Adamantane derivative, process for producing the same, and use t

Details Adamantane derivative, process for producing the same, and use t Adamantane derivative, process for producing the same, and use t

1996-10-08

1997-07-22

Haley, Jacqueline

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514216, 514295, 540593, 546 97, A61K 3155, C07D22314, C07D295096

Patent

active

056504063

DESCRIPTION:

BRIEF SUMMARY
This is a national stage application of PCT/JP5/00740 filed Apr. 17, 1995 and published as WO95/28390.


FIELD OF THE INVENTION

The present invention relates to an adamantane derivative having antischizophrenic action, process for producing the same, and pharmaceutical use thereof.


PRIOR ARTS

A .sigma.-receptor has been defined as one of the opioid receptor including with .mu.-, .delta.- and .kappa.-receptor. At present, the .sigma.-receptor is classified not as opiate but as an independent receptor because an opioid antagonist haloxon has no affinity to .sigma.-receptor.
Psychotomimetic drug phencyclidine has affinities for .sigma.-receptor other than N-methyl-D-aspartic acid (NMDA) receptor, and antipsychotic drug haloperidol has been known to bind strongly with .sigma.-receptor other than dopamine receptor. Therefore, .sigma.-receptor may participate psychic function.
Recently, antischizophrenic drugs with less side effects such as limcazol (Japan. Pat. Unexam. Publ. No. 55-64585) and BMY-14802 (British Patent 2155925) have been developed, and these have been confirmed to show affinity to .sigma.-receptor.
U.S. Pat. No. 4,557,865 discloses a compound of the formula ##STR2##
U.S. Pat. No. 3,328,390 also discloses a compound of the formula ##STR3##
In the above prior arts, neither descriptions on affinities for .sigma.-receptor nor suppression of apomorphine induced climbing model were disclosed.


PROBLEMS TO BE SOLVED BY THE INVENTION

Development of new type of antischizophrenic drugs having different mechanism of action of the known dopamine antagonists has been required.
In the course of screening pharmacological activities of novel synthesized compound, we have found that adamantane derivative of the following general formula (1) has high affinity on .sigma.-receptor without indicating affinities on neurotransmission receptors such as dopamine (D.sub.1 and D.sub.2 ) receptors and serotonin (5-HT.sub.1 and 5-HT.sub.2) receptors, and shows effectiveness for suppressire action of apomorphine induced climbing which was applied for evaluation of antischizophrenic durg. The present invention has been completed upon the above findings.
An object of the present invention is to provide a compound of the formula ##STR4## wherein heterocycling group B is 8-azabicyclo[3.2.2] nonane-3-yl or 4-azatricyclo[4.3.1.1.sup.3.8 ]undecane-4-yl, and R is hydrogen, lower alkyl, lower alkoxy, hydroxy or halogen. [hereinafter sometimes designates as the compound (1)] or nontoxic salt thereof.
Another object of the present invention is to provide a process for producing the compound of the above formula (1) or nontoxic salt thereof comprising reducing a carbony of the formula ##STR5## wherein heterocyclic group B and R have the same meanings hereinbefore.
Further object of the present invention is to provide a medicament for treatment of schizophrenia containing the compound of the formula (1) hereinbefore or nontoxic salt thereof as an active ingredient.
Examples of a group R defined in the formula (1) hereinbefore are hydrogen, lower alkyl, lower alkoxy, hydroxy or halogen. The above substituents may be substituted in any position of carbon atom in adamantane ring. Lower alkyl means alkyl of C.sub.1-4 which may have branched chain, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Lower alkoxy means alkoxy of C.sub.1-4 which may have branched chain, for example, methoxy, ethoxy, propoxy, is opropoxy, butoxy. isobutoxy, sec-butoxy and tert-butoxy. Halogen means chlorine, bromine, fluorine, etc.
Binding position of adamantyl and a group --CH.sub.2 CH.sub.2 --in the formula (1) can be at any position of carbon in the said ring. In case that R is a substituent group other than hydrogen, a stereoisomer will exist depending upon the position of the substituent. In the present invention, not only a mixture of stereoisomer but also a stereoisomer separated by known method is included.
Examples of the compound (1) of the present invention are as follows.
2 -(2-adamantyl) ethyl derivative o

REFERENCES:
patent: 3328390 (1967-06-01), Grogan
patent: 3560481 (1971-02-01), Berezin
patent: 4379160 (1983-04-01), Harfenist et al.
patent: 4557865 (1985-12-01), Georgiev et al.
V. Georgiev et al., "New Substituted 4-Azatricyclo[4.3.1.1.sup.3.8 ] undecane Derivatives", Jul.-Aug. 1986, vol. 23, pp. 1023-1025.
C. Grogan, "w-Azabicyclic Butyrophenones", Jul. 1967, vol. 10, pp. 621-623.
E. Novoselov et al., "Synthesis and reactions of oxaziridines. Adamantane-2-spiro-3'-oxaziridine and its N-alkyl derivatives", Zh. Org. Khim, 1985, vol. 21, No. 1, pp. 107-113.
Chemical Abstracts vol. 122, 1995, abstract No. 213953n.

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