GB2382575A - 1-aza-4-silacyclohexanes as pharmaceuticals - Google Patents

1-aza-4-silacyclohexanes as pharmaceuticals Download PDF

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Publication number
GB2382575A
GB2382575A GB0126035A GB0126035A GB2382575A GB 2382575 A GB2382575 A GB 2382575A GB 0126035 A GB0126035 A GB 0126035A GB 0126035 A GB0126035 A GB 0126035A GB 2382575 A GB2382575 A GB 2382575A
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compound according
silicon
compounds
compound
mmol
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Inventor
Reinhold Tacke
Tilman Heinrich
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Paradigm Therapeutics Ltd
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Amedis Pharmaceuticals Ltd
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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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A compound that has therapeutic utility is of the formula<BR> <BR> <F>X-R<SP>1</SP></F><BR> <BR> wherein X is <EMI ID=1.1 HE=26 WI=113 LX=518 LY=772 TI=CF> <PC>wherein Ar and Ar<SP>1</SP> are substituted or unsubstituted monocyclic aryl groups; Alk is an alkylene of 2 to 6 carbon atoms; n is 1 or 2; m is 0, 1 or 2; and Z is silicon or carbon, and wherein R<SP>1</SP> is a hydroxyl group or O-X', where X' is as defined for X; and wherein, when R<SP>1</SP> is not X', Z is silicon, and when R<SP>1</SP> is X', at least one Z is silicon; or a pharmaceutically acceptable salt thereof or a prodrug thereof. The compounds are sila-haloperidol derivatives useful as anti-psychotics.

Description

<Desc/Clms Page number 1>
SILICON COMPOUNDS Field of the Invention This invention relates to compounds and their therapeutic use.
Background of the Invention Sila-substitution (C/Si-exchange) of drugs is a relatively recent approach for searching for organo-silicon 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).
Haloperidol, i. e. 4- [4- (4-chlorophenyl)-4-hydroxypiperidin-1-yl] -1- (4-fluorophenyl) -1-butanone, is an antipsychotic drug, the preparation of which is disclosed in US-A-3438991. Haloperidol, like most antipsychotics, binds to a variety of receptors in the brain, and causes a variety of side-effects: the link between receptors and side-effects is however controversial. Common side-effects include extrapyramidal symptoms, which include such symptoms as parkinsonian tics, restlessness, abnormal facial movements and tardive dyskinesia (the delayed onset of movement). Lower potency compounds also bind to the ciladrenergic receptor, causing hypertension.
Summary of the Invention The present invention provides compounds containing one or two silicon atoms and which have desirable properties.
Compounds of the invention are silicon analogues of
haloperidol, and have formula 1 : X-R1 wherein X is
<Desc/Clms Page number 2>
wherein Ar and Ar1 are substituted or unsubstituted monocyclic aryl groups ; Alk is an alkylene of 2 to 6 carbon atoms; n is 1 or 2 ; m is 0,1 or 2 ; and Z is silicon or carbon, and wherein R1 is a hydroxyl group or o-x I, where X' is as defined for X ; and wherein, when R1 is not XI, Z is silicon, and when R1 is X I, at least one Z is silicon ; or a pharmaceutically acceptable salt thereof or a prodrug form that is metabolised to form a compound as defined above.
Compounds of the invention, most or all of which are new, have therapeutic utility. The compounds are useful as active ingredients in medicines, for the treatment of psychosis, e. g. schizophrenia, mania, and for the short-term management of psychomotoric agitation and impulsive behaviour.
Compounds of the invention may have an improved pharmacological profile compared to the parent compound.
For example, the compounds may be better tolerated by the patient, have lower side-effects at a therapeutically effective dose, or have a better therapeutic effect in some patients.
Description of the Invention Certain compounds of this invention are preferred. In particular, see the sub-claims.
The Ar and Arl groups can each be phenyl or, if either or each is substituted, it may represent halophenyl such as fluorophenyl, chlorophenyl, bromophenyl or iodophenyl ; alkoxyphenyl such as methoxyphenyl, ethoxyphenyl, dimethoxyphenyl or trimethoxyphenyl ; alkylphenyl such as tolyl, xylyl, isopropylphenyl or tert-butylphenyl. The Alk group is a 2 to 6 carbon group such as ethylene, propylene or butylene. m is preferably 0. n is preferably 2.
A preferred compound of the invention is 4- (4- chlorophenyl)-4-hydroxy-l- [4-oxo-4- (4-fluorophenyl) butyl]-4- silapiperidine or its hydrochloride salt.
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.
<Desc/Clms Page number 3>
Some compounds of the formula may exist in a prodrug form. In this aspect, the group R1 is a group that may be modified or removed under appropriate conditions to provide the compound in an active form. Suitable groups will be apparent to the skilled person, and include groups that replace the OH group on the Si atom and which can be hydrolysed to form the OH group. For example, suitable
2 2 2 2 replacement groups include H, OR2, N (R2) 2 or NHR2, where R2 is a Cl-6 alkyl group, e. g. a methyl group or aryl. Hydrolysable phosphorus-containing or sulphur-containing groups may also be used in the prodrug form.
Some compounds of the invention may exist in a form where the basic structure is repeated. For example, R1 may be a further deprotonated haloperidol or sila-haloperidol compound or derivative. This may offer improved activity compared to the single compound form.
The compounds may form organic or inorganic salts, for example, the compounds may form addition salts with inorganic or organic acids, e. g. hydrochloric acid, hydrobromic acid, fumaric acid, tartaric acid, citric acid and succinic acid. Such compounds may form base addition salts, for example, with alkali metal hydroxides, e. g. sodium hydroxide. It will be appreciated that such salts, provided that they are pharmaceutically acceptable, may be used in therapy in place of compounds of the specified formula. Such salts are prepared by reacting the compound with a suitable acid or base in a conventional manner.
As used hereinafter, the term"active compound"denotes a compound of formula 1 including pharmaceutically acceptable salts thereof. The compounds of the invention are to be used for the treatment of psychosis and dangerous impulsive behaviour. In particular, they may be used in the treatment of schizophrenia and for the short term quietening of disturbed patients suffering from a psychopathology, e. g. brain damage, mania, toxic delirium, agitated depression or acute behavioural disturbance. In therapeutic use, the active compound may be administered orally, rectally, parenterally, topically, by inhalation (pulmonary),
<Desc/Clms Page number 4>
ocularly, nasally, or to the buccal cavity. Oral and intramuscular administration are 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 dosage comprises the active ingredient in an amount of 100 Ag to 500 mg. The excipients used in the preparation of these compositions are the excipients known in the art.
The appropriate administered dose can be determined by the skilled person, and may be similar to that of conventional haloperidol. An initial dose may be from 100 ig to 100 mg daily, preferably 1 mg to 10 mg daily.
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.
Tablets may be prepared from a mixture of the active compound with fillers such as lactose or calcium phosphate, disintegrating agents, for example, maize starch, lubricating agents, for example, magnesium stearate, binders, for example, microcrystalline cellulose or polyvinylpyrrolidone, and other optional ingredients known in the art to permit tableting the mixture by known methods. The tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention.
Compositions for topical administration are also suitable for use in the invention. The pharmaceutically active compound may be dispersed in a pharmaceutically
<Desc/Clms Page number 5>
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 preparation of compounds of the invention.
Unless otherwise stated, the starting materials used in the Examples are commercially available and may be obtained by methods known of those skilled in the art.
Scheme 1 illustrates the synthesis of the preferred compound sila-haloperidol.
<Desc/Clms Page number 6>
Scheme 1
<Desc/Clms Page number 7>
Experimental Section General Procedures : All syntheses were carried out under dry nitrogen Acetonitrile, diethyl ether, n-pentane, toluene, and dichloromethane were dried and purified according to standard procedures and stored under nitrogen.
Preparation of Di (4-chlorophenyl) dimethoxysilane (2). A 0. 87 M solution of 4chlorophenylmagnesium bromide in diethyl ether (300 mL, 261 mmol of 4-Cl-C6H4MgBr) was added dropwise at room temperature within 90 min to a stirred solution of 1 (18.5 g, 122 mmol) in diethyl ether (200 mL). The mixture was stirred at room temperature for 16 h and then heated under reflux for 4 h. The precipitate was filtered off and washed with diethyl ether (3 x 150 mL), and the filtrate and wash solutions were combined. The solvent was removed by distillation at atmospheric pressure and n-pentane (250 mL) added to the residue. The resulting precipitate was filtered off, the filtrate concentrated under reduced pressure, and the residue distilled in vacuo (Vigreux column) to give 2 in 72% yield (27.5 g, 87.8 mmol) as a colorless liquid; bp 115 C/0. 05 mbar. Anal. Calcd. for CiClSi : C, 53.68 ; H, 4.50. Found: C, 53.5 ; H, 4.5.
Preparation of Di (4-chlorophenyl) divinylsilane (3). A 1. 7 M solution of vinylmagnesium chloride in THF (80 mL, 136 mmol ofCH=CHMgCI) was added dropwise at room temperature within 90 min to a stirred solution of 2 (19.5 g, 62.2 mmol) in diethyl ether (200 mL). After the mixture was stirred at room temperature for 16 h and heated under reflux for 6 h, a saturated aqueous NH4CI solution (500 mL) was added at 0 C. The organic phase was separated and the aqueous layer extracted with diethyl ether (3 x 350 mL), and the combined organic extracts were dried over
anhydrous NaSO. The solvent was removed under reduced pressure and the residue distilled in vacuo (Vigreux column) to give rac-3 in 77% yield as a colorless liquid (14. 6 g, 47. 8 mmol) ; bp 126 C/0. 02 mbar. Anal. Calcd. for CHClSi : C, 62. 95 ; H, 4. 62. Found : C, 62. 7 ; H, 4. 7.
Preparation of Di (2-bromoethyl) di (4-chlorophenyl) silane (4). A gas stream of hydrogen bromide was passed for 4 h at room temperature through a stirred solution of 3 (12.0 g, 39.3 mmol) (200 mg) in n-pentane (100 mL) in the presence of dibenzoyl peroxide Water (100 mL) was added to
the reaction mixture at 0 C, and the organic phase was separated and the aqueous layer extracted with diethyl ether (2 x 100 mL). The combined organic extracts were dried over anhydrous NaSO, and the solvent was removed by distillation at atmospheric pressure. The yellowish oily residue was dissolved in diethyl ether (50 mL) and the solution kept at -20 C to afford 4 in 73% yield as a colorless crystalline solid (13. 4 g, 28.7 mmol); mp 48-49 C. Anal. Calcd. for C16H16Br2ClSi : C, 41. 14 ; H, 3.45. Found: C, 41. 1; H, 3. 5.
<Desc/Clms Page number 8>
Preparation of 3-[2-(4-fluorophenyl0-1,3-dioxolan-2-yl]propylamine (5). The compound was synthesized according to ref [1].
Preparation of 4, 4-Di(4-chlorophenl)-1-[4-oxo-4-(4-fluorophenyl)butyl]-4-sila-ipiperidinium chloride (7). A mixture of 4 (5. 00 g, 10. 7 mmol), 5 (2.50 g, 11. 1 mmol), triethylamine (3. 00 g, 29.6 mmol), acetonitrile (30 mL), and toluene (30 mL) was heated for 16 h at 90 C in an 250-mL autoclave. After the reaction mixture was cooled to room temperature, the solid precipitate was removed by filtration. Water (60 mL) was added to the filtrate, and the organic phase was separated and the aqueous layer extracted with toluene (2 x 50 mL). The combined organic extracts were dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to give crude 4,4-di (4chlorophenyl)-1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-4-sila-piperidine (6; crude product). This product was dissolved in acetone (40 mL), and 6 M hydrochloric acid (2 mL) was added and the mixture heated at 60 OC for 2 h. After the mixture was cooled to room temperature, aqueous 6 M NaOH solution (6 mL) and toluene (40 mL) were added. The organic phase was separated and the aqueous layer extracted with toluene (2 x 50 mL), and the combined organic extracts were dried over anhydrous NaSO. After the solution was concentrated by distillation at atmospheric pressure (removal of acetone), a solution of hydrogen chloride in diethyl ether (3.0 M, 5.0 mL, 15.0 mmol HCI) was added dropwise at room temperature and the reaction mixture then cooled to-20 C. The solid formed at-20 C was recrystallized from 2-propanol to give 7 in 63% yield as a colorless crystalline solid (3 5 g, 6.69 mmol) ; mp 181 C. Anal. Calcd. for C26H27Cl3FNO2Si : C, 59. 72; H, 5.20 ; N, 2. 68. Found: C, 59.5 ; H, 5.1 ; N, 2.7.
Preparation of 4- (4-chlorophenyl)-4-hydroxy-l- [4-oxo-4- (4-fluorophenyl) butyll-4-silapiperidinium chloride (Sila-haloperidol hydrochloride, 8'HCI). Trifluoromethane sulfonic acid (1.80 g, 12.0 mrnol) was added dropwise at 0 oC within 1 min to a stirred solution of 7 (2.00 g, 3.82 mmol) in dichloromethane (20 mL), and the resulting mixture was stirred at 0 C for 30 min and at room temperature for 24 h. An aqueous 2 M NaOH solution (8 mL, 16 mmol) was added at 0 C, and the organic phase was separated and the aqueous layer extracted with dichloromethane (2 x 25 mL). The combined organic extracts were dried over anhydrous NaSO, and toluene (15 mL) was added. After the resulting solution was concentrated by distillation at atmospheric pressure (removal of dichloromethane), a solution of hydrogen chloride in diethyl ether (3.0 M, 1.3 mL, 3.9 mmol) was added dropwise at room temperature and the reaction mixture then cooled to -20 C (crystallization) to afford 8. HCI in 13% yield as colorless solid (210 mg, 490 umol) ; mp 160 C.
Anal. Calcd. for CGrNCSi : C, 56.07 ; H, 5.60 ; N, 3. 27. Found: C, 55.9 ; H, 5.6 ; N, 3.2.
[1] A. M. Ismaiel, J de los Angeles, M. Teitler, S. Ingher, R. A. Glennon, J. Med Chem. 1993, 36, 2519-2525.

Claims (11)

  1. CLAIMS 1. A compound of formula 1:
    X-R1 wherein X is
    wherein Ar and Arl are substituted or unsubstituted monocyclic aryl groups; Alk is an alkylene of 2 to 6 carbon atoms; n is 1 or 2; m is 0,1 or 2; and Z is silicon or carbon, and wherein R1 is a hydroxyl group or O-X 1, where X I is as defined for X ; and wherein, when R1 is not X', Z is silicon, and when R1 is XI, at least one Z is silicon; or a pharmaceutically acceptable salt thereof or a prodrug thereof.
  2. 2. A compound according to claim 1, wherein Ar is substituted with a halogen atom.
  3. 3. A compound according to claim 2, wherein Ar is a fluorophenyl group.
  4. 4. A compound according to any of claims 1 to 3, wherein m is 0.
  5. 5. A compound according to any preceding claim, wherein Ar'is chlorophenyl.
  6. 6. A compound according to any preceding claim, wherein R is OH.
  7. 7. A compound according to any preceding claim, which is 4- (4-chlorophenyl)-4-hydroxy-l- [4-oxo-4- (4fluorophenyl) butyl]-4-silapiperidine, or its hydrochloride salt chloride.
  8. 8. A compound according to any of claims 1 to 5, wherein R1 is X'.
  9. 9. A compound according to any preceding claim, for therapeutic use.
    <Desc/Clms Page number 10>
  10. 10. A pharmaceutical composition comprising as an active ingredient a compound according to any of claims 1 to 8, together with a carrier or diluent.
  11. 11. Use of a compound according to any of claims 1 to 8, for the manufacture of a medicament for the treatment of psychosis.
GB0126035A 2001-10-30 2001-10-30 1-aza-4-silacyclohexanes as pharmaceuticals Withdrawn GB2382575A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0299495A2 (en) * 1987-07-17 1989-01-18 Sanwa Kagaku Kenkyusho Co., Ltd. 1-Pyrrolidineacetamide derivatives and use thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0299495A2 (en) * 1987-07-17 1989-01-18 Sanwa Kagaku Kenkyusho Co., Ltd. 1-Pyrrolidineacetamide derivatives and use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Abstracts of JP 4041494 A (Sanwa Kagaku Kenkyusho Co.) *

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