Nitromethylthiobenzene derivatives as inhibitors of aldose...

Details Nitromethylthiobenzene derivatives as inhibitors of aldose... Nitromethylthiobenzene derivatives as inhibitors of aldose...

2000-03-17

2003-01-21

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C514S445000, C514S468000, C514S604000, C514S605000, C549S044000, C549S048000, C549S065000, C564S092000, C564S099000

Reexamination Certificate

active

06509499

ABSTRACT:

The present invention relates to novel nitromethylthiobenzene derivatives, the processes for preparing them and to their therapeutic application, more particularly in the treatment or prevention of diabetic complications.
Diabetes is characterized by a high concentration of glucose in the blood. This glucose is normally metabolized by the enzyme hexokinase during the first step of glycolysis, resulting in degradation to pyruvate. When the glucose concentration is too high, the hexokinase becomes saturated, and a second glucose metabolization route comes into play; this is the polyol route which successively involves two enzymes: aldose reductase which converts the glucose into sorbitol, and sorbitol dehydrogenase which converts the sorbitol into fructose. In the case of diabetes, the excess glucose accelerates the formation of sorbitol, which tends to accumulate. This results in serious metabolic disturbances, such as, for example, an increase in osmotic pressure, which is liable to lead to tissue degeneration. Aldose reductase inhibitors are thus useful for treating or preventing some of the complications induced by diabetes.
Many products are described in the literature as being aldose reductase inhibitors which are active in vitro and in vivo. They are mainly hydantoin derivatives, succinimides and acetic acids. More recently, (phenylsulphonyl)nitromethane derivatives have appeared in European patent 304,190, and in particular the compound 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline in patent WO 90/08761. This compound has generated several derived series, such as the N-acylation products described in European patent 469,887 and the (oxamido- and ureido-phenylsulphonyl)hitromethanes described in European patent 469,889.
The present invention relates to nitromethylthiobenzene derivatives corresponding to the general formula 1,
in which:
P represents
the radical (i): —(CO—NH)
m
—SO
2
—R;
the radical (ii):
or the radical (iii):
R represents a radical chosen from phenyl, benzyl, diphenylmethyl, naphthyl, cycloalkylalkyl in which the alkyl part is C
1
-C
4
and the cycloalkyl part is C
3
-C
7
, and styryl, the said radical optionally being substituted with one or more groups Z which may be identical or different, or alternatively
R represents a C
3
-C
5
aromatic heterocyclic radical comprising 1 or 2 hetero atoms chosen from O, S and N, the said radical optionally being substituted with one or more groups Z, which may be identical or different, and optionally being fused to 1 or 2 phenyl rings which are optionally substituted with one or more groups Z, which may be identical or different; or alternatively
R represents C
1
-C
4
alkyl optionally substituted with one or more halogen atoms, which may be identical or different, C
3
-C
7
cycloalkyl or cyclo(C
3
-C
7
)alkyl(C
1
-C
4
)alkyl;
Z is chosen from a halogen atom, a C
1
-C
4
alkyl, C
1
-C
4
alkoxy, nitro, cyano, trifluoromethyl, trifluoro-methoxy, (C
2
-C
5
)alkylamino, (C
1
-C
4
)alkylsulphonyl, (C
1
-C
4
)alkylthio and phenyl group;
X represents a hydrogen or halogen atom;
m is 0 or 1;
n is 0, 1 or 2;
T
1
and T
2
represent, independently of each other, a hydrogen atom or a C
1
-C
4
alkyl group,
u is 0 or 1;
A represents C
1
-C
8
alkylene or the group
y being an integer chosen from 0, 1, 2, 3 and 4; it being understood that when P represents the radical (ii), A can also represent a bond;
the tautomeric forms thereof and the addition salts thereof with pharmaceutically acceptable bases.
The term “C
1
-C
4
alkyl” denotes a linear or branched saturated hydrocarbon-based radical comprising from 1 to 4 carbon atoms. The alkoxy group consequently denotes the group alkyl-O— in which alkyl has the meaning indicated above.
As C
3
-C
5
aromatic heterocycles comprising 1 or 2 hetero atoms chosen from O, S and N, mention may be made of furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, pyridine, pyridazine, pyrimidine and pyrazine, pyridine and thiophene being preferred.
As it is used herein, term “halogen” denotes a fluorine, bromine, chlorine or iodine atom.
Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. According to the invention, the cycloalkyalkyl group denotes an alkyl group substituted with a cycloalkyl group.
The term “alkylene radical” refers to a linear or branched divalent hydrocarbon-based saturated chain such as —CH
2
—; —CH
2
—CH
2
—CH
2
—; or —CH
2
—CH(CH
3
)—CH
2
—.
The group of formula:
corresponds to one of the following formulae:
in which y represents 0, 1, 2, 3 or 4.
According to the invention, when P represents the radical (ii) of formula:
A is chosen from:
a bond, a C
1
-C
8
alkylene radical, and
the group of formula
in which y is an integer chosen from 0, 1, 2, 3 and 4.
Conversely, when P is —(CO—NH)
m
—SO
2
—R or the radical (iii) of formula:
then A is chosen from:
a C
1
-C
8
alkylene radical, and
the group of formula:
in which y is an integer chosen from 0, 1, 2, 3 and 4.
The possible tautomeric forms of the compounds of formula 1 form an integral part of the invention.
The addition salts, with pharmaceutically acceptable bases, of compounds of formula 1 in which X is a hydrogen atom and n is equal to 1 or 2 also form an integral part of the invention, for example an alkali or alkaline-earth metal salt, such as a sodium, potassium, calcium or magnesium salt, an aluminium salt, an ammonium salt or a salt of an organic base bearing a pharmaceutically acceptable cation.
A first group of preferred compounds consists of the compounds of formula 1 in which:
P represents —(CO—NH)
m
—SO
2
—R
R represents a radical chosen from phenyl, diphenyl-methyl, naphthyl and styryl, the said radical optionally being substituted with one or more groups Z, which may be identical or different, or alternatively
R represents a C
3
-C
5
aromatic heterocyclic radical comprising 1 or 2 hetero atoms chosen from O, S and N, the said radical optionally being substituted with one or more groups Z, which may be identical or different, and optionally being fused to 1 or 2 phenyl rings which are optionally substituted with one or more groups Z, which may be identical or different; or alternatively
R represents C
1
-C
4
alkyl optionally substituted with one or more halogen atoms, which may be identical or different, C
3
-C
7
cycloalkyl or cyclo(C
3
-C
7
)alkyl(C
1
-C
4
)-alkyl;
Z, X, m and n being as defined above for formula (1).
A second group of preferred compounds includes the compounds of formula 1 in which:
P represents —(CO—NH)
m
—SO
2
—R,
R represents phenyl; phenyl substituted with one or more groups Z, which may be identical or different; benzyl; benzyl substituted with one or more groups Z which may be identical or different; C
1
-C
4
alkyl optionally substituted with one or more halogen atoms, which may be identical or different; C
3
-C
7
cycloalkyl; cyclo(C
3
-C
7
)alkyl(C
1
-C
4
)alkyl; styryl; thienyl; pyridyl; naphthyl; dibenzofuryl; or diphenylmethyl;
Z is chosen from a halogen atom, a C
1
-C
4
alkyl, C
1
-C
4
alkoxy, nitro, trifluoromethyl, trifluoromethoxy, (C
2
-C
5
)alkylamino, (C
1
-C
4
)alkylsulphonyl and phenyl group;
X, m and n being as defined above for formula (1).
Among this second group of preferred compounds, the compounds for which:
P represents —(CO—NH)
m
—SO
2
—R,
R represents phenyl; phenyl substituted with one or more groups Z, which may be identical or different; benzyl; benzyl substituted with one or more groups Z which may be identical or different; methyl; C
3
-C
7
cycloalkyl; cyclo(C
3
-C
7
)alkyl(C
1
-C
4
)alkyl; styryl; thienyl; pyridyl; naphthyl; dibenzofuryl; diphenylmethyl or 2,2,2-trifluoroethyl;
Z is chosen from fluoro, chloro, bromo, methyl, methoxy, nitro, trifluoromethyl, trifluoromethoxy, acetamido, methylsulphonyl and phenyl;
X represents hydrogen or chlorine;
m and n being as defined above for formula (1), are particularly advantageous.
A third group of preferred compounds consists of the compounds of formula 1 in which:
P represents —(CO—NH)
m
—SO
2
—R,
R represents

Affiliated with

Also associated with

Rating

Nitromethylthiobenzene derivatives as inhibitors of aldose... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Nitromethylthiobenzene derivatives as inhibitors of aldose..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Nitromethylthiobenzene derivatives as inhibitors of aldose... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3059252