Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-11-23
2001-04-24
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S253020, C544S361000
Reexamination Certificate
active
06221870
ABSTRACT:
The present invention relates to novel ergoline derivatives, their preparation, their use as pharmaceuticals and pharmaceutical compositions comprising them.
More particularly the present invention provides a compound of formula I
wherein
R
1
is hydrogen, (C
1-4
)akyl or a group of formula
wherein n is 1 to 4 and R
7
is fluorine, chlorine, hydroxy, (C
1-4
)alkyl or (C
1-4
)alkoxy,
R
2
is hydrogen, chlorine, bromine, iodine, (C
1-4
)alkyl or (C
1-4
)alkylthio,
R
3
is hydrogen or (C
1-4
)alkyl,
R
4
is (i) a group of formula
wherein R
8
is fluorine, chlorine, nitro or cyano, R
9
and R
10
independently, are hydrogen, fluorine, chlorine, nitro or cyano and R
11
is (C
1-4
)alkyl or (C
2-5
)alkenyl, or (ii) a group of formula
wherein each X independently is O or S, and
R
5
and R
6
are each hydrogen or form together a further bond between the two carbon atoms on which they are located,
provided that R
8
is not 4-NO
2
if R
1
, R
2
, R
9
and R
10
are hydrogen, R
3
is methyl and R
5
and R
6
form together a further bond between the two carbon atoms on which they are located, and that R
8
is not chlorine if R
1
, R
2
, R
9
and R
10
are hydrogen and R
3
is methyl,
in free base or acid addition salt form.
The invention includes the enantiomers as well as their mixtures, e.g. the epimeric or racemic mixtures which may be present on account of the asymrnetrical carbon atoms in positions 5, 8 and 10. The configuration [5R,10R] is preferred (5R corresponding to a 5&bgr; hydrogen). The configuration 8&bgr; is also preferred.
The above-defined alkyl, alkoxy and alkylthio groups preferably represent methyl, methoxy and methylthio.
In a further aspect, the invention provides a process for the production of the compounds of formula I and their acid addition salts, whereby a compound of formula II
wherein R
1
, R
2
, R
3
, R
5
and R
6
are as defined above and M is H or an alkali metal, is reacted with a compound of formula III
wherein R
4
is 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 amide formation methods, for example as described in Example 1. In formula II, M as an alkali metal is for example sodium.
Working up 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 from the free bases in known manner, and vice versa. Suitable acid addition salts for use in accordance with the present invention include for example the hydrochloride.
The starting compounds of formula III may be produced by reacting piperazine with a compound of formula R
4
—Cl, e.g. as described in Example 1.
The compounds of formulae II and R
4
—Cl 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 interesting pharmacological properties when tested in vitro using SRIF receptor expressing cell cultures and in animals, and are therefore useful as pharmaceuticals.
In particular the agents of the invention bind to somatostatin receptors. More particularly they are selective antagonists at Somatostatin sst
1
receptors, previously called SSTR-1 receptors (see Hoyer et al., TIPS, 1995, 16; 86-88), as determined in radioligand binding and second messenger studies [see for example K Kaupmann et al., FEBS LETTERS 1993, 331: 53-59].
The agents of the invention are therefore useful for treatment in anxiety, depression, schizophrenia, neurodegenerative diseases such as dementia, for the treatment of tumors and for vascular disorders and immunological diseases.
The usefulness of the agents of the invention in these indications is confirmed 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 behavior 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 non-social behavior, social investigation and sex, and reduce defensive ambivalence in the treated intruder mouse at doses of about 1 to about 10 mg/kg s.c., suggesting an antidepressant profile like carbamazepine and lithium, a neuroleptic profile like clozapine and an anxiolytic profile like diazepam.
Furthermore at about 3 to about 30 mg/kg p.o. the agents of the invention reduce aggressive behavior (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 behaviors in the intruder mouse test, the compounds of the invention exhibit an ethopharmacological profile which is very similar to that of carbamazepine, lithium chloride and clozapine. 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 behavioral stabilization is desired. In addition, the compounds are indicated in anxiety states, generalized anxiety as well as social and agoraphobia, as well as those behavioral states characterized by social withdrawal e.g. negative symptoms.
In addition, the agents of the invention improve the performance in the step-down passive avoidance paradigm in mice following both pre- (p.o.) and post-trial (i.p.) adrnnistration of about 0.01 to about 10 mg/kg, enhance retrieval-performance in the step-through passive avoidance test (p.o.) [Mondadori et al., Behav. Neural. Biol. 60: 62-68 (1993)] and partially counteract electroshock-induced amnesia (p.o.) [Mondadori et al., Physiol. & Behav. 18: 1103-1109 (1997)]. Finally the agents specifically enhance social recognition of familiar, but not unfamiliar juvenile rats at doses of about 0.03 to about 3 mg/kg p.o. These findings indicate that the agents facilitate learning and memory at low doses. These features combined with the marked anti-aggressive properties and sociotropic effects suggest that the agents of the invention are effective in the treatment of attention deficit and hyperactivity disorders (ADHD).
The agents of the invention are also effective in the treatment of various kinds of tumors, particularly of sst
1
receptor bearing tumors, as indicated in proliferation tests with various different cancer cell lines and in tumor growth experiments in nude mice with hormone dependent tumors [see for example: G. Weckbecker et al., Cancer Research 1994, 54: 6334-6337]. Thus the compounds are indicated in the treatment of, for example, cancers of the breast, the prostate, the colon, the pancreas, the brain and the lung (small cell lung cancer).
For all the above mentioned indications, the appropriate dosage will of course vary depending upon, for example, the compound employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.1 to about 10 mg/kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from about 5 to about 200 mg, preferably about 10 to about 100 mg of the compound conveniently administered in divided doses up to 4 times a day or in sustained release form.
The agent
Neumann Peter
Pfaeffli Paul
Stutz Peter
Swoboda Robert
Borovian Joseph J.
Novartis AG
Schroeder Ben
Shah Mukund J.
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