WO2004058237A1

WO2004058237A1 - Therapeutic use of sibutramine and analogues thereof

Info

Publication number: WO2004058237A1
Application number: PCT/GB2003/005671
Authority: WO
Inventors: John Gary Montana
Original assignee: Amedis Pharmaceuticals Ltd.
Priority date: 2002-12-24
Filing date: 2003-12-23
Publication date: 2004-07-15
Also published as: AU2003295160A1; GB0230134D0

Abstract

Sibutramine and analogues thereof are useful in the treatment of nausea, emesis and related conditions.

Description

THERAPEUTIC USE OF SIBUTRAMINE AND ANALOGUES THEREOF

Field of the Invention

This invention relates to a new therapeutic use of sibutramine and analogues thereof. Background of the Invention

Sibutramine, i.e. [N-1 -[1 -(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-N,N- dimethylamine, is a neuronal monoamine reuptake inhibitor disclosed in US-A- 4746680 and US-A-4806570. Sibutramine inhibits the reuptake of norepinephrine and, to a lesser extent, serotonin and dopamine. See, e.g. Buckett et a/., Prog. Neuro-psychopharm & Biol. Psychiat, 12: 575-584, 1988; King er /., J. Clin. Pharm., 26: 607-611 (1989).

Sibutramine is marketed for the treatment of obesity. It is more selective for noradrenaline reuptake inhibition than for serotonin reuptake inhibition. (R)- Sibutramine has a similar monoamine reuptake inhibition profile to sibutramine. Metabolites of sibutramine, i.e. ((R)-desmethylsibutramine and (R)- didesmethylsibutramine), are more potent inhibitors of noradrenaline reuptake inhibition, but show similar selectivity over serotonin reuptake inhibition. (S)- Didesmethylsibutramine is the most selective noradrenaline reuptake inhibitor of the sibutramine metabolites, showing approximately 1000-fold selectivity over serotonin reuptake inhibition (see for example WO02/060424).

In the clinic, patients treated with selective noradrenaline reuptake inhibitors have been shown to experience a significant reduction in nausea and sexual dysfunction, adverse events that are common among those taking selective serotonin reuptake inhibitors (SSRIs) or noradrenaline serotonin reuptake inhibitors (SNRIs).

Sibutramine has been extensively studied, and reportedly could be used in the treatment of a variety of disorders. For example, US-A-4552828, US-A- 4746680, US-A-4806570 and US-A-4929629 disclose methods of treating depression using racemic sibutramine, and US-A-4871774 and US-A-4989175 disclose methods of treating Parkinson's disease and senile dementia, respectively, using racemic sibutramine. Other uses of sibutramine are disclosed in WO95/20949, W095/21615, W098/11884 and WO98/13033. The optically pure enantiomers of sibutramine have been considered for development. For example, WO94/00047 and WO94/00114 disclose methods of treating depression and related disorders using the (+)-and (-)-enantiomers of sibutramine, respectively. Summary of the Invention

The present invention is based on the discovery that prophylactic or therapeutic administration of sibutramine or derivatives thereof can prevent or diminish the nausea and/or emesis side-effects associated with administration of emetogens such as opiates or cytotoxic agents. This effect may not be limited to sibutramine or its derivatives but may extend to its active metabolites.

Accordingly, a first aspect of the invention is the use of a compound of formula (I)

wherein

Ar is aryl;

R¹ and R² are the same or different and are each hydrogen, alkyl, -CH₂-alkenyl, -CH₂-alkynyl, -CH₂-aryl, -CH₂-cycloalkyl, -CH₂-cycloalkenyl, cycloalkyl, cycloalkenyl, heterocycloaikyl, polycyclyl, -CH₂-heteroaryl, -CH₂-heterocycloalkyl or alkoxycarbonyl; and

R³ is hydrogen, alkyl, -CH₂-alkoxy, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocycloaikyl, polycyclyl, heteroaryl, -CH₂-heterocycloalkyl, alkanoyloxy or alkoxycarbonyl; or a pharmaceutically acceptable salt thereof; for the manufacture of a medicament for the treatment or prevention of a condition selected from nausea, emesis (including anticipatory nausea and vomiting, and morning sickness), drowsiness, somnolence, dizziness, motion sickness, respiratory depression, blurred vision, hallucination, dehydration, constipation, euphoria or vomiting. It will be understood that an active metabolite of the compound may also be used.

The condition may be associated with the administration of another therapeutic agent and therefore another aspect of the invention, is' a pharmaceutical composition comprising a compound of formula (I), a second compound which is a therapeutic agent and a pharmaceutically acceptable diluent or carrier. The compound of formula (I) may be formulated with the second compound in a combined preparation for simultaneous, separate or sequential use, for the treatment or prevention of a condition effected by the second compound.

Compounds of formula (I) may be effective in the treatment or prevention of conditions resulting from the administration of emetogenic compounds, for example opiates or cytotoxic agents. Nausea and emesis are examples of such conditions. Description of Preferred Embodiments

Certain compounds and combinations of substituents are preferred; in particular see the subclaims.

With regard to formula (I), it is preferred that R¹ and R² are each hydrogen or alkyl, more preferably methyl. R³ is preferably alkyl, more preferably isopropyl. Ar is preferably optionally substituted phenyl, more preferably 4-chlorophenyl.

The term "alkyl" as used herein refers to a straight or branched chain alkyl moiety having from one to six carbon atoms, and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like. "Cι-₆ alkyl" has the same meaning.

The term "alkenyl" as used herein refers to a straight or branched chain alkyl moiety having two to six carbon atoms and having in addition at least one double bond, of either E or Z stereochemistry where applicable. This term includes for example, vinyl, 1-propenyl, 1- and 2- butenyl, 2-methyl-2-propenyl etc. "C_2-6 alkenyl" has the same meaning.

The term "alkynyl" as used herein refers to a straight or branched chain alkyl moiety having two to six carbon atoms and having in addition at least one triple bond. "C₂.₆ alkynyl" has the same meaning. The term "alkoxy" as used herein refers to a straight or branched chain alkoxy group containing one to six carbon atoms, and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy and the like. "Cι-₆ alkoxy" has the same meaning.

The term "halogen" as used herein refers to F, Cl, Br or I.

The term "aryl" as used herein refers to optionally substituted aromatic ring systems comprising six to ten ring atoms, and optionally substituted polycyclic ring systems having two or more cyclic rings at least one of which is aromatic. This term includes for example, phenyl and naphthyl. The group may be optionally substituted with the substituents being the same or different in each occurrence and selected from alkyl, alkenyl, alkynyl, cyano, alkoxy, halogen, CF₃ and Si(R)₃. R is alkyl.

The term "cycloalkyl" as used herein refers to a saturated alicyclic moiety having from three to six carbon atoms and includes for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The group may be optionally substituted by any substituent described herein.

The term "cycloalkenyl" as used herein refers to an alicyclic moiety having from three to six carbon atoms and having in addition at least one double bond, and includes for example cyclopentenyl, cyclohexenyl and the like. The group may be optionally substituted by any substituent described herein.

The term "heterocycloaikyl" as used herein refers to a saturated heterocyclic moiety having from four to seven carbon atoms and one or more heteroatoms selected from the group N, 0, S and includes for example azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and the like. The group may be optionally substituted by any substituent described herein.

The term "polycyclyl" as used herein refers to two or more optionally substituted rings in which two or more carbons are common to two adjoining rings e.g. fused or bridged rings. The group may be optionally substituted by any substituent described herein.

The term "heteroaryl" as used herein refers to aromatic ring systems of five to ten atoms or which at least one atom is selected from 0, N and S and includes for example furanyl, thiophenyl, pyridyl, indolyl, quinolyl and the like. The group may be optionally substituted by any substituent described herein. The term "alkanoyloxy" as used herein refers to a straight or branched chain alkanoyloxy moiety containing one to six carbon atoms.

The term "alkoxycarbonyl" as used herein refers to a straight or branched chain alkoxycarbonyl moiety containing two to six carbon atoms.

Compounds of formula (I) are chiral. They may be in the form of a single enantiomer or diastereomer, or a racemate.

The term "active compound" as used herein refers to a compound of formula (I), including pharmaceutically salts and active metabolites thereof. The term "active" refers to a chemical or biological activity which is in accordance with the invention.

Preferred compounds of formula (I) include compounds of the following formulae, in racemic, non-racemic or single enantiomer form:

The specific preferred compounds of these formulae are: (+/-)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl-Λ/,/V-dimethylamine; (+)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl-Λ/,/V-dimethylamine; (-)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl-/V,Λ/-dimethylamine; (+/-)-1-[1-(4-chloroρhenyl)cyclobutyl]-3-methylbutyl-/V-methylamine; (+)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl-Λ/-methylamine; (-)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl-Λ/-methylamine; (+/-)-1 -[1 -(4-chlorophenyl)cyclobutyl]-3-methylbutylamine; (+)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine; and (-)-1 -[1 -(4-chlorophenyl)cyclobutyl]-3-methylbutylamine.

The compounds may be prepared in racemic form, or prepared in individual enantiomeric form by specific synthesis or resolution as will be appreciated in the art. The compounds may, for example, be resolved into their enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid followed by fractional crystallisation and regeneration of the free base. Alternatively, the enantiomers of the novel compounds may be separated by HPLC using a chiral column.

A compound of formula (I) may be in a protected amino form. The term "protected amino" as used herein refers to amino groups which are protected in a manner familiar to those skilled in the art. For example, an amino group can be protected by a benzyloxycarbonyl, tert-butoxycarbonyl, acetyl or like group, or in the form of a phthalimido or like group.

Some compounds of formula (I) may exist in the form of solvates, for example hydrates, which also fall within the scope of the present invention.

Compounds of formula (I) may be in the form of pharmaceutically acceptable salts, for example, addition salts of inorganic or organic acids. Such inorganic acid addition salts include, for example, salts of hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid and sulphuric acid. Organic acid addition salts include, for example, salts of acetic acid, benzenesulphonic acid, benzoic acid, camphorsulphonic acid, citric acid, 2-(4-chlorophenoxy)-2- methylpropionic acid, 1 ,2-ethanedisulphonic acid, ethanesulphonic acid, ethylenediaminetetraacetic acid (EDTA), fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, N-glycolylarsanilic acid, 4-hexylresorcinol, hippuric acid, 2-(4-hydroxybenzoyl)benzoicacid, 1-hydroxy-2-naphthoicacid, 3-hydroxy- 2-naphthoic acid, 2-hydroxyethanesulphonic acid, lactobionic acid, n-dodecyl sulphate, maleic acid, malic acid, mandelic acid, methanesulphonicacid, methyl sulphate, mucic acid, 2-naphthalenesulphonic acid, pamoic acid, pantothenic acid, phosphanilic acid ((4-aminophenyl)phosphonic acid), picric acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, terephthalic acid, p- toluenesulphonic acid, 10-undecenoic acid and the like. The compounds are preferably in the form of salts of hydrochloric acid.

It will be appreciated that such salts, provided that they are pharmaceutically acceptable, may be used in therapy. Such salts may be prepared by reacting the compound with a suitable acid in a conventional manner.

A compound of formula (I) may be prepared by any suitable method known in the art.

Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in a known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallisation, or by the formation of a salt if appropriate or possible under the circumstances.

The activity and selectivity of the compounds may be determined by any suitable assay known in the art.

The compounds may be used in the treatment of numerous ailments, conditions and diseases including, but not limited to those given above.

In therapeutic use, the active compound may be administered orally, intravenously, rectally, parenterally, by inhalation (pulmonary delivery), topically, ocularly, nasally, or to the buccal cavity. Oral or intravenous administration is preferred. Thus, the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for such methods of administration. The compositions may be formulated in a manner known to those skilled in the art so as to give a controlled release, for example rapid release or sustained release, of the compounds of the present invention. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art. The compositions of the invention may contain 0.1-99% by weight of active compound. The compositions of the invention are generally prepared in unit dosage form. Preferably, a unit dose comprises the active ingredient in an amount of 1-500 mg. The excipients used in the preparation of these compositions are the excipients known in the art.

Appropriate dosage levels may be determined by any suitable method known to one skilled in the art. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the disease undergoing treatment.

Compositions for oral administration are preferred compositions of the invention and there are known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oily suspensions. The pharmaceutical composition containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example starch gelatin, acacia, microcrystalline cellulose or polyvinyl pyrrolidone; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p- hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable sweetening, flavouring and colouring agents may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3- butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid, find use in the preparation of injectables.

The compounds of formula (I) may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

Compositions for topical administration are also suitable for use in the invention. The pharmaceutically active compound may be dispersed in a pharmaceutically acceptable cream, ointment or gel. A suitable cream may be prepared by incorporating the active compound in a topical vehicle such as light liquid paraffin, dispersed in a aqueous medium using surfactants. An ointment may be prepared by mixing the active compound with a topical vehicle such as a mineral oil or wax. A gel may be prepared by mixing the active compound with a topical vehicle comprising a gelling agent, topically administrable compositions may also comprise a matrix in which the pharmaceutically active compounds are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally.

Claims

1. Use of a compound of formula (I)

wherein

Ar is aryl;

R³ is hydrogen, alkyl, -CH₂-alkoxy, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocycloaikyl, polycyclyl, heteroaryl, -CH₂-heterocycloalkyl, alkanoyloxy or alkoxycarbonyl; or a pharmaceutically acceptable salt thereof; for the manufacture of a medicament for the treatment or prevention of a condition which is nausea or is linked to nausea.

2. Use according to claim 1 , wherein Ar is optionally substituted phenyl.

3. Use according to claim 1 or claim 2, wherein R¹ and R² are each either hydrogen or alkyl.

4. Use according to any preceding claim, wherein R³ is alkyl.

5. Use according to claim 1 , wherein the compound is selected from (+/-)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl-Λ/,Λ/-dimethylamine; (+)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl-/V,Λ/-dimethylamine; (-)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl-Λ/,Λ/-dimethylamine; (+/-)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl-Λ/-methylamine; (+)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl-/V-methylamine; (-)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl-Λ/-methylamine; (+/-)-1 -[1 -(4-chlorophenyl)cyclobutyl]-3-methylbutylamine; (+)-1 -[1 -(4-chlorophenyl)cyclobutyl]-3-methylbutylamine; and (-)-1 -[1 -(4-chlorophenyl)cyclobutyl]-3-methylbutylamine.

6. Use according to any preceding claim, wherein the condition is emesis, motion sickness, anticipatory nausea, vomiting or morning sickness.

7. Use according to claim 6, wherein the condition is emesis.

8. Use according to claim 6, wherein the condition is post-operative nausea or vomiting.

9. Use according to any preceding claim, wherein the condition is associated with one or more of drowsiness, somnolence, dizziness, respiratory depression, blurred vision, hallucination, constipation and euphoria.

10. Use according to any preceding claim, wherein the subject is also receiving an emetogenic agent.

11. Use according to claim 10, wherein the emetogenic agent is an opiate or cytotoxic drug.

12. A pharmaceutical composition comprising a compound as defined in any of claims 1 to 5, an emetogenic agent, e.g. as defined in claim 11 , and a pharmaceutically acceptable diluent or carrier.

13. A product comprising a compound as defined in any of claims 1 to 5 and an emetogenic agent, e.g. as defined in claim 11 , as a combined preparation for separate, simultaneous or sequential use in therapy for which the emetogenic agent is effective.