Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2002-06-18
2003-07-15
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S423000, C514S620000, C514S623000, C514S365000, C548S200000, C548S540000, C558S170000, C564S164000, C564S188000, C564S189000
Reexamination Certificate
active
06593312
ABSTRACT:
DESCRIPTION OF THE PRIOR ART
A cyclic &agr;-amino-&ggr;-hydroxy acid compound has been described in the journal J. Org. Chem. 1994, 59 (26), 8101-6, without their having been any pharmacological activity mentioned for that compound.
BACKGROUND OF THE INVENTION
In addition to the fact that they are new, the compounds of the present invention have valuable pharmacological properties. They have blood glucose-lowering properties, rendering them beneficial in the treatment of glucose intolerance and disorders associated with hyperglycaemia, such as type II diabetes or obesity.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates more specifically to compounds of formula (I):
wherein:
represents a saturated carbon ring having from 4 to 8 ring members, optionally substituted by one or more linear or branched (C
1
-C
6
)alkyl groups,
R
1
and R
4
, which may be identical or different, each represents a hydrogen atom or a linear or branched (C
1
-C
6
)acyl group,
R
2
and R
3
, which may be identical or different, each represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group,
R
5
and R
6
, which may be identical or different, each represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group,
or R
5
and R
6
together, with the nitrogen atom carrying them, form a nitrogen-containing heterocycle optionally substituted by one or more identical or different groups selected from the groups cyano, CO
2
R
7
(wherein R
7
represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group), COR
7
(wherein R
7
is as defined hereinbefore), nitro, CONR
8a
R
8b
(wherein R
8a
and R
8b
, which may be identical or different, each represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group or R
8a
and R
8b
together form a nitrogen-containing heterocycle), S(O)
n
R
9
(wherein n represents 1, 2 or 3, and R
9
represents a hydrogen atom, a linear or branched (C
1
-C
6
)-alkyl group or an aryl group) and PO
3
R
10a
R
10b
(wherein R
10a
and R
10b
, which may be identical or different, each represents a hydrogen atom or a linear or branched (C
1
-C
6
)-alkyl group),
to stereoisomers thereof, and also to addition salts thereof with a pharmaceutically acceptable acid.
Amongst the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulphonic, benzenesulphonic, camphoric acid, etc.
A nitrogen-containing heterocycle is to be understood as an optionally bridged, saturated mono- or bi-cyclic group having from 5 to 12 ring members and containing one, two or three hetero atoms, one of those hetero atoms being the nitrogen atom and the additional hetero atom or atoms optionally present being selected from the atoms oxygen, nitrogen and sulphur. Preferred nitrogen-containing heterocycles are the groups pyrrolidinyl, thiazolidinyl, piperidyl, morpholinyl, azabicyclo[3.3.0]octyl and piperazinyl.
An aryl group is to be understood as phenyl, biphenylyl, naphthyl or tetrahydronaphthyl, each of those groups optionally being substituted by one or more identical or different atoms or groups selected from the halogen atoms and the groups linear or branched (C
1
-C
6
)alkyl, hydroxy, linear or branched (C
1
-C
6
)alkoxy, linear or branched (C
1
-C
6
)poly-haloalkyl, nitro and (C
1
-C
2
)alkylenedioxy.
Preferred compounds of formula (I) are those wherein
represents a carbon ring having 5 or 6 ring members.
An advantageous variant of the invention concerns compounds of formula (I) wherein R
5
and R
6
together form an optionally substituted nitrogen-containing heterocycle. Among those, preference is given especially to such compounds in which R
5
and R
6
together form an optionally substituted pyrrolidine or an optionally substituted thiazolidine.
Amongst the preferred compounds of the invention, the following may be mentioned more especially:
(1R,2S,1′S)-2-[1′-amino-2′-oxo-2′-(1-pyrrolidinyl)ethyl]cyclohexanol, its (1S,2R,1′R) enantiomer, and also addition salts thereof with a pharmaceutically acceptable acid;
(1R*,2R*,1′R*)-2-[1′-amino-2′-oxo-2′-(1-pyrrolidinyl)ethyl]cyclopentanol, and also addition salts thereof with a pharmaceutically acceptable acid, wherein a (1R*,2R*,1′R*) compound is to be understood as a racemic mixture of the 2 enantiomers having the absolute configurations (1R,2R,1′R) and (1S,2S,1′S);
(1R,2S,1′R)-2-[1′-amino-2′-oxo-2′-(1-pyrrolidinyl)ethyl]cyclopentanol, its (1S, 2R,1′S) enantiomer, and also addition salts therof with a pharmaceutically aceptable acid;
(1R,2S,1′S)-2-[1′-amino-2′-oxo-2′-(1-pyrrolidinyl)ethyl]cyclopentanol, its (1S, 2R,1′R) enantiomer, and also addition salts thereof with a pharmaceutically acceptable acid;
(1R,2S,1′R)-2-[1′-amino-2′-oxo-2′-(1-pyrrolidinyl)ethyl]cyclohexanol, its (1S,2R,1′S) enantiomer, and also addition salts thereof with a pharmaceutically acceptable acid;
and (1R,2S,1′R)-2-[1′-amino-2′-oxo-2′-(1,3-thiazolidin-3-yl)ethyl]cyclohexanol, its (1S,2R,1′S) enantiomer, and also addition salts thereof with a pharmaceutically acceptable acid.
The invention extends also to a process for the preparation of compounds of formula (I), which process is characterised in that chloroacetyl chloride is reacted with a compound of formula (II):
HNR
5
R
6
(II)
wherein R
5
and R
6
are as defined for formula (I),
to yield a compound of formula (III):
wherein R
5
and R
6
are as defined hereinbefore,
which is converted into an amine of formula (IV):
wherein R
5
and R
6
are as defined hereinbefore,
which is reacted with benzaldehyde to yield a compound of formula (V):
wherein R
5
and R
6
are as defined hereinbefore,
which is reacted with a compound of formula (VI):
wherein
R
2
and R
3
are as defined for formula (I),
to yield, after optional acylation of the hydroxy function, a compound of formula (VII), which is of the relative configuration trans:
wherein
R
1
, R
2
, R
3
, R
5
and R
6
are as defined hereinbefore,
which is converted by hydrolysis followed, if desired, by acylation of the amino function, to yield a compound of formula (Ia) of the relative configuration trans, a particular case of the compounds of formula (I):
wherein
R
1
, R
2
, R
3
, R
4
, R
5
and R
6
are as defined hereinbefore,
which is converted, if desired, into a compound of formula (Ib) of the relative configuration cis, a particular case of the compounds of formula (I):
wherein
R
1
, R
2
, R
3
, R
4
, R
5
and R
6
are as defined hereinbefore,
which compounds of formulae (Ia) and (Ib) are separated, if desired, into their isomers by conventional separation techniques, are purified, if necessary, by conventional methods of purification, and are converted, if desired, into addition salts with a pharmaceutically acceptable acid.
The compounds of formula (Ic), a particular case of the compounds of formula (I):
wherein
represents a saturated carbon ring having 6 ring members optionally substituted by one or more linear or branched (C
1
-C
6
)alkyl groups, and R
1
, R
2
, R
3
, R
4
, R
5
and R
6
are as defined for formula (I),
can also be obtained from a compound of formula (VIII):
wherein R
11
represents a hydrogen atom or a phenyl group, and G represents CN or a linear or branched (C
1
-C
6
)alkoxycarbonyl group,
which is reacted with a compound of formula (VIa), a particular case of the compounds of formula (VI):
wherein
R
2
and R
3
are as defined hereinbefore,
to yield a compound of formula (IX) of the relative configuration trans:
wherein
G, R
2
, R
3
and R
11
are as defined hereinbefore,
which compound of formula (IX):
when it is desired to obtain a compound of the relative configuration trans, is hydrolysed un
Boulanger Michelle
Fourquez Jean-Marie
Husson-Robert Bernadette
Levens Nigel
Nosjean Olivier
Les Laboratoires Servier
McKane Joseph K.
Small Andrea D.
The Firm of Hueschen and Sage
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