US4665070A
Expired / Lapsed
US
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2-oxy-4H-3,1-benzoxazin-4-ones and pharmaceutical use
Assignee: Syntex USA LLC
•
Filing: 1985-06-25
•
Granted: 1987-05-12
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Expires: 2005-06-25
Abstract
Abstract 2-Oxy-4H-3,1-benzoxazin-4-ones represented by the formula: <IMAGE> (I) and the pharmaceutically acceptable acid addition salts thereof, wherein: a is an integer of 0-4; 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 1-3 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 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 four carbon atoms, halo, -NO2, -N(R1)2, <IMAGE> -NR1COR2, and <IMAGE> 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, and the pharmaceutically acceptable acid addition salts thereof are useful as serine protease inhibitors in humans and animals.
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 20:25
CPC Classifications
C; C07; C07D; C07D265/00; C07D265/04; C07D265/12; C07D265/14; C07D265/24; C07D265/26; A; A61; A61P; A61P43/00; C07D265/18; C07F; C07F9/00; C07F9/02; C07F9/547; C07F9/6527; C07F9/6533; C07F9/65335
Claims Analysis
Total Claims: 71
Claim 1
Independent Claim
219 words
A compound of the formula: ##STR33## wherein, a is an integer of 0-4; A is a bond, or alkylene having one to eight carbon atoms; R is phenyl, imidazolyl, or cycloalkyl having three to six carbon atoms, wherein the phenyl or cycloalkyl ring is optionally substituted with 1-3 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 thioalkyl having one to four carbon atoms, and each R' is independently selected from the group consisting of lower alkyl having one to six atoms, lower alkenyl having two to six carbon atoms, lower alkoxy having one to six carbon atoms, NO 2 , halo-lower alkyl or lower alkylthio having one to six carbon atoms, halo, --N(R 1 ) 2 , ##STR34## --NR 1 COR 2 and ##STR35## 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 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 carbon atoms, or a pharmaceutically acceptable acid addition salt thereof.
Claim 2
Dependent Claim
219 words
A compound of the formula: ##STR33## wherein, a is an integer of 0-4; A is a bond, or alkylene having one to eight carbon atoms; R is phenyl, imidazolyl, or cycloalkyl having three to six carbon atoms, wherein the phenyl or cycloalkyl ring is optionally substituted with 1-3 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 thioalkyl having one to four carbon atoms, and each R' is independently selected from the group consisting of lower alkyl having one to six atoms, lower alkenyl having two to six carbon atoms, lower alkoxy having one to six carbon atoms, NO 2 , halo-lower alkyl or lower alkylthio having one to six carbon atoms, halo, --N(R 1 ) 2 , ##STR34## --NR 1 COR 2 and ##STR35## 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 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 carbon atoms, or a pharmaceutically acceptable acid addition salt thereof.
Claim 3
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 4
Dependent Claim
16 words
A compound of claim 1 in which A is alkylene having one to four carbon atoms.
Claim 5
Dependent Claim
10 words
A compound of claim 3 in which A is methylene.
Claim 6
Dependent Claim
12 words
A compound of claim 1 in which a is at least one.
Claim 7
Dependent Claim
13 words
A compound of claim 5 in which an R' is in the 5-position.
Claim 8
Dependent Claim
21 words
A compound of claim 6 in which the R' in the 5-position is lower alkyl having one to three carbon atoms.
Claim 9
Dependent Claim
13 words
A compound of claim 5 in which an R' is in the 7-position.
Claim 10
Dependent Claim
35 words
A compound of claim 8 in which A is methylene, R is phenyl, a is 2, and R' is methoxy in the 6- and 7-positions, namely 2-benzyloxy-6,7-dimethoxy-4H-3,1-benzoxazin-4-one, or a pharmaceutically acceptable acid addition salt thereof.
Claim 11
Dependent Claim
13 words
A compound of claim 6 in which an R' is in the 7-position.
Claim 12
Dependent Claim
63 words
A compound of claim 10 in which the R' at the 5-position is lower alkyl having one to six carbon atoms or lower alkenyl having two to six carbon atoms, and the R' at the 7-position is selected from the group consisting of lower alkoxy having one to six carbon atoms, --N(R 1 ) 2 , ##STR36## --NR 1 COR 2 and ##STR37##
Claim 13
Dependent Claim
54 words
A compound of claim 11 in which the R' in the 5-position is lower alkyl having one to three carbon atoms and the R' in 7-position is --N(R 1 ) 2 or --NR 1 COOR 2 in which each R 1 is independently hydrogen, methyl or ethyl and R 2 is methyl or ethyl.
Claim 14
Dependent Claim
178 words
A compound of the formula: ##STR38## 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, wherein said substituent is independently selected from the group consisting of lower alkyl having one to six carbon atoms, lower alkoxy 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 , ##STR39## --NR 1 COR 2 , and ##STR40## 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 carbon atoms, or a pharmaceutically acceptable acid addition salt thereof.
Claim 15
Dependent Claim
178 words
A compound of the formula: ##STR38## 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, wherein said substituent is independently selected from the group consisting of lower alkyl having one to six carbon atoms, lower alkoxy 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 , ##STR39## --NR 1 COR 2 , and ##STR40## 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 carbon atoms, or a pharmaceutically acceptable acid addition salt thereof.
Claim 16
Dependent Claim
16 words
A compound of claim 13 in which A is alkylene having one to four carbon atoms.
Claim 17
Dependent Claim
12 words
A compound of claim 14 in which A is methylene or ethylene.
Claim 18
Dependent Claim
13 words
A compound of claim 15 in which an R' is in the 5-position.
Claim 19
Dependent Claim
13 words
A compound of claim 13 in which an R' is in the 7-position.
Claim 20
Dependent Claim
12 words
A compound of claim 17 in which A is ethylene or methylene.
Claim 21
Dependent Claim
31 words
A compound of claim 18 in which R' is selected from the group consisting of --NO 2 , --N(R 1 ) 2 , ##STR41## --NR 1 COR 2 , and ##STR42##
Claim 22
Dependent Claim
13 words
A compound of claim 16 in which an R' is in the 7-position.
Claim 23
Dependent Claim
19 words
A compound of claim 16 in which A is ethylene, a is 1 and R' is ethyl, namely 2-ethoxy-5-ethyl-4H-3,1-benzoxazin-4-one.
Claim 24
Dependent Claim
19 words
A compound of claim 16 in which A is ethylene, a is 1 and R' is methyl, namely 2-ethoxy-5-methyl-4H-3,1-benzoxazin-4-one.
Claim 25
Dependent Claim
19 words
A compound of claim 16 in which A is ethylene, a is 1 and R' is n-propyl, namely 2-ethoxy-5-n-propyl-4H-3,1-benzoxazin-4-one.
Claim 26
Dependent Claim
19 words
A compound of claim 16 in which A is ethylene, a is 1 and R' is isopropyl, namely 2-ethoxy-5-isopropyl-4H-3,1-benzoxazin-4-one.
Claim 27
Dependent Claim
63 words
A compound of claim 20 in which the R' in the 5-position is lower alkyl havng one to six carbon atoms or lower alkenyl having two to six carbon atoms, and the R' in the 7-position is selected from the group consisting of lower alkoxy having one to six carbon atoms, --N(R 1 ) 2 , ##STR43## --NR 1 COR 2 and ##STR44##
Claim 28
Dependent Claim
55 words
A compound of claim 25 in which the R' in the 5-position is lower alkyl having one to three carbon atoms and the R' in the 7-position is --N(R 1 ) 2 or --NR 1 COOR 2 in which each R 1 is independently hydrogen, methyl or ethyl and R 2 is methyl or ethyl.
Claim 29
Dependent Claim
183 words
A compound of the formula: ##STR45## wherein: a is an integer of 2 to 4; A is alkylene having one to eight carbon atoms; R is hydrogen; and a first R' represents a substituent at the 5-position, and a second R' represents a substituent at the 7-position, and each R' is independently selected from the group consisting of lower alkyl having one to six carbon atoms, lower alkenyl having two to six carbon atoms, lower alkoxy having one to six carbon atoms, halo, halo-lower alkyl having one to six carbon atoms, lower alkylthio having one to six carbon atoms, --NO 2 , --N(R 1 ) 2 , ##STR46## --NR 1 COR 2 , and ##STR47## 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 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 carbon atoms, or a pharmaceutically acceptable acid addition salt thereof.
Claim 30
Dependent Claim
183 words
A compound of the formula: ##STR45## wherein: a is an integer of 2 to 4; A is alkylene having one to eight carbon atoms; R is hydrogen; and a first R' represents a substituent at the 5-position, and a second R' represents a substituent at the 7-position, and each R' is independently selected from the group consisting of lower alkyl having one to six carbon atoms, lower alkenyl having two to six carbon atoms, lower alkoxy having one to six carbon atoms, halo, halo-lower alkyl having one to six carbon atoms, lower alkylthio having one to six carbon atoms, --NO 2 , --N(R 1 ) 2 , ##STR46## --NR 1 COR 2 , and ##STR47## 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 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 carbon atoms, or a pharmaceutically acceptable acid addition salt thereof.
Claim 31
Dependent Claim
13 words
A compound of claim 27 in which an R' is in the 5-position.
Claim 32
Dependent Claim
13 words
A compound of claim 28 in which an R' is in the 7-position.
Claim 33
Dependent Claim
21 words
A compound of claim 28 in which the R' in the 5-position is lower alkyl having one to three carbon atoms.
Claim 34
Dependent Claim
46 words
A compound of claim 29 in which the R' in the 5-position is lower alkyl or lower alkenyl and the R' in the 7-position is selected from the group consisting of lower alkoxy, --N(R 1 ) 2 , ##STR48## --NR 1 COR 2 , and ##STR49##
Claim 35
Dependent Claim
55 words
A compound of claim 31 in which the R' in the 5-position is lower alkyl having one to three carbon atoms and the R' in the 7-position is --N(R 1 ) 2 or --NR 1 COOR 1 in which each R 1 is independently hydrogen, methyl or ethyl and R 2 is methyl or ethyl.
Claim 36
Dependent Claim
237 words
A compound of the formula: ##STR50## 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 thre to six carbon atoms, wherein the phenyl, imidazolyl or cycloalkyl ring is optionally substituted with 1-3 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 thioalkyl having one to four carbon atoms; and each R' and R" are independently selected from the group consisting of 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 COR 2 , ##STR51## 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 37
Dependent Claim
237 words
A compound of the formula: ##STR50## 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 thre to six carbon atoms, wherein the phenyl, imidazolyl or cycloalkyl ring is optionally substituted with 1-3 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 thioalkyl having one to four carbon atoms; and each R' and R" are independently selected from the group consisting of 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 COR 2 , ##STR51## 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 38
Dependent Claim
16 words
A compound of claim 33 in which A is alkylene of one to four carbon atoms.
Claim 39
Dependent Claim
12 words
A compound of claim 34 in which A is methylene or ethylene.
Claim 40
Dependent Claim
26 words
A compound of claim 33 in which R" is lower alkyl having one to six carbon atoms or lower alkenyl having two to six carbon atoms.
Claim 41
Dependent Claim
17 words
A compound of claim 36 in which R" is lower alkyl having one to three carbon atoms.
Claim 42
Dependent Claim
10 words
A compound of claim 37 in which a is zero.
Claim 43
Dependent Claim
12 words
A compound of claim 37 in which a is at least one.
Claim 44
Dependent Claim
13 words
A compound of claim 39 in which an R' is in the 7-position.
Claim 45
Dependent Claim
39 words
A compound of claim 40 in which the R' in the 7-position is selected from the group consisting of lower alkoxy having one to six carbon atoms, --N(R 1 ) 2 , ##STR52## --NR 1 COR 2 and ##STR53##
Claim 46
Dependent Claim
26 words
A compound of claim 41 in which R" is lower alkyl having one to six carbon atoms or lower alkenyl having two to six carbon atoms.
Claim 47
Dependent Claim
52 words
A compound of claim 42 in which the R" is lower alkyl having one to three carbon atoms and the R' in the 7-position is --N(R 1 ) 2 or --NR 1 COOR 1 in which each R 1 is independently hydrogen, methyl or ethyl and R 2 is methyl or ethyl.
Claim 48
Dependent Claim
253 words
A compound of the formula: ##STR54## wherein: a is 1 or 2 and represents the number of R' substituents; 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 or cycloalkyl ring is optionally substituted with 1-3 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 thioalkyl having one to four carbon atoms; and each R' represents a substituent at one of the 5- or 7-positions, wherein said substituent is independently selected from the group consisting of lower alkyl having one to six carbon atoms, lower alkenyl having two to six carbon atoms, lower alkoxy having one to six carbon atoms, halo, --NO 2 , halo-lower alkyl having one to six carbon atoms, lower alkylthio having one to six carbon atoms, --N(R 1 ) 2 , ##STR55## --NR 1 COR 2 , and ##STR56## 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 49
Dependent Claim
253 words
A compound of the formula: ##STR54## wherein: a is 1 or 2 and represents the number of R' substituents; 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 or cycloalkyl ring is optionally substituted with 1-3 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 thioalkyl having one to four carbon atoms; and each R' represents a substituent at one of the 5- or 7-positions, wherein said substituent is independently selected from the group consisting of lower alkyl having one to six carbon atoms, lower alkenyl having two to six carbon atoms, lower alkoxy having one to six carbon atoms, halo, --NO 2 , halo-lower alkyl having one to six carbon atoms, lower alkylthio having one to six carbon atoms, --N(R 1 ) 2 , ##STR55## --NR 1 COR 2 , and ##STR56## 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 50
Dependent Claim
16 words
A compound of claim 44 in which A is alkylene having one to eight carbon atoms.
Claim 51
Dependent Claim
18 words
A compound of claim 45 in which a is 1 and R' is in the 5-position or 7-position.
Claim 52
Dependent Claim
18 words
A compound of claim 45 in which a is 2 and R' is in the 5- and 7-positions.
Claim 53
Dependent Claim
39 words
A compound of claim 47 in which A is ethylene, a first R' is in the 5-position and is lower alkyl, and a second R' is in the 7-position and is --N(R 1 ) 2 or --NO 2 .
Claim 54
Dependent Claim
31 words
A compound of claim 48 in which the first R' is methyl and the second R' is --N(R 1 ) 2 wherein each R 1 is independently hydrogen or lower alkyl.
Claim 55
Dependent Claim
22 words
The compound of claim 49 in which the first R' is methyl and the second R' is --NH 2 , namely 7-amino-2-ethoxy-5-methyl-4H-3,1-benzoxazin-4-one.
Claim 56
Dependent Claim
22 words
The compound of claim 48 in which the first R' is ethyl and the second R' is --NH 2 , namely 7-amino-2-ethoxy-5-ethyl-4H-3,1-benzoxazin-4-one.
Claim 57
Dependent Claim
22 words
A compound of claim 48 in which the first R' is methyl and the second R' is --NO 2 , namely 2-ethoxy-5-methyl-7-nitro-4H-3,1-benzoxazin-4-one.
Claim 58
Dependent Claim
22 words
A compound of claim 48 is which the first R' is ethyl and the second R' is --NO 2 , namely 2-ethoxy-5-ethyl-7-nitro-4H-3,1-benzoxazin-4-one.
Claim 59
Dependent Claim
32 words
A pharmaceutical composition which comprises a therapeutically effective amount of a compound of claim 13, of a pharmaceutically acceptable acid addition salt thereof, in admixture with at least one pharmaceutically acceptable excipient.
Claim 60
Dependent Claim
32 words
A pharmaceutical composition which comprises a therapeutically effective amount of a compound of claim 27, or a pharmaceutically acceptable acid addition salt thereof, in admixture with at least one pharmaceutically acceptable excipient.
Claim 61
Dependent Claim
32 words
A pharmaceutical composition which comprises a therapeutically effective amount of a compound of claim 33, or a pharmaceutically acceptable acid addition salt thereof, in admixture with at least one pharmaceutically acceptable excipient.
Claim 62
Dependent Claim
32 words
A pharmaceutical composition which comprises a therapeutically effective amount of a compound of claim 44, or a pharmaceutically acceptable acid addition salt thereof, in admixture with at least one pharmaceutically acceptable excipient.
Claim 63
Independent Claim
276 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: ##STR57## 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 or cycloalkyl ring is optionally substituted with 1-3 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 thioalkyl having one to four carbon atoms; and at least one R' is represents a substituent at one of the 5- and 7-positions, wherein said substituent is independently selected from the group consisting of lower alkyl having one to six carbon atoms, lower alkenyl having two to six carbon atoms, lower alkoxy having one to six carbon atoms, --NO 2 , halo-lower alkyl having one to six carbon atoms, lower alkylthio having one to six carbon atoms, halo, --N(R 1 ) 2 , ##STR58## --NR 1 COR 2 , and ##STR59## 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 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 64
Independent Claim
276 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: ##STR57## 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 or cycloalkyl ring is optionally substituted with 1-3 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 thioalkyl having one to four carbon atoms; and at least one R' is represents a substituent at one of the 5- and 7-positions, wherein said substituent is independently selected from the group consisting of lower alkyl having one to six carbon atoms, lower alkenyl having two to six carbon atoms, lower alkoxy having one to six carbon atoms, --NO 2 , halo-lower alkyl having one to six carbon atoms, lower alkylthio having one to six carbon atoms, halo, --N(R 1 ) 2 , ##STR58## --NR 1 COR 2 , and ##STR59## 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 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 65
Dependent Claim
14 words
The method of claim 58 in which the serine protease is human leukocyte elastase.
Claim 66
Dependent Claim
12 words
The method of claim 58 in which the serine protease is trypsin.
Claim 67
Dependent Claim
28 words
The method of claim 46 in which a is 1, R' is in the 5-position and is lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkyl, or lower alkylthio.
Claim 68
Dependent Claim
34 words
The method of claim 58 in which a is 1, R' is in the 7-position and R' is --NO 2 , --N(R 1 ) 2 , ##STR60## --NR 1 COR 2 , or ##STR61##
Claim 69
Dependent Claim
68 words
The method of claim 58 in which a is 2, a first R' is in the 5-position and is selected from the group consisting of lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkyl, and lower alkylthio, and a second R' is in the 7-position and is selected from the group consisting of --NO 2 , --N(R 1 ) 2 , ##STR62## --NR 1 COR 2 , and ##STR63##
Claim 70
Dependent Claim
232 words
A compound of the formula ##STR64## wherein: a is an integer of 1 to 3; 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 or cycloalkyl ring is optionally substituted with 1-3 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 thioalkyl having one to four carbon atoms; R"' is hydrogen or lower alkyl having one to six carbon atoms; and each R' is independently selected from the group consisting of lower alkyl having one to six carbon atoms, lower alkenyl having two to six carbon atoms, lower alkoxy having one to six carbon atoms, halo-lower alkyl or lower alkylthio having one to six carbon atoms, halo, --N(R 1 ) 2 , ##STR65## --NR 1 COR 2 , and ##STR66## in which each R 1 is independently hydrogen or lower alkyl having one to four carbon atoms, or together form a piperazine or piperidine 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.
Claim 71
Dependent Claim
232 words
A compound of the formula ##STR64## wherein: a is an integer of 1 to 3; 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 or cycloalkyl ring is optionally substituted with 1-3 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 thioalkyl having one to four carbon atoms; R"' is hydrogen or lower alkyl having one to six carbon atoms; and each R' is independently selected from the group consisting of lower alkyl having one to six carbon atoms, lower alkenyl having two to six carbon atoms, lower alkoxy having one to six carbon atoms, halo-lower alkyl or lower alkylthio having one to six carbon atoms, halo, --N(R 1 ) 2 , ##STR65## --NR 1 COR 2 , and ##STR66## in which each R 1 is independently hydrogen or lower alkyl having one to four carbon atoms, or together form a piperazine or piperidine 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.
References Cited (Backward Citations)
DE2241012A1
Cited
GB1389128A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1990-05-11 | 1990-11-10 | 1991-05-12 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1994-05-11 | 1994-11-10 | 1995-05-12 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1998-05-11 | 1998-11-10 | 1999-05-12 | $7700.00 | Window Closed / Lapsed |