US 4,729,993 AGranted

Carbapenems and 1-methylcarbapenems having an externally alkylated mono- or bicyclic 2-quaternary heteroarylalkyl substituent

AssigneeMerck & Co., Inc.

InventorsBurton G. Christensen, Ronald W. Ratcliffe, James V. Heck, Thomas N. Salzmann, David H. Shih

Life of this patent

Estimating the term…

Abstract

Carbapenems having the formula: ##STR1## wherein ##STR2## is mono- or bicyclic quaternary heteroaryl, their preparation and antibiotic use are disclosed.

Claims21

Dependent claims

A compound having the formula:

##STR135## wherein:
R.sup.1 is hydrogen or methyl;
R.sup.4 and R.sup.5 are independently H, CH.sub.3 --, CH.sub.3 CH.sub.2 --, (CH.sub.3).sub.2 CH--, HOCH.sub.2 --, CH.sub.3 CH(OH)--, (CH.sub.3).sub.2 C(OH)--, FCH.sub.2 --, F.sub.2 CH--, F.sub.3 C--, CH.sub.3 CH(F)--, (CH.sub.3).sub.2 C(F)--;
CH.sub.3 CF.sub.2 --, or
L is a bridging group comprising substituted or unsubstituted C.sub.1 -C.sub.4 straight, C.sub.2 -C.sub.6 branched or C.sub.3 -C.sub.7 cycloalkyl groups wherein the substituents are selected from C.sub.1 -C.sub.6 alkyl, O-C.sub.1 -C.sub.6 alkyl, S-C.sub.1 -C.sub.6 alkyl, CF.sub.3, N(C.sub.1 -C.sub.6 alkyl).sub.2 ;
##STR136## is a mono- or bicyclic heteroarylium group containing from 5-11 ring atoms of which up to 5 are heteroatoms in addition to the quaternary nitrogen;
wherein:
R.sup.2 is
(1) an unsubstituted or substituted C.sub.1 -C.sub.6 alkyl radical;
(2) an unsubstituted or substituted C.sub.2 -C.sub.6 alkenyl radical;
(3) an unsubstituted or substituted C.sub.2 -C.sub.6 alkynyl radical;
(4) a C.sub.3 -C.sub.7 cycloalkyl radical in which the ring is substituted or unsubstituted and one or more atoms may be replaced by a heteroatom;
(5) a C.sub.3 -C.sub.7 cycloalkyl methyl radical in which the ring may be substituted and one or more atoms may be replaced by a heteroatom;
(6) an unsubstituted or substituted C.sub.5 -C.sub.7 cycloalkenyl radical;
(7) an unsubstituted or substituted bivalent C.sub.2 -C.sub.6 alkylidene radical, optionally interrupted by a heteroatom, and joined to the heteroarylium group to form a ring which is carbocyclic or in which one or more atoms is replaced by a heteroatom and wherein the new ring may contain one or more double bonds;
(8) an unsubstituted or substituted phenyl or heteroaryl radical;
(9) an unsubstituted or substituted phenyl (C.sub.1 -C.sub.4 alkyl) or heteroaryl (C.sub.1 -C.sub.4 alkyl) radical;
(10) a cyano (C.sub.1 -C.sub.4 alkyl) radical;
(11) a carboxy (C.sub.1 -C.sub.4 alkyl) radical;
(12) a sulfo (C.sub.1 -C.sub.4 alkyl) radical;
(13) a carbamoyl (C.sub.1 -C.sub.4 alkyl) radical;
(14) a phosphonyl (C.sub.1 -C.sub.4 alkyl) radical;
(15) a hydroxy (C.sub.1 -C.sub.4 alkyl) radical;
or
(16) an amino (C.sub.1 -C.sub.4 alkyl) radical in which the nitrogen atom is unsubstituted or substituted with one to three C.sub.1 -C.sub.4 alkyl groups;
wherein the substituents in the above definitions of R.sup.2 are independently selected from the group consisting of:
(a) a trifluoromethyl group;
(b) a halogen atom;
(c) an unsubstituted or substituted C.sub.1 -C.sub.4 alkoxyl radical;
(d) a hydroxy group;
(e) an unsubstituted or substituted (C.sub.1 -C.sub.6 alkyl) carbonyloxy radical;
(f) a carbamoyloxy radical which is unsubstituted or substituted on nitrogen with one or two C.sub.1 -C.sub.4 alkyl groups;
(g) a C.sub.1 -C.sub.6 alkylthio radical, C.sub.1 -C.sub.6 alkylsulfinyl radical or C.sub.1 -C.sub.6 alkylsulfonyl radical, each of which is unsubstituted or substituted on the alkyl group;
(h) a sulfo group;
(i) a sulfamoyl group which is unsubstituted or substituted on nitrogen by one or two C.sub.1 -C.sub.4 alkyl groups;
(j) a formylamino group;
(k) an unsubstituted or substituted (C.sub.1 -C.sub.6 alkyl)carbonylamino radical;
(l) a (C.sub.1 -C.sub.4 alkoxyl) carbonylamino radical;
(m) a ureido group in which the terminal nitrogen is unsubstituted or substituted with one or two C.sub.1 -C.sub.4 alkyl groups;
(n) an arylsulfonamido or a (C.sub.1 -C.sub.6 alkyl)sulfonamido group;
(o) a cyano group;
(p) a formyl or acetalized formyl radical;
(q) an unsubstituted or substituted (C.sub.1 -C.sub.6 alkyl)carbonyl radical wherein the carbonyl is free or acetalized;
(r) an unsubstituted or substituted phenylcarbonyl or heteroarylcarbonyl radical;
(s) a carboxyl group;
(t) a (C.sub.1 -C.sub.6 alkoxy)carbonyl radical;
(u) a carbamoyl radical which is unsubstituted or substituted on nitrogen by one or two C.sub.1 -C.sub.4 alkyl groups;
(v) an N-hydroxycarbamoyl or N(C.sub.1 -C.sub.4 alkoxy)carbamoyl radical in which the nitrogen atom may be additionally substituted by a C.sub.1 -C.sub.4 alkyl group;
(w) a thiocarbamoyl group;
(x) a 5-(1H)-tetrazolyl group;
(y) a phosphonate group --P(O) (OH)OR' where R' is C.sub.1 -C.sub.3 alkyl;
(z) an alkyl phosphonate group --(CH.sub.2).sub.n P(O) (OH) (OR') where n=1 to 3 and R' is C.sub.1 -C.sub.3 alkyl;
(aa) hydrogen;
(ab) an unsubstituted or substituted C.sub.1 -C.sub.6 alkyl radical;
(ac) an unsubstituted or substituted C.sub.2 -C.sub.6 alkenyl radical;
(ad) an unsubstituted or substituted C.sub.2 -C.sub.6 alkynyl radical;
(ae) a C.sub.3 -C.sub.7 cycloalkyl radical in which the ring is substituted or unsubstituted and one or more atoms may be replaced by a heteroatom;
(af) a C.sub.3 -C.sub.7 cycloalkyl methyl radical in which the ring may be substituted and one or more atoms may be replaced by a heteroatom;
(ag) an unsubstituted or substituted C.sub.5 -C.sub.7 cycloalkenyl radical;
(ah) an unsubstituted or substituted phenyl or heteroaryl radical;
and
(ai) an unsubstituted or substituted phenyl (C.sub.1 -C.sub.4 alkyl) or heteroaryl (C.sub.1 -C.sub.4 alkyl) radical;
and
R.sup.3 is
(a) hydrogen;
(b) an unsubstituted or substituted C.sub.1 -C.sub.6 alkyl radical;
(c) an unsubstituted or substituted C.sub.2 -C.sub.6 alkenyl radical;
(d) an unsubstituted or substituted C.sub.2 -C.sub.6 alkynyl radical;
(e) a C.sub.3 -C.sub.7 cycloalkyl radical in which the ring is substituted or unsubstituted and one or more atoms may be replaced by a heteroatom;
(f) a C.sub.3 -C.sub.7 cycloalkyl methyl radical in which the ring may be substituted and one or more atoms may be replaced by a heteroatom;
(g) an unsubstituted or substituted C.sub.5 -C.sub.7 cycloalkenyl radical;
(h) an unsubstituted or substituted phenyl or heteroaryl radical;
(i) an unsubstituted or substituted phenyl (C.sub.1 -C.sub.4 alkyl) or heteroaryl (C.sub.1 -C.sub.4 alkyl) radical;
and
(j) a trifluoromethyl group;
(k) a halogen atom;
(l) an unsubstituted or substituted C.sub.1 -C.sub.4 alkoxyl radical;
(m) a C.sub.1 -C.sub.6 alkylthio radical, C.sub.1 -C.sub.6 alkylsulfinyl radical or C.sub.1 -C.sub.6 alkylsulfonyl radical, each of which is unsubstituted or substituted on the alkyl group;
(n) a mono (C.sub.1 -C.sub.4 alkyl) amino or di(C.sub.1 -C.sub.4 alkyl)amino group, each of which is unsubstituted or substituted on the alkyl group;
or
(o) a cyano group;
and
Y is
(i) COOH or a pharmaceutically acceptable ester or salt thereof,
(ii) COOR wherein R is a removable carboxy protecting group,
(iii) COOM wherein M is an alkali metal, or
(iv) COO.sup.- ;
provided that when Y is other than (iv) a counterion Z.sup.- is provided.

85 more elements

Dependencies are inferred from the claim text.

Facts

Application: 06/681,179Filed 13 Dec 1984
Granted: 8 Mar 1988
Term ends: Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 477/14
With hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6: with hydrogen atoms, hydrocarbon or substituted…
A61P 31/04
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antibacterial agents
C07F 7/1804
Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages: compounds having Si-O-C linkages
C07F 9/65583
Containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common…: each of…

Family

No related US applications are recorded in the indexed filing history.

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Abstract

Carbapenems having the formula: ##STR1## wherein ##STR2## is mono- or bicyclic quaternary heteroaryl, their preparation and antibiotic use are disclosed.

A compound having the formula:

##STR135## wherein:
R.sup.1 is hydrogen or methyl;
R.sup.4 and R.sup.5 are independently H, CH.sub.3 --, CH.sub.3 CH.sub.2 --, (CH.sub.3).sub.2 CH--, HOCH.sub.2 --, CH.sub.3 CH(OH)--, (CH.sub.3).sub.2 C(OH)--, FCH.sub.2 --, F.sub.2 CH--, F.sub.3 C--, CH.sub.3 CH(F)--, (CH.sub.3).sub.2 C(F)--;
CH.sub.3 CF.sub.2 --, or
L is a bridging group comprising substituted or unsubstituted C.sub.1 -C.sub.4 straight, C.sub.2 -C.sub.6 branched or C.sub.3 -C.sub.7 cycloalkyl groups wherein the substituents are selected from C.sub.1 -C.sub.6 alkyl, O-C.sub.1 -C.sub.6 alkyl, S-C.sub.1 -C.sub.6 alkyl, CF.sub.3, N(C.sub.1 -C.sub.6 alkyl).sub.2 ;
##STR136## is a mono- or bicyclic heteroarylium group containing from 5-11 ring atoms of which up to 5 are heteroatoms in addition to the quaternary nitrogen;
wherein:
R.sup.2 is
(1) an unsubstituted or substituted C.sub.1 -C.sub.6 alkyl radical;
(2) an unsubstituted or substituted C.sub.2 -C.sub.6 alkenyl radical;
(3) an unsubstituted or substituted C.sub.2 -C.sub.6 alkynyl radical;
(4) a C.sub.3 -C.sub.7 cycloalkyl radical in which the ring is substituted or unsubstituted and one or more atoms may be replaced by a heteroatom;
(5) a C.sub.3 -C.sub.7 cycloalkyl methyl radical in which the ring may be substituted and one or more atoms may be replaced by a heteroatom;
(6) an unsubstituted or substituted C.sub.5 -C.sub.7 cycloalkenyl radical;
(7) an unsubstituted or substituted bivalent C.sub.2 -C.sub.6 alkylidene radical, optionally interrupted by a heteroatom, and joined to the heteroarylium group to form a ring which is carbocyclic or in which one or more atoms is replaced by a heteroatom and wherein the new ring may contain one or more double bonds;
(8) an unsubstituted or substituted phenyl or heteroaryl radical;
(9) an unsubstituted or substituted phenyl (C.sub.1 -C.sub.4 alkyl) or heteroaryl (C.sub.1 -C.sub.4 alkyl) radical;
(10) a cyano (C.sub.1 -C.sub.4 alkyl) radical;
(11) a carboxy (C.sub.1 -C.sub.4 alkyl) radical;
(12) a sulfo (C.sub.1 -C.sub.4 alkyl) radical;
(13) a carbamoyl (C.sub.1 -C.sub.4 alkyl) radical;
(14) a phosphonyl (C.sub.1 -C.sub.4 alkyl) radical;
(15) a hydroxy (C.sub.1 -C.sub.4 alkyl) radical;
or
(16) an amino (C.sub.1 -C.sub.4 alkyl) radical in which the nitrogen atom is unsubstituted or substituted with one to three C.sub.1 -C.sub.4 alkyl groups;
wherein the substituents in the above definitions of R.sup.2 are independently selected from the group consisting of:
(a) a trifluoromethyl group;
(b) a halogen atom;
(c) an unsubstituted or substituted C.sub.1 -C.sub.4 alkoxyl radical;
(d) a hydroxy group;
(e) an unsubstituted or substituted (C.sub.1 -C.sub.6 alkyl) carbonyloxy radical;
(f) a carbamoyloxy radical which is unsubstituted or substituted on nitrogen with one or two C.sub.1 -C.sub.4 alkyl groups;
(g) a C.sub.1 -C.sub.6 alkylthio radical, C.sub.1 -C.sub.6 alkylsulfinyl radical or C.sub.1 -C.sub.6 alkylsulfonyl radical, each of which is unsubstituted or substituted on the alkyl group;
(h) a sulfo group;
(i) a sulfamoyl group which is unsubstituted or substituted on nitrogen by one or two C.sub.1 -C.sub.4 alkyl groups;
(j) a formylamino group;
(k) an unsubstituted or substituted (C.sub.1 -C.sub.6 alkyl)carbonylamino radical;
(l) a (C.sub.1 -C.sub.4 alkoxyl) carbonylamino radical;
(m) a ureido group in which the terminal nitrogen is unsubstituted or substituted with one or two C.sub.1 -C.sub.4 alkyl groups;
(n) an arylsulfonamido or a (C.sub.1 -C.sub.6 alkyl)sulfonamido group;
(o) a cyano group;
(p) a formyl or acetalized formyl radical;
(q) an unsubstituted or substituted (C.sub.1 -C.sub.6 alkyl)carbonyl radical wherein the carbonyl is free or acetalized;
(r) an unsubstituted or substituted phenylcarbonyl or heteroarylcarbonyl radical;
(s) a carboxyl group;
(t) a (C.sub.1 -C.sub.6 alkoxy)carbonyl radical;
(u) a carbamoyl radical which is unsubstituted or substituted on nitrogen by one or two C.sub.1 -C.sub.4 alkyl groups;
(v) an N-hydroxycarbamoyl or N(C.sub.1 -C.sub.4 alkoxy)carbamoyl radical in which the nitrogen atom may be additionally substituted by a C.sub.1 -C.sub.4 alkyl group;
(w) a thiocarbamoyl group;
(x) a 5-(1H)-tetrazolyl group;
(y) a phosphonate group --P(O) (OH)OR' where R' is C.sub.1 -C.sub.3 alkyl;
(z) an alkyl phosphonate group --(CH.sub.2).sub.n P(O) (OH) (OR') where n=1 to 3 and R' is C.sub.1 -C.sub.3 alkyl;
(aa) hydrogen;
(ab) an unsubstituted or substituted C.sub.1 -C.sub.6 alkyl radical;
(ac) an unsubstituted or substituted C.sub.2 -C.sub.6 alkenyl radical;
(ad) an unsubstituted or substituted C.sub.2 -C.sub.6 alkynyl radical;
(ae) a C.sub.3 -C.sub.7 cycloalkyl radical in which the ring is substituted or unsubstituted and one or more atoms may be replaced by a heteroatom;
(af) a C.sub.3 -C.sub.7 cycloalkyl methyl radical in which the ring may be substituted and one or more atoms may be replaced by a heteroatom;
(ag) an unsubstituted or substituted C.sub.5 -C.sub.7 cycloalkenyl radical;
(ah) an unsubstituted or substituted phenyl or heteroaryl radical;
and
(ai) an unsubstituted or substituted phenyl (C.sub.1 -C.sub.4 alkyl) or heteroaryl (C.sub.1 -C.sub.4 alkyl) radical;
and
R.sup.3 is
(a) hydrogen;
(b) an unsubstituted or substituted C.sub.1 -C.sub.6 alkyl radical;
(c) an unsubstituted or substituted C.sub.2 -C.sub.6 alkenyl radical;
(d) an unsubstituted or substituted C.sub.2 -C.sub.6 alkynyl radical;
(e) a C.sub.3 -C.sub.7 cycloalkyl radical in which the ring is substituted or unsubstituted and one or more atoms may be replaced by a heteroatom;
(f) a C.sub.3 -C.sub.7 cycloalkyl methyl radical in which the ring may be substituted and one or more atoms may be replaced by a heteroatom;
(g) an unsubstituted or substituted C.sub.5 -C.sub.7 cycloalkenyl radical;
(h) an unsubstituted or substituted phenyl or heteroaryl radical;
(i) an unsubstituted or substituted phenyl (C.sub.1 -C.sub.4 alkyl) or heteroaryl (C.sub.1 -C.sub.4 alkyl) radical;
and
(j) a trifluoromethyl group;
(k) a halogen atom;
(l) an unsubstituted or substituted C.sub.1 -C.sub.4 alkoxyl radical;
(m) a C.sub.1 -C.sub.6 alkylthio radical, C.sub.1 -C.sub.6 alkylsulfinyl radical or C.sub.1 -C.sub.6 alkylsulfonyl radical, each of which is unsubstituted or substituted on the alkyl group;
(n) a mono (C.sub.1 -C.sub.4 alkyl) amino or di(C.sub.1 -C.sub.4 alkyl)amino group, each of which is unsubstituted or substituted on the alkyl group;
or
(o) a cyano group;
and
Y is
(i) COOH or a pharmaceutically acceptable ester or salt thereof,
(ii) COOR wherein R is a removable carboxy protecting group,
(iii) COOM wherein M is an alkali metal, or
(iv) COO.sup.- ;
provided that when Y is other than (iv) a counterion Z.sup.- is provided.

85 more elements

Facts

Application

06/681,179Filed 13 Dec 1984

Granted

8 Mar 1988

Term ends

Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 477/14
With hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6: with hydrogen atoms, hydrocarbon or substituted…
A61P 31/04
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antibacterial agents
C07F 7/1804
Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages: compounds having Si-O-C linkages
C07F 9/65583
Containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common…: each of…