WO2002074288A2

WO2002074288A2 - Treatment and prevention of sexual dysfunction resulting from ssri-therapy by using a tetrahydrobenz cd indole-6-carboxamide

Info

Publication number: WO2002074288A2
Application number: PCT/GB2002/001220
Authority: WO
Inventors: John Blundell Hutchison
Original assignee: Vernalis Research Ltd
Current assignee: Ligand UK Research Ltd
Priority date: 2001-03-15
Filing date: 2002-03-15
Publication date: 2002-09-26
Anticipated expiration: 2003-09-15
Also published as: AU2002246228A1; WO2002074288A3; GB0106446D0

Abstract

The use of an effective amount of compound (I) in the manufacture of a medicament for treatment of sexual dysfunction in a patient who is undergoing or is about to undergo treatment with a selective serotonin re-uptake inhibitor; and the use of an effective amount of compound (I) and one or more selective serotonin re-uptake inhibitor(s) in the manufacture of a medicament for the treatment of depression without inducing sexual dysfunction.

Description

CHEMICAL COMPOUNDS

The present invention relates to pharmaceutical compositions containing a 5HTTA agonist for treating and/or preventing sexual dysfunctions associated with the use of selective serotonin re-uptake inhibitors.

Selective serotonin re-uptake inhibitors (SSRIs) are acknowledged as effective and widely- used antidepressant drugs. They are better tolerated alternatives to the older tricyclic antidepressants (TCAs) for the treatment of depression (Mace, S; Taylor, D. Selective serotonin reuptake inhibitors: A review of efficacy and tolerability in depression. Expert Opin. Pharmacother. (2000), 1(5), 917-933). However, the widespread use of SSRIs has highlighted some unforeseen adverse effects associated with SSRIs, namely hyponatremia, EPSE and sexual dysfunction.

Even though adverse effects associated with antidepressant drug therapy rarely cause significant morbidity or mortality, the successful management of patients with depression requires recognition of potential adverse effects which include the discontinuation of this otherwise effective antidepressant therapy (Settle, E.C., Jr. Antidepressant drugs: disturbing and potentially dangerous adverse effects. J. Clin. Psychiatry (1998), 59(Suppl. 16), 25-30).

Adverse effects related to sexual function are common, esp. with TCAs, SSRIs, and venlafaxine and have been documented with individual drugs (Kennedy, S. H.; Eisfeld, B. S.; Dickens, S. E.; Bacchiochi, J. R.; Bagby, R. M. J. Antidepressant-induced sexual dysfunction during treatment with moclobemide, paroxetine, sertraline, and venlafaxine. Clin. Psychiatry (2000), 61(4), 276-281). Sexual dysfunction (SD) often leads to non- compliance and self-discontinuation of therapy; the increasing use of SSRIs has meant that the latter side-effect has come into sharper focus (Sargent, P. A.; Goodwin, G. M., SSRIs and sexual function, Neurosci. Intell. Unit (1999), 6 (Selective Serotonin Reuptake Inhibitors (SSRIs)), 81-94).

As many as half of patients treated with selective serotonin reuptake inhibitors report delayed orgasm (ejaculation), and virtually all patients treated with clomipramine experience anorgasmia. Although depressed patients do care about their sexual function, they may be reluctant, for fear of embarrassment, to report SD spontaneously to their physicians. SD is probably underreported and may result in covert noncompliance and attendant relapse into depression. As a result of this potentially dangerous scenario, new treatments are being sought for antidepressant-induced sexual dysfunction (Rothschild, A. J. New directions in the treatment of antidepressant-induced sexual dysfunction. Clin. Ther. (2000), 22(Suppl. A), A42-A61.

The non-serotonergic agent Sildenafil has been used in the treatment of sexual dysfunction induced by selective serotonin reuptake inhibitors (Nurnberg, H. G.; Hensley, P. L.; Lauriello, J. Sildenafil in the treatment of sexual dysfunction induced by selective serotonin reuptake inhibitors: an overview. CNS Drugs (2000), 13(5), 321-335).

Some of the potential treatments for sexual dysfunction are serotonergic agents, such as cyproheptadine, a 5HT₂ antagonist with antihistaminergic and adrenolytic properties. This compound has been investigated in a clinical trial (Aizenberg, D.; Zemishlany, Z.; Weizman, A. Cyproheptadine treatment of sexual dysfunction induced by serotonin reuptake inhibitors. Clin. Neuropharmacol. (1995), 18(4), 320-4). A range of 5HT2 receptor ligands have been described in WO 0028993 Al (Nortran Pharmaceuticals Inc.) as being useful as pro-erectile compounds.

A series of oxazole derivatives have been claimed as serotonin-lA receptor agonists in US 6057340 (American Home Products Corporation, USA), and hexahydropyrazinoquinoline derivatives exhibiting serotonin 5-HTi_A receptor agonist effects have been claimed in WO 9623789 Al (Sankyo Co., Ltd., Japan). Some ring-substituted 2-amino- 1,2,3 ,4-tetrahydro- naphthalenes and 3-aminochromans have been claimed as selective agonists at the 5-HT_IA receptor in EP 385658 (Lilly, Eli and Co., USA).

In EP 0633023 (Lilly, Eli and Co., USA), a series of tetrahydrobenz[cd]indole-6- carboxamides are claimed for the prevention of emesis and treatment sexual dysfunction. The present invention provides the use of an effective amount of compound 1 (also referred to herein as a SHT _A agonist) to prepare a medicament for treatment of sexual dysfunction in a patient (preferably a human) who is undergoing or is about to undergo treatment with a selective serotonin re-uptake inhibitor (SSRI).

Compound 1 is (4R)-4-(dipropylamino)-l,3,4,5-tetrahydrobenz[cd3indole~6-carboxamide, also known as (R)-4-(dipropylamino)-l,3,4,5-tetrahydrobenz[cd]indole-6-carboxamide:

Compound 1

The present invention further provides a method of treatment of sexual dysfunction in a patient (preferably a human) who is undergoing or is about to undergo treatment with a selective serotonin re-uptake inhibitor, said method including administering to a patient in need of such treatment an effective amount of compound 1 (also referred to herein as a 5HT_IA agonist).

The present invention further provides a composition comprising compound (1) and one or more selective serotonin re-uptake inhibitors (SSRIs), preferably selected from those set out in any of claims 3 to 8.

The present invention further provides the use of compound (1) and one or more selective serotonin re-uptake inhibitors (SSRIs) in the manufacture of a medicament for the treatment of depression without inducing sexual dysfunction. The present invention further provides a method of treatment of depression without inducing sexual dysfunction, said treatment including administering to a patient in need of such treatment an effective amount of compound (1) and one or more selective serotonin re-uptake inhibitors (SSRIs). Compound (1) and the one or more SSRIs may be present in the same formulation or may be present in different formulations for administration sequentially or simultaneously.

The term "sexual dysfunction", as used herein, means any disorder related to the erectile response in male mammals and the sexual drive and sexual (both arousal and orgasmic) reflexes in male or female mammals. Accordingly, the term "sexual dysfunction" includes male sexual dysfunction including impotence (also known in the art and referred to herein as "male erectile dysfunction"), retarded ejaculation and anorgasm, and female sexual dysfunction including the vasculogenic symptoms of delayed vaginal engorgement, diminished vaginal lubrication, . pain or discomfort with intercourse (dyspareunia), diminished vaginal sensation, diminished vaginal orgasm, diminished clitoral sensation and diminished clitoral orgasm.

Reference to compound 1 herein shall be understood to include all active forms thereof, including the free form thereof; all pharmaceutically acceptable acid addition salts thereof; all prodrugs, polymorphs, hydrates, solvates and stereoisomers (e.g. diastereomers and enantiomers) thereof; and active metabolites thereof.

The term "pharmaceutically acceptable acid addition salts", as used herein, refers to the acid addition salts of the compounds of which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable acid addition salts include those salts prepared by reaction of the free base form of the compound with a pharmaceutically acceptable mineral or organic acid. Pharmaceutically acceptable mineral or organic acids commonly employed to form such salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric and phosphoric acid, as well as organic acids such as paratoluenesulfonic, methane-sulfonic, hippuric, oxalic, parabromophenylsulfonic, carbonic, succinic, citric, benzoic, acetic, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydro-genphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, hydroiodide, acetate, nitrate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, beta -hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-2-sulfonate, p- tolutenesulfonate, mandelate, hippurate, and like salts.

A particularly preferred pharmaceutically acceptable acid addition salt for use in the present invention is the hippurate salt. Such salt form, and processes for preparing same, is disclosed in European Patent Application 444,852, the teachings of which are hereby incorporated by reference.

Experimental procedures

The compound 1 is synthesised as described (Carr, M. A.; Creviston, P. E.; Hutchison, D. R.; Kennedy, J. H.; Khau, N. N.; Kress, T. J.; Leanna, M. R.; Marshall, J. D.; Martinelli, M. J.; Peterson, B. C; Varie, D. L.; Wepsiec, J. P. J. Org. Chem. (1997), 62, 8640-8653). Compound 1 has been described as a selective serotonin 1A agonist (Foreman, M. M.; Fuller, R. W.; Leander, J. D; Benvenga, M. J.; Wong, D. T.; Nelson, D. L.; Calligaro, D. O.; Swanson, S. P.; Lucot, J. B.; Flaugh, M. E. J. Pharmacol. Exp. Ther. (1993), 267, 58- 71).

Animal Models of Sexual Function

Sexual behaviour has been studied in rats following single doses of Compound 1. Latency and stimulus threshold for ejaculation were reduced in rats. The males demonstrated increased sexual activity at relatively low doses (1.0 to 100 μg/kg, s.c.)

Compound 1 facilitated sexual behaviour in male rats by decreasing ejaculatory latency and the number of mounts required for ejaculation (Figure 1). These findings indicate that Compound 1 can lower the latency and stimulus requirements for this sexual reflex as a part of its capacity to improve all aspects of the male rat sexual response.

Compound 1 also induced increases in the efficiency and rate of copulation (Figure 2). The increased copulatory efficiency (number of intromissions/total number of mounts) suggests that Compound 1 improved the capacity of these rats to achieve erections sufficient for intromission. The increased copulatory rate indicates that Compound 1 elevated the sexual drive, thereby providing utility in treating disorders related to erectile response, sexual drive, and orgasmic reflexes.

As mentioned above, the present invention utilizes pharmaceutical compositions. In making these compositions, one or more active ingredients will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

Some examples of suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, saline solution, syrup, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate and mineral oil. The formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents. The compositions may be formulated so as to provide rapid, sustained or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.

The compositions are formulated, preferably in a unit dosage form, such that each dosage contains from about 50 μm to about 500 mg, more usually about 50 μm to about 30 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic or prophylactic effect, in association with one or more suitable pharmaceutical diluents, excipients or carriers. The compound employed in the present invention is effective over a wide dosage range for preventing or treating sexual dysfunction. Thus, as used herein, the term "effective amount" refers to a dosage range of from about 0.5 μm to about 10 mg/kg of body weight per day. In the treatment of adult humans, the range of about 0.5 μm to about 1 mg/kg, in single or divided doses, is preferred. However, it will be understood that the amount of compound actually administered will be determined by a physician, in light of the relevant circumstances including the condition to be treated, the choice of compound to be administered, whether prophylactic or therapeutic effect is desired, the chosen route of administration, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and, therefore, the above dosage ranges are not intended to limit the scope of the invention in any way.

The following formulation examples may employ as active ingredients compounds 1 or any of its pharmaceutically acceptable salts. The examples are illustrative only and are not intended to limit the scope of the invention in any way.

Example 1

Hard gelatin capsules suitable for preventing emesis are prepared using the following ingredients:

Quantity (mg/capsule)

(4R)-4-(dipropylamino)-l,3,4,5-tetrahydrobenz[cd]indole-6-carboxamide hippurate: 250

Starch dried : 200

Magnesium stearate : 10

The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.

Example 2

A tablet suitable for preventing emesis is prepared using the ingredients below: Quantity (mg/tablet)

(4R)-4-(dipropylamino)-l ,3,4,5-tetrahydrobenz[cd]indole-6-carboxamide : 250 Cellulose, microcrystalline : 400 Silicon dioxide : 10 Stearic acid : 5

The components are blended and compressed to form tablets each weighing 665 mg.

Example 3

An aerosol solution suitable for treating sexual dysfunction is prepared containing the following components: Weight

(4R)-4-(dipropylamino)-l ,3,4,5-tetrahydrobenz[cd]indole-6-carboxamide : 0.25 Ethanol : 29.75

-Propellant 22 (Chlorodifluoromethane) : 70.00 .

The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30 DEG C and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. Naive units are then fitted to the container.

Example 4

Tablets suitable for treating sexual dysfunction, each containing 60 mg of active ingredient are made up as follows:

(4R)-4-(dipropylamino)-l,3,4,5-tetrahydrobenz[cd]indole-6-carboxamide : 60 mg

Starch 45 : mg

Microcrystalline cellulose : 35 mg

Polyvinylpyrrolidone (as 10% solution in water) : 4 mg Sodium carboxymethyl starch : 4.5 mg

Magnesium stearate : 0.5 mg

Talc : 1 mg

Total : 150 mg

The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50-60 DEG C and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed by a tablet machine to yield tablets each weighing 150 mg.

Example 5

Capsules suitable for preventing emesis, each containing 80 mg of medicament, are made as follows:

(4R)-4-(dipropylamino)-l,3,4,5-tetrahydrobenz[cd]indole-6-carboxamide : 80 mg Starch : 59 mg Microcrystalline cellulose : 59 mg Magnesium stearate : 2 mg Total : 200 mg

The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities.

Example 6

Suppositories suitable for treating sexual dysfunction, each containing 225 mg of active ingredient, are made as follows:

(4R)-4-(dipropylamino)-l,3,4,5-tetrahydrobenz[cd]indole-6-carboxamide : 225 mg Saturated fatty acid glycerides to 2,000 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.

Example 7 Suspensions suitable for preventing emesis, each containing 50 mg of medicament per 5 ml dose, are made as follows:

(4R)-4-(dipropylamino)-l,3,4,5-tetrahydrobenz[cd]indole-6-carboxamide : 50 mg Sodium carboxymethyl cellulose : 50 mg Syrup : 1.25 mg Benzoic acid solution : 0.10 ml Flavour q.v. Colour q.v. Purified water to 5 ml

The medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and colour are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.

Example 8

Capsules suitable for use in treating sexual dysfunction, each containing 150 mg of medicament, are made as follows: (4R)-4-(dipropylarnino)-l,3,4,5-tetrahydrobenz[cd]indole-6-carboxamide hippurate : 150 mg

Starch : 164 mg

Microcrystalline cellulose : 164 mg

Magnesium stearate : 22 mg Total : 500 mg

The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 500 mg quantities.

Claims

1. The use of an effective amount of compound 1

(1) to prepare a medicament for treatment of sexual dysfunction in a patient who is undergoing or is about to undergo treatment with a selective serotonin re-uptake inhibitor (SSRI).

2. A method of treatment of sexual dysfunction in a patient who is undergoing or is about to undergo treatment with a selective serotonin re-uptake inhibitor (SSRI), said method including administering to a patient in need of such treatment an effective amount of compound 1.

3. Use of an effective amount of compound (1) and one or more selective serotonin re-uptake inhibitors (SSRIs) in the manufacture of a medicament for the treatment of depression without inducing sexual dysfunction.

4. A method of treatment of depression without inducing sexual dysfunction, said treatment including administering to a patient in need of such treatment an effective amount of compound (1) and one or more selective serotonin re-uptake inhibitors (SSRIs).

5. The use of claims 1 or 3 or the method of claims 2 or 4 where the SSRI is citalopram.

6. The use of claims 1 or 3 or the method of claims 2 or 4 where the SSRI is fluoxetine.

7. The use of claims 1 or 3 or the method of claims 2 or 4 where the SSRI is fluvoxamine.

8. The use of claims 1 or 3 or the method of claims 2 or 4 where the SSRI is paroxetine.

9. The use of claims 1 or 3 or the method of claims 2 or 4 where the SSRI is sertraline.

10. The use of claims 1 or 3 or the method of claims 2 or 4 where the SSRI is venlafaxine.

11. A composition comprising compound (1) and one or more selective serotonin reuptake inhibitors (SSRIs).

12. A composition according to claim 9 wherein the SSRI is selected from those set out in any of claims 5 to 10.