Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-11-27
2001-07-17
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S319000, C514S409000, C514S416000, C544S058400, C544S171000, C544S386000, C546S016000, C546S019000, C546S203000, C546S205000, C546S208000, C546S214000, C548S408000, C548S434000, C548S453000, C548S470000
Reexamination Certificate
active
06262060
ABSTRACT:
The subject of the present invention is azacycloalkane derivatives, their preparation and their therapeutic application, especially in the treatment of diabetes, obesity, hyperglycaemia and inflammation.
The azacycloalkane derivatives of the invention correspond to the general formula (I)
in which:
R
1
represents a hydrogen atom, hydroxyl, a C
1-4
alkyl, C
1-4
hydroxyalkyl, C
4-7
cycloalkyl or C
1-4
alkyloxy(C
1-4
alkyl) group, an aminocarbonyl group, a benzyl, a heterocycloalkyl or heteroaryl group comprising from 4 to 5 carbon atoms and a heteroatom, such as nitrogen, sulphur or oxygen, the heterocycloalkyl or heteroaryl group being optionally substituted with one or two substituents such as a hydroxyl, a C
1-4
alkyl group or a halogen;
R
2
, R
3
and R
4
, which may be identical or different, represent independently of each other a hydrogen atom, a C
1-4
alkyl group, a C
4-7
cycloalkyl group, a hydroxyl group, an aminocarbonyl group or a heteroaryl group comprising from 4 to 5 carbon atoms and a heteroatom such as nitrogen, sulphur or oxygen, the heteroaryl group being optionally substituted with one or two substituents such as a hydroxyl group, a C
1-4
alkyl group or a halogen;
or R
1
and R
2
together form a C
3-6
alkylene group, a C
2-3
alkylenedioxy group, a C
2-3
alkylenedithio group, —(O
2
)S—C
2-3
alkylene-S(O
2
)— or a group —CH
2
NHC(O)CH
2
—;
or R
2
and R
3
together form a propylene or butylene group, a C
1-3
alkylenedioxy group, a carbonyldioxy group or a 2-butenylene;
or R
2
and R
3
together form with the atoms carrying them a norbornane or a 5-norbornene or a bond in order to give a double bond between the atoms carrying them, X being a carbon atom;
R
5
represents a hydrogen atom, a hydroxyl group or, when
R
6
represents a hydrogen, a 1-indanyl group;
R
6
represents an aromatic group chosen from the following groups:
or, when R
2
and R
3
together form a C
1-3
alkylenedioxy or carbonyldioxy group, a benzyl optionally substituted with one or two substituents such as a halogen or a C
1-4
alkyl group, or R
6
represents a hydrogen, when R
5
represents a 1-indanyl group;
R
7
represents a hydrogen atom or a C
1-4
alkyl group;
R
8
represents a hydrogen, an acetyl, a benzoyl, a C
1-4
alkyl group, optionally substituted with a hydroxyl; or
a C
1-2
alkylphenyl group, optionally substituted on the alkyl group with a hydroxyl,
X represents a carbon, nitrogen, oxygen or sulphur atom or a sulphonyl group,
Y represents an oxygen or sulphur atom,
n is equal to 1 or 2; l is equal to 1 and m is equal to 0 when X represents a nitrogen atom; l and m are equal to 0 when X represents a sulphur or oxygen atom or a sulphonyl; they are equal to 1 when X represents a carbon atom.
Within the framework of the present invention:
C
x-y
is understood to mean a carbon chain which may have from x to y carbon atoms;
alkyl is understood to mean a linear or branched saturated aliphatic group; for example, a C
1-4
alkyl group represents a linear or branched carbon chain of 1 to 4 carbon atoms, more particularly a methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl radical, the term C
x-y
alkylene denoting a divalent C
x-y
alkyl group;
C
x-y
alkenyl is understood to mean a linear or branched aliphatic group comprising from x to y carbon atoms and 1 or 2 ethylenic unsaturations, the term C
x-y
alkenylene denoting a divalent C
x-y
alkenyl group;
cyclo(C
x-y
alkyl) is understood to mean a cyclic radical comprising x to y carbon atoms;
alkoxy is understood to mean an alkyloxy group containing a linear or branched saturated aliphatic chain;
halogen atom is understood to mean a fluorine, a chlorine, a bromine or an iodine;
heteroaryl is understood to mean a pyrrolyl, pyridyl, thyenyl, furyl or pyranyl group, preferably a pyrrolyl group; and
heterocycloalkyl is understood to mean a pyrrolidinyl, piperidyl, tetrahydrofuranyl and tetrahydropyranyl group, preferably a tetrahydrofuranyl group.
The compounds of formula (I) can form with pharmaceutically acceptable acids and bases salts which form part of the invention. In particular, the compounds for which R
7
is a hydrogen can form salts with bases. The preferred salts of bases are, in this case, the salts of sodium and of calcium, which are such that R
7
represents a sodium or calcium atom.
The compounds of formula (I) possess one or more asymmetric carbon atoms; they may exist in the form of enantiomers, diastereoisomers or of mixtures of these various forms, including racemic mixtures which form part of the invention.
The preferred compounds according to the invention are those for which:
R
2
, R
3
and R
4
, when they are not linked together, represent, independently of each other, a hydrogen atom, a C
1-4
alkyl group or a hydroxyl group, and/or the compounds for which R
8
represents a hydrogen.
Among these, the compounds for which R
4
represent a hydrogen are particularly preferred and in particular those for which R
5
represents a hydrogen.
Moreover, the compounds for which R
6
represents an aromatic group other than a benzyl, more especially an indanyl, are also preferred and in particular those containing the abovementioned preferred groups. Among the latter, R
1
and R
2
preferably form a C
3-6
alkylene group, more especially a C
4
alkylene group.
The compounds of formula (I) may be prepared according to the process represented in scheme 1.
According to this process, the compounds of formula (I), in which Y represents an oxygen and R
7
represents a C
1-4
alkyl group, are prepared by reacting a compound of general formula (II)
in which R
1
, R
2
, R
3
, R
4
, X, l, m and n are defined as in formula (I), with a compound of general formula (III)
in which R
7
represents a C
1-4
alkyl group, R
5
and R
6
are defined as in formula (I) and R
9
represents a halogen atom, such as for example a chlorine or a bromine, or a hydroxyl group, in an aprotic solvent such as dichloromethane, in the presence of triethylamine and/or an acid function activating agent such as isobutyl chloroformate or carbonyldiimidazole.
The compounds of the invention of formula (I), for which Y is a sulphur atom and R
7
represents a C
1-4
alkyl group, may be obtained by reacting the compounds (I), previously obtained, with a thiation agent such as Lawesson's reagent.
The compounds of the invention of formula (I), for which R
7
is a hydrogen atom, may be obtained by hydrolysing the compounds (I), in which R
7
represents a C
1-4
alkyl group, according to methods known to persons skilled in the art, for example sodium hydroxide or hydrochloric acid method.
The compounds of formula (II) may be prepared according to processes well known to persons skilled in the art, or by methods described in the literature, such as, for example in Boll. Chim. Farm., 121 (1), 16-26 (1982), in J. Med. Chem., 33, 62-69 (1990) or in J. Heterocyl. Chem., 30, 1357-59 (1993).
The compounds of formula (III) may be prepared according to processes described in the literature, such as for example in J. Am. Chem. Soc., 90, 3495-3502 (1968) or in J. Med. Chem., 36, 2788-2797 (1993).
The following examples illustrate the invention without however limiting the scope of the claims. Analyses confirm the structure of the compounds.
REFERENCES:
patent: 5280122 (1994-01-01), Chiu et al.
patent: 5869518 (1999-02-01), Zurita et al.
patent: 507 534 (1992-10-01), None
patent: 661 292 (1995-07-01), None
patent: 92/20685 (1992-11-01), None
patent: 96/34870 (1996-11-01), None
Derwent Patent Abstract No. 063821 (1995).
Derwent Patent Abstract No. 063820 (1995).
Patent Abstract of Japan, vol. 18, No. 385 (C-1227) (1994).
Derwent Patent Abstract No. 185860 (1994).
Derwent Patent Abstract No. 410827 (1993).
Derwent Patent Abstract No. 199247 (1992).
Bedoya-Zurita Manuel
Daumas Marc
Diaz Martin Juan Antonio
Alexander Michael D.
Dentz Bernard
Sanofi-Synthelabo
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