Indole derivatives as serotonin antagonists

Abstract: 3,7-disubstituted indole derivatives of formula I wherein R₁, R₂, n, X, Y and Z are as defined in the description, are useful for the treatment of psychiatric disorders.

Description: The present invention relates to 3,7-disubstituted indole derivatives, their production, their use as pharmaceuticals and pharmaceutical compositions containing them. More particularly the present invention provides a compound of formula I wherein R 1 alkyl(1-4C), Y is O or NH and Z is of formula (a) wherein R 2 is methyl, ethyl or propyl and q is 0, 1 or 2, in free form or in salt form. Structurally related compounds are known for example from GB-A-2 193 633, EP-A-0 353 983, EP-A-0 261964, EP-A-0 200 444 and WO 91/01316. None of these documents, however, suggest a 7-alkoxy substitution on the indole cycle. R 1 is preferably methyl. R 4 in (a) is preferably methyl, and q preferably 1 or 2. All optical isomers and their mixtures including the racemic mixtures are part of the present invention. Furthermore depending on the nature of the Y-Z rest, the compounds may present the exo or endo configuration. The exo/endo nomenclature is well known in the literature. Again, both exo and endo forms and their mixtures are part of the present invention. The endo isomers are preferred. The compounds of formula I may exist in free form or in salt form. Suitable salt forms include acid addition salts and quaternary ammonium salts. The compounds of formula I may be prepared over a process comprising condensing a compound of formula II wherein R 1 is as defined above, or a reactive derivative thereof, with a compound of formula III HY-Z wherein Y and Z are as defined above , and recovering the resulting compound of formula I in free form or in salt form. This process to obtain amides or esters may be effected in conventional manner for analogous compounds. For example the carboxylic acid group may be activated in the form of a reactive acid derivative, especially for the production of amides. Suitable reactive acid derivatives may be formed by reaction with N,N'-carbonyl-diimidazole producing an intermediate carboxylic acid imidazolide, or with N-hydroxy-succinimide. Alternatively an acid halogenide, for example an acid chloride, may be used, e.g. produced by reaction with oxalyl chloride. For the production of esters, the alcohol (compound of formula III wherein Y is 0) may be conveniently reacted with a compound of formula II or a reactive derivative thereof. The reaction may be carried out at a temperature between room temperature and 70°C. Conveniently an inert solvent, e.g. ethyl acetate, may be used. The alcohol may also be used e.g. in the form of an alkali metal salt, preferably the lithium salt. Such salts may be produced in conventional manner, e.g. by reaction of n-butyl lithium with the alcohol in tetrahydrofuran. If desired a heterocyclic or tertiary amine, e.g. pyridine or triethylamine may be present, especially for the production of amides. Suitable reaction temperatures may be from about -10°C to about 10°C. Other suitable inert organic solvents include e.g. ether or dimethoxyethane. In these reactions the endo or exo configuration of the Y-Z radical is believed to be maintained. The compound of formula III may be reacted if desired as a mixture of endo and exo isomers and the pure endo or exo isomer isolated, e.g. by chromatography or crystallization. The compounds of formula I may be isolated and purified in conventional manner. Insofar as the production of any starting material is not particularly described herein, it is known or may be produced in analogous manner to known procedures or in analogous manner to that described herein, e.g. the example. Compounds of formula I in free base form may be converted into salt forms. For example acid addition salts may be produced in conventional manner by reaction with a suitable acid, e.g. hydrochloric acid, malonic acid, hydrobromic acid, maleic acid, malic acid, fumaric acid, oxalic acid and tartaric acid. Quaternary ammonium salts of the compounds of formula I may be produced in conventional manner, e.g. by reaction with methyl iodide. In the following example all temperatures are in °C and are uncorrected. EXAMPLE: 7-Methoxy-1H-indol-3-carboxylic acid-(1αH, 5αH)-8-methyl-8-aza-bicyclo[3,2,1]oct-3α-yl-ester 19.1 g of 7-methoxy-1H-indol-3-yl carboxylic acid are suspended in 300 ml ethyl acetate. 10 ml oxalyl chloride are then added over 30 minutes at room temperature. The resulting red brown solution is stirred for 3 hours at room temperature and then concentrated to 2/3 of its original volume. A solution of 14 g tropine in 50 ml ethyl acetate is added dropwise thereto at a temperature of about 50°. The resulting mixture is further stirred for 2 hours at about 50° and then over night at room temperature. The resulting suspension is dissolved by addition of water and the mixture is extracted three times with ethyl acetate and then washed with 2N HCl. The acidic phase is alkalized with potassium carbonate, extracted three times with CH 2 Cl 2 and evaporated, thus yielding the title compound. m.p. 298 - 299° (decomposition) The compounds of formula I in free form or in the form of pharmaceutically acceptable salts and complexes (hereinafter referred to as compounds of the invention) have never been disclosed in the literature as pharmaceuticals. They exhibit valuable pharmacological properties as indicated in animal tests and are therefore indicated for therapy. In particular, the compounds of the invention show sociotropic activity (A.K. Dixon, et al, Adv. Study. Behav., 1990, 19 , 171 - 204) as indicated e.g. by the intruder test with mice as disclosed by A.K. Dixon, Triangle, 1982, 21 , 95 - 105. In this test, the compounds of the invention have a dose-related increase in approach-oriented social activities after administration at dosages of from about 0.01 to 100 µg/kg. These activities are evident after oral and parenteral administration and affect social investigation (increased) and defensive ambivalence (decreased). The compounds of the invention also influence social behavior as demonstrated in the test according to K. A. Dixon et al., Adv. Study Behav., 19 , 171, (1990) where pairs of individually housed males are brought together in a large cage unfamiliar to them both and their behavioural acts and postures are then recorded. In this test, one partner of a pair receives either the compound to be tested or vehicle i.p. 45 minutes before the social encounter. When administered i.p. at dosages from about 0.01 to 100 µg/kg, the compounds of the invention have effects on the social behavior of the mice, e.g. they increase social investigation. The compounds of the invention also reduce the plasma corticosterone rise induced in mice by the presence of an aggressive, but inaccessible male mouse. Compounds of the invention when given p.o. for 14 days at a dosage of from about 0.1 to 10 mg/kg restore the plasma corticosterone level to normal. Furthermore, the compounds of the invention exhibit 5HT 3 antagonistic properties as evidenced by: 1. their potent and selective binding properties to 5-HT3 binding sites, e.g. to N1E-115 cells measured according to the method disclosed by D. Hoyer and H.C. Neijt, Mol. Pharm., 33 , 303 - 309. Example compound has a pK d value of 8.87 ± 0.01. 2. their promoting effect on gastric emptying in rats as indicated in standard in vivo tests when administered i.p. at doses of about 0.01 to about 1 mg/kg. The compounds to be tested are administered 15 min. before the administration of 25 glass spheres and gastric emptying is measured 5, 10, 15 and 30 min. after administration of the spheres. Example compound has an ED 50 of 0.2 mg/kg i.p. 3. their blockade of the Benzold Jarisch Reflex, e.g. as demonstrated in the test method according to J. R. Fozard, Naunyn-Schmiedeberg's Arch. Pharmacol., 326 , 36 - 44 (1984). Example compound has an ID 50 of 70 µg/kg. The compounds of the invention are accordingly indicated for treating psychiatric disorders, particularly for the treatment of anxiety of various genesis and of stress-related disorders. The compounds of the invention are also indicated for the treatment of disorders such as social withdrawal, affective disorders, psychoses, depression, cognitive disorders, disorders of vigilance, e.g. geriatric illnesses, panic disorders, agoraphobia, obsessive compulsive disorders. An indicated daily dosage is in the range from about 0.01 to about 5 mg of the compounds of the invention conveniently administered, for example, in divided doses up to four times a day. The Example compound is preferred. The compounds of the invention may be administered in free form or in pharmaceutically acceptable salt or complex form. Such salts may be prepared in conventional manner and exhibit the same order of activity as the free compounds. The present invention also provides a pharmaceutical composition comprising a compound of the invention in association with a pharmaceutically acceptable diluent or carrier. Such compositions may be formulated in conventional manner. The compounds of the invention may be administered by any conventional route, for example parenterally e.g. in form of injectable solutions or suspensions, enterally, e.g. orally, for example in the form of tablets or capsules or in a nasal or a suppository form. Unit dosage forms contain, for example, from about 2.5 µg to 2.5 mg of a compound of the invention in free form or in pharmaceutically acceptable salt form. In accordance with the foregoing the present invention furthermore provides a compound of the invention for use as a pharmaceutical, particularly for use in the treatment of psychiatric disorders, for example as herein before indicated, e.g. anxiety, stress-related disorders or depression.

Claims: Claims for the following Contracting States : AT, BE, CH, LI, DE, DK, FR, GB, IT, LU, NL, SE A compound of formula I wherein R 1 is alkyl(1-4C), Y is O or NH and Z is of formula (a) wherein R 2 is methyl, ethyl or propyl and q is 0, 1 or 2, in free form or in salt form. A compound of formula I as defined in claim 1 which is the 7-methoxy-1H-indol-3-carboxylic acid-(1αH,5αH)-8-methyl-8-aza-bicyclo[3,2,1]oct-3α-yl-ester in free form or in salt form. A process for the production of a compound of formula I as defined in claim 1, comprising condensing a compound of formula II wherein R 1 is as defined in claim 1, or a reactive derivative thereof, with a compound of formula III HY-Z wherein Y and Z are as defined in claim 1, and recovering the resulting compound of formula I in free form or in salt form. A compound of formula I as defined in claim 1, in free form or in pharmaceutically acceptable salt form, for use as a pharmaceutical. A compound of formula I as defined in claim 1, in free form or in pharmaceutically acceptable salt form, for use in the treatment of psychiatric disorders. A compound of formula I as defined in claim 1, in free form or in pharmaceutically acceptable salt form, for use in the treatment of anxiety, stress-related disorders, social withdrawal, affective disorders, psychoses, depression, cognitive disorders, disorders of vigilance, panic disorders, agoraphobia or obsessive compulsive disorders. A pharmaceutical composition comprising a compound of formula I as defined in claim 1, in free form or in pharmaceutically acceptable salt form, in association with a pharmaceutical carrier or diluent. The use of a compound of formula I as defined in claim 1, in free form or in pharmaceutically acceptable salt form, in the manufacture of a medicament for the treatment of psychiatric disorders, anxiety, stress-related disorders, social withdrawal, affective disorders, psychoses, depression, cognitive disorders, disorders of vigilance, panic disorders, agoraphobia or obsessive compulsive disorders. Claims for the following Contracting States : ES, GR A process for the production of a compound of formula I wherein R 1 is alkyl(1-4C), Y is O or NH and Z is of formula (a) wherein R 2 is methyl, ethyl or propyl and q is 0, 1 or 2, in free form or in salt form, comprising condensing a compound of formula II wherein R 1 is as defined above, or a reactive derivative thereof, with a compound of formula III HY-Z wherein Y and Z are as defined above, and recovering the resulting compound of formula I in free form or in salt form. A process according to claim 1 for the production of the 7-methoxy-1H-indol-3-carboxylic acid-(1αH,5αH)-8-methyl-8-aza-bicyclo[3,2,1]oct-3α-yl-ester in free form or in salt form. A compound of formula I in free form or salt form, whenever produced by a process according to any of claims 1 and 2. A process for the preparation of a pharmaceutical composition comprising a compound of formula I as defined in claim 1, in pharmaceutically acceptable free form or salt form, which comprises mixing such a compound with a pharmaceutical carrier or diluent. A compound of formula I as defined in claim 1, in free form or in salt form. A compound of formula I as defined in claim 1 which is the 7-methoxy-1H-indol-3-carboxylic acid-(1αH,5αH)-8-methyl-8-aza-bicyclo[3,2,1]oct-3α-yl-ester in free form or in salt form. A pharmaceutical composition comprising a compound of formula I as defined in claim 1, in free form or in pharmaceutically acceptable salt form, in association with a pharmaceutical carrier or diluent.

Inventors: DIXON ARNOLD KEITH, GIGER RUDOLF KARL ANDREAS, DIXON, ARNOLD KEITH, GIGER, RUDOLF KARL ANDREAS
Applicants: CIBA GEIGY AG, SANDOZ AG, SANDOZ-ERFINDUNGEN VERWALTUNGSGESELLSCHAFT M.B.H.
Application year: 1991
Main classification: C07D451
IPC codes: A61K31, A61P25, C07D403, C07D471, C07D453, C07D233, C07D451, C07D401, C07D209, A61P43, C07D487