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1. (WO2004101586) NOVEL 14 AND 15 MEMBERED-RING COMPOUNDS
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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(=NR1 °)-;

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 C1-4alkoxy 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

Rδ and R9 together form =CH(CR14R15)faryl, =CH(CR14R15)f heterocyclyl, =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 R18;

R10 is -OR17, C1-6alkyl, -(CH2)garyl, -(CH2)gheterocyclyl or -(CH2)hO(CH2)jOR7, 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:


or


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)kC 1- galkyl, C-|_galkoxy, -(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 R23 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)C 1--alkyl, -C(O)OC1 -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:


,


,

and


U and B are independently a divalent radical selected from -N(R30)-, -O-, -S(O)2-, 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.

2. A compound according to claim 1 wherein A is -C(O)- or -N(R7)-CH2-

3. A compound according to claim 1 or claim 2 wherein X is -U(CH2)vB- or -U(CH2)v.

4. A compound according to any one of the preceding claims wherein d is 2 or 3.

5. A compound according to any one of the preceding claims wherein R1 1 is a heterocyclic group of the following formula:


or


wherein the heterocyclic is linked in the 6 or 7 position and j, R18, R19 and R20 are as defined in claim 1;

a heterocyclic group of the following formula:


wherein the heterocylic is linked in the (ii) or (iii) position, W is -C(R31)- and R31 and R19 are linked to form the bivalent radical -(CH2)t- as defined in claim 1, and j, R18, R19 and R20 are as defined in claim 1; or

a heterocyclic group of the following formula:


wherein the heterocyclic is linked in the 7 or 8 position and j, R18, R19 and R20 are as defined in claim 1.

6. A compound according to claim 1 as defined in any one of Examples 1 to 42, or a pharmaceutically acceptable derivative thereof.

7. A compound selected from:

4"-O-(2-{[2-(3-carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-ylamino)-ethyl]-methylamino}-ethyl)-6-O-methyl-erythromycin A 11,12-carbonate;

4"-O-(3-{[2-(3-carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-ylamino)ethyl]-methylamino}-propyl)-6-O-methyl-erythromycin A 11,12-carbonate;

4"-O-{3-[2-(2-carboxy-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-9-yloxy)-ethylamino]-propyl}-6-O-methyl-erythromycin A 11,12-carbonate;

4"-O-(3-{[3-(3-carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)propyl]-methylamino}-propyl)-6-O-methyl-erythromycin A 11,12-carbonate;

4"-O-(3-{{2-(3-carboxy-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridin-7-ylamino)ethyl]-methylamino}-propyl)-6-O-methyl-erythromycin A 11 ,12-carbonate;

4"-O-{2-[2-(3-carboxy-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridin-7-ylamino)ethyl]-methylamino}-ethyl }-6-O-methyl-erythromycin A;

4"-O-{3-[[3-(3-carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-yl)-propyl]-methylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycin A 11,12-carbamate;

4"-O-{3-[[2-(3-carboxy-1-ethyl-4-oxo-1,4-dihydro-quinolin-6-ylsulfanyl)-ethyl]-methylamino]-propyl}-6-O-methyl-11-desoxy-11-(R)-amino-erythromycin A 11,12-carbamate;

4"-O-{3-[2-(3-carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-ylamino)-ethylcarbamoyl]-propyl}-azithromycin;

4"-O-{2-[2-(3-carboxy-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-7-ylamino)-ethylamino]-ethyl}-azithromycin 11,12-cyclic carbonate;

4"-O-{2-[2-(3-carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-ylamino)-ethylamino]-ethyl}-azithromycin; and

4"-O-{2-[2-(3-carboxy-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-7-ylamino)-ethylamino]-ethyl}-azithromycin;

or a pharmaceutically acceptable derivative thereof.

8. A process for the preparation of a compound as claimed in claim 1 which comprises:

a) reacting a compound of formula (II)


HN(R30)(CH2)vB3R11a HN(R30)(CH2)vR11a

(IIIa) (IIIb)

with a suitable amine (IIIa) or (IIIb), wherein Ba and R11a are B and R11 as defined ir claim 1 or groups convertible to B and R11;

b) reacting a compound of formula (V)


with a compound of formula XaR11a (IV), wherein R11a is R11 as defined in claim 1 or a group convertible to R11 and Xa is -U(CH2)v- or -U(CH2)vB-, or a group convertible to -U(CH2)v or -U(CH2)vB-, in which U is a group selected from -N(R30)- and -S-, and L is suitable leaving group, to produce a compound of formula (I) wherein U is a group selected from -N(R30)- and -S-;

c) converting one compound of formula (I) into another compound of formula (I);

d) where U is -O-, reacting a compound of formula (VII)


with a suitable compound of formula XaR11a in the presence of a catalyst; or

e) where U is -C(O)N(R30)-, reacting a compound of formula (VIII)


with a suitable amine compound,

and thereafter, if required, subjecting the resulting compound to one or more of the following operations:

i) removal of the protecting group R2,

ii) conversion of XaR11 a to XR11 ,

iii) conversion of BaR11a to R11,

iv) conversion of R11a to R11 ,

and

v) conversion of the resultant compound of formula (I) into a pharmaceutically acceptable derivative thereof.

9. A compound as claimed in any one of claims 1 to 7 for use in therapy.

10. The use of a compound as claimed in any one of claims 1 to 7 in the manufacture of a medicament for use in the treatment or prophylaxis of systemic or topical microbial infections in a human or animal body.

11. The use of a compound as claimed in any one of claims 1 to 7 for use in the treatment or prophylaxis of systemic or topical microbial infections in a human or animal body.

12. A method for the treatment of the human or non-human animal body to comba microbial infection comprising administration to a body in need of such treatment of ar effective amount of a compound as claimed in any one of claims 1 to 7.

13. A pharmaceutical composition comprising at least one compound as claimed ir any one of claims 1 to 7 in association with a pharmaceutically acceptable excipient, diluent and/or carrier.

14. 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 C 1-6alkoxy 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:


or


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 C 1-6alkyl;

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)kC 1- galkyl, C 1-6alkoxy, -(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)R28, -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, C-j.-j galkyl, -(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)C 1-6alkyl 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:


and


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.