United States Patent (19) 11 Patent Number: 6,077,850 Carter Et Al
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USOO607785OA United States Patent (19) 11 Patent Number: 6,077,850 Carter et al. (45) Date of Patent: Jun. 20, 2000 54 SUBSTITUTED BENZOPYRAN ANALOGS 59-29681 2/1984 Japan. FOR THE TREATMENT OF 2-22272 1/1990 Japan. NFLAMMATION WO88/04654 6/1988 WIPO .......................... CO7D 311/58 WO94/13659 6/1994 WIPO ... ... CO7D 319/18 WO95/07274 3/1995 WIPO .......................... CO7D 405/12 75 Inventors: SG"SEE,Mark G WO96/4O110 12A 1996 WIPO ............................ A61K 31/35 Devadas, Chesterfield;s sJohn J Talley, WO98/34115 8/1998 WIPO. St. Louis; David L. Brown; Matthew J OTHER PUBLICATIONS Graneto, both of Chesterfield, all of Mo.; Stephen R Bertenshaw, Cheshire, Sabbaramaiah et al., Proc. Soc. Exp. Biol. Med., 216, Conn.; Donald J. Rogier, Jr.; 201: 1997. Srinivasan Raj Nagarajan, both of Hida et al., Anticancer Res., 19, 775-82:1998. Chesterfield, Mo.; Cathleen E. Hanau, Wison, Cancer Res., 58, 2929–34:1998. St. Louis, Mo.; Susan J. Hartmann, Buckman et al., Carcinogensis, 19, 729-29:1998. Kirkwood, Mo.; Cindy L. Ludwig, St. Barnes et al., Lung Biol. Health Dis., 114, 11-27:1998. Louis, Mo.; Suzanne Metz, M. Tsujii et al., Cell, 93, 705–16:1998. Chesterfield, Mo.; Donald E Korte, Bustos, J. Clin. Inverst., 100, 1150–58:1997. Mundelein, Ill. Bagetta et al., Biochem, BiophyS. Res. Commun., 244, 73 Assignee: G.D. Searle & Co., Skokie, Ill. 819-24:1998. Sandhya et al., Brain Res., 788, 233–31:1998. 21 Appl. No.: 09/175,584 Singer et al., Gastroenterology, 115, 297-306:1998. Nogawa et al., Proc. Natl. Acad. Sci., 95, 10966–71:1998. 22 Filed: Oct. 20, 1998 Nasletti, Hypertension, 31, 194–200:1997. Related U.S. Application Data Kawamori et al., Cancer Res., 58, 409-12:1998. Miyamoto et al., Neuro Report, 9, 2331-4:1998. 63 Continuation-in-part of application No. 09/062,537, Apr. 17, Shoup, J. Trauma: inj., Infec., Crit care, 45, 215-21:1998. 1998 60 Provisional application No. 60/044,485, Apr. 21, 1997. Speir et al., Circ. Res., 83, 210-16:1998. Bosch, Curr. Med. Res. Opin., 14, 29–38:1997. 51 Int. Cl." ........................ A61K 31/47; A61K 31/495; Manrao et al., J. Indian. Counc. Chem., 12, 38-41:1996. A61K 31/44; CO7D 215/16; CO7D 221/06 52 U.S. Cl. .......................... 514/311; 514/312; 514/250; Loiodice et al, Tetrahdron, 6, 1001-11:1995. 514/290; 514/285; 514/292; 54.6/156; 54.6/153; Clemence et al., J. Med. Chem., 31, 1453–62:1988. 54.6/101; 546/62; 546/81; 544/350; 544/345 Lazer, et al., J. Med. Chem., 40, 980–89:1997. 58 Field of Search ..................................... 546/156, 153, Bunting et al., Can. J. Chem., 62, 1301-07:1984. 54.6/101, 81, 62; 514/311, 312, 250, 290, Ukhin et al., IZV. Akad. Nauk. Der. Khim., 5, 1222–28:1996. 292, 285 Gupta et al., Indian J. Chem., 21B, 344-347:1982. Rene and Royer, Eur. J. Med. Chem-Chim. Ther., 10, 56) References Cited 72-78: 1975. U.S. PATENT DOCUMENTS Satoh et al., J. Med. Chem. 36,3580-94: 1993. 4,609,744 9/1986 Young et al. ........................... 549/402 Primary Examiner Deborah C. Lambkin 4,665.202 5/1987 Rimbault et al. ... 549/402 Attorney, Agent, or Firm Joseph W. Bullock 4,761,425 8/1988 Girard et al. ... ... 514/456 4,814,346 3/1989 Albert et al. ......... ... 514/454 57 ABSTRACT 5,004,744 4/1991 Weissmiller et al. ... 514/247 5,082,849 1/1992 Huang et al. ........ ... 514/314 A class of ben Zopy ran S, benzothiopy ran S, 5,155,130 10/1992 Stanton et al. ... ... 514/456 dihydroquinolines, dihydronaphthalenes, and analogs 5,250,547 10/1993 Lochead et al. ... 514/337 thereof, is described for use in treating cyclooxygenase-2 5,281,720 1/1994 Young et al. ............................. 549/13 mediated disorders. Compounds of particular interest are 5,348,976 9/1994 Shibata et al. ... ... 514/469 5,447,943 9/1995 Lochead et al. ... 514/337 defined by Formula I' 5,618,843 4/1997 Fisher et al. ..... ... 514/567 I 5,728,713 3/1998 Nilsson et al........ ... 514/312 5,728,846 3/1998 Vulgonda et al. ...... ... 549/16 5,731,312 3/1998 Mederski et al..... ... 514/291 5,807,869 9/1998 Furuya et al. ... ... 514/312 5,811,553 9/1998 Farina et al...... ... 546/153 5,817,674 10/1998 Clemence et al. ....... ... 514/311 5,849,798 12/1998 Charpentier et al. ................... 514/456 5,869,478 2/1999 Ding et al. .............................. 514/212 5,889,021 3/1999 Starke .......... ... 514/313 5,891,878 4/1999 Beasley et al. ......................... 514/247 wherein X, A, A, A, A", R, R", R and Rare as described in the Specification. FOREIGN PATENT DOCUMENTS 412939 2/1991 European Pat. Off. ...... CO7D 311/58 14 Claims, No Drawings 6,077,850 1 2 SUBSTITUTED BENZOPYRAN ANALOGS (1998)), dementia, burn infections (M. Shoup, J. Trauma: FOR THE TREATMENT OF Inj., Infec., Crit care, 45,215-21 (1998)), cytomegalovirus NFLAMMATION infectivity (E. Speir et al., Circ. Res., 83,210-16 (1998)), lumbago (H. Bosch, Curr. Med. Res. Opin., 14, 29–38 RELATED CASES (1997)), among others. The references below that disclose antiinflammatory This is a continuation in part of application Ser. No. activity, Show continuing efforts to find a Safe and effective 09/062.537, filed Apr. 17, 1998, now allowed, which is a antiinflammatory agent. The novel benzopyran, continuation in part of application Ser. No. 60/044,485, filed dihydroquinoline, benzothiopyran and dihydronapthalene Apr. 21, 1997. derivatives disclosed herein are Such Safe and also effective FIELD OF THE INVENTION antiinflammatory agents furthering Such efforts. The Substi tuted benzopyran, dihydroquinoline, benzothiopyran and This invention is in the field of anti-inflammatory phar dihydronapthalene derivatives disclosed herein preferably maceutical agents and Specifically relates to compounds, Selectively inhibit cyclooxygenase-2 over cyclooxygenase compositions and methods for treating cyclooxygenase-2 15 1. mediated disorders, Such as inflammation and inflammation U.S. Pat. No. 5,618,843, to Fisher et al., generically related disorders. describes acid substituted bicyclic moieties as IIb/IIIA antagonists. WO 94/13659, published Jun. 23, 1994, BACKGROUND OF THE INVENTION describes fused benzo compounds for the treatment of CNS Prostaglandins play a major role in the inflammation disorders. Manrao et al. (J. Indian. Counc. Chem., 12,38–41 proceSS and the inhibition of prostaglandin production, (1996)) describes carboxy coumarinimide derivatives and especially production of PGG, PGH and PGE, has been their antifungal activity. U.S. Pat. No. 5,348,976, to Shibata a common target of antiinflammatory drug discovery. et al., describes amide Substituted benzopyrans as antifun However, common non-Steroidal antiinflammatory drugs gals. (NSAIDs) that are active in reducing the prostaglandin 25 WO96/40110, published Dec. 19, 1996, describes ben induced pain and Swelling associated with the inflammation Zopyran derivatives as tyrosine kinase modulators. Loiodice proceSS are also active in affecting other prostaglandin et al. (Tetrahedron, 6, 1001-11 (1995)) describe the prepa regulated processes not associated with the inflammation ration of 6-chloro-2,3-dihydro-4H-1-benzopyran carboxylic process. Thus, use of high doses of most common NSAIDs acids. can produce Severe side effects, including life threatening Clemence et al. (J. Med. Chem., 31, 1453–62, (1988)) ulcers, that limit their therapeutic potential. An alternative to describe 4-hydroxy-3-quinolinecarboxylic acids as Starting NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is material in the preparation of antiinflammatories. Lazer, et involved. al. (J. Med. Chem., 40,980–89 (1997)) describe benzothi 35 opyran carboxylates as Starting material in the preparation of Previous NSAIDs have been found to prevent the pro antiinflammatories. duction of prostaglandins by inhibiting enzymes in the U.S. Pat. No. 5,281,720, to Young et al., describes naph human arachidonic acid/prostaglandin pathway, including thoic acids as lipoxygenase inhibitors. U.S. Pat. No. 5,348, the enzyme cyclooxygenase (COX). The recent discovery of 976, to Shibata et al., describes amide substituted benzopy an inducible enzyme associated with inflammation (named 40 rans as antifungals. U.S. Pat. No. 5,004,744, to Weissmiller “cyclooxygenase-2 (COX-2)” or “prostaglandin G/H syn et al., describes 2H-benzopyran-3-carboxylic acid as an thase II”) provides a viable target of inhibition which more intermediate for pesticides. U.S. Pat. No. 4,814,346, to effectively reduces inflammation and produces fewer and Albert et al., describe S 3-phenylbenzopyrians as less drastic Side effects. 5-lipoxygenase inhibitors. U.S. Pat. No. 4,761,425, to Recently, there has been Significant research into Some of 45 Girard and Rokach, describes 4-oxo-benzopyrans as leukot the roles of cyclooxygenase-2. It has been found that COX-2 riene antagonists. U.S. Pat. No. 4,609,744, to Young et al., is upregulated in benign and malignant tumors (K. Subbara describes 4-oxo-benzopyran-carboxylic acids as leukotriene maiah et al., Proc. Soc. Exp. Biol. Med., 216, 201 (1997)) antagonists. U.S. Pat. No. 5,082,849, to Huang et al., including lung cancer (T. Hida et al., Anticancer Res., 18, describes 4-oxo-benzopyrans as leukotriene antagonists. 775-82 (1998)), Barrett's esophagus (K. Wilson, Cancer 50 WO95/07274, published Mar. 16, 1996, describes Res., 58, 2929–34 (1998)) and skin cancer (S. Buckman et 2H-benzopyran-3-carboxylic acid as intermediates. WO88/ al., Carcinogenesis, 19, 723–29 (1998)). It is expressed in 04654, published Jun. 30, 1988, describes 2H-benzopyran airway cells with implication in asthma (P.