Amidine derivatives as inhibitors of nitric oxide synthase

Details Amidine derivatives as inhibitors of nitric oxide synthase Amidine derivatives as inhibitors of nitric oxide synthase

1998-05-21

2002-12-03

Coleman, Brenda (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S552000

Reexamination Certificate

active

06489322

ABSTRACT:

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)
wherein:
R
1
represents a 2-thienyl or 3-thienyl ring;
and R2 represents hydrogen or C 1 to 4 alkyl;
and optical isomers and racemates thereof and pharmaceutically acceptable salts thereof.
Preferably R
1
represents 2-thienyl.
Preferably R
2
represents hydrogen, methyl or 2-propyl.
Particularly preferred compounds of the invention include:
N-(4-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-2-thiophenecarboximidamide;
N-(4-ethyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl))-2-thiophenecarboximidamide;
N-(4-propyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-2-thiophenecarboximidamide;
N-(4-isopropyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-2-thiophenecarboximidamide;
N-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-2-thiophenecarboximidamide;
N-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-3-thiophenecarboximidamide;
N-(4-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-3-thiophenecarboximidamide; and pharmaceutically acceptable salts thereof.
More especially preferred compounds of the invention include:
N-(4-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-2-thiophenecarboximidamide;
N-(4-isopropyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-2-thiophenecarboximidamide;
N-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-2-thiophenecarboximidamide; and pharmaceutically acceptable salts thereof.
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:
(a) preparing a compound of formula (I) by reacting a corresponding compound of formula (II)
wherein R
2
is as defined above,
with a compound of formula (III) or an acid addition salt thereof
wherein R
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)
wherein R
2
is as defined above and HA is an acid,
with a compound of formula (V)
R
1
—≡N  (V)
wherein R
1
is as defined above;
(c) preparing a compound of formula (I) in which R2 represents C 1 to 4 alkyl by reacting a corresponding compound of formula (I) in which R
2
represents hydrogen with a compound of formula (VI)
R
3
—L  (VI)
wherein R
3
represents C 1 to 4 alkyl and L is a leaving group; or
(d) preparing a compound of formula (I) in which R
2
represents methyl by reacting a corresponding compound of formula (I) in which R
2
represents hydrogen 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 place on stirring a mixture of the reactants in a suitable solvent, for example, N-methyl-2-pyrrolidinone or a lower alkanol such as ethanol, isopropanol or tertiary butanol, at a temperature between room temperature and the reflux temperature of the solvent. The reaction time will depend inter alia on the solvent and the nature of the leaving group, and may be up to 48 hours; however it will typically be from 1 to 24 hours. Suitable leaving groups that L may represent include thioalkyl, sulphonyl, trifluoromethyl sulphonyl, halide, alkyl alcohols, aryl alcohols and tosyl groups; others are recited in ‘Advanced Organic Chemistry’, J. March (1 985) 3rd Edition, on page 315 and are well known in the art.
In process (b), the reaction is preferably performed by refluxing a mixture of the two compounds for several hours in the presence of a suitable solvent whereby the reaction temperature is high enough so that condensation takes place readily, but not sufficiently high to decompose the amidine formed. The reaction temperature can vary from room temperature to about 250° C., although it is preferable to perform the reaction at temperatures from about 100° C. to 200 ° C. We find that o-dichlorobenzene is a particularly suitable solvent. We also find that it is often useful to add 4-dimethylaminopyridine as a catalyst. On cooling, two layers form, the solvent may be decanted, and the reaction worked up by addition of aqueous base. Alternatively, where the reactants are soluble in the solvent, the solvent may be evaporated off under vacuum and the reaction mixture worked up by addition of water. The acid HA may be an organic or inorganic acid, for instance, hydrochloric, hydrobromic, hydroiodic, sulphuric, nitric, phosphoric, acetic, lactic, succinic, fumaric, malic, maleic, tartaric, citric, benzoic or methanesulphonic acid. We prefer that HA is a hydrohalic acid.
In process (c) the reaction will take place under standard conditions, for example by reacting the two compounds in an inert solvent such as DMF under basic conditions at a suitable temperature, typically room temperature, for a period of up to 72 hours or until the reaction is complete. We have frequently found it desirable to treat the amine with NaH before reacting with the compound of formula (VI). Suitable leaving groups L are mentioned above. We prefer that L represents halide, particularly bromide.
In process (d), the reaction will typically take place on refluxing the reaction mixture for up to 4 hours or until reaction is complete.
Salts of compounds of formula (I) may be formed by reacting the free base or a salt, enantiomer, tautomer or protected derivative thereof, with one or more equivalen

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