Polyhydroxyalkylpyrazine derivatives, their preparation and...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C544S336000, C544S358000

Reexamination Certificate

active

06380197

ABSTRACT:

Medicaments containing, as active ingredient, at least one compound of general formula:
or one of its stereoisomers or its salts with an inorganic or organic acid, the new derivatives of formula (I), their stereoisomers, their salts with an inorganic or organic acid and their preparation. In general formula (I)
Rc
1
represents the chain
—CH(OR
4
)CH(OR
3
)CH(OR
2
)CH
2
OR
1
  (II)
and
either Rc
2
represents a hydrogen atom and Rc
3
represents the chain
—CH
2
CH (OR
6
)CH(OR
7
)CH
2
OR
8
  (III)
or Rc
2
represents the chain
—CH(OR
5
)CH(OR
6
)CH(OR
7
)CH
2
OR
8
  (IV)
or
—CH
2
CH(OR
6
)CH(OR
7
)CH
2
OR
8
  (III)
and Rc
3
represents a hydrogen atom, and 1 to 8 of the substituents R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, which are identical or different, represents a radical independently chosen from the radicals
a) —COR
9
,
b) —COOR
10
,
c) —CR
11
R
12
OCOR
13
,
d) —CR
11
R
12
OR
13
,
e) —CONR
14
R
15
, or
f) one or more pairs of the substituents R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, consecutive or separated by one of the other substituents R
2
, R
3
, R
6
, R
7
, may also form a group: —C(O)—;
the other substituents R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, representing hydrogen atoms.
R
9
represents a hydrogen atom, or
an alkenyl radical optionally substituted with one or more identical or different substituents chosen from the following radicals: alkyloxy, carboxyl, alkylcarbonyl, alkyloxycarbonyl, carbamoyl, amino, alkylamino, dialkylamino or a halogen atom; or
an alkyl radical, optionally substituted with one or more identical or different substituents chosen from the following radicals: hydroxyl, alkyloxy, carboxyl, alkylcarbonyl, alkyloxycarbonyl, aralkyloxycarbonyl, aryl, aryloxy, carbamoyl, amino, alkylamino, dialkylamino, carboxycarbonyl, heterocyclyl, or a halogen atom; or
an amino radical, a heterocyclyl radical, a heteroaryl radical, or
an aryl radical optionally substituted with one or more identical or different substituents chosen from the following radicals: aryl, alkyl, alkyloxy, aralkyloxy, alkylcarbonyl, alkyloxyalkyl, alkyloxycarbonyl, alkylcarbonyloxy, nitro, hydroxyl, a halogen atom, an amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carbamoylalkylaminoalkyl, hydroxyalkylaminoalkyl, (hydroxyalkyl)(alkyl)aminoalkyl, dihydroxyalkylaminoalkyl radical, or a heterocyclylalkyl radical, for which the heterocyclyl radical of 5 or 6 atoms, optionally substituted with an alkyl radical on any one of its constituent atoms, contains at least one nitrogen atom and optionally another heteroatom suchas oxygen or nitrogen or sulphur, the said heterocyclyl radical being linked to the alkyl radical by thenitrogen atom, such as piperidinyl, piperazinyl, morpholinyl;
advantageously, in general formula (I), R
9
represents a hydrogen atom, or an alkyl, aralkyl, alkyloxyalkyl, aryloxyalkyl, alkyloxycarbonylalkyl, alkyloxycarbonylalkenyl, carboxyalkyl, aralkyloxycarbonylalkyl, heteroaryl radical, or an aryl radical, the said aryl radical being optionally substituted with one or more identical or different substituents chosen from the following radicals: aryl, alkyl, alkyloxy, aralkyloxy, alkylcarbonyl, alkyloxyalkyl, alkyloxycarbonyl, alkylcarbonyloxy, nitro, hydroxyl, a halogen atom, an amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carbamoylalkylaminoalkyl, hydroxyalkylaminoalkyl, (hydroxyalkyl)(alkyl)aminoalkyl, dihydroxyalkylaminoalkyl radical; or a heterocyclylalkyl radical, for which the heterocyclyl radical of 5 or 6 atoms, optionally substituted with an alkyl radical on any one of its constituent atoms, contains at least one nitrogen atom and optionally another heteroatom such as oxygen or nitrogen or sulphur, the said heterocyclyl radical beinglinked to the alkyl radical by the nitrogen atom, such as piperidinyl, piperazinyl, morpholinyl;
and still more advantageously, R
9
represents a hydrogen atom, or an alkyl, aralkyl, alkyloxyalkyl, alkyloxycarbonylalkyl, alkyloxycarbonylalkenyl, carboxyalkyl, aralkyloxycarbonylalkyl, heteroaryl radical, such as thienyl, or an aryl radical, the said aryl radical being optionally substituted with one or more identical or different substituents chosen from the following radicals: alkyl, alkyloxy, aralkyloxy, hydroxyl, alkylcarbonyl, alkylcarbonyloxy, nitro, a halogen atom, a dialkylamino radical, dialkylaminoalkyl radical, or a heterocyclylalkyl radical for which the heterocyclyl radical of 6 atoms contains at least one nitrogen atom and optionally another heteroatom such as oxygen or nitrogen, the said heterocyclyl radical being linked to the alkyl radical by the nitrogen atom, such as piperidinyl or morpholinyl;
R
10
represents an alkyl radical, an aralkyl radical or an aryl radical such as phenyl optionally substituted with one or more identical or different substituents chosen from the following radicals: alkyl, alkyloxy, alkyloxyalkyl, dialkylaminoalkyl, alkylcarbonyloxy, nitro or a halogen atom;
advantageously, in general formula (I), R
10
represents an alkyl radical;
R
11
, R
12
, R
13
independently represent a hydrogen atom or an alkyl, aryl or aralkyl radical;
R
14
, R
15
independently represent a hydrogen atom, an alkyl radical, an aryl radical, an aralkyl radical, a heterocyclyl radical or alternatively R
14
, R
15
together form with the nitrogen atom to which they are attached a 4- to 7-membered heterocycle which may be substituted with 1 to 3 alkyl radicals or with an aryl radical;
advantageously, in general formula (I), R
14
, R
15
independently represent a hydrogen atom, or an aryl radical or an aralkyl radical.
In the preceding definitions and in those which follow:
the term alkenyl radical represents the hydrocarbon portions containing from 1 to 6 straight- or branched-chain carbon atoms and possessing one or more double bonds, optionally substituted with one or more identical or different substituents chosen from the following radicals: alkyloxy, carboxyl, alkylcarbonyl, alkyloxycarbonyl, carbamoyl, amino, alkylamino, dialkylamino or a halogen atom;
the term alkyl defines saturated straight- or branched-chain hydrocarbon portions containing 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl, optionally substituted with one or more identical or different substituents chosen from the following radicals: hydroxyl, alkyloxy, carboxyl, alkylcarbonyl, alkyloxycarbonyl, aralkyloxycarbonyl, aryl, aryloxy, carbamoyl, amino, alkylamino, dialkylamino, carboxycarbonyl, heterocyclyl, or a halogen atom;
the alkyloxy radicals represent an alkyl group containing 1 to 6 straight- or branched-chain carbon atoms which is attached by an oxygen atom such as, for example, methoxy, ethoxy, propoxy, isopropoxy or tert-butoxy;
the aryl radicals refer to mono- or bi-cyclic hydrocarbons optionally substituted with one or more identical or different substituents chosen from the following radicals: alkyl, alkyloxy, a halogen atom, in which at least one ring is aromatic, it being possible for each ring to contain up to 7 carbon atoms. This term aryl includes in particular phenyl, naphthyl, indanyl or biphenyl;
the term heterocycle represents a mono- or polycyclic carbon system optionally substituted with one or more identical or different substituents chosen from the following radicals: alkyl, alkyloxy, a halogen atom, in which each ring may contain up to 7 carbon atoms, saturated or otherwise, and containing from 1 to 4 heteroatoms chosen from N, O and S, capable of being optionally condensed with an aromatic nucleus. This heterocyclic structure may be attached to any atom or heteroatom. The heterocyclic radicals include in particular and without limitation the radicals azepinyl, azetidinyl, benzimidazolyl, benzisoxazolyl, benzofurazannyl, benzopyranyl, benzothiopyrannyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranylsulphone, fu

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