WO2005035541A1 - Composes de silicium et utilisation de ceux-ci - Google Patents

Composes de silicium et utilisation de ceux-ci Download PDF

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Publication number
WO2005035541A1
WO2005035541A1 PCT/GB2004/004212 GB2004004212W WO2005035541A1 WO 2005035541 A1 WO2005035541 A1 WO 2005035541A1 GB 2004004212 W GB2004004212 W GB 2004004212W WO 2005035541 A1 WO2005035541 A1 WO 2005035541A1
Authority
WO
WIPO (PCT)
Prior art keywords
oxazol
thiazol
trimethylsilyl
vinyl
methyl
Prior art date
Application number
PCT/GB2004/004212
Other languages
English (en)
Inventor
Graham Andrew Showell
Parminder Kaur Ruprah
Louise Marie Walsh
Original Assignee
Amedis Pharmaceuticals Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0323470A external-priority patent/GB0323470D0/en
Priority claimed from GB0405304A external-priority patent/GB0405304D0/en
Application filed by Amedis Pharmaceuticals Ltd. filed Critical Amedis Pharmaceuticals Ltd.
Publication of WO2005035541A1 publication Critical patent/WO2005035541A1/fr

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Classifications

    • 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 System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C07F7/0814—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring is substituted at a C ring atom by Si

Definitions

  • Cyclin-dependent kinases are serine/threonine protein kinases and have key roles in the regulation of the cell cycle. They regulate the cell division cycle, apoptosis, transcription, differentiation and functions within the central nervous system. Aberrant activity of cdks is frequently implicated in cancer. Inhibitors of cdks have their use in the treatment of diseases such as cancer, alopecia, neurodegenerative disorders, viral infections and fungal infections (Knockaert etal. Trends Pharmacol. Sci.2002, 23, 417-425).
  • Cyclin-dependent kinase 2 plays a crucial role in the transition through S phase and is one of the key components of the G1 checkpoint. Checkpoints serve to maintain the proper sequence of cell cycle events and allow the cell to respond to insults or proliferative signals. Loss of proper checkpoint control in cancer cells contributes to tumourigenesis.
  • Inhibitors of cyclin-dependent kinases such as flavopiridol (a potent inhibitor of cdkl , cdk2 and cdk4), are currently in clinical trials.
  • US-A-2002/0137778 and US-A-2002/0165259 describe aminothiazole compounds which are inhibitors of cyclin-dependent kinases.
  • 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). Summary of the Invention According to a first aspect of the invention, a compound has the formula (I)
  • Compounds of the invention may act as inhibitors of cyclin-dependent kinase and as a consequence may have utility in the therapy of diseases in which cyclin-dependent kinases are implicated. Accordingly, another aspect of the invention is the use of a compound of formula (I) for the manufacture of a medicament for the treatment or prevention of cancer, an inflammatory disease, a cardiovascular disease, an infectious disease, pain, a neurodegenerative disease, transplant rejection, glaucoma or alopecia. Another aspect of the invention is a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable diluent or carrier. A composition of the invention may be suitable for use in a combination therapy.
  • B is preferably heteroaryl, more preferably oxazolyl.
  • R 1 is preferably hydrogen.
  • R 2 /-D-E-R 2 is preferably one of the groups recited in the subclaims.
  • R 3 and R 4 are preferably each hydrogen.
  • R 5 is preferably alkyl, more preferably methyl.
  • alkyl refers to a straight or branched chain alkyl moiety having from one to six carbon atoms.
  • alkyl refers to a similar, divalent group.
  • aryl refers to an optionally substituted aromatic ring system comprising from six to fourteen ring atoms.
  • the group may be a polycyclic ring system having two or more rings, at least one of which is aromatic. This term includes, for example, phenyl and naphthyl.
  • the group may be substituted with one or more substituents, the substituents being the same or different and selected from halogen, hydroxyalkyl, -alkyl-NHCH(CH 2 OH) 2 and the like.
  • substituents being the same or different and selected from halogen, hydroxyalkyl, -alkyl-NHCH(CH 2 OH) 2 and the like.
  • cycloalkyl refers to a saturated alicyclic moiety having from three to six carbon atoms. This term includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • heterocycloalkyl refers to an optionally substituted saturated heterocyclic moiety having from three to seven ring carbon atoms and one or more ring heteroatoms selected from nitrogen, oxygen, phosphorus, sulphur and silicon. This term includes, for example, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and the like.
  • the group may be substituted with one or more substituents, the substituents being the same or different and selected from -C(O)-alkyl, -C(O)O-alkyl, -S(O) 2 -alkyl, alkyl, hydroxy, hydroxyalkyl and the like.
  • heteroaryl refers to an optionally substituted aromatic ring system having from five to ten ring atoms, at least one of which is selected from nitrogen, oxygen and phosphorus.
  • the group may be a polycyclic ring system, having two or more rings, at least one of which is aromatic. This term includes, for example, furanyl, thiophenyl, pyridyl, indolyl, quinolyl and the like.
  • the group may be substituted with one or more substituents, the substituents being the same or different and selected from alkyl and the like.
  • heteroarylene refers to a similar, divalent group.
  • Preferred compounds of the invention include: 1-(1-methyl-piperidin-4-yl)-3- ⁇ 5-[2-(5-trimethylsilyl-oxazol-2-yl)-vinyl]- thiazol-2-yl ⁇ -urea; pyrimidin-4-yl- ⁇ 5-[2-(5-trimethylsilyl-oxazol-2-yl)-vinyl]-thiazol-2-yl ⁇ -amine; 1-piperidin-4-yl-3- ⁇ 5-[2-(5-trimethylsilyl-oxazol-2-yl)-vinyl]-thiazol-2-yl ⁇ - urea; pyrimidin-2-yl- ⁇ 5-[2-(5-trimethylsilyl-oxazol-2-yl)-vinyl]-thiazol-2-yl ⁇ -amine; (4-methyl-pyridin-2-yl)- ⁇ 5-[2-(5-trimethylsilyl-oxazol-2-yl)-vin
  • Compounds of the invention may be chiral. They may be in the form of a single enantiomer or diastereomer, or a racemate.
  • a compound of the invention may exist in the form of a single isomer or tautomer.
  • a compound of the invention comprising an alkenylene moiety may exist in the E or Z isomeric form.
  • compounds of the invention such as those comprising a pyridyl or morpholinyl group, may be in the form of an N-oxide; such N-oxides also form part of the present invention.
  • 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.
  • the enantiomers of the novel compounds may be separated by HPLC using a chiral column.
  • a compound of the invention may be in a protected amino, protected hydroxy or protected carboxy form.
  • protected amino refers to amino, hydroxy and carboxy groups which are protected in a manner familiar to those skilled in the art.
  • an amino group can be protected by a benzyloxycarbon l, tert- butoxycarbonyl, acetyl or like group, or in the form of a phthalimido or like group.
  • a carboxyl group can be protected in the form of a readily cleavable ester such as the methyl, ethyl, benzyl or tert-butyl ester.
  • 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.
  • 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, gluconicacid, glutamicacid, N-glycolylarsanilicacid, 4-hexylresorcinol, hippuric acid, 2-(4-hydroxybenzoyl)benzoicacid, 1-hydroxy-2-naphthoicacid, 3-hydroxy- 2-naphthoic acid, 2-hydroxyethanesulphonic acid, lactobi
  • Salts may also be formed with inorganic bases.
  • inorganic base salts include, for example, salts of aluminium, bismuth, calcium, lithium, magnesium, potassium, sodium, zinc and the like.
  • Organic base salts include, for example, salts of N, N'-dibenzylethylenediamine, choline (as a counterion), d ie th a no l am i ne , ethano l am i ne, ethyl ened i ami ne, N , N' - bis(dehydroabietyl)ethylenediamine, N-methylglucamine, procaine, tris(hydroxymethyl)aminomethane ("TRIS”) and the like.
  • TIS tris(hydroxymethyl)aminomethane
  • 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 and/or by the following processes (in which Q is a suitable protecting group):
  • the compounds of the invention may be used in the treatment of numerous ailments, conditions and diseases including, but not limited thereto, cancer, inflammatory diseases (e.g. inflammatory bowel disease, arthritis or glomerulonephntis), cardiovascular diseases (e.g. artherosclerosis, myocardial disease or restenosis), infectious diseases (e.g. HIV infection, AIDS or fungal infection), pain, neurodegenerative diseases, transplant rejection, glaucoma and alopecia.
  • cancer e.g. inflammatory bowel disease, arthritis or glomerulonephntis
  • cardiovascular diseases e.g. artherosclerosis, myocardial disease or restenosis
  • infectious diseases e.g. HIV infection, AIDS or fungal infection
  • pain e.g. HIV infection, AIDS or fungal infection
  • neurodegenerative diseases e.g. HIV infection, AIDS or fungal infection
  • transplant rejection e.g., glaucoma and alopecia.
  • cancer refers to any disease or condition characterised by uncontrolled, abnormal growth of cells and includes all known types of cancer, for example cancer of the bladder, breast, colon, brain, bone, head, blood, eye, neck, skin, lungs, ovaries, prostate and rectum; digestive, gastrointestinal, endometrial, hematological, AIDS-related, muscoskeletal, neurological and gynecological cancers; lympomas, melanomas and leukaemia.
  • 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.
  • compositions of the present invention may take the form of any of the known pharmaceutical compositions for such methods of administration.
  • the compositions may be formulated in a manner known to those skilled in the art so as to give a controlled release, for example rapid release or sustained release, of the compounds of the present invention.
  • Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art.
  • the compositions of the invention may contain 0.1 -99% by weight of active compound.
  • the compositions of the invention are generally prepared in unit dosage form. Preferably, a unit dose comprises the active ingredient in an amount of 1-500 mg.
  • the excipients used in the preparation of these compositions are the excipients known in the art. Appropriate dosage levels may be determined by any suitable method known to one skilled in the art.
  • 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.
  • 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.
  • 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, 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.
  • 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,
  • 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.
  • 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.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • 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.

Abstract

L'invention concerne un composé de formule (1): dans laquelle: A représente -CH2CH2-, -CH=CH- ou -C=-C-; B désigne un aryle ou un hétéroaryle; D est éventuellement présent et représente -C(O)-, -C(O)NH-, -C(O)CH2- ou -C(O)CH2- 0-; E est éventuellement présent et désigne un alkylène ou un hétéroarylène; R1 désigne un hydrogène ou un alkyle; R2 représente un hydrogène, un alkyle, un aryle, un cycloalkyle, un hétéroaryle ou un hétérocycloalkyle; R3 et R4 sont identiques ou différents et représentent individuellement un hydrogène, un alkyle ou un cycloalkyle; et chaque R5 est identique ou différent et représente un alkyle, -alkyl-aryle ou -alkyl-cycloalkyle ou R5-Si-R5 pris ensemble forment un hétérocycloalkyle; ou un sel acceptable sur le plan pharmaceutique de ceux-ci.
PCT/GB2004/004212 2003-10-07 2004-10-05 Composes de silicium et utilisation de ceux-ci WO2005035541A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0323470A GB0323470D0 (en) 2003-10-07 2003-10-07 Compounds and their use
GB0323470.5 2003-10-07
GB0405304A GB0405304D0 (en) 2004-03-09 2004-03-09 Compounds and their use
GB0405304.7 2004-03-09

Publications (1)

Publication Number Publication Date
WO2005035541A1 true WO2005035541A1 (fr) 2005-04-21

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010540610A (ja) * 2007-10-05 2010-12-24 キャンサー・リサーチ・テクノロジー・リミテッド ピラジン−２−イル−ピリジン−２−イル−アミンとピラジン−２−イル−ピリミジン−４−イル−アミン化合物およびそれらの使用
US8372971B2 (en) 2004-08-25 2013-02-12 Targegen, Inc. Heterocyclic compounds and methods of use
US8481536B2 (en) 2004-04-08 2013-07-09 Targegen, Inc. Benzotriazine inhibitors of kinases

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6407124B1 (en) * 1998-06-18 2002-06-18 Bristol-Myers Squibb Company Carbon substituted aminothiazole inhibitors of cyclin dependent kinases
US20020137778A1 (en) * 1999-12-15 2002-09-26 Kim Kyoung S. Aminothiazole inhibitors of cyclin dependent kinases

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6407124B1 (en) * 1998-06-18 2002-06-18 Bristol-Myers Squibb Company Carbon substituted aminothiazole inhibitors of cyclin dependent kinases
US20020165259A1 (en) * 1998-06-18 2002-11-07 Rawlins David B. Carbon substituted aminothiazole inhibitors of cyclin dependent kinases
US20020137778A1 (en) * 1999-12-15 2002-09-26 Kim Kyoung S. Aminothiazole inhibitors of cyclin dependent kinases

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LUKEVICS E.: "Biolgical Activity of Nitrogen containing Organosilicon Compounds", NOBEL SYMP., no. 40, 1978, pages 435 - 445, XP002312113 *
TACKE 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 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8481536B2 (en) 2004-04-08 2013-07-09 Targegen, Inc. Benzotriazine inhibitors of kinases
US8372971B2 (en) 2004-08-25 2013-02-12 Targegen, Inc. Heterocyclic compounds and methods of use
JP2010540610A (ja) * 2007-10-05 2010-12-24 キャンサー・リサーチ・テクノロジー・リミテッド ピラジン−２−イル−ピリジン−２−イル−アミンとピラジン−２−イル−ピリミジン−４−イル−アミン化合物およびそれらの使用

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