Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-11-12
2003-05-06
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S438000, C514S443000, C514S621000, C514S616000, C514S619000, C514S638000, C514S641000, C514S677000
Reexamination Certificate
active
06559185
ABSTRACT:
The present invention relates to new nitromethyl ketones, to their preparation and to their use as medicaments, especially in the treatment or prevention of the complications of diabetes.
Diabetes is characterized by a high concentration of glucose in the blood. This glucose is normally metabolized by the enzyme hexokinase during the first stage of glycolysis, leading to the degradation into pyruvate. When the glucose concentration is too high, hexokinase becomes saturated and a second pathway for glucose metabolism comes into play. It is the polyol pathway which involves two enzymes successively: aldose reductase which converts glucose to sorbitol arid sorbitol dehydrogenase which converts sorbitol to fructose. In the event 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 can lead to tissue degeneration. Aldose reductase inhibitors are therefore useful for treating or preventing certain complications induced by diabetes.
Numerous products are described in the literature, such as aldose reductase inhibitors which are active in vitro and in vivo.
They are mainly derivatives of hydantoins, of succinimides and of acetic acids and more recently derivatives of sulfonylnitromethanes.
SUMMARY OF THE INVENTION
The present invention relates to nitromethyl ketone derivatives and their addition salts with physiologically acceptable bases, corresponding to the general formula (I):
in which
A represents C
6
-C
10
aryl or an optionally aromatic three- to ten-membered heterocycle in which one to four ring atoms are identical or different heteroatoms chosen from O, S and N;
X represents halogen, cyano, C
1
-C
7
alkyl, trifluoromethyl, C
2
-C
7
alkoxy or trifluoromethoxy;
R
1
and R
2
, which are identical or different, represent a hydrogen atom, a C
1
-C
7
alkyl group, a C
3
-C
12
cycloalkyl group, a trifluoromethyl group, a C
1
-C
7
alkoxy group or R
1
or R
2
together form an alkylene chain of the —(CH
2
)
r
— type, where r is chosen from 2, 3 and 4;
is chosen from 0, 1, 2, 3, 4 and 5;
Z represents a bond, the divalent radical —CO—NH— in which the carbonyl function is linked to R
3
, the divalent radical —SO
2
—NH— in which the sulfonyl function is linked to R
3
, a C
2
-C
7
alkenylene radical, a sulfur atom, the sulfinyl group or a sulfonyl group;
R
3
represents a hydrogen atom; a halogen atom; a tri-(C
1
-C
7
-alkyl)silyl group; a C
1
-C
7
alkyl group optionally substituted with one or more identical or different Y radicals; a C
6
-C
10
aryl group optionally substituted with one or more identical or different Y radicals;, a C
6
-C
10
aryloxy group optionally substituted with one or more identical or different Y radicals; a C
3
-C
12
cycloalkyl group optionally substituted with one or more identical or different Y radicals; an optionally aromatic three- to ten-membered heterocycle in which one to four ring atoms are identical or different heteroatoms chosen from O, S and N, the heterocycle being optionally substituted with one or more identical or different Y radicals, or R
3
represents indanyl, 1,3-dihydro-1,3-dioxo-2H-iso-indol-2-yl, 1,3-benzodioxolyl, 2-oxopiperidinyl or 2-[(4-nitromethylcarbonyl-3-chlorophenyl)amino-carbonyl]-1-(phenyl)ethyl;
Y represents a halogen atom, C
1
-C
7
alkyl, C
1
-C
7
alkoxy, trifluoromethyl, carboxy, carbamoyl, (C
1
-C
7
)alkylcarbamoyl, di-(C
1
-C
7
)alkylcarbamoyl, C
1
-C
7
alkoxycarbonyl, amino, C
1
-C
7
-alkylamino, di-(C
1
-C
7
)-alkylamino, nitro, cyano, hydroxy, trifluoromethoxy, C
3
-C
12
cycloalkyl, sulfo, C
1
-C
7
alkylthio, C
1
-C
7
alkylsulfinyl, C
1
-C
7
alkylsulfonyl, C
2
-C
8
alkylcarbonyl, C
2
-C
8
alkylthiocarbonyl, C
2
-C
8
alkylcarbonylamino, or C
6
-C
10
aryl;
E represents a divalent radical chosen from:
(i) —CO—NR
4
— in which the carbonyl group is linked to —(CR
1
R
2
)
p
— and R
4
represents the radical —(CH
2
)
q
—R
5
where q is chosen from 0 and 1; and where R
5
represents a hydrogen atom; a C
1
-C
7
alkyl group; a C
6
-C
10
aryl group or an optionally aromatic three- to ten-membered heterocycle in which one to four ring atoms are identical or different heteroatoms chosen from O, N and S; or R
5
and R
3
together form a bond;
(ii) —SO
2
—NR
4
— in which the sulfonyl group is linked to —(CR
1
R
2
)
p
— and R
4
is as defined above;
(iii) —NR
4
— in which R
4
is as defined above;
(iv) —CH═N— in which the nitrogen atom is linked to A; and
(v) an oxygen atom;
n represents 0 or 1; on the condition that —A(X)—(E)
n
—(CR
1
R
2
)
p
—Z—R
3
does not represent halophenyl, methylphenyl, dichlorophenyl, dimethylphenyl, 4-ethoxy-2-methylaminophenyl, methylindolyl, dimethylindolyl, 2-hydroxyphenyl substituted with a group X, 2-methoxyphenyl substituted with a group X and optionally substituted 2-fluorophenyl as defined above, and on the condition that when A represents pyridyl, X represents methyl and n is equal to 1, E does not represent —NR
4
—.
These compounds are inhibitors of the enzyme aldose reductase and may be used in the treatment or prevention of the complications of diabetes: neurological, peripheral and autonomous complications, renal complications and ocular complications such as cataract and retinopathy.
The physiologically acceptable salts of the compounds of formula (I) comprise the salts formed with metals (such as sodium, potassium, calcium, magnesium, aluminum), or with bases such as ammonium hydroxide or substituted amines (such as diethylamine, triethylamine, piperidine, piperazine, morpholine) or basic amino acids (such as lysine, arginine) or with osamines (such as meglumine) or with amino alcohols (such as 3-aminobutanol, 2-aminoethanol).
The term “aryl” represents an aromatic mono- or bicyclic group comprising 6 to 10 carbon atoms, such as phenyl or naphthyl.
The term “heterocycle” denotes a mono- or bicyclic ring with an aromatic character or otherwise, comprising 3 to 10 ring atoms of which 1 to 4 are identical or different heteroatoms chosen from oxygen, sulfur and nitrogen, such as for example, the aziridinyl, oxiranyl, oxazolyl, furyl, tetrahydrofuranyl, thienyl, imidazolyl, pyridyl, pyrazinyl, benzothienyl, benzopyranyl, benzofuryl, benzothiazolyl, pyrimidinyl, pyridazinyl, piperidinyl, quinolyl, tetrahydroquinolyl, tetrazolyl, phthalazinyl, purinyl, indolyl, chromenyl, chromanyl, isochromanyl and pyrrolyl.
The term “cycloalkyl” denotes saturated hydrocarbon groups containing 3 to 12 carbon atoms, preferably 3 to 8, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecenyl and cyclododecyl.
The term “halogen” represents a fluorine, chlorine, bromine or iodine atom.
The term “alkyl” denotes a linear or branched hydrocarbon radical such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl.
The term “alkoxy” denotes an alkyl group linked to an oxygen atom. Examples thereof are the methoxy, ethoxy, isopropyloxy, butoxy, hexyloxy radicals.
Likewise, “aryloxy” denotes an aryl radical as defined above linked to an oxygen atom, such as phenoxy and naphthyloxy.
According to the invention, “alkenylene” radical is understood to mean, moreover, a divalent hydrocarbon radical, carrying one or more ethylenic double bonds such as, for example, —CH═CH—CH
2
— or CH═CH—CH═CH—.
“Carbamoyl” radical denotes the monovalent radical of formula —CO—NH
2
. The radical “(C
1
-C
7
)alkylcarbamoyl” denotes a carbamoyl radical substituted with. a C
1
-C
7
alkyl group on the nitrogen atom and the radical “di-(C
1
-C
7
)alkylcarbamoyl” denotes a carbamoyl radical substituted on the nitrogen atom with two C
1
-C
7
alkyl groups.
The radical “(C
1
-C
7
)alkoxycarbonyl” denotes a radical R—O—CO— in which R represents a C
1
-C
7
alkyl group.
The radical “(C
1
-C
7
)alkylamino” denotes an amino group substituted on the nitrogen atom with a (C
1
-C
7
)alkyl radical and the radical “di-(C
1
-C
7
)alkylamino” denotes an amino group substitut
Barbanton Jaques
Collonges Francois
Dumas Herve
Durbin Philippe
Lardy Claude
Cook Rebecca
Merck Patent GmbH
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