US 5,348,953 AGranted

Substituted azetidinones as anti-inflammatory and antidegenerative agents

AssigneeMerck & Co., Inc.

InventorsJames B. Doherty, Paul E. Finke, William K. Hagmann, Amy L. Kissinger, Malcolm MacCoss, Shrenik K. Shah

Life of this patent

Estimating the term…

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##

Claims27

Dependent claims

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.

53 more elements

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.

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.

30 more elements

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.

31 more elements

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.

31 more elements

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.

23 more elements

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.

56 more elements

Dependencies are inferred from the claim text.

Facts

Application: 07/992,414Filed 17 Dec 1992 · continuation in part
Priority: 25 Jun 1991
Granted: 20 Sep 1994
Term ends: Not estimatedThe source records don’t support an estimate.

Classification3 codes

C07D 405/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07D 205/08
Having one double bond between ring members or between a ring member and a non-ring member: with one oxygen atom directly attached in position 2,…
C07D
Heterocyclic compounds

Family

Serial720,976Parent of this continuation-in-part · filed 25 Jun 1991
Serial720,977Parent of this continuation-in-part · filed 25 Jun 1991
Serial852,854Parent of this continuation-in-part · filed 17 Mar 1992
Serial891,614Parent of this continuation-in-part · filed 1 Jun 1992
US 5,348,953 AThis patent

From the US filing history. Foreign family members aren’t listed.

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US 5,348,953 AGranted

Substituted azetidinones as anti-inflammatory and antidegenerative agents

AssigneeMerck & Co., Inc.

InventorsJames B. Doherty, Paul E. Finke, William K. Hagmann, Amy L. Kissinger, Malcolm MacCoss, Shrenik K. Shah

Life of this patent

Estimating the term…

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##

Claims27

Dependent claims

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.

53 more elements

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.

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.

30 more elements

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.

31 more elements

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.

31 more elements

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.

23 more elements

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.

56 more elements

Dependencies are inferred from the claim text.

Facts

Application: 07/992,414Filed 17 Dec 1992 · continuation in part
Priority: 25 Jun 1991
Granted: 20 Sep 1994
Term ends: Not estimatedThe source records don’t support an estimate.

Classification3 codes

C07D 405/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07D 205/08
Having one double bond between ring members or between a ring member and a non-ring member: with one oxygen atom directly attached in position 2,…
C07D
Heterocyclic compounds

Family

Serial720,976Parent of this continuation-in-part · filed 25 Jun 1991
Serial720,977Parent of this continuation-in-part · filed 25 Jun 1991
Serial852,854Parent of this continuation-in-part · filed 17 Mar 1992
Serial891,614Parent of this continuation-in-part · filed 1 Jun 1992
US 5,348,953 AThis patent

From the US filing history. Foreign family members aren’t listed.

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