Combinations of aldose reductase inhibitors and selective...

Details Combinations of aldose reductase inhibitors and selective... Combinations of aldose reductase inhibitors and selective...

2000-06-23

2003-04-29

Weddington, Kevin E. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S210030, C514S347000, C514S365000, C514S366000, C514S415000, C514S518000

Reexamination Certificate

active

06555540

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to methods, pharmaceutical compositions and kits comprising an aldose reductase inhibitor (ARI), a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug and a selective cyclooxygenase-2 (COX-2) inhibitor, a prodrug thereof or a pharmaceutically acceptable salts of said selective COX-2 inhibitor or said prodrug. This invention further relates to methods of using such pharmaceutical compositions for the treatment of diabetic complications such as diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, myocardia infarction, cataracts and diabetic cardiomyopathy.
Aldose reductase inhibitors function by inhibiting the activity of the enzyme aldose reductase, which is primarily responsible for regulating the reduction of aldoses, such as glucose and galactose, to the corresponding polyols, such as sorbitol and galactitol, in humans and other animals. In this way, unwanted accumulations of galactitol in the lens of galactosemic subjects and of sorbitol in the lens, peripheral nervous cord and kidneys of various diabetic subjects are prevented or reduced. Accordingly, aldose reductase inhibitors are of therapeutic value for controlling certain diabetic complications, e.g., diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, myocardial infarction, cataracts and diabetic retinopathy.
Two forms of cylcooxygenase (COX) known to exist: COX-1 and COX-2, the former being a constitutive form and the latter being an inducible form. COX-1 exists in the stomach, intestines, kidneys and platelets while COX-2 is expressed during inflammation. Both COX enzyme isoforms metabolize arachidonic by a similar mechanism, but each have different substrate specificities. Selective COX-2 inhibitors are advantageous in the treatment of pain and inflammation while avoiding such side effects as gastric and renal toxicity.
SUMMARY OF THE INVENTION
This invention is directed to pharmaceutical compositions comprising an aldose reductase inhibitor (ARI), a prodrug thereof or a pharmaceutically acceptable salt of said ARI or of said prodrug;
(a) a selective cyclooxygenase-2 (COX-2) inhibitor of formula I,
 a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug,
 wherein the variables of the compound of formula I are defined as follows:
R
1
is hydrogen or (C
1
-C
4
)alkyl; R
2
is C(═L′)R
3
or SO
2
R
4
; Y is a direct bond or (C
1
-C
4
)alkylene; L and L′ are independently oxygen or sulfur;
Q is selected from the following:
(Q-a) (C
1
-C
6
)alkyl;
(Q-b) halo-substituted (C
1
-C
4
)alkyl;
(Q-c) (C
3
-C
7
)cycloalkyl optionally substituted with one or two substituents independently selected from (C
1
-C
4
)alkyl, halo-substituted (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, hydroxy and halo;
(Q-d) phenyl or naphthyl, the phenyl and naphthyl being optionally substituted with one, two or three substituents independently selected from halo, (C
1
-C
4
)alkyl, halo-substituted (C
1
-C
4
)alkyl, hydroxy, (C
1
-C
4
)alkoxy, nitro, halo-substituted (C
1
-C
4
)alkoxy, S(O)
m
R
5
, SO
2
NH
2
, SO
2
N((C
1
-C
4
)alkyl)
2
, amino, (C
1
-C
4
)alkylamino, di-((C
1
-C
4
)alkyl)amino, NR
1
C(O)R
5
, CN, (C
1
-C
4
)alkyl-OH and (C
1
-C
4
)alkyl-OR
5
;
(Q-e) a 5-membered monocyclic aromatic group containing one heteroatom selected from O, S and N and optionally containing one, two or three nitrogen atom(s) in addition to said heteroatom, and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from halo, (C
1
-C
4
)alkyl, halo-substituted (C
1
-C
4
)alkyl, hydroxy, (C
1
-C
4
)alkoxy, halo-substituted (C
1
-C
4
)alkoxy, amino, (C
1
-C
4
) alkylamino, di-((C
1
-C
4
)alkyl)amino, (C
1
-C
4
)alkyl-OH and (C
1
-C
4
)alkyl-OR
5
; and
(Q-f) a 6-membered monocyclic aromatic group containing one nitrogen atom and optionally containing one, two or three additional nitrogen atom(s), and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from halo, (C
1
-C
4
)alkyl, halo-substituted (C
1
-C
4
)alkyl, hydroxy, (C
1
-C
4
)alkoxy, halo-substituted (C
1
-C
4
)alkoxy, amino, (C
1
-C
4
)alkylamino, di-((C
1
-C
4
)alkyl)amino, (C
1
-C
4
)alkyl-OH and (C
1
-C
4
)alkyl-OR
5
;
R
3
is —OR
6
, —NR
7
R
8
, N(OR
1
)R
7
or a group of formula:
 Z is a direct bond, oxygen, sulfur or NR
5
;
R
4
is (C
1
-C
6
)alkyl, halo-substituted (C
1
-C
4
)alkyl, (C
1
-C
4
)alkyl-OH, —NR
7
R
8
, phenyl or naphthyl, the phenyl and naphthyl being optionally substituted with one, two or three substituents independently selected from halo, (C
1
-C
4
)alkyl, halo-substitutued (C
1
-C
4
)alkyl, hydroxy, (C
1
-C
4
)alkoxy and halo-substitutued (C
1
-C
4
)alkoxy;
R
5
is (C
1
-C
4
)alkyl or halo-substituted (C
1
-C
4
)alkyl;
R
6
is (C
1
-C
4
)alkyl, (C
3
-C
7
)cycloalkyl, (C
1
-C
4
)alkyl-(C
3
-C
7
)cycloalkyl, halo-substitutued (C
1
-C
4
)alkyl, (C
1
-C
4
)alkyl-phenyl or phenyl, the phenyl moiety being optionally substituted with one, or two substituents independently selected from halo, (C
1
-C
4
)alkyl, halo-substitutued (C
1
-C
4
)alkyl, hydroxy, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkylthio, amino, di-((C
1
-C
4
)alkyl)amino and nitro;
R
7
and R
8
are independently selected from I hydrogen, (ii) (C
1
-C
6
)alkyl optionally substituted with a substituent independently selected from halo, hydroxy, (C
1
-C
4
)alkoxy, amino, (C
1
-C
4
)alkylamino and di-((C
1
-C
4
)alkyl)amino, (iii) (C
3
-C
7
)cycloalkyl optionally substituted with a substituent independently selected from hydroxy, (C
1
-C
4
)alkyl and (C
1
-C
4
)alkoxy, (iv) (C
1
-C
4
)alkyl-(C
3
-C
7
)cycloalkyl optionally substituted with a substituent independently selected from hydroxy, (C
1
-C
4
)alkyl and (C
1
-C
4
)alkoxy, and (v) (C
1
-C
4
)alkyl-phenyl or phenyl, the phenyl moiety being optionally substituted with one or two substituents independently selected from halo, (C
1
-C
4
)alkyl, halo-substitutued (C
1
-C
4
)alkyl, hydroxy, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkylthio, nitro, amino, di-((C
1
-C
4
)alkyl)amino and CN;
X is independently selected from halo, (C
1
-C
4
)alkyl, halo-substitutued (C
1
-C
4
)alkyl, hydroxy, (C
1
-C
4
)alkoxy, halo-substitutued (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkylthio, nitro, amino, di-((C
1
-C
4
)alkyl)amino and CN;
m is 0, 1 or 2; n is 0, 1, 2 or 3; and r is 1, 2 or 3; or
(b) a selective COX-2 inhibitor of formula XX,
 a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug,
 wherein the variables of the compound of formula XX are defined as follows:
A is a partially unsaturated or unsaturated five membered heterocyclic, or a partially unsaturated or unsaturated five membered carbocyclic, wherein the 4-(sulfonyl)phenyl and the 4-substituted phenyl in the formula XX are attached to ring atoms of Ring A adjacent to each other;
R
1
is aryl or heteroaryl, and the aryl or heteroaryl being optionally substituted by one to four substituents selected from halo, (C
1
-C
4
)alkyl, halo-substituted (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkyl carbonyl, hydroxy, nitro, cyano and amino, with the proviso that when A is pyrazole, R
1
is heteroaryl;
R
2
is (C
1
-C
4
)alkyl, halo-substituted (C
1
-C
4
)alkyl, (C
1
-C
4
)alkylamino, (C
1
-C
4
)dialkylamino or amino;
R
3
, R
4
and R
5
are independently hydrogen, halo, (C
1
-C
4
)alkyl, halo-substituted (C
1
-C
4
)alkyl, (C
2
-C
5
)alkenyl, (C
2
-C
5
)alkynyl, (C
1
-C
4
)alkoxy, hydroxy-(C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy (C
1
-C
4
)alkyl, (C
1
-C
4
)alkanoyl, cyano, nitro, cyano (C
1
-C
4
)alkyl, carboxy, (C
1
-C
4
)alkoxycarbonyl, aminocarbonyl, N—(C
1
-C
4
)alkylaminocarbonyl, N,N-di-(C
1
-C
4
)alkylaminocarbonyl, N-arylaminocarbonyl, N,N-diarylaminocarbonyl, N—(C
1
-C
4
)alkyl-N-arylaminocarbonyl, aryl, aryloxy, aryloxy-(C
1
-C
4
)alkyl, heteroaryl, heteroaryloxy, heteroaryloxy-(C
1
-C
4
)alkyl, morpholino-carbonyl, (C
1
-C
4
)alkoxyaminocarbonyl or (C
1
-C
4
)alkyl-carbonylamino; or two of R
3
, R
4
and R
5
are take

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