User:Jfdwolff/Apixaban
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Fibrin targeted therapeutics, particularly peptidomimetics, their preparation and use in the treatment of thromboembolism, infection, and cancer. McMurry, Thomas J.; Kolodziej, Andrew; Carpenter, Alan P., Jr.; Jones, Simon; Graham, Philip; Looby, Richard; Shrikumar, A. Nair; Wang, Xifang; Overoye-Chen, Kirsten; Barrett, John A. (Epix Pharmaceuticals, Inc., USA). PCT Int. Appl. (2007), 136pp. CODEN: PIXXD2 WO 2007047608 A2 20070426 Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LV, LY, MA, MD, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO 2006-US40430 20061016. Priority: US 2005-726632 20051014; US 2006-800152 20060512. CAN 146:462511 AN 2007:463352 CAPLUS (Copyright (C) 2007 ACS on SciFinder (R))
Abstract
The invention is related to hybrid mols. of formula [D]m-[L]n-[F]q [I; wherein [D] comprises a bioactive moiety for treating thromboembolism, infection, and cancer; [L] comprises a linker moiety; [F] comprises a fibrin-targeting moiety selected from a peptide, peptidomimetic, or a small mol.; m, q = independently 1-20; n = 0-20]. I can provide enhanced efficacy and reduced systemic toxicity relative to a corresponding non-targeted bioactive mol. Thus, a paclitaxel-fibrin binding peptide conjugate II was prepd. using paclitaxel, succinyl anhydride, and peptide III (H-R). II in a dose-responsive manner caused a significant decrease in the no. of cancer cells in lung and breast cancer lines and in the no. of smooth muscle and endothelial cells.
New anticoagulants. Samama, M.-M.; Gerotziafas, G. Service d'hematologie Biologique, Hotel-Dieu, Paris, Fr. Annales Pharmaceutiques Francaises (2007), 65(2), 85-94. Publisher: Elsevier Masson SAS, CODEN: APFRAD ISSN: 0003-4509. Journal; General Review written in French. CAN 146:414118 AN 2007:357858 CAPLUS (Copyright (C) 2007 ACS on SciFinder (R))
Abstract
A review. In contrast to older anticoagulant agents vitamin K antagonists and heparins, the new ones are directed towards a single target in general. The main characteristics of the new agents are: - their site of action in the coagulation cascade and their mechanism of action which is indirect, antithrombin dependent, most often such as Fondaparinux and Idraparinux or direct such as Dabigatran, Rivaroxaban - the specificity of the new mols., since they must not interact with other enzymes: trypsin, kallikrein, t-PA, etc... - their mode of administration parenteral and/or oral; - their pharmacokinetics and their clearance frequently by the kidney (Hirudin, fondaparinux) or through hepatic metab. (argatroban); - tolerance including for all compds. the bleeding risk or an unexpected hepatic intolerance for Ximelagatran; - the availability of a specific antidote and the cost of the drug; - one compd. is registered in France Arixtra Fondaparinux in major orthopedic surgery and in the treatment of venous thromboembolism and in prophylactic treatment in medical patients. However, the main indications of interest for these new drugs is atrial fibrillation. There is a real need in this indication and the no. of patients to treat is growing with the longer life expectancy.
Investigational treatments of venous thromboembolism. Spyropoulos, Alex C. Clinical Thrombosis Center, Lovelace Medical Center, Albuquerque, NM, USA. Expert Opinion on Investigational Drugs (2007), 16(4), 431-440. Publisher: Informa Healthcare, CODEN: EOIDER ISSN: 1354-3784. Journal; General Review written in English. CAN 147:369 AN 2007:320889 CAPLUS (Copyright (C) 2007 ACS on SciFinder (R))
Abstract
A review. The antithrombotic management of venous thromboembolism (VTE) has gone through major developments. Indirect inhibitors such as low mol. wt. heparin and the pentasaccharide fondaparinux represent improvements over traditional drugs such as unfractionated heparin for acute treatment of VTE with more targeted approaches, predictable pharmacokinetic profiles and lack of need for monitoring. Vitamin K antagonists, with inherent limitations of multiple food and drug interactions and frequent need for monitoring, remain the only oral anticoagulants approved for long-term secondary thromboprophylaxis in VTE with the removal of the oral direct thrombin inhibitor ximelagatran from the world market due to safety concerns. Newer anticoagulant drugs such as parenteral pentasaccharides (idraparinux and SSR-126517-E), oral direct thrombin inhibitors (dabigatran), oral direct Factor Xa inhibitors (rivaroxaban, apixaban, YM-150 and DU-176b) and tissue factor-Factor VIIa complex inhibitors (NAPc2) are tailor-made to target specific procoagulant complexes and have the potential to greatly expand our antithrombotic armamentarium for both acute and long-term treatment of VTE, esp. as non-monitored parenteral and oral anticoagulants with a wide therapeutic window and a predictable anticoagulant response.
Factor Xa inhibitor formulation and method. Nassar, Munir N.; Gogate, Uday Shankar; Malloy, Timothy M. (Bristol-Myers Squibb Company, USA). PCT Int. Appl. (2007), 26pp. CODEN: PIXXD2 WO 2007022165 A2 20070222 Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LV, LY, MA, MD, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO 2006-US31801 20060816. Priority: US 2005-709077 20050817; US 2006-464519 20060815. CAN 146:258984 AN 2007:197948 CAPLUS (Copyright (C) 2007 ACS on SciFinder (R))
Abstract
An injectable Factor Xa inhibitor formulation is provided which includes the Factor Xa inhibitor razaxaban or apixaban, a solubilizing agent which is a substituted b-cyclodextrin, preferably, sulfobutyl ether b-cyclodextrin (SBE-CD) or hydroxypropyl-b-cyclodextrin (HPB-CD), and water. A method for preventing or treating venous thrombosis, deep venous thrombosis and acute coronary syndrome employing the above formulation is also provided.
Odiparcil and a factor Xa inhibitor formulations for treatment of thromboembolic disorders. Ohlstein, Eliot H. (Glaxo Group Limited, UK). PCT Int. Appl. (2006), 42pp. CODEN: PIXXD2 WO 2006110726 A2 20061019 Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, LY, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO 2006-US13448 20060411. Priority: US 2005-669985 20050411. CAN 145:443880 AN 2006:1096816 CAPLUS (Copyright (C) 2007 ACS on SciFinder (R))
Abstract
The present invention relates to combinations of 4-methyl-2-oxo-2H-1-benzopyran-7-yl-5-thio-b-D-xylopyranoside (odiparcil)and factor Xa inhibitors, methods for producing the combinations, and methods of using the combinations for the treatment and prevention of various thromboembolic disorders in mammals, particularly humans. Thus, 2 parts odiparcil are combined with 1 part by wt. rivaroxaban. The combined powders are then optionally milled to desired particle size range. The combination of the 2 drugs is then further combined with a wetting agent, disintegrant and/or filler and compressed into tablets of the following strengths: 50 mg odiparcil/25 mg rivaroxaban; 100 mg odiparcil/50 mg rivaroxaban; 200 mg odiparcil/100 mg rivaroxaban; 250 mg odiparcil/125 mg rivaroxaban.
Highly sensitive hematological assay and reagent. Koizumi, Takashi; Yamazaki, Yoshinobu. (Kissei Pharmaceutical Co., Ltd., Japan). PCT Int. Appl. (2006), 26pp. CODEN: PIXXD2 WO 2006106695 A1 20061012 Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, LY, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in Japanese. Application: WO 2006-JP306357 20060328. Priority: JP 2005-106590 20050401. CAN 145:413723 AN 2006:1066558 CAPLUS (Copyright (C) 2007 ACS on SciFinder (R))
Abstract
A reagent/kit usable in a blood coagulation system assay of a direct factor Xa inhibitor is provided, which comprises factor Xa, a phospholipid and a calcium ion, provided that any reagent or kit addnl. including factor V, factor Va, or a factor V activating enzyme is excluded. Also provided is a direct factor Xa inhibitor coagulation system assay method, which is characterized in using this reagent/kit.
Oral anticoagulants in development: focus on thromboprophylaxis in patients undergoing orthopedic surgery. Eriksson, Bengt I.; Quinlan, Daniel J. Department of Orthopaedics Surgery, Sahlgrenska University Hospital/Oestra, Goeteborg, Swed. Drugs (2006), 66(11), 1411-1429. Publisher: Adis International Ltd., CODEN: DRUGAY ISSN: 0012-6667. Journal; General Review written in English. CAN 146:113849 AN 2006:1039594 CAPLUS (Copyright (C) 2007 ACS on SciFinder (R))
Abstract
A review. Current anticoagulant provision is dominated by parenteral heparin and oral warfarin, which act by inhibiting several steps of the coagulation pathway indirectly. Recent research efforts have focused on the identification of small mol. inhibitors of the coagulation enzymes as novel therapies for thrombotic disorders. There has been particular success in developing nonpeptidic, orally available, small mols. to directly inhibit the key proteases, factor IIa and factor Xa. Of the new oral anticoagulants in development, the two agents in the most advanced stage are dabigatran etexilate (BIBR 1048) and rivaroxaban (BAY 59-7939), which inhibit factor IIa and factor Xa, resp. Other agents in the early stages of development include several Xa inhibitors (LY-517717, YM150, DU-176b and apixaban [BMS-562247]), a factor IXa inhibitor (TTP889), and an orally active glycosaminoglycan enhancer (odiparcil [SB-424323]), which indirectly enhances thrombin inhibition via heparin cofactor II. Results have been reported from important, phase II dose-finding studies, and a no. of registration-track phase III studies have been initiated, reflecting the drive towards potentially more effective, but primarily safer and more convenient therapies for the prevention and treatment of venous and arterial thrombosis. Indeed, two unmet needs for anticoagulation that can be easily identified are safety and ease of use. Safety relates primarily to the incidence of major bleeding and this remains the key concern of orthopedic surgeons, over and above any efficacy advantage, and convenience of use, which centers on oral administration replacing the need for injections. The clin. development of these new anticoagulants is following the well tested strategy of dose-ranging and registration studies in major orthopedic surgery, prior to development in arterial indications. There are a no. of subtle issues, including the timing of the first perioperative dose, duration of prophylactic treatment and definition/assessment of study endpoints that can influence study outcome and require careful consideration when evaluating study results with new agents and in the comparison with established agents, and which are considered in this review. It is anticipated that over the next 3 years, at least one of these agents will be successfully licensed for the prevention of venous thromboembolism after major orthopedic surgery, which will act as a springboard for the gradual replacement of current anticoagulants.
Crystallization via high-shear transformation. Wei, Chenkou; Yang, Bing-Shiou. (USA). U.S. Pat. Appl. Publ. (2006), 10 pp. CODEN: USXXCO US 2006160841 A1 20060720 Patent written in English. Application: US 2005-235327 20050926. Priority: US 2005-645056 20050119. CAN 145:145697 AN 2006:710740 CAPLUS (Copyright (C) 2007 ACS on SciFinder (R))
Abstract
A process or app. is described for transforming a first polymorph [e.g., 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide] of a chem. material into a second polymorph of the same chem. material, utilizing an app. comprising a vessel connected to a re-circulation system, the process comprising the steps of: suspending said first polymorph in a soln. (e.g., propylene glycol and water) to form a slurry in the vessel; re-circulating the slurry; and removing the slurry from the vessel. Process flow diagrams are presented.
Use of dipyridamole in combination with antithrombotics for treatment and prevention of thromboembolic diseases. Eisert, Wolfgang. (Boehringer Ingelheim International GmbH, Germany; Boehringer Ingelheim Pharma Gmbh & Co. KG). PCT Int. Appl. (2006), 65 pp. CODEN: PIXXD2 WO 2006045756 A1 20060504 Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, LY, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IS, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO 2005-EP55446 20051021. Priority: EP 2004-25283 20041025. CAN 144:445363 AN 2006:411919 CAPLUS (Copyright (C) 2007 ACS on SciFinder (R))
Abstract
The invention relates to a method for treating and preventing thromboembolic disorders, comprising administering dipyridamole in combination with an antithrombotic selected from direct thrombin inhibitors, factor Xa inhibitors and combined thrombin/factor Xa inhibitors to a patient, as well as pharmaceutical compns. suitable for this method of treatment and the use of dipyridamole for the manuf. of these pharmaceutical compns.
Process for efficient preparation of 4,5-dihydropyrazolo[3,4-c]pyridine-2-one derivatives. Shapiro, Rafael; Rossano, Lucius T.; Mudryk, Boguslaw M.; Cuniere, Nicolas; Oberholzer, Matthew; Zhang, Huiping; Chen, Bang-Chi. (USA). U.S. Pat. Appl. Publ. (2006), 21 pp. CODEN: USXXCO US 2006069258 A1 20060330 Patent written in English. Application: US 2005-235510 20050926. Priority: US 2004-613938 20040928; US 2005-688999 20050609. CAN 144:350673 AN 2006:301745 CAPLUS (Copyright (C) 2007 ACS on SciFinder (R))
Abstract
This invention pertains to a method for prepn. of 4,5-dihydropyrazolo[3,4-c]pyridine-2-one derivs. with general formula of I [wherein R = Me, Et, n-Pr, MeO, EtO, n-PrO, i-PrO, BuO, s-BuO, i-BuO, t-BuO, PhO, PhCH2O, PhCH2CH2O, or Ph(CH3)3O; ring A = (un)substituted Ph; ring D = Ph, 2-fluorophenyl, 3-chlorophenyl, or 4-methoxyphenyl; B = NO2 or (un)substituted NH2]. For example, the compd. II was prepd. in a multi-step synthesis. These compds. can be useful as factor Xa inhibitors (no data).
Synthesis of 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones. Zhou, Jiacheng; Oh, Lynette M.; Ma, Philip; Li, Hui-yin. (Bristol-Myers Squibb Company, USA). PCT Int. Appl. (2003), 143 pp. CODEN: PIXXD2 WO 2003049681 A2 20030619 Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, OM, PH, PL, PT, RO, RU, SD, SE, SG, SK, SL, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM, ZW. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO 2002-US38559 20021203. Priority: US 2001-339085 20011210. CAN 139:53014 AN 2003:472339 CAPLUS (Copyright (C) 2007 ACS on SciFinder (R))
Abstract
A novel process and intermediates thereof for making 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones (shown as I; variables defined below; e.g. 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide) from appropriate Ph hydrazines is described. These compds. are useful as factor Xa inhibitors (no data). I are made from II using an acid, e.g. trifluoroacetic, sulfuric, nitric, hydrochloric. For example, 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-6-(4-iodophenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one was prepd. (95% yield) from 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-6-(4-iodophenyl)-8-morpholino-1,4,5,6,8,9-hexahydro-7H-pyrazolo[3,4-c]pyridin-7-one (1.0 mmol) in CH2Cl2 on treatment with CF3CO2H (2.0 mL). II are made from III and IV in the presence of base (e.g. triethylamine, diisopropylethylamine, and N-methylmorpholine). For example, 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-6-(4-iodophenyl)-8-morpholino-1,4,5,6,8,9-hexahydro-7H-pyrazolo[3,4-c]pyridin-7-one was prepd. (65% yield) from 2,2,2-trifluoro-N-(3-cyano-4-fluorophenyl)ethanehydrazonoyl mesylate (4.0 mmol) and N-(4-iodophenyl)-3-morpholino-5,6-dihydro-2H-pyridin-2-one (4.0 mmol) in toluene (18 mL) in the presence of N-methylmorpholine (16.0 mmol). For I-IV: ring D = 4-chlorophenyl, 4-methoxyphenyl, 2-cyanophenyl, 2-(aminomethyl)phenyl, 2-(PgNHCH2)phenyl, 3-cyanophenyl, 3-(aminomethyl)phenyl, 3-(PgNHCH2)phenyl, 3-cyano-4-fluorophenyl, (3-amino)benz[d]isoxazol-6-yl, and (3-PgNH)benz[d]isoxazol-6-yl (Pg is an amine protecting group). R1 and R2 = C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Ph, and benzyl; alternatively, NR1R2 is a 3-8 membered ring consisting of C atoms, N, and 0-1 O atoms; R1a = H, CH3, CH2CH3, CH2CH2CH3, CH2F, CH2Cl, Br, CH2Br, CN, CH2CN, CF3, CH2CF3, CH2OCH3, CO2CH3, CH2CO2CH3, CO2CH2CH3, CH2CO2CH2CH3, CH2SCH3, S(O)CH3, CH2S(O)CH3, S(O)2CH3, CH2S(O)2CH3, C(O)NH2, CH2C(O)NH2, SO2NH2, CH2SO2NH2, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-2-yl N-oxide, pyridin-3-yl N-oxide, pyridin-4-yl N-oxide, imidazol-1-yl, CH2-imidazol-1-yl, 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl, CH2-1,2,3,4-tetrazol-1-yl, and CH2-1,2,3,4-tetrazol-5-yl, provided that R1a forms other than an N-halo, N-N, N-S, N-O, or N-CN bond. A = Ph substituted with 0-1 R4, pyridyl substituted with 0-1 R4, and pyrimidyl substituted with 0-1 R4; B = B1, Cl, Br, I, OMs, OTs, OSO2Ph, CH2Br, CH2OH, and CHO; alternatively, A-B is H; B1 is Y or X-Y; X = C1-4 alkylene, -CR2(CHR2R2b)(CH2)t-, -C(O)-, -CR2(OR2)-, -CR2(SR2)-, -C(O)CR2R2a-, -CR2R2aC(O), -S(O)p-, - S(O)pCR2R2a-, -CR2R2aS(O)p-, -S(O)2NR2-, -NR2S(O)2-, -NR2S(O)2CR2R2a-, -CR2R2aS(O)2NR2-, -NR2S(O)2NR2-, -C(O)NR2-, -NR2C(O)-, -C(O)NR2CR2R2a-, -NR2C(O)CR2R2a-, -CR2R2aC(O)NR2-, -CR2R2aNR2C(O)-, -NR2C(O)O-, -OC(O)NR2-, -NR2C(O)NR2-, -NR2-, -NR2CR2R2a-, -CR2R2aNR2-, O, -CR2R2aO-, and -OCR2R2a-. Y = C3-10 carbocycle substituted with 0-2 R4a, and 5-10 membered heterocycle contg. = 1-4 heteroatoms N, O, and S, substituted with 0-2 R4a; addnl. details are given in the claims. For III: Z = Cl, Br, I, OSO2Me, OSO2Ph, OSO2C6H4Me-p.
Preparation of heteroaryllactams as Factor Xa inhibitors. Pinto, Donald; Quan, Mimi; Orwat, Michael; Li, Yun-Long; Han, Wei; Qiao, Jennifer; Lam, Patrick; Koch, Stephanie. (Bristol-Myers Squibb Company, USA). PCT Int. Appl. (2003), 441 pp. CODEN: PIXXD2 WO 2003026652 A1 20030403 Designated States W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, OM, PH, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM, ZW. Designated States RW: AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, ML, MR, NE, SN, TD, TG. Patent written in English. Application: WO 2002-US29491 20020917. Priority: US 2001-324165 20010921. CAN 138:287666 AN 2003:261670 CAPLUS (Copyright (C) 2007 ACS on SciFinder (R))
Abstract
P4PMM4 [M = 3-10 membered (substituted) (unsatd.) carbocyclyl, 4-10 membered heeterocyclyl; P = null, 5-7 membered (substituted) (unsatd.) carbocyclyl, heterocyclyl fused to ring M; 1 of P4, M4 = ZAB, the other = G1G; G = (benzo-, pyrido-, pyrimido-, pyrazino-, or pyridazino-fused) (substituted) (unsatd.) 5-6 membered (hetero)cyclyl; G1 = null, (CR3R3a)1-5, etc.; R3, R3a = H, Me, Et, Pr, Ph, PhCH2, etc.; Z = bond, (CR3R3e)1-4, etc.; R3e = H, SO2NHR3, SO2N(R3)2, COR3, (substituted) alkyl, alkenyl, alkynyl, etc.; A = (substituted) 3-10 membered carbocyclyl, 5-12 membered heterocyclyl; Z = XNQ; X = null, CO, SO, SO2, etc.; NQ = 4-8 membered mono- or bicyclic (substituted) (unsatd.) ring contg. a CO or SO2 group adjacent to the N atom; with provisos], were prepd. Thus, 6-(4-iodophenyl)-3-methoxy-1-(4-methoxyphenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one (prepn. given), d-valerolactam, K2CO3, and CuI were refluxed in Me2SO to give 15% 3-methoxy-1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one. Several title compds. inhibited Factor Xa with IC50£ 10 mM.
