Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-08-12
2004-04-06
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...
C514S300000, C514S419000, C546S084000, C546S113000, C548S496000
Reexamination Certificate
active
06716852
ABSTRACT:
The present invention relates to new N-mercaptoacyl amino acid compounds, to a process for their preparation and to pharmaceutical compositions containing them.
Numerous patent applications describe amino acid compounds for use as inhibitors of neutral endopeptidase (NEP) (EP 449 523), as inhibitors of endothelin converting enzyme (ECE) (WO 97/32874), or as mixed inhibitors of NEP and angiotensin I converting enzyme (ACE).
The pharmacological role played by those enzymes is:
for ACE, to convert angiotensin I to angiotensin II and to degrade bradykinin to inactive peptides,
for NEP, to degrade bradykinin and atrial natriuretic peptide to inactive peptides,
for ECE, to convert big endothelin-1 to endothelin-1.
Angiotensin II, endothelin, bradykinin and atrial natriuretic peptide are the most important peptides hitherto implicated in regulating vascular tone, cardiovascular re-modelling and hydroelectrolytic homeostasis. Their metabolism is essentially controlled by those three enzymes. The inhibition of one and/or the other of those enzymes enables optimum peptidergic balance to be restored by favouring vasodilatory, antitrophic and natriuretic peptides (bradykinin, atrial natriuretic peptide) over vasoconstrictive, trophic and anti-natriuretic peptides (angiotensin II, endothelin-1), hence the cardiovascular therapeutic benefit.
The pharmacological properties of the mixed ACE/NEP inhibitors described in the prior art overlook the major cardiovascular role of the endothelin system (Haynes W. G. et al., Journal of Hypertension, 1998, 16 (8), pp. 1081-1098) and the demonstrated implication of NEP in the degradation of endothelin-1 (Vijayaraghavan J. et al., J. Biol. Chem., 1990, 265, pp. 14150-14155). Thus, treatment with mixed ACE/NEP inhibitors results in an increase in levels of endothelin-1 which, in the long term, can have an adverse effect on the expected therapeutic benefit. This problem is solved by obtaining the three types of inhibition within the same molecule, enabling counter-regulation of that activation and so bringing about sustained strengthened therapeutic efficacy. The development of molecules that inhibit those three enzymes thus constitutes a very significant advance in the treatment of arterial hypertension and cardiovascular diseases.
The compounds of the present invention are new and are excellent triple inhibitors, that is to say they are capable of inhibiting NEP, ACE and ECE simultaneously.
The present invention relates more especially to compounds of formula (I):
wherein:
n represents an integer wherein 0≦n≦3,
m represents an integer wherein 0≦m≦6,
R
3
and R
4
together form, with the two carbon atoms carrying them, a phenyl group that is unsubstituted or substituted by from 1 to 3 identical or different groups selected from alkyl, alkenyl, alkynyl, alkoxy, hydroxy, alkylthio, mercapto, cyano, nitro, amino, alkylamino, dialkylamino, polyhaloalkyl, azido, carboxy, alkoxycarbonyl, amido, carbamoyl, formyl, acyl, aryl, heteroaryl and halogen atoms,
B represents a heteroaryl group,
R
2
represents a hydrogen atom or an alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, acyl, aryl, arylalkyl or aroyl group,
R
1
represents a hydrogen atom, an acyl, aroyl or cycloalkylcarbonyl group or a group of formula (II):
wherein m, n, R
2
, R
3
, R
4
and B are as defined hereinbefore,
it being understood that:
“alkyl” is understood to mean an alkyl group having a linear or branched chain containing from 1 to 6 carbon atoms,
“alkenyl” is understood to mean an alkyl group containing from 2 to 6 carbon atoms and one or more double bonds,
“alkynyl” is understood to mean an alkyl group containing from 2 to 6 carbon atoms and one or more triple bonds,
“cycloalkyl” is understood to mean a cyclic alkyl group containing from 3 to 8 carbon atoms,
“acyl” is understood to mean an RCO group wherein R represents an alkyl group as defined hereinbefore,
it being possible for the groups “alkyl”, “alkenyl” and “alkynyl” to be substituted by one or more identical or different groups selected from hydroxy, alkoxy, polyhaloalkyl, amino and halogen atoms,
and it being possible for the groups “cycloalkyl” and “cycloalkylalkyl” to be substituted on the cyclic moiety by one or more identical or different groups selected from hydroxy, alkoxy, polyhaloalkyl, amino and halogen atoms,
“aryl” is understood to mean a phenyl or naphthyl group unsubstituted or substituted by one or more identical or different groups selected from alkyl, alkenyl, alkynyl, alkoxy, hydroxy, alkylthio, mercapto, cyano, nitro, amino, alkylamino, dialkylamino, polyhaloalkyl, azido, carboxy, alkoxycarbonyl, amido, carbamoyl, formyl, acyl and halogen atoms,
“heteroaryl” is understood to mean any mono- or poly-cyclic aromatic group containing from 1 to 3 hetero atoms selected from oxygen, sulphur and nitrogen, those groups being unsubstituted or substituted by one or more identical or different groups selected from alkyl, alkenyl, alkynyl, alkoxy, hydroxy, alkylthio, mercapto, cyano, nitro, amino, alkylamino, dialkylamino, polyhaloalkyl, azido, carboxy, alkoxycarbonyl, amido, carbamoyl, formyl, acyl and halogen atoms, it being possible for the polycyclic groups also to be partially or completely hydrogenated on one of the rings,
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may be mentioned by way of non-limiting example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic 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.
Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
The preferred compounds of the invention are the compounds of formula (I) wherein R
1
represents a hydrogen atom or an acyl group.
The preferred value for m and n is 1.
The preferred R
2
groups are the hydrogen atom and the groups alkyl and arylalkyl.
Advantageously, the invention relates to compounds of formula (I) wherein R
3
and R
4
together form, with the two carbon atoms carrying them, a substituted phenyl group.
More advantageously, the invention relates to compounds of formula (I) wherein R
3
and R
4
together form, with the two carbon atoms carrying them, a phenyl group substituted by a halogen atom and more especially by a bromine atom or substituted by an alkoxy or alkylthio group and more especially by the groups methoxy and methylthio.
More advantageously still, the invention relates to compounds of formula (I) substituted in the 2-position by an indane group substituted in the 5-position by a halogen atom and more especially by a bromine atom or by an alkoxy group and more especially by a methoxy group.
The preferred B groups are heteroaryls containing an NH group, such as, for example, the groups indolyl, imidazolyl, pyrrolopyridinyl, pyrroloquinolinyl, pyrrolyl and pyrrolopyrazinyl, more especially the groups indolyl, 1H-pyrrolo[2,3-b]pyridine and 1H-pyrrolo[3,2-h]quinolinyl.
The preferred configuration of the compounds of formula (I) is 2S-3R, and more especially 2S-3R-4S.
More advantageously still, the invention relates to:
N-[2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]tryptophan,
N-[2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]tryptophan (2S-3R4S),
N-[2-(5-chloro-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]tryptophan,
N-[(2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]tryptophan,
N-[3-mercapto-2-(1,2,3,4-tetrahydro-1-naphthalenyl)propanoyl]tryptophan,
N-[2-(5-methoxy-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]tryptophan,
N-[2-(4-methoxy-2,3-dihydro-1Hinden-1-yl) 3-mercaptopropanoyl]tryptophan,
N-[2-(5-ethoxy-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]trypt
Bennejean Caroline
Fournie-Zaluski Marie-Claude
Inguimbert Nicolas
Poras Hervé
Renard Pierre
Dentz Bernard
Les Laboratories Servier
The Firm of Hueschen and Sage
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