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HHHHHHH USOO5081145A United States Patent (19) 11 Patent Number: 5,081,145 Guindon Et Al

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HHHHHHH USOO5081145A United States Patent (19) 11 Patent Number: 5,081,145 Guindon Et Al HHHHHHH USOO5081145A United States Patent (19) 11 Patent Number: 5,081,145 Guindon et al. 45 Date of Patent: Jan. 14, 1992 (54. INDOLE-2-ALKANOIC ACIDS 4,739,073 4/1988 Kathawala ...................... 548/414 X COMPOSITIONS OF AND ANT ALLERGIC USE THEREOF FOREIGN PATENT DOCUMENTS 50957 5/1982 European Pat. Off. (75. Inventors: Yvan Guindon; John W. Gillard, both 454858 6/1968 Switzerland. of Quebec; Christiane Yoakim, 455777 7/1968 Switzerland . Montreal; Thomas R. Jones, 948460 9/1960 United Kingdom . Kirkland; Rejean Fortin, Montreal-Nord, all of Canada OTHER PUBLICATIONS 73) Assignee: Merck Frosst Canada, Inc., Kirkland, Walton, et al., J. Med. Chen., 8, 204 (1965). Canada E. Walton, et al., J. Med. Chem., 11, 1252 (1968). 21 Appl. No.: 473,551 Primary Examiner-David B. Springer Attorney, Agent, or Firm-Gabriel Lopez; Joseph F. 22 Filed: Feb. 1, 1990 DiPrima 51. Int. Cl. .................. C07D 209/12; A61K 31/405 52 U.S. Cl. .................................... 514/49; 548/492; 57 ABSTRACT 548/494. Indole-2-alkanoic acids are disclosed. The compounds 58 Field of Search ......................... 548/494; 514/419 act as prostaglandin and thromboxane antagonists and 56 References Cited are useful in treating asthma, inflammation, diarrhea, hypertension, angina, platelet aggregation, cerebral U.S. PATENT DOCUMENTS spasm, premature labor, spontaneous abortion and dis 3,196,162 7/1965 Sarett et al. ......................... 260/39 menorrhea and as cytoprotective agents. 3,242,162 3/i966 Sarett et al. 260/21 3,242, 63 3/966 Sarett et al. ......................... 260/21 3,242,193 3/1966 Sarett et al. ......................... 260/319 6 Claims, No Drawings 5,081,145 1. NDOLE-2-ALKANOIC ACIDS COMPOSITIONS OF AND ANT ALLERGIC USE THEREOF CROSS-REFERENCE This is a continuation of application Ser. No. 197,117 filed Jan. 21, 1988 which is a continuation-in-part of patent application U.S.S.N. 624,173, filed June 25, 1984, pending, both abandoned. 10 SUMMARY OF THE INVENTION This invention relates to prostaglandin antagonists useful in treating a variety of conditions, such as allergic asthma where excessive contractile activity of prosta 15 glandins and prostaglandin biosynthetic intermediates CCC. wherein: These compounds antagonize the actions of contrac R is H or alkyl of 1 to 6 carbons or R1 and R8 taken tile prostaglandins, such as PGF2, PGG2, PGH2, 20 together form a group (CH2), wherein v is 1 to 7; PGD2, and TXA2. The use of agents which act as pros R2 is taglandin antagonists offers new approaches to therapy in a number of disease states. For example, certain pros taglandins, such as PGF2, PGD2, PGG2, and PGH2, are potent contractants of bronchial muscle. Indeed 25 human asthmatics have been shown to be especially sensitive to the bronchial constricting action of PGF2. wherein: The compounds of the present invention also produce each R8 is independently H, OH, C1 to C4-O-alkyl antithrombotic effects. Thus, they are useful in the 30 or alkyl of 1 to 4 carbons; or an Ri and an R8 taken treatment and/or prevention of thromboembolic dis together form a group (CH2) wherein v is 1 to 7. eases such as arterial thrombosis. R9 is COOR; CH2OH, CHO, tetrazole; NHSOR10 In addition to the involvement of contractile prosta wherein R10 is OH, alkyl or alkoxy of 1 to 6 carbons, glandins in chronic obstructive lung disease (or asthma), perhaloalkyl of 1 to 6 carbons, phenyl or phenyl substi prostaglandins are known to play a role in other allergic 35 tuted by alkyl or alkoxy groups of 1 to 3 carbons, halo conditions, as well as inflammation, diarrhea, hyperten gen, hydroxy, COOH, CN, formyl or acyl to 1 to 6 Sion, angina, platelet aggregation, cerebral spasm, cere carbons; CONHSO2R10; hydroxymethylketone; CN; or bral ischemia, myocardial ischemia, premature labor, CONGR3)2; spontaneous abortion, dismenorrhea, glomerular ne X is O; S; SO; SO2; NR11 wherein R11 is H, alkyl of 1 phritis, and systemic lupus erythematosis. Conse to 6 carbons, acyl of 1 to 6 carbons, CN; CRR8; or the quently, the compounds of this invention will alleviate unit the above mentioned diseases. In addition to the prostaglandin antagonist actions, R1 R8 the compounds of this invention are inhibitors of the 45 C Co synthesis of leukotrienes. Leukotrienes B4, C4, D4 and E4 are known to contribute to various disease condi wherein the dotted line represents an optional triple tions such as asthma, psoriasis, inflammation, pain, ul bond and in which the R1 and R8substituents are absent cers and systemic anaphylaxis. Thus inhibition of the when a triple bond is present; synthesis of such compounds will alleviate these disease 50 r and q are each independently 0 to 5 and p is 0 or 1 States. provided that the total of p, q and r is 2 to 6; The compounds of the present invention may be used R is H, alkyl of 1 to 6 carbons; phenyl or phenyl to treat or prevent mammalian (especially, human) dis substituted by R; or C1 to CA alkylphenyl or C1 to C4 ease states such as erosive gastritis; erosive esophagitis; 55 alkylphenyl in which the phenyl is substituted by R.'; inflammatory bowel disease; ethanol-induced hemor R, R, R6 and R7 are each independently selected from: rhagic erosions; hepatic ischemia; noxious agent in (1) hydrogen; duced damage or necrosis of hepatic, pancreatic, renal, (2) alkyl having 1 to 6 carbon atoms; or myocardial tissue; liver parenchymal damage caused (3) alkenyl having 2 to 6 carbon atoms; by hepatoxic agents such as CC14 and D-galactosamine; (4) -(CH2)M wherein n is 0 to 3 and M is ischemic renal failure; disease-induced hepatic damage; a) OR12; bile salt induced pancreatic or gastric damage; trauma b) halogen; or stress-induced cell damage; and glycerol-induced c) CF3; renal failure. 65 d) SR12; The present invention relates to a pharmaceutical e) phenyl or substituted phenyl wherein substituted composition comprising a compound of the Formula I: phenyl is as defined below in the definition of R12; f) COOR13; 5,081, 145 3 4. O (H. || || H. g) C-R1; (-,-,-,-,-,-,-) 5 OH. H. H. CH H CH-CH3 h) tetrazole; H. H. H H. H. H. H. H. O (-,-,-,-,-,-,-,-,-,-). i) -NH-C-R1- is 10 OH CH3 OH H OH CH3 H H wherein R15 is C to C6 alkyl, benzyl or phenyl; H. H. H j)-NR13R13; ----, and the like. k) -NHSO2R16 wherein R16 is C1 to C6 alkyl, phenyl, H CH3 H O CF3; 15 The alkyl groups referred to above may be straight O chain or branched or may include cycloalkyl groups. 1) -C-CH2OH: As used herein, the term "lower' as applied to alkyl, acyl, alkoxy and the like, unless stated otherwise refers m) -SOR12; 20 to groups having 1 to 6 carbon atoms. Halogen or halo n) -CONR 13R 13; means fluoro, chloro, bromo and/or iodo. o) -SO2NR13R 13; Pharmaceutically acceptable salts of the compounds described herein are included within the scope of the p) -SO2R12; present invention. Such salts may be prepared from q) NO2; 25 pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from O inorganic bases include sodium, potassium, lithium, r) O-C-R14. ammonium, calcium, magnesium, ferrous, zinc, copper, O 30 manganous, aluminum, ferric, manganic salts and the I like. Particularly preferred are the potassium, sodium s) O-C-NR13R 13. calcium and magnesium salts. Salts derived from phar maceutically acceptable organic non-toxic bases include O salts of primary, secondary, and tertiary amines, substi t) O-C-OR5, 35 tuted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, u) CN; such as isopropylamine, tri-methylamine, diethanol each R12 independently is H; C to C6 alkyl; benzyl; amine, diethylamine, triethylamine, tripropylamine, phenyl or substituted phenyl wherein the substituents ethanolamine, 2-dimethylaminoethanol, 2-die are C1 to C3 alkyl, halogen, CN, CF3, COOR, 40 thylaminoethanol, tomethamine, lysine, arginine, histi CH2COOR13, C1 to C3 alkoxy, or C1 to C4 perfluoroal dine, caffeine, procaine, hydrabamine, choline, inidaz kyl; ole, betaine, ethylenediamine, glucosamine, methylglu camine, theobromine, purines piperazine, N,N-diben each R13 is independently H, phenyl or C to C6 alkyl; zylethylenediamine, piperidine, N-ethylpiperidine, nor and pholine, N-ethylmorpholine, polyamine resins and the each R14 independently is H., (CH2)COOR13 45 like. wherein n is 0 to 4, C1 to C6 alkyl, CF3, phenyl, or Preferred compositions of the present invention com substituted phenyl wherein substituted phenyl is as de prise compounds of the Formula I wherein: fined above in the definition of R12; or a pharmaceuti each R1 is H or alkyl of 1 to 6 carbons or R1 and R8 cally acceptable salt thereof, and a pharmaceutically taken together form a group (CH2) wherein v is 1 to 7; acceptable carrier. 50 R2 is As used herein, the terms "each independently' or the equivalents thereof are employed to describe a num ber of possible position isomers and/or structural varia tions. For example, as described above, R2 is: 55 R1 R wherein: -(+xi-R each R8 is independently H, OH, C1 to C4-O-alkyl R8 R8 60 or alkyl of 1 to 4 carbons; or an R and an R8 taken together form a group (CH2) wherein v is 1 to 7; - The letters r and q, represent possible alkane chains of R9 is COOR1, CH2OH, CHO, tetrazole; CONH from 0 to 5 carbon atoms, each having the R1 and R8 SO2R10 wherein R10 is OH, alkyl or alkoxy of 1 to 6 substituent groups. On each carbon atom of the alkane carbons, perhaloalkyl of 1 to 6 carbons, phenyl or chain, the R and/or R8 substituent may be different.
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