US 6,664,238 B1Granted

Carbamate and carbazate ketolide antibiotics

AssigneePfizer Inc.

InventorsWei-Guo Su, Takushi Kaneko, Yong-Jin Wu

Life of this patent

Estimating the term…

Abstract

This invention relates to compounds of the formula 1 and to pharmaceutically acceptable salts and solvates thereof wherein X1, X2, R2, R15, R16 and R6 are as defined herein. The compounds of formula 1 are antibacterial and antiprotozoal agents that may be used to treat various bacterial and protozoal infections and disorders related to such infections. The invention also relates to pharmaceutical compositions containing the compounds of formula 1 and to methods of treating bacterial and protozoal infections by administering the compounds of formula 1.

Claims10

Dependent claims

A compound of the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein:
X1 is O, —CR13R14— or —NR4—;
X2 is ═O or ═NOR1;
R1 is H, methyl or ethyl;
R2 is —C(R7)(R8)C(R9)(R10)C(R11)(R12)(4-10 membered heterocyclic) or —(CR7R8)r(C3-C7 cycloalkylene)(CR9R10)q(4-10 membered heterocyclic), wherein q and r are each integers independently ranging from 0 to 2, and the heterocyclic moiety of the foregoing groups is substituted by —(CR4R5)t(4-10 membered heterocyclic) or —(CR4R5)t(C6-C10 aryl) wherein t is an integer from 0 to 5, and the aryl and heterocyclic moietes of each of the foregoing groups are optionally substituted by 1 to 4 R3 groups;
each R3 is independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R5, —C(O)OR5, —OC(O)R5, —NR5C(O)R4, —C(O)NR4R5, —NR4R5, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, 4-10 membered heterocyclic, and C1-C6 alkoxy;
each R4 and R5 is independently selected from H and C1-C6 alkyl;
R6 is H or —C(O)(C1-C6 alkyl);
R7, R8, R9, R10, R11, R12, R13 and R14 are each independently selected from H, halo and C1-C6 alkyl, provided that (a) where X1 is —CR13R14— and R2 is —C(R7)(R8)C(R9)(R10)C(R11)(R12)(4-10 membered heterocyclic), at least one of R7, R8, R9, R10, R11, R12, R13 and R14 is halo or C1-C6 alkyl, and (b) where X1 is —NR4— and R2 is —C(R7)(R8)C(R9)(R10)C(R11)(R12)(4-10 membered heterocyclic), at least one of R7, R8, R9, R10, R11, and R12 is halo or C1-C6 alkyl;
or R7 and R8 are taken together with the carbon to which each is attached to form a C3-C7 cycloalkyl group and R9, R10, R11, R12, R13 and R14 are each independently selected from H, halo and C1-C6 alkyl;
or R9 and R10 are taken together with the carbon to which each is attached to form a C3-C6 cycloalkyl group and R7, R8, R11, R12, R13 and R14 are each independently selected from H, halo and C1-C6 alkyl;
or R11 and R12 are taken together with the carbon to which each is attached to form a C3-C7 cycloalkyl group and R7, R8, R9, R10, R13 and R14 are each independently selected from H, halo and C1-C6 alkyl;
R15 is C1-C6 alkyl;
and
R16 is H or C1-C10 alkyl.

12 more elements

A compound selected from the group consisting essentially of:

11-Deoxy-5-O-desosaminyl-11-(3,3-dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(3(R)-methyl-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(3(R)-ethyl-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(3(S)-methyl-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(3(S)-ethyl-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2-(1-(4-pyridin-3-yl-imidazol-1-yl)-cyclopropyl)-ethyl)hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2-(1-(4-pyridin-3-yl-imidazol-1-yl)-cyclobutyl)-ethyl)hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2,2-dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2,2-diethyl-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2,2-difluro-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2,2-dichloro-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2,2-dibromo-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(1-(4-pyridin-3-yl-imidazol-1-yl-methyl)-cyclopropyl)-methyl-hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(1-(4-pyridin-3-yl-imidazol-1-yl-methyl)-cyclobutyl)-methyl-hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2(R)-methyl-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2(R)-ethyl-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2(S)-methyl-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2(S)-ethyl-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2(R)-fluro-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
11-Deoxy-5-O-desosaminyl-11-(2(S)-flurol-3-(4-pyridin-3-yl-imidazol-1-yl-propyl))hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate, 9-E-(O-methyl)oxime;
and the pharmaceutically acceptable salts and solvates of the foregoing compounds.

18 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/459,116Filed 10 Dec 1999 · us provisional application
Priority: 10 Dec 1998
Granted: 16 Dec 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07H 17/08
Heterocyclic radicals containing only oxygen as ring hetero atoms: hetero rings containing eight or more ring members, e.g. erythromycins
A61P 31/04
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antibacterial agents
A61P 33/02
Antiparasitic agents: antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
C07H
Sugars

Family

Application60/111,728Us provisional application · filed 10 Dec 1998
US 6,664,238 B1This patent

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

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Abstract

A compound of the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein:
X1 is O, —CR13R14— or —NR4—;
X2 is ═O or ═NOR1;
R1 is H, methyl or ethyl;
R2 is —C(R7)(R8)C(R9)(R10)C(R11)(R12)(4-10 membered heterocyclic) or —(CR7R8)r(C3-C7 cycloalkylene)(CR9R10)q(4-10 membered heterocyclic), wherein q and r are each integers independently ranging from 0 to 2, and the heterocyclic moiety of the foregoing groups is substituted by —(CR4R5)t(4-10 membered heterocyclic) or —(CR4R5)t(C6-C10 aryl) wherein t is an integer from 0 to 5, and the aryl and heterocyclic moietes of each of the foregoing groups are optionally substituted by 1 to 4 R3 groups;
each R3 is independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R5, —C(O)OR5, —OC(O)R5, —NR5C(O)R4, —C(O)NR4R5, —NR4R5, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, 4-10 membered heterocyclic, and C1-C6 alkoxy;
each R4 and R5 is independently selected from H and C1-C6 alkyl;
R6 is H or —C(O)(C1-C6 alkyl);
R7, R8, R9, R10, R11, R12, R13 and R14 are each independently selected from H, halo and C1-C6 alkyl, provided that (a) where X1 is —CR13R14— and R2 is —C(R7)(R8)C(R9)(R10)C(R11)(R12)(4-10 membered heterocyclic), at least one of R7, R8, R9, R10, R11, R12, R13 and R14 is halo or C1-C6 alkyl, and (b) where X1 is —NR4— and R2 is —C(R7)(R8)C(R9)(R10)C(R11)(R12)(4-10 membered heterocyclic), at least one of R7, R8, R9, R10, R11, and R12 is halo or C1-C6 alkyl;
or R7 and R8 are taken together with the carbon to which each is attached to form a C3-C7 cycloalkyl group and R9, R10, R11, R12, R13 and R14 are each independently selected from H, halo and C1-C6 alkyl;
or R9 and R10 are taken together with the carbon to which each is attached to form a C3-C6 cycloalkyl group and R7, R8, R11, R12, R13 and R14 are each independently selected from H, halo and C1-C6 alkyl;
or R11 and R12 are taken together with the carbon to which each is attached to form a C3-C7 cycloalkyl group and R7, R8, R9, R10, R13 and R14 are each independently selected from H, halo and C1-C6 alkyl;
R15 is C1-C6 alkyl;
and
R16 is H or C1-C10 alkyl.

12 more elements

Facts

Application

09/459,116Filed 10 Dec 1999 · us provisional application

Priority

10 Dec 1998

Granted

16 Dec 2003

Term ends

Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07H 17/08
Heterocyclic radicals containing only oxygen as ring hetero atoms: hetero rings containing eight or more ring members, e.g. erythromycins
A61P 31/04
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antibacterial agents
A61P 33/02
Antiparasitic agents: antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
C07H
Sugars