| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 31.12.02 |
| PATENT TITLE |
Inhibitors of phospholipase enzymes |
| PATENT ABSTRACT | This invention concerns compounds and pharmaceutical compositions useful for treating or preventing inflammatory conditions in a mammal, the methods comprising administration of novel pharmaceutically useful compounds of the general formulae: ##STR1## or pharmaceutically acceptable salts thereof, wherein R.sub.1 -R.sub.5 are as defined in the specification |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | October 11, 2000 |
| PATENT REFERENCES CITED |
Smith, W. Biochem. J. 1989, 259, 315. Wasserman, S. Hospital Practice 1988, 49. Chang, J. et al. Biochemical Pharmacology 1987, 36, 2429. Dennis, E. Drug Development Research 2987, 10, 205. Seilhamer, J. et al. J. Bio. Chem. 1989, 10, 5335. Kramer, R. et al. J. Bio. Chem. 1989, 10, 5768. Kanda, A. et al. Biochem. and Biophys. Research Comm. 1989, 163, 42. Burch, R. et al. Proc. Natl. Acad. Sci. USA 1987, 84, 6374. Leslie, C. et al. Bioch. et Biophys. Acta 1988, 963, 476. Bligh, E. et al. Can. J. Biochem. Physiol. 1959, 37, 911. Kutkevicius, S. et al. Chem. Abstract 1982, 96: 85391. Gadient et al. Chem. Abstract 1980, 93: 71555. Griffin, R. et al. Chem. Abstract 1997, 126: 212151. Yamaguchi Chem. Abstract 1996, 124: 329940b. Geban et al. Chem. Abstract 1996, 124: 219398y. Aldrich Catalogue, 1994, pp. 1116. Cox et al. Chem. Abstract 1988, 108:94553. Rao et al., Chem. Abstract l1980, 93: 167168t. Inoue et al. Chem. Abstract 1975, 82: 16840. Kuranari et al. Chem. Abstract 1968, 68: 29698y. Aka et al. Chem. Abstract 1967, 66: 95044s. Samuelsson et al. Science 1987, 1237, 1171. Ramesha, C. et al. Anal. Biochem. 1991, 192, 173. Chen et al., Chem. Abstracts, 1994, 121: 124872. Yamamoto et al., Chem. Abstracts, 1972, 76: 25103. Dillard et al., J. Med. Chem., 1996, 39, 5137-5158. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed: 1. A compound of the formulae: ##STR69## wherein: R.sub.1 and R.sub.1, are independently selected from the group consisting of H, halogen, --CF.sub.3, --OH, --C.sub.1 -C.sub.10 alkyl, --S--C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxy, --CN, --NO.sub.2, --NH.sub.2, phenyl, --O-phenyl, --S-phenyl, benzyl, --O-benzyl, --S-benzyl; and a moiety of the formulae: ##STR70## Z is O or S; R.sub.6 is selected from the group consisting of H, --CF.sub.3, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxy, phenyl, --O-phenyl, --S-phenyl, benzyl, --O-benzyl, and --S-benzyl, the phenyl and benzyl rings of these group members being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxy, --CHO, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3, and --OH; R.sub.7 is selected from the group consisting of --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --N--(C.sub.1 -C.sub.6 alkyl).sub.2, --(CH.sub.2).sub.n --NH--(C.sub.1 -C.sub.6 alkyl), --CF.sub.3, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.5 cycloalkyl, C.sub.1 -C.sub.6 alkoxy, --NH--(C.sub.1 -C.sub.6 alkyl), --N--(C.sub.1 -C.sub.6 alkyl).sub.2, (CH.sub.2).sub.n phenyl, phenyl, --O -phenyl, benzyl, --O-benzyl, adamantyl, --(CH.sub.2).sub.n -phenyl-O-phenyl, --(CH.sub.2).sub.n -phenyl-CH.sub.2 -phenyl, --(CH.sub.2).sub.n --O-phenyl-CH.sub.2 -phenyl, and --(CH.sub.2).sub.n -phenyl-(O--CH.sub.2 -phenyl).sub.2, the rings of these group members being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --N.sub.2, --NO.sub.2, --CF.sub.3, CO.sub.2 H, and --OH; n is an integer from 0 to 3; R.sub.2 is selected from the group consisting of H, halogen, --CN, --CHO, --CF.sub.3, --OH, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxy, --CHO, --CN, --NO.sub.2, --NH.sub.2, --NH--C.sub.1 -C.sub.6 alkyl, --N(C.sub.1 -C.sub.6 alkyl).sub.2, --N--SO.sub.2 --C.sub.1 -C.sub.6 alkyl, and --SO.sub.2 --C.sub.1 -C.sub.6 alkyl; R.sub.3 is selected from the group consisting of --COOH, --C(O)--COOH, --(CH.sub.2).sub.n --C(O)--COOH, --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --CH.dbd.CH--COOH, ##STR71## and a moiety of the formulae --L.sup.1 --M.sup.1 ; wherein L.sup.1 is a bridging or linking moiety selected from a chemical bond, --(CH.sub.2).sub.n --, --S--, --O--, --SO.sub.2 --, --C(O)--, --CH.sub.2).sub.n --C(O)--, --(CH.sub.2).sub.n --C(O)--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.n --, --C(Z)--N(R.sub.6)--, --C(Z)--N(R.sub.6)--(CH.sub.2).sub.n --, --C(O)--C(Z)--N(R.sub.6)--, --C(O)--C(Z)--N(R.sub.6)--(CH.sub.2).sub.n --, --C(Z)--NH--SO.sub.2 --, --C(Z)--NH--SO.sub.2 --(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --S--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --SO--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --SO.sub.2 --(CH.sub.2).sub.n --, or --(CH.sub.2).sub.n --CH.dbd.CH--(CH.sub.2).sub.n --O--; n is an integer from 0 to 3; M.sup.1 is selected from the group consisting of --COOH, --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --C(O)--COOH, tetrazole, ##STR72## R.sub.8 is --COOH, --(CH.sub.2).sub.n --COOH, or --(CH.sub.2).sub.n --C(O)--COOH; R.sub.9 is H; R.sub.10 is H; n is an integer from 0 to 3; R.sub.4 is selected from the group consisting of H, --CF.sub.3, C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, C.sub.3 -C.sub.10 cycloalkyl, --C.sub.1 -C.sub.6 alkyl-C.sub.3 -C.sub.10 cycloalkyl, --CHO, halogen, and a moiety of the formula --L.sup.2 --M.sup.2 : L.sup.2 indicates a linking or bridging group of the formulae --(CH.sub.2).sub.n --, --S--, --O--, --C(O)--, --(CH.sub.2).sub.n --C(O)--, --(CH.sub.2).sub.n --C(O)--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n ----O--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --S--(CH.sub.2).sub.n --, C(O)C(O)X, or --(CH.sub.2).sub.n --N--(CH.sub.2).sub.n ; where X is O or N n is an integer from 0 to 3; M.sup.2 is selected from the group consisting of H, C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, C.sub.3 -C.sub.10 cycloalkyl, phenyl and benzyl, the cycloalkyl, phenyl and benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxy, --NO.sub.2, --NH.sub.2, --CN, and --CF.sub.3 ; R.sub.5 is a moiety of the formulae --(CH.sub.2).sub.n --A, wherein A is the moiety: ##STR73## wherein D is H; B and C are each phenyl, each optionally substituted by from 1 to 3 substituents selected from the group consisting of H, halogen, --CN, --CHO, --CF.sub.3, --OH, --C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --NH.sub.2, --N(C.sub.1 -C.sub.6).sub.2, --NH(C.sub.1 -C.sub.6), --N--C(O)--(C.sub.1 -C.sub.6), and --NO.sub.2 ; or a pharmaceutically acceptable salt thereof. 2. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sub.4 is hydrogen and R.sub.1, R.sub.2, R.sub.3, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, Z, L.sup.1, M.sup.1, L.sup.2, M.sup.2,n, Y, Z, B, C, and D are as described in claim 1. 3. A compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formulae: ##STR74## wherein R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, Z, L.sup.1, M.sup.1, L.sup.2, M.sup.2, n, Y, Z, B, C, and D are as defined in claim 1. ##STR75## 4. A compound of the formulae: wherein: R.sub.1 is selected from the group consisting of H, halogen, --CF.sub.3, --OH, --C.sub.1 -C.sub.10 alkyl, --S--C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxy, --CN, --NO.sub.2, --NH.sub.2, 13 HN(C.sub.1 -C.sub.6), --N(C.sub.1 -C.sub.6).sub.2, phenyl, --O-phenyl, --S-phenyl, benzyl, --O-benzyl, and --S-benzyl, the phenyl and benzyl rings of these group members being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3, and --OH; R.sub.2 is selected from the group consisting of H, halogen, --CF.sub.3, --OH, --C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxy, --CHO, --CN, --NO.sub.2, --NH.sub.2, --NH--C.sub.1 -C.sub.6 alkyl, --N(C.sub.1 -C.sub.6 alkyl).sub.2, --N--SO.sub.2 --C.sub.1 -C.sub.6 alkyl, and --SO.sub.2 --C.sub.1 -C.sub.6 alkyl; R.sub.3 is a moiety selected from the groups of: ##STR76## wherein L.sup.1 is a bridging or linking moiety selected from a chemical bond, --(CH.sub.2).sub.n' --, --(CH.sub.2).sub.n' --C(O)--(CH.sub.2).sub.n' --, --(CH.sub.2).sub.n' --O--(CH.sub.2).sub.n' --, --(CH.sub.2).sub.n' --S--(CH.sub.2).sub.n' --, --(CH.sub.2).sub.n' --SO--(CH.sub.2).sub.n', --(CH.sub.2).sub.n' --SO.sub.2 --(CH.sub.2).sub.n' --, and --(CH.sub.2).sub.n' --CH.dbd.CH--(CH.sub.2).sub.n --O--; where n' is an integer from 0 to 3; n in each instance is independently selected as an integer from 0 to 3; R.sub.4 is selected from H or --C.sub.1 -C.sub.6 alkyl; R.sub.5 is a moiety of the formulae --(CH.sub.2).sub.n --A, wherein A is the moiety: ##STR77## wherein D is H; B and C are phenyl, each optionally substituted by from 1 to 3 substituents selected from H, halogen, --CF.sub.3, --OH, --C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, and --NO.sub.2 ; or a pharmaceutically acceptable salt thereof. 5. A compound of the formulae: ##STR78## wherein: R.sub.1 is selected from the group consisting of H, halogen, --CF.sub.3, --OH, --CN, --NO.sub.2, --NH.sub.2, --HN(C.sub.1 -C.sub.6), --N(C.sub.1 -C.sub.6).sub.2, phenyl, --N--SO.sub.2 --C.sub.1 -C.sub.6 alkyl, and --SO.sub.2 --C.sub.1 -C.sub.6 alkyl; R.sub.2 is selected from the group consisting of H, halogen, --CF.sub.3, --OH, --CN, --NO.sub.2, --NH.sub.2, --NH--C.sub.1 -C.sub.6 alkyl, --N(C.sub.1 -C.sub.6 alkyl).sub.2, --N--SO.sub.2 --C.sub.1 -C.sub.6 alkyl, and --SO.sub.2 --C.sub.1 -C.sub.6 alkyl; R.sub.3 is a moiety selected from the groups of: ##STR79## wherein L.sup.1 is a bridging or linking moiety selected from a chemical bond, --(CH.sub.2).sub.n' --, --(CH.sub.2).sub.n' --C(O)--(CH.sub.2).sub.n', --(CH.sub.2).sub.n' --O--(CH.sub.2).sub.n' --, --(CH.sub.2).sub.n'--S--(CH.sub.2).sub.n' --, --(CH.sub.2).sub.n' --SO--(CH.sub.2).sub.n' --, --(CH.sub.2).sub.n' --SO.sub.2 --(CH.sub.2).sub.n' --, and --(CH.sub.2).sub.n' --CH.dbd.CH--(CH.sub.2).sub.n' --O--; n' in each instance is independently selected as an integer from 0 to 3; R.sub.4 is selected from the group consisting of H, --C.sub.1 -C.sub.6 alkyl, (CH.sub.2).sub.n C(O)NH.sub.2, --(CH.sub.2).sub.n --O--(C.sub.1 -C.sub.6 alkyl), --(CH.sub.2).sub.n --O--CH.sub.2 -phenyl, --(CH.sub.2).sub.n --N--(C.sub.1 -C.sub.6 alkyl), and --(CH.sub.2).sub.n --N--CH.sub.2 -phenyl, the phenyl rings of which are optionally substituted by 1 or 2 groups selected from H, halogen, --CF.sub.3 and --C.sub.1 -C.sub.6 alkyl; n is an integer from 0-3; or a pharmaceutically acceptable salt thereof. 6. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 7. A method for treating inflammation in a mammal, the method comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof. 8. The method of claim 7 wherein the inflammation is caused by arthritis. 9. The method of claim 7 wherein the inflammation is caused by inflammatory bowel diseases. 10. The method of claim 7 wherein the inflammation is caused by asthma. 11. A compound of claim 1 selected from the group consisting of: a) 4-[(1-benzhydryl-5-{[(butylamino)carbonyl]amino}-1H-indol-3-yl)methyl]-3-m ethoxybenzoic acid; b) 4-({1-benzhydryl-5-[(methylsulfonyl)amino]-1H-indol-3-yl}methyl)-3-methoxy benzoic acid; c) 4-({1-benzhydryl-5-[(cyclopentylcarbonyl)amino]-1H-indol-3-yl}methyl)-3-me thoxybenzoic acid; d) 4-[(1-benzhydryl-5-nitro-1H-indol-3-yl)methyl]-3-methoxybenzoic acid; e) 4-[(1-benzhydryl-5-fluoro-1H-indol-3-yl)methyl]-3-methoxybenzoic acid; f) 4-[(1-benzhydryl-5-methyl-1H-indol-3-yl)methyl]-3-methoxybenzoic acid; g) 4-[(1-benzhydryl-5-cyano-1H-indol-3-yl)methyl]-3-methoxybenzoic acid; and h) 4-{[1-benzhydryl-5-(methylsulfonyl)-1H-indol-3-yl]methyl}-3-methoxybenzoic acid; or a pharmaceutically acceptable salt thereof. 12. A compound of claim 1 selected from the group consisting of: a) 4-[(1-benzhydryl-5-nitro-1H-indol-3-yl)methyl]benzoic acid; b) 4-[(1-benzhydryl-5-bromo-1H-indol-3-yl)methyl]benzoic acid; and c) 4-[(1-benzhydryl-5-{[(cyclopentyloxy)carbonyl]amino}-1H-indol-3-yl)methyl] benzoic acid; or a pharmaceutically acceptable salt form thereof. 13. A compound of claim 1 selected from the group consisting of: a) N-{4-[(1-benzhydryl-5-bromo-1H-indol-3-yl)methyl]benzoyl}(trifluoro)methan esulfonamide; b) 3-[({1-benzhydryl-5-[(cyclopentylcarbonyl)amino]-1H-indol-3-yl}methyl)amin o]benzoic acid; c) 3-{1-benzhydryl-5-[(cyclopentylcarbonyl)amino]-1H-indol-3-yl}propanoic acid; and d) (E)-3-{1-benzhydryl-5-[(cyclopentylcarbonyl)amino]-1H-indol-3-yl}-2-propen oic acid; or a pharmaceutically acceptable salt form thereof. 14. A compound of claim 1 selected from the group consisting of: a) 4-{[1-benzhydryl-5-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)-1H-indol-3 -yl]methyl}-3-methoxybenzoic acid; b) 4-[(1-benzhydryl-5-{[(4-chloro-3-nitrophenyl)sulfonyl]amino}-1H-indol-3-yl )methyl]-3-methoxybenzoic acid; c) 4-[(1-benzhydryl-5-{[(dimethylamino)sulfonyl]amino}-1H-indol-3-yl)methyl]- 3-methoxybenzoic acid; d) 4-{[1-benzhydryl-5-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-1H-indol- 3-yl]methyl}-3-methoxybenzoic acid; e) 4-[(1-benzhydryl-5-{[(2-methylphenyl)sulfonyl]amino}-1H-indol-3-yl)methyl] -3-methoxybenzoic acid; f) 3-[({1-benzhydryl-5-[(cyclopentylcarbonyl)amino]-1H-indol-3-yl}carbonyl)am ino]benzoic acid; and g) 3-[({1-benzhydryl-5-[(cyclopentylcarbonyl)amino]-1H-indol-3-yl}carbonyl)am ino]propanoic acid; or a pharmaceutically acceptable salt form thereof. 15. A compound of claim 1: 2-{4-[(1-benzhydryl-6-chloro-1H-indol-3-yl)methyl]-2,6-dimethylphenoxy}acet ic acid; or a pharmaceutically acceptable salt thereof. 16. A compound of claim 1 selected from the group consisting of: a) 4-{[2-(1-benzhydryl-5-fluoro-2-methyl-1H-indol-3-yl)ethyl]sulfonyl}benzoic acid; and b) 4-{[2-(1-benzhydryl-6-chloro-2-methyl-1H-indol-3-yl)ethyl]sulfonyl}benzoic acid; or a pharmaceutically acceptable salt form thereof. 17. A compound of claim 1 selected from the group consisting of: a) 4-{[2-(1-benzhydryl-4,5-dichloro-2-methyl-1H-indol-3-yl)ethyl]sulfonyl}ben zoic acid; b) 4-{[2-(1-benzhydryl-5,6-dichloro-2-methyl-1H-indol-3-yl)ethyl]sulfonyl}ben zoic acid; c) 4-{[2-(1-benzhydryl-2-methyl-1H-indol-3-yl)ethyl]sulfonyl}benzoic acid; d) 4-{[2-(1-benzhydryl-5-methoxy-2-methyl-1H-indol-3-yl)ethyl]sulfonyl}benzoi c acid; e) 4-[2-(1-benzhydryl-5-bromo-2-methyl-1H-indol-3-yl)ethoxy]benzoic acid; f) 4-{[2-(1-benzhydryl-5-chloro-2-methyl-1H-indol-3-yl)ethyl]sulfanyl}benzoic acid; g) 4-{[2-(1-benzhydryl-5-chloro-2-methyl-1H-indol-3-yl)ethyl]sulfonyl}benzoic acid; i) 4-{[2-(1-benzhydryl-5-chloro-2-methyl-1H-indol-3-yl)ethyl]sulfinyl}benzoic acid; and j) 4-[2-(1-benzhydryl-5-chloro-2-methyl-1H-indol-3-yl)ethoxy]benzoic acid; or a pharmaceutically acceptable salt form thereof. 18. A compound of claim 1 selected from the group consisting of: a) 4-[2-(1-benzhydryl-5-chloro-2-formyl-1H-indol-3-yl)ethoxy]benzoic acid; b) 4-{2-[1-benzhydryl-5-chloro-2-(hydroxymethyl)-1H-indol-3-yl]ethoxy}benzoic acid; c) 4-{2-[1-benzhydryl-5-chloro-2-(methoxymethyl)-1H-indol-3-yl]ethoxy}benzoic acid; d) 4-(2-{1-benzhydryl-5-chloro-2-[(phenylsulfonyl)methyl]-1H-indol-3-yl}ethox y)benzoic acid; e) 4-(2-{1-benzhydryl-5-chloro-2-[(methylsulfonyl)methyl]-1H-indol-3-yl}ethox y)benzoic acid; f) 4-[2-(1-benzhydryl-5-chloro-2-{[(2-nitrobenzyl)oxy]methyl}-1H-indol-3-yl)e thoxy]benzoic acid; g) 4-[2-(1-benzhydryl-5-chloro-2-{[(2,6-difluorobenzyl)oxy]methyl}-1H-indol-3 -yl)ethoxy]benzoic acid; h) 4-({2-[1-benzhydryl-5-chloro-2-(hydroxymethyl)-1H-indol-3-yl]ethyl}sulfony l)benzoic acid; i) 4-(2-{1-benzhydryl-5-chloro-2-[(2-pyridinylmethoxy)methyl]-1H-indol-3-yl}e thoxy)benzoic acid; and j) 4-[2-(1-benzhydryl-5-chloro-2-{[(4-fluorobenzyl)oxy]methyl}-1H-indol-3-yl) ethoxy]benzoic acid; or a pharmaceutically acceptable salt thereof. 19. A compound of claim 1 selected from the group consisting of: a) 4-[2-(1-benzhydryl-5-chloro-2-{[(2,4-difluorobenzyl)oxy]methyl}-1H-indol-3 -yl)ethoxy]benzoic acid; b) 4-[2-(1-benzhydryl-5-chloro-2-{[(4-cynobenzyl)oxy]methyl}-1H-indol-3-yl)et hoxy]benzoic acid; c) 4-{2-[1-benzhydryl-5-chloro-2-({[(E)-3-phenyl-2-propenyl]oxy}methyl)-1H-in dol-3-yl)ethoxy]benzoic acid; d) 3-(4-{2-[1-benzhydryl-5-chloro-2-(hydroxymethyl)-1H-indol-3-yl]ethoxy}phen yl)propanoic acid; e) 3-[4-({2-[1-benzhydryl-5-chloro-2-(hydroxymethyl)-1H-indol-3-yl]ethyl}sulf onyl)phenyl]propanoic acid; f) 3-(4-{[2-(1-Benzhydryl-5-chloro-2-methyl-1H-indol-3-yl)ethyl]sulfonyl}phen yl)propanoic acid; g) 3-(4-{[2-(1-benzhydryl-5-chloro-2-methyl-1H-indol-3-yl)ethyl]sulfanyl}phen yl)propanoic acid; and h) 3-{4-[2-(1-Benzhydryl-5-chloro-2-methyl-1H-indol-3-yl)ethoxy]phenyl}propan oic acid; or a pharmaceutically acceptable salt thereof |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION The present invention relates to chemical inhibitors of the activity of various phospholipase enzymes, particularly phospholipase A.sub.2 enzymes. Leukotrienes and prostaglandins are important mediators of inflammation, each of which classes contributes to the development of an inflammatory response in a different way. Leukotrienes recruit inflammatory cells such as neutrophils to an inflamed site, promote the extravasation of these cells and stimulate release of superoxide and proteases which damage the tissue. Leukotrienes also play a pathophysiological role in the hypersensitivity experienced by asthmatics [See, e.g. B. Samuelson et al., Science, 237:1171-76 (1987)]. Prostaglandins enhance inflammation by increasing blood flow and therefore infiltration of leukocytes to inflamed sites. Prostaglandins also potentiate the pain response induced by stimuli. Prostaglandins and leukotrienes are unstable and are not stored in cells, but are instead synthesized [W. L. Smith, Biochem. J., 259:315-324 (1989)] from arachidonic acid in response to stimuli. Prostaglandins are produced from arachidonic acid by the action of COX-1 and COX-2 enzymes. Arachidonic acid is also the substrate for the distinct enzyme pathway leading to the production of leukotrienes. Arachidonic acid which is fed into these two distinct inflammatory pathways is released from the sn-2 position of membrane phospholipids by phospholipase A.sub.2 enzymes (hereinafter PLA.sub.2). The reaction catalyzed by PLA.sub.2 is believed to represent the rate-limiting step in the process of lipid mediated biosynthesis and the production of inflammatory prostaglandins and leukotrienes. When the phospholipid substrate of PLA.sub.2 is of the phosphotidyl choline class with an ether linkage in the sn-1 position, the lysophospholipid produced is the immediate precursor of platelet activating factor (hereafter called PAF), another potent mediator of inflammation [S. I. Wasserman, Hospital Practice, 15:49-58 (1988)]. Most anti-inflammatory therapies have focussed on preventing production of either prostglandins or leukotrienes from these distinct pathways, but not on all of them. For example, ibuprofen, aspirin, and indomethacin are all NSAIDs which inhibit the production of prostaglandins by COX-1/COX-2, but have no effect on the inflammatory production of leukotrienes from arachidonic acid in the other pathways. Conversely, zileuton inhibits only the pathway of conversion of arachidonic acid to leukotriense, without affecting the production of prostaglandins. None of these widely-used anti-inflammatory agents affects the production of PAF. Consequently the direct inhibition of the activity of PLA.sub.2 has been suggested as a useful mechanism for a therapeutic agent, i.e., to interfere with the inflammatory response. [See, e.g., J. Chang et al, Biochem. Pharmacol., 36:2429-2436 (1987)]. A family of PLA.sub.2 enzymes characterized by the presence of a secretion signal sequenced and ultimately secreted from the cell have been sequenced and structurally defined. These secreted PLA.sub.2 s have an approximately 14 kD molecular weight and contain seven disulfide bonds which are necessary for activity. These PLA.sub.2 s are found in large quantities in mammalian pancreas, bee venom, and various snake venom. [See, e.g., references 13-15 in Chang et al, cited above; and E. A. Dennis, Drug Devel. Res., 10:205-220 (1987).] However, the pancreatic enzyme is believed to serve a digestive function and, as such, should not be important in the production of the inflammatory mediators whose production must be tightly regulated. The primary structure of the first human non-pancreatic PLA.sub.2 has been determined. This non-pancreatic PLA.sub.2 is found in platelets, synovial fluid, and spleen and is also a secreted enzyme. This enzyme is a member of the aforementioned family. [See, J. J. Seilhamer et al, J. Biol. Chem., 264:5335-5338 (1989); R. M. Kramer et al, J. Biol. Chem., 264:5768-5775 (1989); and A. Kando et al, Biochem. Biophys. Res. Comm., 163:42-48 (1989)]. However, it is doubtful that this enzyme is important in the synthesis of prostaglandins, leukotrienes and PAF, since the non-pancreatic PLA.sub.2 is an extracellular protein which would be difficult to regulate, and the next enzymes in the biosynthetic pathways for these compounds are intracellular proteins. Moreover, there is evidence that PLA.sub.2 is regulated by protein kinase C and G proteins [R. Burch and J. Axelrod, Proc. Natl. Acad. Sci. U.S.A., 84:6374-6378 (1989)] which are cytosolic proteins which must act on intracellular proteins. It would be impossible for the non-pancreatic PLA.sub.2 to function in the cytosol, since the high reduction potential would reduce the disulfide bonds and inactivate the enzyme. A murine PLA.sub.2 has been identified in the murine macrophage cell line, designated RAW 264.7. A specific activity of 2 mols/min/mg, resistant to reducing conditions, was reported to be associated with the approximately 60 kD molecule. However, this protein was not purified to homogeneity. [See, C. C. Leslie et al, Biochem. Biophys. Acta., 963:476-492 (1988)]. The references cited above are incorporated by reference herein for information pertaining to the function of the phospholipase enzymes, particularly PLA.sub.2. A cytosolic phospholipase A.sub.2 (hereinafter "cPLA.sub.2 ") has also been identified and cloned. See, U.S. Pat. Nos. 5,322,776 and 5,354,677, which are incorporated herein by reference as if fully set forth. The enzyme of these patents is an intracellular PLA.sub.2 enzyme, purified from its natural source or otherwise produced in purified form, which functions intracellularly to produce arachidonic acid in response to inflammatory stimuli. It is now desirable to identify pharmaceutically useful compounds which inhibit the actions of these phospholipase enzymes for use in treating or preventing inflammatory conditions, particularly where inhibition of production of prostaglandins, leukotrienes and PAF are all desired results. There remains a need in the art for an identification of such anti-inflammatory agents for therapeutic use in a variety of disease states. Numerous pieces of evidence have supported the central role of cPLA.sub.2 in lipid mediator biosynthesis: cPLA.sub.2 is the only enzyme which is highly selective for phospholipids containing arachidonic acid in the sn-2 position (Clark et al., 1991, 1995; Hanel & Gelb, 1993); activation of cPLA.sub.2 or its increased expression have been linked with increased leukotriene and prostaglandin synthesis (Lin et al., 1992a, 1992b, 1993); and following activation, cPLA.sub.2 translocates to the nuclear membrane, where it is co-localized with the cyclooxygenase and lipoxygenase that metabolize arachidonate to prostaglandins and leukotrienes (Schievella et al., 1995; Glover et al., 1995). Although these data are compelling, the most definitive evidence for the central role of cPLA.sub.2 in eicosanoid and PAF production came from mice made deficient in cPLA.sub.2 through homologous recombination (Uozumi et al., 1997; Bonventre et al., 1997). Peritoneal macrophages derived from these animals failed to make leukotrienes, prostaglandins, or PAF. The cPLA.sub.2 deficient mice have also been informative of the role of cPLA.sub.2 in disease, since these mice are resistant to bronchial hyperreactivity in an anaphylaxis model used to mimic asthma (Uozumi et al., 1997). Thus, despite the size of the phospholipase A.sub.2 superfamily, cPLA.sub.2 is essential for prostaglandin, leukotriene, and PAF production. Clark, J. D., Lin, L.-L., Kriz, R. W., Ramesha, C. S., Sultzman, L. A., Lin, A. Y., Milona, N., and Knopf, J. L. (1991). A novel arachidonic acid-selective cytosolic PLA.sub.2 contains a Ca.sup.2+ -dependent translocation domain with homology to PKC and GAP. Cell 65,1043-1051. Hanel, A. M., and Gelb, M. H. (1993). Processive interfacial catalysis by mammalian 85-kilodalton phospholipase A.sub.2 enzymes on product-containing vesicles: application to the determination of substrate preferences. Biochemistry 32, 5949-5958. Lin, L.-L., Lin, A. Y., and DeWitt, D. L. (1992a) IL-1_ induces the accumulation of cPLA2 and the release of PGE.sub.2 in human fibroblasts. J. Biol. Chem. 267, 23451-23454. Lin, L.-L., Lin, A. Y., and Knopf, J. L. (1992b) Cytosolic phospholipase A.sub.2 is coupled to hormonally regulated release of arachidonic acid. Proc. Natl. Acad. Sci. USA 89, 6147-6151. Lin, L.-L., Wartmann, M., Lin, A. Y., Knopf, J. L., Seth, A., and Davis, R. J. (1993) cPLA.sub.2 is phosphorylated and activated by MAP kinase. Cell 72, 269-278. Glover, S., de Carvalho, M., Bayburt, T., Jonas, M., Chi, E., Leslie, E., and Gelb, M. (1995) Translocation of the 85-kDa phospholipase A.sub.2 from cytosol to the nuclear envelope in rat basophilic leukemia cells stimulated with calcium ionophore or IgE/antigen. J. Biol. Chem. 270, 15359-15367. Schievella, A. R., Regier, M. K., Smith, W. L., and Lin, L.-L. (1995). Calcium-mediated translocation of cytosolic phospholipase A.sub.2 to the nuclear envelope and endoplasmic reticulum. J. Biol. Chem. 270, 30749-30754. Uozumi, N., Kume, K., Nagase, T., Nakatani, N., Ishii, S., Tashiro, F., Komagata, Y., Maki, K., Ikuta, K., Ouchi, Y., Miyazaki, J.-i., & Shimizu, T. (1997). Role of cytosolic phospholipase A.sub.2 in allergic response and parturition. Nature 390, 618-622. Bonventre, J. V., Huang, Z., Reza Taheri, M., O'Leary, E., Li, E., Moskowitz, M. A., and Sapirstein, A. (1997) Reduced fertility and postischaeric brain injury in mice deficient in cytosolic phospholipase A.sub.2. Nature 390, 622-625. SUMMARY OF THE INVENTION Compounds of this invention have the following formulae: ##STR2## wherein: R.sub.1 and R.sub.1, are independently selected from H, halogen, --CF.sub.3, --OH, --C.sub.1 -C.sub.10 alkyl, preferably --C.sub.1 -C.sub.6 alkyl, --S--C.sub.1 -C.sub.10 alkyl, preferably --S--C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CN, --NO.sub.2, --NH.sub.2, phenyl, --O-phenyl, --S-phenyl, benzyl, --O-benzyl, --S-benzyl; or a ring moiety of the groups a), b) or c), below, directly bonded to the indole ring or bonded to the indole ring by a --S--, --O-- or --(CH.sub.2).sub.n -- bridge; a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3 ; or b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CHO, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3 or --OH; or c) a bicyclic ring moiety optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CHO, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3 or --OH; or d) a moiety of the formulae: ##STR3## Z is O or S; R.sub.6 is selected from the relevant members of the group H, --CF.sub.3, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, phenyl, --O-phenyl, --S-phenyl, benzyl, --O-benzyl, or --S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CHO, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3, or --OH; R.sub.7 is selected from --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --N--(C.sub.1 -C.sub.6 alkyl).sub.2, --(CH.sub.2)--NH--(C.sub.1 -C.sub.6 alkyl), --CF.sub.3, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.5 cycloalkyl, C.sub.1 -C.sub.6 alkoxy, --NH--(C.sub.1 -C.sub.6 alkyl), --N--(C.sub.1 -C.sub.6 alkyl).sub.2, pyridinyl, thienyl, furyl, pyrrolyl, quinolyl, (CH.sub.2).sub.n phenyl, phenyl, --O-phenyl, benzyl, --O-benzyl, adamantyl, or morpholinyl, --(CH.sub.2).sub.n -phenyl-O-phenyl, --(CH.sub.2).sub.n -phenyl-CH.sub.2 -phenyl, --(CH.sub.2).sub.n -O-phenyl-CH.sub.2 -phenyl, --(CH.sub.2).sub.n -phenyl-(O--CH.sub.2 -phenyl).sub.2, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --NH.sub.2, --NO.sub.2, --CF.sub.3,CO.sub.2 H, or --OH; or a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --NO.sub.2, --NH.sub.2, --CN, or --CF.sub.3 ; or b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CHO, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3 or --OH; or c) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CHO, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3 or --OH; n is an integer from 0 to 3; R.sub.2 is selected from H, halogen, --CN, --CHO, --CF.sub.3, --OH, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CHO, --CN, --NO.sub.2, --NH.sub.2, --NH--C.sub.1 -C.sub.6 alkyl, --N(C.sub.1 -C.sub.6 alkyl).sub.2, --N--SO.sub.2 --C.sub.1 -C.sub.6 alkyl, or --SO.sub.2 --C.sub.1 -C.sub.6 alkyl; R.sub.3 is selected from --COOH, --C(O)--COOH, --(CH.sub.2).sub.n --C(O)--COOH, --(CH.sub.2).sub.n --COOH, (CH.sub.2).sub.n --CH.dbd.CH--COOH, --(CH.sub.2).sub.n -tetrazole, ##STR4## or a moiety selected from the formulae --L.sup.1 --M.sup.1 ; wherein L.sup.1 is a bridging or linking moiety selected from a chemical bond, --(CH.sub.2).sub.n --, --S--, --O--, --SO.sub.2 --, --C(O)--, --(CH.sub.2).sub.n --C(O)--, --(CH.sub.2).sub.n --C(O)--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.n --, --C(Z)--N(R.sub.6)--, --C(Z)--N(R.sub.6)--(CH.sub.2).sub.n --, --C(O)--C(Z)--N(R.sub.6)--, --C(O)--C(Z)--N(R.sub.6)--(CH.sub.2).sub.n --, --C(Z)--NH--SO.sub.2 --, --C(Z)--NH--SO.sub.2 --(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --S--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --SO--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --SO.sub.2 --(CH.sub.2).sub.n --, or --(CH.sub.2).sub.n --CH.dbd.CH--(CH.sub.2).sub.n --O--; n is an integer from 0 to 3 M.sup.1 is selected from the group of --COOH, --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --C(O)--COOH, tetrazole, ##STR5## R.sub.8, in each appearance, is independently selected from H, --COOH, --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --C(O)--COOH, tetrazole, --C(O)--NH.sub.2, --(CH.sub.2).sub.n --C(O)--NH.sub.2, ##STR6## R.sub.9 is selected from H, halogen, --CF.sub.3, --OH, --COOH, --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --C(O)--COOH, --C.sub.1 -C.sub.6 alkyl, --O--C.sub.1 -C.sub.6 alkyl, --O--(CH.sub.2).sub.n --COOH, --O--CH.sub.2 --C.dbd.C--COOH, --O--C.dbd.C--CH.sub.2 --COOH, --NH(C.sub.1 -C.sub.6 alkyl), --N(C.sub.1 -C.sub.6 alkyl).sub.2, --N--C(O)--(CH.sub.2).sub.n --COOH, --N--SO.sub.2 --(CH.sub.2).sub.n --COOH, --C(O)--N--(CH.sub.2).sub.n --COOH; R.sub.10 is selected from the group of H, halogen, --CF.sub.3, --OH, --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --C(O)--COOH, --C.sub.1 -C.sub.6 alkyl, --O--C.sub.1 -C.sub.6 alkyl, --O--(C.sub.1 -C.sub.6 alkyl)--(OH).sub.n, --NH(C.sub.1 -C.sub.6 alkyl), --N(C.sub.1 -C.sub.6 alkyl).sub.2, --N--C(O)--N--(C.sub.1 -C.sub.6 alkyl)-(OH).sub.2, ##STR7## R.sub.11 is selected from H, C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 cycloalkyl, --CF.sub.3, --COOH, --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --C(O)--COOH, ##STR8## with a proviso that the complete moiety at the indole or indoline 3-position created by any combination of R.sub.3, L.sup.1, M, R.sub.8, R.sub.9, R.sub.10, and/or R.sub.11 shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: --C(O)--NH.sub.2, --(CH.sub.2).sub.n --C(O)--NH.sub.2, ##STR9## n is an integer from 0 to 3; R.sub.4 is selected from H, --CF.sub.3, C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, C.sub.3 -C.sub.10 cycloalkyl, --C.sub.1 -C.sub.6 alkyl-C.sub.3 --C.sub.10 cycloalkyl, --CHO, halogen, or a moiety of the formula --L.sup.2 --M.sup.2 : L.sup.2 indicates a linking or bridging group of the formulae --(CH.sub.2).sub.n --, --S--, --O--, --C(O)--, --(CH.sub.2).sub.n --C(O)--, --(CH.sub.2).sub.n --C(O)--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.n --, or --(CH.sub.2).sub.n --S--(CH.sub.2).sub.n --, C(O)C(O)X, or --(CH.sub.2).sub.n --N--(CH.sub.2).sub.n ; where X is O or N n is an integer from 0 to 3 M.sup.2 is selected from: a) H, the group of C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, C.sub.3 -C.sub.10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --NO.sub.2, --NH.sub.2, --CN, or --CF.sub.3 ; or b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --NO.sub.2, --NH.sub.2, --CN, or --CF.sub.3 ; or c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CHO, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3 or --OH; or d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 0 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 0 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CHO, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3 or --OH; R.sub.5 is selected from C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, --(CH.sub.2).sub.n --C.sub.3 -C.sub.10 cycloalkyl, --(CH.sub.2).sub.n --S--(CH.sub.2).sub.n --C.sub.3 -C.sub.10 cycloalkyl, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.n --C.sub.1 -C.sub.10 cycloalkyl, or the groups of: a) --(CH.sub.2).sub.n -phenyl-O-phenyl, --(CH.sub.2).sub.n -phenyl-CH.sub.2 -phenyl, --(CH.sub.2).sub.n --O--phenyl-CH.sub.2 -phenyl, --(CH.sub.2).sub.n -phenyl-(O--CH.sub.2 -phenyl).sub.2, --CH-phenyl-C(O)-benzothiazole or a moiety of the formulae: ##STR10## wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C.sub.3 -C.sub.6 cycloalkyl, phenyl, biphenyl, each optionally substituted by from 1 to 3 groups selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --NO.sub.2, --NH.sub.2, --CN, or --CF.sub.3 ; or a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3, or by one phenyl ring, the phenyl ring being optionally substituted by by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3 ; or b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CHO, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3 or --OH; or c) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CHO, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3 or --OH; d) a moiety of the formulae --(CH.sub.2).sub.n --A, --(CH.sub.2).sub.n --S--A, or --(CH.sub.2).sub.n --O--A, wherein A is the moiety: ##STR11## wherein D is H, C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, --CF.sub.3 or --(CH.sub.2).sub.n --CF.sub.3 ; B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, --CN, --CHO, --CF.sub.3, --OH, --C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --NH.sub.2, --N(C.sub.1 -C.sub.6).sub.2, --NH(C.sub.1 -C.sub.6), --N--C(O)--(C.sub.1 -C.sub.6), --NO.sub.2, or by a 5- or 6-membered heterocyclic or heteroaromatic ring containing 1 or 2 heteroatoms selected from O, N or S, such as, for example, morpholino; or a pharmaceutically acceptable salt thereof. One group of compounds within this invention are those in which the indole or indoline 2-position (R.sub.4) is substituted only by hydrogen and the substituents at the other indole or indoline positions are as described above. Another R.sub.3 is --L.sup.1 --M.sup.1, wherein L.sup.1 is as defined above, more preferably wherein L.sup.1 is a chemical bond, and M.sup.1 is the moiety: ##STR12## and R.sub.9 is as defined in the broad genus above. Another group of this invention comprises compounds in which R.sub.2 and R.sub.4 are hydrogen and the groups at R.sub.1, R.sub.1', R.sub.3, and R.sub.5 are as defined above. Within this group are two further preferred groups. In the first, R.sub.1 is in the indole or indoline 5 position and in the second R.sub.1 is in the indole or indoline 6 position. In a further preferred group herein, R.sub.1 is in the indole or indoline 5-position and is benzyloxy, R.sub.2 and R.sub.4 are hydrogen and R.sub.3 and R.sub.4 are as defined above. Among the more preferred compounds of this invention are those of the following formulae: ##STR13## wherein: R.sub.1 is selected from H, halogen, --CF.sub.3, --OH, --C.sub.1 -C.sub.10 alkyl, preferably --C.sub.1 -C.sub.6 alkyl, --S--C.sub.1 -C.sub.10 alkyl, preferably --S--C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CN, --NO.sub.2, --NH.sub.2, phenyl, --O-phenyl, --S-phenyl, benzyl, --O-benzyl, --S-benzyl or a moiety of the formulae: ##STR14## R.sub.6 is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, phenyl, --O-phenyl, benzyl, --O-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3, or --OH; R.sub.7 is selected from --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --N--(C.sub.1 -C.sub.6 alkyl).sub.2, --(CH.sub.2).sub.n --NH--(C.sub.1 -C.sub.6 alkyl), --CF.sub.3, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.5 cycloalkyl, C.sub.1 -C.sub.6 alkoxy, --NH--(C.sub.1 -C.sub.6 alkyl), --N--(C.sub.1 -C.sub.6 alkyl).sub.2, pyridinyl, thienyl, furyl, pyrrolyl, quinolyl, (CH.sub.2).sub.n phenyl, phenyl,--O-phenyl, benzyl, --O-benzyl, adamantyl, or morpholinyl, --(CH.sub.2).sub.n -phenyl-O-phenyl, --(CH.sub.2).sub.n -phenyl-CH.sub.2 -phenyl, --(CH.sub.2).sub.n --O-phenyl-CH.sub.2 -phenyl, --(CH.sub.2).sub.n -phenyl-(O--CH.sub.2 -phenyl).sub.2, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --NH.sub.2, --NO.sub.2, --CF.sub.3,CO.sub.2 H, or --OH; R.sub.2 is selected from H, halogen, --CF.sub.3, --OH, --C.sub.1 -C.sub.10 alkyl, preferably --C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CHO, --CN, --NO.sub.2, --NH.sub.2, --NH--C.sub.1 -C.sub.6 alkyl, --N(C.sub.1 -C.sub.6 alkyl).sub.2, --N--SO.sub.2 --C.sub.1 -C.sub.6 alkyl, or --SO.sub.2 --C.sub.1 -C.sub.6 alkyl; R.sub.3 is selected from --COOH, --C(O)--COOH, --(CH.sub.2).sub.n --C(O)--COOH, --(CH.sub.2).sub.n --COOH, --CH.dbd.CH--COOH, --(CH.sub.2).sub.n --tetrazole, ##STR15## or a moiety selected from the formulae --L.sup.1 --M.sup.1 ; wherein L.sup.1 is a bridging or linking moiety selected from a chemical bond, --S--, --O--, --(CH.sub.2).sub.n --, --SO.sub.2 --, --C(O)--, --(CH.sub.2).sub.n --C(O)--, --(CH.sub.2).sub.n --C(O)--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --S--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --SO--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --SO.sub.2 --(CH.sub.2).sub.n --, or --(CH.sub.2).sub.n --CH.dbd.CH--(CH.sub.2).sub.n --O--; --C(Z)--N(R.sub.6)--, --C(Z)--N(R.sub.6)--(CH.sub.2).sub.n --, --C(O)--C(Z)--N(R.sub.6)--, --C(O)--C(Z)--N(R.sub.6)--(CH.sub.2).sub.n --, --C(Z)--NH--SO.sub.2 --, or --C(Z)--NH--SO.sub.2 --(CH.sub.2).sub.n --; n is an integer from 0 to 3 M.sup.1 is selected from the group of --COOH, --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --C(O)--COOH, tetrazole, ##STR16## R.sub.8, in each appearance, is independently selected from H, --COOH, --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --C(O)--COOH, tetrazole, ##STR17## R.sub.9 is selected from H, halogen, --CF.sub.3, --OH, --COOH, --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --C(O)--COOH, --C.sub.1 -C.sub.6 alkyl, --O--C.sub.1 C.sub.6 alkyl, --NH(C.sub.1 -C.sub.6 alkyl), or --N(C.sub.1 -C.sub.6 alkyl).sub.2 ; R.sub.10 is selected from the group of H, halogen, --CF.sub.3, --OH, --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --C(O)--COOH, --C.sub.1 -C.sub.6 alkyl, --O--C.sub.1 -C.sub.6 alkyl, --NH(C.sub.1 -C.sub.6 alkyl), --N(C.sub.1 -C.sub.6 alkyl).sub.2, ##STR18## R.sub.11 is selected from H, C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 cycloalkyl, --CF.sub.3, --COOH, --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --C(O)--COOH, ##STR19## with a proviso that the complete moiety at the indole or indoline 3-position created by any combination of R.sub.3, L.sup.1, M.sup.1, R.sub.8, R.sub.9, R.sub.10, and/or R.sub.11 shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: --C(O)--NH.sub.2, --(CH.sub.2).sub.n --C(O)--NH.sub.2, ##STR20## n is an integer from 0 to 3; R.sub.4 is selected from H, --CF.sub.3, C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, C3-C.sub.10 cycloalkyl, --C.sub.1 -C.sub.6 alkyl-C.sub.3 -C.sub.10 cycloalkyl, --CHO, halogen, or a moiety of the formula --L.sup.2 --M.sup.2 : L.sup.2 indicates a linking or bridging group of the formulae --(CH.sub.2).sub.n --, --S--, --O--, --C(O)--, --(CH.sub.2).sub.n --C(O)--, --(CH.sub.2).sub.n --C(O)--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.n --, or --(CH.sub.2).sub.n --S--(CH.sub.2).sub.n --; M.sup.2 is selected from the group of H, C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, C.sub.3 -C.sub.10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --NO.sub.2, --NH.sub.2, --CN, or --CF.sub.3 ; or a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --NO.sub.2, --NH.sub.2, --CN, or --CF.sub.3 ; or b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to pyridine, pyrimidine, piperidine, piperazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CHO, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3 or --OH; or c) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, indole, indoline, napthalene, purine, or quinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CHO, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3 or --OH; n is an integer from 0 to 3 R.sub.5 is selected from C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, --(CH.sub.2).sub.n --C.sub.3 -C.sub.10 cycloalkyl, --(CH.sub.2).sub.n --S--(CH.sub.2).sub.n --C.sub.3 -C.sub.10 cycloalkyl, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.n --C.sub.3 -C.sub.10 cycloalkyl, or the groups of: a) --(CH.sub.2).sub.n -phenyl-O-phenyl, --(CH.sub.2).sub.n -phenyl-CH.sub.2 -phenyl, --(CH.sub.2).sub.n --O-phenyl-CH.sub.2 -phenyl, --(CH.sub.2).sub.n -phenyl-(O--CH.sub.2 -phenyl).sub.2, --CH.sub.2 -phenyl-C(O)-benzothiazole or a moiety of the formulae: ##STR21## wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C.sub.3 --C.sub.5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl, benzothiazole and pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, --CF.sub.3, --OH, --C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --CN, --NH.sub.2, --NO.sub.2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O; or b) a moiety of the formulae --(CH.sub.2).sub.n --A, --(CH.sub.2).sub.n --S--A, or --(CH.sub.2).sub.n --O--A, wherein A is the moiety: ##STR22## wherein D is H, C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, --CF.sub.3 or --(CH.sub.2).sub.n --CF.sub.3 ; B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, --CF.sub.3, --OH, --C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --NH.sub.2 or --NO.sub.2 ; or a pharmaceutically acceptable salt thereof. One group of compounds within this invention are those in which the indole or indoline 2-position (R.sub.4) is substituted only by hydrogen and the substituents at the other indole or indoline positions are as described above. In an another preferred group of this invention R.sub.1 is in the indole or indoline 5 or 6 position and is cyclopentylcarboxamide or cyclopentyloxycarbonylamino, R.sub.2 and R.sub.4 are hydrogen, and R.sub.3 and R.sub.5 are as defined above. A further preferred group of this invention consists of R.sub.1 and R.sub.2 at the indole or indoline 5 and or 6 position and are each selected from the group consisting of C.sub.1 -C.sub.6 alkoxy, cyano, sulfonyl and halo, R.sub.2 and R.sub.4 are hydrogen, and R.sub.3 and R.sub.5 are as defined above. Another group of this invention comprises compounds in which R.sub.2 and R.sub.4 are hydrogen and the groups at R.sub.1, R.sub.3, and R.sub.5 are as defined above. Within this group are two further preferred groups. In the first, R.sub.1 is in the indole or indoline 5 position and in the second R.sub.1 is in the indole or indoline 6 position. In a further preferred group herein, R.sub.1 is in the indole or indoline 5-position and is benzyloxy, R.sub.2 and R.sub.4 are hydrogen and R.sub.3 and R.sub.5 are as defined above. A preferred group of compounds of this invention have the following formulae: ##STR23## wherein: R.sub.1 is selected form H, halogen, --CF.sub.3, --OH, --C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --NO.sub.2, --NH.sub.2, CN, phenyl, --O-phenyl, benzyl, --O-benzyl, --S-benzyl or a moiety of the formulae: ##STR24## R.sub.6 is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, phenyl, --O-phenyl, benzyl, --O-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --NH.sub.2, --NO.sub.2, --CF.sub.3, or --OH; R.sub.7 is selected from --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --N--(C.sub.1 -C.sub.6 alkyl).sub.2, --(CH.sub.2).sub.n --NH--(C.sub.1 -C.sub.6 alkyl), --CF.sub.3, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.5 cycloalkyl, C.sub.1 -C.sub.6 alkoxy, --NH--(C.sub.1 -C.sub.6 alkyl), --N--(C.sub.1 -C.sub.6 alkyl).sub.2, pyridinyl, thienyl, furyl, pyrrolyl, quinolyl, (CH.sub.2).sub.n phenyl, phenyl,--O-phenyl, benzyl, --O-benzyl, adamantyl, or morpholinyl, --(CH.sub.2).sub.n -phenyl-O-phenyl, --(CH.sub.2).sub.n -phenyl-CH.sub.2 -phenyl, --(CH.sub.2).sub.n --O-phenyl-CH.sub.2 -phenyl, --(CH.sub.2).sub.n -phenyl-(O--CH.sub.2 -phenyl).sub.2, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 --C.sub.6 alkoxy, --NH2, --NO.sub.2, --CF.sub.3,CO.sub.2 H, or --OH; R.sub.2 is selected from H, halogen, --CN, --CHO, --CF.sub.3, --OH, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CHO, --CN, --NO.sub.2, --N.sub.2, --NH--C.sub.1 -C.sub.6 alkyl, --N(C.sub.1 -C.sub.6 alkyl).sub.2, --N--SO.sub.2 --C.sub.1 -C.sub.6 alkyl, or --SO.sub.2 --C.sub.1 -C.sub.6 alkyl; R.sub.3 is selected from --COOH, --C(O)--COOH, --(CH.sub.2).sub.n --C(O)--COOH, --(CH.sub.2).sub.n --COOH, --CH.dbd.CH--COOH, --(CH.sub.2).sub.n --tetrazole, ##STR25## or a moiety selected from the formulae --L.sup.1 --M.sup.1 ; wherein L.sup.1 is a bridging or linking moiety selected from a chemical bond, --S--, --O--, --C(O)--, --(CH.sub.2).sub.n --, --SO.sub.2 --, --C(O)--, --(CH.sub.2).sub.n --C(O)--, --(CH.sub.2).sub.n --C(O)--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.n --,--(CH.sub.2).sub.n --S--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --SO--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --SO.sub.2 --(CH.sub.2).sub.n --, or --(CH.sub.2).sub.n --CH.dbd.CH--(CH.sub.2).sub.n --O--; --C(Z)--N(R.sub.6)--, --C(Z)--N(R.sub.6)--(CH.sub.2).sub.n ----C(O)--C(Z)--N(R.sub.6)--, --C(O)--C(Z)--N(R.sub.6)--(CH.sub.2).sub.n --, --C(Z)--NH--SO.sub.2 --, or --C(Z)--NH--SO.sub.2 --(CH.sub.2).sub.n --; n is an integer from 0 to 3 M.sup.1 is selected from the group of --COOH, --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --C(O)--COOH, tetrazole, ##STR26## R.sub.8, in each appearance, is independently selected from H, --COOH, --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --C(O)--COOH, tetrazole, ##STR27## R.sub.9 is selected from H, halogen, --CF.sub.3, --OH, --COOH, --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --C(O)--COOH, --C.sub.1 -C.sub.6 alkyl, --O--C.sub.1 -C.sub.6 alkyl, --NH(C.sub.1 -C.sub.6 alkyl), --N(C.sub.1 -C.sub.6 alkyl).sub.2 ; R.sub.10 is selected from the group of H, halogen, --CF.sub.3, --OH, --COOH, --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --C(O)--COOH, --C.sub.1 -C.sub.6 alkyl, --O--C.sub.1 -C.sub.6 alkyl, --NH(C.sub.1 -C.sub.6 alkyl), --N(C.sub.1 -C.sub.6 alkyl).sub.2, ##STR28## R.sub.11 is selected from H, C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 cycloalkyl, --CF.sub.3, --COOH, --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --C(O)--COOH, ##STR29## with a proviso that the complete moiety at the indole or indoline 3-position created by any combination of R.sub.3, L.sup.1, M.sup.1, R.sub.8, R.sub.9, R.sub.10, and/or R.sub.11 shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: --C(O)--NH.sub.2, --(CH.sub.2).sub.n --C(O)--NH.sub.2, ##STR30## n is an integer from 0 to 3; R.sub.4 is selected from H, --CF.sub.3, C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, C.sub.3 -C.sub.10 cycloalkyl, --C.sub.1 -C.sub.6 alkyl-C.sub.3 -C.sub.10 cycloalkyl, --CHO, halogen, or a moiety of the formula --L.sup.2 --M.sup.2 : L.sup.2 indicates a linking or bridging group of the formulae --(CH.sub.2).sub.n --, --S--, --O--, --C(O)--, --(CH.sub.2).sub.n --C(O)--, --(CH.sub.2).sub.n --C(O)--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.n --, or --(CH.sub.2).sub.n --S--(CH.sub.2).sub.n --; M.sup.2 is selected from: a) H, the group of C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, C.sub.3 -C.sub.10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --NO.sub.2, --NH.sub.2, --CN, or --CF.sub.3 ; or b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, pyrazole, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --NO.sub.2, --NH.sub.2, --CN, or --CF.sub.3 ; or c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyridine, pyrazine, pyrimidine, piperidine, piperazine, thiazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CHO, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3 or --OH; or d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CHO, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3 or --OH; R.sub.5 is selected from C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, --(CH.sub.2).sub.n --C.sub.3 -C.sub.5 cycloalkyl, --(CH.sub.2).sub.n --S--(CH.sub.2).sub.n --C.sub.1 -C.sub.5 cycloalkyl, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.n --C.sub.3 -C.sub.5 cycloalkyl, or the groups of: a) --(CH.sub.2).sub.n -phenyl-O-phenyl, --(CH.sub.2).sub.n -phenyl-CH.sub.2 -phenyl, --(CH.sub.2).sub.n --O-phenyl-CH.sub.2 -phenyl, --(CH.sub.2).sub.n -phenyl-(O--CH.sub.2 -phenyl).sub.2, --CH.sub.2 -phenyl-C(O)-benzothiazole or a moiety of the formulae: ##STR31## wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C.sub.3 -C.sub.5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl benzothiazole or pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, --CF.sub.3, --OH, --C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --NO.sub.2, --NH.sub.2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O; or b) a moiety of the formulae --(CH.sub.2).sub.n --A, --(CH.sub.2).sub.n --S--A, or --(CH.sub.2).sub.n --O--A, wherein A is the moiety: ##STR32## wherein D is H, C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, --(CH.sub.2).sub.n --CF.sub.3 or --CF.sub.3 ; B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, --CF.sub.3, --OH, --C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --NH.sub.2 or --NO.sub.2 ; or a pharmaceutically acceptable salt thereof. A preferred group among the compounds above are those in which the R.sub.1 substitution is at the indole or indoline ring's 5-position and the other substituents are as defined above. Another preferred group of this invention are those of the formulae: ##STR33## wherein: R.sub.1 is selected from H, halogen, --CF.sub.3, --OH, --C.sub.1 -C.sub.10 alkyl, preferably --C.sub.1 -C.sub.6 alkyl, --S--C.sub.1 -C.sub.10 alkyl, preferably --S--C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CN, --NO.sub.2, --NH.sub.2, --HN(C.sub.1 -C.sub.6), --N(C.sub.1 -C.sub.6).sub.2, phenyl, --O-phenyl, --S-phenyl, benzyl, --O-benzyl, --S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3, or --OH; or a moiety of the formulae: ##STR34## R.sub.6 is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, phenyl, --O-phenyl, benzyl, --O-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --NO.sub.2, --CF.sub.3, or --OH; R.sub.7 is selected from --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --N--(C.sub.1 -C.sub.6 alkyl).sub.2, --(CH.sub.2).sub.n --NH--(C.sub.1 -C.sub.6 alkyl), --CF.sub.3, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.5 cycloalkyl, C.sub.1 -C.sub.6 alkoxy, --NH--(C.sub.1 -C.sub.6 alkyl), --N--(C.sub.1 -C.sub.6 alkyl).sub.2, pyridinyl, thienyl, furyl, pyrrolyl, quinolyl, (CH.sub.2).sub.n phenyl, phenyl,--O-phenyl, benzyl, --O-benzyl, adamantyl, or morpholinyl, --(CH.sub.2).sub.n -phenyl-O-phenyl, --(CH.sub.2).sub.n -phenyl-CH.sub.2 -phenyl, --(CH.sub.2).sub.n --O-phenyl-CH.sub.2 -phenyl, --(CH.sub.2).sub.n -phenyl-(O--CH.sub.2 -phenyl).sub.2, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --NH.sub.2, --NO.sub.2, --CF.sub.3,CO.sub.2 H, or --OH; R.sub.2 is selected from H, halogen, --CN, --CHO, --CF.sub.3, --OH, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CHO, --CN, --NO.sub.2, --NH.sub.2, --NH--C.sub.1 -C.sub.6 alkyl, --N(C.sub.1 -C.sub.6 alkyl).sub.2, --N--SO.sub.2 --C.sub.1 -C.sub.6 alkyl, or --SO.sub.2 --C.sub.1 -C.sub.6 alkyl; R.sub.3 is selected from --COOH, --C(O)--COOH, --(CH.sub.2).sub.n --C(O)--COOH, --(CH.sub.2).sub.n --COOH, --CH.dbd.CH--COOH, --(CH.sub.2).sub.n -tetrazole, ##STR35## or a moiety selected from the formulae --L.sup.1 --M.sup.1 ; wherein L.sup.1 is a bridging or linking moiety selected from a chemical bond, , --(CH.sub.2).sub.n --, --SO.sub.2 --, --C(O)--, --(CH.sub.2).sub.n --C(O)--, --(CH.sub.2).sub.n --C(O)--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.n --,--(CH.sub.2).sub.n --S--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --SO--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --SO.sub.2 --(CH.sub.2).sub.n --, or --(CH.sub.2).sub.n --CH.dbd.CH--(CH.sub.2).sub.n --O--; n is an integer from 0 to 3 M.sup.1 is selected from the group of --COOH, --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --C(O)--COOH, tetrazole, ##STR36## R.sub.8, in each appearance, is independently selected from H, --COOH, --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --C(O)--COOH, tetrazole, --C(O)--NH.sub.2, --(CH.sub.2).sub.n --C(O)--NH.sub.2, ##STR37## n is an integer from 0 to 3; R.sub.9 is selected from H, halogen, --CF.sub.3, --OH, --COOH, --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --C(O)--COOH, --C.sub.1 -C.sub.6 alkyl, --O--C.sub.1 -C.sub.6 alkyl, --NH(C.sub.1 -C.sub.6 alkyl), --N(C.sub.1 -C.sub.6 alkyl).sub.2 ; R.sub.4 is selected from H, --CF.sub.3, C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, C.sub.3 -C.sub.10 cycloalkyl, --C.sub.1 -C.sub.6 alkyl-C.sub.3 -C.sub.10 cycloalkyl, --CHO, halogen, or a moiety of the formula --L.sup.2 --M.sup.2 : L.sup.2 indicates a linking or bridging group of the formulae --(CH.sub.2).sub.n --, --S--, --O--, --C(O)--, --(CH.sub.2).sub.n --C(O)--, --(CH.sub.2).sub.n --C(O)--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.n --, or --(CH.sub.2).sub.n --S--(CH.sub.2).sub.n --; M.sup.2 is selected from: a) H, the group of C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, C.sub.3 -C.sub.10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --NO.sub.2, --NH.sub.2, --CN, or --CF.sub.3 ; or b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, pyrazole, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --NO.sub.2, --NH.sub.2, --CN, or --CF.sub.3 ; or c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyridine, pyrazine, pyrimidine, piperidine, piperazine, thiazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CHO, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3 or --OH; or d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CHO, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3 or --OH; R.sub.5 is selected from C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, --(CH.sub.2).sub.n --C.sub.3 -C.sub.5 cycloalkyl or --(CH.sub.2).sub.n --A, --(CH.sub.2).sub.n --S--A, or --(CH.sub.2).sub.n --O--A wherein A is selected from: ##STR38## D is H, C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, or --CF.sub.3 ; R.sub.12 is H, C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, or --CF.sub.3 ; or a pharmaceutically acceptable salt thereof. Other compounds of this invention have the following formulae: ##STR39## wherein: R.sub.1 is selected from H, halogen, --CF.sub.3, --OH, --C.sub.1 -C.sub.10 alkyl, preferably --C.sub.1 -C.sub.6 alkyl, --S--C.sub.1 -C.sub.10 alkyl, preferably --S--C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CN, --NO.sub.2, --NH.sub.2, --HN(C.sub.1 -C.sub.6), --N(C.sub.1 -C.sub.6).sub.2, phenyl, --O-phenyl, --S-phenyl, benzyl, --O-benzyl, --S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3, or --OH; ##STR40## R.sub.6 is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, phenyl, --O-phenyl, benzyl, --O-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --NH.sub.2, --NO.sub.2, --CF.sub.3, or --OH; R.sub.7 is selected from --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --N--(C.sub.1 -C.sub.6 alkyl).sub.2, --(CH.sub.2).sub.n --NH--(C.sub.1 -C.sub.6 alkyl), --CF.sub.3, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.5 cycloalkyl, C.sub.1 -C.sub.6 alkoxy, --NH--(C.sub.1 -C.sub.6 alkyl), --N--(C.sub.1 -C.sub.6 alkyl).sub.2, pyridinyl, thienyl, furyl, pyrrolyl, quinolyl, (CH.sub.2).sub.n phenyl, phenyl,--O-phenyl, benzyl, --O-benzyl, adamantyl, or morpholinyl, --(CH.sub.2).sub.n -phenyl-O-phenyl, --(CH.sub.2).sub.n -phenyl-CH.sub.2 -phenyl, --(CH.sub.2).sub.n --O-phenyl-CH.sub.2 -phenyl, --(CH.sub.2).sub.n -phenyl-(O--CH.sub.2 -phenyl).sub.2, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --NH.sub.2, --NO.sub.2, --CF.sub.3,CO.sub.2 H, or --OH; R.sub.2 is selected from H, halogen, --CN, --CHO, --CF.sub.3, --OH, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CHO, --CN, --NO.sub.2, --NH.sub.2, --NH--C.sub.1 -C.sub.6 alkyl, --N(C.sub.1 -C.sub.6 alkyl).sub.2, --N--SO.sub.2 --C.sub.1 -C.sub.6 alkyl, or --SO.sub.2 --C.sub.1 -C.sub.6 alkyl; R.sub.3 is selected from --COOH, --C(O)--COOH, --(CH.sub.2).sub.n --C(O)--COOH, --(CH.sub.2).sub.n --COOH, (CH.sub.2).sub.n --CH.dbd.CH--COOH, --(CH.sub.2).sub.n --tetrazole, ##STR41## or a moiety selected from the formulae --L.sup.1 --M.sup.1 or L.sup.2 M.sup.2 ; L.sup.1 is a bridging or linking moiety selected from a chemical bond, --(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --C(O)--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.n --,--(CH.sub.2).sub.n --S--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --SO--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --SO.sub.2 --(CH.sub.2).sub.n --, or --(CH.sub.2).sub.n --CH.dbd.CH--(CH.sub.2).sub.n --O--; M.sup.1 is selected from the group of --COOH, --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --C(O)--COOH, tetrazole, ##STR42## L.sup.2 is a bridging or linking moiety selected from a chemical bond --(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --C(O)--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.n --,--(CH.sub.2).sub.n --S--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --SO--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --SO.sub.2 --(CH.sub.2).sub.n --, or --(CH.sub.2).sub.n --CH.dbd.CH--(CH.sub.2).sub.n --O--; --C(Z)--N(R.sub.6)--, --C(Z)--N(R.sub.6)--(CH.sub.2).sub.n --, --C(O)--C(Z)--N(R.sub.6)--, --C(O)--C(Z)--N(R.sub.6)--(CH.sub.2).sub.n --, --C(Z)--NH--SO.sub.2 --, or --C(Z)--NH--SO.sub.2 --(CH.sub.2).sub.n --; M.sup.2 is the moiety ##STR43## R.sub.8, in each appearance, is independently selected from H, --COOH, --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --C(O)--COOH, tetrazole, --C(O)--NH.sub.2, --(CH.sub.2).sub.n --C(O)--NH.sub.2 ##STR44## R.sub.9, is selected from H, halogen, --CF.sub.3, --OH, --COOH, --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --C(O)--COOH, --C.sub.1 -C.sub.6 alkyl, --O--C.sub.1 -C.sub.6 alkyl, --NH(C.sub.1 -C.sub.6 alkyl), --N(C.sub.1 -C.sub.6 alkyl).sub.2 ; R.sub.10 is selected from the group of H, halogen, --CF.sub.3, --OH, --COOH, --(CH.sub.2).sub.n --COOH, --(CH.sub.2).sub.n --C(O)--COOH, --C.sub.1 -C.sub.6 alkyl, --O--C.sub.1 -C.sub.6 alkyl, --NH(C.sub.1 -C.sub.6 alkyl), --N(C.sub.1 -C.sub.6 alkyl).sub.2, ##STR45## with a proviso that the complete moiety at the indole or indoline 3-position created by any combination of R.sub.3, L.sup.1, M.sup.1, L.sup.2, M.sup.2, R.sub.8, R.sub.9, R.sub.10, shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: --C(O)--NH.sub.2, --(CH.sub.2).sub.n --C(O)--NH.sub.2 ##STR46## n is an integer from 0 to 3; R.sub.4 is selected from H, --CF.sub.3, C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, C.sub.3 -C.sub.10 cycloalkyl, --C.sub.1 -C.sub.6 alkyl, --C.sub.3 -C.sub.10 cycloalkyl, --CHO, halogen, (CH.sub.2).sub.n C(O)NH.sub.2, or a moiety of the formula --L.sup.3 --M.sup.3 : L.sup.3 indicates a linking or bridging group of the formulae --(CH.sub.2).sub.n --, --C(O)--, --(CH.sub.2).sub.n --C(O)--, --(CH.sub.2).sub.n --C(O)--(CH.sub.2).sub.n --, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.n --, or --(CH.sub.2).sub.n --S--(CH.sub.2).sub.n --, C(O)C(O)X, --(CH.sub.2).sub.n --N--(CH.sub.2).sub.n ; M.sup.3 is selected from: a) H, the group of C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, C.sub.3 -C.sub.10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.10 alkyl, preferably C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --NO.sub.2, --NH.sub.2, --CN, or --CF.sub.3 ; or R.sub.5 is selected from the groups of: a) a moiety of the formulae --(CH.sub.2).sub.n --A, --(CH.sub.2).sub.n --S--A, or --(CH.sub.2).sub.n --O--A, wherein A is the moiety: ##STR47## wherein D is H, C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, --CF.sub.3 or --(CH.sub.2).sub.n --CF.sub.3 ; B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, --CF.sub.3, --OH, --C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --NH.sub.2 or --NO.sub.2 ; or a pharmaceutically acceptable salt thereof. Another preferred group of this invention are those of the formulae: ##STR48## wherein: R.sub.1 and R.sub.1' are independently selected from H, halogen, --CF.sub.3, --OH, --C.sub.1 -C.sub.10 alkyl, preferably --C.sub.1 -C.sub.6 alkyl, --S--C.sub.1 -C.sub.10 alkyl, preferably --S--C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CN, --NO.sub.2, --NH.sub.2, --HN(C.sub.1 -C.sub.6), --N(C.sub.1 -C.sub.6).sub.2, phenyl, --O-phenyl, --S-phenyl, benzyl, --O-benzyl, --S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3, or --OH; R.sub.2 is selected from H, halogen, --CF.sub.3, --OH, --C.sub.1 -C.sub.10 alkyl, preferably --C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CHO, --CN, --NO.sub.2, --NH.sub.2, --NH--C.sub.1 -C.sub.6 alkyl, --N(C.sub.1 -C.sub.6 alkyl).sub.2, --N--SO.sub.2 --C.sub.1 -C.sub.6 alkyl, or --SO.sub.2 --C.sub.1 -C.sub.6 alkyl; R.sub.3 is a moiety selected from the groups of: ##STR49## wherein L.sup.1 is a bridging or linking moiety selected from a chemical bond, --(CH.sub.2).sub.n' --, --(CH.sub.2).sub.n' --C(O)--(CH.sub.2).sub.n' --, --(CH.sub.2).sub.n' --O--(CH.sub.2).sub.n' --,--(CH.sub.2).sub.n' --S--(CH.sub.2).sub.n' --, --(CH.sub.2).sub.n' --SO--(CH.sub.2).sub.n' --, --(CH.sub.2).sub.n' --SO.sub.2 --(CH.sub.2).sub.n' --, or --(CH.sub.2).sub.n' --CH.dbd.CH--(CH.sub.2).sub.n' --O--; where n' is an integer from 0 to 5; R.sub.9 is selected from halogen, --CF.sub.3, --C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --NH(C.sub.1 -C.sub.6 alkyl), or --N(C.sub.1 -C.sub.6 alkyl).sub.2, n in each instance is independently selected as an integer from 0 to 3; R.sub.4 is selected from H, --C.sub.1 -C.sub.10 alkyl, preferably --C.sub.1 -C.sub.6 alkyl, --(CH.sub.2).sub.n --OH, (CH.sub.2).sub.n C(O)NH.sub.2, --(CH.sub.2).sub.n --O--(C.sub.1 -C.sub.6 alkyl), --(CH.sub.2).sub.n --O--CH.sub.2 -phenyl, --(CH.sub.2).sub.n --N--(C.sub.1 -C.sub.6 alkyl), --(CH.sub.2).sub.n --N--CH.sub.2 -phenyl, the phenyl rings of which are optionally substituted by 1 or 2 groups selected from H, halogen, --CF.sub.3 or --C.sub.1 -C.sub.6 alkyl; n is an integer from 0-3 R.sub.5 is selected from C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, --(CH.sub.2).sub.n --C.sub.3 -C.sub.5 cycloalkyl or --(CH.sub.2).sub.n --A, --(CH.sub.2).sub.n --S--A, or --(CH.sub.2).sub.n --O--A wherein A is selected from: ##STR50## D is H, C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, or --CF.sub.3 ; R.sub.12 is H, C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, or --CF.sub.3 ; or a pharmaceutically acceptable salt thereof. The compounds of this invention have the following formulae: ##STR51## wherein: R.sub.1 is selected from H, halogen, --CF.sub.3, --OH, --C.sub.1 -C.sub.10 alkyl, preferably --C.sub.1 -C.sub.6 alkyl, --S--C.sub.1 -C.sub.10 alkyl, preferably --S--C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CN, --NO.sub.2, --NH.sub.2, --HN(C.sub.1 -C.sub.6), --N(C.sub.1 -C.sub.6).sub.2, phenyl, --O-phenyl, --S-phenyl, benzyl, --O-benzyl, --S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --NO.sub.2, --NH.sub.2, --CN, --CF.sub.3, or --OH; R.sub.2 is selected from H, halogen, --CF.sub.3, --OH, --C.sub.1 -C.sub.10 alkyl, preferably --C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.10 alkoxy, preferably C.sub.1 -C.sub.6 alkoxy, --CHO, --CN, --NO.sub.2, --NH.sub.2, --NH--C.sub.1 -C.sub.6 alkyl, --N(C.sub.1 -C.sub.6 alkyl).sub.2, --N--SO.sub.2 --C.sub.1 -C.sub.6 alkyl, or --SO.sub.2 --C.sub.1 -C.sub.6 alkyl; R.sub.3 is a moiety selected from the groups of: ##STR52## wherein L.sup.1 is a bridging or linking moiety selected from a chemical bond, --(CH.sub.2).sub.n' --, --(CH.sub.2).sub.n' --C(O)--(CH.sub.2).sub.n' --, --(CH.sub.2).sub.n' --O--(CH.sub.2).sub.n' --,--(CH.sub.2).sub.n' --S--(CH.sub.2).sub.n' --, --(CH.sub.2).sub.n' --SO--(CH.sub.2).sub.n' --, --(CH.sub.2).sub.n' --SO.sub.2 --(CH.sub.2).sub.n' --, or --(CH.sub.2).sub.n' --CH.dbd.CH--(CH.sub.2).sub.n' --O--; where n' is an integer from 0 to 5; R.sub.9 is selected from halogen, --CF.sub.3, --C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, --NH(C.sub.1 -C.sub.6 alkyl), or --N(C.sub.1 -C.sub.6 alkyl).sub.2, n in each instance is independently selected as an integer from 0 to 3 or a pharmaceutically acceptable salt thereof R.sub.4 is selected from H, --C.sub.1 -C.sub.10 alkyl, preferably --C.sub.1 -C.sub.6 alkyl, --(CH.sub.2).sub.n --OH, (CH.sub.2).sub.n C(O)NH.sub.2, --(CH.sub.2).sub.n --O--(C.sub.1 -C.sub.6 alkyl), --(CH.sub.2).sub.n --O--CH.sub.2 -phenyl, --(CH.sub.2).sub.n --N--(C.sub.1 -C.sub.6 alkyl), --(CH.sub.2).sub.n --N--CH.sub.2 -phenyl, the phenyl rings of which are optionally substituted by 1 or 2 groups selected from H, halogen, --CF.sub.3 or --C.sub.1 -C.sub.6 alkyl; n is an integer from 0-3 R.sub.5 is a moiety of the formulae --(CH.sub.2).sub.n --A, --(CH.sub.2).sub.n --S--A, or --(CH.sub.2).sub.n --O--A, wherein A is the moiety: ##STR53## wherein D is H, C.sub.1 -C.sub.6 lower alkyl, C.sub.1 -C.sub.6 lower alkoxy, or --CF.sub.3 ; B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, --CF.sub.3, --OH, --C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, or --NO.sub.2 ; or a pharmaceutically acceptable salt thereof. Yet another preferred group herein are the compounds of the formulae: ##STR54## wherein: R.sub.1 is selected from H, halogen, --CF.sub.3, --OH, --CN, --NO.sub.2, --NH.sub.2, --HN(C.sub.1 -C.sub.6), --N(C.sub.1 -C.sub.6).sub.2, phenyl, --N--SO.sub.2 --C.sub.1 -C.sub.6 alkyl, or --SO.sub.2 --C.sub.1 -C.sub.6 alkyl; R.sub.2 is selected from H, halogen, --CF.sub.3, --OH, , --CN, --NO.sub.2, --NH.sub.2, --NH--C.sub.1 -C.sub.6 alkyl, --N(C.sub.1 -C.sub.6 alkyl).sub.2, --N--SO.sub.2 --C.sub.1 -C.sub.6 alkyl, or --SO.sub.2 -C.sub.1 -C.sub.6 alkyl; R.sub.3 is a moiety selected from the groups of: ##STR55## wherein L.sup.1 is a bridging or linking moiety selected from a chemical bond, --(CH.sub.2).sub.n' --, --(CH.sub.2).sub.n' --C(O)--(CH.sub.2).sub.n' --, --(CH.sub.2).sub.n' --O--(CH.sub.2).sub.n' --,--(CH.sub.2).sub.n' --S--(CH.sub.2).sub.n' --, --(CH.sub.2).sub.n' --SO--(CH.sub.2).sub.n' --, --(CH.sub.2).sub.n' --SO.sub.2 --(CH.sub.2).sub.n' --, or --(CH.sub.2).sub.n' --CH.dbd.CH--(CH.sub.2).sub.n' --O--; n' in each instance is independently selected as an integer from 0 to 5; R.sub.4 is selected from H, --C.sub.1 -C.sub.10 alkyl, preferably --C.sub.1 -C.sub.6 alkyl, --(CH.sub.2).sub.n --OH, (CH.sub.2).sub.n C(O)NH.sub.2, --(CH.sub.2).sub.n --O--(C.sub.1 -C.sub.6 alkyl), --(CH.sub.2).sub.n --O--CH.sub.2 -phenyl, --(CH.sub.2).sub.n --N--(C.sub.1 -C.sub.6 alkyl), --(CH.sub.2).sub.n --N--CH.sub.2 -phenyl, the phenyl rings of which are optionally substituted by 1 or 2 groups selected from H, halogen, --CF.sub.3 or --C.sub.1 -C.sub.6 alkyl; n is an integer from 0-3 or a pharmaceutically acceptable salt thereof |
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