Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-03-28
2004-04-06
Powers, Flona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S365000, C514S403000, C514S422000, C514S423000, C544S141000, C548S200000, C548S356100, C548S518000, C548S540000
Reexamination Certificate
active
06716843
ABSTRACT:
DESCRIPTION OF THE PRIOR ART
DPP TV-inhibitors have been described in the literature, in particular amide compounds in Patent Application EP 0 490 379 and in the journal Adv. Exp. Med. Biol. 1997, 421, 157-160, and carbamate compounds in Patent Application DE 19826972.
BACKGROUND OF THE INVENTION
Dipeptidyl-peptidase IV is a membrane serine protease present in numerous human tissues and involved in numerous pathologies:
DPP IV has been shown to be responsible for inactivation of GLP-1 (glucagon-like peptide-1). GLP-1, being an important stimulator of the secretion of insulin in the pancreas, has a direct beneficial effect on the level of glucose in the blood.
Inhibition of DPP IV accordingly represents an extremely promising approach in the treatment of glucose intolerance and in disorders associated with hyperglycaemia such as, for example, non-insulin-dependent diabetes (type II diabetes) or obesity.
DPP IV has also been shown to play a part in the immune response. Expressed by T-CD
4+
lymphocytes, where it is synonymous with the antigen CD26, it plays an important part in the mechanism of transplant rejection (Transplantation 1997, 63 (10), 1495-500).
By allowing more selective suppression of the immune response, inhibition of DPP IV accordingly represents an extremely promising approach in the prevention of transplant rejection in transplant patients.
It has been also shown that endothelial DPP IV of the lung, by binding to the fibronectin of cancerous cells, promotes metastasis of those cells (J. Biol. Chem. 1998, 273 (37), 24207-24215).
DPP IV-inhibitors are accordingly useful in the treatment of cancer and the prevention of cancerous metastases.
DPP IV also plays an important part in the infection of T-CD
4+
lymphocytes by the HIV-1 virus (Res. Virol. 1997, 148 (4), 255-266). By preventing the virus from penetrating into the cells, DPP IV-inhibitors are accordingly especially promising for prevention of transmission of the HIV-1 virus. DPP IV has also been shown to be responsible for the inactivation of chemokines such as the factors SDF-1&agr; and SDF-1&bgr;, which are known for their chemotactic and antiviral activity (Proc. Natl. Acad. Sci. USA 1998, 95 (11), 6331-6336).
DPP IV is likewise said to play an important part in the pathogenesis of periodontitis (Infect. Immun. 2000, 68 (2), 716-724).
Finally, DPP IV has been shown to be responsible for the inactivation of GLP-2, a factor facilitating recovery of the intestine after major resection (J. Surg. Res. 1999, 87 (1), 130-133).
DPP IV-inhibitors are accordingly potentially useful in recovery of the intestine.
DETAILED DESCRIPTION OF THE INVENTION
More specifically, the present invention relates to compounds of formula (I):
wherein:
represents a 5-membered, nitrogen-containing heterocycle optionally substituted by a cyano group,
R
1
represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)acyl, prolyl, alanyl, histidylprolyl or phenylalanylprolyl group,
Ak represents a linear or branched (C
1
-C
6
)alkylene chain or a heteroalkylene chain,
X represents a single bond or a phenylene group optionally substituted by one or more identical or different groups selected from halogen atoms and linear or branched (C
1
-C
6
)alkyl, hydroxy, linear or branched (C
1
-C
6
)alkoxy and linear or branched (C
1
-C
6
)polyhaloalkyl groups,
R
2
represents a linear or branched (C
1
-C
6
)alkyl group (optionally substituted by one or more identical or different groups selected from aryl, linear or branched (C
1
-C
6
)alkylsulphonyl, (C
3
-C
7
)cycloalkylsulphonyl, (C
3
-C
7
)cycloalkyl group and halogen atoms), a (C
3
-C
10
)cycloalkyl group, or —NR
2a
R
2b
wherein R
2a
and R
2b
, which may be the same or different, each represent a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group or, together with the nitrogen atom carrying them, form a nitrogen-containing heterocycle,
Y represents a group
R
3
represents a hydrogen atom or a group selected from linear or branched (C
1
-C
6
) alkyl group, (C
3
-C
7
) cycloalkyl and aryl,
R
4
, R
5
and R
6
, which may be the same or different, each represent a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group, or R
4
and R
6
, or R
5
and R
6
, together with the atoms carrying them, form an imidazolidine or dihydrobenzimidazole ring,
to their optical isomers and to addition salts thereof with a pharmaceutically acceptable acid.
Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid, oxalic acid etc.
A nitrogen-containing heterocycle is understood to mean a saturated, monocyclic, 5- to 7-membered group containing one, two or three hetero atoms, one of those hetero atoms being the nitrogen atom and the additional hetero atom(s) optionally present being selected from oxygen, nitrogen and sulphur atoms.
Preferred nitrogen-containing heterocycles are pyrrolidinyl, thiazolidinyl, isoxazolidinyl, morpholinyl and pyrazolidinyl groups.
A heteroalkylene chain is understood to mean a linear or branched (C
1
-C
6
) alkylene chain wherein a —CH
2
— member has been replaced by an oxygen or sulphur atom.
Preferred compounds of formula (I) are those wherein
represents a 1-pyrrolidinyl group optionally substituted by a cyano group, or a 1,3-thiazolidin-3-yl group optionally substituted by a cyano group.
Preferred compounds of formula (I) are those wherein X represents a single bond.
Preferred compounds of formula (I) are those wherein the configuration &agr; to the
amide function is (S)
An advantageous aspect of the invention relates to compounds of formula (I) wherein R
2
represents a linear or branched (C
1
-C
6
)alkyl group and Y represents a group
Another advantageous aspect of the invention relates to compounds of formula (I) wherein R
2
represents a (C
3
-C
10
)cycloalkyl group and Y represents an —NH— group.
Among the preferred compounds of the invention there may be mentioned more especially:
(S)-1-[N
5
-{(imino)-(methylsulphonylamino)-methyl}-ornithyl]-pyrrolidine, its optical isomers and also addition salts thereof with a pharmaceutically acceptable acid;
(S)-N-[4-amino-5-oxo-5-(1-pyrrolidinyl)-pentyl]-cyclohexanesulphonamide, its optical isomers and also addition salts thereof with a pharmaceutically acceptable acid;
(2S)-2-cyano-1-[N
6
-{(imino)-(methylsulphonylamino)-methyl}-(S)-ornithyl]-pyrrolidine, its optical isomers and also addition salts thereof with a pharmaceutically acceptable acid;
and (2S)-2-cyano-1-[N
6
-{(imino)-(methylsulphonylamino)-methyl}-(S)-lysyl]-pyrrolidine, its optical isomers and also addition salts thereof with a pharmaceutically acceptable acid.
The invention relates also to a process for the preparation of compounds of formula (I), which process is characterised in that a compound of formula (II):
wherein Ak, X and Y are as defined for formula (I), R′
1
represents a protecting group for the amino function, or a linear or branched (C
1
-C
6
)alkyl group, a linear or branched (C
1
-C
6
)acyl group, a prolyl group optionally protected by an amino-function-protecting group, an alanyl group optionally protected by an amino-function-protecting group, a histidylprolyl group optionally protected by an amino-function-protecting group, or a phenylalanylprolyl group optionally protected by an amino-function-protecting group, and P
2
represents a hydrogen atom or a protecting group for the amino function,
is reacted with a compound of formula (III):
wherein
is as defined for formula (I), under conventional conditions of peptide coupling,
to yield, after deprotection—where necessary—of the group Y, the compound of formula (IV):
wherein
Ak, X, Y and R′
Benoist Alain
De Nanteuil Guillaume
Husson-Robert Bernadette
Levens Nigel
Nosjean Olivier
Les Laboratoires Servier
Powers Flona T.
The Firm of Hueschen and Sage
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