EP0160408A1
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Benzothiophenes, their production and use, and compositions containing them
Assignee: Merck and Co Inc
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Filing: 1985-04-01
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Granted: —
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Expires: 2005-04-01
Abstract
Abstract N-Alkenyl-3-hydroxybenzo [b] thiophene-2-carboxamide derivatives of formula) and their pharmaceutically acceptable salts, are novel. In the formula, each of R, R 1 , R 2 , R 3 and R 4 is selected from various hydrocarbons (including heteroaryl), acyl, and acyl- substituted hydrocarbon groups and their ring-substituted derivatives; or R 1 , R 2 and R 3 can be halo, or R' and R 2 joined to form certain tricyclic bivalent residues, or R 4 is -CR 1 =CR 2 R 3 , and n is 0, 1, or 2. These compounds are prepared by (1) treating a substituted 2-halobenzoate with thioacetamide followed by N-alkenylation with appropriate agents, such as aldehydes, ketones, enol ethers, epoxides, acetals or ketals; (2) treating a substituted thiosalicylate with an appropriately substituted halocetamide, followed by dehydration; and (3) further synthetic modification of compounds prepared above. These compounds have been found to be effective inhibitors of both cyclooxygenase and lipoxygenase and thereby useful in the treatment of pain, fever, inflammation, arthritic conditions, asthma, allergic disorders, skin diseases, cardiovascular disorders, psoriasis, inflammatory bowel disease, glaucoma or other prostaglandins and/or leukotriene mediated diseases. Furthermore, these compounds have been found to exhibit cytoprotective activity which does not involve the inhibition of gastric acid secretion but can be used as relatively low dosages for increasing the resistance of gastro-intestinal mucosa to strong irritants. They are included in pharmaceutical compositions.
Inventors
- 👤 Allan N. Tischler
- 👤 Philippe L. Durette
- 👤 Bruce E. Witzel
- 👤 Kathleen M. Rupprecht
- 👤 Timothy F. Gallagher
- 👤 Marvin M. Goldenberg
- 👤 Debra L. Allison
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-10-23 13:15
CPC Classifications
C; C07; C07D; C07D333/00; C07D333/50; C07D333/52; C07D333/54; C07D333/56; C07D409/00; C07D409/02; C07D409/12; C07C; C07C247/00; C07D303/00; C07D303/02; C07D303/04; C07D333/62; C07D333/68; C07D333/70
Claims Analysis
Total Claims: 19
Claim 1
Independent Claim
442 words
A compound of formula: or a compound that is a pharmaceutically acceptable salt thereof, in which R is (a) H; (b) loweralkyl; (c) substituted or unsubstituted aryl; (d) lowercycloalkyl; (e) haloloweralkyl; (f) heteroaryl, either substituted or unsubstituted; (g) benzyl or ring-substituted benzyl; (h) loweralkynyl; (i) loweralkenyl; (j) phenylloweralkenyl, either unsubstituted or ring-substituted; (k) phenylloweralkynyl, either unsubstituted or ring-substituted; in which R is a radical or atom of the type defined for R in sections (a) to (k) above; in which R 6 is as defined for R 5 and can be the same as or different from R 5 ; in which m is 1 or 2; (q) -(CH 2 ) m OR 5 ; -(CH 2 ) m NR 5 R 6 ; (s) -(CH 2 ) m NR 5 R 6 ; or each of X 1 , X 2 , X 3 and X 4 , independently of the others, is a radical or atom of the type defined for R, or a radical or atom X 5 , where X 5 is (1) Q, where Q is H, loweralkyl, haloloweralkyl, phenyl or substituted phenyl, or naphthyl; (2) halo; (3) loweralkenyl; (4) loweralkynyl; (5) -SQ; (6) -OQ; (7) -CHQCOQ 1 , where Q is Q and can be the same as or different from Q 1 ; (8) -CHQCOOQ 1 (10) -CH 2 SQ or -CHQSQ 1 ; (11) -CH 2 OQ or -CHQOQ 1 ; (12) -COQ; (13) -COOQ; (14) -OCOQ; (15) -NQQ 1 ; (16) -NQCOQ 1 ; (17) -NQ(OQ 1 ); (18) -NQ(SQ 1 ); (19) -NQSO 2 Q 1 ; (20 -SO 2 NQQ 1 ; (21) -SOQ; (22) -SO 2 Q; (23) -SO 3 Q; (24) -CN; (25) -NO 2 ; (26) -CONQQ 1 ; (27) -NO; (28) -CSQ; (29) -CSNQQ 1 ; (30) -CF 2 SQ; (31) - CF 2 0Q; (32) -NQCONHQ 1 or NQCONQ 1 Q 2 ; each of R 1 , R 2 and R 3 , independently of the others, is a halogen atom or a radical or atom of the type defined for R or R 2 and R 3 are joined together to form a ring of formula: where each of X 5 and X6, which are the same or different, is as previously defined for X 5 , and Y is (CH 2 ) n , O, S, SO, SO 2 or NQ; R 4 is a radical or atom of the type defined for R or is -CR 1 =CR 2 R 3 , where R 1 , R 2 and R 3 are as defined above; and n is 0, 1 or 2.
Claim 2
Dependent Claim
442 words
A compound of formula: or a compound that is a pharmaceutically acceptable salt thereof, in which R is (a) H; (b) loweralkyl; (c) substituted or unsubstituted aryl; (d) lowercycloalkyl; (e) haloloweralkyl; (f) heteroaryl, either substituted or unsubstituted; (g) benzyl or ring-substituted benzyl; (h) loweralkynyl; (i) loweralkenyl; (j) phenylloweralkenyl, either unsubstituted or ring-substituted; (k) phenylloweralkynyl, either unsubstituted or ring-substituted; in which R is a radical or atom of the type defined for R in sections (a) to (k) above; in which R 6 is as defined for R 5 and can be the same as or different from R 5 ; in which m is 1 or 2; (q) -(CH 2 ) m OR 5 ; -(CH 2 ) m NR 5 R 6 ; (s) -(CH 2 ) m NR 5 R 6 ; or each of X 1 , X 2 , X 3 and X 4 , independently of the others, is a radical or atom of the type defined for R, or a radical or atom X 5 , where X 5 is (1) Q, where Q is H, loweralkyl, haloloweralkyl, phenyl or substituted phenyl, or naphthyl; (2) halo; (3) loweralkenyl; (4) loweralkynyl; (5) -SQ; (6) -OQ; (7) -CHQCOQ 1 , where Q is Q and can be the same as or different from Q 1 ; (8) -CHQCOOQ 1 (10) -CH 2 SQ or -CHQSQ 1 ; (11) -CH 2 OQ or -CHQOQ 1 ; (12) -COQ; (13) -COOQ; (14) -OCOQ; (15) -NQQ 1 ; (16) -NQCOQ 1 ; (17) -NQ(OQ 1 ); (18) -NQ(SQ 1 ); (19) -NQSO 2 Q 1 ; (20 -SO 2 NQQ 1 ; (21) -SOQ; (22) -SO 2 Q; (23) -SO 3 Q; (24) -CN; (25) -NO 2 ; (26) -CONQQ 1 ; (27) -NO; (28) -CSQ; (29) -CSNQQ 1 ; (30) -CF 2 SQ; (31) - CF 2 0Q; (32) -NQCONHQ 1 or NQCONQ 1 Q 2 ; each of R 1 , R 2 and R 3 , independently of the others, is a halogen atom or a radical or atom of the type defined for R or R 2 and R 3 are joined together to form a ring of formula: where each of X 5 and X6, which are the same or different, is as previously defined for X 5 , and Y is (CH 2 ) n , O, S, SO, SO 2 or NQ; R 4 is a radical or atom of the type defined for R or is -CR 1 =CR 2 R 3 , where R 1 , R 2 and R 3 are as defined above; and n is 0, 1 or 2.
Claim 3
Dependent Claim
27 words
A compound as claimed in Claim 1, in which R is of the formula: in which X 5 and X 6 are as defined in Claim 1.
Claim 4
Dependent Claim
33 words
A compound of formula: in which X 2 , X 3 , R, R 1 , R 2 , R 3 , R 4 and n are defined in Claim 1 or 2.
Claim 5
Dependent Claim
31 words
A compound of formula: in which X 2 , X 3 , R 1 , R 2 , R 3 and R 4 are as defined in Claim 1 or 2.
Claim 6
Dependent Claim
48 words
A compound of formula: in which X 2 is (a) H; (b) loweralkyl; (c) haloloweralkyl; or (d) loweralkenyl; and R 2 and R 3 independently are: (a) loweralkyl; (b) phenyl or substituted phenyl; (c) heteroaryl or substituted heteroaryl; and R 4 is H or -CH= CHR 2 .
Claim 7
Dependent Claim
48 words
A compound of formula: in which X 2 is (a) H; (b) loweralkyl; (c) haloloweralkyl; or (d) loweralkenyl; and R 2 and R 3 independently are: (a) loweralkyl; (b) phenyl or substituted phenyl; (c) heteroaryl or substituted heteroaryl; and R 4 is H or -CH= CHR 2 .
Claim 8
Dependent Claim
30 words
A pharmaceutical composition for treating inflammation, fever and pain in mammalian species comprising a pharmaceutically acceptable carrier and a compound as claimed in any one of Claims 1 to 5.
Claim 9
Dependent Claim
25 words
A compound as claimed in any one of Claims 1 to 5 for use in the treatment of inflammation, fever and pain in mammalian species.
Claim 10
Dependent Claim
19 words
A compound as claimed in any one of Claims 1 to 5 for use in the treatment of glaucoma.
Claim 11
Dependent Claim
102 words
A process for the preparation of a compound as claimed in Claim 1 comprising treating a compound of formula (II) with an N-alkenylation agent of formula (a) R 1 COCHR 2 R 3 ; (b) HC OCHR 2 R 3 ; (c) R°OCH=CR 2 R 3 or R°SCH=CR 2 R 3 where q represents 2 or 3, R° represents C 1-6 alkyl, phenyl or benzyl; and R, R 1 , R 2 , R 3 , X 1 , X 2 , X 3 and X 4 are as defined in Claim 1 or 2, in the presence of a strong acid.
Claim 12
Dependent Claim
3 words
CLAIMS FOR AUSTRIA
Claim 13
Independent Claim
481 words
A method of preparing a compound of formula: or a compound that is a pharmaceutically acceptable salt thereof, in which R is (a) H; (b) loweralkyl; (c) substituted or unsubstituted aryl; (d) lowercycloalkyl; (e) haloloweralkyl; (f) heteroaryl, either substituted or unsubstituted; (g) benzyl or ring-substituted benzyl; (h) loweralkynyl; (i) loweralkenyl; (j) phenylloweralkenyl, either unsubstituted or ring-substituted; (k) phenylloweralkynyl, either unsubstituted or ring-substituted; in which R 5 is a radical or atom of the type defined for R in sections (a) to (k) above; in which R is as defined for R and can be the same as or different from R 5 ; in which m is 1 or 2; (s) -(CH 2 ) m NR 3 R 6 ; or each of X 1 , X 2 , X 3 and X 4 , independently of the others, is a radical or atom of the type defined for R, or a radical or atom X5 , where X 5 is (1) Q, where Q is H, loweralkyl, haloloweralkyl, phenyl or substituted phenyl, or naphthyl; (2) halo; (3) loweralkenyl; (4) loweralkynyl; (5) -SQ; (6) -OQ; (7) -CHQCOQ 1 , where Q is Q 1 and can be the same as or different from Q 1 ; (8) -CHQCOOQ 1 (10) -CH 2 SQ or -CHQSQ 1 ; (11) -CH 2 OQ or -CHQOQ 1 ; (12) -COQ; (13) -COOQ; (14) -OCOQ; (15) -NQQ 1 ; (16) -NQCOQ 1 ; (17) -NQ(OQ 1 ); (18) -NQ(SQ 1 ); (19) -NQSO 2 Q 1 ; (20 -SO 2 NQQ 1 ; (21) -SOQ; (22) -SO 2 Q; (23) -S 0 3 Q; (24) -CN; (25) -N 0 2 ; (26) -CONQQ 1 ; (27) -NO; (28) -CSQ; (29) -CSNQQ 1 ; (30) -CF 2 SQ; (31) -CF 2 OQ; (32) -NQCONHQ 1 or NQCONQ 1 Q 2 ; each of R 1 , R 2 and R 3 , independently of the others, is a halogen atom or a radical or atom of the type defined for R or R 2 and R 3 are joined together to form a ring of formula: where each of X 5 and X 6 , which are the same or different, is as previously defined for X 5 , and Y is (CH 2 ) n , O, S, SO, S0 2 or NQ; R is a radical or atom of the type defined for R or is -CR 1 =CR 2 R 3 , where R 1 , R 2 and R 3 are as defined above; and n is 0, 1 or 2 comprising treating a compound of formula (II) with an N-alkenylation agent of formula (a) R 1 COCHR 2 R 3 ; (b) HC OCHR 2 R 3 ; (c) R°OCH=CR 2 R 3 or R°SCH=CR 2 R 3 where q represents 2 or 3 in the presence of a strong acid.
Claim 14
Independent Claim
481 words
A method of preparing a compound of formula: or a compound that is a pharmaceutically acceptable salt thereof, in which R is (a) H; (b) loweralkyl; (c) substituted or unsubstituted aryl; (d) lowercycloalkyl; (e) haloloweralkyl; (f) heteroaryl, either substituted or unsubstituted; (g) benzyl or ring-substituted benzyl; (h) loweralkynyl; (i) loweralkenyl; (j) phenylloweralkenyl, either unsubstituted or ring-substituted; (k) phenylloweralkynyl, either unsubstituted or ring-substituted; in which R 5 is a radical or atom of the type defined for R in sections (a) to (k) above; in which R is as defined for R and can be the same as or different from R 5 ; in which m is 1 or 2; (s) -(CH 2 ) m NR 3 R 6 ; or each of X 1 , X 2 , X 3 and X 4 , independently of the others, is a radical or atom of the type defined for R, or a radical or atom X5 , where X 5 is (1) Q, where Q is H, loweralkyl, haloloweralkyl, phenyl or substituted phenyl, or naphthyl; (2) halo; (3) loweralkenyl; (4) loweralkynyl; (5) -SQ; (6) -OQ; (7) -CHQCOQ 1 , where Q is Q 1 and can be the same as or different from Q 1 ; (8) -CHQCOOQ 1 (10) -CH 2 SQ or -CHQSQ 1 ; (11) -CH 2 OQ or -CHQOQ 1 ; (12) -COQ; (13) -COOQ; (14) -OCOQ; (15) -NQQ 1 ; (16) -NQCOQ 1 ; (17) -NQ(OQ 1 ); (18) -NQ(SQ 1 ); (19) -NQSO 2 Q 1 ; (20 -SO 2 NQQ 1 ; (21) -SOQ; (22) -SO 2 Q; (23) -S 0 3 Q; (24) -CN; (25) -N 0 2 ; (26) -CONQQ 1 ; (27) -NO; (28) -CSQ; (29) -CSNQQ 1 ; (30) -CF 2 SQ; (31) -CF 2 OQ; (32) -NQCONHQ 1 or NQCONQ 1 Q 2 ; each of R 1 , R 2 and R 3 , independently of the others, is a halogen atom or a radical or atom of the type defined for R or R 2 and R 3 are joined together to form a ring of formula: where each of X 5 and X 6 , which are the same or different, is as previously defined for X 5 , and Y is (CH 2 ) n , O, S, SO, S0 2 or NQ; R is a radical or atom of the type defined for R or is -CR 1 =CR 2 R 3 , where R 1 , R 2 and R 3 are as defined above; and n is 0, 1 or 2 comprising treating a compound of formula (II) with an N-alkenylation agent of formula (a) R 1 COCHR 2 R 3 ; (b) HC OCHR 2 R 3 ; (c) R°OCH=CR 2 R 3 or R°SCH=CR 2 R 3 where q represents 2 or 3 in the presence of a strong acid.
Claim 15
Dependent Claim
34 words
A method as claimed in Claim 1, as applied to the preparation of a compound in which R is of formula in which X 5 and X 6 are as defined in Claim 1.
Claim 16
Dependent Claim
47 words
A method as claimed in Claim 1, as applied to the preparation of a compound of formula: in which X 2 , X 3 , R , R 1 , R 2 , R 3 , R 4 and n are defined in Claim 1 or 2.
Claim 17
Dependent Claim
43 words
A method as claimed in Claim 1, as applied to the preparation of a compound of formula: in which X 2 , X 3 , R 1 , R 2 , R 3 and R are as defined in Claim 1 or 2.
Claim 18
Dependent Claim
63 words
A method as claimed in Claim 1, as applied to the preparation of a compound of formula: in which X 2 is (a) H; (b) loweralkyl; (c) haloloweralkyl; or (d) loweralkenyl; and R 2 and R 3 independently are: (a) loweralkyl; (b) phenyl or substituted phenyl; (c) heteroaryl or substituted heteroaryl; and R 4 is H or -C H = CHR 2 .
Claim 19
Independent Claim
41 words
A method of preparing a pharmaceutical composition for treating inflammation, fever and pain in mammalian species comprising preparing a compound by a method as claimed in any one of Claims 1 to 5 and incorporating it in a pharmaceutically acceptable carrier.
References Cited (Backward Citations)
US3745175A
Cited
US3907826A
Cited
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