Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Utility Patent
1999-06-28
2001-01-02
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S517000, C514S524000, C514S603000, C514S619000, C514S654000, C514S655000, C558S048000, C558S418000, C558S420000, C564S086000, C564S164000, C564S167000, C564S374000, C564S391000, C564S428000
Utility Patent
active
06169116
ABSTRACT:
The present invention relates to novel amino-tetralines (tetrahydro-naphthalenamines), their preparation, their use as pharmaceuticals and pharmaceutical compositions containing them.
In accordance with the invention, there are provided, in a first aspect, 1,2,3,4-tetrahydro-2-naphthalenamines bearing a phenyl substituent on the aromatic ring and acid addition salt thereof.
The phenyl substituent is preferably in position 5 of the 2-naphthalenamine.
The phenyl substituent may bear further substituents, for example as in the case of formula I below.
Further substituents may also be present conveniently but not exclusively on the aromatic ring, e.g. in position 8 of the 2-naphthalenamine when the phenyl group is in position 5.
More particularly the present invention provides a compound of formula I
wherein
R
1
and R
2
, independently, are hydrogen, (C
1-4
)alkyl, (C
1-4
)alkoxy, (C
1-4
)alkylthio, halogen, trifluoromethyl, trifluoromethoxy, cyano, (C
2-5
)alkanoyl, (C
1-4
)alkylsulfonyl or sulfamoyl,
R
3
is hydrogen, hydroxy, (C
1-4
)alkyl, (C
1-4
)alkoxy, halogen, cyano, (C
2-5
)alkanoyl, carbamoyl, (C
1-4
)alkylsulfonyloxy or trifluoromethylsulfonyloxy, and
R
4
and R
5
, independently, are hydrogen, (C
1-4
)alkyl, hydroxy(C
2-4
)alkyl or phenyl(C
1-4
)alkyl, or form together with the nitrogen atom to which they are attached a pyrrolidinyl, piperidino or piperazinyl group,
in free base or acid addition salt form.
Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
Any alkyl, alkoxy and alkylthio radicals preferably are straight chain radicals. They preferably have 1 to 3 carbon atoms, more preferably they are methyl, methoxy and methylthio groups.
The following significances and their combinations are preferred:
R
1
and R
2
, independently, are hydrogen, (C
1-4
)alkyl, (C
1-4
)alkoxy, halogen or trifluoromethyl,
R
3
is hydrogen, hydroxy, (C
1-4
)alkoxy, cyano or carbamoyl,
R
4
and R
5
, independently, are hydrogen or (C
1-4
)alkyl, or form together with the nitrogen to which they are attached a piperidino group.
In a particular group of compounds of formula I, R
1
and R
2
, independently, are hydrogen, (C
1-4
)alkyl, (C
1-4
)alkoxy, (C
1-4
)alkylthio, halogen, trifluoromethyl, cyano or (C
2-5
)alkanoyl, R
3
is as defined on line 5 and 6 and R
4
and R
5
, independently, are hydrogen, (C
1-4
)alkyl or phenyl(C
1-4
)alkyl, or form together with the nitrogen atom to which they are attached a pyrrolidinyl, piperidino or piperazinyl group.
The compounds of the invention possess an asymmetrical carbon atom in position 2. They may therefore appear in optically active form or in form of mixtures of optical isomers, e.g. in form of racemic mixtures. All optical isomers and their mixtures including the racemic mixtures are part of the present invention.
When a compound of the invention is in optically active form, the R configuration is preferred.
In a further aspect, the invention provides a process for the production of the compounds of the invention, whereby a 1,2,3,4-tetrahydro-2-naphthalenamine bearing a halogen on the aromatic ring is reacted with optionally substituted phenylboronic acid and the resulting compound is recovered in free base form or in acid addition salt form.
More particularly the invention provides a process for the production of the compounds of the invention, whereby a compound of formula II
wherein R
3
, R
4
and R
5
are as defined above and Hal is halogen, is reacted with a compound of formula III
wherein R
1
and R
2
are as defined above, and the resulting compound is recovered in free base form or in acid addition salt form.
The reaction may be effected in known manner, preferably by transition metal-catalyzed aryl-aryl coupling, e.g. as described in Example 1. Hal is preferably bromine or iodine, particularly bromine.
Working up of the reaction mixtures obtained according to the above process and purification of the compounds thus obtained may be carried out in accordance to known procedures.
Acid addition salts may be produced in known manner from the free base forms and vice-versa. Suitable pharmaceutically acceptable acid addition salts for use in accordance with the present invention include for example the hydrochloride, the hydrogen maleate, the hydrogen fumarate and the hydrogen malonate.
Racemic compounds of the invention may be obtained from racemic starting materials. Optically active isomers may be obtained form optically active starting materials or from the racemate. The enantiomers may be obtained from the racemate by known methods, for example by fractional crystallization of diastereoisomeric salts, e.g. their salts with (+)-di-O,O′-p-toluoyl-D-tartaric acid or (−)-di-O,O′-p-toluoyl-L-tartaric acid.
The starting materials of formula II may be produced by halogenating compounds of formula IV
wherein R
3
, R
4
and R
5
are as defined above, in accordance to known procedures, e.g. as described in Example 1.
The starting materials of formulae III and IV are known or may be produced in analogous manner to known procedures.
Compounds of the invention, e.g. compounds of formula I and their pharmaceutically acceptable acid addition salts, hereinafter referred to as agents of the invention, exhibit pharmacological activity and are, therefore, useful as pharmaceuticals.
The agents of the invention provide long-lasting protection against maximal electroshock-induced convulsions in mice at doses of about 1 to 100 mg/kg p.o. and about 0.32 to 32 mg/kg i.p. [cf. E. A. Swinyard, J. Am. Pharm. Assoc. Scient. Ed. 38, 201 (1949) and J. Pharmacol. Exptl. Therap. 106, 319 (1952)].
The agents of the invention are therefore useful in the treatment of epilepsy and other convulsive states such as high pressure neurological syndrome.
Furthermore, the agents of the invention reduce ischemia-induced neuronal damage and ensuing symptoms in the middle cerebral artery (MCA) occlusion model in rats at a dosage of 1-30 mg/kg i.p, i.v. and p.o. [cf. A. Tamura et al., J. Cereb. Blood Flow Metabol. 1, 53-60 (1981)), A. Sauter, M. Rudin, Stroke 17, 1228-1234 (1986)].
The agents of the invention are therefore useful in the treatment of any clinical condition involving a component of cerebral anoxia, hypoxia and/or ischemia, e.g. ischemic damage to grey and white matter, stroke, subarachnoid hemorrhage, brain and spinal cord injury/trauma, high intracranial pressure, mult-infarct dementia or vascular dementia, and any surgical procedure potentially associated with cerebral anoxia, hypoxia and/or ischemia (e.g. cardiac bypass, operations on extracerebral vessels).
The agents of the invention display binding to the veratridine-sensitive sodium channel with IC
50
S of from about 0.1 to about 100 &mgr;M. For the binding procedure see for example J. B. Brown, Journal of Neuroscience 6, 2064-2070 (1986). They block veratridine-induced glutamate release in rat hippocampal slice preparations at concentrations of about 0.1-1 &mgr;M.
The experiment is performed according to a modification of M. J. Leach et al. in Epilepsia 27, 490-497 (1986) and Stroke 24, 1063-1067 (1993), using exogenous glutamate.
As a result, the agents of the invention are indicated for the treatment of any pathology, disorder or clinical condition involving glutamate release in their etiology, including psychiatric disorders (such as schizophrenia, depression, anxiety, panic attacks, attention deficit and cognitive disorders, social withdrawal), hormonal conditions (excess GH [e.g. in the treatment of diabetes mellitus, angiopathy and acromegaly] or LH [prostate hypertrophy, menopausal syndrome] secretion, corticosterone secretion in stress), metabolic induced brain damage (hypolycemia, non-ketotic hyperglycinaemia [glycine encephalopathy], sulphite oxidase deficiency, hepatic encephalopathy associated with liver failure), emesis, spasticity, tinnitus, pain (e.g. cancer pain, arthritis) and drug (ethanol, opiates [including synthetics with opiate-like effects, e.g. pethidine, methadone etc.&rs
Borovian Joseph J.
Novartis AG
Raymond Richard L.
LandOfFree
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