3′-epimeric k-252a derivatives

Details 3′-epimeric k-252a derivatives 3′-epimeric k-252a derivatives

2000-02-15

2002-09-17

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S211010, C514S540000

Reexamination Certificate

active

06451786

ABSTRACT:

FIELD OF THE INVENTION
The field of the invention is pharmaceutical chemistry.
BACKGROUND OF THE INVENTION
K-252a is an indolocarbazole whose stereochemistry is shown below (Formula I):
K-252a inhibits protein kinase C (PKC), which plays a role in regulating cell functions. K-252a has various activities, e.g., inhibiting smooth muscle contraction (
Jap. J. Pharmacol.
43 (suppl.): 284, 1987), inhibiting serotonin secretion (
Biochem. Biophys. Res. Commun.
144: 35, 1987), inhibiting elongation of neuraxone (
J. Neurosci.
8:715, 1988) inhibiting histamine release (
Allergy
43:100, 1988), inhibiting smooth muscle MLCK (
J. Biol. Chem.
263:6215, 1988), anti-inflammatory action (
Acta Physiol. Hung.
80:423, 1992), and promotion of cell survival (
J. Neurochem.
64:1502, 1995). K-252a also inhibits IL-2 production (
Exper. Cell Res.
193:175-182, 1991). The total synthesis of the natural (+) isomer of K252a and its enantiomeric (−) isomer (all three chiral carbons of the sugar moiety inverted), has been achieved (Wood et al.,
J. Am. Chem. Soc.
117:10413, 1995; and WO 97/07081).
SUMMARY OF THE INVENTION
We have discovered that certain 3′-epimeric derivatives of K-252a are biologically active. These compounds have the following general formula (Formula II):
wherein:
R
1
and R
2
independently are:
hydrogen; lower alkyl; halogen; acyl; nitro;
sulfonic acid;
—CH═NR
4
, wherein R
4
is guanidino, heterocyclic, or —NR
5
R
6,
wherein R
5
or R
6
is hydrogen or lower alkyl, and the other is hydrogen, lower alkyl, acyl, aryl, heterocyclic, carbamoyl or lower alkylaminocarbonyl;
—NR
5
R
6
;
—CH(SR
7
)
2
wherein R
7
is lower alkyl or alkylene;
—(CH
2
)
j
R
8
, wherein j is 1-6, and R
8
is halogen; substituted aryl; unsubstituted aryl; substituted heteroaryl; unsubstituted heteroaryl; N
3
;
—CO
2
R
9
, wherein R
9
is hydrogen, substituted lower alkyl, unsubstituted lower alkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, or unsubstituted heteroaryl;
—C(═O)NR
10
R
11
, wherein R
10
and R
11
independently are hydrogen, substituted lower alkyl, unsubstituted lower alkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted aralkyl, unsubstituted aralkyl, lower alkylaminocarbonyl, or lower alkoxycarbonyl, or R
10
and R
11
are combined with a nitrogen atom to form a heterocyclic group;
—OR
12
, wherein R
12
is hydrogen, substituted lower alkyl, unsubstituted lower alkyl, substituted aryl, unsubstituted aryl; or —C(═O) R
13
, wherein R
13
is hydrogen, NR
10
R
11
, substituted lower alkyl, unsubstituted lower alkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted aralkyl, or unsubstituted aralkyl;
—NR
10
R
11
;
—C(═O)R
14
, wherein R
14
is hydrogen, lower alkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, or unsubstituted heteroaryl;
—S(═O)
r
R
15
, wherein r is 0 to 2, and R
15
is hydrogen, substituted lower alkyl, unsubstituted lower alkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted aralkyl, unsubstituted aralkyl, thiazolinyl, (CH
2
)
a
CO
2
R
16
, wherein a is 1 or 2, and R
16
is hydrogen or lower alkyl, or —(CH
2
)
a
C(═O) NR
10
R
11
;
—OR
17
, wherein R
17
is hydrogen, lower alkyl, or —C(═O)R
18
, wherein R
18
is substituted lower aIkyl, unsubstituted lower alkyl, substituted aryl, or unsubstituted aryl;
—C(═O)(CH
2
)
j
R
19
, wherein R
19
is hydrogen, halogen, NR
10
R
11
, N
3
, SR
15
, or OR
20
, wherein R
20
is hydrogen, substituted lower alkyl, unsubstituted lower alkyl, or C(═O)R
14
;
—CH(OH)(CH
2
)
j
R
19
;
—(CH
2
)
d
CHR
21
CO
2
R
16A
, wherein d is 0-5, and R
21
is hydrogen, CONR
10
R
11
, or CO
2
R
16
A, wherein R
16
A is the same as R
16
;
—(CH
2
)
d
CHR
21
CONR
10
R
11
;
—CH═CH(CH
2
)
m
R
22
, wherein m is 0-4, and R
22
is hydrogen, lower alkyl, CO
2
R
9
, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, OR
12
, or NR
10
R
11
;
—CH═C(CO
2
R
16A
)
2
;
—C═—C(CH
2
)
m
R
22
;
—SO
2
NR
23
R
24
, wherein R
23
and R
24
independently are hydrogen, lower alkyl, or groups that form a heterocycle with the adjacent nitrogen atoms;
—OCO
2
R
13A
, wherein R
13A
is the same as R
13
; or
—OC(═O)NR
10
R
11
;
R
3
is hydrogen; lower alkyl; carbamoyl; amino; tetrahydropyranyl; hydroxyl; C(═O)H; aralkyl; lower alkanoyl; or CH
2
CH
2
R
25
, wherein R
25
is halogen, amino, di-lower alkylamino, hydroxyl, or hydroxysubstituted lower alkylamino;
X is hydrogen; formyl; carboxyl; lower alkoxycarbonyl; lower alkylhydrazinocarbonyl; —CN; lower alkyl;
—C(═O)NR
26
R
27
, wherein R
26
and R
27
independently are hydrogen, unsubstituted lower alkyl, or unsubstituted aryl; or R
26
and R
27
are combined with a nitrogen atom to form a heterocyclic group;
—CH(R
34
)W, wherein R
34
is hydrogen or lower alkyl, and W is —N═CHN(alkyl)
2
; guanidino; N
3
; NR
28
R
29
, wherein R
28
or R
29
is hydrogen or lower alkyl, and the other is hydrogen, allyl, alkanoyl, aryloxycarbonyl, unsubstituted alkyl, or the residue of an &agr;-amino acid in which the hydroxy group of the carboxyl group is excluded; —CO
2
R
9
; —C(═O)NR
10
R
11
; —S(═O)
r
R
30
, wherein R
30
is substituted or unsubstituted lower alkyl, aryl, or heteroaryl; or —OR
31
, wherein R
31
is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkanoyl;
—CH═N—R
32
, wherein R
32
is hydroxyl, lower alkoxy, amino, guanidino, ureido, imidazolylamino, carbamoylamino, or NR
26
R
27A
(wherein R
26A
is the same as R
26
and R
27A
is the same as R
27
); or
—CH
2
Q wherein Q is a sugar residue represented by
 wherein V represents hydrogen, methyl, ethyl, benzyl, acetyl, or trifluoroacetyl;
Y is hydrogen; —OH; —OC(═O)R
33
, wherein R
33
is alkyl, aryl, or amino; —OCH
2
O-alkyl; —O-alkyl; aralkyloxy; or X and Y are combined as —X—Y—to form, —CH
2
OCO
2
— or —CH
2
N(R
16B
)CO
2
— (wherein R
16B
is the same as R
16
);
A
1
and A
2
are hydrogen, or both are combined to represent O; or B
1
and B
2
are hydrogen, or both are combined to represent O; or a pharmaceutically acceptable salt thereof; with the proviso that at least one of A
1
,A
2
or B
1
,B
2
represents O; and with the further proviso that both X and Y are not simultaneously hydrogen.
Preferably, X is —C(═O)NR
26
R
27
, carboxyl, lower alkoxycarbonyl, formyl, lower alkyl, —CH
2
OR
31
, —CH
2
NR
28
R
29
, or —CH
2
S(O)
r
R
30
. Preferably, R
1
and R
2
are H. Preferably, R
3
is hydrogen or a protecting group. Particularly preferred are Compounds VI, VII, VIII, X, XII, XIV, XV, XVI, XVII, XVIII, XIX, XXV, and XXVII, shown below:
In some embodiments of the invention, 3′-epimeric K252a derivatives are formulated into pharmaceutical compositions.
The invention also provides a method for inhibiting the activity of a tyrosine kinase, for example, protein kinase C (PKC). The method includes contacting the tyrosine kinase with a compound of claim
1
. The tyrosine kinase can be in vivo or in vitro.
The invention also provides a method for inhibiting the phosphorylation of a tyrosine kinase by a second kinase. The method includes contacting the second kinase with a compound of claim 1. The tyrosine kinase can be in vivo or in vitro.
The invention also provides a method for enhancing the function of a cholinergic neuron. The method includes contacting the cholinergic neuron with a compound of claim 1. The cholinergic neuron can be in vivo or in vitro.
The invention also provides a method for enhancing the survival of a cholinergic neuron. The method includes contacting the cholinergic neuron with a compound of claim 1. The cholinergic neuron can be in vivo or in vitro.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present application, i

Affiliated with

Also associated with

Rating

3′-epimeric k-252a 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 3′-epimeric k-252a derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 3′-epimeric k-252a derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2840953