Phenylalkylaminoalcohol carbamates and process for preparing the

Details Phenylalkylaminoalcohol carbamates and process for preparing the Phenylalkylaminoalcohol carbamates and process for preparing the

1996-07-01

1999-09-21

Shippen, Michael L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

N-c doai

560163, A61K 3127

Patent

active

059554991

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of the Invention
The present invention relates, in general, to pharmaceutically novel and useful organic compounds and, more particularly, to O-carbamoylphenylalaninol compounds including their racemates and enantiomers and the pharmaceutically acceptable salts thereof, useful to treat the diseases of the central nervous system, especially for depression. Also, the present invention is concerned with a process for preparing the same.
2. Description of the Prior Art
Organic alkyl carbamates have been effectively used for controlling various central nervous system (CNS) disorders. For example, U.S. Pat. Nos. 2,884,444, 2,937,119 and 3,313,697 disclose function of carbamate in CNS disorders, especially as antiepileptic and centrally acting muscle relaxant.
Phenylethylamine derivatives, one important class of therapeutical medicines useful for managing CNS diseases, have been used mainly to treat obesity, narcolepsy, minimal brain dysfunction and mild depression.
Recent design of pharmacologically useful compounds has been based on amino acids or the derivatives thereof, which is mainly attributable to the fact that many of the compounds found in biological systems come from amino acids or the derivatives thereof. In addition, in most cases, the function of a pharmaceutically useful compound is effected after it binds to an enzyme or receptor, which may trigger the regulatory mechanisms of the enzyme or receptor.


SUMMARY OF THE INVENTION

As a result of intensive and thorough research, the present inventors found that O-carbamoyl derivatives from (D/L)-phenylalaninol, (D)-phenylalaninol and (L)-phenylalaninol are pharmaceutically useful for CNS disorders, especially for depression.
Accordingly, it is a principal object of the present invention to provide novel phenylalkylaminoalcohol carbamate compounds, represented by the following structural formulas I, II and III: ##STR2## and pharmaceutically acceptable salts thereof.
It is another object of the present invention to provide a method for preparing the O-carbamoyl derivatives from (D/L)-phenylalaninol, (D)-phenylalaninol and (L)-phenylalaninol, represented by the structural formulas I, II and III.


DETAILED DESCRIPTION OF THE INVENTION

By virtue of the basic nitrogen atom, the novel compounds of the present invention form into pharmaceutically acceptable acid addition salts with organic or inorganic acids. Concrete examples of the acids suitable for the formation of pharmaceutically acceptable salts include hydrochloric, sulfuric, phosphoric, acetic, benzoic, citric, malonic, salicylic, malic, fumaric, oxalic, succinic, tartaric, lactic, gluconic, ascorbic, maleic, aspartic, benzenesulfonic, methanesulfonic, ethanesulfonic, hydroxymethanesulfonic, and hydroxyethanesulfonic and the like. Additional acids can refer to "Pharmaceutical Salts", J. Pharm. Sci., 1977; 66(1): 1-19.
In accordance with the present invention, the compounds of Structural Formulas I, II and III are prepared as set forth in the following Reaction Schemes I, II and III, respectively. Following is of the preparation of the novel compounds in conjunction with the reaction schemes.
The compound of Structural Formula I is prepared as shown in Reaction Scheme I below.


REACTION SCHEME I
##STR3##
In Reaction Scheme I, first, phenylalaninol (IV) is converted to N-benzyloxycarbonylphenylalaninol (V) by reaction with benzyl chloroformate in a basic aqueous solution, which is subjected to carbamoylation with phosgene, followed by the ammonolysis with excess of concentrated ammonium hydroxide aqueous solation, to afford O-carbamoyl-N-benzyloxycarbonylphenylalaninol (VI). Removal of the benzyloxycarbonyl group, a nitrogen protecting group, by hydrogenolysis gives O-carbamoylphenylalaninol (I), which is, then, treated with ethereal hydrogen chloride provides O-carbamoylphenylalaninol hydrochloride salt (VII).
Details of the reaction conditions described in Reaction Scheme I is as follows. In the first step, the concentration of the starting material (IV) is b

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