US2013231298A1PendingUtilityA1
Anti-bacterial activity of 9-hydroxy derivatives of 6,11-bicyclolides
Est. expiryMay 9, 2028(~1.8 yrs left)· nominal 20-yr term from priority
A61P 29/00A61P 31/04A61K 31/706C07H 17/08A61K 31/7056
50
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Claims
Abstract
The present invention discloses compounds of formula (I) or pharmaceutically acceptable salts, esters, or prodrugs thereof: which exhibit superior antibacterial properties, particularly against Haemophilus influenzae . The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject in need of antibiotic treatment. The invention also relates to methods of treating a bacterial infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention. The invention further includes process by which to make the compounds of the present invention.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . Compounds represented by formula (I):
or a racemate, enantiomer, diastereomer, geometric isomer, tautomer, solvate, pharmaceutically acceptable salt, ester and prodrug thereof,
wherein V is selected from the group consisting of:
(a) —R 1 —, where R 1 is substituted or unsubstituted —C 1 -C 8 alkylene-, —C 2 -C 8 alkenylene- or —C 2 -C 8 alkynylene- each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(b) —R 1 —(C═O)—R 2 —, where R 2 is independently selected from R 1 ;
(c) —R 1 —(C═N-E-R 3 )—R 2 —, where E is absent, O, NH, NH(C═O), NH(C═O)NH or NHSO 2 ; where R 3 is independently selected from the group consisting of:
(i) hydrogen;
(ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(iii) —R 4 , where R 4 is substituted or unsubstituted —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; and
(iv) —R 5 , where R 5 is substituted and unsubstituted —C 3 -C 12 cycloalkyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(d) —R 1 —(C═CH-J-R 6 )—R 2 —; where J is absent, O, CO, SO 2 , NH, NH(C═O), NH(C═O)NH or NHSO 2 ; and wherein R 6 is independently selected from halogen and R 3 ;
(e) —R 1 —[C(OR 7 )(OR 8 )]—R 2 —, where R 7 and R 8 are selected from the group consisting of C 1 -C 12 alkyl, aryl or substituted aryl; or R 7 and R 8 taken together is —(CR a R b ) r —, where r is 2 or 3; R a and R b are independently selected from hydrogen, aryl, and R 4 ; or
(f) —R 1 —[C(SR 7 )(SR 8 )]—R 2 —;
R is selected from the group consisting of:
(a) —R 3 ;
(b) —C(O)R 3 ;
(c) —C(O)OR 3 ;
(d) —S(O) 2 R 3 ;
(e) hydroxy prodrug group;
(f) hydroxy protecting group; and
(g) —C(O)N(R 9 R 10 ); where R 9 and R 10 are each independently selected from R 3 ;
alternatively, R 9 and R 10 taken together with the nitrogen atom to which they are connected form a substituted or unsubstituted 3- to 10-membered ring which may optionally contain one or more heterofunctions selected from the group consisting of: —O—, —N(R 3 )—, —S(O) n —, wherein n=0, 1 or 2;
W is selected from:
(a) hydrogen;
(b) hydroxy prodrug group;
(c) —R 4 ;
(d) —C(O)R 3 ;
(e) —C(O)O—R 3 ; and
(f) —C(O)N(R 9 R 10 );
one of A and B is R u and the other is OR 11 , wherein R 11 is independently selected from:
(a) hydrogen;
(b) —R 4 ;
(c) —C(O)R 3 ;
(d) —C(O)NHR 3 ;
(e) —S(O) 2 R 3 ;
(f) monosaccharide; and
(g) -disaccharide;
alternatively, A and B taken together with the carbon atom to which they are attached to form:
(a) C═O; or
(b) C═CH-J-R 6 ;
L is independently selected from R 4 ;
Q is:
(a) —R 3 ;
(b) —(C═O)R 3 ;
(c) —(C═O)NHR 3 ;
(d) —(C═O)OR 3 ;
(e) —(SO) 2 R 3 ;
(f) monosaccharide;
(g) disaccharide; or
(h) trisaccharide;
Z is:
(a) hydrogen;
(b) —N 3 ;
(c) —CN;
(d) —NO 2 ;
(e) —CONH 2 ;
(f) —COOH;
(g) —CHO;
(h) —R 4 ;
(i) —COOR 4 ;
(j) —(C═O)R 4 ; or
(k) —(C═O)NR 9 R 10 ; and
each of X and Y is independently:
a) hydrogen;
b) hydroxy;
c) halogen; or
d) —R 4 .
2 . A compound according to claim 1 represented by formula (II):
or a pharmaceutically acceptable salt, ester or salt thereof, where Z 1 and Z 2 are independently selected from:
(a) hydrogen;
(b) deuterium;
(c) halogen;
(d) —R 3 , where R 3 is independently selected from the group consisting of:
(i) hydrogen;
(ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl; and
(iii) —R 4 , where R 4 is substituted or unsubstituted —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, or —C 2 -C 6 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; and
(iv) —R 5 , where R 5 is substituted and unsubstituted —C 3 -C 12 cycloalkyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(e) —C(O)-J 1 -R 3 , wherein J 1 is absent, O, or S and R 3 is as previously defined;
(f) —OR 3 ;
(g) —O(C═O)R 3 ;
(h) —O(C═O)OR 3 ;
(i) —O(C═O)NHR 3 ;
(j) —NH(C═O)R 3 ;
(k) —NH(C═O)NHR 3 ;
(l) —NH(C═O)OR 3 ;
(m)—NH(SO 2 )R 3 ;
(n) —NH(SO 2 )NHR 3 ;
(o) —NR 9 R 10 , where R 9 and R 10 are each independently selected from R 3 ;
alternatively, R 9 and R 10 taken together with the nitrogen atom to which they are connected form a 3- to 10-membered ring which may optionally contain one or more heterofunctions selected from the group consisting of: —O—, —N(R 3 )—, —S(O) n —, wherein n=0, 1 or 2; and
(p) —C(O)—NR 9 R 10 ;
alternatively, Z 1 and Z 2 taken together with the carbon atom to which they are attached are:
(a) C═O;
(b) C(OR 7 )(OR 8 ), where R 7 and R 8 are selected from the group consisting of C 1 -C 12 alkyl, aryl or substituted aryl; or R 7 and R 8 taken together is —(CR a R b ) r —, where r is 2 or 3; R a and R b are independently selected from hydrogen, aryl, and R 4 ;
(c) C(SR 7 )(SR 8 );
(d) C═CHR 3 , where R 3 is as previously defined; or
(e) C═N-E-R 3 , where E is absent, O, NH, NH(C═O), NH(C═O)NH or NHSO 2 ;
R p is hydrogen, hydroxy protecting group, ester or hydroxy prodrug group; and A, B, R, W, Y, R 9 , and R 10 are as previously defined in claim 1 .
3 . A compound according to claim 2 represented by formula (III):
or a pharmaceutically acceptable salt, ester or prodrug thereof where R, W, Z 1 , Z 2 , Rp, R 9 and R 10 are as previously defined in claim 2 .
4 . A compound according to claim 2 represented by formula (IV):
or a pharmaceutically acceptable salt, ester or salt thereof, where R, W, Y, Z 1 , Z 2 , Rp, R 9 and R 10 are as previously defined in claim 2 .
5 . A compound according to claim 1 represented by formula (V):
or a pharmaceutically acceptable salt, ester or prodrug thereof where W, R, Y, Rp, R 3 , R 9 and R 10 are as previously defined in claim 1 .
6 . A compound according to claim 1 represented by formula (VI):
or a pharmaceutically acceptable salt, ester or prodrug thereof where W, R, Y, Rp, R 6 , R 9 and R 10 are as previously defined in claim 1 .
7 . A compound of claim 1 having the Formula A, selected from compounds 1-28 of Table 1:
wherein Y and R 3 is delineated for each example in Table 1:
TABLE 1
Compound No.
Y
—R 3
(1)
H
(2)
H
(3)
H
(4)
H
(5)
H
(6)
H
(7)
H
(8)
H
(9)
H
(10)
F
(11)
F
(12)
F
(13)
F
(14)
F
(15)
F
(16)
F
(17)
F
(18)
F
(19)
H
(20)
H
(21)
F
(22)
F
(23)
F
(24)
F
(25)
F
(26)
H
(27)
H
(28)
H
8 . 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.
9 . A method for treating a bacterial infection in a subject, comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition according to claim 8 .
10 . A method of treating cystic fibrosis in subject, comprising administering to said subject, a therapeutically effective amount of a pharmaceutical composition of claim 8 .
11 . A method of treating inflammation in a subject comprising administering to said subject, therapeutically effective amount of a pharmaceutical composition of claim 8 .
12 . A process for preparing a compound of formula I, comprising the step of:
(a) reacting a compound represented by the formula
wherein R, A, B, X, Y and PG are as defined in claim 1 , with alkylating agent of formula
where R 50 is —C 1 -C 12 alkyl, —C 1 -C 12 alkenyl, or —C 1 -C 12 alkynyl, in the presence of a palladium catalyst;
(b) oxidizing the double bond to the corresponding ketone;
(c) reacting the compound from step (b) with R 3 ONH 2 , where R 3 is defined in claim 1 , in the presence of an acid or a base; and
(d) optionally deprotecting the compound from step (c).Join the waitlist — get patent alerts
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