United States Patent (19) 11 Patent Number: 6,069,254 Costanz0 Et Al

US006069254A United States Patent (19) 11 Patent Number: 6,069,254 Costanz0 et al. (45) Date of Patent: *May 30, 2000 54). CARBOXAMIDE DERIVATIVES OF 56) References Cited PPERDINE FOR THE TREATMENT OF THROMBOSIS DISORDERS U.S. PATENT DOCUMENTS 75 Inventors: Michael J. Costanzo, Ivyland; WilliamO O 5,639,765 6/1997 Ruminski ................................ 514/329 J. Hoekstra, Villanova; Bruce E. OTHER PUBLICATIONS Maryanoff, Forest Grove, all of Pa. Hoekstra et al., Bioorganic & Medicinal Chemistry Letters, 73 Assignee: Ortho Pharmaceutical Corp., Raritan, 6(20)pp. -2371-2376, Pergamon Press Oct. 20, 1996. N.J. Costa, B.R. et al., J. Med. Chem., 1994, 37(2), pp. 314-321, online Search results relied upon. * Notice: This patent issued on a continued pros ecution application filed under 37 CFR Primary Examiner Alan L. Rotman 1.53(d), and is subject to the twenty year Attorney, Agent, or Firm-Ralph R. Palo patent term provisions of 35 U.S.C. 154(a)(2). 57 ABSTRACT Carboxamide derivatives of pyrrolidine, piperidine, and 21 Appl. No.: 08/841,016 hexahydroazepine of formula (I): 22 Filed: Apr. 29, 1997 (I) Related U.S. Application Data 10 Rs 60 Provisional application No. 60/016,675, May 1, 1996. ( 51) Int. Cl." ...................... C07D 401/12; CO7D 401/14; N CO7D 403/14; A61K 31/445 X M-A 52 U.S. Cl. .......................... 546/189: 546/176; 546/187; 514/314; 514/316 are disclosed as useful in treating platelet-mediated throm 58 Field of Search ..................................... 546,193, 198, botic disorders. 546/208, 212, 187, 189, 176; 514/316, 318, 323,324, 314 2 Claims, No Drawings 6,069,254 1 2 CARBOXAMIDE DERVATIVES OF PIPERDINE FOR THE TREATMENT OF (I) THROMBOSIS DISORDERS R10 Rs This application claims benefit of Provisional Applica t tion number 60/016,675, filed May 1, 1996. N X BACKGROUND OF THE INVENTION M-A 1O Platelet aggregation constitutes the initial hemostatic wherein A, X, M, Rs, Rio, and n are as hereinafter defined. response to curtail bleeding induced by vascular injury. These platelet aggregation inhibitors are useful in treating However, pathological eXtension of this normal hemoStatic platelet-mediated thrombotic disorderS Such as arterial and proceSS can lead to thrombus formation. The final, common venous thrombosis, acute myocardial infarction, reocclusion pathway in platelet aggregation is the binding of fibrinogen 15 following thrombolytic therapy and angioplasty, to activated, exposed platelet glycoprotein IIb/IIIa (GPIb/ inflammation, unstable angina, and a variety of Vaso IIIa). Agents which interrupt binding of fibrinogen-to GPIb/ occlusive disorders. These compounds are also useful as IIIa, therefore, inhibit platelet aggregation. These agents are, antithrombotics used in conjunction with fibrinolytic therapy (e.g., t-PA or Streptokinase). Pharmaceutical com therefore, useful in treating platelet-mediated thrombotic positions containing Such compounds are also part of the disorderS Such as arterial and venous thrombosis, acute present invention. myocardial infarction, unstable angina, reocclusion follow ing thrombolytic therapy and angioplasty, inflammation, and DETAILED DESCRIPTION OF THE a variety of Vaso-occlusive disorders. The fibrinogen recep INVENTION tor (GPIb/IIIa) is activated by stimuli such as ADP, 25 More particularly, the present invention is directed to collagen, and thrombin exposing binding domains to two compounds of the following formula (I): different peptide regions of fibrinogen: C-chain Arg-Gly Asp (RGD) and Y-chain His-His-Leu-Gly-Gly-Ala-Lys-Gln (I) Ala-Gly-Asp-Val (HHLGGAKQAGDV, Y400-411). Since R10 R5 these peptide fragments themselves have been shown to inhibit fibrinogen binding to GPIIb/IIIa, a mimetic of these fragments would also serve as an antagonist. In fact, prior to tN this invention, potent RGD-based antagonists have been revealed which inhibit both fibrinogen binding to GPIb/IIIa 35 and platelet aggregation e.g., Ro-438857 (L. Alig, J. Med. Chem. 1992, 35, 4393) has an ICs of 0.094 uM against in wherein M is (CH), or piperidin-1-yl; Vitro thrombin-induced platelet aggregation. Some of these wherein A is Selected from any of piperidin-2-yl, agents have also shown in Vivo efficacy as antithrombotic piperidin-3-yl, pipe ridin-4-yl, pipe raZin-1-yl, agents and, in Some cases, have been used in conjunction 40 pyrrolidin-2-yl, pyrrolidin-3-yl, NHR, or with fibrinolytic therapy e.g., t-PA or Streptokinase, as well (J. A. Zablocki, Current Pharmaceutical Design 1995, 1, 533). As demonstrated by the results of the pharmacological Studies described hereinafter, the compounds of the present 45 N invention show the ability to block fibrinogen binding to isolated GPIb/IIIa (IC's 0.0002–1.39 uM), inhibit platelet aggregation in vitro in the presence of a variety of platelet wherein Ro is selected from any of H, alkyl, CH(NH), stimuli (0.019-65.0 uM vs. thrombin), and furthermore, CMe(NH) or acyl, preferably Ro is hydrogen; inhibit eX Vivo platelet aggregation in animal models. 50 wherein R is H or C(O)N(R')YZ Additionally, these agents exhibit efficacy in animal throm wherein R is selected from H or cycloalkyl; bosis models as their progenitors had shown ("Nipecotic wherein R is selected from any of H, alkyl or acyl. Acid Derivatives AS Antithrombotic Compounds,’ applica Preferably, R is hydrogen; tion Ser. No. 08/213,772, filed Mar. 16, 1994). The com 55 wherein Rs is H or C(O)NHQ(CHW),CORs; wherein Q pounds of the present invention show efficacy as antithrom is selected from CH, CH-aryl, CH-heteroaryl, botic agents by virtue of their ability to prevent platelet CH-substituted-heteroaryl or CH-alkyl; preferably Q is aggregation. Additionally, because the compounds of this CH, CH-substituted-heteroaryl or CH-heteroaryl; W is invention inhibit integrin-mediated cell-cell or cell-matrix selected from Hor N(R)T-R, preferably W is H when adhesion, they may also be useful against inflammation, 60 Q is CH, and N(R)-T-R, when Q is CH; wherein R bone resorption, tumor cell metastasis, etc. (D. Cox, Drug is Selected from any of H, alkyl or acyl, preferably R News&Perspectives 1995, 8, 197). is hydrogen, T is selected fron C(O), C(N-CN) or SO, preferably T is C(O) and R, is selected from any DISCLOSURE OF THE INVENTION of alkyl, aryl, aralkyl, alkoxy, or aminoalkyl, and Rs is 65 selected from H, alkyl or aralkyl; preferably Rs is H. The present invention is directed to compounds repre wherein m is the integer 1, 2, or 3. Preferably m is 1 or Sented by the following general formula (I): 2, 6,069,254 3 4 wherein X is selected from any of C(O), C(O)O, C(O)NH, n-hexyl, 2-hexyl and 2-methylpentyl. Alkoxy radicals are CH, or SO; oxygen ethers formed from the previously described Straight wherein n is the integer 1, 2, or 3; or branched chain alkyl groups. Cycloalkyl groups contain 5-8 ring carbons and preferably 6-7 carbons. wherein r is 0 or 1, The term “aryl”, “heteroaryl' or “substituted heteroaryl' wherein Y is selected from any of (CH), CH(R)(CH), as used herein alone or in combination with other terms (CH2)CH(R), (CH(COR")CH,), (CH2)CHOH or indicates aromatic or heteroaromatic groupS. Such as phenyl, piperidine-3-carboxylic acid; with the proviso that naphthyl, pyridyl, thienyl, furanyl, or quinolinyl wherein the when Y is (CH), and p is 2, X is other than C(O) or Substituent is an alkyl group. The term “aralkyl means an when X is C(O) then either R is other than H or R is alkyl group Substituted with an aryl group. other than H, and with the proviso that when Y is The term “acyl as used herein means an organic radical (CH(CO.R")CH.), X is other than C(O) or CH; having 2–6 carbon atoms derived from an organic acid by wherein p is 2 or 3; removal of the hydroxyl group. The compounds of the present invention may also be wherein q is 1, 2, or 3. Preferably, q is 1. present in the form of a pharmaceutically acceptable Salt. wherein R is alkyl, C-Cs alkenyl, C-Cs alkynyl, aryl, 15 The pharmaceutically acceptable Salt generally takes a form aralkyl or heteroaryl; in which the nitrogen on the 1-piperidine (pyrrolidine, wherein R" is H or alkyl or cycloalkyl. Preferably, R" is piperazine) Substituent is protonated with an inorganic or hydrogen. organic acid. Representative organic or inorganic acids wherein Z is COH, CO-alkyl, SOH, POH, or include hydrochloric, hydrobromic, hydriodic, perchloric, 5-tetrazole; provided that at least one of Rs and Rio is Sulfuric, nitric, phosphoric, acetic, propionic, glycolic, hydrogen; lactic, Succinic, maleic, fumaric, malic, tartaric, citric, or the enantiomer or the pharmaceutically acceptable Salt ben Zoic, man de lic, me thane Sulfonic, thereof. hydroxyethaneSulfonic, beneZeneSulfonic, oxalic, pamoic, Preferably, the group C(O)N(R')YZ is attached to the ring 2-naphthale n e Sulfonic, p - to lue n e Sulfonic, carbon of the central azacycle at the 3- or 4-position 25 cyclohexanesulfamic, Salicylic, Saccharinic or trifluoroace (4-position when larger than a five-membered ring), and tic. most preferably the 3-position. Particularly preferred compounds of the present invention AS used herein, unless otherwise noted alkyl and alkoxy include those compounds shown in Table 1, where “Subst” whether used alone or as part of a Substituent group, include indicates the position of attachment of the group C(O)N(R') Straight and branched chains having 1-8 carbons. For YCOH to the centralazacycle and where the letter “R” after example, alkyl radicals include methyl, ethyl, propyl, the numeral “3” indicates the absolute configuration (Cahn isopropyl, n-butyl, isobutyl, Sec-butyl, t-butyl, n-pentyl, Ingold-Prelog rules).

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