Spiro-Azabicyclic Compounds useful in therapy

Details Spiro-Azabicyclic Compounds useful in therapy Spiro-Azabicyclic Compounds useful in therapy

1995-09-18

1999-05-11

Berch, Mark L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

546 18, 546137, 548216, 548512, 514375, C07D498/20;453/02

Patent

active

059028149

DESCRIPTION:

BRIEF SUMMARY
This invention relates to novel compounds, processes for preparing them, compositions containing them and their use in therapy.
Spiro-azabicyclic compounds are known to have therapeutic activity in a range of disorders of the central nervous system. Taiwan Patent Application 201312, European Patent Application 452101 (both of Israel Institute of Biological Research), International Patent Application WO 95/03303 (Israel Institute of Biological Research; published after the earliest priority date of this application) and European Patent Application 350118 (Merck Sharpe and Dohme) disclose azabicyclic compounds including azabicyclo(2.2.2) octane and/or azabicyclo(2.2.1)heptane derivatives spiro-connected to 5-membered rings which have muscarinic agonist activity and which are indicated for the treatment of diseases caused by deficiency in central cholinergic function. European Patent Application 337547 (Merck, Sharpe and Dohme) discloses azabicyclic compounds spiro-connected to 5-membered rings which are antagonists of 5-HT.sub.3 receptors and which are indicated for the treatment of inter alia schizophrenia, nausea, migraine and Alzheimer's disease.
We have now identified a new group of spiro-azabicyclic compounds which have useful pharmacological properties.
Thus, according to the invention, we provide a compound of formula I: ##STR2## wherein R represents hydrogen or methyl; and
We prefer compounds of formula I in which R represents hydrogen. We prefer compounds of formula I in which n represents 2.
As a second aspect of the invention we provide a process for the preparation of a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, which comprises: cyclising a corresponding compound of formula II ##STR3## wherein n is as defined above; (b) preparing a compound of formula I by reacting a corresponding compound of formula III ##STR4## wherein n and R are as defined above with a carbonyl donating compound; or alkylating a corresponding compound of formula I in which R represents hydrogen; one enantiomer from a mixture of enantiomers; I, or an acid addition salt thereof, to a pharmaceutically acceptable acid addition salt thereof, or vice versa.
In process (a) the reaction will take place on warming the compound of formula II in a polar protic solvent e.g. water.
In process (b), examples of carbonyl donating compounds include carbonyldiimidazole, carbonyldichloride (phosgene) and triphosgene. The ring closure reaction will take place on heating or refluxing the compound of formula III with carbonyldiimidazole in a polar organic solvent such as THF for 1-4 hours or until reaction is complete. Alternatively phosgene can be bubbled through a solution of the compound of formula III in an organic solvent such as THF or toluene at elevated temperature for 1-4 hours or until reaction is complete.
In process (c), the alkylation reaction will take place under conditions well known in the art, for example, by treating the compound of formula I in which R represents hydrogen with a strong base followed by a methyl halide e.g. methyliodide.
Compounds of formula II may be prepared by Curtius rearrangement of a compound of formula IV: ##STR5## wherein n is as defined above.
Typical reaction conditions for the Curtius rearrangement are discussed in J March "Advanced Organic Chemistry" (1985) 3rd Edition, pages 984-5 however we prefer to perform the reaction by treating the compound of formula IV in water with sodium nitrite and warming to approximately 85.degree. C. for approximately 1 hour. The compound of formula II is not isolated and the cyclisation reaction described in process (a) proceeds directly in situ.
Compounds of formula IV may be prepared by treatment of a compound of formula V ##STR6## wherein n is as defined above, and R' is an alkyl or aryl group, with anhydrous hydrazine.
This reaction may be performed in a polar protic solvent at ambient temperature over 4-12 hours. We prefer that R' represents alkyl, typically methyl, ethyl or t-butyl.
Compounds of formula V may be prepared

REFERENCES:
patent: 5073560 (1991-12-01), Wu
patent: 5137895 (1992-08-01), Munson
patent: 5534520 (1996-07-01), Fisher
Abstract of Taiwan Patent Application No. 201312-A.
Nakanishi, Chem Abs 80, 133284 (1974).
Maillard. Chem Abs 78 71968t (1973).
Trigo, I Het Chem 18, 1507 (1981).
Sivilotti, Science 269, 1681, Sep. 1995.

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