Tachykinin antagonists

Details Tachykinin antagonists Tachykinin antagonists

1999-07-14

2000-08-22

Shah, Mukund J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

5142305, 514260, 514367, 514375, 514395, 544 50, 544 90, 544 92, 544287, 544292, 548162, 548222, 5483061, 548538, A61K 31517, A61K 31536, A61K 315415, C07D40304, C07D41304

Patent

active

061072931

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to novel compounds having tachykinin antagonist activity, processes for their production, pharmaceutical compositions comprising them and their use as pharmaceuticals.
More particularly the present invention provides a compound of formula I ##STR2## wherein X is --CH.sub.2 --, --CO-- or a direct linkage,
In formula I, the following significances are preferred, individually or in any combination or sub-combination:
Compounds of formula I in which X is --CH.sub.2 -- or --CO-- and Y is --NH-- exist in tautomeric form, e.g. comprising the structures ##STR3##
The present invention is to be understood as including such tautomeric forms and formula I, as well as the formulae for corresponding intermediates as hereinafter described, are accordingly to be understood as embracing both the structures A and B.
Compounds of formula I exist in free form and in acid addition salt form. The present invention is to be understood as including both free compounds of formula I and their acid addition salts. Suitable pharmaceutically acceptable acid addition salts for use in accordance with the present invention include e.g. hydrochloride salts.
Compounds of the invention comprise two asymmetric carbon atoms [marked (a) and (b) in formula I]. The compounds accordingly exhibit optical isomerism. Individual isomers may be obtained in conventional manner, e.g. by synthesis using optically active starting materials or by separation of initially obtained isomeric mixtures, for example employing chromatographic techniques using a chiral support or by recrystallisation of diastereomeric salt forms. The present invention is to be understood as embracing both individual isomers of compounds of formula I in pure or substantially pure form as well as mixtures, e.g. racemic and diastereomeric mixtures thereof unless otherwise specified.
In formula I each of the carbon atoms (a) and (b) suitably has the (S)-configuration. More suitably both carbon atoms (a) and (b) have the (S)-configuration. Accordingly, in a preferred aspect the present invention provides a compound of formula I as hereinbefore defined wherein the carbon atoms (a) and (b) both have the (S)-configuration in pure or substantially pure form, e.g. comprising less than 10%, more preferably less than 5%, e.g. less than 2% of other isomeric forms.
The present invention further provides a process for the production of a compound of formula I as hereinbefore defined or acid addition salt thereof, which process comprises ##STR4## wherein R.sub.1, R.sub.2 and R.sub.3 have the meanings given for formula I with a compound of formula III ##STR5## wherein X and Y have the meanings given for formula I and Z' is a leaving group; is --O-- or --S--, reacting a compound of the formula II as defined above with a compound of formula IV ##STR6## wherein Z" is a leaving group and Y' is --O-- or --S--; or c) for the production of a compound of formula I wherein X is --CO-- and Y is --NH--, treating a compound of formula V ##STR7## wherein R.sub.1, R.sub.2 and R.sub.3 have the meanings given for formula I with an alkyl halide; addition salt form.
Suitable leaving groups as Z' for process step a) are halogen or, when X is --CH.sub.2 -- also --NCN. Process step (a) may be carried out in accordance with standard procedures, e.g., when Z' is halogen in the presence of an acid binding agent, e.g. organic base such as triethylamine, in an inert organic solvent at elevated temperature. Suitably, when Z' is halogen this is chlorine. Suitable solvent media include, for example, isopropyl acetate (e.g. when X is --CO--) dioxane (e.g. when X is a direct bond and Y=--O-- or --S--), xylene (e.g. when X is a direct bond and Y=--NH--), or isopropanol (e.g. when X is --CH.sub.2 --), with reaction at temperatures of e.g. from 50.degree. to 80.degree. C. up to reflux.
In one variant according to process step (a), X is --CO-- and Y is --NH--. In accordance with this variant Z' may be halogen, e.g. chlorine. Also R.sub.2 may be hydrogen and R.sub.3 may be methyl. A procedure for carryin

REFERENCES:
Krantz et al., J. Med. Chem. 1990, 33, pp. 464-479.

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