WO2004094436A1 - 1-(2-amino-1-phenyl-ethyl) 1- silacyclohexan-1- ol derivatives and use thereof in the preparation of a medicament - Google Patents

1-(2-amino-1-phenyl-ethyl) 1- silacyclohexan-1- ol derivatives and use thereof in the preparation of a medicament Download PDF

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Publication number
WO2004094436A1
WO2004094436A1 PCT/GB2004/001781 GB2004001781W WO2004094436A1 WO 2004094436 A1 WO2004094436 A1 WO 2004094436A1 GB 2004001781 W GB2004001781 W GB 2004001781W WO 2004094436 A1 WO2004094436 A1 WO 2004094436A1
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Prior art keywords
ethyl
silacyclohexan
methoxyphenyl
hydroxyphenyl
agent
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PCT/GB2004/001781
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French (fr)
Inventor
Graham Andrew Showell
David Miller
Ajay Kumar Mandal
Reinhold Tacke
Juergen Daiss
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Amedis Pharmaceuticals Ltd.
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Priority claimed from GB0309321A external-priority patent/GB0309321D0/en
Priority claimed from GB0317280A external-priority patent/GB0317280D0/en
Application filed by Amedis Pharmaceuticals Ltd. filed Critical Amedis Pharmaceuticals Ltd.
Publication of WO2004094436A1 publication Critical patent/WO2004094436A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0834—Compounds having one or more O-Si linkage
    • C07F7/0836—Compounds with one or more Si-OH or Si-O-metal linkage

Definitions

  • This invention relates to compounds and their therapeutic use.
  • Background of the Invention 5 Noradrenaline, 5-hydroxytryptamine (5-HT, serotonin) and dopamine are mammalian monoamine neurotransmitters.
  • Noradrenaline acts as a neurotransmitter in the sympathetic nervous system and as a hormone throughout the body. Its neurotransmitter effects include regulation of mood, whilst its hormone effects include the control of blood
  • 5-HT is widely distributed throughout the body, including blood platelets, intestinal wall and the central nervous system (CNS). 5-HT plays a role in inflammatory responses similar to histamine. It also acts as a neurotransmitter in the CNS, playing a role in mood control. Dopamine is a catecholamine, and acts on dopamine and
  • Dopamine affects brain processes that control movement, emotional response and the ability to experience pleasure and pain. Dopamine has been implicated substantially in Parkinson's Disease and also plays a role in addiction.
  • 5-HT and noradrenaline pathways are also thought to play a role in modulation of endorphin effects. These monoamines may therefore play an important role in transmission of chronic pain signals.
  • Venlafaxine i.e.1-[2-dimethylamino-1-(4-methoxyphenyl)ethyl]cyclohexan-1-ol
  • Venlafaxine is a serotonin/noradrenaline reuptake inhibitor. There are, however, side-effects associated with its use as a medicament, including nausea, insomnia, headache, dizziness, sweating and occasionally convulsions. Certain metabolites of Venlafaxine are active as re-uptake inhibitors in in vitro assays; see for example Howell et a/, Zenobiotica, 1993, 23, 349-359.
  • 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 sila-venlafaxine also forms a number of metabolites having desirable properties.
  • the compounds may be useful as re-uptake inhibitors and in therapy, particularly for the treatment or prevention of neuropathic pain and emesis.
  • the compounds may prevent or diminish emesis side-effects associated with emetogenic agents such as opiates or cytotoxic agents. They may also be used in combination with one or more anti-emetic agents such as 5-HT 3 receptor antagonists, NK1 receptor antagonists, dopamine antagonists or steroids.
  • a first aspect of the invention is a compound selected from:
  • a second aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention together with a pharmaceutically acceptable carrier or diluent.
  • the composition may further comprise an emetogenic agent and/or an anti- emetic agent.
  • Another aspect of the invention is a product comprising a compound of the invention, and an emetogenic agent, as a combined preparation for separate, simultaneous or sequential use in therapy for which the emetogenic agent is effective.
  • Another aspect of the invention is the use of a compound of the invention, for the manufacture of a medicament for the treatment or prevention of psoriasis, panic attack, addiction, anxiety, depression, sexual dysfunction, hypertension, migraine, Alzheimer's disease, obesity, emesis, psychosis, schizophrenia, Parkinson's disease, restless leg syndrome, sleeping disorders, attention deficit hyperactivity disorder, irritable bowel syndrome, premature ejaculation, menstrual dysphoria syndrome, premenstrual tension, urinary incontinence, pain (e.g. inflammatory, chronic or neuropathic pain), chronic headache, Lesche-Nyhane disease, Wilson's disease or Tourette's syndrome.
  • pain e.g. inflammatory, chronic or neuropathic pain
  • chronic headache e.g. inflammatory, chronic or neuropathic pain
  • Lesche-Nyhane disease Wilson's disease or Tourette's syndrome.
  • Compounds of the invention may have an improved pharmacological profile compared to their parent compounds.
  • the compounds may be better tolerated by the patient, or have an improved pharmacokinetic profile.
  • Preferred compounds of the invention include:
  • the compounds of the invention may be prepared in racemicform, 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 enanfiomers 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.
  • 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.
  • protected amino refers to an amino group which is protected in a manner familiar to those skilled in the art.
  • 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.
  • the hydroxy (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.
  • suitable replacement groups include H, OR, N(R) 2 and NHR, where R 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.
  • 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, ben ⁇ enesulphonic acid, benzoicacid, 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, hippuncacid, 2-(4-hydroxybenzoyl)benzoicacid, 1-hydroxy-2-naphthoic acid, 3-hydroxy-2-naphthoic acid, 2-hydroxyethanesulphonic acid, lactobionic acid, n- dodecyl sulphuric acid, maleicacid, malic acid, mandelic acid, methanesulphonicacid, methyl sulphuric acid,
  • 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 processes:
  • 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 term "active compound” denotes a compound of the invention 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, panic disorder, addiction, anxiety, depression, sexual dysfunction, hypertension, migraine, Alzheimer's disease, obesity, emesis, psychosis, schizophrenia, Parkinson's disease, restless leg syndrome, sleeping disorders, attention deficit hyperactivity disorder, irritable bowel syndrome, premature ejaculation, menstrual dysphoria syndrome, premenstrual tension, urinary incontinence, pain, including inflammatory pain, neuropathic pain, chronic headache and chronic pain, Lesche-Nyhane disease, Wilson's disease or Tourette's syndrome.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • an inert solid diluent for example calcium carbonate, calcium phosphate or kaolin
  • 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.
  • 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, orcondensation 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.
  • suspending agents for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth
  • 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.
  • 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.
  • 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 to administer the compounds transdermally.
  • Example 1 (R)-1-[2-Dimethylamino-1 -(4-hydroxyphenyl)ethyl]-1 -silacyclohexan-1 - ol Step 1: 1,1-Dichloro-1-silacyclohexane. This compound was prepared using the method described in J. Am. Chem. Soc.
  • the mixture was stirred vigorously (to prevent agglomeration) at 20 °C for 3 days, and the resulting suspension was then added via a dropping funnel at 0 °C within 20 minutes to a vigorously stirred solution of 1,1-dichloro-1-silacyclohexane (50.3 g, 297 mmol) in n-hexane (150 mL).
  • the mixture was stirred at 0 °C for a further 15 min and then at 20 °C for 6 hours, followed by dropwise addition of methanol (13.1 g, 409 mmol) within a period of 5 minutes (warming to approximately 30-40 °C; formation of a precipitate).
  • Step 3 1 -[1 -(4 ⁇ S ⁇ flethoxyphenyl)vinyl]-1 - ⁇ 2,4,6-trimethoxyphenyl)-1 -silacyclohexane.
  • a 2.5 M solution of n-butyllithium in n-hexane (75.0 mL, 188 mmol of n-BuLi) was added dropwise at -78 °C over 20 minutes to a stirred mixture consisting of finely ground 4-methoxyacetophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (40.0 g, 92.9 mmol), TMEDA (31.0 g, 267 mmol), and n-hexane (300 mL).
  • the solution was then cooled to 20 °C and was kept at this temperature for 16 hours (change of colour from orange to yellow), followed by addition of silica gel (50 g, 32-63 ⁇ m, ICN 02826).
  • the resulting suspension was shaken for 2 minutes and then purified by flash chromatography (column diameter, 5.5 cm; column length, 50 cm; silica gel, 520 g, 32-63 ⁇ m, ICN 02826), using petroleum ether (40-65 °C)/diethyl ether/triethylamine [55:40:5 (v/v/v)] as the eluent.
  • the stirred mixture was allowed to warm to -20 °C over 2 hours and was then stirred at 0 °C for a further 1 hour.
  • the mixture was allowed to warm to 20 °C over 1 hour, and the solvent was removed under reduced pressure at 5-15 °C until a residual volume of approximately 10 mL was obtained.
  • This solution was diluted with diethyl ether (20 mL) and then added in one single portion at 0 °C to a stirred two-phase mixture of diethyl ether (10 mL) and 2 M potassium acetate/acetic acid buffer (pH 4.5, 50 mL).
  • the pH of the aqueous phase changed to pH 5.7 within approximately 10 minutes and was readjusted to pH 5.0 by addition of small portions of glacial acetic acid.
  • the mixture was stirred for a further 1 hour at 0 °C, with the pH of the aqueous phase remaining constantly at pH 5.0 during this time.
  • the aqueous layer was separated, the organic phase was extracted with 1 M potassium acetate/acetic acid buffer (pH 5.0, 3 x 20 mL), and the aqueous solutions were combined. Diethyl ether (20 mL) was added to the combined aqueous extracts, and the pH of the aqueous phase was adjusted to pH 10.5 by addition of small portions of saturated aqueous potassium carbonate solution.
  • the organic layer was separated, the aqueous phase was extracted with diethyl ether (4 x 20 mL) and the organic extracts were combined, followed by addition of n-hexane (80 L).
  • the solvent was removed under reduced pressure at 5-15 °C until a residual volume of approximately 50 mL was obtained, whereupon residual water separated from the organic phase (formation of a two-phase system).
  • the organic layer was separated, the aqueous phase was extracted with n-hexane (2 x 15 mL), and the organic solutions were combined.
  • Step 6 (R)-(-)-1 -[2-Dimethylamino-1 -(4-methoxyphenyl)ethyl]-1 -silacyclohexan-1 -ol and (S)-(+)-1 -[2-Dimethylamino-1 -(4-methoxyphenyl)ethyl]-1 -silacyclohexan-1 -ol.
  • the enantiomers, as their hydrochloride salts, were obtained from the racemate in Step 5 using the procedure described in WO-A-03/037905.
  • Step 7 (R)-1-[2-Dimethylamino-1-(4-hydroxyphenyl)ethyl]-1 -silacyclohexan-1 - ol.
  • Example 4 (RS)-1-[2-Methylamino-1-(4-methoxyphenyl)ethyl]-1 -silacyclohexan-1 -ol Step 1 : 1-[1-(4-Methoxyphenyl)vinyl]silacyclohexane.
  • Step 2 (RS)-1-(N-Benzyl-l ⁇ l-methylamino)-1-[2-(ISI-benzyl-N-methylamino)-1-(4- methoxyphenyl)ethyl]-1 -silacyclohexane
  • Step3 (RS)-1-[2-Benzylmethylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan- 1-ol.
  • Step 4 (RS)-1 -[2-Methylamino-1 -(4-methoxyphenyl)ethyl]-1 -silacyclohexan-1 -ol.
  • a mixture of (RS)-1-[2-benzylmethylamino-1-(4-methoxyphenyl)ethyl]-1- silacyclohexan- 1-ol (40 mg, 0.1 mmol), 5 % palladium on carbon catalyst (40 mg) and 2-propanol (2 mL) was stirred at ambient temperature under an atmosphere of hydrogen for 22 hours.
  • the reaction mixture was filtered through short pad of celite, which was then washed several times with diethyl ether (3 x 10 mL).

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Abstract

A compound selected from: (RS)-1-[2-methylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol; (R)-1-[2-methylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol; (S)-1-[2-methylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol; (RS)-1-[2-amino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol; (R)-1-[2-amino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol (S)-1-[2-amino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol; (RS)-1-[2-dimethylamino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol; (R)-1-[2-dimethylamino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol; (S)-1-[2-dimethylamino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol; (RS)- 1-[2-amino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol; (R)-1-[2-amino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol; (S)-1-[2-amino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol; (RS)- 1-[2-methylamino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol; (R)-1-[2-methylamino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol; (S)-1-[2-methylamino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol; (RS)-1-[2-dimethyl amino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1,4-diol; (R)-1-[2-dimethylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-l,4-diol; and (S)-1-[2-dimethylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1,4-diol; or a pharmaceutically acceptable salt thereof or a prodrug form that is hydrolysable to a compound as defined above.

Description

l- ( 2-AMINO-l-PHENYL-ETHYL) l-SI ACYC OHEXAN-l-OL DERIVATIVES AND USE THEREOF
IN THE PREPARATION OF A MEDICAMENT
Field of the Invention
This invention relates to compounds and their therapeutic use. Background of the Invention 5 Noradrenaline, 5-hydroxytryptamine (5-HT, serotonin) and dopamine are mammalian monoamine neurotransmitters.
Noradrenaline (norepinephrine) acts as a neurotransmitter in the sympathetic nervous system and as a hormone throughout the body. Its neurotransmitter effects include regulation of mood, whilst its hormone effects include the control of blood
10 pressure, heart rate, breathing and contraction of the gastrointestinal tract.
5-HT is widely distributed throughout the body, including blood platelets, intestinal wall and the central nervous system (CNS). 5-HT plays a role in inflammatory responses similar to histamine. It also acts as a neurotransmitter in the CNS, playing a role in mood control. Dopamine is a catecholamine, and acts on dopamine and
15 adrenergic receptors throughout the body. It also stimulates the release of noradrenaline from nerve endings. Dopamine affects brain processes that control movement, emotional response and the ability to experience pleasure and pain. Dopamine has been implicated substantially in Parkinson's Disease and also plays a role in addiction.
20 Compounds that selectively modulate the activity of these neurotransmitters, either individually or in any combination, may serve as effective therapeutic agents for the treatment of a wide variety of diseases of the central or peripheral nervous systems. For example, the mechanisms involved in the generation of chronic pain syndromes such as neuropathic pain are not well understood, but supraspinal and spinal events,
25 which modulate nociceptive transmission from the periphery to the CNS, could be mediated by 5-HT and noradrenaline pathways. 5-HT pathways are also thought to play a role in modulation of endorphin effects. These monoamines may therefore play an important role in transmission of chronic pain signals.
Venlafaxine, i.e.1-[2-dimethylamino-1-(4-methoxyphenyl)ethyl]cyclohexan-1-ol,
30 is an antidepressant drug, the preparation of which is disclosed in US 4535186. A review of its pharmacology and clinical efficacy is contained in Montgomery, J. Clin. Psychiatry, 54, 119-126 (1993). Venlafaxine is a serotonin/noradrenaline reuptake inhibitor. There are, however, side-effects associated with its use as a medicament, including nausea, insomnia, headache, dizziness, sweating and occasionally convulsions. Certain metabolites of Venlafaxine are active as re-uptake inhibitors in in vitro assays; see for example Howell et a/, Zenobiotica, 1993, 23, 349-359.
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 sila-venlafaxine also forms a number of metabolites having desirable properties. The compounds may be useful as re-uptake inhibitors and in therapy, particularly for the treatment or prevention of neuropathic pain and emesis. In particular, the compounds may prevent or diminish emesis side-effects associated with emetogenic agents such as opiates or cytotoxic agents. They may also be used in combination with one or more anti-emetic agents such as 5-HT3 receptor antagonists, NK1 receptor antagonists, dopamine antagonists or steroids. Accordingly, a first aspect of the invention is a compound selected from:
(RS)-1-[2-methylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol;
(R)-1-[2-methylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol;
(S)-1-[2-methylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol;
(RS)-1-[2-amino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol; (R)-1 -[2-amino-1 -(4-methoxyphenyl)ethyl]-1 -silacyclohexan-1 -ol
(S)-1-[2-amino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol;
(RS)-1-[2-dimethylamino-1-(4-hydroxyphenyl)ethyl]-1 -silacyclohexan-1 -ol;
(R)-1-[2-dimethylamino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol;
(S)-1-[2-dimethylamino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol; (RS)-1-[2-amino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol;
(R)-1-[2-amino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol;
(S)-1-[2-amino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol;
(RS)-1-[2-methylamino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol;
(R)-1-[2-methylamino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol; (S)-1-[2-methylamino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol;
(RS)-1-[2-dimethylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1,4-diol;
(R)-1-[2-dimethylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1,4-diol; and
(S)-1-[2-dimethylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1,4-diol; or a pharmaceutically acceptable salt thereof or a prodrug form that is metabolised to a compound as defined above. A second aspect of the invention is a pharmaceutical composition comprising a compound of the invention together with a pharmaceutically acceptable carrier or diluent. The composition may further comprise an emetogenic agent and/or an anti- emetic agent. Another aspect of the invention is a product comprising a compound of the invention, and an emetogenic agent, as a combined preparation for separate, simultaneous or sequential use in therapy for which the emetogenic agent is effective.
Another aspect of the invention is the use of a compound of the invention, for the manufacture of a medicament for the treatment or prevention of psoriasis, panic attack, addiction, anxiety, depression, sexual dysfunction, hypertension, migraine, Alzheimer's disease, obesity, emesis, psychosis, schizophrenia, Parkinson's disease, restless leg syndrome, sleeping disorders, attention deficit hyperactivity disorder, irritable bowel syndrome, premature ejaculation, menstrual dysphoria syndrome, premenstrual tension, urinary incontinence, pain (e.g. inflammatory, chronic or neuropathic pain), chronic headache, Lesche-Nyhane disease, Wilson's disease or Tourette's syndrome.
Compounds of the invention may have an improved pharmacological profile compared to their parent compounds. For example, the compounds may be better tolerated by the patient, or have an improved pharmacokinetic profile. Description of the Invention
The general structures of compounds of the invention are shown below:
Figure imgf000004_0001
Figure imgf000004_0002
Figure imgf000005_0001
Figure imgf000005_0002
Figure imgf000005_0003
Figure imgf000005_0004
the corresponding general names of which are, respectively:
1-[2-methylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol;
1 -[2-amino-1 -(4-methoxyphenyl)ethyl]-1 -silacyclohexan-1 -ol;
1-[2-dimethylamino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-oI;
1-[2-amino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol; 1-[2-methylamino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol; and 1-[2-dimethylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1,4-diol. Preferred compounds of the invention include:
(R)-1-[2-dimethylamino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol; and (S)-1-[2-dimethylamino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol. 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 racemicform, 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 enanfiomers 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 hydroxy (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, OR, N(R)2 and NHR, where R 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, ben∑enesulphonic acid, benzoicacid, 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, hippuncacid, 2-(4-hydroxybenzoyl)benzoicacid, 1-hydroxy-2-naphthoic acid, 3-hydroxy-2-naphthoic acid, 2-hydroxyethanesulphonic acid, lactobionic acid, n- dodecyl sulphuric acid, maleicacid, malic acid, mandelic acid, methanesulphonicacid, methyl sulphuric acid, mucic acid, 2-naphthalenesulphonic acid, pamoic acid, pantothenic acid, phosphanilic acid ((4-aminophenyl)phosphonic acid), picric acid, salicyclicacid, stearicacid, succinicacid, tannicacid, tartaricacid, terephthalic acid, p- toluenesulphonic acid, 10-undecenoic acid and the like. A preferred salt is a salt of hydrochloric 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 processes:
Scheme 1
Figure imgf000008_0001
Scheme 2
Figure imgf000008_0002
It will be appreciated that the processes described above are 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.
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 the invention 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, panic disorder, addiction, anxiety, depression, sexual dysfunction, hypertension, migraine, Alzheimer's disease, obesity, emesis, psychosis, schizophrenia, Parkinson's disease, restless leg syndrome, sleeping disorders, attention deficit hyperactivity disorder, irritable bowel syndrome, premature ejaculation, menstrual dysphoria syndrome, premenstrual tension, urinary incontinence, pain, including inflammatory pain, neuropathic pain, chronic headache and chronic pain, Lesche-Nyhane disease, Wilson's disease or Tourette's syndrome.
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.
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 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, orcondensation 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 the invention 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 to administer the compounds transdermally.
The following Examples illustrate the invention. In the Examples, the following LC-MS conditions were used: Conditions A; mass spectrometer- electrospray source operating in positive and negative ion mode. System running at 1.5 ml/min, detection mode is through a Hexa- pole Mass Spectrometry detector and a Diode-Array detector for UV. Mobile phase: acetonitrile-water (running from 5 - 95% acetonitrile) with either 0.05 % formic acid (Conditions A) or 0.05 % ammonium hydroxide (Conditions B) added.
Except for the hydrolytic conversions, all syntheses were carried out under dry nitrogen. Tetrahydrofuran, diethyl ether, 1,2-bis(dimethylamino)ethane (TMEDA), and n-hexane were dried and purified according to standard procedures and stored under nitrogen.
Example 1 : (R)-1-[2-Dimethylamino-1 -(4-hydroxyphenyl)ethyl]-1 -silacyclohexan-1 - ol Step 1: 1,1-Dichloro-1-silacyclohexane. This compound was prepared using the method described in J. Am. Chem. Soc.
1954, 76, 6012-6014. Step 2: 1-Methoxy-1-(2,4,6-trimethoxyphenyl)-1-silacyclohexane.
A suspension of 1 ,3,5-trimethoxybenzene (50.0 g, 297 mmol) in a mixture of n- hexane (175 mL) and 1,2-bis(dimethylamino)ethane (TMEDA; 35.7 g, 307 mmol) was heated to approximately 50 °C to dissolve the 1 ,3,5-trimethoxybenzene. After the heat source was removed, a 2.5 M solution of n-butyllithium in n-hexane (121 mL, 303 mmol of n-BuLi) was added dropwise over 30 minutes to the vigorously stirred mixture. During the addition, the heat of the reaction caused the mixture to heat to reflux, and a white precipitate was formed. After the addition was complete, the mixture was stirred vigorously (to prevent agglomeration) at 20 °C for 3 days, and the resulting suspension was then added via a dropping funnel at 0 °C within 20 minutes to a vigorously stirred solution of 1,1-dichloro-1-silacyclohexane (50.3 g, 297 mmol) in n-hexane (150 mL). The mixture was stirred at 0 °C for a further 15 min and then at 20 °C for 6 hours, followed by dropwise addition of methanol (13.1 g, 409 mmol) within a period of 5 minutes (warming to approximately 30-40 °C; formation of a precipitate). The stirred mixture was allowed to cool to 20 °C over 1 hour and was then stirred at this temperature for a further 16 hours. The resulting suspension was filtered, the filter cake was washed with n-hexane (2 x 300 mL) and the filtrate and wash solutions were combined. The solvent was removed under reduced pressure (rotary evoporator, 40 °C), and the liquid residue was distilled in vacuo [Kugelrohr apparatus; first fraction, ≤120 °C/0.001 mbar, discarded; second fraction, 120-170 °C/0.001 mbar, crude product (65.2 g of a colourless liquid)]. The crude product was redistilled in vacuo (Vigreux column, 10 cm) to give the title product as a colourless liquid (58.3 g, 66%, 197 mmol); b.p. 105 °C/0.001 mbar. After the liquid was kept at 15-20 °C for 7 days, it solidified to give a colourless crystalline solid; m.p. 24-25 °C. Anal. Calcd for C15H24O4Si: C, 60.78%; H, 8.16%. Found: C, 60.7%; H, 7.8%. Step 3: 1 -[1 -(4~S\flethoxyphenyl)vinyl]-1 -{2,4,6-trimethoxyphenyl)-1 -silacyclohexane. A 2.5 M solution of n-butyllithium in n-hexane (75.0 mL, 188 mmol of n-BuLi) was added dropwise at -78 °C over 20 minutes to a stirred mixture consisting of finely ground 4-methoxyacetophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (40.0 g, 92.9 mmol), TMEDA (31.0 g, 267 mmol), and n-hexane (300 mL). The resulting yellow mixture was stirred at -78 °C for 2 hours and then allowed to warm to 0 °C [evolution of nitrogen; change of colour to orange; formation of 1-(4- methoxyphenyl)vinyllithium]. After the nitrogen evolution was finished, the resulting clear solution was stirred for a further 10 minutes at 20 °C and then added dropwise at this temperature over25 minutes to a solution of 1-methoxy-1-(2,4,6-trimethoxyphenyl)- 1 -silacyclohexane (27.5 g, 92.8 mmol) in n-hexane (200 mL). During the addition, the mixture warmed to approximately 30 °C. The solution was then cooled to 20 °C and was kept at this temperature for 16 hours (change of colour from orange to yellow), followed by addition of silica gel (50 g, 32-63 μm, ICN 02826). The resulting suspension was shaken for 2 minutes and then purified by flash chromatography (column diameter, 5.5 cm; column length, 50 cm; silica gel, 520 g, 32-63 μm, ICN 02826), using petroleum ether (40-65 °C)/diethyl ether/triethylamine [55:40:5 (v/v/v)] as the eluent. The relevant fraction that contained the crude product was concentrated under reduced pressure (rotary evaporator, 40 °C), the liquid residue was distilled in vacuo (Kugelrohr) and the crude product was crystallized from n-hexane (120 mL, -20 °C, 3 days). The resulting crystalline product was isolated by decantation, washed with cold (-20 °C) n-pentane (10 mL), recrystallized from n-hexane (90 mL, -20 °C, 4 days), washed with cold (-20 °C) n-pentane (10 mL), and dried in vacuo to give the title compound as a colourless crystalline solid (17.5 g, 47%, 43.9 mmol); m.p. 45-46 °C. Anal. Calcd for C23H30O4Si: C, 69.31%; H, 7.59%. Found: C, 69.1%; H, 7.5%. Step 4: 1-Chloro-1-[1-(4-methoxyphenyl)vinyl]-1 -silacyclohexane .
A 2.0 M ethereal HCI solution (11.5 mL, 23.0 mmol of HCI) was added to a solution of 1-[1-(4-methoxyphenyl)vinyl]-1-(2,4,6-trimethoxyphenyl)-1-silacyclohexane (8.70 g, 21.8 mmol) in diethyl ether (30 mL) in one single portion at 0 °C, and the resulting mixture was stirred at 0 °C for 10 minutes. The solvent and the excess hydrogen chloride were removed under reduced pressure at 5-15 °C, the residue was dried in vacuo (0.001 mbar, 20 °C, 1 hour) and dissolved in n-hexane (40 mL), and the resulting solution was then left standing at -20 °C for 2 days (crystallisation of 1,3,5- trimethoxybenzene). The solution was isolated by filtration, the solid residue was washed with cold (-20 °C) n-hexane (20 mL), the filtrate and wash solution were combined and the solvent was removed under reduced pressure at 5-15 °C. The oily residue was distilled in vacuo (vigreux column, 5 cm) to give the title compound as a colourless liquid (4.46 g, 77%, 16.7 mmol); b.p. 120-122 °C/0.001 mbar. Anal. Calcd for C14H19CIOSi: C, 63.02%; H, 7.18%. Found: C, 62.9%; H, 7.2%. Step5: (RS)-1-[2-Dimethylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol. A 2.5 M solution of n-butyllithium in n-hexane (4.2 mL, 10.5 mmol of n-BuLi) was added dropwise at -50 °C over 2 minutes to a stirred solution of dimethylamine (6.91 g, 153 mmol) in tetrahydrofuran (20 mL). The resulting mixture was allowed to warm to -25 °C over 90 minutes and was then cooled to -40 °C, followed by dropwise addition of a solution of 1-chloro-1-[1-(4-methoxyphenyl)vinyl]-1-silacyclohexane (1.35 g, 5.06 mmol) in tetrahydrofuran (8 mL) over 4 minutes. The stirred mixture was allowed to warm to -20 °C over 2 hours and was then stirred at 0 °C for a further 1 hour. The mixture was allowed to warm to 20 °C over 1 hour, and the solvent was removed under reduced pressure at 5-15 °C until a residual volume of approximately 10 mL was obtained. This solution was diluted with diethyl ether (20 mL) and then added in one single portion at 0 °C to a stirred two-phase mixture of diethyl ether (10 mL) and 2 M potassium acetate/acetic acid buffer (pH 4.5, 50 mL). The pH of the aqueous phase changed to pH 5.7 within approximately 10 minutes and was readjusted to pH 5.0 by addition of small portions of glacial acetic acid. The mixture was stirred for a further 1 hour at 0 °C, with the pH of the aqueous phase remaining constantly at pH 5.0 during this time. The aqueous layer was separated, the organic phase was extracted with 1 M potassium acetate/acetic acid buffer (pH 5.0, 3 x 20 mL), and the aqueous solutions were combined. Diethyl ether (20 mL) was added to the combined aqueous extracts, and the pH of the aqueous phase was adjusted to pH 10.5 by addition of small portions of saturated aqueous potassium carbonate solution. The organic layer was separated, the aqueous phase was extracted with diethyl ether (4 x 20 mL) and the organic extracts were combined, followed by addition of n-hexane (80 L). The solvent was removed under reduced pressure at 5-15 °C until a residual volume of approximately 50 mL was obtained, whereupon residual water separated from the organic phase (formation of a two-phase system). The organic layer was separated, the aqueous phase was extracted with n-hexane (2 x 15 mL), and the organic solutions were combined. The solvent was removed completely under reduced pressure at 5-15 °C to give a colourless oil, which was dried in vacuo (0.001 mbar, 20 °C, 1 hour) and then crystallized from n-pentane (25 mL, -26 °C, 3 days). The product was isolated by quick decantation of the cold solvent, followed by drying in vacuo (0.001 mbar, 20 °C, 6 hours) to give the title compound in as a colourless crystalline solid (1.27 g, 86%, 4.33 mmol); m.p. 33 °C. Anal. Calcd for C16H27NO2Si: C, 65.48%; H, 9.27%; N, 4.77%. Found: C, 65.6%; H, 9.5%; N, 4.7%. The hydrochloride salt had m.p. 160 °C (from dichloromethane/diethyl ether).
Step 6: (R)-(-)-1 -[2-Dimethylamino-1 -(4-methoxyphenyl)ethyl]-1 -silacyclohexan-1 -ol and (S)-(+)-1 -[2-Dimethylamino-1 -(4-methoxyphenyl)ethyl]-1 -silacyclohexan-1 -ol. The enantiomers, as their hydrochloride salts, were obtained from the racemate in Step 5 using the procedure described in WO-A-03/037905. Step 7: (R)-1-[2-Dimethylamino-1-(4-hydroxyphenyl)ethyl]-1 -silacyclohexan-1 - ol.
To a solution of (R)-1-[2-dimethylamino-1-(4-methoxyphenyl)ethyl]-1- silacyclohexan- 1-ol hydrochloride (150 mg, 0.46 mmol) in distilled water (5 mL) was added aqueous sodium hydroxide solution (2.5 M, 5 mL, 13.75 mol. equivalents). This mixture was extracted with dichloromethane (3 x 10 mL) and the combined extracts dried (magnesium sulphate) to afford a clear glassy solid (137 mg, 0.46 mmol). A stirred solution of this material in dry dichloromethane (10 mL) was cooled in a dry ice/acetone bath while boron tribromide(1.0 M in dichloromethane, 0.92 mL, 2.0 mol. equivalents) was added dropwise. The cooling bath was replaced with an ice/water bath and stirring continued for 3 hours after which time a further portion of boron tribromide (0.92 mL, 2.0 mol. equivalents) was added. After a further hour aqueous sodium hydroxide solution (2.5 M, 5 mL) was added and the resulting mixture stirred for 30 minutes at room temperature. The dichloromethane was removed by evaporation under reduced pressure and the aqueous phase was extracted with ethyl acetate (3 x 10 mL), dried (MgSO4) and concentrated in vacuo. The resulting gum was triturated with dichloromethane (2 x 10 mL) and the mother liquors evaporated under reduced pressure to afford the title compound as a cream solid (56 mg, 44%, 0.20 mmol). 1H NMR (400 MHz, DMSO) δ 0.35 (2H, t, J = 7.1
Hz), 0.56 (2H, t, J = 0.6 Hz), 1.15-1.66 (6H, m), 2.07 (6H, s), 2.28 (1H, m), 2.49 (1H, m), 2.74 (1H, t, J = 10.6 Hz), 5.51 (1H, s), 6.62 (2H, d, J = 8.6 Hz), 6.90 (2H, d, J = 8.6 Hz) and 8.94 ( H, s). LC-MS: Rt = 3.32 min, m/z = 280 [MH+] Conditions A; Rt = 4.65 min, m/z = 280 [MH+] Conditions B. Example 2: (S)- 1-[2-Dimethylamino-1-(4-hydroxyphenyl)ethyl]-1- silacyclohexan-1 -ol
The title compound was synthesised from (S)-1-[2-dimethylamino-1-(4- methoxyphenyl)ethyl]-1-silacyclohexan-1-ol according to the procedure described in Example 1 , yield 76%. LC-MS: m/z = 280 [MH+].
Example 3: (RS)- 1-[2-Dimethylamino-1-(4-hydroxyphenyl)ethyl3-1- silacyclohexan-1 -ol
The title compound was synthesised from (RS)-1-[2-dimethylamino-1-(4- methoxyphenyl)ethyl]-1 -silacyclohexan-1 -ol according to the procedure described in Example 1 , yield 77%. LC-MS: m/z = 280 [MH+].
Example 4: (RS)-1-[2-Methylamino-1-(4-methoxyphenyl)ethyl]-1 -silacyclohexan-1 -ol Step 1 : 1-[1-(4-Methoxyphenyl)vinyl]silacyclohexane.
To a stirred solution of 1-[1-(4-methoxyphenyl)vinyl-1-(2,4,6-trimethoxyphenyl)-1- silacyclohexane (2.9 g, 7.28 mmol) in diethyl ether (20 mL) was added a 2.0 M ethereal hydrogen chloride solution (5.5 mL, 11.0 mmol) in a single portion at 0 °C. The resulting mixture was stirred at 0 °C for 45 minutes before the reaction was allowed to warm to room temperature and lithium aluminium hydride (1.45 g, 38 mmol) was added cautiously. The resulting solution was stirred for 1.5 hours at room temperature before the mixture was quenched with hydrochloric acid (20 mL, 1 M) and extracted with diethyl ether (20 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (2 x 10 mL), dried (magnesium sulphate) and concentrated under reduced pressure. The residue was purified by column chromatography (silica, diethyl ether-light petroleum, 1:19) to afford the crude product (1.5 g, 89 %), Rf 0.76 (Et2O-light petroleum, 1:19). The residue was distilled to afford the title compound in a homogeneous form (1.4 g, 84%), b.p. 180 °C/0.1 mmHg. 1H NMR (400 MHz, CD2CI2) δ 0.69-0.85 (2H, m), 0.95-1.95 (2H, m), 1.23-1.42 (1 H, m), 1.57-1.72 (3H, m), 1.82-1.96 (2H, m), 4.30 (1 H, m), 5.62 ( H, d, J = 2.5 Hz), 6.01 (1 H, d, J = 2.5 Hz), 6.88 (2H, d, J = 8.8 Hz), 7.28 ( 2H, d, J = 8.8 Hz). Step 2: (RS)-1-(N-Benzyl-l\l-methylamino)-1-[2-(ISI-benzyl-N-methylamino)-1-(4- methoxyphenyl)ethyl]-1 -silacyclohexane
To a cooled (-50 °C), stirred solution of Λ/-benzylmethylamine (0.62 mL, 4.6 mmol) in tetrahydrofuran (2 mL) was added a 2.0 M solution of n-butyllithium in hexane (2.86 mL, 4.58 mmol) dropwise over 5 minutes The resulting mixture was allowed to warm to -20 °C over 1.5 hours and was then cooled to -40 °C, followed by dropwise addition of a solution of 1-[1-(4-methoxyphenyl)vinyl]silacyclohexane (0.45 g, 1.9 mmol) in tetrahydrofuran (2 mL) over 5 minutes. The stirred mixture was allowed to warm to -20 °C over 2 hours and was then stirred at ambient temperature for 16 hours. The solvent was removed under reduced pressure and the residue was diluted with diethyl ether (2 x 15 mL). The mixture was filtered through a pad of celite and evaporated under reduced pressure. The residue was purified by column chromatography (on silica using diethyl ether) to afford the title compound as a colourless oil (0.46 g, 66%). 1H NMR (400 MHz, CD2CI2) δ 0.54-0.92 (4H, m), 1.25-1.80 (6H, m), 2.11 (3H, s), 2.22 (3H, s), 2.56-2.65 (2H, m), 3.04 (1H, t, J = 13.1 Hz), 3.31 (1 H, d, J = 13.1 Hz), 3.64 (1H, d, J = 13.1 Hz), 3.69-3.79 (2H, m), 3.81 (3H, s), 6.82 (2H, d, J = 8.8 Hz), 6.96 (2H, d, J = 8.8 Hz), 7.15-7.44 (10H, m). LC-MS: Rt = 2.78 min, m/z = 370 [MH+] Conditions A; Rt = 4.78 min, m/z = 369 [M+] Conditions B.
Step3: (RS)-1-[2-Benzylmethylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan- 1-ol. (RS)-1-(N-Benzyl-N-methylamino)-1-[2-(N-benzyl-N-methylamino)-1-(4- methoxyphenyI)ethyl]-1 -silacyclohexane (0.23 g, 0.48 mmol) was dissolved in acetonitrile (8 mL) and water (2 mL). The resulting mixture was heated at reflux for 5 hours under nitrogen. The solvent was evaporated under reduced pressure and the residue was extracted with diethyl ether (2 x 10 mL), dried (magnesium sulphate) and evaporated in vacuo. The resulting oil was distilled under reduced pressure to afford (RS)-1-[2-benzylmethylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol (145mg, 82 %). H NMR (400 MHz, CD2CI2) δ 0.40-0.78 (4H, m), 1.25-1.83 (6H, m), 2.25 (3H, s), 2.58 (1 H, dd, J = 5.3 and 12.1 Hz), 2.65 (1 H, dd, J = 5.3 and 12.1 Hz), 3.26 (1H, t, J = 12.1 Hz), 3.48 (1 H, d, J = 12.6 Hz), 3.69 (1 H, d, J = 12.6 Hz), 3.79 (3H, s), 6.83 (2H, d, J = 8.8 Hz), 6.99 ( 2H, d, J = 8.8 Hz), 7.25-7.45 (5H, m). LC-MS: Rt = 2.78 min, m/z = 370 [MH+] Conditions A.
Step 4: (RS)-1 -[2-Methylamino-1 -(4-methoxyphenyl)ethyl]-1 -silacyclohexan-1 -ol. A mixture of (RS)-1-[2-benzylmethylamino-1-(4-methoxyphenyl)ethyl]-1- silacyclohexan- 1-ol (40 mg, 0.1 mmol), 5 % palladium on carbon catalyst (40 mg) and 2-propanol (2 mL) was stirred at ambient temperature under an atmosphere of hydrogen for 22 hours. The reaction mixture was filtered through short pad of celite, which was then washed several times with diethyl ether (3 x 10 mL). The filtrate was evaporated under reduced pressure to afford the title compound (22 mg, 79%). 1H NMR (400 MHz, CD2CI2) δ 0.49-0.76 (4H, m), 1.30-1.43 (2H, m), 1.48-1.82 (4H, m), 2.34 (1H, m), 2.42 (3H, s), 3.05 (1 H, dd, J = 6.3 and 11.4 Hz), 3.14 (1H, dd, J = 8.8 and 11.4 Hz), 3.79 (3H, s), 6.85 (2H, d, J = 8.6 Hz), 7.06 ( 2H, d, J = 8.6 Hz). LC-MS: Rj = 3.73 min, m/z = 279 [MH+] Conditions B.

Claims

1. A compound selected from: (RS)-1-[2-methylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol; (R)-1-[2-methylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol; (S)-1-[2-methylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol;
(RS)-1-[2-amino-1-(4-melhoxyphenyl)ethyl]-1-silacyclohexan-1-ol;
(R)-1-[2-amino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol
(S)-1-[2-amino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol;
(RS)-1-[2-dimethylamino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol; (R)-1-[2-dimethylamino-1-(4-hydroxyphenyl)ethyl]-1 -silacyclohexan-1 -ol;
(S)-1-[2-dimethylamino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol;
(RS)-1-[2-amino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol;
(R)-1-[2-amino-1-(4-hydroxyphenyl)ethyl]-1 -silacyclohexan-1 -ol;
(S)-1-[2-amino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol; (RS)-1-[2-methylamino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol;
(R)-1-[2-methylamino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol;
(S)-1-[2-methylamino-1-(4-hydroxyphenyl)ethyl]-1-silacyclohexan-1-ol;
(RS)-1-[2-dimethylamino-1-(4-methoxyphenyl)ethyl]-1 -silacyclohexan-1, 4-diol;
(R)-1-[2-dimethylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1,4-diol; and (S)-1-[2-dimethylamino-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1, 4-diol; or a pharmaceutically acceptable salt thereof or a prodrug form that is hydrolysable to a compound as defined above.
2. A compound according to claim 1, for therapeutic use.
3. A pharmaceutical composition comprising a compound of claim 1, together with a pharmaceutically acceptable carrier or diluent.
4. A composition according to claim 3, which further comprises an emetogenic agent.
5. A composition according to claim 4, wherein the emetogenic agent is an opiate or cytotoxic agent.
6. A composition according to any of claims 3 to 5, which further comprises an anti- emetic agent.
7. A composition according to claim 6, wherein the anti-emetic agent is a 5-HT3 receptor antagonist, NK1 receptor antagonist, dopamine receptor antagonist or a steroid.
8. A product comprising a compound of claim 1 and an emetogenic agent, as a combined preparation for separate, simultaneous or sequential use in therapy for which the emetogenic agent is effective.
9. A product according to claim 8, wherein the emetogenic agent is an opiate or cytotoxic agent.
10. A product according to claim 8 or claim 9, which further comprises an anti- emetic agent.
11. A product according to any of claims 8 to 10, wherein the anti-emetic agent is as defined in claim 7.
12. Use of a compound of claim 1, for the manufacture of a medicament for the treatment or prevention of psoriasis, panic disorder, addiction, anxiety, depression, sexual dysfunction, hypertension, migraine, Alzheimer's disease, obesity, psychosis, schizophrenia, Parkinson's disease, restless leg syndrome, sleeping disorders, attention deficit hyperactivity disorder, irritable bowel syndrome, premature ejaculation, menstrual dysphoria syndrome, premenstrual tension, urinary incontinence, pain, chronic headache, Lesche-Nyhane disease, Wilson's disease or Tourette's syndrome.
13. Use according to claim 12, for the treatment or prevention of neuropathic pain.
14. Use according to claim 12, for the treatment or prevention of emesis.
15. Use according to claim 14, wherein the subject is also receiving an emetogenic agent.
16. Use according to claim 15, wherein the agent is an opiate or cytotoxic agent.
17. Use according to any of claims 14 to 16, wherein the subject is also receiving an anti-emetic agent.
18. Use according to claim 17, wherein the anti-emetic agent is as defined in claim 7.
PCT/GB2004/001781 2003-04-24 2004-04-23 1-(2-amino-1-phenyl-ethyl) 1- silacyclohexan-1- ol derivatives and use thereof in the preparation of a medicament WO2004094436A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0112669A2 (en) * 1982-12-13 1984-07-04 American Home Products Corporation Phenethylamine derivatives and intermediates therefor
WO2003037905A1 (en) * 2001-10-30 2003-05-08 Amedis Pharmaceuticals Limited Silicon compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0112669A2 (en) * 1982-12-13 1984-07-04 American Home Products Corporation Phenethylamine derivatives and intermediates therefor
WO2003037905A1 (en) * 2001-10-30 2003-05-08 Amedis Pharmaceuticals Limited Silicon compounds

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
TAKCE R ET AL: "SILA-SUBSTITUTION - A USEFUL STRATEGY FOR DRUG DESIGN?", ENDEAVOUR, PERGAMON PRESS, OXFORD, GB, vol. 10, no. 4, 1986, pages 191 - 197, XP008002622, ISSN: 0160-9327 *
YARDLEY J P ET AL: "2-PHENYL-2-(1-HYDROXYCYCLOALKYL)ETHYLAMINE DERIVATIVES: SYNTHESIS AND ANTIDEPRESSANT ACTIVITY", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 33, 1990, pages 2899 - 2905, XP000891765, ISSN: 0022-2623 *

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