Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-09-18
2003-10-21
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S253040, C514S253050, C544S254000, C544S263000, C544S281000, C544S362000, C544S363000
Reexamination Certificate
active
06635647
ABSTRACT:
The present invention relates to novel decahydro-isoquinoline derivatives, their preparation, their use as pharmaceuticals and pharmaceutical compositions containing them.
More particularly the invention provides a compound of formula I
wherein R is hydrogen or (C
1-4
)alkyl and A and B, independently, are groups of formula (a), (b), (c), (d) or (e)
wherein
X, X
1
and X
2
, independently, are —CR
1
═ or —N=
Y is —O—, —S—, —CH═CH— or —NH—
R
1
and R′
1
, independently, are hydrogen, (C
1-4
)alkyl or (C
1-4
)alkoxy,
R
2
is hydrogen, (C
1-4
)alkyl, (C
1-4
)alkoxy, (C
1-4
)alkoxycarbonyl or halogen, and
R
3
and R
4
, independently, are hydrogen, nitro, cyano, trifluoromethyl, (C
1-4
)alkyl, (C
1-4
) alkoxy, (C
1-4
)alkoxycarbonyl or (C
1-4
)alkanoyl,
in free base or acid addition salt form.
On account of the asymmetrical carbon atoms which are present in the compounds of formula I and their salts, the compounds may 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.
Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine. The above-defined alkyl and alkoxy groups preferably represent methyl and methoxy.
In a further aspect, the invention provides a process for the production of the compounds of formula I and their salts, whereby a compound of formula II
wherein B is as defined above, is reacted with a compound of formula III
wherein A and R are as defined above, and the compounds of formula I thus obtained are recovered in free base or acid addition salt form.
The reaction can be effected according to known amine formation methods.
Working up the reaction mixtures 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 from the free bases in known manner and vice-versa
The compounds of formula II may be produced from known compounds using conventional procedures, for example by amidation of a compound of formula IV
wherein B is as defined above, with tert.-butoxycarbonyl-octahydro-isoquinoline-4-carboxylic acid, which can be prepared from isoquinoline-4-carboxylic acid ethyl ester, e.g. as described in Example 1, steps b) to e).
The compounds of formula III may be produced in conventional manner from compounds of formula V
wherein A and R are as defined above, e.g. as described in Example 1, steps h) and i).
The compounds of formula V may be produced in conventional manner, e.g. from compounds of formulae VI and VII
wherein A and R are as defined above, as described in Example 1, steps f) and g) or from compounds of formulae VIII and IX
wherein A and R are as defined above. A resulting compound of formula V may be converted into another compound of formula V e.g. as described in Example 1, step h).
The starting compounds of formulae IV, VI and VII are known or may be produced in analogous manner to known compounds.
Compounds of formula I and their pharmaceutically acceptable acid addition salts, hereinafter referred to as agents of the invention, exhibit valuable pharmacological properties when tested in vitro using somatostatin (somatotropin release inhibiting factor, SRIF) receptor expressing cell cultures and in animals, and are therefore useful as pharmaceuticals.
In particular the agents of the invention show high affinity to somatostatin receptors. More particularly they are selective antagonists at Somatostatin sst
3
receptors, previously called SSTR-3 receptors (see Hoyer et al., TIPS, 1995, 16; 86-88), as determined in radioligand binding and second messenger studies [see for example K. Kaupmain et al., FEBS LETTERS 1993, 331: 53-59, S. Siehler et al. Naunyn Schmiedeberg's Arch Pharmacol, 1999, 360: 488-499] where they exhibit selective affinity for sst
3
receptors with pKd values between about 7.5 and 9.0.
The agents of the invention are therefore useful for treatment in anxiety, depression, social phobia, panic disorders, post traumatic stress disorders, ADHD (attention deficit and hyperactivity disorders), bipolar disorders, schizophrenia, including negative symptoms, neurodegenerative diseases such as learning/memory disorders, dementia, age associated memory impairment, SDAT, for the treatment of tumours and for vascular disorders and immunological diseases, as confirm in a range of standard tests as indicated below:
At doses of about 0.3 to 3 mg/kg p.o., the agents of the invention increase exploratory behaviour of mice in the open half of the half enclosed platform, a model which is predictable for anxiolytic activity (Psychopharmacology, 1986, 89:31-37).
In the same half enclosed platform model, the agents of the invention at the above indicated doses also increase vigilance of the mice. The compounds are therefore indicated for the treatment of depression, schizophrenia and dementia, in particular of senile dementia of the Alzheimer type (SDAT).
In the intruder mouse test [Triangle, 1982, 21: 95-105; J. Clin. Psychiatry, 1994, 55:9 (suppl. B) 4-7], the agents of the invention increase social investigation and reduce defensive ambivalence in the treated intruder mouse at doses of about 1 to about 10 mg/kg s.c., suggesting an antimanic profile like carbamazepine and lithium, a neuroleptic profile like clozapine and an anxiolytic profile like diazepam.
In the stress-induced hyperthermia- and the elevated plus-maze paradigm in mice [Lecci et al., Psychopharmacology 101:255-261 (1990) and Rodgers R. J. Behav. Pharmacol. 8: 477-496 (1998), respectively] the agents of the invention reduced the increase in body-temperature and increased the time spent on the open arms, respectively. They are therefore indicated for the treatment of anxiety disorders and panic disorders.
Futhermore at said doses the agents of the invention (given acutely) increase aggressive behaviour (attacks, chases, bites) in the Matched Pairs Situation test in mice [Dixon et al., J. Clin. Psychiatry 55: (9) [Suppl. B] 4-7 (1994)]. Since as mentioned above they additionally attenuate defensive behaviours in the intruder mouse test, the agents of the invention exhibit an ethopharmacological profile which is very similar to that of clozapine and to some extent to that of antimanic agents (Lithium, carbamazepine, valproate). They are therefore indicated for the treatment of affective disorders including bipolar disorders e.g. manic-depressive psychoses, extreme psychotic states e.g. mania, schizophrenia, and excessive mood swings where behavioural stabilisation is desired. In addition, the compounds are indicated in anxiety states, generalised anxiety as well as social stress and agoraphobia, as well as those behavioural states characterised by social withdrawal e.g. negative symptoms [Dixon AK Brit.J.Med.Psychol. 71:,417-445, Dixon AK Fisch HU Neuroscience and Biobehavioural Reviews. 23 (1990) 345-358] and post traumatic stress disorders.
Moreover when given at doses of about 0.03 to 3 mg/kg p.o. to rodents, the agents of the invention counteract electroshock-induced amnesia, increase retention performance in a passive avoidance paradigm (Mondadori et. al., Pharmacology Communications 1992, 2: 93-97) and improve social recoin (Mondadori et al., Behavioural Brain Research 1996, 77: 227-229). The compounds are therefore indicated for the tent of cognitive disturbances and learning/memory disorders.
The positive effects on memory acquisition/retention combined with the sociotropic components displayed by the agents of the invention, suggest that these will prove useful in the treatment of ADHD and various types of dementias, including Alzheimer's disease.
The agents of the invention are also effective in the treatment of various kinds of tumours, particularly of sst
3
receptor bearing tumours, as indicated in proliferation tests with various different cancer cell lines and in tumour growth experiments in n
Bernhardt Emily
Borovian Joseph J.
Novartis AG
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