Substituted [2-(1-piperazinyl)ethoxy]methyl compounds

Details Substituted [2-(1-piperazinyl)ethoxy]methyl compounds Substituted [2-(1-piperazinyl)ethoxy]methyl compounds

1998-10-09

2000-10-31

Ford, John M.

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

544389, 544391, 544398, 544399, 544400, C07D295104, C07D295185

Patent

active

061405019

DESCRIPTION:

BRIEF SUMMARY
DESCRIPTION

The present invention relates to novel compounds, substituted [2-(1-piperazinyl)ethoxy]methyl compounds of formula ##STR2## in which R.sub.1 represents a --CONH.sub.2, --CN, --COOH, --COOM or --COOR.sub.3 group, M being an alkali metal and R.sub.3 being an alkyl radical having from 1 to 4 carbon atoms; and where R.sub.4 is chosen from the groups --OR.sub.6 or --R.sub.7, in which carbon atoms, a haloalkyl, alkylaryl, alkylnitroaryl or alkylhaloaryl radical, and the preparation of compounds of formula ##STR3## in which R.sub.1 has the same meaning as in formula I and X.sub.1 and X.sub.2 independently represent a hydrogen, fluorine, chlorine or bromine atom. In the case where R.sub.1 represents a --COOH group and where X.sub.1 represents a chlorine atom in position 4 and X.sub.2 represents a hydrogen atom, the compound of formula II is 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid of formula ##STR4##
In the case where R.sub.1 represents a --CONH.sub.2, --CN, --COOM or --COOR.sub.3 group, M being an alkali metal and R.sub.3 being an alkyl radical having from 1 to 4 carbon atoms and where X.sub.1 represents a chlorine atom in position 4 and X.sub.2 a hydrogen atom, the compounds of formula II are valuable intermediates for the preparation of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid of formula III; as well as pharmaceutically acceptable salts thereof. 2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid dihydrochloride, a product which is also known under the common international name of cetirizine, is described in U.S. Pat. No. 4,525,358 and has been introduced as a medicament for the treatment of allergic syndromes, for instance chronic and acute allergic rhinitis, allergic conjunctivitis, pruritus, urticaria, etc. In its therapeutic application, this product proved to be remarkably free of side effects on the central nervous system, such as drowsiness, attenuated mental performance, etc. (cfr. D. P. TASHKIN et al., Annals of Allergy, Part II, 59, (1987), 49-52, as well as F. M. GENGO et al., Annals of Allergy, Part II, 59, (1987), 53-57).
In the case where R.sub.1 represents a --COOH group and where X.sub.1 and X.sub.2 each represent a fluorine atom in position 4, the compound of formula II is 2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic acid of formula ##STR5##
In the case where R.sub.1 represents a --CONH.sub.2, --CN, --COOM or --COOR.sub.3 group, M being an alkali metal and R.sub.3 being an alkyl radical having from 1 to 4 carbon atoms and where X.sub.1 and X.sub.2 each represent a fluorine atom in position 4, the compounds of formula II are valuable intermediates for the preparation of 2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic acid of formula IV as well as pharmaceutically acceptable salts.
2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic acid dihydrochloride is also known under the common international name of efletirizine. The use of efletirizine for the treatment of rhinitis or rhino-conjunctivitis of allergic origin has been suggested in several recent communications (51.sup.st Annual Meeting or American Academy of Allergy and Immunology, reproduced in J. Allergy Clin. Immunol., 95/1 (1995), part 2, Abstract 229 and XV.sup.th Congress of Allergology and Clinical Immunology, reproduced in Allergy & Clin. Immunol. News, (1994) suppl. No. 2, abstracts 428, 1136, 1496, and 1864). These communications indicate that the intranasal administration of efletirizine might provide an effective therapeutic treatment of rhinitis or rhino-conjunctivitis or allergic origin. U.S. Pat. No. 4,525,358, in the name of the Applicant, describes the synthesis of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid and its dihydrochloride. In this synthesis, the starting material is 1-[(4-chlorophenyl)phenylmethyl]piperazine, which may be reacted with methyl (2-chloroethoxy)acetate or 2-(2-chloroethoxy)acetamide to form respectively methyl 2-[2-[4-[(4-chlorophenyl)

REFERENCES:
patent: 4525358 (1985-06-01), Baltes et al.

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