WO2004075902A1

WO2004075902A1 - Use of silicon derivatives of venlafaxine for the treatment or prevention of psoriasis or panic disorder

Info

Publication number: WO2004075902A1
Application number: PCT/GB2004/000662
Authority: WO
Inventors: Graham Andrew Showell
Original assignee: Amedis Pharmaceuticals Ltd.
Priority date: 2003-02-28
Filing date: 2004-02-19
Publication date: 2004-09-10

Abstract

Use of a compound of formula (I): wherein R1 and R2 are, independently, hydrogen or alkyl or together, with the nitrogen atom, are heterocyclyl; R3 and R4 are, independently, hydrogen, hydroxyl, alkyl, alkoxy, alkanoyloxy, cyano, nitro, alkylmercapto, amino, alkylamino, dialkylamino, alkanamido, halogen or trifluoromethyl; R5 is hydrogen or alkyl; and n is 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof or a prodrug form that is hydrolysable to a compound as defined above; for the manufacture of a medicament for the treatment or prevention of psoriasis or panic disorder.

Description

OF SILICON DERIVATIVES OF VENLΆFAXINE FOR THE REATMENT OR PREVENTION PSORIASIS OR PANIC DISORDER

Field of the Invention

This invention relates to compounds and their therapeutic use. Background of the Invention Psoriasis is a chronic and painful skin disorder which typically does not discriminate on the basis of patient age or gender. The immune system sends incorrect signals to the body, acting as if the area affected by psoriasis were injured. This stimulates the skin cells to grow faster to heal the area. The build-up of excess skin cells leads to skin inflammation and the characteristic psoriatic scaling. Presently, there is no cure for psoriasis, and not all patients respond to current therapies.

Treatment options currently available to patients suffering from psoriasis include a variety of topical medications, phototherapies and systemically administered medications. Topical treatments include steroids, coal tar, anthranlin, vitamin D3 (and its analogues), retinoids and UV phototherapy. Side effects associated with these topical treatments include skin thinning, stretch marks, burns, irritation and photosensitivity. The use of steroids may lead to resistance, rendering subsequent steroid treatment ineffective. Phototherapy is in the form of medically supervised administration of psoralen in combination with ultraviolet light A. Long term use of this therapy can increase the incidence of skin cancers. Internal medications include the administration of methotrexate, oral retinoids, and cyclosporin. The use of methotrexate requires careful monitoring to avoid liver damage. Oral retinoids must be carefully controlled in women because of the potential for severe birth defects. Cyclosporin is an immunosuppresant and is reserved for patients that have failed other systemic treatments. A direct link exists between the severity of the skin inflammation in psoriasis and the patients' stress and anxiety levels. Severe psoriasis itself causes stress and anxiety, which makes the psoriasis symptoms more severe. Noradrenaline reuptake inhibitors have been used for the treatment of anxiety and depression.

Panic disorder is a serious condition that affects approximately one in seventy five people. Although the exact causes are unclear, there appears to be a connection with major life transitions that are potentially stressful. A panic attack is a sudden surge of overwhelming fear that arrives without warning and without any obvious reason. Symptoms of a panic attack include racing heartbeat, breathing difficulties, terror, dizziness, trembling, sweating, shaking, chest pains, hot flushes and sudden chills. Tricyclic anti-depressants, MAO inhibitors and high-potency benzodiazepines (for example alprazolam, clonazepam and Iroazepam) are used in blocking the autonomic expression of panic itself. Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line treatment for panic disorder, although up to 30% of patients either do not respond to SSRIs or withdraw due to adverse events.

Reboxetine, a selective norepinephrine reuptake inhibitor (NRI), is effective in treating depression and may alleviate depression-related anxiety. Reboxetine appears to be effective in the treatment of SSRI-refractory panic disorder patients (Human Psychopharmacology, 2002, 17(7), 329-333). In a clinical study, at a dose of 6 mg/day to 8 mg/day, reboxetine was more effective than placebo in reducing the number of panic attacks per week and reducing phobic symptomology.

Sila-substitution (C/Si-exchange) of drugs is a relatively recent approach for searching for organosilicon compounds which have beneficial biological properties. The approach involves the replacement of specific carbon atoms in compounds by silicon, and monitoring how the biological properties of the compounds have changed. A review of this approach is provided in Tacke and Zilch, Endeavour, New Series, 10, 191-197 (1986).

WO - A- 03/037905 describes a class of compounds which are silicon derivatives of venlafaxine, a serotonin/noradrenaline reuptake inhibitor. The compounds may be used in the treatment of addiction, anxiety, depression and the like. Summary of the Invention

The present invention is based on the discovery that silicon derivatives of venlafaxine and related compounds may be used in the treatment or prevention of psoriasis or panic disorder.

Accordingly, the present invention is the use of a compound formula I:

wherein R¹ and R² are, independently, hydrogen or alkyl or together, with the nitrogen atom, form a heterocyclic ring;

R³ and R⁴ are, independently, hydrogen, hydroxyl, alkyl, alkoxy, alkanoyloxy, cyano, nitro, alkylmercapto, amino, alkylamino, dialkylamino, alkanamido, halogen or trifluoromethyl;

R⁵ is hydrogen or alkyl; and n is O, 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof or a prodrug form that is metabolised to a compound as defined above; forthe manufacture of a medicament forthe treatment or prevention of psoriasis or panic disorder.

Compounds of formula I may have an improved pharmacological profile compared to the parent compound. For example, the compounds may be better tolerated by the patient, or have an improved pharmacokinetic profile. Description of the Invention

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. "C₁ alkyl" 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. "C,.₆ alkoxy" has the same meaning.

The term "halogen" as used herein refers to F, CI, Br or I. The term "heterocyclyl" as used herein refers to a saturated or unsaturated heterocyclic ring moiety having from four to seven carbon atoms and one or more heteroatoms selected from N, O, S, P and Si, and includes, for example, piperidinyl, pyrrolidinyl, morpholinyl and the like.

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

The term "alkylmercapto" as used herein refers to a straight or branched chain alkylmercapto moiety containing one to six carbon atoms and includes, for example, methylmercapto.

The term "alkylamino" refers to a straight or branched chain alkylamino moiety containing one to six carbon atoms and includes, for example, methylamino. The term "dialkylamino" refers to a dialkylamino moiety wherein each alkyl group is as defined above. This term includes, for example, dimethylamino.

The term "alkanamido" refers to a straight or branched chain alkanamido moiety containing two to six carbon atoms, and includes, for example, methanamido. With regard to formula I, R¹ is preferably hydrogen or C,.₃ alkyl, more preferably methyl. R² is preferably C,.₃ alkyl, more preferably methyl. R¹ and R² may also form a heterocyclic ring, for example, NR¹R² may form a morpholinyl or piperidinyl group. R³ and R⁴ are preferably H or alkoxy. More preferably, R³ is hydrogen and R⁴ is hydroxyl or methoxy. R⁵ is preferably hydrogen. It is also preferred that n is 0, 1 or 2. More preferably, n is 2.

Preferred compounds of the invention include:

1-[2-dimethylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol;

1-[2-dimethylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclopentan-1-ol; and

1-[2-dimethylamino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol; in either racemic or enantiomeric form.

Compounds of the invention are chiral. They may be in the form of a single enantiomer or diastereomer, or a racemate.

The compounds of the invention 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. The compounds of the invention may be in a protected amino form. The term

"protected amino" as used herein refers to an amino group which is 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 the formula may exist in the form of solvates, for example hydrates, which also fall within the scope of the present invention.

The compounds of the invention may exist in a prodrug form. In this aspect, the hydroxyl (OH) group attached to the silicon atom may comprise a group that is modified or removed under appropriate conditions to provide the compound in the active form. Suitable groups will be apparent to the skilled person, and include groups that replace the OH group on the silicon atom and which can be hydrolysed to form the OH group. For example, suitable replacement groups include H, OR⁶, N(R⁶)₂, or NHR⁶, where R⁶ is an alkyl group, preferably methyl. Hydrolysable phosphorus-containing or sulphur- containing groups may also be used in the prodrug forms. Compounds of the invention 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, hippuricacid, 2-(4-hydroxybenzoyl)benzoicacid, 1-hydroxy-2-naphthoic acid, 3-hydroxy-2-naphthoic acid, 2-hydroxyethanesulphonic acid, lactobionic acid, n- dodecyl sulphate, maleic acid, malic acid, mandelic acid, methanesulphonic acid, methyl sulphate, mucic acid, 2-naphthalenesulphonic acid, pamoic acid, pantothenic acid, phosphanilic acid ((4-aminophenyl)phosphonic acid), picric acid, salicyclic acid, stearic acid, succinic acid, tannic acid, tartaric acid, terephthalic acid, p- toluenesulphonic acid, 10-undecenoic acid and the like. Preferred salt forms include those of hydrochloric acid and camphorsulphonic acid.

Salts may also be formed with inorganic bases. Such inorganic base salts include, for example, salts of aluminium, bismuth, calcium, lithium, magnesium, potassium, sodium, zinc and the like.

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 or base in a conventional manner.

A compound of the invention may be prepared by any suitable method known in the art (see, for example, WO - A - 03/037905) and/or by the following process:

It will be understood that the process detailed above is solely for the purpose of illustrating the invention and should not be construed as limiting. A process utilising similar or analogous reagents and/or conditions known to one skilled in the art may also be used to obtain a compound of the invention. 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.

As used herein, the term "active compound" denotes a compound of formula I including pharmaceutically acceptable salts thereof.

The compounds of the invention may be used in the treatment of numerous ailments, conditions and diseases including, but not limited thereto, psoriasis and panic disorder.

In therapeutic use, the active compound may be administered orally, rectally, parenterally, by inhalation (pulmonary delivery), topically, ocularly, nasally, or to the buccal cavity. Oral 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. The administered dose is preferably similar to that of venlafaxine. For example, an initial dose may be 10-100 mg, 2-3 times daily or up to 150-400 mg daily in severely affected patients.

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 forthe 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 of the present invention are dispersed so that the compounds are held in contact with the skin in order io administer the compounds transdermally.

Claims

1. Use of a compound of formula I:

wherein R¹ and R² are, independently, hydrogen or alkyl or together, with the nitrogen atom, are heterocyclyl;

R⁵ is hydrogen or alkyl; and n is O, 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof or a prodrug form that is hydrolysable to a compound as defined above; forthe manufacture of a medicament for the treatment or prevention of psoriasis or panic disorder.

2. Use according to claim 1, wherein R¹ and R² are, independently, hydrogen or C_|.₃ alkyl.

3. Use according to claim 2, wherein R¹ and R² are the same or different and are each C_1-3 alkyl.

4. Use according to any of claims 1 to 3, wherein R³ is hydrogen and R⁴ is hydroxyl or alkoxy.

5. Use according to claim 4, wherein R⁴ is methoxy.

6. Use according to any preceding claim, wherein n is 0, 1 or 2.

7. Use according to claim 6, wherein n is 2.

8. Use according to any preceding claim, wherein R⁵ is hydrogen.

9. Use according to claim 1 , wherein the compound is selected from: 1-[2-dimethylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol; 1-[2-dimethylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclopentan-1-ol; and 1-[2-dimethylamino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol; in either racemic or enantiomeric form.

10. Use according to claim 9, wherein the compound is selected from

(R)-1-[2-dimethylamino-1-(4-methoxyphenyI)ethyl]-1-silacyclohexan-1-ol; and (R)-1-[2-dimethylamino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol.