IL96797A - Manufacture of pharmaceutical compositions containing 1,2,3,9- tetrahydro-3-((1H-imidazol-1-YL)methyl)-4H-carbazol-4-one for treatment of impaired approach oriented behavior in stressful situations, for increasing vigilance and for treatment of rhinitis or lung embolism - Google Patents

Description

96797/2 -!?itN7»n>N-lH)]-3-n-pnN-)oo-9,3,2,l o>t?>DQn mnpn > >νο v -n > >mai nnpi? niN cmn niAnjnm i?i >o? , } ηκ>-ι η>ηοη IN ηΝ nip?in Manufacture of pharmaceutical compositions containing 1,2,3,9-tetrahydro-3-[(lH-imidazol-l-yl)methyl]-/tH-carbazol-fff:-/t-one for treatment of impaired approach oriented behavior in stressful situations, for increasing vigilance and for treatment of rhinitis or lung embolism SANDOZ AG. , C: 82391 _ 9 _ 96797/3 This invention relates to new uses of specific imidazolyl carbazols, e.g. imidazolylmethylcarbazols, e.g. of formula la as defined hereinafter, for preparing pharmaceutical compositions · The compounds may be used in any pharmaceutically acceptable form, including the free base and in acid addition and quaternary ammonium salt forms.

These compounds are referred to hereinafter as compounds of the invention.

The above mentioned imidazolyl carbazols have in general 5-HT3 antagonist activity which may have not been previously recognized. These carbazols are in general known for example from Belgian patents 897117, 900425 and 901274. These compounds are described therein as being 5-HT3 receptor antagonists or serotonin M receptor antagonists (serotonin M receptors have been reclassified as 5-HT3 receptors).

The compounds are indicated for use as anti-migraine agents, antiarrhythmics, and for treatment of serotonin-induced gastro-intestinal disorders including emesis, e.g. induced by anti-cancer agents.

Other classes of the compounds of the invention are knovn from e.g. European patent publications 13138A, and 214772A and British Patent publication 2153821A.

Ve have nov discovered that these compounds have interesting nev uses which have been hitherto unrecognized.

The present invention relates to the uses of specific 5-HT3 antagonists in the manufacture of a medicament suitable for the treatment of impaired approach oriented behaviour in stressful situations, for increasing vigilance, for treating rhinitis or for treating lung embolism.

The new uses of the compound indol-3-yl carboxylic acid endo-8-methyl-8-aza-bicyclo[3.2.11oct-3-yl ester [hereinafter compound EJ [ICS], a known 5-HT3 antagonist, are described and claimed in Israel Patent applications Nos. 83363 from which the present application was divided and 96976. Data for this compound a mentioned herein illustrates the use of the other compounds the invention.

The invention in one aspect provides the use of a 5-HT3 antagonist which is an imidazolyl carbazol, or an imidazolylmethylcarbazol, in the manufacture of a medicament for improving approach oriented behaviour in the treatment of stress-induced psychiatric disorders, or of a medicament for increasing vigilance, for treating rhinitis or or treating lung embolism. 96797/4: 4-19 The invention provides the use of a compound of formula la vherein R15 is hydrogen, (C1_10)alkyl, (C3_9 )cycloalkyl, (C3_6alkenyl, phenyl or henylCC^ )alkyl and one of the groups R16, R1 and Rl8 is hydrogen, (d_6)alkyl, (C3_7)cycloalkyl, (C2_6 )alkenyl or phenyl(C]._3 )alkyl and the others independently are hydrogen or (Ci.^alk l, in the manufacture of a medicament for improving approach oriented behaviour in stressful situations, for increasing vigilance, treatment of stress-related psychiatric disorders, for the treatment of rhinitis or for treating lung embolism.

We have now found e.g. from ethological and endocrinological tests that the compounds of the invention are useful for the treatment of approach-oriented behaviour in behaviour perturbed by stress, including stress related-social phobias and social withdrawal. -20- 100-6939/III The compounds of the invention also increase vigilance, e.g. in geriatrics.

Trials have been carried out on the effects of the compounds of the invention on approach-oriented behaviour in mice. The compounds increase approach-oriented behaviour in stress-situations normally inhibitory to social responses. Thus situations involving unfamiliar surroundings, contact with foreign aggressive opponents, competition for food, were created under reversed lighting conditions whereby observations were performed during the darkphase. Under these conditions, untreated rodents exhibit high levels of flight, particularly defensive ambivalence and escape behaviour, but low levels of social behaviour involving approach activity. Anxiolytics like diazepam reduce the ambivalent behaviour and can increase social behaviour. In food deprived mice under white light, certain antidepressants, e.g. bupropion and impramine, but also atypical anxiolytics, as well as the compounds of the invention, increase approach-oriented social behaviours. -21 - 100-6939 Intruder test Study A A foreign male mouse (intruder), placed for 6 minutes, into the cage of an isolated male is attacked and responds with defensive escape patterns collectively known as "flight". Flight and associated defensive activities override the intruders tendency to approach the attacker so that much of the behaviour includes social forms of ambivalence.

Intruders recei vi ng oral doses of benzodiazepines show less of these defensive activities and more approach- ori ented behavi ourf A.K. Dixon Triangle 1982, 21 , 95-105 ; M.Krisak, Br . J . Pharmacol . 1975 , 55_, 141-150), e.g. investigation, aggression and sexual activity.

The compounds of the invention are administered 1 hour before the encounter per-orally at from about 0.1 to about 10 mg/kg. Groups of 8 mice pairs are used. The frequency and duration of social and non-social behaviour of the mice were recorded using ethological techniques.

The compounds increase social oriented activity.

In this test compound E at a dose of 1 mg/kg increased the frequency (from ca 60 to 80) and duration of social interaction (from ca 90 to 120 seconds). -22- 100-6939 Study B Study A was modified using a large cage (59 x 38.5 x 20cm) which al lowed greater freedom of movement so that elements of defense could be separated more clearly from the approach-oriented social activities. The compounds of the invention were given i .p. at doses from about 0.01 to about 100 icrogon/kg 45 minutes before the encounter.

Indruders received the drug. It was found that the compounds of the invention clearly promoted . the approach-oriented social activities. They also reduced escape behaviour, a special form of flight. In this test at a dose of 1 micro-gram/kg compound E promoted 8 elements of approach oriented §ocial activities by about 40 per cent. Compound E also reduced escape behaviour. Compound H at the same dose promoted 3 elements of approach-oriented social activities by about 40 per cent. Iti effect » escape behaviour was less. It did however increase cage exploratory behaviour indicative of a stimulant effect.

Competitive feeding Study C In this test 8 pairs of male OF-l mice deprived of food for 6 hours are forced to compete over 6 minutes for a single food pellet. Because of the close proximity of the mice the tendency to eat is competitively offset by the tendency to interact socially. One partner receives a compound of the invention at an oral dose from about 0.01 to about 1 mg/kg 1 or 2 hour before the encounter. Frequencies and durations of social activities were recorded for both animals with the aid of a posture and timer machine (K.Hausamann ,A .K.Di on , Physiol .Behav. 1982 , 28 , 743-745).

In this test benzodiazepines increase eating behaviour more than social interactions. Anti-depressants may increase such social activities. The compounds of the invention increase approach-oriented social behaviour, more than eating.

Compound E at a dose of 0.1 mg/kg p.o. given 2 hours before the encounter increased, relative to controls, the frequency (54 per cent) and duration (321 per cent) of social interactions. In contrast frequency of feeding increased by only 4 per cent and their duration 55 per cent.

Stretched Attend Postures (SAP) Mice placed upon an unfamiliar elevated platform in a novel environment display characteristic stretched body postures called SAP's which signify amibivalence. Drugs which have putative anxiolytic reactions, e.g. benzodiazepines, barbiturates, and buspirone reduce the incidence of SAP's (H.P. asermann, Psychopharmacology 1986, 89, 31-37).

The compounds of the invention administered p.o. at a dose of from about 0.1 to about 10 mg/kg. 2 hours before the test reduce the duration of SAP when placed on the platform for 2 minutes under conditions where no other mice are present.

The durations in the case of compound E at 0.1 mg/kg were similar to that observed with clobazam at the same dose' and at higher doses the effect was less. - 24 - Corti costerone levels (Endocrinological profile) Mice subjected to a novel envi ronment , e.g. on transferring them from one room to another via a trolley, exhibit a rise in plasma corti costerone typical of stress related disturbances which' are reduced . . . by benzodiazepines and barbiturates (Lahti R . A . , Borsulm C. , .. Res, Comm.Chem.Path.Pharm.il : 596-603; G.Le Fur et al . , J.Pharm.exp.Ther. 211: 305-308), reduction is observed with the compounds of the invention at from about 0.1 to 10 mg/kg Ρ·°. compound E. reduces such stress-induced cortico-sterone at about 1 to 10 mg/kg p. o. whilst lower doses from about 0.1 to about 0.3 mg/kg increase basal plasma levels of this hormone. This profile is analogous to that observed with diazepam.

Taken together, the results of these studies also' show that compounds of the invention promote approach-oriented social behaviour in stressful situations. This suggests that the compounds of invention are of use in stress-related psychiatric disorders , e.g. where the treatment of social withdrawal, affective disorders, and other stress-related illnesses is desired.

The increases in corti costerone also suggest that compounds of invention increase vigilance, thus indicating a potential use for the compounds i-n disorders of vigilance e.g. geriatric illnesses. -25- 100-6939 The compounds of the invention may be administered in similar manner to known standards, e.g. bupropion. The preferred compound E and bupropion have been found to have a pronounced effect on promoting social interaction under stress related conditions. For example, compound E increased the mean frequency of social interactions in the competitive feeding experiment study c) by 54 per qent at 0.01 mg/kg compared to bupropion provoking an increase of 179 per cent at 2.5 mg/kg. It is indicated that compound, E. wi.ll be useful in the treatment of stress -rel ated psychiatric disorders at a daily oral dose of from 0.1 mg which could be increased up to 50 mg. 96797/2 - 26 - For these 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 are indicated to be obtained at daily dosages from about 0.001 mg/kg to about.50 mg/kg animal body weight. In . .r humans, an indicated daily dosage is in the range from about 0.1 mg to about 50 mg of a compound of the invention conveniently administered, for example, in divid'ed doses up to four times a day.

In a further aspect the present invention provides use of a mono or bicylic carboxylic or heterocyclic carboxylic acid esters or amides of a cyclic alcohol or amine containing nitrogen as a ring atom in free base form or in acid addition salt or quaternary ammonium salt form as a 5-HTg antagonists in the manufacture of a medicament suitable for the treatment of serotonin induced psychiatric disorders, e.g. when., chosen from one of the following: -27- 100-6939 anxiety, social withdrawal , affective disorders , psychoses and other stress-related illnesses, disorders of vigilance, e.g. geriatric illnesses Preferred compounds include:- Indol-3-yl carboxylic acid endo-8-methyl -8-aza-bi cycl o- [ 3 , 2 , 1 ]oc t-3-yl ester [hereinafter compound E],[ICSj Benzo[b]thi phen-3-yl carboxylic acid endo-9-methyl -aza- i cycl o[3 , 3 , 1 ]non-3-y 1 ester [hereinafter compound F]. 5-fl uoro-1 -methyl -i ndol -3-yl carboxylic acid endo-9-methy 1 - 9-aza-bicylco[3,3,l ]non-3-yl ester [hereinafter compound G]. 1 ,2,3,9-tetrahydro-9-methyl-3-[(2-methyl -IH-im dazol -1 -yl ) - methyl 3-4H-carbazol -4-one (hereinafter compound. H) .Cfifi 38032FJ 1 -methyl -indazol-3-yl-carboxyl c ac d 9-methyl-9-aza-bicyc1o-/ [ 3 , 3 , 1 ]non-3 -y 1 -ami de (hereinafter compound I), and especially compound E. -29- 100-6939 The compounds of the invention may be administered in free base form or, when they can be formed, in pharmaceutically acceptable acid addition salt form or in a quaternary ammonium salt form, Such salts may be prepared in conventional manner and are in general known. They exhibit the same order of activity as the free base form and pharmaceutical compositions comprise a compound of the invention in free base or pharmaceutically acceptable acid addition salt form or quaternary ammonium salt form in association with pharmaceutical carrier or diluent. Such compositions may be manufactured in conventional manner.

The compounds may be administered by any conventional route, in particular enterally, preferably orally, e.g. in the form of tablets or capsules or parenterally, e.g. in the form of injectable solutions or suspensions.

Suitable pharmaceutical carriers and diluents for oral administration include polyethylene glycol , polyvinylpyrrolidone, mannitol , lactose etc. granulating agents, and disintegrating agents such as starch and algenic acid, binding agents such as stearic and gelatine, lubricating agents such as magnesium stearate, stearic acid and talc. Suspensions may contain conserving agents like ethyl p-hydroxy-benzoate , suspending agents such as methyl -eel 1 ul ose , tenside etc. For parenteral forms the compositions are preferably bufferred, aqueous solutions (pH between 4 and 5). -30- 100-6939 We have moreover found that the compounds of the invention may be administered nasally and have an especially interesting resorption profile.

Furthermore the compounds of the invention increase the nasal resorption or bioavailability of other active agents such as peptides particularly when administered by the nasal route.

The compounds of the invention moreover are useful in the treatment of rhinitis and serotonin-induced nasal disorders as indicated by an inhibition of nasal secretions on administration of the compounds of the invention.

The testing may be effected as follows:- The bioavailability and pharmacokinetic profile of the compounds of the invention may be determined in conventional manner, e.g. in mammals including rhesus monkeys and humans. The concentrations of the compounds of the invention in the blood plasma after administration of from about 0.01 to about 10 mg/kg to each nostril , e.g. 7.5 mg in the case of compound E, locally to the nasal mucous membrane, e.g. as a spray, may be determined in conventional manner by e.g. radioimmunoassay or HPLC methods. The compounds of the invention are rapidly absorbed, e.g. over about 10 minutes.

Even after ca. 5 to 10 minutes following nasal administration, 200 ng of the compound i ndol -3-yl,-c-arboxy 1 i c a.ci d- endo-8-methyl -S-aza-bicycl. CS.Z, H'OC't-3-yl ester may b detected in 1 ml of plasma. Upon oral administration, this concentration of active ingredient in the plasma is reached only after ca. 30 to 40 minutes. The general bioavailability -31- 100-6939/III of the compounds of the invention over a period of 6 hours is the same for nasal administration as for oral administration.

Nasal secretions are also inhibited. Additionally, the compounds of the invention when administered, e.g. at a dose of from 0.01 to 10 mg/kg with a therapeutically effective dosage of another compound, e.g. a peptide, such as salmon calcitonin increases the absorption thereof.

For example, inthe case of compound E (15 mg) and salmon calcitonin (100 IU) half of which is applied to each nostril, the bioavailability of salmon calcitonin (AUC up to 2 hours) is increased from 0.08 IU/ml/hr plasma to 1.632 IU/ml/hr/plasma in the rhesus monkey.

For the rhinitis and nasal serotonin-induced disorder indications, the appropriate dosage will, of course, vary depending upon, for example, the compound of invention employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results are indicated to be obtained at daily dosages from about 0.01 mg/kg to about 10 mg/kg animal body weight. In humans, an indicated daily dosage for oral administration is in the range from about 5 mg to about 300 mg of a compound of formula I conveniently administered, for example, in divided doses up to four times a day, e.g. in the range of about AO mg p.o. in the -case of compound E.

In another aspect the present invention provides a pharmaceutical composition comprising (i) a 5-HT3 antagonist of formula I as defined above other than indol-3-yl carboxylic acid endo-8-methyl-8-aza-bicyclo- [ 3.2.1 loct-3-yl ester, and (ii) a pharmaceutically acceptable peptide. -32- 100-6939 When a compound., of tne invention is co-administered with another active agent,, the appropriate dosage will , of course, vary depending upon, for example, the ..active agent of the compound of the invention and other active agent employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general , satisfactory results are- i ndi cated to be obtained at daily dosages from about one half to one tenth the usual dose of the other active agent. The compound of the invention is indicated to be 'admi ni stered at about one half, to one tenth the usual dose.

The compounds of the invention may be administered for the rhinitis and nasal serotonin-induced disorders and for co-admi nistra on with' another active agent, e.g.; ,a peptide, by any .conventi onal route,, in particular entera-lly, preferably 'orally, e.g. , in the form of tablets or capsules, or parenterally, e.g. , in the form of injectable solutions or suspensions. The local application by the nasal route is preferred, i For the nasal administration route, the appropriate dosage will , of course, vary depending upon, for example, the compound of the invention employed, the host, and the nature and- severity of the condition being treated. However, in general , sat sfactory results in animals are indicated to be obtained at daily dosages from about 0.001 mg/kg to about 10 mg/kg animal body weight. In humans, an indicated dosage per actuation is in the range from about 0.01 mg to about 1 mg of a compound of the invention conveniently administered, for example, in doses up to four times a day. -33- 100-6939 Thus for gastrointestinal disorders or for migraine prophylaxis a compound according to the invention is indicated to be administered to the body nasally in a dosage of 0.13 to 0,4 mg kg body . weight, i.e. ca. 10 to 30 mg or 1 to 3 pumps of the nasal spray per patient, and in order to control arrhythmia, it should be ^given in a dosage which is ca, 10 times higher, i.e. from 1,3 to 4 mg per kg body weight or 100 to 300 mg, or resp. 10 to 30 pumps of the nasal spray per patient.

The compound E is the preferred compound for the rhinitis and nasal route administration. It is indicated that the compound of example may be administered at daily dosages of about 0,1 mg nasally to humans.

The compounds of the invention may be administered nasally in any pharmacologically active form, e.g. in free base form, in acid addition salt form or in quaternary ammonium salt form.

The nasal mode of administration creates a simple method of administration which rapidly gives results and can be easily carried out by the patient himself, e.g.by administering a liquid form for nasal admin stration, for example a nasal spray or drop solution using a nasal applicator, or by inserting a gelatinous sponge or lyophi- lisate soaked in the active substance, or by blowing the galenic form in powder form into the nostrils.

The compounds of the invention may be present in the liquid form for nasal administration in a proportion of 1 to 30%, preferably 5 to 20%, especially 10 to 15% (weight/ vol ume ) . -34- 100-6939/III The present invention accordingly relates also to a liquid form for nasal administration, containing 1) a compound of the invention 2) a preservative, especially benzalkonium chloride, and 3) a liquid diluent or a carrier, suitable for application to the nasal mucous membrane.

In another aspect the invention provides a liquid nasal pharmaceutical composition containing a compound of formula I as defined above wherein A is of formula II', other than indol-3-yl carboxylic acid endo-8-methyl-8-aza-bicyclo-[3.2. l]oct-3-yl ester, a preservative, and a liquid diluent or carrier suitable for application to the nasal mucous membrane.

The proportion of benzalkonium chloride in the compositions according to the invention is preferably ca. 0.002 to ca,. 0.02, especially ca. 0.01% (weight/volume) of the total composition.

In accordance with the invention, the above-mentioned forms of administration may be administered to the nasal mucous membrane, e.g. as drops or as a spray. As described hereinafter, however, they are preferably administered as a spray, i.e. as finely dispersed droplets. One further possible way of bringing the above-mentioned liquid form for nasal administration into contact with the nasal mucous membrane is to soak a gelatinous sponge (SP0NG0STA - Registered Trade Hark) or lyophilisate with the substance and then to insert the sponge into the nostrils.

The liquid diluent or carrier employed is conveniently water (pharmaceutical grade). An aqueous salt solution is preferred in particular. The liquid forms for nasal administration according to the invention are formulated such that they allow administration to be effected nasally. With this in mind, they can e.g. also contain minimal amounts of further desired components or excipients, e.g. additional preservatives, or e.g. ciliary stimulants such as caffeine. -35- 100-6939 The liquid forms for nasal admin stration according to the invention preferably have a pH value of 5.5 to 6.

The liquid forms for nasal administ ation should also have an appropriate isotonicity and viscosity . They preferably have an osmotic pressure of ca, 260 to ca. 380 mOsm/litre. The desired viscosity of the compositions according to the invention depends on the relevant form of administration, e.g. whether nasal drops or a nasal spray are administered. For nasal drops, a viscosity of ca. 2 to ca. 40 x 10"3 Pa.S is suitable. For nasal sprays, a viscosity of less than 2 x 10 Pa.S is suitable.

If desired, the liquid forms for nasal administration may also contain further components, especially conventional pharmaceutically available surface-active agents. In this connection and as a further aspect of the present invention, it was found that the use of surface-active compounds in the nasal administration of the compounds of the invention increases their resorption through the nasal mucous membrane and improves the initial bio-availability. In this case, preference is given to non-ionic surface-acti e agents, for example polyoxyal kyl ene ethers of higher alcohols, e.g. of the general formula, wherein R0 signifies the radical of a higher alkanol , especially a higher alkanol such as lauryl or cetyl alcohol , or of an al kyl ephenol , or a sterol , especially lanosterol , d hydrochol esterol or cholesterol , as well as mixtures of two or several such ethers. Preferred polyoxy-alkylene ethers which can be used for the present inven- -36 100-6939 tion are polyoxyethyl ene- and polyoxypropyl ene-ethers (i.e. wherein n in the above-mentioned formula is 2 or 3), especially lauryl-, cetyl- and chol es teryl ol yoxyethy 1 ene-and -polyoxypropyl ene-ethers , as well as mixtures of two or several such ethers.

Especially suitable polyethers for use according to the invention are those in which the average value of the recurring units in the polyoxyal kylene component (x in the above formula) lies between 4 and 75, especially between 8 and 30 and particularly between 16 and 26. The polyethers may be obtained in accordance with known methods. A large choice of such products 1s available commercially and is sold e.g. by Amerchol under the trade name Solulan by KAO Soap, ICI and Atlas under the trade names Emalex, Brij and Laureth, and by Croda under the trade name Cetomacrogol .

SOLULAN, EMALEX AND LAURETH as used herein are Registered Trade Marks.

Examples of polyoxyal kylene ethers which are suitable for use according to the invention, e.g. )P0E = polyoxyethyl ene ethers: POP = polyoxypropyl ene ether; x = average value of the recurring units in the POE/POP component) are listed in the following:- - 37 - 1. Cholesterylethers ; 1.1 Solulan(R) C-24 - POE, x = 24 2. Ethers of lanolin alcohols; 2.1 Solulan(R) 16 - POE, x = 16 2.2 Solulan(R) 26 - POE, x = 25 2.3 Solulan(R) 75 - POE, x = 75 2.4 Solulan(R) PB-IO - PPE, x = 10 2.5 Solulan(R) 98 - POE, x = 10 - partly acetylated 2.6 Solulan(R) 97 - POE, x = 9 - wholly acetylated 3. Laurylethers ; 1 3.1 Emalex(R) 709 / Laureth (R) 9 - POE, x = 9 3.2 Laureth (R) 4 / Brij (R) 30 - POE, x = 4 3.3 Laureth(R) 23 / Brij (RJ 35 - POE, x = 23 4. Cetylethers ; 4.1 Cetomacrogol (R) - POE, x = 20 to 24 Lanolin alcohols are also known as wool fat alcohols and are a mixture of cholesterol, dihydrocholesterol and lanosterol.

Preferred polyethers for use according to the invention are cholesteryl polyoxyethylene ethers, e.g. polyethers of the above formula, wherein n = 2 and RO is a cholesteryl radical, in particular polyethers wherein the number of recurring units in the polyoxy- - 38 - ethylene component is 16 to 26, especially about 24.

These polyethers are preferably free from impurities, and especially from other polyoxyalkylene ethers. They preferably contain at least 75%, most particularly at least 85% and especially at least 90% (weight) of the pure cholesteryl poly-oxyethylene ether.

If a surface-active agent, e.g. a polyoxyalkylene ether, is used, the amount present in the compositions according to the invention will depend on the surface-active agent used in particular, the form of administration (e.g. drops or spray) and the desired effect.

In general, the amount of surface-active agent employed is between ca. 2.0 and ca. 200 (preferably up to ca. 100, especiall up to ca. 20) , especially between ca. 5 and ca. 30 (preferably up to ca. 15) and in particular ca. 10 mg/ml.

For nasal administration, the liquid fores for nasal administrate are preferably placed in an applicator, which is equipped with a device that enables the composition to be applied to the nasaJ mucous membrane, e.g. a nasal spray applicator.

Such applicators are known per se and include those which are suitable for the administration of liquid preparations as drops or as a spray to the nasal mucous membrane. Since the dosing of the compounds of the invention should be as exact as possible, the use of spray applicators in which an exact controJ over the quantity administered is possible is generally preferre - 39 - Suitable app Vi ances f or administration are e-.g. atomizers such as pump dispensers or aerosol cans. In the latter case, the applicator contains a composition according to the invention as well as a propellant which is suitable for use in a nasal spray applicator. The atomizer appliance is provided with an appropriate spray device which enables the composition to be applied to the nasal mucous membrane. Such devices are known in general .

The container, e.g. a nasal spray applicator, may contain a quantity of the composition which is sufficient for a single nasal dose or for administration several doses, e.g. over a period of several days or weeks. The amounts of the individual doses will preferably correspond to the ' above-mentioned doses.

Applicators as defined above are preferably spray applicators for nasal usage. They preferably enable the composition contained therein to be administered in single doses of ca, Q.05 to ca. 0.15 ml , e.g. ca. 0,1 ml.

Suitable compositions, as well as the individual components 1 ,2 and 3 for use in an applicator, are those which have been previously described. The dosages which are suitable for use similarly correspond to the dosages given previously.

Furthermore, the invention relates to a process for the pro< duction of a liquid form for nasal administration, containing 1) compounds according to the invention 2) a preservative, especially benzal koni urn chloride, and 3) a liquid diluent or a carrier ,whi ch are suitable for administering to the nasal mucous membrane, as well as optionally a surface-active agent which is suitable for administering to the nasal mucous membrane. -40- 100-6939 characterised in that the components are intimately mixed together, and if desired, the composition obtained is placed in an applicator which is provided with a spray device which enables the composition thus obtained to be administered to the nasal mucous membrane. Furthermore, a sponge (SP0NG0-STAN) may be soaked with the composition obtained and the soaked sponge can be inserted into the nostrils.

The stability of the composition according to the invention can be determined in the usual way.

The compositions according to the invention containing benz-alkonium chloride are stable towards contamination by germs, e.g. as in standard tests such as those described by S.Urban et al.in Zbl . Bakt.Hyg . I Abt.Orig.B.1972, 478-484 (1981) and S.Urban.Acta Pharm. Techno! .22 , 247-253 (1976).

For example, the cell count of the standard bacteria, namely E.coli ATCC 8739, Pseud. aeruginosa ATCC 9027, Staph. aureus ATCC 6538, Strept. pyogenes ATCC 8668 and standard fungi Cand.al icans ATCC 10231, Sacch.cerevisae ATCC 9763, Aspergillus niger ATCC 16404 and Pen.steckil ATCC 10499, is reduced to Q.1% or less within 24 hours after injecting them withthe composition, as can be shown in standard tests.

In a stability test, the nasal spray composition of the following example 1 was kept for 3 months at 30°C under a nitrogen atmosphere in a glass container. Pseud, aerugi nosa ATCC 9027, Staph. aureus ATCC 6538, Strept. pyogenes ATCC 8668 and the fungi cand , al bi cans ATCC 10231, Sacch.cerevisae ATCC 9763, Aspergillus niger ATCC 16404 and Pen.stechii ATCC 10499 were added until a cell count of ca. 2 x 105 organisms was reached in the injected liquid. Within 2 hours, the germ count had reduced to less than 0.1¾, Within 4 weeks, the germs could no longer be detected. - 41 - Equally favourable results are obtained if the compounds of the invention are administered in a galenic form, which is in the form of a powder and is introduced by blowing into the nostrils.

The compounds of the invention other than compounds of formula! wherein A is 3 , 5-di chTorophenyl , B is CO, C is 0 and is tropanyl · antagonise the pulmonary depressor reflex in animal s .

The action of the compounds may be-observed in spontaneously breathing rabbits which are anesthetized by a continuous infusion of sodium pentobarb tal . Both vagi are intact and the systolic , arterial blood pressure, heert beat, breathing rate and platelet count are normal.

Pulmonary embolism is produced by injecting 1 mg Sephadex 25 G- beads suspended in 0.2 ral de-xtran (6¾) in 1 minute intervals in 6 animals into the right atrium, Preti-eatment with the compounds of the invention i .v. at a dose of from 0.1 to 1 mg/kg produces a reduction in mortality and an improvement in the cardiovascular and breathing reflex parameters resulting during the developing lung embolism. -42- 100-6939 For this indication, the appropriate dosage w ll , of course, vary depending upon, for example, the compound of the invention 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 daily dosages from about 0.1 mg/kg to about 5 mg/kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from about 5 mg to about 50 mg of a compound of the invention conveniently administered, for example, in divided doses up to four times a day, preferably parenteral ly , The compounds are preferably administered in the form of a pharmaceutical composition e.g. as described above.

The compounds of the invention may be administered for the lung embolism, by any conventional route, in particular enterally (if appropriate), preferably orally, e.g., in the form of tablets or capsules, or parenterally (if appropriate), e.g. , in the form of injectable solutions or suspensions, or by the nasal route. - 43 - The compounds of the invention also inhibit cancer therapy induced emesis in animals as indicated by standard tests, e.g. an inhibition of cis-platinin (10 mg/kg i.v.) induced emesis in ferrets at a dose of from about 0.005 'to about 0.5 mg/kg i , v, The compounds of the invention furthermore are useful in the treatment of other serotonin HT.. - 1 nduced gas tro- ntes ti na 1 disorders, e.g. as indicated in activity in tests indicated in EP 189002 at the same order of activity.

The compounds are useful in the treatment of disorders resulting from increased peristaltic movements in the intestines and intestinal disorders arising or from activation of 5-HT3 receptors, including diarrhea, e.g. sercretory diarrhea,, i bacterial induced diarrhea, choleic diarrhea, traveller's diarrhea and psychogenic diarrhea, Crohn's disease, spastic colon and irritable bowel syndrome. The compounds are also indicated to be useful in the treatment of disorders due to hypersecretion in the intestines, e.g. as a result of inflammation such as arising out of gastritis, peptic ulcer, biliary dyskinesia, appendicitis, ulcerative colitis and due to carcinoid syndrome leading to increased 5-HT secre-ti on .

Furthermore, the compounds are useful in the treatment of disorders arising from decreased peristaltic movements in the stomach and/or stomach disorders arising from activation of δ-ΗΤ^ receptors, including those arising from decreased gastric emp^ ing, including treatment of oesophageal motility disturbances, achalasia, hiatus hernia, cardiac insufficiency, gastroesophageal and gas troduodenal reflux, stomach hypotonia and pylorus hyperplasia.

- - The compounds are moreover useful in treatment of schizophrenia and mania and anxiety.

For all these indications, the compounds may be administered in the same manner as for the rhi ni ti s " i ndi cat ons and in the same manner as described in European Patent Publication No. 189002.

Toxicity and Tol e rab 1 i ty : Toxicity and Tolerability studies may be effected in conventional manner with the compounds of the invention to determine the upper dosage.

Toxicity studies may be effected for example in the rat and the dog over for example 26 weeks.

For compound E over 26 weeks the no toxic effect bowel in the dog was 5-20 mg/kg/daily p.o.. For the rat it was 16 to 45 mg/kg per day p.o.. Other compounds of the invention may have the same order of tolerability. In healthy human volunteers single doses up to 150 mg were well tolerated without relevant side effects. - 45 - 96797/2 The following examples illustrate the invention.

EXAMPLE 1 : Tablets for; oj- l_admumtration Tablets containing the constituents as specified below were produced in conventional manner and are used in the indications specified above. l-methyl-N-(endo-9-methyl-9-aza-bicyclo-[3,3,l] indol-3-yl) carboxylic acid amide in form of the hydrochloride 16.9 mg (corresponding to 15 mg free base) Hydroxy-propyl -eel lulose 1.2 mg Corn Starch 12.0 mg Lactose 92.8 mg Silica 0.6 mg Magnesium stearate 1.5. mg Tablet weight 125.0 mg EXAMPLE 2: a£sul es_f or_oraJ_ a_dmi n_i s_tr_ation_ Capsules containing the constituents as specified below are produced in conventional manner and are used in the indications specified above. 1 -methyl -N- ( endo-9-methyl-9-aza-bicyclo-C3,3, 1] indol-3-yl ) carboxylic acid amide in form of the hydrochloride ( corresponding to 15 mg base) 16.9 mg Lactose 28.7 mg Silica 1.5 mg Magnesium stearate _3 g_ Capsule Content weight of 50.1 mg - 46 - 96797/2 EXAMPLE 3: Injectum soUi t_i on f o r_i ^v^ administration A composition for injection is made up in conventional manner and is used at a dose of 10 mg a day. 1-methyl-N— ( endo-9-methyl A 8 C -9-aza-bicyclo-[3 , 3,1] indol-3-yl) carboxylic acid amide in form of the hydrochloride 1 1..113^1 } ? 2. 275566^2) 1 111. ,282 Acetic acid (99 to 100%)* 1.2 0. 6 0. ,6 Sodium acetate 3. H.O* 1.8 3. ,18 3. ,18 Sodium chloride 8 7. ,5 6. ,5 Water for injection to 1.0 ml 1 ) 2 ) = 1 mg free base, = 2 mg free base, "" = 10 mg free base pH value 4.3;*8uffer used 1/30 molar EXAMPLE 4: a£S u 1 es_f or_o raj_ a dm i n i s t r a_t i o n_ 5 mg and 15 mg capsules (A and B respectively) containing the constituents as specified below were produced in conventional manner and are used in the indications specified above 2 - 4 times a day in the case of A and once a day in the case of B.

A mg B mg l-methyl-N-(endo-9-methyl -9-aza-bicyclo-[3,3,l] indol-3-yl) carboxylic acid amide in form of the hydrochloride 5.641 16. .92 Lactose 200 mesh 84.929 79, .29 Lactose 100 mesh 84.43 79, .29 Corn starch 120.00 120, .00 Silica 1.5 1. .5 Magnesium stearate 3.0 3, .0 300 mg 300 mg Capsules containing other weights can be formulated in conventional manner. - 47 96797/2 EXAMPLE 5: as_aJ_ J_iqui_d_Com£os_Uion Quantity of Components components l-methyl-N-(endo-9-methyl-9-aza-bicyclo-[3,3,l] indol-3-yl) carboxylic acid amide in form of the hydrochloride ] 00 mg benzalkonium chloride 0.1 mg NaCl (0.9% aqueous solution) 0.6 ml di sti 1 led water 0.4 ml The solution obtained is filtered (e.g. through a 0.2 yum filter) and fi l led into a nasal canister, or a gelatinous foam (SP0NG0STAN) is soaked with the solution. It is administered e.g. for the treatment of rhinitis, lung embolism or to improve the absorption of other active agents .

EXAMPLE 6: Na s_aj_ _H S l _C om DO s_i _t i on Quantity of Components components l-methyl-N-(endo-9-methyl-9-aza- bicyclo-[3,3,l] indol-3-yl) carboxylic acid amide in form of the hydrochloride 50 mg benzalkonium chloride 0.1 mg NaCl (0.9% aqueous solution) 0.83 ml di sti 1 led water 0.17 ml The solution obtained is fi ltered (e.g. through a 0.2 jjm fi lter) and fi l led into a nasal spray canister, or a gelatinous foam (SP0NG0STAN) is soaked with the solution. It is administered in analogous manner to that di sclosed in example 5. - 48 - 96797/2 The aforegoing description may contain subject matter which is not within the scope of the claims, but is retained herein for the sake of completeness of the description. 96797/3 - 49 -

Claims (4)

1. Use of a compound of formula la wherein R1S is hydrogen, (Ci.10)alkyl, (C3.9)cycloalkyl, (Cj.6)alkenyl, phenyl or phenyl(C1.3)alkyl and one of the groups Ri6, R17 and Rlg is hydrogen, (Ci.6)alkyl, (C3.7)cycloalkyl, ( .^alkenyl or phenyl(C1.3)alkyl, and the others independendy are hydrogen, or (Cw)alkyl, in the manufacture of a medicament suitable for the treatment of impaired approach oriented behaviour in stressful situations, for increasing vigilance, for treating rhinitis or for treating lung embolism, substantially as described in the specification.

2. Use according to claim 1, wherein the compound of formula la is 1, 2, 3, 9-tetrahydro-9-methyl- 3-[(2-methyl-lH-imidazol-l-yl)-methyl-4H-carbazol-4-one.

3. A compound of formula la as defined in claim 1, for use as a medicament suitable for the treatment of impaired approach oriented behaviour in stressful situations, for increasing vigilance, for treating rhinitis or for treating lung embolism.

4. 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-memyl-lH-irriidazol-l-yl)-memyl-4H-carbazol-4-on for use as a medicament suitable for the treatment of impaired approach oriented behaviour in stressful situations, for increasing vigilance, for treating rhinitis or for treating lung embolism. For the Applicants, DR. REINHOLA COHN AND PARTNERS