Compounds

Details Compounds Compounds

1998-05-21

2000-12-26

Seaman, D. Margaret

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

546145, A61K 3147, C07D21726, C07D21700

Patent

active

061660302

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

This invention relates to new amidine derivatives, processes for their preparation, compositions containing them and their use in therapy.


BACKGROUND OF THE INVENTION

Nitric oxide is produced in mammalian cells from L-arginine by the action of specific nitric oxide synthases (NOSs). These enzymes fall into two distinct classes--constitutive NOS (cNOS) and inducible NOS (iNOS). At the present time, two constitutive NOSs and one inducible NOS have been identified. Of the constitutive NOSs, an endothelial enzyme (ecNOS) is involved with smooth muscle relaxation and the regulation of blood pressure and blood flow, whereas the neuronal enzyme (ncNOS) serves as a neurotransmitter and appears to be involved in the regulation of various biological functions such as cerebral ischaemia. Inducible NOS has been implicated in the pathogenesis of inflammatory diseases. Specific regulation of these enzymes should therefore offer considerable potential in the treatment of a wide variety of disease states.
Compounds of various structures have been described as inhibitors of NOS and their use in therapy has been claimed. See, for example, WO 95/09619 (The Wellcome Foundation) and WO 95/11231 (G. D. Searle). The applicant has previously disclosed in WO 95/05363 and WO 96/01817 amidine derivatives which are NOS inhibitors which display some selectivity for inhibition of the neuronal enzyme, ncNOS.
We now disclose a group of amidines that are within the generic scope of WO 96/01817, but which are not specifically exemplified in WO 96/01817. These compounds display surprisingly advantageous properties and are the subject of the present application.


DISCLOSURE OF THE INVENTION

According to the invention we provide a compound of formula (I) ##STR2## wherein: R.sup.1 represents a 2-thienyl or 3-thienyl ring; salts thereof.
Preferably R.sup.1 represents 2-thienyl.
Particularly preferred compounds of the invention include: de;
A more especially preferred compound of the invention is:
Unless otherwise indicated, the term "C 1 to 4 alkyl" referred to herein denotes a straight or branched chain alkyl group having from 1 to 4 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl.
The present invention includes compounds of formula (I) in the form of salts, in particular acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable although salts of non-pharmaceutically acceptable acids may be of utility in the preparation and purification of the compound in question. Thus, preferred salts include those formed from hydrochloric, hydrobromic, sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.
According to the invention, we further provide a process for the preparation of compounds of formula (I), and optical isomers and racemates thereof and pharmaceutically acceptable salts thereof, which comprises: compound of formula (II) ##STR3## wherein R.sup.2 is as defined above, with a compound of formula (III) or an acid addition salt thereof ##STR4## wherein R.sup.1 is as defined above and L is a leaving group; (b) preparing a compound of formula (I) by reacting a corresponding compound of formula (IV) ##STR5## wherein R.sup.2 is as defined above and HA is an acid, with a compound of formula (V) ##STR6## wherein R.sup.1 is as defined above; (c) preparing a compound of formula (I) by reacting a compound of formula (VI) ##STR7## wherein R.sup.1 is as defined above, with a compound of formula (VII) by reacting a compound of formula (VI) with formaldehyde and formic acid;
and where desired or necessary converting the resultant compound of formula (I), or another salt thereof, into a pharmaceutically acceptable salt thereof, or vice versa, and where desired converting the resultant compound of formula (I) into an optical isomer thereof.
In process (a), the reaction will take pla

REFERENCES:
Chemical Abstracts 124:289248, MacDonald, 1996.
Chemical Abstracts 126:238314, MacDonald, 1997.
CA 126:238314, MacDonald, 1997.
CA 124:289248, MacDonald, 1996.

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