US4745116A
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2-oxy-4H-3,1-benzoxazin-4-ones and related compounds and pharmaceutical use
Assignee: Syntex USA LLC
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Filing: 1986-12-23
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Granted: 1988-05-17
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Expires: 2006-12-23
Abstract
Abstract 2-Oxy-4H-3,1-benzoxazin-4-ones, useful as serine protease inhibitors, represented by the formula: <IMAGE> (I) and the pharmaceutically acceptable acid addition salts thereof, wherein: a is an integer of 1 to 4; A is a bond, or alkylene having one to eight carbon atoms; R is hydrogen, phenyl, imidazolyl or cycloalkyl having three to six carbon atoms, wherein the phenyl, imidazolyl or cycloalkyl ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of lower alkyl having one to four carbon atoms, lower alkoxy having one to four carbon atoms, -N(R1)2, -NO2, halo or lower alkylthio having one to four carbon atoms, and, each R' is independently selected from the group consisting of hydroxy, benzyloxy, lower alkyl having one to six atoms, lower alkenyl having two to six carbon atoms, lower alkoxy having one to six carbon atoms, lower alkylthio or halo-lower alkyl having one to six carbon atoms, halo, -NO2, -N(R1)2, -NR1CO2R2, -NR1COR2, and -NR1C(O)N(R1)2, in which each R1 is independently hydrogen or lower alkyl having one to four carbon atoms, or together form a piperidine or a piperazine ring optionally substituted at the ring nitrogen by lower alkyl having one to four carbon atoms or -CH2CH2OH; each R2 is independently lower alkyl having one to four carbon atoms, A is an alkylene group if R is hydrogen, or a pharmaceutically acceptable acid addition salt thereof.
Inventors
- 👤 Alexander Krantz
- 👤 Robin Spencer
- 👤 Tim Tam
- 👤 Teng J. Liak
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-05 14:30
CPC Classifications
C; C07; C07D; C07D265/00; C07D265/04; C07D265/12; C07D265/14; C07D265/24; C07D265/26; C07F; C07F9/00; C07F9/02; C07F9/547; C07F9/6527; C07F9/6533; C07F9/65335
Claims Analysis
Total Claims: 42
Claim 1
Independent Claim
255 words
A compound of the formula: ##STR19## wherein: a is an integer of 0 to 3; A is a bond, or alkylene having one to eight carbon atoms; R is hydrogen, imidazolyl, phenyl, or cycloalkyl having three to six carbon atoms, wherein the phenyl, imidazolyl or cycloalkyl ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of lower alkyl having one to four carbon atoms, lower alkoxy having one to four carbon atoms, --N(R 1 ) 2 , --NO 2 , halo, and lower alkylthio having one to four carbon atoms; and each R' and R" are independently selected from the group consisting of hydroxy, benzyloxy, lower alkyl having one to six carbon atoms, lower alkenyl having two to six carbon atoms, halo, lower alkoxy having one to six carbon atoms, halo-lower alkyl having one to six carbon atoms, lower alkylthio having one to six carbon atoms, --NO 2 , --N(R 1 ) 2 , --NR 1 CO 2 R 2 , --NR 1 C(O)R 2 , and --NR 1 C(O)N(R 1 ) 2 , in which each R 1 is independently hydrogen or lower alkyl having one to six carbon atoms, or together form a piperidine or piperazine ring optionally substituted at the ring nitrogen with lower alkyl having one to four carbon atoms, or --CH 2 CH 2 OH; each R 2 is independently lower alkyl having one to four carbon atoms, and A is alkylene if R is hydrogen, or a pharmaceutically acceptable acid addition salt thereof.
Claim 2
Dependent Claim
255 words
A compound of the formula: ##STR19## wherein: a is an integer of 0 to 3; A is a bond, or alkylene having one to eight carbon atoms; R is hydrogen, imidazolyl, phenyl, or cycloalkyl having three to six carbon atoms, wherein the phenyl, imidazolyl or cycloalkyl ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of lower alkyl having one to four carbon atoms, lower alkoxy having one to four carbon atoms, --N(R 1 ) 2 , --NO 2 , halo, and lower alkylthio having one to four carbon atoms; and each R' and R" are independently selected from the group consisting of hydroxy, benzyloxy, lower alkyl having one to six carbon atoms, lower alkenyl having two to six carbon atoms, halo, lower alkoxy having one to six carbon atoms, halo-lower alkyl having one to six carbon atoms, lower alkylthio having one to six carbon atoms, --NO 2 , --N(R 1 ) 2 , --NR 1 CO 2 R 2 , --NR 1 C(O)R 2 , and --NR 1 C(O)N(R 1 ) 2 , in which each R 1 is independently hydrogen or lower alkyl having one to six carbon atoms, or together form a piperidine or piperazine ring optionally substituted at the ring nitrogen with lower alkyl having one to four carbon atoms, or --CH 2 CH 2 OH; each R 2 is independently lower alkyl having one to four carbon atoms, and A is alkylene if R is hydrogen, or a pharmaceutically acceptable acid addition salt thereof.
Claim 3
Dependent Claim
23 words
A compound of claim 1 in which R is hydrogen, phenyl, or benzyl and A is alkylene having one to four carbon atoms.
Claim 4
Dependent Claim
13 words
A compound of claim 2 in which A is isopropylene, methylene, or ethylene.
Claim 5
Dependent Claim
26 words
A compound of claim 3 in which R" is lower alkyl having one to six carbon atoms or lower alkenyl having two to six carbon atoms.
Claim 6
Dependent Claim
17 words
A compound of claim 4 in which R" is lower alkyl having one to three carbon atoms.
Claim 7
Dependent Claim
16 words
A compound of claim 5 in which a is one and R' is in the 7-position.
Claim 8
Dependent Claim
26 words
A compound of claim 6 in which R' is selected from the group consisting of hydroxy, benzyloxy, and lower alkoxy having one to six carbon atoms.
Claim 9
Dependent Claim
17 words
A compound of claim 7 in which A is isopropylene, R is hydrogen and R' is hydroxy.
Claim 10
Dependent Claim
12 words
A compound of claim 8 in which R" is methyl, namely 7-hydroxy-2-isopropoxy-5-methyl-4H-3,1-benzoxazin-4-one.
Claim 11
Dependent Claim
12 words
A compound of claim 8 in which R" is ethyl, namely 5-ethyl-7-hydroxy-2-isopropoxy-4H-3,1-benzoxazin-4-one.
Claim 12
Dependent Claim
12 words
A compound of claim 8 in which R" is isopropyl, namely 2-isopropoxy-5-isopropyl-7-hydroxy-4H-3,1-benzoxazin-4-one.
Claim 13
Dependent Claim
17 words
A compound of claim 7 in which A is ethylene, R is hydrogen, and R' is hydroxy.
Claim 14
Dependent Claim
12 words
A compound of claim 12 in which R" is methyl, namely 2-ethoxy-5-methyl-7-hydroxy-4H-3,1-benzoxazin-4-one.
Claim 15
Dependent Claim
17 words
A compound of claim 7 in which A is isopropylene, R is hydrogen, and R' is benzyloxy.
Claim 16
Dependent Claim
12 words
A compound of claim 14 in which R" is methyl, namely 7-benzyloxy-2-isoporpoxy-5-methyl-4H-3,1-benzoxazin-4-one.
Claim 17
Dependent Claim
12 words
A compound of claim 14 in which R" is ethyl, namely 7-benzyloxy-5-ethyl-2-isopropoxy-4H-3,1-benzoxazin-4-one.
Claim 18
Dependent Claim
13 words
A compound of claim 14 in which R" is isopropyl, namely 7-benzyloxy-2-isopropoxy-5-isopropyl- 4H-3,1-benzoxazin-4-one.
Claim 19
Dependent Claim
17 words
A compound of claim 7 in which A is ethylene, R is hydrogen, and R' is benzyloxy.
Claim 20
Dependent Claim
12 words
A compound of claim 18 in which R" is methyl, namely 7-benzyloxy-2-ethoxy-5-methyl-4H-3,1-benzoxazin-4-one.
Claim 21
Dependent Claim
26 words
A compound of claim 5 in which a is two, and a first R' is in the 7-position and a second R' is in the 8-position.
Claim 22
Dependent Claim
40 words
A compound of claim 20 in which the first R' is selected from the group consisting of --NO 2 and --NH 2 and the second R' is selected from the group consisting of lower alkyl, lower alkenyl and lower alkoxy.
Claim 23
Dependent Claim
18 words
A compound of claim 21 in which R is hydrogen and the first R' is --NO 2 .
Claim 24
Dependent Claim
21 words
A compound of claim 22 in which A is ethylene, R" is ethyl and the second R' is ethyl, namely 2-ethoxy-5,8-diethyl-7-nitro-4H-3,1-benzoxazin-4-one.
Claim 25
Dependent Claim
21 words
A compound of claim 22 in which A is isopropylene, R" is methyl, and the second R' is methyl, namely 2-isopropoxy-5,8-dimethyl-7-nitro-4H-3,1-benzoxazin-4-one.
Claim 26
Dependent Claim
18 words
A compound of claim 21 in which R is hydrogen and the first R' is --NH 2 .
Claim 27
Dependent Claim
21 words
A compound of claim 25 in which A is ethylene, R" is methyl, and the second R' is isopropyl, namely 2-ethoxy-8-isopropyl-5-methyl-7-nitro-4H-31,1-benzoxazin-4-one.
Claim 28
Dependent Claim
21 words
A compound of claim 25 in which A is ethylene, R" is ethyl, and the second R' is ethyl, namely 7-amino-2-ethoxy-5,8-diethyl-4H-3,1-benzoxazin-4-one.
Claim 29
Dependent Claim
21 words
A compound of claim 25 in which A is ethylene, R" is methyl, and the second R' is methyl, namely 7-amino-2-ethoxy-5,8-dimethyl-4H-3,1-benzoxazin-4-one.
Claim 30
Dependent Claim
21 words
A compound of claim 25 in which A is ethylene, R" is methyl, and the second R' is isopropyl, namely 7-amino-2-ethoxy-8-isopropyl-5-methyl-4H-31,1-benzoxazin-4-one.
Claim 31
Dependent Claim
184 words
A compound of the formula: ##STR20## wherein: a is an integer of 1 to 4; A is alkylene having one to eight carbon atoms; R is hydrogen; and at least one R' represents a substituent at one of the 5- and 7-positions, and each R' is independently selected from the group consisting of hydroxy, benzyloxy, lower alkyl having one to six carbon atoms, lower alkenyl having two to six carbon atoms, halo-lower alkyl having one to six carbon atoms, lower alkylthio having one to six carbon atoms, halo, --NO 2 , --N(R 1 ) 2 , --NR 1 CO 2 R 2 , --NR 1 COR 2 , and --NR 1 C(O)N(R 1 ) 2 , in which each R 1 is independently hydrogen or lower alkyl having one to four carbon atoms, or together form a piperidine or piperazine ring optionally substituted at the ring nitrogen by lower alkyl having one to four carbon atoms or --CH 2 CH 2 OH, and each R 2 is independently lower alkyl having one to four carbons atoms, or a pharmaceutically acceptable acid addition salt thereof.
Claim 32
Dependent Claim
184 words
A compound of the formula: ##STR20## wherein: a is an integer of 1 to 4; A is alkylene having one to eight carbon atoms; R is hydrogen; and at least one R' represents a substituent at one of the 5- and 7-positions, and each R' is independently selected from the group consisting of hydroxy, benzyloxy, lower alkyl having one to six carbon atoms, lower alkenyl having two to six carbon atoms, halo-lower alkyl having one to six carbon atoms, lower alkylthio having one to six carbon atoms, halo, --NO 2 , --N(R 1 ) 2 , --NR 1 CO 2 R 2 , --NR 1 COR 2 , and --NR 1 C(O)N(R 1 ) 2 , in which each R 1 is independently hydrogen or lower alkyl having one to four carbon atoms, or together form a piperidine or piperazine ring optionally substituted at the ring nitrogen by lower alkyl having one to four carbon atoms or --CH 2 CH 2 OH, and each R 2 is independently lower alkyl having one to four carbons atoms, or a pharmaceutically acceptable acid addition salt thereof.
Claim 33
Dependent Claim
34 words
A compound of claim 30 in which a is 1 and R' is in the 7-position and selected from the group consisting of hydroxy, benzyloxy, or lower alkoxy having one to six carbon atoms.
Claim 34
Dependent Claim
18 words
A compound of claim 31 in which A is isopropylene, R is hydrogen, and R' hydroxy, namely 7-hydroxy-2-isopropoxy-4H-3,1-benzoxazin-4-one.
Claim 35
Independent Claim
288 words
A method of inhibiting serine proteases in humans and animals which method comprises administering to a human or animal in need of such treatment a compound of the formula: ##STR21## wherein: a is an integer of 1 to 4; A is a bond, or alkylene having one to eight carbon atoms; R is hydrogen, phenyl, imidazolyl or cycloalkyl having three to six carbon atoms, wherein the phenyl, imidazolyl or cycloalkyl ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of lower alkyl having one to four carbon atoms, lower alkoxy having one to four carbon atoms, --N(R 1 ) 2 , --NO 2 , halo or lower alkylthio having one to four carbon atoms, and, at least one R' represents a substituent at one of the 5- and 7-positions, and each R' is independently selected from the group consisting of hydroxy, benzyloxy, lower alkyl having one to six atoms, lower alkenyl having two to six carbon atoms, lower alkoxy having one to six carbon atoms, lower alkylthio or halo-lower alkyl having one to six carbon atoms, halo, --NO 2 , --N(R 1 ) 2 , --NR 1 CO 2 R 2 , --NR 1 COR 2 , and --NR 1 C(O)N(R 1 ) 2 , in which each R 1 is independently hydrogen or lower alkyl having one to four carbon atoms, or together form a piperidine or a piperazine ring optionally substituted at the ring nitrogen by lower alkyl having one to four carbon atoms or --CH 2 CH 2 OH; each R 2 is independently lower alkyl having one to four carbon atoms, A is an alkylene group if R is hydrogen, or a pharmaceutically acceptable acid addition salt thereof.
Claim 36
Independent Claim
288 words
A method of inhibiting serine proteases in humans and animals which method comprises administering to a human or animal in need of such treatment a compound of the formula: ##STR21## wherein: a is an integer of 1 to 4; A is a bond, or alkylene having one to eight carbon atoms; R is hydrogen, phenyl, imidazolyl or cycloalkyl having three to six carbon atoms, wherein the phenyl, imidazolyl or cycloalkyl ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of lower alkyl having one to four carbon atoms, lower alkoxy having one to four carbon atoms, --N(R 1 ) 2 , --NO 2 , halo or lower alkylthio having one to four carbon atoms, and, at least one R' represents a substituent at one of the 5- and 7-positions, and each R' is independently selected from the group consisting of hydroxy, benzyloxy, lower alkyl having one to six atoms, lower alkenyl having two to six carbon atoms, lower alkoxy having one to six carbon atoms, lower alkylthio or halo-lower alkyl having one to six carbon atoms, halo, --NO 2 , --N(R 1 ) 2 , --NR 1 CO 2 R 2 , --NR 1 COR 2 , and --NR 1 C(O)N(R 1 ) 2 , in which each R 1 is independently hydrogen or lower alkyl having one to four carbon atoms, or together form a piperidine or a piperazine ring optionally substituted at the ring nitrogen by lower alkyl having one to four carbon atoms or --CH 2 CH 2 OH; each R 2 is independently lower alkyl having one to four carbon atoms, A is an alkylene group if R is hydrogen, or a pharmaceutically acceptable acid addition salt thereof.
Claim 37
Dependent Claim
14 words
The method of claim 33 in which the serine protease is human leukocyte elastase.
Claim 38
Dependent Claim
12 words
The method of claim 33 in which the serine protease is trypsin.
Claim 39
Dependent Claim
283 words
A pharmaceutical composition which comprises a therapeutically effective amount of a compound of the formula: ##STR22## wherein: a is an integer of 1 to 4; A is a bond, or alkylene having one to eight carbon atoms; R is hydrogen, phenyl, imidazolyl or cycloalkyl having three to six carbon atoms, wherein the phenyl, imidazolyl or cycloalkyl ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of lower alkyl having one to four carbon atoms, lower alkoxy having one to four carbon atoms, --N(R 1 ) 2 , --NO 2 , halo or lower alkylthio having one to four carbon atoms, and, at least one R' represents a substituent at one of the 5- and 7-positions, and each R' is independently selected from the group consisting of hydroxy, benzyloxy, lower alkyl having one to six atoms, lower alkenyl having two to six carbon atoms, lower alkoxy having one to six carbon atoms, lower alkylthio or halo-lower alkyl having one to six carbon atoms, halo, --NO 2 , --N(R 1 ) 2 , --NR 1 CO 2 R 2 , --NR 1 COR 2 , and --NR 1 C(O)N(R 1 ) 2 , in which each R 1 is independently hydrogen or lower alkyl having one to four carbon atoms, or together form a piperidine or a piperazine ring optionally substituted at the ring nitrogen by lower alkyl having one to four carbon atoms or --CH 2 CH 2 OH; each R 2 is independently lower alkyl having one to four carbon atoms, A is an alkylene group if R is hydrogen,, or a pharmaceutically acceptable acid addition salt thereof, in admixture with at least one pharmaceutically acceptable excipient.
Claim 40
Dependent Claim
283 words
A pharmaceutical composition which comprises a therapeutically effective amount of a compound of the formula: ##STR22## wherein: a is an integer of 1 to 4; A is a bond, or alkylene having one to eight carbon atoms; R is hydrogen, phenyl, imidazolyl or cycloalkyl having three to six carbon atoms, wherein the phenyl, imidazolyl or cycloalkyl ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of lower alkyl having one to four carbon atoms, lower alkoxy having one to four carbon atoms, --N(R 1 ) 2 , --NO 2 , halo or lower alkylthio having one to four carbon atoms, and, at least one R' represents a substituent at one of the 5- and 7-positions, and each R' is independently selected from the group consisting of hydroxy, benzyloxy, lower alkyl having one to six atoms, lower alkenyl having two to six carbon atoms, lower alkoxy having one to six carbon atoms, lower alkylthio or halo-lower alkyl having one to six carbon atoms, halo, --NO 2 , --N(R 1 ) 2 , --NR 1 CO 2 R 2 , --NR 1 COR 2 , and --NR 1 C(O)N(R 1 ) 2 , in which each R 1 is independently hydrogen or lower alkyl having one to four carbon atoms, or together form a piperidine or a piperazine ring optionally substituted at the ring nitrogen by lower alkyl having one to four carbon atoms or --CH 2 CH 2 OH; each R 2 is independently lower alkyl having one to four carbon atoms, A is an alkylene group if R is hydrogen,, or a pharmaceutically acceptable acid addition salt thereof, in admixture with at least one pharmaceutically acceptable excipient.
Claim 41
Dependent Claim
32 words
A pharmaceutical composition which comprises a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable acid addition salt thereof, in admixture with at least one pharmaceutically acceptable excipient.
Claim 42
Dependent Claim
32 words
A pharmaceutical composition which comprises a therapeutically effective amount of a compound of claim 30, or a pharmaceutically acceptable acid addition salt thereof, in admixture with at least one pharmaceutically acceptable excipient.
References Cited (Backward Citations)
DE2241012A1
Cited
US4665070A
Cited
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| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
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| 3.5 Years (Year 4) | 1991-05-17 | 1991-11-16 | 1992-05-17 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1995-05-17 | 1995-11-16 | 1996-05-17 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1999-05-17 | 1999-11-16 | 2000-05-17 | $7700.00 | Window Closed / Lapsed |