Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-04-21
1996-10-01
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514648, 514649, 514653, 544297, 564316, 564343, 564345, 564355, A61K 31135, A61K 31505, C07C21530, C07D23942
Patent
active
055611354
DESCRIPTION:
BRIEF SUMMARY
THIS APPLICATION IS A 371 OF PCT/EP94/02363, FILED JUL. 18, 1994.
DESCRIPTION
The present invention relates to new N,N,N'N'-tetra-substituted-1,2 -ethanediamine compounds of the general formula (I): ##STR2## wherein X is a carbonyl (CO), hydroxymethylen (CHOH) or p-fluorophenyl-methylen (p--F--C.sub.6 H.sub.4 --CH) group and R is a benzyl group optionally substituted in p- with an halogen, or R is a 2-pyrimidinyl group with the proviso that simultaneously X may not be p-fluorophenyl-methylen (p--F--C.sub.6 H.sub.4 --CH) and R may not be an unsubstituted benzyl group, as well as their pharmaceutically acceptable additions salts.
In the compounds of the general formula (I), the halogen that optionally substitutes the benzyl group p-position is preferably fluorine. Among the pharmaceutically acceptable salts, hydrochlorides and sulfates are preferred.
The compounds of the present invention are obtained according ##STR3##
In effect, the alkylation of N,N'-dimethyl-1,2-ethanediamine with a halogenide of the general formula (II), wherein Y is chlorine or bromine and R is as defined in (I) leads to the intermediates of the general formula (III) wherein R is as defined in (I) . Applicants have found out that the use of chlorinated compounds ( II, Y=Cl) is advantageous for alkylation reactions. Thus, preferred compounds of the general formula (II) for use in this reaction include benzyl chloride, p-fluorobenzyl chloride, 2- chloropyrimidine and the like.
Subsequent alkylation of the intermediates of general formula (III) with 2-(4-fluorophenyl)-2-(3-halopropyl)-1,3-dioxolane (IVa), wherein Z is preferably chlorine, leads to the intermediates of general formula (V), 1,3-dioxolane derivatives. This reaction occurs conveniently in the presence of a base that reacts with the hydracid formed, Applicants have found out that carbonate- and acid carbonate-like mineral bases, such as potassium carbonate, are extremely appropriate for this reaction. It is also convenient the addition of a catalytic amount of potassium iodide in order to accelerate the reaction course. Usually, acetonitrile-like inert solvent is recommended as reaction medium. The reaction occurs in the presence of heat, preferably at the boiling temperature of the mixture.
Acid hydrolysis of 1,3-dioxolanes (V) provides the final compounds of general formula (I) of this invention, wherein X is carbonyl (CO) and R is defined as aforesaid. This reaction occurs conveniently in a hydroalcohol medium, which preferably includes a mixture of water and an alkanol having four carbon atoms at most, preferably ethanol. A mineral acid is selected as choice acid, such as hydrochloric acid, hydrobromic acid and the like.
The compounds (I, X=CO) obtained as described in the preceding paragraph provide by reduction the final compounds of general formula (I), wherein X is hydroxymethylen (CHOH) and R is as defined. The reduction is conveniently carried out using a hydride-like reductor such as sodium borohydride, and in an anhydrous alkanol medium such as absolute ethanol.
Unlike the final products (I) when X is a carbonyl group (CO), the final products (I) when X is p-fluorophenylmethylene (p--F--C.sub.6 H.sub.4 --CH) are obtained from the intermediates of general formula (III) by a single-step reaction. This reaction is carried out with an alkylating agent selected from a 1,1'-(4-halobutyliden)bis(4-fluorobenzene) (IVb). This alkylation is essentially similar to that performed with (IVa) and is carried out in the presence of the same coadjuvants and solvents. In (IVb), the Z halogen atom has the same nature as in (IVa).
U.S. Pat. No. 4588728 describes the treatment of psychosis with cis-9- [3- (3,5-dimethylpiperazinyl)propyl]carbazole. U.S. Pat. No. 4709094 describes the preparation of 1,3-disubstituted guanidines as well as their utility in the diagnosis and treatment of hallucinations associated with psychotic disorders and chronic mental depression. U.S. Pat. No. 4929734 describes the preparation of N-substituted 1-(1,2,3,6-tetrahydro-3-piridinyl)oximes and N-substit
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Castell o Josep M.
Foguet Rafael
Gubert Santiago
Ortiz Jos e
Sacrist an Aurelio
Ferrer Internacional S.A.
Raymond Richard L.
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