , aryl Ci-8 alkyl, amino, amino Ci-8 alkyl, Ci-j acylamino, Ci-3 acylamino Ci-8 alkyl, Cl-6 alkylamino, Cl-6 alkylamino Ci-8 alkyl, Cl -6 dialkylamino, Cl-6 dialkylamino Cl-8 alkyl, Cl-4 alkoxy, Cl-4 alkoxy Cl -6 alkyl, carboxy, carboxy 1-6 alkyl, Ci-3 alkoxycarbonyl, Cl-3 alkoxycarbonyl Cl -6 alkyl, carboxy Cl-6 alkyloxy, hydroxy, and hydroxy Cl -6 alkyl;
• n is an integer from 0-2;
• p and q are integers independently chosen from 0-6, and wherein methylene units are unsubstituted or substituted with one or more groups chosen from Rl and R2; provided that when B is (CH2)p, A must contain at least one heteroatom;
• R6, R7, R8 ? R9 ⁇ R10 ? a nd Rl 1 are independently chosen from:
• R l 2 is hydroxy
• X is a 5- to 6- membered monocyclic aromatic ring system containing 1 or 2 nitrogen atoms and either unsubstituted or substituted with
• Y optionally present, is Cl-8 alkyl
• n' is 1 , 2, or 3;
• E is -CH- or -N-;
• G is -CH- or -N-;
• p and q are integers independently chosen from 0-6;
• R ⁇ , R !0, R 2 and R 2 are as previously defined.
• R8 is hydrogen
• R lO is hydrogen, -NHCOR 2 ,
• R 2 is as previously defined. In a group of this subclass of compounds are those having the following structure
• X is an aromatic heterocyclic ring seletced from the group consisting of:
• R is -hydrogen
• fibrinogen receptor antagonist activity is based on evaluation of inhibition of ADP- stimulated platelets. Aggregation requires that fibrinogen bind to and occupy the platelet fibrinogen receptor site. Inhibitors of fibrinogen binding inhibit aggregation.
• human platelets are isolated from fresh blood, collected into acid citrate/dextrose by differential centrifugation followed by gel filtration on Sepharose 2B in divalent ion-free Tyrode's buffer (pH 7.4) containing 2% bovine serum albumin.
• Platelet aggregation is measured at 37°C in a Chronolog aggregometer.
• the reaction mixture contains gel-filtered human platelets (2 x 108 per ml), fibrinogen (100 micrograms per ml (ug/ml)), Ca2+ (1 mM), and the compound to be tested.
• the aggregation is initiated by adding 10 mM ADP 1 minute after the other components are added.
• the reaction is then allowed to proceed for at least 2 minutes.
• the extent of inhibition of aggregation is expressed as the percentage of the rate of aggregation observed in the absence of inhibitor.
• the IC50 is the dose of a particular compound inhibiting aggregation by 50% relative to a control lacking the compound. The following representative compounds were tested and found to have IC50 values within the range of 0.08 and 64 ⁇ M.
• salts shall mean non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
• Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methyl
• Prodrugs such as ester derivatives of described compounds, are compound derivatives which, when absorbed into the bloodstream of a warm-blooded animal, cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.
• pharmaceutically effective amount shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought by a researcher or clinician.
• anti-coagulant shall include heparin, and warfarin.
• thrombolytic agent shall include agents such as streptokinase and tissue plasminogen activator.
• platelet anti-aggregation agent shall include agents such as aspirin and dipyridamole.
• alkyl means straight or branched alkane containing 1 to about 10 carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexy, octyl radicals and the like, straight or branched alkene containing 2 to about 10 carbon atoms, e.g., propylenyl, buten-1-yl, isobutenyl, pentenylen-1-yl, 2,2-methylbuten-l-yl, 3-methylbuten-l-yl, hexen-1-yl, hepten-1-yl, and octen-1 -yl radicals and the like, or straight or branched alkyne containing 2 to about 10 carbon atoms, e.g., ethyny
• aryl means a 5- or 6-membered aromatic ring containing 0, 1 , or 2 heteroatoms selected from O, N, and S, e.g., phenyl, pyridine, pyrimidine, imidazole, thiophene, oxazole, isoxazole, thiazole, and amino- and halogen- substituted derivatives thereof.
• alkyloxy or “alkoxy” include an alkyl portion where alkyl is as defined above, e.g., methyloxy, propyloxy, and butyloxy.
• arylalkyl and “alkylaryl” include an alkyl portion where alkyl is as defined above and to include an aryl portion where aryl is as defined above.
• arylalkyl include benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and thienylpropyl.
• alkylaryl examples include toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine, propylpyridine, butylpyridine, butenylpyridine, and pentenylpyridine.
• halogen includes fluorine, chlorine, iodine and bromine.
• oxy means an oxygen (O) atom.
• thio means a sulfur (S) atom.
• S sulfur
• the terminal portion of the designated side chain is described first followed by the adjacent functionality toward the point of attachment.
• a Cl -6 alkyl substituted with Cl-5 alkyl-carbonylamino is equivalent to
• L- or D-amino acids suitable for compounds of the present invention include naturally occurring L- or D-amino acids include, for example, those naturally occurring L-amino acids present in humans, e.g., protein amino acids, including L-alanine, L-arginine, L- asparagine, L-aspartic acid, L-cysteine, L-glutamine, L-glutamic acid, L-glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L- tyrosine, and L-valine, and those naturally occurring D-amino acids which are non-protein amino acids, such as those found, for example, in antibiotic substances produced by bacteria and fungi, including D- valine, D-asparagine, D-glutamate, D-ornithine,
• BOP Benzotriazol- 1 -yloxytris(dimethylamino)phosphonium, hexafluorophosphate
• EDC 1 -(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
• Oxone potassium peroxymonosulfate
• LDA Lithium diisopropylamide
• the compounds of the present invention can be administered in such oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
• intravenous bolus or infusion
• intraperitoneal subcutaneous
• intramusculsar form all using forms well known to those of ordinary skill in the pharmaceutical arts.
• An effective but non-toxic amount of the compound desired can be employed as an anti -aggregation agent.
• Compounds of the invention may be administered to patients where prevention of thrombosis by inhibiting binding of fibrinogen to the platelet membrane glycoprotein complex Ilb/IIIa receptor is desired. They are useful in surgery on peripheral arteries (arterial grafts, carotid endarterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and consumption. The aggregated platelets may form thrombi and thromboemboli. Compounds of this invention may be administered to these surgical patients to prevent the formation of thrombi and thromboemboli.
• Extracorporeal circulation is routinely used for cardiovascular surgery in order to oxygenate blood. Platelets adhere to surfaces of the extracorporeal circuit. Adhesion is dependent on the interaction between gp Ilb/IIIa on the platelet membranes and fibrinogen adsorbed to the surface of the circuit. (Gluszko et al, Amer. J. Physiol, 252(H), 615-621 (1987)). Platelets released from artificial surfaces show impaired hemostatic function. Compounds of the invention may be administered to prevent adhesion.
• the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
• An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
• Oral dosages of the present invention when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day and preferably 0.01-100 mg/kg/day and most preferably 0.01-20 mg/kg/day.
• oral dosages for an adult patient are, for example, 1 mg, 10 mg or 100 mg.
• the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion.
• compounds of the present invention may be administered in divided doses of two, three, or four times daily.
• preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
• the dosage administration will, or course, be continuous rather that intermittent throughout the dosage regime.
• the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with convention pharmaceutical practices.
• carrier suitable pharmaceutical diluents, excipients or carriers
• the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, distintegrating agents and coloring agents can also be incorporated into the mixture.
• suitable binders, lubricants, distintegrating agents and coloring agents can also be incorporated into the mixture.
• Suitable binders include starch, gelatin, natural sugars such as glucose or beta- lactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
• Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
• Disintegrators include, without limitation, starch methyl cellulose, agar, bentonite, xanthan gum and the like.
• the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
• Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
• Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
• the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
• Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxy- ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
• the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
• a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
• the compounds of the present invention can also be co- administered with suitable anticoagulation agents or thrombolytic agents such as plasminogen activators or streptokinase in the treatment of various vascular pathologies. They may also be combined with heparin, aspirin, or warfarin. Coadministration includes administration together or separately in order to achieve beneficial thrombosis prevention or thrombolysis.
• suitable anticoagulation agents or thrombolytic agents such as plasminogen activators or streptokinase in the treatment of various vascular pathologies. They may also be combined with heparin, aspirin, or warfarin.
• Coadministration includes administration together or separately in order to achieve beneficial thrombosis prevention or thrombolysis.
• novel compounds of the present invention were prepared according to the procedure of the following examples.
• the most preferred compounds of the invention are any or all of those specifically set forth in these examples. These compounds are not, however, to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus.
• the examples which follow illustrate procedures for preparing compounds of the invention where X is a 5- or 6-membered monocyclic aromatic ring system, using starting materials such as vinyl pyridine, imidazole, etc.
• Compounds of the invention where X is a 9-membered polycyclic aromatic fused ring system can be prepared by reacting a substituted 5-membered ring starting material such as 2-amino-3- bromothiophene, 2-nitro-3-bromothiophene, 2-amino-3-bromopyrrole, and 2-amino-3-bromofuran, with an appropriate compound under suitable ring closure conditions to effect formation of the 9-membered fused ring system.
• a substituted 5-membered ring starting material such as 2-amino-3- bromothiophene, 2-nitro-3-bromothiophene, 2-amino-3-bromopyrrole, and 2-amino-3-bromofuran
• Compounds of the invention where X is a 10-membered polycyclic aromatic ring system can be prepared using a starting material such as naphthyridin (Hamada, Y. et al, Chem. Pharm. Bull. Soc, 1971 , 79(9), 1857-1862), or by reacting an aminoaldehyde pyridine with a suitable ketone under suitable ring closure conditions to effect formation of the 10-membered fused ring system.
• a starting material such as naphthyridin (Hamada, Y. et al, Chem. Pharm. Bull. Soc, 1971 , 79(9), 1857-1862)
• an aminoaldehyde pyridine with a suitable ketone under suitable ring closure conditions to effect formation of the 10-membered fused ring system.
• the examples also illustrate procedures for preparing compounds of the invention where B is -(CH2)mC(0)NR3(CH2)n-, e.g. -CH2C(0)NH-.
• B is -(CH2)m R 3 C(0)(CH2)n, e.g. -CH2NHC(0)CH2
• an acid such as compound 1-8 can be subjected to a Curtius reaction to form the amine, and subsequent condensation to give the final product.
• B is -(CH2)mNR 3 (CH2)n-, e.g.
• an acid such as compound 1 -8 can be reduced to its corresponding alcohol with borane, the alcohol converted to a bromide with carbon tetrabromide/phosphorous tribromide, and the bromide alkylated to form the final product.
• starting materials such as compound 19 in United States Patent 5,281,585, col. 26, line 5, and col. 58, lines 5-24, can be used.
• the combined filtrate was transferred to a dry 5 L four- necked round bottom flask equipped with a mechanical stirrer, an addition funnel, nitrogen inlet, cooling unit and a thermometer probe.
• the solution was cooled to -10°C and n-butyllithium (1.6 M in hexane, 1.06 L, 1.695 mol) was slowly added over a 60 min period, keeping the internal temperature less than 0°C.
• the mixture turned milky when ⁇ 50% of n-BuLi was charged.
• n-Butyllithium could be charged over 2- 4 h while maintaining the internal temperature ⁇ 5°C without deterioration on the final yield.
• the only drawback was the slight increase in viscosity of the milky mixture.
• reaction mixture was stirred at 0- 5°C for 1 h.
• the reaction mixture was cooled to -10°C, and ethyl bromoacetate (283.1 g, 1.695 mol) was added over 15 min while maintaining the internal temperature less than 0°C.
• Ethyl bromoacetate could be charged over 0.5-1 h while maintaining the internal temperature ⁇ 20°C without deterioration on the final yield.
• the reaction mixture was stirred at 0°C for 15 min and then allowed to warm to 23 °C and aged at this temperature for a 2 h period (or overnight if needed).
• the reaction mixture was cooled to between -5 and 0°C and quenched into a solution of NaCl (170 g) in 2 N HCl (1.78 L), keeping the internal temperature less than 20°C.
• the resulting aqueous phase had a pH of 6.
• the mixture was transferred to a 12 L separatory funnel and the two layers were separated.
• the aqueous layer was extracted with i-propyl acetate (3 x 1 L).
• the combined organic layers were concentrated to near dryness and then azeotropically dried with acetonitrile (3 x 600 mL) (50°C, house vacuum).
• the mixture was filtered to remove a small amount of NaCl after the azeotropic distillation.
• the filter cake was washed with 500 mL acetonitrile.
• the brown solution was used as is in the next step. Pure solid product was isolated by crystallization from isopropyl acetate/hexane. mp: 70-71 °C.
• the resulting mixture was cooled to -5-0°C, and 4- vinylpyridine (13.09 g, 124.2 mmol) was added dropwise over a 2 h period, while keeping the internal temperature below 0°C.
• the reaction was aged at 0°C for 1-2 h, then quenched by slow addition (10 minutes) into a cold (0°C) solution of 1 N HCl (140 mL), while keeping the internal temperature ⁇ 20°C.
• the final pH was 1.5-2.5.
• the acidic solution (pH ⁇ 2) was extracted with 50% IPAC/Hexane (2 x 160 mL). Piperidone-ester a2 (5-7%), triethylsiloxane and residual neutral species were removed during the extractions.
• the aqueous solution was extracted with toluene (2 x 150 mL). About 0.1 % product remained in the aqueous layer after the extractions.
• the combined organic layers were washed with saturated aqueous sodium bicarbonate (3 x 50 mL). Three washes were required to remove 95+% of Et3N»HI/NaI. Less than 0.5% of product was lost to the bicarbonate washes.
• the resulting organics has a total volume of 460 mL and a KF of 5.1 mg/ mL.
• the organic layer was azeotropically dried by distillation at
• the combined filtrate was assayed to contain product al. It was concentrated in vacuo (50°C, 100 mBar). After distilling most of the solvent, the batch was flushed with IPA (3 x 100 mL) to give a final concentration of 25 wt% (86 g) in IPA. This solution was used as is in the next step.
• the combined filtrate contained acid a4 in quantitative yield as determined by HPLC analysis.
• pyridine acid a4 (12.04 g, 96.6% pure, 44.34 mmol), quinine (14.89 g, 45.90 mmol) and isopropyl alcohol (80.8 mL; KF ⁇ 0.1 mg/mL) were combined.
• the mixture was heated at 65°C for 15 min under a nitrogen atmosphere to dissolve all the solid.
• the resulting solution was allowed to cool to 20°C.
• the solution reached 45 °C, it was seeded with -10 mg of 99.5% ee quinine salt 9zl- After stirring overnight, the mixture was cooled to 5-6°C and aged for 0.5-1 h.
• the mixture was heated at reflux (83-85°C) for 5 h.
• the filtrate was concentrated under vacuum at 45°C and flushed with toluene (3 x 300 mL) to remove water, followed by isopropyl alcohol (3 x 300 mL) to remove toluene.
• the KF of the mixture should be less than 500 mg/mL after the flushes.
• Isopropyl alcohol (750 mL) was added to the batch to give a final concentration of 3 mL IPA per gram of quinine salt.
• the mixture was heated at 70-75°C for 15-30 min under a nitrogen atmosphere to dissolve all the solid.
• the resulting solution was allowed to cool gradually to ambient.
• the batch temperature reached 45°C, the mixture was seeded with 0.1 g of quinine salt 9-1.
• the pyridine amide benzyl ester Z solution in isopropyl acetate from last step was concentrated under vacuum (40°C pot temperature) to a volume of 8 L and then 10 L methanol was added and the solution concentrated again to 8 L (KF ⁇ 500 mg/mL).
• the ester is hydrolyzed to form the corresponding acid 8-2.
• the aqueous layer is acidified with 10% KHSO4 to pH4 and extracted with EtOAc.
• the EtOAc layers were combined, dried with brine and MgS04, filtered and evaporated to give 4 ⁇ 2 as a hygroscopic white solid.
• the impure product was purified by preparative HPLC (reverse phase, 95:5 0.1 % TFA in H2 ⁇ /0.1 % TFA in CH3CN to 80-20 gradient) followed by column chromatography (25-35% iso ⁇ ropanol/CH2Cl2) to give 6 as a white solid.
• N,N-diethylbromoacetamide was prepared as follows:
• Ester 93 (125 mg, 0.24 mmol) was dissolved in 3 mL 50% aqueous THF, and 1 N LiOH (0.5 mL, 0.5 mmol) was added. After 2 h the reaction was concentrated. Flash chromatography (silica, 40:1 :1 EtOH/H2 ⁇ /NH4 ⁇ H) provided acid (9-4) as a white solid.
• Ester 93 (1.93 g, 3.78 mmol) was dissolved in 20 mL EtOH, 10% Pd/C (200 mg) was added, and the reaction was stirred under a balloon of H2 for 2 d. After filtering through Celite, concentration provided amine 93 as a yellow oil.
• 2-oxazolidinone ( 10-3) Ti(i-PrO)4 (2.19 mL, 7.37 mmol) was added to a solution of TiCl4 (1M in CH2CI2, 22.1 mL, 22.1 mmol) in 40 mL CH2CI2 at 0°C. After 15 min, DIPEA (5.15 mL, 30 mmol) was added and the solution turned deep red. After stirring for 10 min, a solution of the oxazolidinone 10-2 (2.6 g, 5.92 mmol) in 10 mL CH2CI2 was added, and after 1 h at 0°C, acrylonitrile (3.90 mL, 59 mmol) was added and the reaction was stirred at RT overnight.
• Nitrile 10-3 (9.48 g, 24.2 mmol) was dissolved in 200 mL i-PrOH sat. with NH3. 5% Rh on alumina (10.69 g) was added, and the mixture was hydrogenated on a Parr shaker at 50 psi H2 pressure.
• reaction mixture was filtered through Celite, re-saturated with NH3, treated with fresh 5% Rh on alumina (3.00 g), and hydrogenated at 50 psi for 1 d more. After filtering through Celite, the mixture was concentrated and purified by flash chromatography (silica,
• Lactam 10-4 (246 mg, 1.12 mmol) was dissolved in 32 mL THF, cooled to -78°C, and NaHMDS (1M, 1.35 mL, 1.35 mmol) was added. After 15 min t-butyl bromoacetate (218 ⁇ l, 1.35 mmol) was added to the stirring suspension, and after 1 h the reaction was quenched by addition of water. After warming to RT the mixture was extracted with EtOAc (3x), the combined organic layers were washed with water and brine, dried (MgS ⁇ 4), filtered and concentrated. Flash chromatography (silica, CH2CI2, then 10% then 20% NH3 sat. EtOH/CH2Cl2) provided ester 10-5.
• ester 10-7 (76 mg, 0.187 mmol), trifluoroacetic acid (2 mL), and CH2CI2 (2 mL) was stirred at ambient temperature for 20 minutes. The reaction mixture was then concentrated and the residual trifluoroacetic acid removed azeotropically with toluene. Flash chromatography (silica, 50% EtO Ac/10:1 :1 EtOH/NH4/OH/H2 ⁇ ) afforded ⁇ Q3 as a white solid.
• Ester 10-9 (145 mg, 0.32 mmol) was dissolved in 3.5 mL EtOH, 10% Pd/C (100 mg) was added and the reaction was stirred under a balloon of H2 for 6 hrs. The mixture was filtered through celite and concentrated to an oil. Flash chromatography (silica, 50% EtOAc/10: l :1 EtOH/ NH4OH/H2O) provided 10-10 as a white solid.
• N,0-dimethylhydroxylamine HCl (0.51 g, 5.2 mmol) was added, and the reaction mixture was stirred at rt overnight.

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• 1996
  • 1996-10-15 EP EP96936505A patent/EP0866705A4/de not_active Withdrawn
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