# US 5,348,953 A · Substituted azetidinones as anti-inflammatory and antidegenerative agents

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- Number: US 5,348,953 A
- Document ID: US5348953A
- Status: Granted
- Kind: A
- Application number: 07/992,414
- Filed: 1992-12-17
- Granted: 1994-09-20
- Earliest claimed: 1991-06-25
- Assignees: Merck & Co., Inc.
- Inventors: James B. Doherty; Paul E. Finke; William K. Hagmann; Amy L. Kissinger; Malcolm MacCoss; Shrenik K. Shah
- Web page: https://patentgrep.com/patent/US5348953A

## CPC

- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 205/08: with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

New substituted azetidinones of the general formula (I) which have been found to be potent elastase inhibitors and thereby useful anti-inflammatory and antidegenerative agents are described. ##STR1##

## Claims

### Claim 1

A compound of formula I ##STR37## wherein R is C.sub.1-6 alkyl;
R.sup.1 is C.sub.1-6 alkyl or C.sub.1-6 alkoxy-C.sub.1-6 alkyl;
M is
(1) hydrogen,
(2) C.sub.1-6 alkyl,
(3) hydroxy C.sub.1-6 alkyl,
(4) halo C.sub.1-6 alkyl,
(5) C.sub.2-6 alkenyl, or
(6) C.sub.1-6 alkoxy-C.sub.1-6 alkyl;
R.sup.2 and R.sup.3 are each independently
(1) hydrogen,
(2) C.sub.1-6 alkyl,
(3) halo,
(4) carboxy,
(5) C.sub.1-6 alkoxy,
(6) phenyl,
(7) C.sub.1-6 alkylcarbonyl,
(8) di-(C.sub.1-6 alkyl)amino, or
R.sup.2 and R.sup.3 are joined together to form the group 3,4-methylenedioxy or a furan ring;
R.sub.4 is ##STR38## wherein R.sub.5 and R.sub.6 are each individually hydrogen or C.sub.1-3 alkyl;
Y is
(a) ##STR39## R.sub.7 and R.sub.8 are each individually (a) hydrogen,
(b) C.sub.1-6 alkyl,
(c) hydroxy C.sub.2-6 alkyl,
(d) C.sub.3-5 cycloalkyl,
(e) C.sub.1-6 alkylcarbonyl,
(f) C.sub.1-6 alkyloxy carbonyl,
(g) amino carbonyl C.sub.1-6 alkyl, wherein the amino is optionally mono or di substituted with C.sub.1-6 alkyl, or
(h) carboxy C.sub.1-6 alkyl,
(i) C.sub.1-6 alkoxycarbonyl C.sub.1-6 alkyl,
(j) mono or di substituted benzyl or mono or di substituted pyridylmethyl, wherein the substitutents are X.sub.1 and X.sub.2,
wherein
X.sub.1 is
(1) hydrogen,
(2) halo,
(3) C.sub.1-6 alkyl,
(4) halo-C.sub.1-6 alkyl,
(5) C.sub.2-6 alkenyl,
(6) hydroxy-C.sub.1-6 alkyl,
(7) C.sub.1-6 alkylcarbonyl, or
(8) C.sub.1-6 alkylcarbonylamino; and
X.sub.2 is hydrogen, halo or C.sub.1-6 alkyl;
n is 1, 2 or 3; and
R.sub.9, R.sub.10 and R.sub.11 are each independently selected from hydrogen, C.sub.1-4 alkyl, and C.sub.1-3 alkoxy C.sub.1-3 alkyl; or
wherein R.sub.7 and R.sub.8 are joined together to form mono or di substituted ring of 5, 6, or 7 atoms selected from
(1) piperidinyl,
(2) piperazinyl,
(3) morpholinyl,
(4) pyrroylidinyl,
(5) pyrryl, and
(6) imidazolyl,
wherein the substituents are each selected from the group consisting of hydrogen and C.sub.1-3 alkyl; or R.sub.8 and R.sub.9 are joined together with the nitrogens to which they are attached there is formed a saturated monocyclic ring of 6 to 7 atoms having two hetero atoms; or R.sub.9 and R.sub.10 are joined together with the nitrogen to which R.sub.9 is attached there is formed a saturated monocyclic ring of 5 to 7 atoms having one hetero atom.

### Claim 2

A compound which is
2-(S)-2[2-[4-methyl-piperazin-1-yl]-2-oxoethoxy]-3,3-diethyl-N-[1-(R)-(4-me thylphenyl)butyl]-4-oxo-1-azetidinecarboxamide; or
2-(S)-2-[2-[4-methyl-piperazin-1-oxo-ethoxy]-3,3-diethyl-N-[1-(R)-(3,4-meth ylenedioxyphenyl)butyl]-4-oxo-1-azetidinecarboxamide.

### Claim 3 (depends on 2)

A compound according to claim 2 wherein at least one of R.sub.5 and R.sub.6 is other than hydrogen.

### Claim 4

A compound of Formula I ##STR40## or a pharmaceutically acceptable salt thereof wherein: wherein
R is C.sub.1-3 alkyl;
R.sub.1 is C.sub.1-3 alkyl;
M is
(a) C.sub.1-6 alkyl, or
(b) C.sub.2-6 alkenyl;
R.sup.2 is
(a) hydrogen
(b) C.sub.1-6 alkyl, or C.sub.1-6 alkoxy, and
R.sup.3 is hydrogen, or
R.sup.2 and R.sup.3 are joined together to form the group 3,4-methylenedioxy or a furan ring;
R.sub.4 is ##STR41## R.sub.5 is hydrogen or C.sub.1-3 alkyl; R.sub.6 is hydrogen;
Y is ##STR42## R.sub.7 and R.sub.8 are each independently selected from (a) hydrogen,
(b) C.sub.1-3 alkyl,
(c) C.sub.1-3 alkoxy C.sub.2-3 alkyl,
(d) aminocarbonylmethyl,
(e) substituted benzyl wherein the substituents are X.sub.1 and X.sub.2
wherein X.sub.1 is hydrogen and X.sub.2 is
(1) hydrogen,
(2) halo, or
(3) C.sub.1-3 alkyl;
n is 1, 2 or 3, and
R.sub.9, R.sub.10 and R.sub.11 are each independently selected from hydrogen,
C.sub.1-4 alkyl, and C.sub.1-3 alkoxy C.sub.1-3 alkyl; or
R.sub.7 and R.sub.8 are joined together to form a substituted ring selected from
(a) piperidinyl,
(b) piperazinyl, and
(c) morpholinyl; or
R.sub.8 and R.sub.9 are joined together with the nitrogens connecting them to form an unsubstituted saturated monocyclic ring of 6 to 7 atoms having two hetero atoms; or R.sub.9 and R.sub.10 are joined together with the atoms connecting them to form an unsubstituted saturated monocyclic ring of 5 to 7 atoms having one hereto atom.

### Claim 5 (depends on 4)

A compound according to claim 4 wherein
R is methyl or ethyl;
R.sub.1 is methyl or ethyl;
M is
(a) C.sub.1-4 alkyl, or
(b) C.sub.2-3 alkenyl;
R.sup.2 is
(a) hydrogen,
(b) C.sub.1-3 alkyl, or C.sub.1-3 alkoxy, and
R.sup.3 is hydrogen, or
R.sup.2 and R.sup.3 are joined together to form the group 3,4-methylenedioxy or a furan ring;
Y is ##STR43## n is 1 or 2; R.sub.7 and R.sub.8 are each independently selected from
(a) hydrogen,
(b) C.sub.1-3 alkyl,
(c) C.sub.1-3 alkoxy C.sub.2-3 alkyl,
(d) aminocarbonylmethyl,
(e) substituted benzyl wherein the substituents are X.sub.1 and X.sub.2
wherein X.sub.1 is hydrogen and X.sub.2 is
(1) hydrogen,
(2) halo, or
(3) C.sub.1-3 alkyl;
R.sub.9, R.sub.10 and R.sub.11 are each independently selected from
(a) hydrogen,
(b) C1-3 alkyl, or
(c) Ci.sub.1-3 alkoxy C.sub.1-3 alkyl,
R.sub.7 and R.sub.8 are joined together to form a substituted ring selected from
(a) piperidinyl, and
(c) morpholinyl.

### Claim 6 (depends on 2)

A compound according to claim 2 wherein R.sub.5 and R.sub.6 are each hydrogen.

### Claim 7 (depends on 6)

A compound according to claim 6 wherein
R is C.sub.1-3 alkyl;
R.sub.1 is C.sub.1-3 alkyl;
M is
(a) C.sub.1-6 alkyl, or
(b) C.sub.2-6 alkenyl;
R.sup.2 is
(a) hydrogen
(b) C.sub.1-6 alkyl, or C.sub.1-6 alkoxy, and
R.sup.3 is hydrogen, or
R.sup.2 and R.sup.3 are joined together to form the group 3,4-methylenedioxy or a furan ring;
Y is ##STR44## R.sub.7 and R.sub.8 are each independently selected from (a) hydrogen,
(b) C.sub.1-3 alkyl,
(c) C.sub.1-3 alkoxy C.sub.2-3 alkyl,
(d) aminocarbonylmethyl wherein the amino is optionally mono or di substituted with C.sub.1-3 alkyl,
(e) substituted benzyl or pyridylmethyl wherein the substituents are X.sub.1 and X.sub.2
wherein X.sub.1 is hydrogen and X.sub.2 is
(1) hydrogen
(2) halo or
(3) C.sub.1-3 alkyl;
n is 1, 2 or 3; and
R.sub.9, R.sub.10 and R.sub.11 are each independently selected from hydrogen, C.sub.1-4 alkyl, and C.sub.1-3 alkoxy C.sub.1-3 alkyl; or
wherein R.sub.7 and R.sub.8 are joined together to form mono or di substituted ring of 5, 6, or 7 atoms selected from
(1) piperidinyl,
(2) piperazinyl,
(3) morpholinyl,
(4) pyrroylidinyl,
(5) pyrryl, and
(6) imidazolyl,
wherein the substituents are each selected from the group consisting of hydrogen and C.sub.1-3 alkyl; or R.sub.8 and R.sub.9 are joined together with the nitrogens connecting them to form an unsubstituted saturated monocyclic ring of 6 to 7 atoms having two hetero atoms; or R.sub.9 and R.sub.10 are joined together with the atoms connecting them to form an unsubstituted saturated monocyclic ring of 5 to 7 atoms having one hetero atom.

### Claim 8 (depends on 7)

A compound according to claim 7 wherein
R is methyl or ethyl;
R.sub.1 is methyl or ethyl;
M is
(a) C.sub.1-4 alkyl, or
(b) C.sub.2-3 alkenyl;
R.sup.2 is
(a) hydrogen,
(b) C.sub.1-3 alkyl, or C.sub.1-3 alkoxy, and
R.sup.3 is hydrogen, or
R.sup.2 and R.sup.3 are joined together to form the group 3,4-methylenedioxy or a furan ring;
Y is ##STR45## R.sub.7 and R.sub.8 are each independently selected frown (a) hydrogen,
(b) C.sub.1-3 alkyl,
(c) C.sub.1-3 alkoxy C.sub.2-3 alkyl,
(d) aminocarbonylmethyl
n is 1, 2 or 3; and
R.sub.9, R.sub.10 and R .sub.11 are each independently selected from hydrogen,
C.sub.1-4 alkyl, and C.sub.1-3 alkoxy C.sub.1-3 alkyl; or
wherein R.sub.7 and R.sub.8 are joined together to form mono or di substituted ring of 5, 6, or 7 atoms selected from
(1) piperidinyl,
(2) morpholinyl, and
(3) imidazolyl,
wherein the substituents are each selected from the group consisting of hydrogen and C.sub.1-3 alkyl; or R.sub.8 and R.sub.9 are joined together with the nitrogens connecting them to form an unsubstituted saturated monocyclic ring of 6 to 7 atoms having two hereto atoms; or R.sub.9 and R.sub.10 are joined together with the atoms connecting them to form an unsubstituted saturated monocyclic ring of 5 to 7 atoms having one hetero atom.

### Claim 9

A compound of the Formula (I) ##STR46## or a pharmaceutically acceptable salt thereof wherein: R is C.sub.1-6 alkyl;
R.sup.1 is C.sub.1-6 alkyl or C.sub.1-6 alkoxy-C.sub.1-6 alkyl;
M is
(1) hydrogen,
(2) C.sub.1-6 alkyl,
(3) hydroxy C.sub.1-6 alkyl,
(4) halo C.sub.1-6 alkyl,
(5) C.sub.2-6 alkenyl, or
(6) C.sub.1-6 alkoxy-C.sub.1-6 alkyl;
R.sup.2 and R.sup.3 are each independently
(1) hydrogen,
(2) C.sub.1-6 alkyl,
(3) halo,
(4) carboxy,
(5) C.sub.1-6 alkoxy,
(6) phenyl,
(7) C.sub.1-6 alkylcarbonyl,
(8) di-(C.sub.1-6 alkyl)amino, or
R.sup.2 and R.sup.3 are joined together to form the group 3,4-methylenedioxy or a furan ring;
R.sub.4 is ##STR47## R.sub.5 and R.sub.6 are each individually hydrogen or C.sub.1-3 alkyl; Y is ##STR48## R.sub.7 and R.sub.8 are each individually (a) hydrogen,
(b) C.sub.1-6 alkyl,
(c) C.sub.1-6 alkyloxy C.sub.2-6 alkyl;
n is 1, 2 or 3; and R.sub.10 and R.sub.11 are each independently selected from hydrogen, C.sub.1-4 alkyl, and C.sub.1-3 alkoxy C.sub.1-3 alkyl; or
wherein R.sub.7 and R.sub.8 are joined together to form mono or di substituted ring of 5, 6, or 7 atoms selected from
(1) piperidinyl,
(2) piperazinyl,
(3) morpholinyl,
(4) pyrroylidinyl,
(5) pyrryl, and
(6) imidazolyl,
wherein the substituents are each selected from the group consisting of hydrogen and C.sub.1-3 alkyl.

### Claim 10 (depends on 9)

A compound according to claim 9 wherein R.sub.5 and R.sub.6 are each hydrogen.

### Claim 11 (depends on 10)

A compound according to claim 10 wherein
R is C.sub.1-3 alkyl;
R.sub.1 is C.sub.1-3 alkyl;
M is
(a) C.sub.1-6 alkyl, or
(b) C.sub.2-6 alkenyl;
R.sup.2 is
(a) hydrogen
(b) C.sub.1-6 alkyl, or C.sub.1-6 alkoxy, and
R.sup.3 is hydrogen, or
R.sup.2 and R.sup.3 are joined together to form the group 3,4-methylenedioxy or a furan ring;
Y is ##STR49## n is 1 or 2; R.sub.7 and R.sub.8 are each independently selected from
(a) hydrogen,
(b) C.sub.1-3 alkyl,
(c) C.sub.1-3 alkoxy C.sub.2-3 alkyl,
or
R.sub.7 and R.sub.8 are joined together to form a
substituted ring selected from
(a) piperidinyl,
(b) piperazinyl,
(c) morpholinyl, and
(d) imidazolyl.

### Claim 12 (depends on 11)

A compound according to claim 11 wherein
R is methyl or ethyl;
R.sub.1 is methyl or ethyl;
M is
(a) C.sub.1-4 alkyl, or
(b) C.sub.2-3 alkenyl;
R.sup.2 is
(a) hydrogen,
(b) C.sub.1-3 alkyl, or C.sub.1-3 alkoxy, and
R.sup.3 is hydrogen, or
R.sup.2 and R.sup.3 are joined together to form the group 3,4-methylenedioxy or a furan ring;
Y is ##STR50## n is 1; R.sub.7 and R.sub.8 are each independently selected from
(a) C.sub.1-3 alkyl,
(b) C.sub.1-3 alkoxy C.sub.2-3 alkyl,
or
R.sub.7 and R.sub.8 are joined together to form a substituted ring selected from
(a) piperidinyl,
(b) morpholinyl, and
(c) imidazolyl.

### Claim 13

A compound of the Formula (I) ##STR51## or a pharmaceutically acceptable salt thereof wherein: R is C.sub.1-6 alkyl;
R.sup.1 is C.sub.1-6 alkyl or C.sub.1-6 alkoxy-C.sub.1-6 alkyl;
M is
(1) hydrogen,
(2) C.sub.1-6 alkyl,
(3) hydroxy C.sub.1-6 alkyl,
(4) halo C.sub.1-6 alkyl,
(5) C.sub.2-6 alkenyl, or
(6) C.sub.1-6 alkoxy-C.sub.1-6 alkyl;
R.sup.2 and R.sup.3 are each independently
(1) hydrogen,
(2) C.sub.1-6 alkyl,
(3) halo,
(4) carboxy,
(5) C.sub.1-6 alkoxy,
(6) phenyl,
(7) C.sub.1-6 alkylcarbonyl,
(8) di-(C.sub.1-6 alkyl)amino, or
R.sub.2 and R.sub.3 are joined together to form the group 3,4-methylenedioxy or a furan ring;
R.sub.4 is ##STR52## R.sub.5 and R.sub.6 are each individually hydrogen or C.sub.1-6 alkyl; Y is
(a) ##STR53## or (b) a co-valent bond;
R.sub.7 and R.sub.8 are each individually
(a) hydrogen,
(b) C.sub.1-6 alkyl,
(c) C.sub.1-6 alkyloxy C.sub.2-3 alkyl, or wherein R.sub.7 and R.sub.8 are joined together to form mono or di substituted ring of 5, 6, or 7 atoms selected from
(1) piperidinyl,
(2) piperazinyl,
(3) morpholinyl,
(4) pyrroylidinyl,
(5) pyrryl, and
(6) imidazolyl,
wherein the substituents are each selected from the group consisting of hydrogen and C.sub.1-3 alkyl; and wherein n is 0, 1, 2 or 3 and wherein R.sub.10 and R.sub.11, are each independently selected from hydrogen, C.sub.1-3 alkyl, and C.sub.1-3 alkoxy C.sub.1-3 alkyl.

### Claim 14 (depends on 13)

A compound according to claim 13 wherein R.sub.5 and R.sub.6 are each hydrogen.

### Claim 15 (depends on 14)

A compound according to claim 14 wherein
R is C.sub.1-3 alkyl;
R.sub.1 is C.sub.1-3 alkyl;
M is
(a) C.sub.1-6 alkyl, or
(b) C.sub.2-6 alkenyl;
R.sup.2 is
(a) hydrogen
(b) C.sub.1-6 alkyl, or C.sub.1-6 alkoxy, and
R.sup.3 is hydrogen, or
R.sup.2 and R.sup.3 are joined together to form the group 3,4-methylenedioxy or a furan ring;
Y is ##STR54## or (b) a co-valent bond;
R.sub.7 and R.sub.8 are each independently selected from
(a) hydrogen,
(b) C.sub.1-3 alkyl,
(c) C.sub.1-3 alkoxy C.sub.2-3 alkyl,
or
R.sub.7 and R.sub.8 are joined together to form a substituted ring selected from
(a) piperidinyl,
(b) piperazinyl,
(c) pyrrolidinyl,
(d) morpholinyl, and
(e) imidazolyl.

### Claim 16 (depends on 15)

A compound according to claim 15 wherein
R is methyl or ethyl;
R.sub.1 is methyl or ethyl;
M is
(a) C.sub.1-4 alkyl, or
(b) C.sub.2-3 alkenyl;
R.sub.2 is
(a) hydrogen,
(b) C.sub.1-3 alkyl, or C.sub.1-3 alkoxy, and
R.sub.3 is hydrogen, or
R.sup.2 and R.sup.3 are joined together to form the group 3,4-methylenedioxy or a furan ring;
R.sub.5 and R.sub.6 are each individually hydrogen;
Y is
(a) ##STR55## or (b) a co-valent bond;
n is 0 or 1;
R.sub.7 and R.sub.8 are each independently selected from
(a) C.sub.1-3 alkyl,
(b) C.sub.1-3 alkoxy C.sub.2-3 alkyl,
or
R.sub.7 and R.sub.8 are joined together to form a substituted ring selected from
(a) piperidinyl,
(b) morpholinyl, and
(c) imidazolyl.

### Claim 17

A compound selected from the group consisting of
(a) 2-(S)-[2-[[2-((Aminocarbonylmethyl)ethylamino)ethyl]-ethylamino]-2-oxoetho xy]-3,3-diethyl-N-[1-(R)-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamid e;
(b) 2-(S)-[2-[[2-(Dimethylamino)ethy]-ethylamino]-2-oxo-ethoxy]-3,3-diethyl-N- [1-(R)-(benzofuran-5-yl) butyl]-4-oxo-1-azetidinecarboxamide;
(c) 2-(S)-[2-[[2-(Diethylamino)ethy]-ethylamino]-2-oxoethoxy]-3,3-diethyl-N-[1 -(R)-(benzofuran-5-yl)butyl]-4-oxo-1-azetidinecarboxamide;
(d) 2-(S)-[2-[[2-(Diethylamino)ethy]-methylamino]-2-oxoethoxy]-3,3-diethyl-N-[ 1-(R)-(benzofuran-5-yl)butyl]-4-oxo-1-azetidinecarboxamide;
(e) 2-(S)-[2-[[2-(Dimethylamino)ethy]-methylamino]-2-oxoethoxy]-3,3-diethyl-N- [1-(R)-(benzofuran-5-yl)butyl]-4-oxo-1-azetidinecarboxamide;
(f) 2-(S)-[2-[[2-(Dimethylamino)ethy]-ethylamino]-2-oxo-ethoxyphenyl]-3,3-diet hyl-N-[1-(R)-(3,4-methylenedioxyphenyl)-butyl]-4-oxo-1-azetidinecarboxamide
(g) 2-(S)-[2-[[2-(Diethylamino)ethy]-ethylamino]-2-oxoethoxy]-3,3-diethyl-N-[1 -(R)-(3,4-methylenedioxyphenyl)butyl]-4-oxo-1-azetidinecarboxamide; and
(h) 2-(S)-[2-[[2-(2-Methoxyethyl)methylamino)ethy]-ethylamino]-2-oxoethoxy]-3, 3-diethyl-N-[1-(R)-(3,4-methylenedioxyphenyl)butyl]-4-oxo-1-azetidinecarbox amide.

### Claim 18

A compound selected from the group consisting of
(1) 2-(S)-[2-[[2-(Diethylamino)ethyl]propylamino]-2-oxoethoxy]-3,3-diethyl-N-[ 1-(R)-(4-methylphenyl) butyl]-4-oxo-1-azetidinecarboxamide;
(2) 2-(S)-[2-[[2-((2-Methoxyethyl)-ethylamino)ethyl]isopropylamino]-2-oxoethox y]-3,3-diethyl-N-[1-(R)-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide ;
(3) 2-(S)-[2-[[2-((2-Methoxyethyl)-methylamino)ethyl]ethylamino]-2-oxoethoxy]- 3,3-diethyl-N-[1-(R)-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide;
(4) 2-(S)-[2-[[2-(Isopropylmethylamino)ethyl]methylamino]-2-oxoethoxy]-3,3-die thyl-N-[1-(R)-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide;
(5) 2-(S)-[2-[[2-(Dimethylamino)ethyl]methylamino]-2-oxo-(1-(S)-methyl)ethoxy] -3,3-diethyl-N-[1-(R)-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide;
(6) 2-(S)-[2-[[2-(Diethylamino)ethyl]amino]-2-oxo-(1-(S)-methyl)ethoxy]-3,3-di ethyl-N-[1-(R)-(4-methyl-phenyl)butyl]-4-oxo-1-azetidinecarboxamide;
(7) 2-(S)-[2-[[2-(Dimethylamino)ethyl]amino]-2-oxo-(1-(S)-methyl)ethoxy]-3,3-d iethyl-N-[1-(R)-(4-methyl-phenyl)butyl]-4-oxo-1-azetidinecarboxamide;
(8) 2-(S)-[2-[[2-(Morpholin-1-yl)ethyl]amino]-2-oxo-1-(S)-methyl)ethoxy]-3,3-d iethyl-N-[1-(R)-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide;
(9) 2-(S)-[2-[[2-(Diisopropylamino)ethyl]amino]-2-oxo-(1-(S)-methyl)ethoxy]-3, 3-diethyl-N-[1-(R)-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide;
(10) 2-(S)-[2-[[2-(Dimethylamino)ethyl]ethylamino]-2-oxo-(1-(S)-methyl)ethoxy]- 3,3-diethyl-N-[1-(R)-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide; and
(11) 2-(S)-[2-[[2-(Diethylamino)ethyl]methylamino]-2-oxo-(1-(S)-methyl)ethoxy]- 3,3-diethyl-N-[1-(R)-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide;
(12) 2-(S)-[4-Ethylamino-2-oxo-butoxy]-3,3-diethyl-N-[1-(R)-(4-methylphenyl)but yl]-4-oxo-1-azetidinecarboxamide;
(13) 2-(S)-[4-Diethylamino-2-oxo-butoxy]-3,3-diethyl-N-[1-(R)-(4-methylphenyl)b utyl]-4-oxo-1-azetidinecarboxamide;
(14) 2-(S)-[2-[[2-(Ethylmethylamino)ethyl]-ethylamino]-2-oxoethoxy]-3,3-diethyl -N-[1-(R)-(4-methyl- phenyl)-butyl]-4-oxo-1-azetidinecarboxamide;
(15) 2-(S)-[2-[[2-Methylaminoethyl]-ethylamino]-2-oxoeth-oxy]-3,3-diethyl-N-[1- (R)-(4-methylphenyl) butyl]-4-oxo-1-azetidinecarboxamide;
(16) 2-(S)-[2-[[2-ethylamino-ethyl]-methylamino]-2-oxoethoxy]-3,3-diethyl-N-[1- (R)-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide;
(17) 2-(S)-[2-[[2-Aminoethyl]-ethylamino]-2-oxo-ethoxy]-3,3-diethyl-N-[1-(R)-(4 -methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide;
(18) 2-(S)-[2-[[2-ethylaminoethyl]-amino]-2-oxoethoxy]-3,3-diethyl-N-[1-(R)-(4- methylphenyl)-butyl]-4-oxo-1-azetidinecarboxamide;
(19) 2-(S)-[2-[[2-(Dimethylamino)ethyl]ethylamino]-2-oxo-1,1-dimethyl-ethoxy]-3 ,3-diethyl-N-[1-(R)-(4-methyl-phenyl)butyl]-4-oxo-1-azetidinecarboxamide;
(20) 2-(S)-[2-[[2-(Dimethylamino)ethyl]methylamino]-2-oxo-1,1-dimethyl-ethoxy]- 3,3-diethyl-N-[1-(R)-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide;
(21) 2-(S)-[2-[[2-(Diethylamino)ethyl]ethylamino]-2-oxo-1,1-dimethyl-ethoxy]-3, 3-diethyl-N-[1-(R)-(4- methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide;
(22) 2-(S)-[2-[[2-(Isopropylmethylamino)ethyl]methylamino]-2-oxo-1,1-dimethyl-e thoxy]-3,3-diethyl-N-[1-(R)-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxa mide;
(23) 2-(S)-[2-[[2-((2-Methoxyethyl)-methylamino)-ethyl]ethylamino]-2-oxo-1,1-di methyl-ethoxy]3,3-diethyl-N-[1-(R)-(4-methylphenyl)butyl]-4-oxo-1- azetidinecarboxamide; and
(24) 2-(S)-[2-(4-Morpholinyl)-2-oxoethoxy]-3,3-diethyl-N-[1-(R)-(4-methylphenyl )butyl]-4-oxo-1- azetidinecarboxamide.

### Claim 19 (depends on 1)

A pharmaceutical composition for the inhibition of human leukocyte elastase which comprises a nontoxic therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 20 (depends on 1)

A method of treatment for the inhibition of human leukocyte elastase which comprises the administration to a subject in need of such inhibition a nontoxic therapeutically effective amount of a compound of claim 1.

### Claim 21

A compound which is
2-(S)-[2-[[2-(Dimethylamino)ethyl]methylamino]-2-oxoethoxy]-3,3-diethyl-N-[ 1-(R)-(4-methylphenyl) butyl]-4-oxo-1-azetidinecarboxamide;
2-(S)-[2-[[2-(Dimethylamino)ethyl]ethylamino]-2-oxoethoxy]-3,3-diethyl-N-[1 -(R)-(4-methylphenyl) butyl]-4-oxo-1-azetidinecarboxamide or the L-malic acid salt thereof; or
2-(S)-[2-[[2-((2-Methoxyethyl)-methylamino)ethyl] ethylamino]-2-oxoethoxy]-3,3-diethyl-N-[1-(R)-(4-methylphenyl)butyl]-4-oxo -1-azetidinecarboxamide.

### Claim 22 (depends on 21)

A pharmaceutical composition for the inhibition of human leukocyte elastase which comprises a nontoxic therapeutically effective amount of a compound of claim 21 and a pharmaceutically acceptable carrier.

### Claim 23

A compound of the Formula (I) ##STR56## or a pharmaceutically acceptable salt thereof wherein: R is C.sub.1-6 alkyl;
R.sup.1 is C.sub.1-6 alkyl or C.sub.1-6 alkoxy-C.sub.1-6 alkyl;
M is
(1) hydrogen,
(2) C.sub.1-6 alkyl,
(3) hydroxy C.sub.1-6 alkyl,
(4) halo C.sub.1-6 alkyl,
(5) C.sub.2-6 alkenyl, or
(6) C.sub.1-6 alkoxy-C.sub.1-6 alkyl;
R.sup.2 and R.sup.3 are each independently
(1) hydrogen,
(2) C.sub.1-6 alkyl,
(3) halo,
(4) carboxy,
(5) C.sub.1-6 alkoxy,
(6) phenyl,
(7) C.sub.1-6 alkylcarbonyl,
(8) di-(C.sub.1-6 alkyl)amino, or
R.sup.2 and R.sup.3 are joined together to form the group 3,4-methylenedioxy or a furan ring;
R.sub.4 is ##STR57## wherein R.sub.5 and R.sub.6 are each individually hydrogen or C.sub.1-3 alkyl;
Y is ##STR58## R.sub.7 and R.sub.8 are each individually (a) hydrogen,
(b) C.sub.1-6 alkyl,
(c) hydroxy C.sub.2-6 alkyl,
(d) C.sub.3-5 cycloalkyl,
(e) C.sub.1-6 alkylcarbonyl,
(f) C.sub.1-6 alkyloxy carbonyl,
(g) amino carbonyl C.sub.0-6 alkyl, wherein the amino is optionally mono or di substituted with C.sub.1-6 alkyl, or
(h) carboxy C.sub.1-6 alkyl,
(i) C.sub.1-6 alkoxycarbonyl C.sub.1-6 alkyl,
(j) mono or di substituted benzyl or mono or di substituted pyridylmethyl, wherein the substitutents are X.sub.1 and X.sub.2,
wherein
X.sub.1 is
(1) hydrogen,
(2) halo,
(3) C.sub.1-6 alkyl,
(4) halo-C.sub.1-6 alkyl,
(5) C.sub.2-6 alkenyl,
(6) hydroxy-C.sub.1-6 alkyl,
(7) C.sub.1-6 alkylcarbonyl, or
(8) C.sub.1-6 alkylcarbonylamino; and
X.sub.2 is hydrogen, halo or C.sub.1-6 alkyl;
n is 1, 2 or 3;
R.sub.9, R.sub.10 and R.sub.11 are each independently selected from hydrogen, C.sub.1-4 alkyl, and C.sub.1-3 alkoxy C.sub.1-3 alkyl; or
wherein R.sub.7 and R.sub.8 are joined together to form mono or di substituted ring of 5, 6, or 7 atoms selected from
(1) piperidinyl,
(2) piperazinyl,
(3) morpholinyl,
(4) pyrroylidinyl,
(5) pyrryl, and
(6) imidazolyl,
wherein the substituents are each selected from the group consisting of hydrogen and C.sub.1-3 alkyl; or
R.sub.8 and R.sub.9 may be joined together with the atoms connecting them to form a mono or di substituted monocyclic saturated ring of 6 to 7 atoms and having two hetero atoms including the nitrogens to which they are attached; R.sub.9 and R.sub.10 may be joined together with the atoms connecting them to form a mono or di substituted monocyclic saturated ring of 5 to 7 atoms and having one hetero atom including the nitrogen to which R.sub.9 is attached; or R.sub.8 and R.sub.10 may be joined together with the atoms connecting them to form a mono or di substituted monocyclic saturated ring of 5 to 7 atoms including the atoms to which they are attached, said ring having one hetero atom;
wherein the substituents on the rings formed by R.sub.8 and R.sub.10 or R.sub.8 and R.sub.9 are selected from hydrogen, C.sub.1-3 alkyl and cyclopropyl; and the substitutents on the ring formed by joining R.sub.9 and R.sub.10 is selected from hydrogen and C.sub.1-3 alkyl.

### Claim 24 (depends on 23)

A compound according to claim 23 wherein
R is C.sub.1-6 alkyl;
R.sup.1 is C.sub.1-6 alkyl or C.sub.1-6 alkoxy-C.sub.1-6 alkyl;
M is
(1) hydrogen,
(2) C.sub.1-6 alkyl,
(3) hydroxy C.sub.1-6 alkyl,
(4) halo C.sub.1-6 alkyl,
(5) C.sub.2-6 alkenyl, or
(6) C.sub.1-6 alkoxy-C.sub.1-6 alkyl;
R.sup.2 and R.sup.3 are each independently
(1) hydrogen,
(2) C.sub.1-6 alkyl,
(3) halo,
(4) carboxy,
(5) C.sub.1-6 alkoxy,
(6) phenyl,
(7) C.sub.1-6 alkylcarbonyl,
(8) di-(C.sub.1-6 alkyl)amino, or
R.sup.2 and R.sup.3 are joined together to form the group 3,4-methylenedioxy or a furan ring;
R.sub.4 is ##STR59## wherein R.sub.5 and R.sub.6 are each individually hydrogen or C.sub.1-3 alkyl;
Y is ##STR60## R.sub.7 is (a) C.sub.1-3 alkyl, 2-hydroxyethyl or cyclopropyl,
(b) C.sub.1-3 alkoxy C.sub.2-3 alkyl,
(c) acetyl,
(d) C.sub.1-3 alkoxycarbonylmethyl,
(e) aminocarbonyl methyl,
(f) hydrogen,
(g) mono or di substituted benzyl or mono or di substituted pyridylmethyl, wherein the
substitutents are X.sub.1 and X.sub.2,
wherein
X.sub.1 is
(1) hydrogen,
(2) halo,
(3) C.sub.1-6 alkyl,
(4) halo-C.sub.1-6 alkyl,
(5) C.sub.2-6 alkenyl,
(6) hydroxy-C.sub.1-6 alkyl,
(7) C.sub.1-6 alkylcarbonyl, or
(8) C.sub.1-6 alkylcarbonylamino; and
X.sub.2 is hydrogen, halo or C.sub.1-6 alkyl;
n is 1, 2 or 3; and
R.sub.10 and R.sub.11 are each independently selected from hydrogen, C.sub.1-4 alkyl, and C.sub.1-3 alkoxy C.sub.1-3 alkyl; and
R.sub.8 and R.sub.9 are joined together so that together with the nitrogens to which they are attached there is formed a mono or di substituted saturated monocyclic ring which is piperazinyl or homopiperazinyl, wherein the substitutents are independently selected from H C.sub.1-3 alkyl and cyclopropyl.

### Claim 25 (depends on 24)

A compound according to claim 24 wherein R.sub.5 and R.sub.6 are each hydrogen and n is 1.

### Claim 26 (depends on 25)

A compound according to claim 25 wherein
R is C.sub.1-3 alkyl;
R.sub.1 is C.sub.1-3 alkyl;
M is
(a) C.sub.1-6 alkyl, or
(b) C.sub.2-6 alkenyl;
R.sup.2 is
(a) hydrogen
(b) C.sub.1-6 alkyl, or C.sub.1-6 alkoxy, and
R.sup.3 is hydrogen, or
R.sup.2 and R.sup.3 are joined together to form the group 3,4-methylenedioxy or a furan ring;
Y is ##STR61## R.sub.7 is (a) C.sub.1-3 alkyl, 2-hydroxyethyl or cyclopropyl,
(b) C.sub.1-3 alkoxy C.sub.2-3 alkyl,
(c) acetyl,
(d) C.sub.1-3 alkoxycarbonylmethyl,
(e) aminocarbonyl methyl,
(f) hydrogen,
(g) substituted benzyl wherein the substituents are X.sub.1 and X.sub.2
wherein X.sub.1 is hydrogen and X.sub.2 is
(1) hydrogen,
(2) halo, or
(3) C.sub.1-3 alkyl;
R.sub.10 and R.sub.11 are each independently selected from hydrogen, C.sub.1-4 alkyl, and C.sub.1-3 alkoxy C.sub.1-3 alkyl; and
R.sub.8 and R.sub.9 are joined together so that together with the nitrogens to which they are attached there is formed a mono substituted saturated monocyclic ring which is substituted piperazinyl or homopiperazinyl wherein the substitutent is selected from H C.sub.1-3 alkyl and cyclopropyl.

### Claim 27 (depends on 26)

A compound according to claim 26 wherein
R is methyl or ethyl;
R.sub.1 is methyl or ethyl;
M is
(a) C.sub.1-4 alkyl, or
(b) C.sub.2-3 alkenyl;
R.sup.2 is
(a) hydrogen,
(b) C.sub.1-3 alkyl, or C.sub.1-3 alkoxy, and
R.sup.3 is hydrogen, or
R.sup.2 and R.sup.3 are joined together to form the group 3,4-methylenedioxy or a furan ring;
Y is ##STR62## R.sub.10 and R.sub.11 are each hydrogen or methyl; R.sub.7 is selected from
(a) hydrogen,
(b) C.sub.1-3 alkyl,
(c) C.sub.1-3 alkoxy C.sub.2-3 alkyl,
(d) aminocarbonyl C.sub.1-3 alkyl
(e) 2-hydroxyethyl,
(f) cyclopropyl, and
R.sub.8 and R.sub.9 are joined together so that together with the nitrogens to which they are attached there is formed a mono substituted saturated monocyclic ring which is piperazinyl, wherein the substitutent is H, methyl or cyclopropyl.