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WO2004113353A1 - Silicon-comprising aminothiazole derivatives as cdk inhibitors - Google Patents

Silicon-comprising aminothiazole derivatives as cdk inhibitors Download PDF

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Publication number
WO2004113353A1
WO2004113353A1 PCT/GB2004/002572 GB2004002572W WO2004113353A1 WO 2004113353 A1 WO2004113353 A1 WO 2004113353A1 GB 2004002572 W GB2004002572 W GB 2004002572W WO 2004113353 A1 WO2004113353 A1 WO 2004113353A1
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WIPO (PCT)
Prior art keywords
oxazol
thiazol
ylmethylthio
trimethylsilyl
alkyl
Prior art date
Application number
PCT/GB2004/002572
Other languages
French (fr)
Inventor
John Gary Montana
Parminder Kaur Ruprah
Graham Andrew Showell
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 GB0314293A external-priority patent/GB0314293D0/en
Priority claimed from GB0405306A external-priority patent/GB0405306D0/en
Application filed by Amedis Pharmaceuticals Ltd. filed Critical Amedis Pharmaceuticals Ltd.
Publication of WO2004113353A1 publication Critical patent/WO2004113353A1/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
    • C07F7/0803—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

  • Cycl in-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 and differentiation. Cdks also regulate 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 et al. Trends Pharmacol. Sci. 2002, 23, 417- 425).
  • Cdk2 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 cdks such as f lavopiridol (a potent inhibitor of cdkl , cdk2 and cdk4), are currently in clinical trials.
  • a compound has the formula
  • R 1 and R 2 are the same or different and are each hydrogen, halogen or alkyl
  • R 3 is aryl or heteroaryl, either of which is substituted at least once with -Si(R 7 ) 3 , and with the proviso that -Si(R 7 ) 3 is bound to a carbon atom of R 3 ;
  • R 4 is R 8 , -C(0)-R 8 , -C(0)NH-R 8 , -C(0)0-R 8 , -S(0) 2 -R 8 , -C(NHCN)NH-R 8 , -C(NN0 2 )NH-R 8 , -C(NH)NH-R 8 , -C(NH)NHC(0)-R 8 or -C(NOR 8 )NH-R 8 ;
  • R 5 and R 6 are the same or different and are each hydrogen or alkyl; each R 7 is the same or different and is alkyl, -alkyl-aryl or -alkyl-cycloalkyl, or R 7 -Si-R 7 taken together form heterocycloalkyl; each R 8 is the same or different and is alkyl, cycloalkyl, aryl, -alkyl- cycloalkyl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, -heterocycloalkyl or -alkyl- heterocycloalkyl; m is 0, 1 or 2; and n is 1 , 2 or 3; or a pharmaceutically acceptable salt thereof.
  • Compounds of the invention may act as inhibitors of cdks and as a consequence may have utility in the therapy of diseases or conditions in which cdks are implicated.
  • 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.
  • 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.
  • R 1 and/or R 2 is hydrogen or fluorine.
  • R 3 is preferably heteroaryl substituted with -Si(R 7 ) 3 , more preferably a group of formula (i) as described herein.
  • R 4 is preferably -C(0)-alkyl, -C(NHCN)N-aryl, heteroaryl, aryl, -C(0)-heterocycloalkyl, -C(O)-heteroaryl, -C(0)-alkyl-aryl, -NH-aryl, -C(0)NH-aryl, -C(0)-alkyl-heterocycloalkyl or -C(0)NH-heterocycloalkyl.
  • R 5 is preferably hydrogen or methyl.
  • R 6 is preferably hydrogen.
  • m and n are 0 and 1 respectively.
  • alkyl refers to a straight or branched chain alkyl moiety having from one to six carbon atoms. This term includes, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like.
  • C.,. 6 alkyl has the same meaning.
  • aryl refers to an optionally substituted aromatic ring system having 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 andthe 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(0)-alkyl, -C(0)0-alkyl, -S(0) 2 -alkyl, alkyl, 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 sulphur. 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 in each occurrence and selected from -alkylamino-alkylhydroxy, -S(0) 2 - alkyl, -S(0) 2 -alkylamino-alkylhydroxy and the like.
  • Preferred compounds of the invention include:
  • Compounds of the invention may be chiral. They may be in the form of a single enantiomer or diastereomer, or a racemate.
  • the compounds may exist in isomeric or tautomeric form; such isomers or tautomers 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 benzyloxycarbonyl, 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.
  • 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)benzoic acid, 1 -hydroxy-2-naphthoic acid, 3-hydroxy- 2-naphthoic acid, 2-hydroxyethanesulphonic acid, lactobionic acid, n-dodecyl sulphuric acid, maleic acid, malic acid, mandelic acid, methanesulphonic acid, methyl sulph
  • 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), diethano lam ine , ethano lam ine , ethyle nediamine , N , N'- bis(dehydroabietyl)ethylenediamine, N-methylglucamine, procaine, tris(hydroxymethyl)aminomethane ("TRIS”) and the like.
  • TIS tris(hydroxymethyl)aminomethane
  • 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 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 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 glomerulonephritis), 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 glomerulonephritis
  • 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, rectally, parenterally, by inhalation (pulmonary delivery), topically, ocularly, nasally, or to the buccal cavity.
  • Oral 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.
  • 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, 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.
  • suspending agents for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum
  • 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
  • colouring agents for example ethyl or n-propyl p- hydroxybenzoate
  • flavouring agents such as sucrose or saccharin.
  • 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.
  • 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 i ⁇ jectables.
  • 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.
  • 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.
  • R f values were determined by TLC, using silica-based plates.
  • Example 2 N-(5-((5-(Trimethylsilyl)oxazol-2-yl)methylthio)thiazol-2- yl)piperidine-4-carboxamide dihydrochloride terf-Butyl-4-(5-((5-(trimethylsilyl)oxazol-2-yl)methylthio)thiazol-2- ylcarbamoyl)piperidine-1-carboxylate (540 mg, 1.1 mmol) was stirred in an anhydrous ethereal solution containing hydrogen chloride gas (2M solution, 10 mL) for 18 h. The mixture was concentrated under reduced pressure.
  • 2M solution 2M solution, 10 mL

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Abstract

A compound of formula (I), wherein R1 and R2 are the same or different and are each hydrogen, halogen or alkyl; R3 is aryl or heteroaryl, either of which is substituted at least once with -Si(R7)3, and with the proviso that -Si(R7)3 is bound to a carbon atom of R3, R4 is R8, -C(O)-R8, -C(O)O-R8, -S(O)2-R8, -C(NHCN)NH-R8, -C(NNO2)NH-R8, -C(NH)NH-R8, -C(NH)NHC(O)-R8 or -C(NOR8)NH-R8, R5 and R6 are the same or different and are each hydrogen or alkyl; each R7 is the same or different and is alkyl, -alkyl-aryl or -alkyl-cycloalkyl, or R7-Si-R7 taken together form heterocycloalkyl; each R8 is the same or different and is alkyl, cycloalkyl, aryl, -alkyl-cycloalkyl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, -heterocycloalkyl or -alkyl-heterocycloalkyl; m is 0, 1 or 2; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.

Description

SILICON-COMPRISING AMINOTHIAZOLE DERIVATIVES AS CDK INHIBITORS
Field of the Invention
This invention relates to silicon compounds and their use in therapy. Background to the Invention Cycl in-dependent kinases (cdks) are serine/threonine protein kinases and have key roles in the regulation of the cell cycle. They regulate the cell division cycle, apoptosis, transcription and differentiation. Cdks also regulate 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 et al. Trends Pharmacol. Sci. 2002, 23, 417- 425). Targeting a single cdk to cause cell-cycle arrest in a particular phase could be desirable. For example, suppression of tumour growth by arrest in the G1 phase of the cycle could reduce the stress for normal cells, as they spend most of their time resting in the G0-G1 phase. Cdk2 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 cdks, such as f lavopiridol (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)
Figure imgf000003_0001
wherein R1 and R2 are the same or different and are each hydrogen, halogen or alkyl;
R3 is aryl or heteroaryl, either of which is substituted at least once with -Si(R7)3, and with the proviso that -Si(R7)3 is bound to a carbon atom of R3;
R4 is R8, -C(0)-R8, -C(0)NH-R8, -C(0)0-R8, -S(0)2-R8, -C(NHCN)NH-R8, -C(NN02)NH-R8, -C(NH)NH-R8, -C(NH)NHC(0)-R8 or -C(NOR8)NH-R8;
R5 and R6 are the same or different and are each hydrogen or alkyl; each R7 is the same or different and is alkyl, -alkyl-aryl or -alkyl-cycloalkyl, or R7-Si-R7 taken together form heterocycloalkyl; each R8 is the same or different and is alkyl, cycloalkyl, aryl, -alkyl- cycloalkyl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, -heterocycloalkyl or -alkyl- heterocycloalkyl; m is 0, 1 or 2; and n is 1 , 2 or 3; or a pharmaceutically acceptable salt thereof. Compounds of the invention may act as inhibitors of cdks and as a consequence may have utility in the therapy of diseases or conditions in which cdks 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. Description of the Invention
Certain compounds and combinations of substituents are preferred; in particular see the subclaims.
With regard to formula (I), it is preferred that R1 and/or R2is hydrogen or fluorine. R3 is preferably heteroaryl substituted with -Si(R7)3, more preferably a group of formula (i) as described herein. R4 is preferably -C(0)-alkyl, -C(NHCN)N-aryl, heteroaryl, aryl, -C(0)-heterocycloalkyl, -C(O)-heteroaryl, -C(0)-alkyl-aryl, -NH-aryl, -C(0)NH-aryl, -C(0)-alkyl-heterocycloalkyl or -C(0)NH-heterocycloalkyl. R5 is preferably hydrogen or methyl. R6 is preferably hydrogen. Preferably, m and n are 0 and 1 respectively. The term "alkyl" as used herein refers to a straight or branched chain alkyl moiety having from one to six carbon atoms. This term includes, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like. "C.,.6 alkyl" has the same meaning.
The term "aryl" as used herein refers to an optionally substituted aromatic ring system having 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(CH2OH)2andthe like.
The term "cycloalkyl" as used herein 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.
The term "heterocycloalkyl" as used herein 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(0)-alkyl, -C(0)0-alkyl, -S(0)2-alkyl, alkyl, hydroxyalkyl and the like. The term "heteroaryl" as used herein 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 sulphur. 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 in each occurrence and selected from -alkylamino-alkylhydroxy, -S(0)2- alkyl, -S(0)2-alkylamino-alkylhydroxy and the like.
Preferred compounds of the invention include:
/V-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)-thiazol-2-yl]-acetamide;
Λ/-methyl-Λ/-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)-thiazol-2-yl]- isobutyramide; pyridin-2-yl-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)-thiazol-2-yl]-amine;
{3-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)-thiazol-2-ylamino]-phenyl}- methanol; pyridin-4-yl-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)-thiazol-2-yl]-amine; N-(5-((5-(trimethylsilyl)oxazol-2-yl)methylthio)thiazol-2-yl)piρeridine-4- carboxamide; piperidine-3-carboxylic acid [5-(5-trimethylsilyl-oxazol-2-ylmethylthio)- thiazo!-2-yl]-amide;
Λ/-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)-thiazol-2-yl]-isonicotinamide; Λ/-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)-thiazol-2-yl]-nicotinamide;
1-acetyl-piperidine-4-carboxylic acid [5-(5-trimethylsily!-oxazol-2- ylmethylthio)-thiazol-2-yl]-amide;
1 -acetyl-piperidine-3-carboxylic acid [5-(5-trimethylsilyl-oxazol-2- ylmethylthio)-thiazol-2-yl]-amide; 1-methanesulphonyl-piperidine-4-carboxylic acid [5-(5-trimethylsilyl- oxazol-2-ylmethylthio)-thiazol-2-ylJ-amide; 1 -methanesulphonyl-piperidine-3-carboxylic acid [5-(5-trimethylsilyl- oxazol-2-ylmethylthio)-thiazol-2-yl]-amide; piperazine-1 -carboxylic acid [5-(5-trimethylsilyl-oxazol-2-ylmethylthio)- thiazol-2-yl]-amide; piperazine-2-carboxylic acid [5-(5-trimethylsilyl-oxazol-2-ylmethylthio)- thiazol-2-yl]-amide;
4-methyl-piperazine-1 -carboxylic acid [5-(5-trimethylsilyl-oxazol-2- ylmethylthio)-thiazol-2-yl]-amide;
1 -methyl-piperidine-3-carboxylic acid [5-(5-trimethylsilyl-oxazol-2- ylmethylthio)-thiazol-2-yl]-amide;
1 -methyl-piperidine-4-carboxylic acid [5-(5-trimethylsilyl-oxazol-2- ylmethylthio)-thiazol-2-yl]-amide;
4-hydroxymethyl-piperidine-1 -carboxylic acid [5-(5-trimethylsilyl-oxazol-2- ylmethylthio)-thiazol-2-yl]-amide; 2-{4-[(2-hydroxy-1 -hydroxymethyl-ethylamino)-methyl]-phenyl}-Λ/-[5-(5- trimethylsilyl-oxazol-2-ylmethylthio)-thiazol-2-yl]-acetamide;
1-(2,6-dichloro-phenyl)-3-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)- thiazol-2-yl]-urea;
1-{4-[(2-hydroxy-1-hydroxymethyl-ethylamino)-methyl]-phenyl}-3-[5-(5- trimethylsilyl-oxazol-2-ylmethylthio)-thiazol-2-yl]-urea;
1-(2,6-difluoro-phenyl)-3-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)-thiazol- 2-yl]-urea;
2-piperidin-4-yl-Λ/-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)-thiazol-2-yl]- acetamide; 1-piperidin-4-yl-3-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)-thiazol-2-yl]- urea;
2-(1-methyl-piperidin-4-yl)-Λ/-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)- thiazol-2-yl]-acetamide;
1-(1-methyl-piperidin-4-yl)-3-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)- thiazol-2-yl]-urea; piperidine-4-carboxylicacid{5-[5-(1-methyl-1-sila-cyclopentyl)-oxazol-2- ylmethylthio]-thiazol-2-yl}-amide; piperidine-3-carboxylicacid{5-[5-(1-methyl-1-sila-cyclopentyl)-oxazol-2- ylmethylthio]-thiazol-2-yl}-amide;
Λ/-{5-[5-(1-methyl-1-sila-cyclopentyl)-oxazol-2-ylmethylthio]-thiazol-2-yl}- isonicotinamide; Λ/-{5-[5-(1 -methyl-1 -sila-cyclopentyl)-oxazol-2-ylmethylthio]-thiazol-2-yl}- nicotinamide; piperidine-4-carboxylic acid {5-[5-(1 -methyl-1 -sila-cyclohexyl)-oxazol-2- ylmethylthio]-thiazol-2-yl}-amide; tert-butyl-4-(5-((5-(trimethylsilyl)oxazol-2-yl)methylthio)thiazol-2- ylcarbamoyl)piperidine-1 -carboxylate;
3-((6-(5-((5-(trimethylsilyl)oxazol-2-yl)methylthio)thiazol-2-ylamino)pyridin- 3-yl)methylamino)-2,2-dimethylpropan-1 -ol; and
2-((6-(5-((5-(trimethylsilyl)oxazol-2-yl)methylthio)thiazol-2-ylamino)pyridin- 3-yl)sulphonamido)ethan-1 -ol; the corresponding structures of which are shown below, respectively:
Figure imgf000008_0001
Figure imgf000008_0002
Figure imgf000008_0003
Figure imgf000009_0001
Figure imgf000009_0002
Figure imgf000010_0001
Figure imgf000010_0002
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000012_0002
Figure imgf000012_0003
Figure imgf000013_0001
Compounds of the invention may be chiral. They may be in the form of a single enantiomer or diastereomer, or a racemate. The compounds may exist in isomeric or tautomeric form; such isomers or tautomers 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. Alternatively, 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. The terms "protected amino", "protected hydroxy" and "protected carboxy" as used herein refer to amino, hydroxy and carboxy groups which are protected in a manner familiar to those skilled in the art. For example, an amino group can be protected by a benzyloxycarbonyl, tert- butoxycarbonyl, acetyl or like group, or in the form of a phthalimido or like group. 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)benzoic acid, 1 -hydroxy-2-naphthoic acid, 3-hydroxy- 2-naphthoic acid, 2-hydroxyethanesulphonic acid, lactobionic acid, n-dodecyl sulphuric acid, maleic acid, malic acid, mandelic acid, methanesulphonic acid, methyl sulphuric acid, mucic acid, 2-naphthalenesulphonic acid, pamoic acid, pantothenic acid, phosphanilic acid ((4-aminophenyl)phosphonic acid), picric acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, terephthalic acid, p-toluenesulphonic acid, 10-undecenoic acid and the like.
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. Organic base salts include, for example, salts of N, N'-dibenzylethylenediamine, choline (as a counterion), diethano lam ine , ethano lam ine , ethyle nediamine , N , N'- bis(dehydroabietyl)ethylenediamine, N-methylglucamine, procaine, tris(hydroxymethyl)aminomethane ("TRIS") 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 and/or by the following processes:
B r.n
Figure imgf000016_0001
1MHCI(aq) 65 °C, acetone
Figure imgf000016_0002
i. n-BuLi(1.5eq), THF -78 °C, 20 min ii. R7R7R7SiCI
Figure imgf000016_0003
Figure imgf000016_0004
Dithiothreitol
Figure imgf000016_0005
Figure imgf000016_0006
KOtBu
Figure imgf000017_0001
Figure imgf000017_0002
Figure imgf000017_0003
(Some of the intermediates above may be obtained according to Wang et al, Tetrahedron, 2002, 58, 7663-7679; Morwick et al, Organic Letters, 2002, 4(16), 2665-2668; Ki et al, J. Med. Chem, 2002, 45, 3905-3927; and US-A- 2002/0137778.) It will be understood that the processes detailed 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 to obtain a compound of the invention.
Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in a known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallisation, or by the formation of a salt if appropriate or possible under the circumstances.
The activity and selectivity of the compounds may be determined by any suitable assay known in the art.
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 glomerulonephritis), 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.
The term "cancer" as used herein 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.
In therapeutic use, the active compound may be administered orally, rectally, parenterally, by inhalation (pulmonary delivery), topically, ocularly, nasally, or to the buccal cavity. Oral administration is preferred. Thus, the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for such methods of administration. The compositions may be formulated in a manner known to those skilled in the art so as to give a controlled release, for example rapid release or sustained release, of the compounds of the present invention. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art. The compositions of the invention may contain 0.1-99% by weight of active compound. The compositions of the invention are generally prepared in unit dosage form. Preferably, a unit dose comprises the active ingredient in an amount of 1-500 mg. The excipients used in the preparation of these compositions are the excipients known in the art.
Appropriate dosage levels may be determined by any suitable method known to one skilled in the art. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the disease undergoing treatment.
Compositions for oral administration are preferred compositions of the invention and there are known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oily suspensions. The pharmaceutical composition containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example starch gelatin, acacia, microcrystalline cellulose or polyvinyl pyrrolidone; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p- hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable sweetening, flavouring and colouring agents may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3- butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid, find use in the preparation of iηjectables. 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, Rf values were determined by TLC, using silica-based plates.
Intermediate 1 : 2-(benzyloxy)-N-(2,2-dimethoxyethyl)acetamide
To a solution of benzyloxyacetic acid (19.5 g, 0.1 mol) and aminoacetaldehyde dimethyl acetal (11.4 mL, 0.1 mol) in dic loromethane (400 mL) at room temperature was added 1-(3-dimethylaminopropyl)-3- ethylcarbodiimidehydrochloride (20.1 g, 0.1 mol) followed by triethylamine (14.6 mL, 0.1 mol). The reaction mixture was stirred at room temperature for 16 h and then added to water (250 mL) and the layers separated. The organic phase was washed sequentially with 1M hydrochloric acid solution (250 mL) and saturated aqueous sodium bicarbonate solution (250 mL), dried (magnesium sulphate) and concentrated under reduced pressure to give the title compound as a colourless oil (22.6 g, 85 %). Rf (95:5 dichloromethane:methanol): 0.51. 1H NMR (CDCI3, 400 MHz): δH 3.42 (6H, s), 3.47 (2H, t, J = 5.4 Hz), 4.01 (2H, s), 4.42 (1 H, t, J = 5.4 Hz), 4.59 (2H, s), 6.81 (1H, broad s), 7.42-7.33 (5H, m). Intermediate 2: 2-(Benzyloxy)-N-(formylmethyl)acetamide
A solution of 2-(benzyloxy)-N-(2,2-dimethoxyethyl)acetamide (22.6 g, 89 mmol) in aqueous 1M hydrochloric acid (300 mL) and acetone (300 mL) was heated at 65 °C for 1.5 h. The solution was allowed to cool to room temperature and extracted with dichloromethane (3 * 200 mL). The combined organic extracts were dried (magnesium sulphate) and solvent evaporated under reduced pressure to give the title compound as a pale yellow oil (18.5 g, >99%). Rf (95:5 dichloromethane:methanol): 0.10. 1H NMR (CDCI3, 400 MHz): δH 4.07 (2H, s), 4.25 (2H, J - 5.3 Hz), 4.63 (2H, s), 7.43-7.34 (5H, m), 9.68 (1H, s). Intermediate 3: 2-((Benzyloxy)methyl)oxazole
A solution of hexachloroethane (31.8 g, 0.13 mol) and triphenylphosphine (35.2 g, 0.13 mol) in acetonitrile (350 mL) at room temperature was treated with a solution of 2-(benzyloxy)-N-
(formylmethyl)acetamide (13.9 g, 67 mmol) in acetonitrile (110 mL). The resulting solution was stirred at room temperature for 30 minutes. Pyridine (10.9 mL, 0.13 mol) was added and the reaction stirred at room temperature for a further 16 h. Diethyl ether (300 mL) and water (300 mL) were added and the layers separated. The organic phase was dried (magnesium sulfate) and concentrated under reduced pressure. Diethyl ether (100 mL) was added to the residue and the mixture filtered and washed with several portions of ether. The filtrate was concentrated under reduced pressure and resulting residue purified by column chromatography (silica; 1:1 petroleum ether: ethyl acetate) to give the title compound as a colourless oil (4.1 g, 32 %).
Rf (1:1 petroleum etheπethyl acetate): 0.34. 1H NMR (CDCI3, 400 MHz): δH 4.65 (4H, s), 7.14 (1H, s), 7.40-7.29 (5H, m), 7.70 (1H, s). Intermediate 4: 2-((Benzyloxy)methyl)-5-(trimethylsilyl)oxazole
To a solution of 2-((benzyloxy)methyl)oxazole (512 mg, 2.7 mmol) in tetrahydrofuran (20 mL) at -78 °C was added π-BuLi (2.5 mL, 4.1 mmol) dropwise and the resulting mixture stirred at this temperature for 20 min. The reaction mixture was then treated with chlorotrimethylsilane (0.69 ml, 5.4 mmol) and stirred at -78 °C for a further 25 min. Water (10 mL) was added and the mixture allowed to warm up to room temperature and extracted with ether (2 20 mL). The combined organic extracts were dried (magnesium sulphate), concentrated under reduced pressure and purification of the resulting residue by column chromatography (silica; 9:1 petroleum etheπethyl acetate) isolated the title compound as a colourless oil (230 mg, 33 %). Rf (1:1 petroleum etheπethyl acetate): 0.55. H NMR (CDCI3, 400 MHz): δH 0.32 (9H, s), 4.65 (2H, s), 4.66 (2H, s), 7.21 (1H, s), 7.40-7.30 (5H, m). Intermediate 5: (5-(trimethylsilyl)oxazol-2-yl)methanol A mixture of 2-((benzyloxy)methyl)-5-(trimethylsilyl)oxazole (1.1 g, 4.2 mmol) and Pd(OH)2/C (761 mg, 20 % wt) in ethanol (30 mL) was stirred under an atmosphere of hydrogen (balloon pressure) for 16 h. The mixture was filtered through celite and residues washed with several portions of ethyl acetate. The filtrate was concentrated under reduced pressure to give the desired title compound as a pale yellow oil (975 mg, 94 %). Rf (1 :1 petroleum etheπethyl acetate): 0.24. 1H NMR (CDCI3, 400 MHz): δH 0.31 (9H, s), 4.79 (2H, s), 7.19 (1H, s).
Intermediate 6: (5-(Trimethylsilyl)oxazol-2-yl)methyl methanesulfonate A solution of (5-(trimethylsilyl)oxazol-2-yl)methanol (102 mg, 0.6 mmol) in dichloromethane (4 mL) at -20 °C was treated with triethylamine (0.17 mL, 1.2 mmol) and the mixture stirred at this temperature for 30 min. Methanesulfonyl chloride (92 μl, 1.2 mmol) was then added and the reaction stirred for a further 30 min. The solution was allowed to warm to room temperature and was quenched via the addition of aqueous 1M hydrochloric acid (5 mL). The resulting mixture was extracted with dichloromethane (2 x 10 mL) and combined organic extracts were dried (magnesium sulphate), concentrated under reduced pressure and purified by column chromatography (silica; 1:1 petroleum ether: ethyl acetate) to isolate the title compound as a colourless oil (110 mg, 74 %).Rf (1:1 petroleum etheπethyl acetate): 0.30. 1H NMR (CDCI3, 400 MHz): δH 0.33 (9H, s), 3.12 (3H, s), 5.35 (2H, s), 7.26 (1H, s). Example 1 : tert-Butyl 4-(5-((5-(trimethylsilyl)oxazol-2-yl)methylthio)t iazol- 2-ylcarbamoyl)piperidine-1-carboxylate
To a solution of ferf-butyl 4-(5-thiocyanatothiazol-2- ylcarbamoyl)piperidine-1-carboxylate (549 mg, 1.5 mmol) [synthesised according to the procedures described by Kim ef al., J Med Chem, 2002, 45, 3905-3927 and US 2002/0137778] in methanol (20 mL) at room temperature was added dithiothreitol (459 mg, 3 mmol).The solution stirred for 2 h and then concentrated under reduced pressure. The residue was dissolved in dimethylformamide (4 mL) and a solution of (5-(trimethylsilyl)oxazol-2- yl)methyl methanesulphonate (371 mg, 1.5 mmol) in dimethylformamide (1 mL + 0.5 mL wash) followed by potassium carbonate (247 mg, 1.8 mmol) was added. The mixture was stirred at room temperature for 2 h and then water (5 mL) was added. The mixture was filtered and the precipitate washed with water. The solid was then taken up in dichloromethane and filtered through a plug of silica, washing with 5 % methanol in dichloromethane, to give the title compound as a light yellow powder (554 mg, 74 %). Rf (95:5 dichloromethane:methanol): 0.10. H NMR (CDCi3, 400 MHz): δH 0.28 (9H, s), 1.49 (9H, s), 1.79 (2H, td, J = 11.5, 4.4 Hz), 1.93-1.86 (2H, m), 2.54 (1 H, tt, J = 11.4, 3.8 Hz), 2.92-2.81 (2H, broad m), 4.04 (2H, s), 4.19 (2H, broad s), 7.14 (1H, s), 7.32 (1H, s), 10.75 (1H, broad s).
Example 2: N-(5-((5-(Trimethylsilyl)oxazol-2-yl)methylthio)thiazol-2- yl)piperidine-4-carboxamide dihydrochloride terf-Butyl-4-(5-((5-(trimethylsilyl)oxazol-2-yl)methylthio)thiazol-2- ylcarbamoyl)piperidine-1-carboxylate (540 mg, 1.1 mmol) was stirred in an anhydrous ethereal solution containing hydrogen chloride gas (2M solution, 10 mL) for 18 h. The mixture was concentrated under reduced pressure. The crude product was triturated from diethyl ether to give the title compound as a yellow powder (431 mg, 91 %). 1H NMR (DMSO, 400 MHz): δH 0.21 (9H, s), 1.87-1.75 (2H, broad m), 2.00-1.92 (2H, broad m), 2.79 (1 H, tt, J = 11.1 , 3.8 Hz), 2.95-2.83 (2H, broad m (q, J = 11.5 Hz)), 3.32-3.26 (2H, broad m (d, J = 12.6 Hz)), 4.14 (2H, s), 6.54 (broad s), 7.30 (1H, s), 7.40 (1H, s), 8.98-8.88 (1 H, broad m), 9.26-9.18 (1H, broad m), 12.46 (1H, broad s). MS: ES+ 397 (M- 2HCI + 1).

Claims

1. A compound of formula (I)
Figure imgf000027_0001
wherein
R1 and R2 are the same or different and are each hydrogen, halogen or alkyl;
R3 is aryl or heteroaryl, either of which is substituted at least once with -Si(R7)3, and with the proviso that -Si(R7)3 is bound to a carbon atom of R3;
R4 is R8, -C(O)-R8, -C(0)NH-R8, -C(0)0-R8, -S(0)2-R8, -C(NHCN)NH- R8, -C(NN02)NH-R8, -C(NH)NH-R8, -C(NH)NHC(0)-R8 or -C(NOR8)NH-R8;
R5 and R6 are the same or different and are each hydrogen or alkyl; each R7 is the same or different and is alkyl, -alkyl-aryl or -alkyl- cycloalkyl, or R7-Si-R7 taken together form heterocycloalkyl; each R8 is the same or different and is alkyl, cycloalkyl, aryl, -alkyl- cycloalkyl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, -heterocycloalkyl or -alkyl- heterocycloalkyl; m is 0, 1 or 2; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein R1 and R2 are the same or different and are each hydrogen or fluorine.
3. A compound according to claim 2, wherein R1 and R2 are each hydrogen.
4. A compound according to any preceding claim, wherein R3 is heteroaryl substituted with -Si(R7)3.
5. A compound according to claim 4, wherein R3 is a group of formula (i)
Figure imgf000028_0001
wherein one of R9 and R10 is -Si(R7)3 or -alkyl-Si(R7)3, and the other is hydrogen, alkyl, ~Si(R7)3 or -alkyl-Si(R7)3.
6. A compound according to claim 5, wherein R9 is -Si(R7)3, and wherein each R7 is the same or different and is alkyl.
7. A compound according to claim 6, wherein each R7 is methyl.
8. A compound according to any of claims 5 to 7, wherein R10 is hydrogen.
9. A compound according to any preceding claim, wherein each R7 is alkyl.
10. A compound according to any preceding claim, wherein each R7 is methyl.
11. A compound according to any preceding claim, wherein R4 is -C(O)- alkyl, -C(NHCN)N-aryl, heteroaryl, aryl, -C(0)-heterocycloalkyl, -C(O)- heteroaryl, -C(0)-alkyl-aryl, -NH-aryl, -C(0)NH-aryl, -C(0)-alkyl- heterocycloalkyl or -C(0)NH-heterocycloalkyl.
12. A compound according to any preceding claim, wherein R5 is hydrogen or methyl.
13. A compound according to any preceding claim, wherein R6 is hydrogen.
1 . A compound according to any preceding claim, wherein m is 0.
15. A compound according to any preceding claim, wherein n is 1.
16. A compound according to claim 1 , selected from: Λ/-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)-thiazol-2-yl]-acetamide; Λ/-methyl-/V-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)-thiazol-2-yl]- isobutyramide; pyridin-2-yl-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)-thiazol-2-yl]- amine;
{3-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)-thiazol-2-ylamino]-phenyl}- methanol; pyridin-4-yl-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)-thiazol-2-yl]- amine;
N-(5-((5-(trimethylsilyl)oxazol-2-yl)methylthio)thiazol-2-yl)piperidine-4- carboxamide; piperidine-3-carboxylic acid [5-(5-trimethylsilyl-oxazol-2-ylmethylthio)- thiazo!-2-yl]-amide; Λ/-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)-thiazol-2-yl]- isonicotinamide;
Λ/-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)-thiazol-2-yl]-nicotinamide;
1 -acetyl-piperidine-4-carboxylic acid [5-(5-trimethylsilyl-oxazol-2- ylmethylthio)-thiazol-2-yl]-amide; 1 -acetyl-piperidine-3-carboxylic acid [5-(5-trimethylsilyl-oxazol-2- ylmethylthio)-thiazol-2-yl]-amide;
1 -methanesulphonyl-piperidine-4-carboxylic acid [5-(5-trimethylsilyl- oxazol-2-ylmethylthio)-thiazol-2-yl]-amide;
1 -methanesulphonyl-piperidine-3-carboxylic acid [5-(5-trimethylsilyl- oxazol-2-ylmethylthio)-thiazol-2-yl]-amide; piperazine-1 -carboxylic acid [5-(5-trimethylsilyl-oxazol-2-ylmethylthio)- thiazol-2-yl]-amide; piperazine-2-carboxylic acid [5-(5-trimethylsilyl-oxazol-2-ylmethylthio)- thiazol-2-yl]-amide; 4-methyl-piperazine-1 -carboxylic acid [5-(5-trimethylsilyl-oxazol-2- ylmethylthio)-thiazol-2-yl]-amide;
1 -methyl-piperidine-3-carboxylic acid [5-(5-trimethylsilyl-oxazol-2- ylmethylthio)-thiazol-2-yl]-amide;
1 -methyl-piperidine-4-carboxylic acid [5-(5-trimethylsilyl-oxazol-2- ylmethylthio)-thiazol-2-yl]-amide;
4-hydroxymethyl-piperidine-1 -carboxylic acid [5-(5-trimethylsilyl- oxazol-2-ylmethylthio)-thiazol-2-yl]-amide; 2-{4-[(2-hydroxy-1-hydroxymethyl-ethylamino)-methyl]-phenyl}-Λ/-[5-(5- trimethylsilyl-oxazol-2-ylmethylthio)-thiazol-2-yl]-acetamide;
1-(2,6-dichloro-phenyl)-3-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)- thiazol-2-yl]-urea; 1 -{4-[(2-hydroxy-1 -hydroxymethyl-ethylamino)-methyl]-phenyl}-3-[5-(5- trimethylsilyl-oxazol-2-ylmethylthio)-thiazol-2-yl]-urea;
1-(2,6-difluoro-phenyl)-3-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)- thiazol-2-yl]-urea;
2-piperidin-4-yl-W-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)-thiazol-2- yl]-acetamide;
1-piperidin-4-yl-3-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)-thiazol-2- yl]-urea;
2-(1-methyl-piperidin-4-yl)-Λ/-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)- thiazol-2-yl]-acetamide; 1 -(1 -methyl-piperidin-4-yl)-3-[5-(5-trimethylsilyl-oxazol-2-ylmethylthio)- thiazol-2-yl]-urea; piperidine-4-carboxylic acid {5-[5-(1 -methyl-1 -sila-cyclopentyl)-oxazol- 2-ylmethylthio]-thiazol-2-yl}-amide; piperidine-3-carboxylic acid {5-[5-(1 -methyl-1 -sila-cyclopentyl)-oxazol- 2-ylmethylthio]-thiazol-2-yl}-amide;
Λ/-{5-[5-(1 -methyl-1 -sila-cyclopentyl)-oxazol-2-ylmethylthio]-thiazol-2- yl}-isonicotinamide;
Λ/-{5-[5-(1 -methyl-1 -sila-cyclopentyl)-oxazol-2-ylmethylthio]-thiazol-2- yl}-nicotinamide; piperidine-4-carboxylic acid {5-[5-(1 -methyl-1 -sila-cyclohexyl)-oxazol-2- ylmethylthio]-thiazol-2-yl}-amide; and tert-butyl-4-(5-((5-(trimethylsilyl)oxazol-2-yl)methylthio)thiazol-2- ylcarbamoyl)piperidine-1-carboxylate.
17. A compound according to claim 1 , selected from: 3-((6-(5-((5-(trimethylsilyl)oxazol-2-yl)methylthio)thiazol-2- ylamino)pyridin-3-yl)methylamino)-2,2-dimethylpropan-1 -ol; and
2-((6-(5-((5-(trimethylsilyl)oxazol-2-yl)methylthio)thiazol-2- ylamino)pyridin-3-yl)sulphonamido)ethan-1-ol.
18. A compound according to any preceding claim, which is in the form of a single enantiomer, diastereomer or tautomer.
19. A compound according to any preceding claim, for therapeutic use.
20. A pharmaceutical composition comprising a compound of any of claims 1 to 18 and a pharmaceutically acceptable diluent or carrier.
21. A composition according to claim 20, which further comprises a second compound which is a therapeutic agent.
22. Use of a compound of any of claims 1 to 18, for the manufacture of a medicament for the treatment or prevention of the progression of cancer.
23. Use according to claim 22, for the treatment or the prevention of the progression of melanoma or leukaemia, or lung, brain, prostate, renal, ovarian, stomach, breast, pancreatic, esophagus or colorectal cancer.
24. Use of a compound of any of claims 1 to 18, for the manufacture of a medicament for the treatment or prevention of an inflammatory disease.
25. Use according to claim 24, for the treatment or prevention of inflammatory bowel disease, arthritis or glomerulonephritis.
26. Use of a compound of any of claims 1 to 18, for the manufacture of a medicament for the treatment or prevention of a cardiovascular disease.
27. Use according to claim 26, for the treatment or prevention of artherosclerosis, myocardial disease or restenosis.
28. Use of a compound of any of claims 1 to 18, for the manufacture of a medicament for the treatment or prevention of a neurodegenerative disease.
29. Use of a compound of any of claims 1 to 18, for the manufacture of a medicament for the treatment or prevention of transplant rejection.
30. Use of a compound of any of claims 1 to 18, for the manufacture of a medicament for the treatment or prevention of glaucoma.
31. Use of a compound of any of claims 1 to 18, for the manufacture of a medicament for the treatment or prevention of alopecia.
32. Use of a compound of any of claims 1 to 18, for the manufacture of a medicament for the treatment or prevention of an infectious disease.
33. Use according to claim 32, for the treatment or prevention of HIV infection or AIDS.
34. Use according to claim 32, for the treatment or prevention of a fungal infection.
PCT/GB2004/002572 2003-06-19 2004-06-16 Silicon-comprising aminothiazole derivatives as cdk inhibitors WO2004113353A1 (en)

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WO2013124335A1 (en) 2012-02-24 2013-08-29 F. Hoffmann-La Roche Ag Antiviral compounds
US8563741B2 (en) 2007-09-10 2013-10-22 Curis, Inc. CDK inhibitors containing a zinc binding moiety
CN114560779A (en) * 2022-01-25 2022-05-31 杭州华东医药集团浙江华义制药有限公司 Synthesis method of mirabegron key intermediate

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US20020137778A1 (en) * 1999-12-15 2002-09-26 Kim Kyoung S. Aminothiazole inhibitors of cyclin dependent kinases

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
US8563741B2 (en) 2007-09-10 2013-10-22 Curis, Inc. CDK inhibitors containing a zinc binding moiety
WO2013124335A1 (en) 2012-02-24 2013-08-29 F. Hoffmann-La Roche Ag Antiviral compounds
CN114560779A (en) * 2022-01-25 2022-05-31 杭州华东医药集团浙江华义制药有限公司 Synthesis method of mirabegron key intermediate

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