USRE39591EExpiredUtilityPatentIndex 63
6-O-substituted ketolides having antibacterial activity
Est. expirySep 4, 2016(expired)· nominal 20-yr term from priority
A61P 31/00A61P 31/04Y02P20/55C07H 1/00C07H 17/08C07H 17/00
63
PatentIndex Score
2
Cited by
27
References
19
Claims
Abstract
Antimicrobial compounds having the formula as well as pharmaceutically acceptable salts, esters or prodrugs thereof; pharmaceutical compositions comprising such compounds; methods of treating bacterial infections by the administration of such compounds; and processes for the preparation of the compounds.
Claims
exact text as granted — not AI-modified1. A compound having the formula
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein
either,
Y and Z taken together define a group X, wherein
X is selected from the group consisting of
(1) ═O,
(2) ═N—OH,
(3) ═N—O—R 1 where R 1 is selected from the group consisting of
(a) unsubstituted C 1 -C 12 -alkyl,
(b) C 1 -C 12 -alkyl substituted with aryl,
(c) C 1 -C 12 -alkyl substituted with substituted aryl,
(d) C 1 -C 12 -alkyl substituted with heteroaryl,
(e) C 1 -C 12 -alkyl substituted with substituted heteroaryl,
(f) C 3 -C 12 -cycloalkyl, and
(g) —Si—(R 2 )(R 3 )(R 4 ) wherein R 2 , R 3 and R 4 are each independently selected from C 1 -C 12 -alkyl and Aryl; and
(4) ═N—O—C(R 5 )(R 6 )—O—R 1 where R 1 is as previously defined and R 5 and R 6 are each independently selected from the group consisting of
(a) hydrogen,
(b) unsubstituted C 1 -C 12 -alkyl,
(c) C 1 -C 12 -alkyl substituted with aryl,
(d) C 1 -C 12 -alkyl substituted with substituted aryl,
(e) C 1 -C 12 -alkyl substituted with heteroaryl, and
(f) C 1 -C 12 -alkyl substituted with substituted heteroaryl, or
R 5 and R 6 taken together with the atom to which they are attached form a C 3 -C 12 -cycloalkyl ring;
or,
one of Y and Z is hydrogen and the other is selected from a group consisting of
(1) hydrogen,
(2) hydroxy,
(3) protected hydroxy, and
(4) NR 7 R 8 wherein R 7 and R 8 are independently selected from the group consisting of hydrogen and C 1 -C 6 -alkyl, or R 7 and R 8 are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring which, when the ring is a 5- to 7-membered ring, may optionally contain a hetero function selected from the group consisting of —O—, —NH—, —N(C 1 -C 6 -alkyl-)-, —N(aryl)-, —N(aryl-C 1 -C 6 -alkyl-)-, —N(substituted-aryl-C 1 -C 6 -alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C 1 -C 6 -alkyl-)-, —N(substituted-heteroaryl-C 1 -C 6 -alkyl-)-, and —S— or —S(O) n —,
wherein n is 1 or 2,
R a is hydrogen or hydroxy;
R b is selected from the group consisting of hydroxy, —O—C(O)—NH 2 and —O—C(O)-imidazolyl;
R c is hydrogen or a hydroxy protecting group;
L is methylene or carbonyl, provided that when L is methylene, T is —O—,
T is selected from the group consisting of —O—, —NH—, and —N(W—R d )—, wherein
W is absent or is selected from the group consisting of —O—, —NH—CO—, —N═CH— and —NH—; and
R d is selected from the group consisting of
(1) hydrogen,
(2) C 1 -C 6 -alkyl optionally substituted with one or more substituents selected from the group consisting of
(a) aryl,
(b) substituted-aryl,
(c) heteroaryl,
(d) substituted-heteroaryl,
(e) hydroxy,
(f) C 1 -C 6 -alkoxy,
(g) NR 7 R 8 , wherein R 7 and R 8 are as defined previously independently selected from the group consisting of hydrogen and C 1 -C 6 - alkyl, or R 7 and R 8 are taken with the nitrogen atom to which they are connected to form a 3 to 7 membered ring which, when the ring is a 5 to 7 membered ring, may optionally contain a hetero function selected from the group consisting of —O—, —NH—, —N ( C 1 -C 6 - alkyl -), —N ( aryl )-, —N ( aryl C 1 -C 6 - alkyl -)-, — N ( substituted aryl C 1 -C 6 - alkyl -)-, —N ( heteroaryl )-, —N ( heteroaryl C 1 -C 6 - alkyl -)-, —N ( substituted heteroaryl C 1 -C 6 alkyl -)-, —S— and —S ( O ) n — where n is 1 or 2 , and
(h) —CH 2 —M—R 9
wherein M is selected from the group consisting of:
(i) —C(O)—NH—,
(ii) —NH—C(O)—,
(ii) —NH—,
(iv) —N═,
(v) —N(CH 3 )—,
(vi) —NH—C(O)—O—
(vii) —NH—C(O)—NH—
(viii) —O—C(O)—NH—
(ix) —O—C(O)—O—
(x) —O—,
(xi) —S(O) n —, wherein n is 0, 1 or 2,
(xii) —C(O)—O—,
(xiii) —O—C(O)—, and
(xiv) —C(O)—, and
R 9 is selected from the group consisting of:
(i) C 1 -C 6 -alkyl, optionally substituted with a substituent selected from the group consisting of
(aa) aryl,
(bb) substituted-aryl,
(cc) heteroaryl, and
(dd) substituted-heteroaryl,
(ii) aryl,
(iii) substituted-aryl,
(iv) heteroaryl,
(v) substituted-heteroaryl, and
(vi) heterocycloalkyl,
(3) C 3 -C 7 -cycloalkyl,
(4) aryl,
(5) substituted-aryl,
(6) heteroaryl, and
(7) substituted-heteroaryl;
R is selected from the group consisting of
(1) methyl substituted with a moiety selected from the group consisting of
(a) CN,
(b) F,
(c) —CO 2 R 10 wherein R 10 is selected from the group consisting of C 1 -C 3 -alkyl or aryl substituted C 1 -C 3 -alkyl, or and heteroaryl substituted C 1 -C 3 -alkyl,
(d) S(O) n R 10 where n is 0, 1 or 2 and R 10 is as previously defined
(e) NHC(O)R 10 where R 10 is as previously defined,
(f) NHC(O)NR 11 R 12 wherein R 11 and R 12 are independently selected from the group consisting of hydrogen, C 1 -C 3 -alkyl, C 1 -C 3 -alkyl substituted with aryl, substituted aryl, heteroaryl, and substituted heteroaryl,
(g) aryl,
(h) substituted aryl,
(i) heteroaryl, and
(j) substituted heteroaryl,
(2) C 2 -C 10 -alkyl,
(3)( 2 ) C 2 -C 10 -alkyl substituted with one or more substituents selected from the group consisting of
(a) halogen, (b) hydroxy, (c) C 1 -C 3 -alkoxy, (d) C 1 -C 3 -alkoxy-C 1 -C 3 -alkoxy, (e) oxo, (f) —N 3 , (g) —CHO, (h) O—SO 2 -(substituted C 1 -C 6 -alkyl), (i) —NR 13 R 14 wherein R 13 and R 14 are selected from the group consisting of
(i) hydrogen,
(ii) C 1 -C 12 -alkyl,
(iii) substituted C 1 -C 12 -alkyl,
(iv) C 1 -C 12 -alkenyl, C 2 -C 12 - alkenyl,
(v) substituted C 1 -C 12 -alkenyl, C 2 -C 12 - alkenyl,
(vi) C 1 -C 12 -alkynyl, C 2 -C 12 - alkynyl,
(vii) substituted C 1 -C 12 -alkynyl, C 2 -C 12 - alkynyl,
(viii) aryl,
(ix) C 3 -C 8 -cycloalkyl,
(x) substituted C 3 -C 8 -cycloalkyl,
(xi) substituted aryl,
(xii) heterocycloalkyl,
(xiii) substituted heterocycloalkyl,
(xiv) C 1 -C 12 -substituted with aryl,
(xv) C 1 -C 12 -substituted with substituted aryl,
(xvi) C 1 -C 12 -alkyl substituted with heterocycloalkyl,
(xvii) C 1 -C 12 -alkyl substituted with substituted heterocycloalkyl,
(xviii) C 1 -C 12 -alkyl substituted with C 3 -C 8 -cycloalkyl,
(xix) C 1 -C 12 -alkyl substituted with substituted C 3 -C 8 -cycloalkyl,
(xx) heteroaryl,
(xxi) substituted heteroaryl,
(xxii) C 1 -C 12 -alkyl substituted with heteroaryl, and
(xxiii) C 1 -C 12 -alkyl substituted with substituted heteroaryl, or
R 13 and R 14 are taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring which may be is optionally substituted with one or more substituents independently selected from the group consisting of
(i) halogen,
(ii) hydroxy,
(iii) C 1 -C 3 -alkoxy,
(iv) C 1 -C 3 -alkoxy-C 1 -C 3 -alkoxy,
(v) oxo,
(vi) C 1 -C 3 -alkyl,
(vii) halo-C 1 -C 3 -alkyl, and
(vii) C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl,
(j) —CO 2 R 10 wherein R 10 is as previously defined, (k) —C(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined, (l) ═N—O—R 10 wherein R 10 is as previously defined, (m) —C≡N, (n) O—S(O) n R 10 wherein n is 0, 1 or 2 and R 10 is as (o) aryl, (p) substituted aryl, (q) heteroaryl, (r) substituted heteroaryl, (s) C 3 -C 8 -cycloalkyl, (t) substituted C 3 -C 8 -cycloalkyl, (u) C 1 -C 12 -alkyl substituted with heteroaryl, (v) heterocycloalkyl, (w) substituted heterocycloalkyl, (x) NHC(O)R 10 where R 10 is as previously defined, (y) NHC(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined, (z) ═N—NR 13 R 14 wherein R 13 and R 14 are as previously defined, (aa) ═N—R 9 wherein R 9 is as previously defined, (bb) ═N—NHC(O)R 10 wherein R 10 is as previously defined, and (cc) ═N—NHC(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined;
(4)( 3 ) C 3 -alkenyl substituted with a moiety selected from the group consisting of
(a) halogen, (b) —CHO, (c) —CO 2 R 10 where R 10 is as previously defined, (d) —C(O)—R 9 where R 9 is as previously defined, (e) —C(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined, (f) —C≡N, (g) aryl, (h) substituted aryl, (i) heteroaryl, (j) substituted heteroaryl, (k) C 3 -C 7 -cycloalkyl, and (l) C 1 -C 12 -alkyl substituted with heteroaryl,
(5)( 4 ) C 4 -C 10 -alkenyl;
(6)( 5 ) C 4 -C 10 -alkenyl substituted with one or more substituents selected from the group consisting of
(a) halogen, (b) C 1 -C 3 -alkoxy, (c) oxo, (d) —CHO, (e) —CO 2 R 10 where R 10 is as previously defined, (f) —C(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined, (g) —NR 13 R 14 wherein R 13 and R 14 are as previously defined, (h) ═N—O—R 10 where R 10 is as previously defined, (i) —C≡N, (j) O—S(O) n R 10 where n is 0, 1 or 2 and R 10 is as previously defined, (k) aryl, (l) substituted aryl, (m) heteroaryl, (n) substituted heteroaryl, (o) C 3 -C 7 -cycloalkyl, (p) C 1 -C 12 -alkyl substituted with heteroaryl, (q) NHC(O)R 10 where R 10 is as previously defined, (r) NHC(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined, (s) ═N—NR 13 R 14 wherein R 13 and R 14 are as previously defined, (t) ═N—R 9 wherein R 9 is as previously defined, (u) ═N—NHC(O)R 10 where R 10 is as previously defined, and (v) ═N—NHC(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined;
(7)( 6 ) C 3 -C 10 -alkynyl; and
(8)( 7 ) C 3 -C 10 -alkynyl substituted with one or more substituents selected from the group consisting of
(a) trialkylsilyl, (b) aryl, (c) substituted aryl, (d) heteroaryl, and (e) substituted heteroaryl.
and
A, B, D and E, with the provision that at least two of A, B, D and E are hydrogen, are 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:
(i) aryl;
(ii) substituted-aryl;
(iii) heteroaryl;
(iv) substituted heteroaryl;
(v) heterocycloalkyl;
(vi) hydroxy;
(vii) C 1 -C 6 -alkoxy;
(viii) halogen consisting of Br, Cl, F or I; and
(ix) NR 7 R 8 , wherein R 7 and R 8 are as previously defined;
(c) C 3 -C 7 -cycloalkyl;
(d) aryl;
(e) substituted-aryl;
(f) heteroaryl;
(g) substituted-heteroaryl;
(h) heterocycloalkyl; and
(i) a group selected from option (b) above further substituted with —M—R 9 , wherein M and R 9 are as previously defined;
or
any one pair of substituents, consisting of AB, AD, AE, BD, BE or DE, is taken together with the atom or atoms to which they are attached to form a 3- to 7-membered ring optionally containing a hetero function selected from the group consisting of —O—, —NH—, —N(C 1 -C 6 -alkyl-)-; —N(aryl-C 1 -C 6 -alkyl-)-, —N(substituted-aryl-C 1 -C 6 -alkyl-)-, —N(heteroaryl-C 1 -C 6 -alkyl-)-, —N(substituted-heteroaryl-C 1 -C 6 -alkyl-)-, —S— or —S(O) n —, wherein n is 1 or 2, —C(O)—NH—, —C(O)—NR 12 —, wherein R 12 is as previously defined, —NH—C(O)—, —NR 12 —C(O)—, wherein R 12 is as previously defined, and —C(═NH)—NH—.
2. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier.
3. A method for controlling a bacterial infection in a mammal comprising administering to an mammal a therapeutically-effective pharmaceutical composition containing a compound according to claim 1 .
4. A compound according to claim 1 which is selected from the group consisting of:
Compound of Formula (III): Rc is acetyl, L is CO, T is NH, R is —CH 2 CH═CH 2 ;
Compound of Formula (III): R c is acetyl, L is CO, T is NH, R is —CH 2 CH═CH-(3-quinolyl);
Compound of Formula (III): R c is benzoyl, L is CO, T is NH, R is —CH 2 CH═CH-(3-quinolyl);
Compound of Formula (III): R c is propanoyl, L is CO, T is NH, R is —CH 2 CH═CH-(3-quinolyl); and
Compound of Formula (III): R c is ethylsuccinoyl, L is CO, T is NH, R is —CH 2 CH═CH-(3-quinolyl).
5. A compound according to claim 1 having the formula (IX)
wherein L, T and R are as defined therein.
6. A compound according to claim 13 claim 5 which is selected from the group consisting of:
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH═CH 2 ;
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH═CH-phenyl;
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH 2 CH 2 -Phenyl —CH 2 CH 2 CH 2 - phenyl ;
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH═CH-(4-chlorophenyl);
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH═CH-(3-quinolyl);
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH 2 CH 3 ;
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH 2 NH 2 ;
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH═NOH;
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH 2 CH 2 OH;
Compound of Formula (IX): L is CO, T is O, R is —CH 2 F;
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH 2 -phenyl;
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH 2 -(4-pyridyl);
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH 2 -(4-quinolyl);
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH (OH)CN;
Compound of Formula (IX): L is CO, T is O, R is —CH(C(O)OCH 3 )CH 2 -phenyl;
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CN;
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH═CH-(4-methoxyphenyl);
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH═CH-(4-fluorophenyl);
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH═CH-(8-quinolyl);
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH 2 NHCH 2 -phenyl;
Compound of Formula (IX): L is CO, T is O, R is —CH 2 -phenyl;
Compound of Formula (IX): L is CO, T is O, R is —CH 2 -(4-pyridyl);
Compound of Formula (IX): L is CO, T is O, R is —CH 2 -(4-quinolyl);
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH═CH-(4-pyridyl);
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH 2 CH 2 -(4-pyridyl);
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH═CH-(4-quinolyl);
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH 2 CH 2 -(4-quinolyl);
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH═CH-(5-quinolyl);
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH 2 CH 2 -(5-quinolyl);
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH═CH-(4-benzoxazolyl);
Compound of Formula (IX): L is CO, T is O, R is —CH 2 CH═CH-(4-benzimidazolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH 2 ;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-Phenyl —CH 2 CH═CH - phenyl ;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH 2 CH 3 ;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH 2 NH 2 ;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═NOH;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH 2 CH 2 OH;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 F;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH 2 -phenyl;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH 2 -(4-pyridyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH(OH)CN;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH 2 -(4-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH(C(O)OCH 3 )CH 2 -phenyl;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CN;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(4-chlorophenyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(4-fluorophenyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH 2 CH 2 -(4-methoxyphenyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(4-methoxyphenyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(3-chloro-6-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH 2 NHCH 2 CH 2 -(2-chlorophenyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 -phenyl;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 -(4-pyridyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 -(4-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(4-pyridyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH 2 CH 2 -(4-pyridyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(3-fluoro-6-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH 2 CH 2 -(4-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(3-cyano-6-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH 2 CH 2 -(5-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(4-benzoxazolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(4-benzimidazolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(3-methoxy-6-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 -(2-naphthyl);
Compound of Formula (IX): L is CO, T is N(CH 3 ), R is —CH 2 CH═CH 2 ;
Compound of Formula (IX): L is CO, T is N(CH 3 ), R is —CH 2 CH═CH-(3-quinolyl);
Compound of Formula (IX): L is CO, T is N(CH 2 CH 2 N(CH 3 ) 2 ), R is —CH 2 CH═CH 2 ;
Compound of Formula (IX): L is CO, T is N(CH 2 CH 2 N(CH 3 ) 2 ), R is —CH 2 CH═CH-(3-quinolyl);
Compound of Formula (IX): L is CO, T is N(CH 2 CH═CH 2 ), R is —CH 2 CH═CH 2 ;
Compound of Formula (IX): L is CO, T is T is N(CH 2 CH═C-(3-quinolyl)), R is —CH 2 CH═CH-(3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(3-pyridyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(2-naphthyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(4-isoquinolinyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(3,4-ethylenedioxyphenyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(8-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(5-indolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(6-chloro-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(3,4-ethylenedioxyphenyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(3-nitrophenyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(6-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(6-nitroquinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(5-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(2-methyl-6-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R c is acetyl; R is —CH 2 CH═CH-(3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(5-isoquinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(7-nitro-6-quinoxalinyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(6-amino-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(1,8-naphthyridin-3-yl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(6-acetylamino)-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(3-carbazolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(5-benzimidazolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(-3-hydroxy-2-(N-(2-methoxyphenyl)amido)-7-naphthyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(6-quinoxalinyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(6-hydroxy-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(6-methoxy-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(5-nitro-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(8-nitro-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(2-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(4-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(4-carboxyl-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(6-fluoro-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(6-methoxycarbonyl-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(6-aminocarbonyl-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(6-cyano-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(3-bromo-6-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 C(O)H;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH 2 NHCH 2 Phenyl —CH 2 CH 2 NHCH 2 phenyl ;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH 2 NHCH 2 CH 2 Phenyl —CH 2 CH 2 NHCH 2 CH 2 phenyl ;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH 2 NHCH 2 CH 2 CH 2 Phenyl —CH 2 CH 2 NHCH 2 CH 2 CH 2 phenyl ;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH 2 NHCH 2 CH 2 CH 2 CH 2 Phenyl —CH 2 CH 2 NHCH 2 CH 2 CH 2 CH 2 phenyl ;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH 2 NHCH 2 CH 2 CH 2 -(3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH 2 NHCH 2 (3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH 2 NHCH 2 (6-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═NO(phenyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═NOCH 2 (phenyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═NOCH 2 (4-NO 2 -phenyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═NOCH 2 (4-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═NOCH 2 (2-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═NOCH 2 (3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═NOCH 2 -(6-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═NOCH 2 -(1-naphthyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═NOCH 2 -(2-naphthyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH 2 NHOCH 2 -(phenyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH 2 NHOCH 2 -(4-NO 2 -phenyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 C(O)-phenyl;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 C(O)-(4-F-phenyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═NNHC(O)phenyl;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH 2 CH 2 -(3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 -(2-(3-quinolyl)cyclopropyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 —C≡C—H;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 —C≡C-(3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 —C≡C-(6-nitro-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 —C═C-phenyl;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 —C≡C-naphthyl;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 —C≡C-(2-naphthyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 —C≡C-(6-methoxy-2-naphthyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 —C≡C-(6-chloro-2-naphthyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 —C≡C-(6-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 —C≡C-(2-methyl-6-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 —C≡C-(5-(N-(2-pyridyl)amino)carbonyl)furanyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 —C≡C-(1-phenylethenyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 —C═C—Br;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 -(2,2-dimethyl-1,3-dioxolan-4-yl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH(OH)-phenyl;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH(OH)CH 2 OH;
Compound of Formula (IX): L is CO, T is NH NH 2 , R is —CH 2 CH═CH 2 ;
Compound of Formula (IX): L is CO, T is NH NH 2 , R is —CH 2 CH═CH-(3-quinolyl);
Compound of Formula (IX): L is CO, T is NH NH 2 , R is —CH 2 CH 2 CH 2 -(3-quinolyl);
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 CH═CH-naphthyl;
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 CH═CH-(3-(2-firanyl)-6-quinolyl);
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 CH═CH-(8-chloro-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 CH═CH-(4-chloro-2-trifluoromethyl-6-quinolyl);
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 CH═CH-(9-fluorenone-2-yl);
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 CH═CH-(6-benzoyl-2-naphthyl;
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 CH═CH-(7-methoxy-2-naphthyl);
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 CH═CH-(3-phenyl-6-quinolyl);
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 CH═CH-(3-(2-pyridyl)-6-quinolyl);
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 CH═CH-(3-(2-thiophenyl)-6-quinolyl;
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 CH═CH-(4-methylnaphthyl);
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 CH═CH-(6-β-D-galactopyranosyl-2-naphthyl);
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 CH═CH-(7-quinolyl);
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 CH═CH-(4-fluoronaphthyl);
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 CH═CH-(3-biphenyl);
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 CH═CH-(5-nitronaphthyl);
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 CH═CH-(4-pyrrolylphenyl);
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 CH═CH-(6-methoxy-2-naphthyl);
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 CH═CH-(3,5-dichlorophenyl);
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 -(3-iodophenyl);
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 -(3-(2-furanyl)phenyl);
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 CH═CH-(6-hydroxy-2-naphthyl);
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 CH═CH-(6-(2-bromoethoxy)-2-naphthyl);
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 CH═CH-(6-(2-(tetrazolyl)ethoxy-2-naphthyl);
Compound of Formula (IX): L is CO, T is NH 2 , R is —CH 2 CH═CH-naphthyl;
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 —C≡C-(2-phenylethenyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 CH═CH-(5-(3-isoxazolyl)-2-thiophenyl);
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 —CH═CH-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl); and
Compound of Formula (IX): L is CO, T is NH, R is —CH 2 —CH═CH-(5-(2-pyridyl)aminocarbonyl-2-furanyl).
7. A process for the preparation of 6-O-substituted macrolide compounds having the Formula:
wherein:
R c is hydrogen or a hydroxy protecting group;
L is carbonyl and T is —O—, and
R is selected from the group consisting of
(1) methyl substituted with a moiety selected from the group consisting of
(a) CN,
(b) F,
(c) —CO 2 R 10 wherein R 10 is selected from the group consisting of C 1 -C 3 -alkyl or aryl substituted C 1 -C 3 -alkyl , or and heteroaryl substituted C 1 -C 3 -alkyl,
(d) S(O) n R 10 where n is 0, 1 or 2 and R 10 is as previously defined,
(e) NHC(O)R 10 where R 10 is as previously defined,
(f) NHC(O)NR 11 R 12 wherein R 11 and R 12 are independently selected from the group consisting of hydrogen, C 1 -C 3 -alkyl, C 1 -C 3 -alkyl substituted with aryl, substituted aryl, heteroaryl, and substituted heteroaryl,
(g) aryl,
(h) substituted aryl,
(i) heteroaryl, and
(j) substituted heteroaryl,
(2) C 2 -C 10 -alkyl,
(3)( 2 ) C 2 -C 10 -alkyl substituted with one or more substituents selected from the group consisting of
(a) halogen, (b) hydroxy, (c) C 1 -C 3 -alkoxy, (d) C 1 -C 3 -alkoxy-C 1 -C 3 -alkoxy, (e) oxo, (f) —N 3 , (g) —CHO, (h) O—SO 2 -(substituted C 1 -C 6 -alkyl), (i) —NR 13 R 14 wherein R 13 and R 14 are selected from the group consisting of
(i) hydrogen,
(ii) C 1 -C 12 -alkyl,
(iii) substituted C 1 -C 12 -alkyl,
(iv) C 1 2 -C 12 -alkenyl,
(v) substituted C 1 2 -C 12 -alkenyl,
(vi) C 1 2 -C 12 -alkynyl,
(vii) substituted C 1 2 -C 12 -alkynyl,
(viii) aryl,
(ix) C 3 -C 8 -cycloalkyl,
(x) substituted C 3 -C 8 -cycloalkyl,
(xi) substituted aryl,
(xii) heterocycloalkyl,
(xiii) substituted heterocycloalkyl,
(xiv) C 1 -C 12 -substituted with aryl,
(xv) C 1 -C 12 -substituted with substituted aryl,
(xvi) C 1 -C 12 -alkyl substituted with heterocycloalkyl,
(xvii) C 1 -C 12 -alkyl substituted with substituted heterocycloalkyl,
(xviii) C 1 -C 12 -alkyl substituted with C 3 -C 8 -cycloalkyl,
(xix) C 1 -C 12 -alkyl substituted with substituted C 3 -C 8 -cycloalkyl,
(xx) heteroaryl,
(xxi) substituted heteroaryl,
(xxii) C 1 -C 12 -alkyl substituted with heteroaryl, and
(xxiii) C 1 -C 12 -alkyl substituted with substituted heteroaryl, or
R 13 and R 14 are taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring which may be is optionally substituted with one or more substituents independently selected from the group consisting of
(i) halogen,
(ii) hydroxy,
(iii) C 1 -C 3 -alkoxy,
(iv) C 1 -C 3 -alkoxy-C 1 -C 3 -alkoxy,
(v) oxo,
(vi) C 1 -C 3 -alkyl,
(vii) halo-C 1 -C 3 -alkyl, and
(vii) C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl,
(j) —CO 2 R 10 wherein R 10 is as previously defined, (k) —C(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined, (l) ═N—O—R 10 wherein R 10 is as previously defined, (m) —C≡N, (n) O—S(O) n R 10 wherein n is 0, 1 or 2 and R 10 is as previously defined, (o) aryl, (p) substituted aryl, (q) heteroaryl, (r) substituted heteroaryl, (s) C 3 -C 8 -cycloalkyl, (t) substituted C 3 -C 8 -cycloalkyl, (u) C 1 -C 12 -alkyl substituted with heteroaryl, (v) heterocycloalkyl, (w) substituted heterocycloalkyl, (x) NHC(O)R 10 where R 10 is as previously defined, (y) NHC(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined, (z) ═N—NR 13 R 14 wherein R 13 and R 14 are as previously defined, (aa) ═N—R 9 wherein R 9 is as previously defined, (bb) ═N—NHC(O)R 10 wherein R 10 is as previously defined, and (cc) ═N—NHC(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined;
(4)( 3 ) C 3 -alkenyl substituted with a moiety selected from the group consisting of
(a) halogen, (b) —CHO, (c) —CO 2 R 10 where R 10 is as previously defined, (d) —C(O)—R 9 where R 9 is as previously defined, (e) —C(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined, (f) —C≡N, (g) aryl, (h) substituted aryl, (i) heteroaryl, (j) substituted heteroaryl, (k) C 3 -C 7 -cycloalkyl, and
(l) C 1 -C 12 -alkyl substituted with heteroaryl,
(5)( 4 ) C 4 -C 10 -alkenyl;
(6)( 5 ) C 4 -C 10 -alkenyl substituted with one or more substituents selected from the group consisting of
(a) halogen, (b) C 1 -C 3 -alkoxy, (c) oxo, (d) —CHO, (e) —CO 2 R 10 where R 10 is as previously defined, (f) —C(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined, (g) —NR 13 R 14 wherein R 13 and R 14 are as previously defined, (h) ═N—O—R 10 where R 10 is as previously defined, (i) —C≡N, (j) O—S(O) n R 10 where n is 0, 1 or 2 and R 10 is as previously defined, (k) aryl, (l) substituted aryl, (m) heteroaryl, (n) substituted heteroaryl, (o) C 3 -C 7 -cycloalkyl, (p) C 1 -C 12 -alkyl substituted with heteroaryl, (q) NHC(O)R 10 where R 10 is as previously defined, (r) NHC(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined, (s) ═N—NR 13 R 14 wherein R 13 and R 14 are as previously defined, (t) ═N—R 9 wherein R 9 is as previously defined, (u) ═N—NHC(O)R 10 where R 10 is as previously defined, and (v) ═N—NHC(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined;
(7)( 6 ) C 3 -C 10 -alkynyl;
and
(8)( 7 ) C 3 -C 10 -alkynyl substituted with one or more substituents selected from the group consisting of
(a) trialkylsilyl, (b) aryl, (c) substituted aryl, (d) heteroaryl, and (e) substituted heteroaryl;
the method comprising:
treating a compound having the formula
wherein R is as defined previously and R c is a hydroxy protecting group, with carbonyldiimidazole and sodium hexamethyldisilazide to give make the desired compound wherein R c is a hydroxy protecting group, optionally deprotecting, and isolating the desired compound of the formula
wherein R, R c , L and T are as previously defined .
8. A process for the preparation of 6-O-substituted macrolide compounds having the Formula:
wherein:
R c is hydrogen or a hydroxy protecting group;
L is carbonyl,
T is selected from the group consisting of —NH—, and —N(W—R d )—, wherein
W is absent or is selected from the group consisting of —O—, —NH—CO—, —N═CH— and —NH—; and
R d is selected from the group consisting of
(1) hydrogen,
(2) C 1 -C 6 -alkyl optionally substituted with one or more substituents selected from the group consisting of
(a) aryl,
(b) substituted-aryl,
(c) heteroaryl,
(d) substituted-heteroaryl,
(e) hydroxy,
(f) C 1 -C 6 -alkoxy,
(g) NR 7 R 8 , wherein R 7 and R 8 are independently selected from the group consisting of hydrogen and C 1 -C 6 -alkyl, or R 7 and R 8 are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring which, when the ring is a 5- to 7-membered ring, may optionally contain a hetero function selected from the group consisting of —O—, —NH—, —N(C 1 -C 6 -alkyl-)-, —N(aryl)-, —N(aryl-C 1 -C 6 -alkyl-)-, —N(substituted-aryl-C 1 -C 6 -alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C 1 -C 6 -alkyl-)-, —N(substituted-heteroaryl-C 1 -C 6 -alkyl-)-, and —S— or and —S(O) n —, wherein n is 1 or 2, and
(h) —CH 2 —M—R 9
wherein M is selected from the group consisting of:
(i) —C(O)—NH—,
(ii) —NH—C(O)—,
(ii) —NH—,
(iv) —N═,
(v) —N(CH 3 )—,
(vi) —NH—C(O)—O—
(vii) —NH—C(O)—NH—
(viii) —O—C(O)—NH—
(ix) —O—C(O)—O—
(x) —O—,
(xi) —S(O) n —, wherein n is 0, 1 or 2,
(xii) —C(O)—O—,
(xiii) —O—C(O)—, and
(xiv) —C(O)—, and
R 9 is selected from the group consisting of:
(i) C 1 -C 6 -alkyl, optionally substituted with a substituent selected from the group consisting of
(aa) aryl,
(bb) substituted-aryl,
(cc) heteroaryl, and
(dd) substituted-heteroaryl,
(ii) aryl,
(iii) substituted-aryl,
(iv) heteroaryl,
(v) substituted-heteroaryl, and
(vi) heterocycloalkyl,
(3) C 3 -C 7 -cycloalkyl,
(4) aryl,
(5) substituted-aryl,
(6) heteroaryl, and
(7) substituted-heteroaryl;
and
R is selected from the group consisting of
(1) methyl substituted with a moiety selected from the group consisting of
(a) CN,
(b) F,
(c) —CO 2 R 10 wherein R 10 is selected from the group consisting of C 1 -C 3 -alkyl or aryl substituted C 1 -C 3 -alkyl, or and heteroaryl substituted C 1 -C 3 -alkyl,
(d) S(O) n R 10 where n is 0, 1 or 2 and R 10 is as previously defined,
(e) NHC(O)R 10 where R 10 is as previously defined,
(f) NHC(O)NR 11 R 12 wherein R 11 and R 12 are independently selected from the group consisting of hydrogen, C 1 -C 3 -alkyl, C 1 -C 3 -alkyl substituted with aryl, substituted aryl, heteroaryl, and substituted heteroaryl,
(g) aryl,
(h) substituted aryl,
(i) heteroaryl,
(j) substituted heteroaryl,
(2) C 2 -C 10 -alkyl,
(3)( 2 ) C 2 -C 10 -alkyl substituted with one or more substituents selected from the group consisting of
(a) halogen, (b) hydroxy, (c) C 1 -C 3 -alkoxy, (d) C 1 -C 3 -alkoxy-C 1 -C 3 -alkoxy, (e) oxo, (f) —N 3 , (g) —CHO, (h) O—SO 2 -(substituted C 1 -C 6 -alkyl), (i) —NR 13 R 14 wherein R 13 and R 14 are selected from the group consisting of
(i) hydrogen,
(ii) C 1 -C 12 -alkyl,
(iii) substituted C 1 -C 12 -alkyl,
(iv) C 1 2 -C 12 -alkenyl,
(v) substituted C 1 2 -C 12 -alkenyl,
(vi) C 1 2 -C 12 -alkynyl,
(vii) substituted C 1 2 -C 12 -alkynyl,
(viii) aryl,
(ix) C 3 -C 8 -cycloalkyl,
(x) substituted C 3 -C 8 -cycloalkyl,
(xi) substituted aryl,
(xii) heterocycloalkyl,
(xiii) substituted heterocycloalkyl,
(xiv) C 1 -C 12 -alkyl substituted with aryl,
(xv) C 1 -C 12 -alkyl substituted with substituted aryl,
(xvi) C 1 -C 12 -alkyl substituted with heterocycloalkyl,
(xvii) C 1 -C 12 -alkyl substituted with substituted heterocycloalkyl,
(xviii) C 1 -C 12 -alkyl substituted with C 3 -C 8 -cycloalkyl,
(xix) C 1 -C 12 -alkyl substituted with substituted C 3 -C 8 -cycloalkyl,
(xx) heteroaryl,
(xxi) substituted heteroaryl,
(xxii) C 1 -C 12 -alkyl substituted with heteroaryl, and
(xxiii) C 1 -C 12 -alkyl substituted with substituted heteroaryl, or
R 13 and R 14 are taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring which may be is optionally substituted with one or more substituents independently selected from the group consisting of
(i) halogen,
(ii) hydroxy,
(iii) C 1 -C 3 -alkoxy,
(iv) C 1 -C 3 -alkoxy-C 1 -C 3 -alkoxy,
(v) oxo,
(vi) C 1 -C 3 -alkyl,
(vii) halo-C 1 -C 3 -alkyl, and
(vii)( viii ) C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl,
(j) —C O O 2 R 10 wherein R 10 is as previously defined, (k) —C(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined, (l) ═N—O—R 10 wherein R 10 is as previously defined, (m) —C≡N, (n) O—S(O) n R 10 wherein n is 0, 1 or 2 and R 10 is as previously defined, (o) aryl, (p) substituted aryl, (q) heteroaryl, (r) substituted heteroaryl, (s) C 3 -C 8 -cycloalkyl, (t) substituted C 3 -C 8 -cycloalkyl, (u) C 1 -C 12 -alkyl substituted with heteroaryl, (v) heterocycloalkyl, (w) substituted heterocycloalkyl, (x) NHC(O)R 10 where R 10 is as previously defined, (y) NHC(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined, (z) ═N—NR 13 R 14 wherein R 13 and R 14 are as previously defined, (aa) ═N—R 9 wherein R 9 is as previously defined, (bb) ═N—NHC(O)R 10 wherein R 10 is as previously defined, and (cc) ═N—NHC(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined;
(4)( 3 ) C 3 -alkenyl substituted with a moiety selected from the group consisting of
(a) halogen, (b) —CHO, (c) —CO 2 R 10 where R 10 is as previously defined, (d) —C(O)—R 9 where R 9 is as previously defined, (e) —C(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined, (f) —C≡N, (g) aryl, (h) substituted aryl, (i) heteroaryl, (j) substituted heteroaryl, (k) C 3 -C 7 -cycloalkyl, and (l) C 1 -C 12 -alkyl substituted with heteroaryl,
(5)( 4 ) C 4 -C 10 -alkenyl;
(6)( 5 ) C 4 -C 10 -alkenyl substituted with one or more substituents selected from the group consisting of
(a) halogen, (b) C 1 -C 3 -alkoxy, (c) oxo, (d) —CHO, (e) —CO 2 R 10 where R 10 is as previously defined, (f) —C(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined, (g) —NR 13 R 14 wherein R 13 and R 14 are as previously defined, (h) ═N—O—R 10 where R 10 is as previously defined, (i) —C≡N, (j) O—S(O) n R 10 where n is 0, 1 or 2 and R 10 is as previously defined, (k) aryl, (l) substituted aryl, (m) heteroaryl, (n) substituted heteroaryl, (o) C 3 -C 7 -cycloalkyl, (p) C 1 -C 12 -alkyl substituted with heteroaryl, (q) NHC(O)R 10 where R 10 is as previously defined, (r) NHC(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined, (s) ═N—NR 13 R 14 wherein R 13 and R 14 are as previously defined, (t) ═N—R 9 wherein R 9 is as previously defined, (u) ═N—NHC(O)R 10 where R 10 is as previously defined, and (v) ═N—NHC(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined;
(7)( 6 ) C 3 -C 10 -alkynyl; and
(8)( 7 ) C 3 -C 10 -alkynyl substituted with one or more substituents selected from the group consisting of
(a) trialkylsilyl, (b) aryl, (c) substituted aryl, (d) heteroaryl, and (e) substituted heteroaryl;
the method comprising:
(a) treating a compound having the formula
wherein R is as defined previously, and R c R p is a hydroxy protecting group, by treatment treating with sodium hexamethyldisilazide and carbonyldiimidazole to give make a compound having the formula
(b) (1) treating the compound from step (a) with a reagent selected from the group consisting of ammonia, R e —NH 2 , hydrazine, substituted hydrazine, hydroxylamine, and substituted hydroxylamine to give make a compound having the formula
wherein R e is H or W—R d , wherein W is absent or is selected from the group consisting of —O—, —NH—CO—, —N═CH— and —NH—, and R d is as defined previously,
(c) optionally treating the compound from step (b) wherein W is absent or is —NH— with an alkylating agent selected from the group consisting of of the formula R d -halogen to give make a compound wherein W is absent or is —NH— and R d is as defined above;
(d) optionally treating the compound from step (b) wherein W is —NH— and R d is H with an acylating agent selected from the group consisting of R d —C(C O)-halogen or and (R d —C(C O)) 2 — O) 2 —to give make a compound wherein W is —NH—CO— and R d is as defined above;
(e) optionally treating the compound from step (b) wherein W is —NH— and R d is H with an aldehyde R d —CHO, wherein R d as defined above to give make a compound wherein W is —N═CH— and R d is as defined above; and
(f) optionally deprotecting, and isolating the desired compound of the formula
wherein R, R c , L and T are as previously defined .
9. A process for preparing a compound having the formula
wherein R and R p
R is selected from the group consisting of
(1) methyl substituted with a moiety selected from the group consisting of
(a) CN,
(b) F,
(c) —CO 2 R 10 wherein R 10 is selected from the group consisting of C 1 -C 3 -alkyl or aryl substituted C 1 -C 3 -alkyl, or and heteroaryl substituted C 1 -C 3 -alkyl,
(d) S(O) n R 10 where n is 0, 1 or 2 and R 10 is as previously defined,
(e) NHC(O)R 10 where R 10 is as previously defined,
(f) NHC(O)NR 11 R 12 wherein R 11 and R 12 are independently selected from the group consisting of hydrogen, C 1 -C 3 -alkyl, C 1 -C 3 -alkyl substituted with aryl, substituted aryl, heteroaryl, and substituted heteroaryl,
(g) aryl,
(h) substituted aryl,
(i) heteroaryl, and
(j) substituted heteroaryl,
(2) C 2 -C 10 -alkyl,
(3)( 2 ) C 2 -C 10 -alkyl substituted with one or more substituents selected from the group consisting of
(a) halogen, (b) hydroxy, (c) C 1 -C 3 -alkoxy, (d) C 1 -C 3 -alkoxy-C 1 -C 3 -alkoxy, (e) oxo, (f) —N 3 , (g) —CHO, (h) O—SO 2 -(substituted C 1 -C 6 -alkyl), (i) —NR 13 R 14 wherein R 13 and R 14 are selected from the group consisting of
(i) hydrogen,
(ii) C 1 -C 12 -alkyl,
(iii) substituted C 1 -C 12 -alkyl,
(iv) C 1 2 -C 12 -alkenyl,
(v) substituted C 1 2 -C 12 -alkenyl,
(vi) C 1 2 -C 12 -alkynyl,
(vii) substituted C 1 2 -C 12 -alkynyl,
(viii) aryl,
(ix) C 3 -C 8 -cycloalkyl,
(x) substituted C 3 -C 8 -cycloalkyl,
(xi) substituted aryl,
(xii) heterocycloalkyl,
(xiii) substituted heterocycloalkyl,
(xiv) C 1 -C 12 -alkyl substituted with aryl,
(xv) C 1 -C 12 -alkyl substituted with substituted aryl,
(xvi) C 1 -C 12 -alkyl substituted with heterocycloalkyl,
(xvii) C 1 -C 12 -alkyl substituted with substituted heterocycloalkyl,
(xviii) C 1 -C 12 -alkyl substituted with C 3 -C 8 -cycloalkyl,
(xix) C 1 -C 12 -alkyl substituted with substituted C 3 -C 8 -cycloalkyl,
(xx) heteroaryl,
(xxi) substituted heteroaryl,
(xxii) C 1 -C 12 -alkyl substituted with heteroaryl, and
(xxiii) C 1 -C 12 -alkyl substituted with substituted heteroaryl, or
R 13 and R 14 are taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring which may be is optionally substituted with one or more substituents independently selected from the group consisting of
(i) halogen,
(ii) hydroxy,
(iii) C 1 -C 3 -alkoxy,
(iv) C 1 -C 3 -alkoxy-C 1 -C 3 -alkoxy,
(v) oxo,
(vi) C 1 -C 3 -alkyl,
(vii) halo-C 1 -C 3 -alkyl, and
(vii) C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl,
(j) —CO 2 R 10 wherein R 10 is as previously defined, (k) —C(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined, (l) ═N—O—R 10 wherein R 10 is as previously defined, (m) —C≡N, (n) O—S(O) n R 10 wherein n is 0, 1 or 2 and R 10 is as previously defined, (o) aryl, (p) substituted aryl, (q) heteroaryl, (r) substituted heteroaryl, (s) C 3 -C 8 -cycloalkyl, (t) substituted C 3 -C 8 -cycloalkyl, (u) C 1 -C 12 -alkyl substituted with heteroaryl, (v) heterocycloalkyl, (w) substituted heterocycloalkyl, (x) NHC(O)R 10 where R 10 is as previously defined, (y) NHC(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined, (z) ═N—NR 13 R 14 wherein R 13 and R 14 are as previously defined, (aa) ═N—R 9 wherein R 9 is as previously defined, (bb) ═N—NHC(O)R 10 wherein R 10 is as previously defined, and (cc) ═N—NHC(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined;
(4)( 3 ) C 3 -alkenyl substituted with a moiety selected from the group consisting of
(a) halogen, (b) —CHO, (c) —CO 2 R 10 where R 10 is as previously defined, (d) —C(O)—R 9 where R 9 is as previously defined, (e) —C(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined, (f) —C≡N, (g) aryl, (h) substituted aryl, (i) heteroaryl, (j) substituted heteroaryl, (k) C 3 -C 7 -cycloalkyl, and (l) C 1 -C 2 -alkyl substituted with heteroaryl,
(5)( 4 ) C 4 -C 10 -alkenyl;
(6)( 5 ) C 4 -C 10 -alkenyl substituted with one or more substituents selected from the group consisting of
(a) halogen, (b) C 1 -C 3 -alkoxy, (c) oxo, (d) —CHO, (e) —CO 2 R 10 where R 10 is as previously defined, (f) —C(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined, (g) —NR 13 R 14 wherein R 13 and R 14 are as previously defined, (h) ═N—O—R 10 where R 10 is as previously defined, (i) —C≡N, (j) O—S(O) n R 10 where n is 0, 1 or 2 and R 10 is as previously defined, (k) aryl, (l) substituted aryl, (m) heteroaryl, (n) substituted heteroaryl, (o) C 3 -C 7 -cycloalkyl, (p) C 1 -C 12 -alkyl substituted with heteroaryl, (q) NHC(O)R 10 where R 10 is as previously defined, (r) NHC(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined, (s) ═N—NR 13 R 14 wherein R 13 and R 14 are as previously defined, (t) ═N—R 9 wherein R 9 is as previously defined, (u) ═N—NHC(O)R 10 where R 10 is as previously defined, and (v) ═N—NHC(O)NR 11 R 12 wherein R 11 and R 12 are as previously defined;
(7)( 6 ) C 3 -C 10 -alkynyl; and
(8)( 7 ) C 3 -C 10 -alkynyl substituted with one or more substituents selected from the group consisting of
(a) trialkylsilyl, (b) aryl, (c) substituted aryl, (d) heteroaryl, and (e) substituted heteroaryl;
R e is H or W—R d , wherein W is absent or is selected from the group consisting of —O—, —NH—CO—, 13 N═CH— and —NH—, and R d is selected from the group consisting of
(1) hydrogen,
(2) C 1 -C 6 -alkyl optionally substituted with one or more substituents selected from the group consisting of
(a) aryl,
(b) substituted-aryl,
(c) heteroaryl,
(d) substituted-heteroaryl,
(e) hydroxy,
(f) C 1 -C 6 -alkoxy,
(g) NR 7 R 8 , wherein R 7 and R 8 are independently selected from the group consisting of hydrogen and C 1 -C 6 -alkyl, or R 7 and R 8 are taken with the nitrogen atom to which they are connected to form a 3- or 7-membered ring which, when the ring is a 5- to 7-membered ring, may optionally contain a hetero function selected from the group consisting of —O—, —NH—, —N(C 1 -C 6 -alkyl-)-, —N(aryl)-, —N(aryl-C 1 -C 6 -alkyl-)-, —N(substituted-aryl-C 1 -C 6 -alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C 1 -C 6 -alkyl-)-, —N(substituted-heteroaryl-C 1 -C 6 -alkyl-)-, and —S— or and —S(O) n —, wherein n is 1 or 2, and
(h) —CH 2 —M—R 9
wherein M is selected from the group consisting of:
(i) —C(O)—NH—,
(ii) —NH—C(O)—,
(iii) —NH—,
(iv) —N═,
(v) —N(CH 3 )—,
(vi) —NH—C(O)—O—
(vii) —NH—C(O)—NH—
(viii) —O—C(O)—NH—
(ix) —O—C(O)—O—
(x) —O—,
(xi) —S(O) n —, wherein n is 0, 1 or 2,
(xii) —C(O)—O—,
(xiii) —O—C(O)—, and
(xiv) —C(O)—, and
R 9 is selected from the group consisting of:
(i) C 1 -C 6 -alkyl, optionally substituted with a substituent selected from the group consisting of
(aa) aryl,
(bb) substituted-aryl,
(cc) heteroaryl, and
(dd) substituted-heteroaryl,
(ii) aryl,
(iii) substituted-aryl,
(iv) heteroaryl,
(v) substituted-heteroaryl, and
(vi) heterocycloalkyl,
(3) C 3 -C 7 -cycloalkyl,
(4) aryl,
(5) substituted-aryl,
(6) heteroaryl, and
(7) substituted-heteroaryl; and
R p is a hydroxy protecting group;
the method comprising
(a) treating a compound having the formula
wherein R is and R p are as previously defined, R p is a hydroxy protecting group and Z′ is 4″-hydroxy-protected cladinose, with sodium hexamethyldisilazide and carbonyldiimidazole to give make a compound having the formula
(b) treating the compound from step (a) with a reagent selected from the group consisting of ammonia, R c —NH 2 , hydrazine, substituted hydrazine, hydroxylamine, and substituted hydroxylamine to give make a compound having the formula
wherein R e is H or W—R d , wherein W is absent or is selected from the group consisting of —O—, —NH—CO—, —N═CH— and —NH—, and R d is as defined previously,
(c) optionally treating the compound from step (b) wherein R c is H with an alkylating agent having the formula R d -halogen, wherein R d is as defined previously, to give make a compound of the formula shown in of step (b) wherein R e is W—R d , W is absent and R d is as defined previously;
(d) optionally treating the compound from step (b) wherein R e is W—R d and W is —NH— and R d is H, with an alkylating agent selected from the group consisting of R d -halogen, wherein R d is as defined previously, to give make a compound of the formula shown in step (b) wherein R e is W—R d , W is —NH— and R d is as defined above;
(e) optionally treating the compound from step (b) wherein R e is W—R d and W is —NH— and R d is H, with an alkylating agent selected from the group consisting of R d —C(C O)— halogen or and (R d —C(C O))— 2 O) 2 to give make a compound wherein R e is W—R d , W is —NH—CO— and R d is as defined above;
(f) optionally treating the compound from step (b) wherein R e is W—R d and W is —NH— and R d is H, with an aldehyde having the formula R d —CHO, wherein R d as defined above to give make a compound wherein R e is W—R d , W is —N═CH— and R d is as defined above;
(g) removing the cladinose moiety by hydrolysis with acid to give make a compound having the formula
(h) oxidizing the 3-hydroxyl group; and
(i) optionally deprotecting, and isolating the desired compound of the formula
where R, R e and R p are as defined above .
10. A process according to claim 9 wherein R is selected from the group consisting of allyl and propargyl, wherein the allyl or propargyl moiety is further substituted with a moiety selected from the group consisting of 2-chlorophenyl, 2-fluorenyl, 2-methyl-6-quinolyl, 2-naphthyl, 2-phenylethenyl, 2-quinolyl, 3-(2-furanyl)-6-quinolyl, 3-(2-pyridyl)-6-quinolyl, 3-quinolyl, 3-(2-thiophenyl)-6-quinolyl, 3-biphenyl, 3-bromo-6-quinolyl, 3-carbazolyl, 3-chloro-6-quinolyl, 3-cyano-6-quinolyl, 3-fluoro-6-quinolyl, 3-hydroxy-2-(N-(2-methoxyphenyl)amido)-7-naphthyl, 3-iodophenyl, 3-methoxy-6-quinolyl, 3-nitrophenyl, 3-phenyl-6-quinolyl, 3-quinolyl, 4-benzoxazolyl, 4-carboxyl-3-quinolyl, 4-chloro-2-trifluoromethyl-6-quinolyl, 4-chlorophenyl, 4-fluoronaphthyl, 4-fluorophenyl, 4-isoquinolinyl, 4-methoxyphenyl, 4-methylnaphthyl, 4-pyridyl, 4-pyrrolylphenyl, 4-quinolyl, 5-(2-pyridyl)aminocarbonyl-2-furanyl, 5-(3-isoxazolyl)-2-thiophenyl, 5-benzimidazolyl, 5-indolyl, 5-isoquinolyl, 5-nitro-3-quinolyl, 5-nitronaphthyl, 5-quinolyl, 6-(acetylamino)-3-quinolyl, 6-(2-(tetrazolyl)ethoxy-2-naphthyl, 6-(2-bromoethoxy)-2-naphthyl, 6-amino-3-quinolyl, 6-aminocarbonyl-3-quinolyl, 6-β-D-galactopyranosyl-2-15 naphthyl, 6-benzoyl-2-naphthyl, 6-cyano-3-quinolyl, 6-fluoro-3-quinolyl, 6-hydroxy-2-naphthyl, 6-hydroxy-3-quinolyl, 6-methoxy-2-naphthyl, 6-methoxy-3-quinolyl, 6-methoxycarbonyl-3-quinolyl, 6-nitroquinolyl, 6-quinolyl, 6-quinoxalinyl, 7-methoxy-2-naphthyl, 7-nitro-6-quinoxalinyl, 7-quinolyl, 8-chloro-3-quinolyl, 8-nitro-3-quinolyl, 8-quinolyl, 9-oxofluoren-2-yl, 1,3-dimethyl-2,4-dioxo-5-pyrimidinyl, 1,8-naphthyridin-3-yl, 3,4-methylenedioxyphenyl, 3,5-dichlorophenyl, naphthyl, and phenyl, and in step (b) the reagent is selected from the group consisting of ammonia and R e —NH 2 ; optional steps (c), (d) and (e) are omitted; and in step (g) the oxidizing reagent is selected from N-chlorosuccinimide-dimethyl sulfide and carbodiimide-dimethylsulfoxide; and in step (h) the optional deprotection is carried out by stirring in methanol.
11. A process according to claim 10 wherein R is selected from the group consisting of allyl and propargyl, wherein the allyl or propargyl moiety is further substituted with a moiety selected from the group consisting of 2-methyl-6-quinolyl, 2-quinolyl, 3-(2-furanyl)-6-quinolyl, 3-(2-pyridyl)-6-quinolyl, 3-quinolyl, 3-(2-thiophenyl)-6-quinolyl, 3-bromo-6-quinolyl, 3-chloro-6-quinolyl, 3-cyano-6-quinolyl, 3-fluoro-6-quinolyl, 3-methoxy-6-quinolyl, 3-phenyl-6-quinolyl, 3-quinolyl, 4-carboxyl-3-quinolyl, 4-chloro-2-trifluoromethyl-6-quinolyl, 4-isoquinolinyl, 4-quinolyl, 5- isoquinolyl, 5-nitro-3-quinolyl, 5-quinolyl, 6-(acetylamino)-3-quinolyl, 6-amino-3-quinolyl, 6-aminocarbonyl-3-quinolyl, 6-cyano-3-quinolyl, 6-fluoro-3-quinolyl, 6-hydroxy-3-quinolyl, 6-methoxy-3-quinolyl, 6-methoxycarbonyl-3-quinolyl, 6-nitroquinolyl, 6-quinolyl, 7-quinolyl, 8-chloro-3-quinolyl, 8-nitro-3-quinolyl and 8-quinolyl.
12. A process for preparing a compound having the formula
wherein R e is H or W—R d , wherein W is absent or is selected from the group consisting of —O—, —NH—CO—, —N═CH— and —NH—, and
R d is selected from the group consisting of
(1) hydrogen,
(2) C 1 -C 6 -alkyl optionally substituted with one or more substituents selected from the group consisting of
(a) aryl,
(b) substituted-aryl,
(c) heteroaryl,
(d) substituted-heteroaryl,
(e) hydroxy,
(f) C 1 -C 6 -alkoxy,
(g) NR 7 R 8 wherein R 7 and R 8 are independently selected from the group consisting of hydrogen and C 1 -C 6 -alkyl, or R 7 and R 8 are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring which, when the ring is a 5- to 7-membered ring, may optionally contain a hetero function selected from the group consisting of —O—, —NH—, —N(C 1 -C 6 -alkyl-)-, —N(aryl)-, —N(aryl-C 1 -C 6 -alkyl-)-, —N(substituted-aryl-C 1 -C 6 -alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C 1 -C 6 -alkyl-)-, —N(substituted-heteroaryl-C 1 -C 6 -alkyl-)-, and —S—or and —S(O) n —, wherein n is 1 or 2, and
(h) —CH 2 —M—R 9
wherein M is selected from the group consisting of:
(i) —C(O)—NH—,
(ii) —NH—C(O)—,
(iii) —NH—,
(iv) —N═,
(v) —N(CH 3 )—,
(vi) —NH—C(O)—O—
(vii) —NH—C(O)—NH—
(viii) —O—C(O)—NH—
(ix) —O—C(O)—O—
(x) —O—,
(xi) —S(O) n —, wherein n is 0, 1 or 2,
(xii) —C(O)—O—,
(xiii) —O—C(O)—, and
(xiv) —C(O)—, and
R 9 is selected from the group consisting of:
(i) C 1 -C 6 -alkyl, optionally substituted with a substituent selected from the group consisting of
(aa) aryl,
(bb) substituted-aryl,
(cc) heteroaryl, and
(dd) substituted-heteroaryl,
(ii) aryl,
(iii) substituted-aryl,
(iv) heteroaryl,
(v) substituted-heteroaryl, and
(vi) heterocycloalkyl,
(3) C 3 -C 7 -cycloalkyl,
(4) aryl,
(5) substituted-aryl,
(6) heteroaryl, and
(7) substituted-heteroaryl;
and R 10 is selected from the group consisting of H or, C 1 -C 3 -alkyl, aryl substituted C 1 -C 3 -alkyl, orand heteroaryl substituted C 1 -C 3 -alkyl, and
R p is a hydroxyl protecting group,
the method comprising
(a) treating a compound having the formula
with ozone to give make a compound having the formula
(b) treating the resultant compound of step (a) with a hydroxylamine compound having the formula NH 2 —O—R 10 , wherein R 10 is as previously defined; and
(c) optionally deprotecting, and isolating the desired compound of the formula
where R e , R p and R 10 are as previously defined .
13. A process according to claim 12 wherein R e is H.
14. A process for preparing a compound having the formula
wherein R e is H or W—R d , wherein W is absent or is selected from the group consisting of —O—, —NH—CO—, —N═CH— and —NH—, and
R d is selected from the group consisting of
(1) hydrogen,
(2) C 1 -C 6 -alkyl optionally substituted one or more substituents selected from the group consisting of
(a) aryl,
(b) substituted-aryl,
(c) heteroaryl,
(d) substituted-heteroaryl,
(e) hydroxy,
(f) C 1 -C 6 -alkoxy,
(g) NR 7 R 8 wherein R 7 and R 8 are independently selected from the group consisting of hydrogen and C 1 -C 6 -alkyl, or R 7 and R 8 are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring which, when the ring is a 5- to 7-membered ring, may optionally contain a hetero function selected from the group consisting of —O—, —NH—, —N(C 1 -C 6 -alkyl-)-, —N(aryl)-, —N(aryl-C 1 -C 6 -alkyl-)-, —N(substituted-aryl-C 1 -C 6 -alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C 1 -C 6 -alkyl-)-, —N(substituted-heteroaryl-C 1 -C 6 -alkyl-)-,and —S— or and —S(O) n —, wherein n is 1 or 2, and
(h) —CH 2 —M—R 9
wherein M is selected from the group consisting of
(i) —C(O)—NH—,
(ii) —NH—C(O)—,
(iii) —NH—,
(iv) —N═,
(v) —N(CH 3 )—,
(vi) —NH—C(O)—O—
(vii) —NH—C(O)—NH—
(viii) —O—C(O)—NH—
(ix) —O—C(O)—O—
(x) —O—,
(xi) —S(O) n —, wherein n is 0, 1 or 2,
(xii) —C(O)—O—,
(xiii) —O—C(O)—, and
(xiv) —C(O)—, and
R 9 is selected from the group consisting of:
(i) C 1 -C 6 -alkyl, optionally substituted with a substituent selected from the group consisting of
(aa) aryl,
(bb) substituted-aryl,
(cc) heteroaryl, and
(dd) substituted-heteroaryl,
(ii) aryl,
(iii) substituted-aryl,
(iv) heteroaryl,
(v) substituted-heteroaryl, and
(vi) heterocycloalkyl,
(3) C 3 -C 7 -cycloalkyl,
(4) aryl,
(5) substituted-aryl,
(6) heteroaryl, and
(7) substituted-heteroaryl; and
R 15 is selected from the group consisting of
(1) C 1 -C 12 -alkyl substituted with aryl,
(2) C 1 -C 12 -alkyl substituted with substituted aryl,
(3) C 1 -C 12 -alkyl substituted with heteroaryl, and
(4) C 1 -C 12 -alkyl substituted with substituted heteroaryl, and
R
p
is a hydroxyl protecting group,
the method comprising
(a) reductively aminating a compound having the formula
with an amine compound having the formula NH 2 —R 15 , wherein R 15 is as previously defined; and
(b) optionally deprotecting, and isolating the desired compound of the formula
where R e , R p and R 15 are as previously defined .
15. A compound having the formula
where L is CO, T is O, R is —CH 2 CH═CH -( 3 - quinolyl ) and R c is H.
16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 15 in combination with a pharmaceutically acceptable carrier.
17. A method for controlling a bacterial infection in a mammal comprising administering to a mammal, a therapeutically- effective pharmaceutical composition containing the compound of claim 15 .
18. A process according to claim 7 where L is CO, T is O, R is —CH 2 CH═CH -( 3 - quinolyl and R c is H.
19. A process according to claim 8 where L is CO, T is O, R is —CH 2 CH═CH -( 3 - quinolyl and R c is H.Cited by (0)
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