Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-12
2002-06-25
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S383000, C514S385000, C514S382000, C514S407000, C514S408000, C548S252000, C548S266600, C548S315100, C548S375100, C548S376100, C548S527000
Reexamination Certificate
active
06410582
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new thienylazolylalkoxyethanamines of general formula (I), as well as their physiologically acceptable salts, to the procedures for their preparation, to their application as medicaments in human and/or veterinary therapy and to the pharmaceutical compositions that contain them.
The new compounds object of the present invention can be used in the pharmaceutical industry as intermediates and for the preparation of medicaments.
The invention also relates to new derivatives of thienylazolylcarbinols, of general formula (IV), useful as starting materials or intermediates in the synthesis of the compounds of general formula (I).
BACKGROUND OF THE INVENTION
In our patent application EP 289380 we have described different derivatives of phenylpyrazolylcarbinols, of general formula (II)
in which R1 represents a hydrogen atom or an alkyl group; R2 represents an aminoalkyl radical and Het represents an azol.
We have now discovered that substituting a benzene ring for a thiopheno ring gives rise to new compounds of general formula (I) that show some interesting biological properties. These properties make the new compounds particularly useful for use in human and/or veterinary therapy. The compounds object of this patent are useful as agents with analgesic activity.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides new compounds with potent analgesic activity.
The compounds object of the present invention correspond to the general formula (I)
in which
R1 represents a hydrogen atom, a halogen atom or a lower alkyl radical; R2, R3 and R4 represent a hydrogen atom or a lower alkyl radical; and Az represents an nitrogenated heterocyclic aromatic five-member ring, N-methyl substituted, that contains from one to three atoms of nitrogen, of general formula (III)
in which Z1, Z2 and Z3, independently, represent an atom of nitrogen or CH. with the condition that, at least, one of Z1, Z2 or Z3 is CH.
The term “lower alkyl” represents a linear or branched carbon chain that includes from 1 to 4 atoms of carbon, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and terc-butyl for example.
The new compounds of general formula (I) have at least one asymmetric carbon and so can be prepared enantiomerically pure or as racemates. The racemates of the compounds (I) can be resolved into their optical isomers by conventional methods, such as for example separation by chiral chromatography or fractionated crystallisation of their diastereoisomeric salts, which can be prepared by reaction of the compounds (I) with enantiomerically pure acids. Similarly, they can also be obtained by enantioselective synthesis using chiral precursors, preferably enantiomerically pure thienylazolylcarbinols.
The present invention relates equally to the physiologically acceptable salts of the compounds of general formula (I), in particular the addition salts of mineral acids such as hydrochloric, hydrobromic, phosphoric, sulphuric, nitric acids and organic acids such as citric, malic, fumaric, tartaric or its derivatives, p-toluensulphonic, methanesulphonic, canphosulfonic, etc., acids.
In an embodiment, the invention provides a compound of formula (I) wherein R1 is a halogen atom wherein said halogen atom represents a fluorine, chlorine, or bromine atom.
In a particular embodiment, the invention provides a compound of formula (I) selected from the following group:
[1] 5-{&agr;-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol;
[2] Citrate of 5-{&agr;-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol;
[3] 5-{&agr;-[2-(dimethylamino)ethoxy]-3-thienylmethyl}-1-methyl-1H-pyrazol;
[4] 2-{&agr;-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-imidazol;
[5] 5-{&agr;-[2-(dimethylamino)ethoxy]-3-methyl-2-thienylmethyl}-1-methyl-1H-pyrazol;
[6] 5-{&agr;-[2-(dimethylamino)ethoxy]-5-methyl-2-thienylmethyl}-1-methyl-1H-pyrazol;
[7] 5-{&agr;-[2-(dimethylamino)ethoxy]-5-bromo-2-thienylmethyl}-1-methyl-1H-pyrazol;
[8] 5-{&agr;-[2-(dimethylamino)ethoxy]-4-bromo-2-thienylmethyl}-1-methyl-1H-pyrazol;
[9] 5-{1-[2-(dimethylamino)ethoxy]-1-(2-thienyl)ethyl}-1-methyl-1H-pyrazol;
[10] (+)-5-{&agr;-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol;
[11] (−)-5-{&agr;-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol;
[12] Citrate of (+)-5-{&agr;-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol;
[13] Citrate of (−)-5-{&agr;-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol;
[14] D-toluoyltartrate of (+)-5-{&agr;-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol; and
[15] D-toluoyltartrate of (−)-5-{&agr;-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol.
The new derivatives of general formula (I), in which R1, R2, R3, R4 and Az have the aforementioned meaning, can be prepared according to the methods that are now described:
Method A
By reaction of a compound of general formula IV
with a compound of general formula V
in which R1 to R4 and Az have the aforementioned meaning and X represents a halogen atom, preferably chlorine, or a leaving group such as tosiloxy or mesiloxy.
The reaction of the compound of general formula IV with a compound of general formula V in the form a base or salt, is carried out in the presence of an appropriate solvent such as a hydrocarbon such as benzene or toluene for example or in halogenated solvents such as chloromethane or tetrachloromethane or in ethers such as tetrahydrofurane or in aprotic dipolar solvents such as dimethylsulphoxide or dimethylformamide.
The reaction is preferably carried out in the presence of an appropriate base such as the mineral bases such as sodium hydroxide or potassium hydroxide or the carbonates or bicarbonates of sodium or potassium for example.
The reaction is preferably carried out in the presence of a phase transfer catalyst such as tetrabutylamonium bromide, triethylbenzylamonium chloride or crown ethers, in a temperature range lying between room temperature and the solvent reflux temperature.
Method B
By reaction of a compound of general formula VI
with a compound of general formula VII
in which R1 to R4 and Az have the aforementioned meaning and Y represents a halogen atom, preferably chlorine, a leaving group such as tosiloxy or mesiloxy or a hydroxyl radical.
The reaction of the compound of general formula VI with a compound of general formula VII in the form a base or salt, is carried out in the presence of an appropriate solvent such as a hydrocarbon such as benzene or toluene for example or in halogenated solvents such as chloromethane or tetrachloromethane or in ethers such as tetrahydrofurane or in aprotic dipolar solvents such as dimethylsulphoxide or dimethylformamide.
The reaction is preferably carried out in the presence of an appropriate base such as the mineral bases such as sodium hydroxide or potassium hydroxide or the carbonates or bicarbonates of sodium or potassium for example.
The reaction can be carried out in the presence of a phase transfer catalyst such as tetrabutylamonium bromide, triethylbenzylamonium chloride or the crown ethers, in a temperature range lying between room temperature and the solvent reflux temperature.
When Y represents a hydroxyl radical the reaction is preferably carried out in the presence of a strong acid such as sulphuric acid, in or not in the presence of an appropriate solvent such as benzene and in a temperature range lying between room temperature and the reflux temperature of the solvent.
Method C
By reduction of a compound of general formula VIII
in whic
Andaluz-Mataró Blas
Frigola-Constansa Jordi
Merce-Vidal Ramon
Higel Floyd D.
Laboratorios Del Dr. Esteve, S.A.
Ladas & Parry
Sackey Ebenezer
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