EP0749422A1 - Indole derivatives as cck receptor antagonists - Google Patents

Abstract

A novel cholecystokinin antagonist of formula (I) with good bioavailability useful as an agent in the treatment of obesity, hypersecretion of gastric acid in the gut, gastrin-dependent tumors, or as an antipsychotic is disclosed. Further, the compound is an antianxiety agent and antiulcer agent. It is useful for preventing the response to the withdrawal from chronic treatment with use of nicotine, diazepam, alcohol, cocaine, coffee, or opioids. The compound of the invention is also useful in treating and/or preventing panic. Also disclosed is a pharmaceutical composition and processes for preparing the compound. An important feature of the instant invention is the absolute oral bioavailability of the compound.

Description

INDOLE DERIVATIVES AS CCK RECEPTOR ANTAGONISTS **********************************************

BACKGROUND OF THE INVENTION

Agents acting at central cholecystokinin (CCK) receptors may induce satiety (Schick, Yaksh, and Go, Regulatory Peptides 14:277-291, 1986). They are also expected to act as analgesics (Hill, Hughes, and Pittaway, Neuropharmacology 26:289-300, 1987), and as anticonvulsants (MacVicar, Kerrin, and Davison, Brain Research 406:130-135, 1987).

Reduced levels of CCK-peptides have been found in the brains of schizophrenic patients compared with controls (Roberts, Ferrier, Lee, Crow, Johnstone,

Owens, Bacarese-Hamilton, McGregor, O'Shaughnessey, Polak, and Bloom, Brain Research 288:199-211, 1983). It has been proposed that changes in the activity of CCK neurones projecting to the nucleus accumbens may play a role in schizophrenic processes by influencing dopaminergic function (Totterdell and Smith, Neuroscience 19:181-192, 1986). This is consistent with numerous reports that CCK peptides modulate dopaminergic function in the basal ganglia and particularly the nucleus accumbens (Weiss, Tanzer, and Ettenberg, Pharmacology, Biochemistry and Behaviour 30:309-317, 1988; Schneider, Allpert, and Iversen, Peptides 4:749-753, 1983). It may therefore be expected that agents modifying CCK receptor activity may have therapeutic value in conditions associated with disturbed function of central dopaminergic function such as schizophrenia and Parkinson's disease.

CCK and gastrin peptides share a common carboxy terminal pentapeptide sequence and CCK peptides can bind to the gastrin receptor of the stomach mucosa and elicit acid secretion in many species including human (Konturek, Gastrointestinal Hormones, Ch. 23, pp 529-564, 1980, ed. G. B. J. Glass, Raven Press, NY) . Antagonists of the CCK-B receptor would also be expected to be antagonists at the stomach gastrin receptor and this would also be of value for conditions involving excessive acid secretion.

CCK and gastrin peptides have trophic effects on the pancreas and various tissues of the gastro¬ intestinal tract (Johnson, ibid., pp 507-527), actions which are associated with increased DNA and RNA synthesis. Moreover, gastrin secreting cells are associated with certain gastrointestinal tumors as in the Zollinger-Ellison syndrome (Stadil, ibid., pp 729-739) , and some colorectal tumors may also be gastrin/CCK dependent (Singh, Walker, Townsend, and

Thompson, Cancer Research 46:1612, 1986; Smith, J. P., Gastroenterology 95:1541, 1988). Antagonists of CCK/gastrin receptors could therefore be of therapeutic value as antitumor agents. The CCK peptides are widely distributed in various organs of the body including the gastrointestinal tract, endocrine glands, and the nerves of the peripheral and central nervous systems. Various biologically active forms have been identified including a 33-amino acid hormone and various carboxyl- terminus fragments of this peptide (e.g., the octapeptide CCK26-33 and the tetrapeptide CCK30-33) . (G. J. Dockray, Br. Med. Bull. 38 (3) :253-258, 1982). The various CCK peptides are thought to be involved in the control of smooth muscle contractility, exocrine and endocrine gland secretion, sensory nerve transmission, and numerous brain functions. Administration of the native peptides cause gall bladder contraction, amylase secretion, excitation of central neurons, inhibition of feeding, anticonvulsive actions and other behavioral effects. (Cholecystokinin: Isolation, Structure and Functions, G. B. J. Glass, Ed., Raven Press, New York, 1980, pp 169-221; J. E. Morley, Life Sciences 27:355-368, 1980; Cholecystokinin in the Nervous System, J. de Belleroche and G. J. Dockray, Ed., Ellis Horwood, Chichester, England, 1984, pp 110-127.)

The high concentrations of CCK peptides in many brain areas also indicate major brain functions for these peptides (G. J. Dockray, Br. Med. Bull. 38 (3) :253-258, 1982) . The most abundant form of brain CCK found is CCK26-33, although small quantities of CCK30-33 exist (Rehfeld and Gotterman, J. Neurochem. 32:1339-1341, 1979). The role of central nervous system CCK is not known with certainty, but it has been implicated in the control of feeding (Della-Fera and Baile, Science 206:471-473, 1979).

Currently available appetite suppressant drugs either act peripherally, by increasing energy expenditure (such as thyroxine) , or in some other manner (such as the biguanides) , or act by exerting a central effect on appetite or satiety.

Centrally acting appetite suppressants either potentiate central catecholamine pathways and tend to be stimulants (for example, amphetamine), or influence serotonergic pathways (for example, fenfluramine) . Other forms of drug therapy include bulking agents which act by filling the stomach, thereby inducing a "feeling" of satiety.

CCK is known to be present in some cortical inter- neurones which also contain gamma-aminobutyric acid (GABA) (H. Demeulemeester et al, J. Neuroscience 8:988-1000, 1988). Agents that modify GABA action may have utility as anxiolytic or hypnotic agents (S. C. Harvey, The Pharmacological Basis of Therapeutics (7th ed.) 1985, pp 339-371, MacMillan) .

Thus, agents which modify CCK action may have parallel anxiolytic or hypnotic activities. The role of CCK in anxiety is disclosed in TIPS 11:271-273, 1990, and is fully detailed in Woodruff, G. N. and Hughes, J., 1991, Ann. Rev. Pharmacol, and Toxicol. 31, 469-501.

WO 92/04045 published March 19, 1992, concerns dipeptoids useful, for example, as anxiolytics.

SUMMARY OF THE INVENTION

The invention relates to a novel compound of the formula

and the pharmaceutically acceptable salts thereof.

The present invention relates to a pharmaceutical composition containing an effective amount of a compound according to Formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for appetite suppression.

The compounds are also useful as anxiolytics, antipsychotics, especially for treating schizophrenic behavior, as agents in treating disorders of the extrapyramidal motor system, as agents for blocking the trophic and growth stimulating actions of CCK and gastrin, and as agents for treating gastrointestinal motility. Compounds of the invention are also useful as analgesics, and they potentiate the effect of morphine. They can be used as an adjunct to morphine and other opioids in the treatment of severe pain such as cancer pain, and reduce the dosage of morphine required in the treatment of pain where morphine is contraindicated.

An additional use for compounds of the invention is that a suitable radiolabeled isotope gives an agent suitable for treatment of gastrin dependent tumors such as those found in colonic cancers. 1-125 radiolabeled compounds of the invention can also be used as diagnostic agents by localization of gastrin and CCK-B receptors in both peripheral and central tissue. The invention further relates to a method of appetite suppression in mammals which comprises administering an amount effective to suppress appetite of the composition described above to a mammal in need of such treatment.

The invention also relates to a pharmaceutical composition for reducing gastric acid secretion containing an effective amount of a compound of Formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for reducing gastric acid secretion. The invention also relates to a method for reducing gastric acid secretion in mammals which comprises administering an amount effective for gastric acid secretion reduction of the composition described above to a mammal in need of such treatment. The invention also relates to a pharmaceutical composition containing an effective amount of a compound of Formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for reducing anxiety. The invention also relates to a method for reducing anxiety in mammals which comprises administering an amount effective for anxiety reduction of the composition described above to a mammal in need of such treatment.

The invention also relates to a pharmaceutical composition containing an effective amount of a compound of Formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for treating gastrointestinal ulcers.

The invention further relates to a method for treating gastrointestinal ulcers in mammals which comprises administering an amount effective for gastrointestinal ulcer treatment of the composition as described above to a mammal in need of such treatment. The invention also relates to a pharmaceutical composition containing an effective amount of a compound of Formula I in combination with a pharma¬ ceutically acceptable carrier in unit dosage form effective for treating psychosis, i.e., schizophrenia. The invention further relates to a method for treating psychosis in mammals which comprises ^• administering an amount effective for treating psychoses of a composition as described above to a mammal in need of such treatment.

The invention also relates to pharmaceutical compositions effective for stimulating or blocking CCK or gastrin receptors, for altering the activity of brain neurons, for schizophrenia, for treating disorders of the extrapyramidal motor system, for blocking the trophic and growth stimulating actions of CCK and gastrin, and for treating gastrointestinal motility.

The invention also relates to a pharmaceutical composition for preventing the withdrawal response produced by chronic treatment for abuse of drugs or alcohol. The invention further relates to a method for treating the withdrawal response produced by withdrawal from chronic treatment or withdrawal from abuse of drugs or alcohol. Such drugs include benzodiazepines, especially diazepam, cocaine, alcohol, and nicotine.

Withdrawal symptoms are treated by administration of an effective withdrawal treating amount of a compound of the invention.

The invention also relates to a pharmaceutical composition containing an effective amount of a compound of Formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for treating and/or preventing panic. The invention also relates to a method for treating and/or preventing panic in mammals which comprises administering an amount effective for panic treatment and/or prevention of the composition described above to a mammal in need of such treatment. The invention further relates to the use of the compounds of Formula I to prepare pharmaceutical and diagnostic compositions for the treatment and diagnosis of the conditions described above.

The invention further provides processes for the preparation of compounds of Formula I. The compound of Formula I and its pharmaceutically acceptable salts have an absolute oral bioavailability in rats of 30%. This bioavailability is substantially higher than other CCK-B antagonists of the dipeptoid type. DETAILED DESCRIPTION

The compounds of the present invention are represented by the formula

and its pharmaceutically acceptable salts. Any solvates or hydrates of the compounds are also included. The compounds of the present invention have multiple chiral centers. In particular, the compounds of the present invention exist as diastereomers, mixtures of diastereomers, or as the mixed or the individual optical enantiomers. The present invention contemplates all such forms of the compounds. The mixtures of diastereomers are typically obtained as a result of the reactions described more fully below. Individual diastereomers may be separated from mixtures of the diastereomers by conventional techniques such as column chromatography, HPLC, or repetitive recrystallizations. Individual enantiomers may be separated by convention method well known in the art such as conversion to a salt with an optically active compound, followed by separation by chromatography or recrystallization and reconversion to the nonsalt form. Alternatively, they were synthesized by utilizing enantiomerically pure trans-(S,S)-2-aminocyclohexanol and trans- (R,R)-2-aminocyclohexanol prepared as shown in Scheme I (see Overman L.E., et. al., J. Org. Chem. 50:4154, 1985; also Aube J., et. al., Syn. Comm. 22(20) :3003, 1992) . Coupling reaction of the trans- (S,S) -2-aminocyclohexanol with R-2-Adoc-o-methyl-Trp using coupling reagent such as DCC, HOBt afforded compound of Example 6.

SCHEME I

A 1:1

Exainple 6

The individual substituted alpha amino acid starting materials are generally known or, if not known, may be synthesized and, if desired, resolved by methods within the skill of the art. (Synthesis of race ic [DL]-o-methyl tryptophan methyl ester - see Brana, M. F., et al, J. Heterocyclic Chem., 1980, 17:829.)

A key intermediate in the preparation of compounds of Formula I is a compound of formula

wherein R is selected from 9-fluorenylmethyl, Bz, and other suitable N-blocking groups. These are useful as intermediates in the preparation of compounds of Formula I. The compounds wherein R is 1-adamantyl,

2-adamantyl, 4-protoadamantyl, exo-bornyl, endo-bornyl, exo-norbornyl, endo-norbornyl, 2-methylcyclohexyl, 2-chlorocyclohexyl, or camphoryl are novel and are preferred. The disclosure of U.S. 4,757,151 is hereby incorporated by reference. It describes the 9-fluorenylmethyl blocking group.

Compounds of Formula II are prepared by reacting

ROH III wherein R is as defined above, with phosgene or a phosgene substitute to produce a corresponding compound of formula

R0C0C1 IV

and then reacting a compound of Formula IV with o-methyltryptophan to produce the desired compound of Formula II above. Alternatively, a compound of Formula IV can be reacted with an α-methyltryptophan methyl ester to produce

which can be converted to a compound of Formula II by known means such as hydrolysis with aqueous lithium hydroxide.

The compound of Formula I exhibits an absolute bioavailability of 30%. It is, therefore, unique in the area of CCK selective dipeptoids.

Single 20-mg/kg PO gavage or 20-mg/kg IV doses of the compound were given to fasted male Wistar rats (four per route) . For both routes, drug was administered as a solution of the compound in 0.1N HCl in ethanol:50% w/v hydroxypropyl-β-cyclodextrin in normal saline (30:70). Blood samples were drawn from jugular vein cannulae into syringes containing heparin before dosing and at different times up to 24 hours postdose. Plasma was harvested from blood by centrifugation and stored frozen until analysis. Plasma samples were analyzed for the compound using a validated liquid chromatographic method. The method involved liquid-liquid extraction of the compound and internal standard carbamic acid, (R)-[2- [ (hexahydro- lH-azepin-1-yl)amino]-1- (lH-indol-3-ylmethyl)-1-methyl- 2-oxoethyl]-, tricyclo[3.3.l.l^3,7]dec-2-yl ester, liquid chromatographic separation of the analytes on a C-18 column, and quantitation by fluorescence detection. Mean (±SD) pharmacokinetic parameters are presented in Table 1. Following IV dosing, the compound plasma concentrations declined rapidly in a multiexponential manner with a harmonic mean terminal elimination half-life of 0.87 (±0.02) hours. Following PO administration, absorption was generally rapid as demonstrated by a mean (±SD) tmax value of 1.8 (±1.6) hours. Corresponding mean (±SD) Cmax value was 756 (±264) ng/mL. Harmonic mean terminal elimination half-life after PO dosing was 0.99 (±0.28) hours, comparable to the IV half-life. Mean (±SD) absolute PO bioavailability, based on ratio of mean PO and IV AUC(0-~) values, was 30 (±8)%.

Absorption of the compound in rats following oral solution administration was generally rapid. Absolute oral bioavailability was 30%.

TABLE I. Summary of Mean (±SD) Compound 6 Pharmacokinetic Parameters in Fasted Male Wistar Rats Following a Single 20-mg/kg PO or IV Dose

Dose = mg/ g.

Cmax = Maximum observed drug plasma concentration (ng/ml) . tmax = Time to reach Cmax (hr) . t = Terminal elimination half-life, harmonic mean (hr) . AUC(O-tldc) = Area under the plasma concentration-time curve from zero to time of last detectable concentration (ng*hr/mL) .

AUC(0-») = Area under the plasma concentration-time curve from zero to infinite time (ng*hr/ιr_L) .

%F = Absolute bioavailability based on ratio of mean PO and IV AUC(0-«) values.

For preparing pharmaceutical compositions from the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

For preparing suppository preparations, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify. The powders and tablets preferably contain 5% to about 70% of the active component. Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.

Preferred pharmaceutically acceptable salts are the N-methyl glucamine salt and sodium.

Pharmaceutically acceptable salts are acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium acetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate. estolate, esylate, fumarate, glucaptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate) , pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannata, tartrate, teoclate, triethiodide, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. The term "preparation" is intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included.

Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.

Liquid form preparations include solutions, suspensions, and emulsions. Sterile water or water- propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration. Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art. Preferably the pharmaceutical preparation is in unit dosage form. In such form, the preparation is divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.

EXAMPLES

EXAMPLE 1 Carbamic acid, N-[2-[ (2-hydroxycyclohexyl)amino]-1- (1H- indol-3-ylmethyl)-l-methyl-2-oxoethyl]-,tricyclo-

[3.3.1.1³'⁷]dec-2-ylester, [lα(R) ,2β]

The title compound was synthesized by coupling trans-2-aminocyclohexanol with (R)-2-adamantyloxycarbonyl-2-methyltryptophan using DCC and HOBt.

Analysis for C₂9H₃₉N₃0₄ - 0. 5 H₂0 :

Calc : C, 69.29 ; H, 8 . 02 ; N, 8 . 35.

Found : C, 69 . 38 ; H, 8 . 46; N, 8 . 00 .

EXAMPLES 2 AND 3

Carbamic acid, [2-[ (2-hydroxycyclohexyl)amino]-1- (1H- indol-3-ylmethyl)-l-methyl-2-oxoethyl]-,tricyclo-

[3.3.1.1³'⁷]dec-2-ylester Isomer 1 TRP Center is R; Ring center unknown Carbamic acid, [2- [ (2-hydroxycyclohexyl) amino]-1- (1H- indol-3-ylmethyl)-l-methyl-2-oxoethyl]-,tricyclo- [3.3.1.l^3,7]dec-2-ylester Isomer 2 TRP Center is R; Other center unknown Individual diastereomers of Example 1 were separated by Waters Model 46K HPLC using 6 μm silica column (Prep Nova Pak®) . The mobile phase was ethyl acetate-hexane (60:40) and flow rate was 15 mL/minute. The first diastereomer (Example 2) (mp 130-137°C) had retention time of 11.92 minutes. The second diastereomer (Example 3) (mp 125-130°C) had retention time of 13.87 minutes.

EXAMPLE 4 (1S,2S)-trans-2- [ (R)- (α-Methylbenzyl)amino]cyclohexanol (A) and (1R,2R)-trans-2-[ (R)- (α)-Methylbenzyl)amino]- cyclohexanol (B)

To a well stirred solution of (R)-α-methyl- benzylamine (6.06 g, .005 mol) in methylene chloride (60 mL) was added dropwise a solution of Me₃Al

(27.5 mL, 2.0 M solution in toluene, 0.055 mol) at 0-5°C. The resulting solution was stirred at 0°C for additional 45 minutes, and then a solution of cyclohexene epoxide in methylene chloride (15 mL) was added dropwise at 0°C. The reaction mixture was stirred overnight at room temperature. The aluminate salt was decomposed at 0°C by adding NaF (8.82 g, 0.21 mol) followed by 6.0 mL of H₂0. After stirring at room temperature for 1 hour, the reaction mixture was passed through celite, dried over MgS0₄ and concentrated. Flash column chromatography (ethyl acetate/hexane/Et₃N 1:1:0.1) gave Compound A (4.5 g, 39.2% R_f = 0.5) in first fraction and Compound B (4.5 g, 39.2% R_f = 0.32) in the later fraction. EXAMPLE 5 (IS,2S) -trans-2-Aminocyclohexanol

A mixture of (IS,2S) -trans-2-[ (R) - (α-methyl- benzyl) amino]cyclohexanol (2.2 g, 0.01 mol), 10% Pd/C and ammonium formate (0.38 g, 0.06 mol) in methanol

(75 mL) was stirred overnight at room temperature. The reaction mixture was passed through celite and concentrated. The residue was then diluted with ethyl acetate, washed with water, dried and concentrated to give 0.92 g (80%) of the titled compound.

EXAMPLE 6 Tricyclo[3.3.1.1.³'⁷]dec-2-yl ester [lS-[loc(S*)2β] [2- [ (2-hydroxycyclohexyl) amino]- 1- (lH-indol-3-ylmethyl)-l-methyl-2-oxoethyl]carbamate A solution of (R)-2-adamantyloxycarbonyl- α-methyltryptophan (0.79 g, 0.002 mol) in ethyl acetate (60 mL) was treated with dicyclohexylcarbodiimide (0.495 g, 0.002 mol) and 1-hydroxybenzotriazole hydrate (0.35 g, 0.0022 mol). After stirring for 2 hours at room temperature, the precipitated dicyclohexyl urea was removed by filtration. To the clear filtrate (1S,2S)-trans-2-aminocyclohexanol (0.23 g, 0.002 mol) was added. The reaction mixture was stirred at room temperature overnight. The ethyl acetate solution was washed with 5% HCl, 5% NaHC0₃, and brine. The organic phase was dried over MgS0₄ and concentrated to yield a white foam. The crude product was chromatographed over silica gel using 50% ethyl acetate/hexane to give 0.72 g of white solid which was further purified by

Waters HPLC (Model 46K) using 6 urn silica column (Prep Nova Pak) . The mobile phase was ethyl acetate/hexane (1:1), flow rate was 15 mL/minute, and retention time of 9.54 minutes. Yield of the title compound 0.4 g (39.5%), mp 137-142°C. Analysis for C2₉H3₉N3O:

Calc: C, 70.56; H, 7.96; N, 8.51

Found: C, 70.76; H, 8.31; N, 7.94

Claims

1. A compound named tricyclo [3.3.1.1.^3,7]dec-2-yl ester

[1S-[1α(S*)2β] [2-[(2-hydroxycyclohexyl)amino]- 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]- carbamate or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a

therapeutically effective amount of a compound according to Claim 1 and a pharmaceutically acceptable carrier.

3. A method of suppressing appetite in a mammal in need of such treatment comprising administering a therapeutically effective amount of a compound according to Claim 1.

4. A method of reducing gastric acid secretion in a mammal in need of such treatment comprising administering a therapeutically effective amount of a compound according to Claim 1.

5. A method of reducing anxiety in a mammal in need of such treatment comprising administering a therapeutically effective amount of a compound according to Claim 1.

6. A method of treating gastrointestinal ulcers in a mammal in need of such treatment comprising administering a therapeutically effective amount of a compound according to Claim 1.

7. A method of treating psychosis in a mammal in need of such treatment comprising administering a therapeutically effective amount of a compound according to Claim 1.

8. A method of blocking drug or alcohol withdrawal reaction in a mammal in need of such treatment comprising administering a therapeutically effective amount of a compound according to Claim 1.

9. A method of treating pain in a mammal in need of such treatment comprising administering a therapeutically effective amount of a compound according to Claim 1.

10. A method of treating and/or preventing panic in a mammal in need of such treatment comprising administering a therapeutically effective amount of a compound according to Claim 1.