US2005009763A1PendingUtilityA1
6,11-4-Carbon bridged erythromycin derivatives
Priority: Jul 25, 2002Filed: May 7, 2004Published: Jan 13, 2005
Est. expiryJul 25, 2022(expired)· nominal 20-yr term from priority
C07H 17/08
56
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Claims
Abstract
Novel 6, 11-4-carbon bridged erythromycin derivatives and pharmaceutically-acceptable compositions comprising a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically-acceptable carrier are described. Also described are methods for treating bacterial infections by administering to an animal a pharmaceutical composition containing a therapeutically effective amount of a compound of the invention and processes for the preparation of such compounds.
Claims
exact text as granted — not AI-modified1 . A compound represented by the formula:
or a pharmaceutically acceptable salt, ester or prodrug thereof wherein
W is selected from the group consisting of:
(a) —CH 2 —C(A)═C(B)—CH 2 —;
wherein,
A and B are independently selected from the group consisting of:
(i) hydrogen;
(ii) deuterium;
(iii) halogen;
(iv) R 1 , wherein R 1 is selected from the group consisting of:
a. C 1 -C 6 alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
b. C 2 -C 6 alkenyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and
c. C 2 -C 6 alkynyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
(v) R 2 , wherein R 2 is selected from the group consisting of:
a. aryl;
b. heteroaryl;
c. substituted aryl; and
d. substituted heteroaryl;
(vi) —(C 1 -C 3 -alkyl)-M-(C 1 -C 3 -alkyl)-R 2 , wherein M=—O—, —NH—, —N(CH 3 )—, —NHC(O)— or —S(O) n —, wherein n=0, 1 or 2, and R 2 is as previously defined;
(vii) —(C 1 -C 3 -alkyl)-M-R 2 , wherein M and R 2 are as previously defined;
(viii) —C(O)-J-R 3 , wherein J is absent, O or S, and R 3 is H, R 1 or R 2 ;
where R 1 and R 2 are as previously defined; and
(ix) —C(O)—NR 11 R 12 , wherein R 11 and R 12 are each independently selected from the group consisting of:
a. hydrogen;
b. C 1 -C 6 -alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
c. C 2 -C 6 -alkenyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
d. C 2 -C 6 -alkynyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and
e. R 1 and R 12 taken together with the nitrogen atom to which they are connected form a 3- to 7-membered ring which may optionally contain one or more heterofunctions selected from the group consisting of: —O—, —NH—, —N(C 1 -C 6 -alkyl)-, —N(R 2 )—, —S(O) n —, wherein n and R 2 are as previously defined;
(b) —CH 2 —CH(A)-C(B)=CH—, wherein A and B are as previously defined;
(c) —CH 2 —CH(E)-CH(G)-CH 2 —;
wherein E and G are independently selected from the group consisting of:
(i) A, wherein A is as previously defined;
(ii) —OH;
(iii) —O—R 9 , wherein R P is a hydroxy protecting group;
(iv) —O—R 9 , wherein R 9 is R 1 or R 2 , and wherein R 1 and R 2 are as previously defined;
(v) —S(O) n R 9 , wherein n and R 9 are as previously defined;
(vi) —NHC(O)R 3 , wherein R 3 is as previously defined;
(vii) —NHC(O)NR 11 R 3 , wherein R 11 and R 3 are as previously defined;
(viii) —NHS(O) 2 R 9 , wherein R 9 is as previously defined;
(ix) —NHR 13 , wherein R 13 is an amino protecting group; and
(x) —NR 11 R 12 , wherein R 11 and R 12 are as previously defined;
(d)
wherein:
(i) -Q- is selected from the group consisting of: —O—; —O—C(O)—CH(R 7 )—; —N(R 7 )—; —O—C(O)—N(R 7 )—; —O—C(O)—O—; —N(R 7 )—N═N—; —C(R 7 )═N—O—; and —CH(R 7 )—N(R 8 )—O—; wherein R 7 and R 9 are independently selected from R 3 , wherein R 3 is as previously defined; or
(ii) -Q- taken together with the two carbon atoms it is attached to is selected from the group consisting of:
a. cycloalkylene;
b. cycloalkenylene; and
c. heterocycloalkylene; and
(e) —CH 2 —C(R4)(R 5 )—CH 2 —CH 2 —;
wherein R 4 and R 5 taken together with the carbon atom to which they are attached are selected from the group consisting of:
(i) C═O;
(ii) C(OR 1 ) 2 , wherein R 1 is as previously defined;
(iii) C(SR 1 ) 2 , wherein R 1 is as previously defined;
(iv) C[—O(CH 2 ) m ] 2 , wherein m is 2 or 3;
(v) C[—S(CH 2 ) m ] 2 , wherein m is as previously defined,
(vi) C═CHR 3 , wherein R 3 is as previously defined;
(vii) C═N—O—R 3 , wherein R 3 is as previously defined;
(viii) C═NNHR 3 , wherein R 3 is as previously defined;
(ix) C═NNHC(O)R 3 , wherein R 3 is as previously defined;
(x) C═NNHC(O)NR 11 R 3 , wherein R 11 and R 3 are as previously defined;
(xi) C═NNHS(O) 2 R 9 , wherein R 9 is as previously defined;
(xii) C═NNHR 13 , wherein R 13 is as previously defined; and
(xiii) C═NR 9 , wherein R 9 is as previously defined;
X and Y are:
(a) independently selected from the group consisting of:
(i) hydrogen;
(ii) deuterium;
(iii) —OH;
(iv) —OR P , wherein R P is as previously defined; and
(v) —NR 14 R 15 , wherein R 14 and R 15 are each independently selected from the group consisting of:
a. hydrogen;
b. C 1 -C 12 alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl; and
c. R 14 and R 15 , taken together with the nitrogen atom to which they are attached form a 3 to 10 membered heterocycloalkyl ring optionally substituted with one or more hetero atoms selected from the group consisting of O, S and N; or
(b) taken together with the carbon atom to which they are attached are selected from the group consisting of:
(i) C═O;
(ii) C═NR 3 , wherein R 3 is as previously defined;
(iii) C═NC(O)R 3 , wherein R 3 is as previously defined;
(iv)C═N—OR 6 , wherein R 6 is selected from the group consisting of:
a. hydrogen;
b. —CH 2 O(CH 2 ) 2 OCH 3 ;
c. —CH 2 O(CH 2 O) n CH 3 , wherein n is as previously defined;
d. C 1 -C 12 alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
e. C 3 -C 12 cycloalkyl;
f. C(O)—C 1 -C 12 alkyl;
g. C(O)—(C 3 -C 12 cycloalkyl);
h. C(O)—R 2 , wherein R 2 is as previously defined; and
i. —Si(R a )(R b )(R c ), wherein R a , R b and R c are each independently selected from the group consisting of C 1 -C 12 alkyl, aryl and substituted aryl; and
(v) C═N—O—C(R 16 )(R 17 )—O—R 18 , wherein R 16 and R 17 taken together with the carbon atom to which they are attached form a C 3 to C 12 cycloalkyl group or each independently is selected from the group consisting of: hydrogen, and C 1 -C 12 alkyl; and R 18 is selected from the group consisting of:
a. hydrogen;
b. —CH 2 O(CH 2 ) 2 OCH 3 ;
c. —CH 2 O(CH 2 O) n CH 3 , wherein n is as previously defined;
d. C 1 -C 12 alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
e. C 3 -C 12 cycloalkyl; and
f. —Si(R a )(R b )(R c ), wherein R a , R b and R c are as previously defined;
L is selected from the group consisting of:
(a) —CH(OH)CH 3 ;
(b) C 1 -C 6 alkyl, optionally substituted with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
(c) C 2 -C 6 alkenyl, optionally substituted with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and
(d) C 2 -C 6 alkynyl, optionally substituted with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
K is selected from the group consisting of:
(a) R 10 , wherein R 10 is selected from the group consisting of:
(i) hydrogen;
(ii) —OR P , wherein R P is as previously defined;
(iii) —OR 3 , wherein R 3 is as previously defined;
(iv) —OC(O)R 3 , wherein R 3 is as previously defined;
(v) —OC(O)NR 11 R 3 , wherein R 11 and R 3 are as previously defined; and
(vi) —S(O) n R 9 , wherein n and R 9 are as previously defined; and
(b)
wherein R 3 ″ is hydrogen or methyl; R 4 ″ is hydrogen or R P , wherein R P is as previously defined; and
R x is hydrogen or R P , wherein R P is as previously defined.
2 . A compound according to claim 1 wherein X and Y taken together with the carbon atom to which they are attached are selected from the group consisting of: C═O, C═NR 3 , C═N—O—R 6 , C═N—C(O)R 3 and C═N—O—C(R 16 )(R 17 )—O—R 18 , wherein R 3 , R 6 , R 16 , R 17 and R 18 are as defined in claim 1 .
3 . A compound according to claim 2 wherein X and Y taken together with the carbon atom to which they are attached are selected from the group consisting of:
C═NC(O)CH 3 and C═N—O—CH 2 —O—CH 3 .
4 . A compound according to claim 1 represented by the formula:
wherein A, B, X, Y, Rx and R 4 ″ are as defined in claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof.
5 . A compound according to claim 4 wherein X and Y taken together with the carbon atom to which they are attached are selected from the group consisting of: C═O, C═NR 3 , C═N—O—R 6 , C═N—C(O)R 3 and C═N—O—C(R 16 )(R 17 )—O—R 18 , wherein R 3 , R 6 , R 16 , R 17 and R 18 are as defined in claim 1 .
6 . A compound according to claim 1 represented by the formula:
wherein A, B, X, Y, R 10 and R x are as defined in claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof.
7 . A compound according to claim 6 wherein X and Y taken together with the carbon atom to which they are attached are selected from the group consisting of: C═O, C═NR 3 , C═N—O—R 6 , C═N—C(O)R 3 and C═N—O—C(R 16 )(R 17 )—O—R 18 , wherein R 3 , R 6 , R 10 , R 16 , R 17 and R 18 are as defined in claim 1 .
8 . A compound according to claim 1 represented by the formula:
wherein A, B, X, Y, R x and R 4 are as defined in claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof
9 . A compound according to claim 8 wherein X and Y taken together with the carbon atom to which they are attached are selected from the group consisting of: C═O, C═NR 3 , C═N—O—R 6 , C═N—C(O)R 3 and C═N—O—C(R 16 )(R 17 )—O—R 18 , wherein R 3 , R 6 , R 16 , R 17 and R 18 are as defined in claim 1 .
10 . A compound according to claim 1 represented by the formula:
wherein A, B, X, Y, R 10 and R x are as defined in claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof.
11 . A compound according to claim 1 represented by the formula:
wherein A, B, X, Y, R x and R 4 are as defined in claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof.
12 . A compound according to claim 1 represented by the formula:
wherein A, B, X, Y, R 10 and R x are as defined in claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof.
13 . A compound according to claim 1 represented by the formula:
wherein Q, X, Y, R x and R 4 ″ are as defined in claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof.
14 . A compound according to claim 1 represented by the formula:
wherein Q, X, Y, R 10 and R x are as defined in claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof.
15 . A compound according to claim 1 represented by the formula:
wherein E, G, X, Y, R x and R 4 ″ are as defined in claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof.
16 . A compound according to claim 1 represented by the formula:
wherein E, G, X, Y, R 10 and R x are as defined in claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof.
17 . A compound according to claim 1 represented by the formula:
wherein X, Y, R 4 , R 5 , R x and R 4 are as defined in claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof.
18 . A compound according to claim 1 represented by the formula:
wherein X, Y, R 4 , R 5 , R 10 and R x are as defined in claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof.
19 . A compound according to claim 1 represented by the formula:
wherein X, Y, R 4 , R 5 , R x and R 4 ″ are as defined in claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof.
20 . A compound according to claim 1 represented by the formula:
wherein X, Y, R 4 , R 5 , R 10 and R x are as defined in claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof.
21 . A compound according to claim 1 selected from the group consisting of:
Compound of Formula (II): A=B=H; X and Y taken together with the carbon atom they are attached to=C═N—OH; R x =H and R 4 ″=C(O)C 6 H 5 ; Compound of Formula (IV): A=3-quinolyl; B=H; X and Y taken together with the carbon atom they are attached to=C═N—OH; R x =H and R 4 ″=C(O)CH 3 ; Compound of Formula (II): A=C(O)OCH 3 ; B=H; X and Y taken together with the carbon atom they are attached to=C═N—OH; R x =H and R 4 ″=C(O)C 6 H 5 ; Compound of Formula (II): A=B=H; X and Y taken together with the carbon atom they are attached to=C═N—C(O)CH 3 ; R x =H and R 4 ″=C(O)C 6 H 5 ; Compound of Formula (VIII): Q=—C(C 6 H 5 )═N—O—; X and Y taken together with the carbon atom they are attached to=C═N—C(O)CH 3 ; R x =H and R 4 ″=C(O)C 6 H 5 ; Compound of Formula (VIII): Q=—O—C(O)—O—; X and Y taken together with the carbon atom they are attached to=C═N—C(O)CH 3 ; R x =H and R 4 ″=C(O)C 6 H 5 ; Compound of Formula (VIII): Q=—O—; X and Y taken together with the carbon atom they are attached to=C═N—C(O)CH 3 ; R x =H and R 4 ″=C(O)C 6 H 5 ; Compound of Formula (VIII): Q=—O—; X and Y taken together with the carbon atom they are attached to=C═N—C(O)CH 3 ; R x =H and R 4 ″=H; Compound of Formula (II): A=B=H; X and Y taken together with the carbon atom they are attached to=C═NC(O)CH 2 OCH 3 ; R x =H and R 4 ″=C(O)C 6 H 5 ; Compound of Formula (II): A=B=H; X and Y taken together with the carbon atom they are attached to=C═N—C(O)—CH 2 OCH 3 ; R x =H and R 4 ″=H; Compound of Formula (IV): A=3-quinolyl; B=H; X and Y taken together with the carbon atom they are attached to=C═N—C(O)CH 3 ; R x =H and R 4 ″=C(O)C 6 H 5 ; Compound of Formula (IV): A=3-quinolyl; B=H; X and Y taken together with the carbon atom they are attached to=C═N—C(O)CH 3 ; R x =H and R 4 ″=H; Compound of Formula (II): A=C(CH═CH—C 6 H 5 ); B=H; X and Y taken together with the carbon atom they are attached to=C═N—C(O)CH 3 ; R x =H and R 4 ″=C(O)C 6 H 5 ; Compound of Formula (II): A=C(CH═CH—C 6 H 5 ); B=H; X and Y taken together with the carbon atom they are attached to=C═NC(O)CH 3 ; R x =H and R 4 ″=H; Compound of Formula (II): A=C(CH═CH—C 6 H 5 ); B=H; X and Y taken together with the carbon atom they are attached to=C═N—C(O)CH 3 ; R x =H and R 4 ″C(O)C 6 H 5 ; Compound of Formula (II): A=C(CH═CH—C 6 H 5 ); B=H; X and Y taken together with the carbon atom they are attached to=C═NC(O)CH 3 ; R x =H and R 4 ″=H; Compound of Formula (II): A=H; B=H; X and Y taken together with the carbon atom they are attached to=C═N—Ac; R x =H and R 4 ″=H; Compound of Formula (II): A=C(O)—OH; B=H; X and Y taken together with the carbon atom they are attached to=C═N—OH; R x =H and R 4 ″=H; and Compound of Compound of Formula (II): A=B=H, X and Y taken together with the carbon atom they are attached to=C═O, R x =H and R 4 ″=C(O)CH 3 .
22 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable carrier.
23 . A method for controlling a bacterial infection in an animal comprising administering to an animal a therapeutically effective amount of a pharmaceutical composition according to claim 22 .
24 . A process for preparing a compound of formula:
wherein A, B, and RX are as defined in claim 1 , V taken together with the carbon atom it is attached to is selected from the group consisting of: C═O, C═NR 3 , C═N—O—R 6 , C═N—C(O)R 3 and C═N—O—C(R 16 )(R 17 )—O—R 18 , where R 3 , R 6 , R 16 , R 17 and R 18 are as defined in claim 1 , and R 4 ″ is a hydroxy protecting group;
comprising the step of reacting a compound of the formula:
wherein R 4 ″, RX and V are as defined previously,
with an alkylating agent of the formula:
wherein R 19 is C 1 -C 6 alkyl and A and B are as defined in claim 1 , in an aprotic solvent in the presence of a palladium catalyst at a temperature between room temperature and 80° C. to produce the claimed compound.
25 . A process for preparing a compound of formula:
wherein R 4 ″ is a hydroxy protecting group and A, B and R x are as defined in claim 1 , the process comprising the steps:
(a) hydrolyzing a compound of formula:
wherein R 4 ″ is a hydroxy protecting group and A, B, R 6 and R x are as defined in claim 1 ,
in a protic solvent optionally with aqueous acid or base to obtain the compound of formula:
wherein R 4. ″ A, B and R x are as defined previously; and
(b) reducing the product of step (a) with a reducing agent to obtain the claimed compound.
26 . A process for preparing a compound of formula:
wherein A, B, R 3 , R x and R 4 ″ are as defined in claim 1;
the process comprising the step of acylating a compound of formula:
wherein A, B R x and R 4 are as previously defined, with R 3 C(O)T or (R 3 C(O)) 2 O, where R 3 is as defined in claim 1 and T is a hydroxy group or halogen, under basic conditions using an acylating agent in an aprotic solvent, optionally using an activation agent.
27 . A process for preparing a compound of formula:
wherein R 4 ″ is a hydroxy protecting group, and A, B and R x are as defined in claim 1;
the process comprising the steps:
(a) reacting a compound of the formula:
wherein R 4 ″ and V are as defined in claim 1 and R x is as previously defined, with an alkylating agent of the formula:
wherein R 19 is C 1 -C 6 alkyl and A and B are as previously defined, in an aprotic solvent in the presence of a palladium catalyst at a temperature between room temperature and 80° C. to produce the compound of formula:
wherein R 6 is as defined in claim 1 , R P 1 is H or R P 1 where R P is as defined in claim 1 , and R 4, ″ A, B and R x , are as defined previously;
(b) reacting the compound from step (a) with a protic solvent optionally with aqueous base followed by reduction with a reducing agent to produce a compound of formula:
wherein R 4, ″ A, B, R P 1 and R x are as previously defined;
(c) removing the R P 1 protecting group from the compound of step (b) and acylating the resulting hydroxy group with di-tert-butoxycarbonate to produce compound of formula:
wherein Boc is a tert-butoxycarbonyl group and wherein R 4, ″ A, B and R x are as previously defined; and
(d) reacting the compound from step (b) with a palladium catalyst and a phosphorous ligand to obtain the claimed compound.Join the waitlist — get patent alerts
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