Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-10-30
2002-07-16
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
Reexamination Certificate
active
06420341
ABSTRACT:
The present invention relates to new sulphur derivatives containing a retroamide bond, their preparation process, the new intermediates obtained, their use as medicaments, the pharmaceutical compositions containing them and the new use of such derivatives.
A subject of the present invention is the products of formula (I):
in which:
R
1
represents an phenyl or biphenyl radical optionally substituted by one or more radicals chosen from halogen atoms, the following radicals: optionally protected hydroxyl, linear or branched alkoxy containing up to 4 carbon atoms, cyano, free, salified, esterified or amidified carboxy, benzyloxy and the dioxol radical, n1 and n2, identical or different, represent the integer 0 or 1,
R
2
represents a hydrogen atom or a methyl radical substituted by a phenyl, phenylthio or indolyl radical and optionally by a second phenyl radical, these phenyl, phenylthio and indolyl radicals being optionally substituted by one or more radicals chosen from halogen atoms and the following radicals: optionally protected hydroxyl, linear or branched alkoxy containing up to 4 carbon atoms, cyano, free, salified, esterified or amidified carboxy, benzyloxy, thienyl, naphthyl and phenyl, these three last radicals being themselves optionally substituted by one or more radicals chosen from halogen atoms and the following radicals: optionally protected hydroxyl, linear or branched alkoxy containing up to 4 carbon atoms, cyano and free, salified, esterified or amidified carboxy,
A represents the free, salified, esterified or amidified carboxy radical, the free or salified tetrazolyl radical, or an alkyl radical, containing up to 10 carbon atoms and substituted by a radical chosen from the following radicals: free, salified, esterified or amidified carboxy, the optionally protected hydroxyl, alkoxy containing up to 4 carbon atoms, phenoxy, phenyl, naphthyl, thienyl, indolyl and pyridyl, these radicals being optionally substituted by one or more radicals chosen from halogen atoms and the following radicals: optionally protected hydroxyl, linear or branched alkoxy containing up to 4 carbon atoms, cyano and free, salified, esterified or amidified carboxy,
1 and 2 indicating, if appropriate, the asymmetric centres of the products of formula (I), said products of formula (I) being in all possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with mineral and organic acids or with the mineral and organic bases of said products of formula (1).
In the products of formula (I) and in what follows:
the term linear or branched alkyl radical designates the following radicals: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and also heptyl, octyl, nonyl and decyl as well as their linear or branched position isomers,
the term linear or branched alkoxy radical designates the following radicals: methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or tertiary butoxy, pentoxy or hexoxy as well as their linear or branched position isomers,
the term halogen atom preferably designates the chlorine atom, but can also represent a fluorine, bromine or iodine atom.
The hydroxyl radical can in particular be in the form of the trifluoromethylsulphonyloxy radical.
The carboxy radical or radicals of the products of formula (I) can be salified or esterified by the various groups known to a person skilled in the art among which there can be mentioned, for example:
among the salification compounds, mineral bases such as, for example, an equivalent of sodium, of potassium, of lithium, of calcium, of magnesium or of ammonium or organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methyl-glucamine.
The sodium or potassium salts are preferred,
among the esterification compounds, the alkyl radical in order to form alkoxy carbonyl or arylalkoxycarbonyl groups, such as, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxy- and isopropoxy-carbonyl, n-butoxy-, isobutoxy- and tert-butoxy-carbonyl or benzyloxycarbonyl, these alkyl radicals can be substituted by radicals chosen for example from halogen atoms, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl radicals such as, for example, in the chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzyl or phenethyl groups.
There can also be mentioned the radicals formed with the remainders of easily cleavable esters such as the methoxymethyl, ethoxymethyl radicals; the acyloxyalkyl radicals such as pivaloyloxymethyl, pivaloyloxyethyl, acetoxymethyl or acetoxyethyl; the alkyloxycarbonyloxy alkyl radicals such as methoxycarbonyloxy methyl or ethyl radicals, the isopropyloxycarbonyloxy methyl or ethyl radicals.
A list of such ester radicals can be found for example in the European Patent EP 0 034 536.
By amidified carboxy is meant the groups of —CON(R
6
) (R
7
) type in which the identical or different R
6
and R
7
radicals represent a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl radicals.
Among the —CON(R
6
) (R
7
) groups defined above, those in which the —N(R
6
) (R
7
) radical represents the amino, mono or dimethylamino radical are preferred.
The N(R
6
) (R
7
) radical can also represent a heterocycle which may or may not contain an additional heteroatom. There can be mentioned the pyrrolyl, imidazolyl, indolyl, piperidino, morpholino, piperazinyl radicals. The piperidino or morpholino radicals are preferred.
Examples of the protective group of the protected hydroxyl radical are given in particular in the usual book known to a person skilled in the art: Protective Groups in Organic Synthesis, Theodora W. Greene, Harvard University, printed in 1981 by Wiley-Interscience Publishers, John Wiley & Sons.
The addition salts with mineral or organic acids of the products of formula (I) can be, for example, the salts formed with the following acids: hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric, phosphoric, propionic, acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulphonic acids such as for example methanesulphonic acid, ethanesulphonic acid, propanesulphonic acid, alkyldisulphonic acids such as for example methanedisulphonic acid, alpha, beta-ethanedisulphonic acid, arylmonosulphonic acids such as benzenesulphonic acid and aryldisulphonic acids.
More particularly there can be mentioned the salts formed with hydrochloric or methanesulphonic acids for example.
It should be remembered that the stereoisomerism can be defined in its widest sense as the isomerism of compounds having the same structural formulae, but the different groups of which are arranged differently in space.
It is understood that the definition of the products of formula (I) as defined above includes all possible stereoisomers, all racemic modifications, all optical isomers and all mixtures of these products which would have the activity indicated hereafter.
The products of formula (I) contain in particular two centres {circle around (1)} and {circle around (2)}, {circle around (1)} being asymmetrical and {circle around (2)} being asymmetrical when R
2
does not represent a hydrogen atom. A particular subject of the present invention is the products of formula (I) in which the first asymmetrical centre {circle around (1)} is preferably in R form, the second centre {circle around (2)} can preferably be in racemic or enantiomeric R or S form.
A particular subject of the present invention is the products of formula (I) as defined above, in which R
1
, R
2
, and n2 have the meanings indicated above, n1 represents the integer 1, and A represent the free, salified, esterified ou amidified carboxy radical or an alkyl radical, conta
Deprez Pierre
Dumas Jacques
Guillaume Jacques
Aventis Pharma S.A.
Bierman, Muserlian and Lucas
Fay Zohreh
LandOfFree
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