US 7,001,897 B2Granted

1-methylcarbapenem derivatives

AssigneeSankyo Company, Limited

InventorsYoshiyuki Kobayashi, Tsuyoshi Shinozuka, Osamu Kanno

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Abstract

A 1-methylcarbapenem compound represented by the formula (I): having antibacterial activity, pharmacologically acceptable esters or salts thereof and pharmaceutical compositions (particularly antibacterial agents) containing them as an active ingredient are described. In addition, the invention includes the use of these compounds, ester derivatives or salts for the manufacture of pharmaceutical compositions, or a method for the prevention or treatment of diseases (particularly bacterial infections) by administering a pharmacologically effective amount of the compounds, ester derivatives or salts to warm-blooded animals (particularly human beings).

Claims41

Dependent claims

A 1-methylcarbapenem compound represented by the formula (I):

wherein:
R1 is selected from the group consisting of
(1) a group represented by the formula COOR3
wherein R3 is selected from the group consisting of a hydrogen atom, a C1-C6 alkyl group and a C3-C6 cycloalkyl group,
(2) a group represented by the formula CONR4R5
wherein R4 and R5 may be the same or different and each is selected from the group consisting of a hydrogen atom, a C1-C6 alkyl group which is optionally substituted by one or two groups, which are the same or different and are selected from substituent group A below, a C3-C6 cycloalkyl group, a 3- to 6-membered heterocyclic group which is a saturated heterocyclic group including one or two hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur atoms and a C6-C10 aryl group which is optionally substituted by one or two groups which are the same or different arid are selected from substituent group B below, or R4 and R5, together with the nitrogen atom to which they are bonded, represent a 3- to 6-membered nitrogen-containing heterocycle which is a saturated heterocyclic group containing one or two nitrogen atoms and optionally, oxygen or sulfur and is optionally substituted by one or two groups which are the same or different and are selected from substituent group B below,
(3) a cyano group,
(4) a group represented by the formula CH2OR6
wherein R6 is selected from the group consisting of a hydrogen atom, a C1-C6 alkyl group and a C3-C6 cycloalkyl group or
(5) a group represented by the formula CH2NR7R8
wherein R7 is selected from the group consisting of a hydrogen atom, a C1-C6 alkyl group and a C3-C6 cycloalkyl group, and R8 is selected from the group consisting of a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkanoyl group, a (C6-C10 aryl)carbonyl group which is optionally substituted by one or two groups which are the same or different and are selected from substituent group B below, a (C1-C6 alkoxy)carbonyl group, a 5- or 6-membered aromatic heterocyclylcarbonyl group wherein the heterocyclic moiety is a heterocycle containing 1 to 3 hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur, a C1-C6 alkylsulfonyl group and a C6-C10 arylsulfonyl group, or R7 and R8, together with the nitrogen atom to which they are bonded, represent a succinimide group which is optionally condensed with a phenyl group;
R2 is selected from the group consisting of a hydrogen atom and a C1-C6 alkyl group;
n is 1, 2 or 3;
X is selected from the group consisting of a sulfur atom and an oxygen atom;
substituent group A consists of a hydroxyl group;
an amino group which is optionally substituted by one or two C1-C6 alkyl groups;
a carbamoyl group the amino moiety of which is optionally substituted by one or two C1-C6 alkyl groups;
a carboxyl group;
a cyano group and a C1-C6 alkoxy group;
and substituent group B consists of a hydroxy-C1-C4-alkyl group;
an amino-C1-C4-alkyl group the amino moiety of which is optionally substituted by one or two C1-C6 alkyl groups;
a carbamoyl group the amino moiety of which is optionally substituted by one or two C1-C6 alkyl groups;
a carboxyl group;
a hydroxyl group;
an amino group which is optionally substituted by one or two C1-C6 alkyl groups;
a C1-C6 alkoxy group and a C1-C6 alkyl group;
or a pharmacologically acceptable salt or ester thereof.

24 more elements

A 1-methylcarbapenem compound selected from the following group of compounds:

(1R,5S,6S)-2-[1-(4-carbamoyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-[1-(4-carbamoyl-1,3-oxazol-2-yl)azetidin-3-yl]thio-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-[1-(4-hydroxymethyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-[1-(4-hydroxymethyl-1,3-oxazol-2-yl)azetidin-3-yl]thio-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-[1-(4-cyano-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-[1-(4-cyano-1,3-oxazol-2-yl)azetidin-3-yl]thio-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-[1-(4-morpholinocarbonyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-[1-(4-morpholinocarbonyl-1,3-oxazol-2-yl)azetidin-3-yl]thio-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-[1-(4-azetidinocarbonyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-[1-(4-azetidinocarbonyl-1,3-oxazol-2-yl)azetidin-3-yl]thio-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-{1-[4-(3-aminoazetidino)carbonyl-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-{1-[4-(3-aminoazetidino)carbonyl-1,3-oxazol-2-yl]azetidin-3-yl}thio-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-{1-[4-(3-hydroxyazetidino)carbonyl-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-{1-[4-(3-hydroxyazetidino)carbonyl-1,3-oxazol-2-yl]azetidin-3-yl}thio-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-[1-(4-thiomorpholinocarbonyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-[1-(4-thiomorpholinocarbonyl-1,3-oxazol-2-yl)azetidin-3-yl]thio-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-{1-[4-(piperidin-4-ylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-{1-[4-(piperidin4-ylcarbamoyl)-1,3-oxazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-{1-[4-(azetidin-3-ylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-{1-[4-(azetidin-3-ylcarbamoyl)-1,3-oxazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-{1-[4-((3S)-pyrrolidin-3-ylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-{1-[4-((3S)-pyrrolidin-3-ylcarbamoyl)-1,3-oxazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-{1-[4-((3R)-pyrrolidin-3-ylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-{1-[4-((3R)-pyrrolidin-3-ylcarbamoyl)-1,3-oxazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-{1-[4-(piperazine-1-carbonyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-{1-[4-(piperazine-1-carbonyl)-1,3-oxazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-{1-[4-(2-aminoethylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-{1-[4-(2-aminoethylcarbamoyl)-1,3-oxazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-{1-[4-((1S)-1-aminomethyl-2-methyl-propylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-{1-[4-((1S)-1-aminomethyl-2-methyl-propylcarbamoyl)-1,3-oxazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-(1-{4-[N-(2-aminoethyl)-N-isopropylcarbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-(1-{4-[N-(2-aminoethyl)-N-isopropylcarbamoyl]-1,3-oxazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-(1-{4-[N-(2-hydroxyethyl)-N-isopropylcarbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-(1-{4-[N-(2-hydroxyethyl)-N-isopropylcarbamoyl]-1,3-oxazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-[1-(4-aminomethyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-[1-(4-aminomethyl-1,3-oxazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-{1-[4-(benzoylaminomethyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-{1-[4-(benzoylaminomethyl)-1,3-oxazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-{1-[4-(benzenesulfonylaminomethyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-{1-[4-(benzenesulfonylaminomethyl)-1,3-oxazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-(1-{4-[(thiophene-2-carbonylamino)methyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-(1-{4-[(thiophene-2-carbonylamino)methyl]-1,3-oxazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid,
(1R,5S,6S)-2-(1-{4-[(furan-2-carbonylamino)methyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid, and
(1R,5S,6S)-2-(1-{4-[(furan-2-carbonylamino)methyl]-1,3-oxazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid;
or a pharmacologically acceptable salt or ester thereof.

42 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/439,198Filed 15 May 2003 · continuation in part
Priority: JP 2000-35006316 Nov 2000
Published: US 2004/0014962 A122 Jan 2004
Granted: 21 Feb 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification4 codes

C07D 477/20
With hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical,…:…
A61P 31/04
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antibacterial agents
C07D
Heterocyclic compounds
A61P
Therapeutic uses of medicines

Family

PCT/JP01/09960Parent of this continuation-in-part · filed 14 Nov 2001
US 2004/0014962 A1Pre-grant publication · published 22 Jan 2004
US 7,001,897 B2This patent

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

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Abstract

A 1-methylcarbapenem compound represented by the formula (I):

wherein:
R1 is selected from the group consisting of
(1) a group represented by the formula COOR3
wherein R3 is selected from the group consisting of a hydrogen atom, a C1-C6 alkyl group and a C3-C6 cycloalkyl group,
(2) a group represented by the formula CONR4R5
wherein R4 and R5 may be the same or different and each is selected from the group consisting of a hydrogen atom, a C1-C6 alkyl group which is optionally substituted by one or two groups, which are the same or different and are selected from substituent group A below, a C3-C6 cycloalkyl group, a 3- to 6-membered heterocyclic group which is a saturated heterocyclic group including one or two hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur atoms and a C6-C10 aryl group which is optionally substituted by one or two groups which are the same or different arid are selected from substituent group B below, or R4 and R5, together with the nitrogen atom to which they are bonded, represent a 3- to 6-membered nitrogen-containing heterocycle which is a saturated heterocyclic group containing one or two nitrogen atoms and optionally, oxygen or sulfur and is optionally substituted by one or two groups which are the same or different and are selected from substituent group B below,
(3) a cyano group,
(4) a group represented by the formula CH2OR6
wherein R6 is selected from the group consisting of a hydrogen atom, a C1-C6 alkyl group and a C3-C6 cycloalkyl group or
(5) a group represented by the formula CH2NR7R8
wherein R7 is selected from the group consisting of a hydrogen atom, a C1-C6 alkyl group and a C3-C6 cycloalkyl group, and R8 is selected from the group consisting of a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkanoyl group, a (C6-C10 aryl)carbonyl group which is optionally substituted by one or two groups which are the same or different and are selected from substituent group B below, a (C1-C6 alkoxy)carbonyl group, a 5- or 6-membered aromatic heterocyclylcarbonyl group wherein the heterocyclic moiety is a heterocycle containing 1 to 3 hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur, a C1-C6 alkylsulfonyl group and a C6-C10 arylsulfonyl group, or R7 and R8, together with the nitrogen atom to which they are bonded, represent a succinimide group which is optionally condensed with a phenyl group;
R2 is selected from the group consisting of a hydrogen atom and a C1-C6 alkyl group;
n is 1, 2 or 3;
X is selected from the group consisting of a sulfur atom and an oxygen atom;
substituent group A consists of a hydroxyl group;
an amino group which is optionally substituted by one or two C1-C6 alkyl groups;
a carbamoyl group the amino moiety of which is optionally substituted by one or two C1-C6 alkyl groups;
a carboxyl group;
a cyano group and a C1-C6 alkoxy group;
and substituent group B consists of a hydroxy-C1-C4-alkyl group;
an amino-C1-C4-alkyl group the amino moiety of which is optionally substituted by one or two C1-C6 alkyl groups;
a carbamoyl group the amino moiety of which is optionally substituted by one or two C1-C6 alkyl groups;
a carboxyl group;
a hydroxyl group;
an amino group which is optionally substituted by one or two C1-C6 alkyl groups;
a C1-C6 alkoxy group and a C1-C6 alkyl group;
or a pharmacologically acceptable salt or ester thereof.

24 more elements

Facts

Application

10/439,198Filed 15 May 2003 · continuation in part

Priority

JP 2000-35006316 Nov 2000

Published

US 2004/0014962 A122 Jan 2004

Granted

21 Feb 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification4 codes

C07D 477/20
With hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical,…:…
A61P 31/04
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antibacterial agents
C07D
Heterocyclic compounds
A61P
Therapeutic uses of medicines