US 2007/0185117 A1Published application

Novel 14 and 15 membrered ring compounds

AssigneesGlaxo Group Limited, Pliva-Istrazivacki Institut

InventorsSulejman Alihodzic, Andrew Forrest, Richarl Jarvest, Gorjana Lazarevski, Drazen Pavlovic

Life of this patent

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Abstract

The present invention relates to 14- or 15-membered macrolides substituted at the 4″ position of formula (I) and pharmaceutically acceptable derivatives thereof, to processes for their preparation and their use in therapy or prophylaxis of systemic or topical microbial infections in a human or animal body.

Claims13

Dependent claims

A compound of formula (I)

wherein
A is a bivalent radical selected from —C(O)—, —C(O)NH—, —NHC(O)—, —N(R7)—CH2—, —CH2—N(R7)—, —CH(NR8R9)— and —C(═NR10)—;
R1 is —O(CH2)dXR11;
R2 is hydrogen or a hydroxyl protecting group;
R3 is hydrogen, C1-4alkyl, or C3-6alkenyl optionally substituted by 9 to 10 membered fused bicyclic heteroaryl;
R4 is hydroxy, C3-6alkenyloxy optionally substituted by 9 to 10 membered fused bicyclic heteroaryl, or C1-6alkoxy optionally substituted by C1-6alkoxy or —O(CH2)eNR7R12,
R5 is hydroxy, or
R4 and R5 taken together with the intervening atoms form a cyclic group having the following structure:
wherein Y is a bivalent radical selected from —CH2—, —CH(CN)—, —O—, —N(R13)— and —CH(SR13)—;
R6 is hydrogen or fluorine;
R7 is hydrogen or C1-6alkyl;
R8 and R9 are each independently hydrogen, C1-6alkyl, —C(═NR10)NR14R15 or —C(O)R14, or
R8 and R9 together form ═CH(CR14R15)faryl, ═CH(CR14R15)fheterocyclyl, ═CR14R15 or ═C(R14)C(O)OR14, wherein the alkyl, aryl and heterocyclyl groups are optionally substituted by up to three groups independently selected from R16;
R10 is —OR17, C1-6alkyl, —(CH2)garyl, —(CH2)gheterocyclyl or —(CH2)hO(CH2)iOR7, wherein each R10 group is optionally substituted by up to three groups independently selected from R16;
R11 is a heterocyclic group having the following structure:
R12 is hydrogen or C1-6alkyl;
R13 is hydrogen or C1-4alkyl optionally substituted by a group selected from optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl and optionally substituted 9 to 10 membered fused bicyclic heteroaryl;
R14 and R15 are each independently hydrogen or C1-6alkyl;
R16 is halogen, cyano, nitro, trifluoromethyl, azido, —C(O)R21, —C(O)OR21, —OC(O)R21, —OC(O)OR21, —NR22C(O)R23, —C(O)NR22R23, —NR22R23, hydroxy, C1-6alkyl, —S(O)kC1-6alkyl, C1-6alkoxy, —(CH2)maryl or —(CH2)mheteroaryl, wherein the alkoxy group is optionally substituted by up to three groups independently selected from —NR14R15, halogen and —OR14, and the aryl and heteroaryl groups are optionally substituted by up to five groups independently selected from halogen, cyano, nitro, trifluoromethyl, azido, —C(O)R24, —C(O)OR24, —OC(O)OR24, —NR25C(O)R26, —C(O)NR25R26, —NR25R26, hydroxy, C1-6alkyl and C1-6alkoxy;
R17 is hydrogen, C1-6alkyl, C3-7cycloalkyl, C3-6alkenyl or a 5 or 6 membered heterocyclic group, wherein the alkyl, cycloalkyl, alkenyl and heterocyclic groups are optionally substituted by up to three substituents independently selected from optionally substituted 5 or 6 membered heterocyclic group, optionally substituted 5 or 6 membered heteroaryl, —OR27, —S(O)nR27, —NR27R28, —CONR27R28, halogen and cyano;
R18 is hydrogen, —C(O)OR29, —C(O)NHR29, —C(O)CH2NO2 or —C(O)CH2SO2R7;
R19 is hydrogen, C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy, C3-7cycloalkyl, or optionally substituted phenyl or benzyl;
R20 is halogen, C1-4alkyl, C1-4thioalkyl, C1-4alkoxy, —NH2, —NH(C1-4alkyl) or —N(C1-4alkyl)2;
R21 is hydrogen, C1-10alkyl, —(CH2)paryl or —(CH2)pheteroaryl;
R22 and R23 are each independently hydrogen, —OR14, C1-6alkyl, —(CH2)qaryl or —(CH2)qheterocyclyl;
R24 is hydrogen, C1-10alkyl, —(CH2)raryl or —(CH2)rheteroaryl;
R25 and R26 are each independently hydrogen, —OR14, C1-6alkyl, —(CH2)saryl or —(CH2)sheterocyclyl;
R27 and R28 are each independently hydrogen, C1-4alkyl or C1-4alkoxyC1-4alkyl;
R29 is hydrogen,
C1-6alkyl optionally substituted by up to three groups independently selected from halogen, cyano, C1-4alkoxy optionally substituted by phenyl or C1-4alkoxy, —C(O)C1-6alkyl, —C(O)C1-6alkyl, —OC(O)C1-6alkyl, —OC(O)OC1-6alkyl, —C(O)NR32R33, —NR32R33 and phenyl optionally substituted by nitro or —C(O)OC1-6alkyl,
—(CH2)wC3-7cycloalkyl,
—(CH2)wheterocyclyl,
—(CH2)wheteroaryl,
—(CH2)waryl,
C3-6alkenyl, or
C3-6alkynyl;
R30 is hydrogen, C1-4alkyl, C3-7cycloalkyl, optionally substituted phenyl or benzyl, acetyl or benzoyl;
R31 is hydrogen or R20, or R31 and R19 are linked to form the bivalent radical —O(CH2)2— or —(CH2)t—;
R32 and R33 are each independently hydrogen or C1-6alkyl optionally substituted by phenyl or —C(O)OC1-6alkyl, or
R32 and R33, together with the nitrogen atom to which they are bound, form a 5 or 6 membered heterocyclic group optionally containing one additional heteroatom selected from oxygen, nitrogen and sulfur;
X is —U(CH2)vB—, —U(CH2)v— or a group selected from:
U and B are independently a divalent radical selected from —N(R30)—, —O—, —S(O)z—, —N(R30)C(O)—, —C(O)N(R30)— and —N[C(O)R30]—;
W is —C(R31)— or a nitrogen atom;
d is an integer from 2 to 6;
e is an integer from,2 to 4;
f, g, h, m, p, q, r, s and w are each independently integers from 0 to 4;
i is an integer from 1 to 6;
j, k, n and z are each independently integers from 0 to 2;
t is 2 or 3;
v is an integer from 1 to 8;
or a pharmaceutically acceptable derivative thereof.

48 more elements

A compound of formula (IA)

wherein
A is a bivalent radical selected from —C(O)—, —C(O)NH—, —NHC(O)—, —N(R7)—CH2—, —CH2—N(R7)—, —CH(NR8R9)— and —C(═NR10)—;
R1 is —O(CH2)dXR11;
R2 is hydrogen or a hydroxyl protecting group;
R3 is hydrogen, C1-4alkyl, or C3-6alkenyl optionally substituted by 9 to 10 membered fused bicyclic heteroaryl;
R4 is hydroxy, C3-6alkenyloxy optionally substituted by 9 to 10 membered fused bicyclic heteroaryl, or C1-6alkoxy optionally substituted by C1-6alkoxy or —O(CH2)eNR7R12,
R5 is hydroxy, or
R4 and R5 taken together with the intervening atoms form a cyclic group having the following structure:
wherein Y is a bivalent radical selected from —CH2—, —CH(CN)—, —O—, —N(R13)— and —CH(SR13)—;
R6 is hydrogen or fluorine;
R7 is hydrogen or C1-6alkyl;
R8 and R9 are each independently hydrogen, C1-6alkyl, —C(═NR10)NR14R15 or —C(O)R14, or
R8 and R9 together form ═CH(CR14R15)faryl, ═CH(CR14R15)fheterocyclyl, ═CR14R15 or ═C(R14)C(O)OR14, wherein the alkyl, aryl and heterocyclyl groups are optionally substituted by up to three groups independently selected from R16;
R10 is —OR17, C1-6alkyl, —(CH2)garyl, —(CH2)gheterocyclyl or —(CH2)hO(CH2)iOR7, wherein each R10 group is optionally substituted by up to three groups independently selected from R16;
R11 is a heterocyclic group having the following structure:
R12 is hydrogen or C1-6alkyl;
R13 is hydrogen or C1-4alkyl substituted by a group selected from optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl and optionally substituted 9 to 10 membered fused bicyclic heteroaryl;
R14 and R15 are each independently hydrogen or C1-6alkyl;
R16 is halogen, cyano, nitro, trifluoromethyl, azido, —C(O)R21, —C(O)OR21, —OC(O)R21, —OC(O)OR21, —NR22C(O)R23, —C(O)NR22R23, —NR22R23, hydroxy, C1-6alkyl, —S(O)kC1-6alkyl, C1-6alkoxy, —(CH2)maryl or —(CH2)mheteroaryl, wherein the alkoxy group is optionally substituted by up to three groups independently selected from —NR14R15, halogen and —OR14, and the aryl and heteroaryl groups are optionally substituted by up to five groups independently selected from halogen, cyano, nitro, trifluoromethyl, azido, —C(O)R24, —C(O)OR24, —OC(O)OR24, —NR25C(O)R26, —C(O)NR25R26, —NR25R26, hydroxy, C1-6alkyl and C1-6alkoxy;
R17 is hydrogen, C1-6alkyl, C3-7cycloalkyl, C3-6alkenyl or a 5 or 6 membered heterocyclic group, wherein the alkyl, cycloalkyl, alkenyl and heterocyclic groups are optionally substituted by up to three substituents independently selected from optionally substituted 5 or 6 membered heterocyclic group, optionally substituted 5 or 6 membered heteroaryl, —OR27, —S(O)nR27, —NR27R28, —CONR27R28, halogen and cyano;
R18 is hydrogen, —C(O)OR29, —C(O)NHR29 or —C(O)CH2NO2;
R19 is hydrogen, C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy, C3-7cycloalkyl, or optionally substituted phenyl or benzyl;
R20 is halogen, C1-4alkyl, C1-4thioalkyl, C1-4alkoxy, —NH2, —NH(C1-4alkyl) or —N(C1-4alkyl)2;
R21 is hydrogen, C1-10alkyl, —(CH2)paryl or —(CH2)pheteroaryl;
R22 and R23 are each independently hydrogen, —OR14, C1-6alkyl, —(CH2)qaryl or —(CH2)qheterocyclyl;
R24 is hydrogen, C1-10alkyl, —(CH2)raryl or —(CH2)rheteroaryl;
R25 and R26 are each independently hydrogen, —OR14, C1-6alkyl, —(CH2)saryl or —(CH2)sheterocyclyl;
R27 and R28 are each independently hydrogen, C1-4alkyl or C1-4alkoxyC1-4alkyl;
R29 is hydrogen or C1-6alkyl optionally substituted by up to three groups independently selected from halogen, C1-4alkoxy, —OC(O)C1-6alkyl and —OC(O)OC1-6alkyl;
R30 is hydrogen, C1-4alkyl, C3-7cycloalkyl, optionally substituted phenyl or benzyl, acetyl or benzoyl;
R31 is hydrogen or R20, or R31 and R19 are linked to form the bivalent radical —O(CH2)2— or —(CH2)t—;
X is —U(CH2)vB—, —U(CH2)v— or a group selected from:
U and B are independently a divalent radical selected from —N(R30)—, —O—, —S(O)z—, —N(R30)C(O)—, —C(O)N(R30)— and —N[C(O)R30]—;
W is —C(R31)— or a nitrogen atom;
d is an integer from 2 to 6;
e is an integer from 2 to 4;
f, g, h, m, p, q, r and s are each independently integers from 0 to 4;
i is an integer from 1 to 6;
j, k, n and z are each independently integers from 0 to 2;
t is 2 or 3;
v is an integer from 2 to 8;
or a pharmaceutically acceptable derivative thereof.

39 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of formula (I)

wherein
A is a bivalent radical selected from —C(O)—, —C(O)NH—, —NHC(O)—, —N(R7)—CH2—, —CH2—N(R7)—, —CH(NR8R9)— and —C(═NR10)—;
R1 is —O(CH2)dXR11;
R2 is hydrogen or a hydroxyl protecting group;
R3 is hydrogen, C1-4alkyl, or C3-6alkenyl optionally substituted by 9 to 10 membered fused bicyclic heteroaryl;
R4 is hydroxy, C3-6alkenyloxy optionally substituted by 9 to 10 membered fused bicyclic heteroaryl, or C1-6alkoxy optionally substituted by C1-6alkoxy or —O(CH2)eNR7R12,
R5 is hydroxy, or
R4 and R5 taken together with the intervening atoms form a cyclic group having the following structure:
wherein Y is a bivalent radical selected from —CH2—, —CH(CN)—, —O—, —N(R13)— and —CH(SR13)—;
R6 is hydrogen or fluorine;
R7 is hydrogen or C1-6alkyl;
R8 and R9 are each independently hydrogen, C1-6alkyl, —C(═NR10)NR14R15 or —C(O)R14, or
R8 and R9 together form ═CH(CR14R15)faryl, ═CH(CR14R15)fheterocyclyl, ═CR14R15 or ═C(R14)C(O)OR14, wherein the alkyl, aryl and heterocyclyl groups are optionally substituted by up to three groups independently selected from R16;
R10 is —OR17, C1-6alkyl, —(CH2)garyl, —(CH2)gheterocyclyl or —(CH2)hO(CH2)iOR7, wherein each R10 group is optionally substituted by up to three groups independently selected from R16;
R11 is a heterocyclic group having the following structure:
R12 is hydrogen or C1-6alkyl;
R13 is hydrogen or C1-4alkyl optionally substituted by a group selected from optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl and optionally substituted 9 to 10 membered fused bicyclic heteroaryl;
R14 and R15 are each independently hydrogen or C1-6alkyl;
R16 is halogen, cyano, nitro, trifluoromethyl, azido, —C(O)R21, —C(O)OR21, —OC(O)R21, —OC(O)OR21, —NR22C(O)R23, —C(O)NR22R23, —NR22R23, hydroxy, C1-6alkyl, —S(O)kC1-6alkyl, C1-6alkoxy, —(CH2)maryl or —(CH2)mheteroaryl, wherein the alkoxy group is optionally substituted by up to three groups independently selected from —NR14R15, halogen and —OR14, and the aryl and heteroaryl groups are optionally substituted by up to five groups independently selected from halogen, cyano, nitro, trifluoromethyl, azido, —C(O)R24, —C(O)OR24, —OC(O)OR24, —NR25C(O)R26, —C(O)NR25R26, —NR25R26, hydroxy, C1-6alkyl and C1-6alkoxy;
R17 is hydrogen, C1-6alkyl, C3-7cycloalkyl, C3-6alkenyl or a 5 or 6 membered heterocyclic group, wherein the alkyl, cycloalkyl, alkenyl and heterocyclic groups are optionally substituted by up to three substituents independently selected from optionally substituted 5 or 6 membered heterocyclic group, optionally substituted 5 or 6 membered heteroaryl, —OR27, —S(O)nR27, —NR27R28, —CONR27R28, halogen and cyano;
R18 is hydrogen, —C(O)OR29, —C(O)NHR29, —C(O)CH2NO2 or —C(O)CH2SO2R7;
R19 is hydrogen, C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy, C3-7cycloalkyl, or optionally substituted phenyl or benzyl;
R20 is halogen, C1-4alkyl, C1-4thioalkyl, C1-4alkoxy, —NH2, —NH(C1-4alkyl) or —N(C1-4alkyl)2;
R21 is hydrogen, C1-10alkyl, —(CH2)paryl or —(CH2)pheteroaryl;
R22 and R23 are each independently hydrogen, —OR14, C1-6alkyl, —(CH2)qaryl or —(CH2)qheterocyclyl;
R24 is hydrogen, C1-10alkyl, —(CH2)raryl or —(CH2)rheteroaryl;
R25 and R26 are each independently hydrogen, —OR14, C1-6alkyl, —(CH2)saryl or —(CH2)sheterocyclyl;
R27 and R28 are each independently hydrogen, C1-4alkyl or C1-4alkoxyC1-4alkyl;
R29 is hydrogen,
C1-6alkyl optionally substituted by up to three groups independently selected from halogen, cyano, C1-4alkoxy optionally substituted by phenyl or C1-4alkoxy, —C(O)C1-6alkyl, —C(O)C1-6alkyl, —OC(O)C1-6alkyl, —OC(O)OC1-6alkyl, —C(O)NR32R33, —NR32R33 and phenyl optionally substituted by nitro or —C(O)OC1-6alkyl,
—(CH2)wC3-7cycloalkyl,
—(CH2)wheterocyclyl,
—(CH2)wheteroaryl,
—(CH2)waryl,
C3-6alkenyl, or
C3-6alkynyl;
R30 is hydrogen, C1-4alkyl, C3-7cycloalkyl, optionally substituted phenyl or benzyl, acetyl or benzoyl;
R31 is hydrogen or R20, or R31 and R19 are linked to form the bivalent radical —O(CH2)2— or —(CH2)t—;
R32 and R33 are each independently hydrogen or C1-6alkyl optionally substituted by phenyl or —C(O)OC1-6alkyl, or
R32 and R33, together with the nitrogen atom to which they are bound, form a 5 or 6 membered heterocyclic group optionally containing one additional heteroatom selected from oxygen, nitrogen and sulfur;
X is —U(CH2)vB—, —U(CH2)v— or a group selected from:
U and B are independently a divalent radical selected from —N(R30)—, —O—, —S(O)z—, —N(R30)C(O)—, —C(O)N(R30)— and —N[C(O)R30]—;
W is —C(R31)— or a nitrogen atom;
d is an integer from 2 to 6;
e is an integer from,2 to 4;
f, g, h, m, p, q, r, s and w are each independently integers from 0 to 4;
i is an integer from 1 to 6;
j, k, n and z are each independently integers from 0 to 2;
t is 2 or 3;
v is an integer from 1 to 8;
or a pharmaceutically acceptable derivative thereof.

48 more elements