Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-03-29
2002-06-04
Kifle, Bruck (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S202000
Reexamination Certificate
active
06399638
ABSTRACT:
The present invention relates to compounds of the formula
Q is selected from the group consisting of
G is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, hetrocyclo,
L is O, S, SO, SO
2
or NR
13
or CR
14
R
15
;
W is O or NR
16
;
X is O, S, CHR
17
or H, R
18
;
Z is O; S; H, R
19
or R
20
, R
21
;
Y is selected from the group consisting of O; H, H; H, OR
22
; OR
23
, OR
23
; NOR
24
; H, NOR
25
; H, NR
26
R
27
; NHNR
28
R
29
; H, NHNR
30
R
31
; or CHR
32
; where OR
23
, OR
23
can be a cyclic ketal;
B
1
and B
2
are selected from the group consisting of H, OR
33
, OCOR
34
, OCONR
35
R
36
, NR
37
R
38
or NR
39
CONR
40
R
41
;
D is selected from the group consisting of NR
42
R
43
or heterocyclo;
M is selected from the group consisting of S, C═O, S═O, SO
2
, NR
44
, or CR
45
R
46
;
J, E, U, and V are selected from carbon, oxygen, nitrogen or sulfur; or V may be absent;
R
1
, R
2
, R
3
, and R
4
, are selected from H, lower alkyl;
R
5
, R
8
, R
9
, R
10
and R
11
are selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo or substituted heterocyclo;
R
6
and R
7
are selected from the group consisting of H, alkyl, substituted alkyl, halogen, nitro, cyano, OR
47
, NR
48
R
49
, R
50
C═O;
R
17
, R
18
, R
22
and R
23
are selected from the group consisting of H, alkyl, and substituted alkyl;
R
20
, R
21
, R
24
, R
25
, R
26
, R
28
, R
30
, R
32
, R
33
, R
34
, R
35
, R
36
, R
37
, R
39
, R
40
, R
41
, R
42
, R
47
, R
48
, R
50
, R
51
, R
52
, R
53
, R
54
, R
56
, R
57
, R
58
, R
59
and R
61
are selected from the group of H, alkyl, substituted alkyl, aryl or substituted aryl;
R
12
, R
13
, R
16
, R
27
, R
29
, R
31
, R
38
, R
43
, R
44
, R
49
, R
55
and R
60
are selected from the group consisting of H, alkyl, substituted alkyl, substituted aryl, cycloalkyl, heterocyclo, R
51
C═O, R
52
OC═O, R
53
SO
2
, hydroxy, O-alkyl or O-substituted alkyl; when X is O then R
16
is not R
51
C═O, R
52
OC═O, and R
53
SO
2
; and wherein R
44
is further amino and
R
14
and R
15
are selected from the group consisting of H, halogen, alkyl, or substituted alkyl;
R
19
is selected from the group consisting of H, alkyl, substituted alkyl, O-alkyl, O-substituted alkyl, NR
54
R
55
, R
56
C═O; when L is O, S, or NR
13
then R
19
is not O-alkyl, O-substituted alkyl, NR
54
R
55
.
R
45
and R
46
are selected from the group consisting of H, halogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo, R
56
C═O, R
57
OC═O, R
58
NHC═O, hydroxy, O-alkyl or O-substituted alkyl, NR
59
R
60
;
and any salts, solvates or hydrates thereof, with the proviso that
when Q is
M is CR
45
R
46
then W is only NR
16
.
BACKGROUND OF THE INVENTION
Epothilones are macrolide compounds which find utility in the pharmaceutical field. For example, Epothilones A and B having the structures:
have been found to exert microtubule-stabilizing effects similar to TAXOL and hence cytotoxic activity against rapidly proliferating cells, such as, tumor cells or other hyperproliferative cellular disease, see Hofle et al., Angew. Chem. Int. Ed. Engl., 1996, Vol. 35, No. 13/14, pp. 1569.
DETAILED DESCRIPTION OF THE INVENTION
Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.
The term “alkyl” refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms. The expression “lower alkyl” refers to unsubstituted alkyl groups of 1 to 4 carbon atoms.
The term “substituted alkyl” refers to an alkyl group substituted by, for example, one to four substituents, such as, halo, phenyl, substituted phenyl, heterocyclo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkyoxy, heterocylooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl, alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g. SO
2
NH
2
), substituted sulfonamido, nitro, cyano, carboxy, carbamyl (e.g. CONH
2
), substituted carbamyl (e.g. CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclos, such as, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. Where noted above where the substituent is further substituted it will be with halogen, alkyl, alkoxy, aryl or aralkyl.
The term “halogen” or “halo” refers to fluorine, chlorine, bromine and iodine.
The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl and diphenyl groups, each of which may be substituted.
The term “aralkyl” refers to an aryl group bonded directly through an alkyl group, such as benzyl.
The term “substituted aryl” refers to an aryl group substituted by, for example, one to four substituents such as alkyl; substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thiol, alkylthio, cycloalkylthio, heterocyclothio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, alkysulfonyl, sulfonamido, aryloxy and the like. The substituent may be further substituted by halo, hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl.
The term “cycloalkyl” refers to optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C
3
-C
7
carbocyclic ring. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and adamantyl. Exemplary substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
The terms “heterocycle”, “heterocyclic” and “heterocyclo” refer to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, dioxanyl, isoth
Höfle Gerhard
Kim Soong-Hoon
Vite Gregory D.
Bristol--Myers Squibb Company
Kifle Bruck
Patel Rena
LandOfFree
12,13-modified epothilone derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 12,13-modified epothilone derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 12,13-modified epothilone derivatives will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2943473