WO2004113352A1 - Silylated heterocyclylurea derivatives as cytokine-inhibitors - Google Patents

Silylated heterocyclylurea derivatives as cytokine-inhibitors Download PDF

Info

Publication number
WO2004113352A1
WO2004113352A1 PCT/GB2004/002562 GB2004002562W WO2004113352A1 WO 2004113352 A1 WO2004113352 A1 WO 2004113352A1 GB 2004002562 W GB2004002562 W GB 2004002562W WO 2004113352 A1 WO2004113352 A1 WO 2004113352A1
Authority
WO
WIPO (PCT)
Prior art keywords
urea
pyrazol
trimethylsilyl
tolyl
naphthalen
Prior art date
Application number
PCT/GB2004/002562
Other languages
French (fr)
Inventor
David John Miller
John Gary Montana
Graham Andrew Showell
Julie Belinda Hazel Warneck
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 GB0314292A external-priority patent/GB0314292D0/en
Priority claimed from GB0328149A external-priority patent/GB0328149D0/en
Priority claimed from GB0401244A external-priority patent/GB0401244D0/en
Application filed by Amedis Pharmaceuticals Ltd. filed Critical Amedis Pharmaceuticals Ltd.
Publication of WO2004113352A1 publication Critical patent/WO2004113352A1/en

Links

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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • Tumour necrosis factor (TNF) and interleukin-1 (IL-1 ) are important biological entities, and collectively referred to as proinflammatory cytokines. These, along with several other related molecules, mediate the inflammatory response associated with the immunological recognition of infectious agents. The inflammatory response plays an important role in limiting and controlling pathogenic infections.
  • Elevated levels of proinflammatory cytokines are also associated with a number of diseases of autoimmunity such as toxic shock syndrome, rheumatoid arthritis, osteoarthritis, diabetes and inflammatory bowel disease (Dinarello etal, 1984, Rev. Infect. Disease, 6, 51 and Koch et al, 1995, J. Invest. Med. 43, 28- 38).
  • An important and accepted therapeutic approach for potential drug intervention in these diseases is the reduction of proinflammatory cytokines such as TNF (also referred to in its secreted cell-free form as TNF ⁇ ) and IL-1 ⁇ (Rankin et al, 1997, British J. Rheum.
  • Inhibitors of cytokine production are expected to block inducible cyclooxygenase (COX-2) expression.
  • COX-2 expression has been shown to be increased by cytokines, and it is believed to be the isoform of cyclooxygenase that is responsible for inflammation (O'Banion et al, 1992, Proc. Natl. Acad. Sci. U.S.A. 89, 4888).
  • inhibitors of cytokines such as IL-1 would be expected to exhibit efficacy against those disorders currently treated with COX inhibitors, (e.g. NSAIDs). These disorders include acute and chronic pain, as well as symptoms of inflammation and cardiovascular disease.
  • cytokines Elevation of several cytokines has been demonstrated during active inflammatory bowel disease (IBD) (Cominelli et al, 1996, Aliment. Pharmacol. Ther. 10, 49).
  • Proinflammatory cytokines such as TNF ⁇ and IL-1 ⁇ are also important mediators of septic shock and associated cardiopulmonary dysfunction, acute respiratory distress syndrome (ARDS) and multiple organ failure.
  • TNF ⁇ has also been implicated in cachexia and muscle degradation, associated with HIV infection (Lahdiverta et al, 1988, Amer. J. Med. 85, 289).
  • Compounds which modulate the release of one or more of the aforementioned inflammatory cytokines can be useful in treating diseases associated with release of these cytokines.
  • WO-A-98/52558, WO- A-00/43384, WO-A-01/04115 and WO-A-03/005999 disclose heteroaryl urea compounds which may be useful in treating cytokine-mediated diseases.
  • 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
  • a first aspect of the invention is a compound of formula (I)
  • R 1 , R 2 and R 3 are the same or different and are each alkyl, -aikyl-aryl or -alkyl-cycloalkyl; or R 1 -Si-R 2 taken together form heterocycloalkyl;
  • R 4 is aryl or heteroaryl, either of which optionally substituted with -Y-R 5 ;
  • R 5 is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
  • W is heterocyclylene optionally substituted with alkyl, -aikyl-aryl, -alkyl- cycloalkyl, aryl, heteroaryl, -alkyl-heteroaryl or -alkyl-heterocycloalkyl;
  • X is oxygen or sulphur;
  • Y is a bond, -NH-, -O-, -S-, -Si(R 6 )(R 7 )-, alkylene, alkenylene, -O-alkyl-, -S-alkyl-, -NH-alkyl- or -Si(R 6 )(R 7 )-alkyl-;
  • R 6 and R 7 are the same or different and are each alkyl; with the proviso that -Si(R 1 )(R 2 )(R 3 ) is bound to a ring carbon atom of W; or a pharmaceutically acceptable salt thereof, or a prodrug form that is oxidisable or hydrolysable to form a compound as defined above.
  • Compounds of the invention may act as cytokine inhibitors and as a consequence may have utility in the therapy of diseases or conditions in which cytokines 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 an inflammatory disease, an autoimmune disease, acute pain, chronic pain, neuropathic pain, contact dermatitis, atherosclerosis, glomerulonephritis, reperfusion injury, a bone resorption disease, asthma, stroke, myocardial infarction, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, dermatoses with acute inflammatory components, acute purulent meningitis, necrotising entrerocolitis, a syndrome associated with hemodialysis, septic shock, leukopherisis, granulocyte transfusion, acute or chronic inflammation of the lung caused by smoke inhalation, endometriosis, Behcet's disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme disease, restenosis following percutaneous transluminal coronary angioplasty, Alzheimer's disease, traumatic arthritis, se
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable diluent or carrier.
  • R 1 , R 2 and R 3 are preferably each alkyl, more preferably optionally substituted methyl or ethyl. Another preference is that R 1 -Si-R 2 taken together form silacyclohexyl.
  • R 4 is preferably phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indanyl, indenyl or indolyl, any of which is optionally substituted.
  • R 4 is substituted with halogen, alkoxy and/or -Y-R 5 .
  • Y is preferably alkylene, alkenylene, -O-alkyl-, -S-alkyl- or -Si(R 6 )(R 7 )-alkyk
  • R 5 is preferably morpholin-4-yl orthiomorpholin-4-yl, optionally substituted with alkyl or oxo. Another preference is that R 5 is pyridin-4-yl, imidazolyl or pyridin-3-yl.
  • W is preferably pyrrolylene, pyrrolidinylene, pyrazolylene, imidazolylene, oxazolylene, thiazolylene, furanylene or thiophenylene, any of which is optionally substituted.
  • W is pyrazolyene, optionally substituted with aryl, heteroaryl, alkyl or cycloalkyl.
  • X is preferably oxygen.
  • alkyl refers to an optionally substituted 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.
  • the group may be substituted with one or more of substituents, the substituents being the same or different and selected from hydroxy and the like.
  • C ⁇ -6 alkyl has the same meaning.
  • Alkylene refers to a similar, divalent group.
  • alkenyl refers to a straight or branched chain alkyl moiety having from two to six carbon atoms and having, in addition, at least one double bond, of either E or Z stereochemistry where applicable. This term includes, for example, vinyl, 1 -propenyl, 1 - and 2- butenyl, 2- methyl-2-propenyl and the like. "C 2 . 6 alkenyl” has the same meaning. "Alkenylene” refers to a similar, divalent group.
  • alkoxy refers to a straight or branched chain alkoxy group containing from one to six carbon atoms. This term includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy and the like. "C ⁇ -6 alkoxy” has the same meaning.
  • halogen refers to F, CI, Br or I.
  • 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 alkyl, alkoxy, cycloalkyl, halogen, hydroxy, trifluoromethyl, cyano and the like.
  • cycloalkyl refers to an optionally substituted saturated alicyclic moiety having from three to six carbon atoms. This term includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • the group may be optionally substituted with one or more substituents, the substituents being the same or different and selected from alkyl, alkoxy, hydroxy, oxo 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 alkyl, alkoxy, hydroxy, oxo 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.
  • 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, cycloalkyl, halogen, hydroxy, trifluoromethyl, cyano and the like.
  • heterocyclyl refers to an optionally substituted saturated (e.g. heterocycloalkyl) or unsaturated (e.g. heteroaryl) heterocyclic moiety having from four to ten ring atoms, at least one of which is selected from nitrogen, oxygen, phosphorus, sulphur and silicon.
  • This term includes, for example, pyrazolyl, piperidinyl, pyrrolidinyl, morpholinyl and the like.
  • the group may be substituted with one or more substituents, the substituents being the same or different and selected from alkyl, alkoxy, hydroxy, oxo and the like.
  • Heterocyclylene (e.g. pyrazolylene) refers to a similar, divalent group.
  • Preferred compounds of the invention include:
  • a particularly preferred compound is 1-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-1-yl]-3-(2-p-tolyl-5-trimethylsilyl-2H-pyrazol-3-yl)-urea.
  • 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. It will be appreciated that compounds of the invention, such as those comprising a pyridyl or morpholinyl group, may be in the form of a 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 or protected carboxy form.
  • protected amino and “protected carboxy” as used herein refer to amino 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.
  • 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, gluconic acid, glutamic acid, N-glycolylarsanilic acid, 4-hexylresorcinol, hippuric acid, 2-(4-hydroxybenzoyl)benzoicacid, 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 sulphuri
  • salts may be prepared by reacting the compound with a suitable acid 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 R 4 -NH 2 may be obtained according to the procedures described in Regan et al, J. Med. Chem. 2002, 45, 2994; Shvedov et al, Zhumal Organicheskoi Khimii, 1969, 5,2221; WO-A-03/087087; GB-A-0781390; or US3300506):
  • oxidant for example, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
  • 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, inflammatory diseases (e.g. rheumatoid arthritis, multiple sclerosis, Guillain- Barre syndrome, Crohn's disease, ulcerative colitis, psoriasis, graft versus host disease, systemic lupus, erythematosus or insulin-dependent diabetes mellitus), autoimmune diseases (e.g.
  • toxic shock syndrome osteoarthritis, diabetes or inflammatory bowel disease
  • acute pain chronic pain
  • neuropathic pain contact dermatitis, atherosclerosis, glomerulonephritis, reperfusion injury, bone resorption diseases, asthma, stroke, myocardial infarction, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, dermatoses with acute inflammatory components, acute purulent meningitis, necrotising entrerocolitis, syndromes associated with hemodialysis, septic shock, leukopherisis, granulocyte transfusion, acute or chronic inflammation of the lung caused by smoke inhalation, endometriosis, Behcet's disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme disease, restenosis following percutaneous transluminal coronary angioplasty, Alzheimer's disease, traumatic arthritis, sepsis, chronic obstructive pulmonary disease, congestive heart failure, osteoporosis, cachexia,
  • 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.
  • 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 com 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.
  • 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.
  • Suitable 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 diglyce des.
  • fatty acids such as oleic acid, find use in the preparation of injectables.
  • 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.
  • LC-MS spectra were run using Conditions A1 or A2; Mass spectrometry - electrospray source operating in positive and negative ion mode. The system ran at 1.5 mL/min, and the detection mode was through a Hexa-pole Mass Spectrometry detector and a Diode-Array detector for UV.

Abstract

A compound of formula (I) Wherein R1, R2 and R3 are the same or different and are each alkyl, -aikyl-aryl or -alkyl-cycloalkyl; or R1-Si-R2 taken together form heterocycloalkyl; R4 is aryl or heteroaryl, either of which is optionally substituted with -Y-R5; R5 is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; W is heterocyclylene optionally substituted with alkyl, -aikyl-aryl, -alkyl­ cycloalkyl, aryl, heteroaryl, -alkyl-heteroaryl or -alkyl-heterocycloalkyl; X is oxygen or sulphur; Y is a bond, -NH-, -0-, -S-, -Si(R6)(R7)-, alkylene, alkenylene, -0-alkyl-, -S-alkyl-, -NH-alkyl- or -Si(R6)(R7)-alkyl-; R6 and R7 are the same or different and are each aikyl; with the proviso that -Si(R1)(R2)(R3) is bound to a ring carbon atom of W; or a pharmaceutically acceptable salt thereof, or a prodrug form that is oxidisable or hydrolysable to form a compound as defined above.

Description

SI YLATED HETEROCYC Y UREA DERIVATIVES AS CYTOKINE-INHIBITORS
Field of the Invention
This invention relates to silicon compounds and their use in therapy. Background to the Invention Tumour necrosis factor (TNF) and interleukin-1 (IL-1 ) are important biological entities, and collectively referred to as proinflammatory cytokines. These, along with several other related molecules, mediate the inflammatory response associated with the immunological recognition of infectious agents. The inflammatory response plays an important role in limiting and controlling pathogenic infections.
Elevated levels of proinflammatory cytokines are also associated with a number of diseases of autoimmunity such as toxic shock syndrome, rheumatoid arthritis, osteoarthritis, diabetes and inflammatory bowel disease (Dinarello etal, 1984, Rev. Infect. Disease, 6, 51 and Koch et al, 1995, J. Invest. Med. 43, 28- 38). An important and accepted therapeutic approach for potential drug intervention in these diseases is the reduction of proinflammatory cytokines such as TNF (also referred to in its secreted cell-free form as TNFα) and IL-1 β (Rankin et al, 1997, British J. Rheum. 35, 334-342; Stack et al, 1997, Lancet 349, 521- 524; Brower et al, 1997, Nature Biotechnology 15, 1240; Renzefti et al, 1997, Inflamm. Res. 46, S143; Chevalier 1997, Biomed. Pharmacother. 51 , 58; and Evans et al, 1996, J. Bone Miner. Res. 11 , 300).
Inhibitors of cytokine production are expected to block inducible cyclooxygenase (COX-2) expression. COX-2 expression has been shown to be increased by cytokines, and it is believed to be the isoform of cyclooxygenase that is responsible for inflammation (O'Banion et al, 1992, Proc. Natl. Acad. Sci. U.S.A. 89, 4888). Accordingly, inhibitors of cytokines such as IL-1 would be expected to exhibit efficacy against those disorders currently treated with COX inhibitors, (e.g. NSAIDs). These disorders include acute and chronic pain, as well as symptoms of inflammation and cardiovascular disease. Elevation of several cytokines has been demonstrated during active inflammatory bowel disease (IBD) (Cominelli et al, 1996, Aliment. Pharmacol. Ther. 10, 49). Proinflammatory cytokines such as TNFα and IL-1β are also important mediators of septic shock and associated cardiopulmonary dysfunction, acute respiratory distress syndrome (ARDS) and multiple organ failure. TNFα has also been implicated in cachexia and muscle degradation, associated with HIV infection (Lahdiverta et al, 1988, Amer. J. Med. 85, 289). Compounds which modulate the release of one or more of the aforementioned inflammatory cytokines can be useful in treating diseases associated with release of these cytokines. For example, WO-A-98/52558, WO- A-00/43384, WO-A-01/04115 and WO-A-03/005999 disclose heteroaryl urea compounds which may be useful in treating cytokine-mediated diseases. 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
A first aspect of the invention is a compound of formula (I)
Figure imgf000003_0001
wherein
R1, R2 and R3 are the same or different and are each alkyl, -aikyl-aryl or -alkyl-cycloalkyl; or R1-Si-R2 taken together form heterocycloalkyl;
R4 is aryl or heteroaryl, either of which optionally substituted with -Y-R5; R5 is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; W is heterocyclylene optionally substituted with alkyl, -aikyl-aryl, -alkyl- cycloalkyl, aryl, heteroaryl, -alkyl-heteroaryl or -alkyl-heterocycloalkyl; X is oxygen or sulphur;
Y is a bond, -NH-, -O-, -S-, -Si(R6)(R7)-, alkylene, alkenylene, -O-alkyl-, -S-alkyl-, -NH-alkyl- or -Si(R6)(R7)-alkyl-;
R6 and R7 are the same or different and are each alkyl; with the proviso that -Si(R1)(R2)(R3) is bound to a ring carbon atom of W; or a pharmaceutically acceptable salt thereof, or a prodrug form that is oxidisable or hydrolysable to form a compound as defined above.
Compounds of the invention may act as cytokine inhibitors and as a consequence may have utility in the therapy of diseases or conditions in which cytokines 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 an inflammatory disease, an autoimmune disease, acute pain, chronic pain, neuropathic pain, contact dermatitis, atherosclerosis, glomerulonephritis, reperfusion injury, a bone resorption disease, asthma, stroke, myocardial infarction, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, dermatoses with acute inflammatory components, acute purulent meningitis, necrotising entrerocolitis, a syndrome associated with hemodialysis, septic shock, leukopherisis, granulocyte transfusion, acute or chronic inflammation of the lung caused by smoke inhalation, endometriosis, Behcet's disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme disease, restenosis following percutaneous transluminal coronary angioplasty, Alzheimer's disease, traumatic arthritis, sepsis, chronic obstructive pulmonary disease, congestive heart failure, osteoporosis, cachexia, Parkinson's disease, a periodontal disease, gout, an allergic disease, age-related macular degeneration, infection or cystic fibrosis.
Another aspect of the invention is a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable diluent or carrier. Description of the Invention
Certain compounds and combinations of substituents are preferred; in particular see the subclaims. With regard to the formula (I), groups R1, R2 and R3 are preferably each alkyl, more preferably optionally substituted methyl or ethyl. Another preference is that R1-Si-R2 taken together form silacyclohexyl. R4 is preferably phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indanyl, indenyl or indolyl, any of which is optionally substituted. Preferably R4 is substituted with halogen, alkoxy and/or -Y-R5. Y is preferably alkylene, alkenylene, -O-alkyl-, -S-alkyl- or -Si(R6)(R7)-alkyk R5 is preferably morpholin-4-yl orthiomorpholin-4-yl, optionally substituted with alkyl or oxo. Another preference is that R5 is pyridin-4-yl, imidazolyl or pyridin-3-yl. W is preferably pyrrolylene, pyrrolidinylene, pyrazolylene, imidazolylene, oxazolylene, thiazolylene, furanylene or thiophenylene, any of which is optionally substituted. Preferably, W is pyrazolyene, optionally substituted with aryl, heteroaryl, alkyl or cycloalkyl. X is preferably oxygen. The term "alkyl" as used herein refers to an optionally substituted 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. The group may be substituted with one or more of substituents, the substituents being the same or different and selected from hydroxy and the like. "Cι-6 alkyl" has the same meaning. "Alkylene" refers to a similar, divalent group.
The term "alkenyl" as used herein refers to a straight or branched chain alkyl moiety having from two to six carbon atoms and having, in addition, at least one double bond, of either E or Z stereochemistry where applicable. This term includes, for example, vinyl, 1 -propenyl, 1 - and 2- butenyl, 2- methyl-2-propenyl and the like. "C2.6 alkenyl" has the same meaning. "Alkenylene" refers to a similar, divalent group.
The term "alkoxy" as used herein refers to a straight or branched chain alkoxy group containing from one to six carbon atoms. This term includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy and the like. "Cι-6 alkoxy" has the same meaning.
The term "halogen" as used herein refers to F, CI, Br or I. The term "aryl" as used herein 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 alkyl, alkoxy, cycloalkyl, halogen, hydroxy, trifluoromethyl, cyano and the like.
The term "cycloalkyl" as used herein refers to an optionally substituted saturated alicyclic moiety having from three to six carbon atoms. This term includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The group may be optionally substituted with one or more substituents, the substituents being the same or different and selected from alkyl, alkoxy, hydroxy, oxo 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 alkyl, alkoxy, hydroxy, oxo 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. 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, cycloalkyl, halogen, hydroxy, trifluoromethyl, cyano and the like.
The term "heterocyclyl" as used herein refers to an optionally substituted saturated (e.g. heterocycloalkyl) or unsaturated (e.g. heteroaryl) heterocyclic moiety having from four to ten ring atoms, at least one of which is selected from nitrogen, oxygen, phosphorus, sulphur and silicon. This term includes, for example, pyrazolyl, piperidinyl, pyrrolidinyl, morpholinyl and the like. The group may be substituted with one or more substituents, the substituents being the same or different and selected from alkyl, alkoxy, hydroxy, oxo and the like. "Heterocyclylene" (e.g. pyrazolylene) refers to a similar, divalent group. Preferred compounds of the invention include:
1-(4-chlorophenyl)-3-(2-p-tolyl-5-trimethylsilyl-2H-pyrazol-3-yl)-urea;
1-(4-methoxyphenyl)-3-(2-p-tolyl-5-trimethylsilyl-2H-pyrazol-3-yl)-urea;
1-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-3-(2-p-tolyl-5- trimethylsilyl-2H-pyrazol-3-yl)-urea; 1-[5-(ethyl-dimethyl-silyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-1 -yl]-urea;
1 -(4-methoxy-naphthalen-1-yl)-3-(2-p-tolyl-5-trimethylsilyl-2H-pyrazol-3- yl)-urea;
1-indan-5-yl-3-(2-p-tolyl-5-trimethylsilyl-2H-pyrazol-3-yl)-urea; 1-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(2-p-tolyl-5-trimethylsilyl-2H- pyrazol-3-yl)-urea;
1 -[5-(1 -methyl-1 -silacyclohexyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea;
1 -[5-(1 -methyl-1 -silacyclohexyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2- morpholin-4-yl-ethoxy)-phenyl]-urea;
1-[5-(hydroxymethyl-dimethyl-silyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea;
1-[2-(3-hydroxy-4-methyl-phenyl)-5-trimethylsilyl-2H-pyrazol-3-yl]-3-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea; 1 -{4-[2-(trans-2,6-dimethyl-morpholin-4-yl)-ethoxy]-naphthalen-1 -yl}-3-(2- p-tolyl-5-trimethylsilyl-2H-pyrazol-3-yl)-urea;
1 -[5-(diethyl-methyl-silyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-1 -yl]-urea;
1 -[2-(4-hydroxymethyl-phenyl)-5-trimethylsilyl-2H-pyrazol-3-yl]-3-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-1 -yl]-urea;
1-{4-[2-(3-oxo-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-3-(2-p-tolyl-5- trimethylsilyl-2H-pyrazol-3-yl)-urea; 1-{4-[2-(cis-2,6-dimethyl-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-3-(2-p- tolyl-5-trimethylsilyl-2H-pyrazol-3-yl)-urea;
1 -[4-(2-piperidin-1 -yl-ethoxy)-naphthalen-1 -yl]-3-(2-p-tolyl-5-trimethylsilyI- 2H-pyrazol-3-yl)-urea; 1 -[4-(2-pyridin-4-yl-ethoxy)-naphthalen-1 -yl]-3-(2-p-tolyl-5-trimethylsilyl-
2H-pyrazol-3-yl)-urea;
1-[2-(6-methyl-pyridin-3-yl)-5-trimethylsilyl-2H-pyrazol-3-yl]-3-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-1 -yl]-urea;
1 -[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-3-(2-phenyl-5- trimethylsilyl-2H-pyrazol-3-yl)-urea;
1 -[4-(2-thiomorpholin-4-yl-ethoxy)-naphthalen-1-yl]-3-(2-p-tolyl-5- trimethylsilyl-2H-pyrazol-3-yl)-urea;
1 -{4-[2-(1 -oxo-thiomorpholin-4-yl)-ethoxy]-naphthalen-1 -yI}-3-(2-p-tolyI-5- trimethylsilyl-2H-pyrazol-3-yl)-urea; 1-[2-(6-methoxy-pyridin-3-yl)-5-trimethylsilyl-2H-pyrazol-3-yl]-3-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea;
1 -(2-ethyl-5-trimethylsilyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-1 -yl]-urea;
1 -[4-(2-morpholin-4-yl-ethylsulphanyl)-naphthalen-1-yl]-3-(2-p-tolyl-5- trimethylsilyl-2H-pyrazol-3-yl)-urea;
1 -(2-methyl-5-trimethylsilyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-1 -yl]-urea;
1-(2-cyclopentyl-5-trimethylsilyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-1 -yl]-urea; 1 -[4-(2-thiomorpholin-4-yl-ethylsulphanyl)-naphthalen-1 -yl]-3-(2-p-tolyl-5- trimethylsilyl-2H-pyrazol-3-yl)-urea;
1-{4-[dimethyl-(2-morpholin-4-yl-ethyl)-silyl]-naphthalen-1-yl}-3-(2-p-tolyl- 5-trimethylsilyl-2H-pyrazol-3-yl)-urea;
1 -[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1 -yl]-3-(2-p-tolyl-5- trimethylsilyl-1 H-pyrrol-3-yl)-urea;
1 -(3-(2-(pyridin-4-yl)ethyl)-1 H-indol-5-yl)-3-(1 -p-tolyl-3-(trimethylsilyl)-1 H- pyrazol-5-yl)urea; (E)-1 -(3-(2-(pyridin-4-yl)vinyl)-1 H-indol-5-yl)-3-(1 -p-tolyl-3-(trimethylsilyl)- 1 H-pyrazol-5-yl)urea;
1 -(3-(2-(pyridin-3-yl)ethyl)-1 H-indol-5-yl)-3-(1 -p-tolyl-3-(trimethylsilyl)-1 H- pyrazol-5-yl)urea; 1 -(3-(2-(piperidin-4-yl)ethyl)-1 H-indol-5-yl)-3-(1 -p-tolyl-3-(trimethylsilyl)-
1 H-pyrazol-5-yl)urea;
1 -(3-(2-morpholinoethyl)-1 H-indol-5-yl)-3-(1 -p-tolyl-3-(trimethylsilyl)-1 H- pyrazol-5-yl)urea;
1 -(3-(2-(piperazin-1 -yl)ethyl)-1 H-indol-5-yl)-3-(1 -p-tolyl-3-(trimethylsilyl)- 1 H-pyrazol-5-yl)urea;
1 -(3-(2-morpholinoethyl)-1 H-pyrrolo[2,3-b]pyridin-5-yl)-3-(1 -p-tolyl-3- (trimethylsilyl)-1 H-pyrazol-5-yl)urea;
1 -(3-(2-(pyridin-4-yl)ethyl)-1 H-pyrrolo[2,3-b]pyridin-5-yl)-3-(1 -p-tolyl-3- (trimethylsilyl)-1 H-pyrazol-5-yl)urea; 1 -(3-(2-morpholinoethyl)-3H-benzo[d]imidazol-5-yl)-3-(1 -p-tolyl-3-
(trimethylsilyl)-1 H-pyrazol-5-yl)urea;
1 -(1 -(2-morpholinoethyl)-1 H-indol-6-yl)-3-(1 -p-tolyl-3-(trimethylsilyl)-1 H- pyrazol-5-yl)urea;
1-(3-(2-(pyridin-4-yl)ethyl)-3H-benzo[d]imidazol-5-yl)-3-(1-p-tolyl-3- (trimethylsilyl)-l H-pyrazol-5-yl)urea;
1 -(1 -(2-(pyridin-4-yl)ethyl)-1 H-indol-6-yl)-3-(1 -p-tolyl-3-(trimethylsilyl)-1 H- pyrazol-5-yl)urea;
1 -(4-(2-(1 H-imidazol-1 -yl)ethoxy)naphthalen-1 -yl)-3-(2-p-tolyl-5- (trimethylsilyl)-2H-pyrazol-3-yl)urea; 1 -(4-(2-(1 H-imidazol-1 -yl)ethoxy)phenyl)-3-(2-p-tolyl-5-(trimethylsilyl)-2H- pyrazol-3-yl)urea; and
1-(4-(2-(pyridin-3-yl)ethoxy)naphthalen-1-yl)-3-(2-p-tolyl-5-(trimethylsilyl)- 2H-pyrazol-3-yl)urea; the corresponding structures of which are shown below, respectively:
Figure imgf000010_0001
Figure imgf000010_0002
Figure imgf000010_0003
Figure imgf000010_0004
Figure imgf000011_0001
Figure imgf000011_0002
Figure imgf000011_0003
Figure imgf000011_0004
Figure imgf000012_0001
Figure imgf000012_0002
Figure imgf000012_0003
Figure imgf000013_0001
Figure imgf000013_0002
Figure imgf000013_0003
13
Figure imgf000014_0001
Figure imgf000014_0002
Figure imgf000014_0003
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000016_0002
Figure imgf000016_0003
Figure imgf000016_0004
Figure imgf000017_0001
Figure imgf000017_0002
Figure imgf000017_0003
17
Figure imgf000018_0001
Figure imgf000018_0002
18
Figure imgf000019_0001
Figure imgf000019_0002
Figure imgf000019_0003
Figure imgf000020_0001
Figure imgf000020_0002
Figure imgf000021_0001
21
Figure imgf000022_0001
Figure imgf000022_0002
Of the above, a particularly preferred compound is 1-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-1-yl]-3-(2-p-tolyl-5-trimethylsilyl-2H-pyrazol-3-yl)-urea.
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. It will be appreciated that compounds of the invention, such as those comprising a pyridyl or morpholinyl group, may be in the form of a 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. 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 or protected carboxy form. The terms "protected amino" and "protected carboxy" as used herein refer to amino 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, gluconic acid, glutamic acid, N-glycolylarsanilic acid, 4-hexylresorcinol, hippuric acid, 2-(4-hydroxybenzoyl)benzoicacid, 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.
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 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 R4-NH2 may be obtained according to the procedures described in Regan et al, J. Med. Chem. 2002, 45, 2994; Shvedov et al, Zhumal Organicheskoi Khimii, 1969, 5,2221; WO-A-03/087087; GB-A-0781390; or US3300506):
Figure imgf000025_0001
Method B
Figure imgf000025_0002
Method C
Figure imgf000025_0003
Figure imgf000025_0004
oxidant = for example, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
Method E
R-B(OH)2 ,Cu(OAc)2 02Et pyridine, 4A powdered sieves,
Figure imgf000026_0001
room temperature
Figure imgf000026_0002
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, inflammatory diseases (e.g. rheumatoid arthritis, multiple sclerosis, Guillain- Barre syndrome, Crohn's disease, ulcerative colitis, psoriasis, graft versus host disease, systemic lupus, erythematosus or insulin-dependent diabetes mellitus), autoimmune diseases (e.g. toxic shock syndrome, osteoarthritis, diabetes or inflammatory bowel disease), acute pain, chronic pain, neuropathic pain, contact dermatitis, atherosclerosis, glomerulonephritis, reperfusion injury, bone resorption diseases, asthma, stroke, myocardial infarction, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, dermatoses with acute inflammatory components, acute purulent meningitis, necrotising entrerocolitis, syndromes associated with hemodialysis, septic shock, leukopherisis, granulocyte transfusion, acute or chronic inflammation of the lung caused by smoke inhalation, endometriosis, Behcet's disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme disease, restenosis following percutaneous transluminal coronary angioplasty, Alzheimer's disease, traumatic arthritis, sepsis, chronic obstructive pulmonary disease, congestive heart failure, osteoporosis, cachexia, Parkinson's disease, periodontal diseases, gout, allergic diseases, age-related macular degeneration, infection and cystic fibrosis.
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 com 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 diglyce des. In addition, fatty acids such as oleic acid, find use in the preparation of injectables.
The compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. Compositions for topical administration are also suitable for use in the invention. The pharmaceutically active compound may be dispersed in a pharmaceutically acceptable cream, ointment or gel. A suitable cream may be prepared by incorporating the active compound in a topical vehicle such as light liquid paraffin, dispersed in a aqueous medium using surfactants. An ointment may be prepared by mixing the active compound with a topical vehicle such as a mineral oil or wax. A gel may be prepared by mixing the active compound with a topical vehicle comprising a gelling agent. Topically administrable compositions may also comprise a matrix in which the pharmaceutically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally. The following Example illustrates the invention. In the Example, the terms "petrol" and "ether" refer to light petroleum
(b.p. 40-60 °C) and diethyl ether respectively.
All 1H NMR spectra were run at 400 MHz, using CDCI3 as solvent unless otherwise stated.
LC-MS spectra were run using Conditions A1 or A2; Mass spectrometry - electrospray source operating in positive and negative ion mode. The system ran at 1.5 mL/min, and the detection mode was through a Hexa-pole Mass Spectrometry detector and a Diode-Array detector for UV.
Mobile phase: acetonitrile-water (running from 5-95% acetonitrile) with either 0.05% formic acid (conditions A1) or 0.05% ammonium hydroxide (conditions A2) added.
Intermediate 1: Ethyl 5-trimethylsilylpyrazole-3-carboxylate
Prepared according to a modified procedure based on Birkofer et al, Chem. Ber., 1972, 105, 1759.
A mixture of ethyl diazoacetate (5.71 g, 50 mmol) and trimethylsilyl acetylene (4.91 g, 50 mmol) was gently heated to reflux overnight. Upon cooling, the yellow solid was triturated with petrol, collected by vacuum filtration and washed with a further quantity of petrol. The resulting white crystals were dried in a vacuum oven (50°C, 1 mbar, 2 hours) to afford the pure title compound (7.2 g, 72 % yield). 1H NMR δ 6.93 (1 H, s), 4.35 (2 H, q, J = 7.1 Hz), 1.32 (3 H, t, J = 7.1 Hz) and 0.31 (9 H, s). LC-MS (Conditions A1) Rt = 3.66 min, m/z = 214 (M+H+) and 213 (M+). Intermediate 2: Ethyl .V-(4-tolyl)-3-trimethylsilylpyrazole-5-carboxylate
Prepared using the general procedure of Lam et al, Tetrahedron Lett., 1998, 39, 2941.
To a mixture of Intermediate 1 (746 mg, 3.5 mmol), 4-tolyl boronic acid (956 mg, 7.0 mmol), copper (II) acetate (956 mg, 5.25 mmol) and dichloromethane (50 mL) was added pyridine (565 mL, 7.0 mmol) followed by powdered 4 A molecular sieves (which had been activated by heating to 150°C for > 2 hours). The mixture was allowed to stir at room temperature overnight before being filtered through Celite, which was then washed through with methyl alcohol (100 mL). The combined eluents were concentrated and the crude mixture was purified by column chromatography (silica, 5:1 to 1:1 petrol/ether) to afford the desired regioisomer. 1H NMR δ 7.33 (2 H, d, J = 8.3 Hz), 7.26 (2 H, m), 7.13 (1 H, s), 4.25 (2 H, q, J = 7.1 Hz), 2.43 (3 H, s), 1.29 (3 H, t, J = 7.1 Hz) and 0.35 (9 H, s). LC-MS (Conditions A1 ) Rt = 4.75 min, m/z = 304 (M+H+) and 303 (M+).
Also isolated from this reaction was ethyl Λ/-(4-tolyl)-5- trimethyIsilylpyrazole-3-carboxylate as a minor product. 1H NMR δ 7.32 (2 H, d, J = 7.8 Hz), 7.28 (2 H, d, J = 7.8 Hz), 7.08 (1 H, s), 4.45 (2 H, q, J= 7.1 Hz), 2.43 (3 H, s), 1.40 (3 H, t, J = 7.1 Hz) and 0.11 (9 H, s). LC-MS (Conditions A1 ) Rt = 4.56 min, m/z = 304 (M+H+) and 303 (M+).
Intermediate 3: iV-(4-Tolyl)-3-trimethylsilylpyrazole-5-carboxylic acid
To a solution of Intermediate 2 (250 mg, 0.83 mmol) in industrial methylated spirits (10 mL) was added an aqueous solution of sodium hydroxide (1.0 M solution, 1.65 mL). The resulting mixture was heated to reflux for 1 hour before being allowed to cool and then concentrated in vacuo. The resulting crude solid was redissolved in water (5 mL), cooled in an ice-bath and then acidified to pH 1 with 1 M hydrochloric acid. The resulting precipitate, which was colourless initially but rapidly darkened, was filtered off and dried (vacuum oven at 50° C, 1 mbar, 2 hours) to afford the title compound (196 mg, 86 %), mp 128-130°C (tBuOMe). 1H NMR (DMSO) δ 7.29 (2 H, d, J = 8.1 Hz), 7.27 (2 H, d, J = 8.1 Hz), 7.11 (1 H, s), 2.37 (3 H, s) and 0.29 (9 H, s). LC-MS (Conditions A1 ) Rt = 4.04 min, m/z = 276 (M+H+) and 275 (M+).
Example:1-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-3-(2-p-tolyl-5- trimethylsilyl-2H-pyrazol-3-yl)-urea.
To a cooled (0°C) stirred mixture of Intermediate 3 (250 mg, 0.909 mmol), triethylamine (316 mL, 2.28 mmol) and anhydrous Λ/,Λ/-dimethylformamide (5 mL) was added diphenylphosphoryl azide (197 mL, 0.909 mmol) in one portion. The reaction mixture was stirred at this temperature for 30 minutes before the cooling bath was removed and the mixture allowed to stir for a further 1 hour. 1-Amino-4- (2-morpholin-4-yl-ethoxy)naphthalene dihydrochloride (prepared as described in Regan et a., J. Med. Chem., 2002, 45, 2994; 280 mg, 0.909 mmol) was added and the mixture was heated to reflux for 1 hour. Upon cooling the reaction mixture was treated with water (75 mL) and ethyl acetate (50 mL) and shaken. The organic portion was separated and the aqueous layer was extracted with a further volume of ethyl acetate (100 mL) before the combined organic extracts were washed with water (5 x 50 mL), dried (magnesium sulphate) and concentrated in vacuo. The resulting mixture was purified by column chromatography (silica, 19:1 dichloromethane - methyl alcohol) to afford the title compound (208 mg, 42 %). 1H NMR δ 8.31 (1 H, m), 7.84 (1 H, m), 7.57 (2 H, m), 7.33 (1 H, d, J = 8.1 Hz), 6.95 (4 H, m), 6.71 (1 H, d, J = 7.8 Hz), 6.63 (1 H, s), 6.5 (1 H, br, s), 6.40 (1 H, br, s), 4.30 (2 H, m), 3.77 (4 H, m), 2.99 (2 H, m), 2.69 (4 H, m), 2.33 (3 H, s) and 0.32 (9 H, s). LC-MS (Conditions A1) Rt = 3.99 min, m/z = 544 (M+H+).

Claims

1. A compound of formula (I)
Figure imgf000034_0001
(I)
wherein
R1, R2 and R3 are the same or different and are each alkyl, -aikyl-aryl or -alkyl-cycloalkyl; or R1-Si-R2 taken together form heterocycloalkyl;
R4 is aryl or heteroaryl, either of which is optionally substituted with -Y-R5; R5 is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
W is heterocyclylene optionally substituted with alkyl, -aikyl-aryl, -alkyl- cycloalkyl, aryl, heteroaryl, -alkyl-heteroaryl or -alkyl-heterocycloalkyl; X is oxygen or sulphur;
Y is a bond, -NH-, -O-, -S-, -Si(R6)(R7)-, alkylene, alkenylene, -O-alkyl-, -S-alkyl-, -NH-alkyl- or -Si(R6)(R7)-alkyl-;
R6 and R7 are the same or different and are each alkyl; with the proviso that -Si(R1)(R2)(R3) is bound to a ring carbon atom of W; or a pharmaceutically acceptable salt thereof, or a prodrug form that is oxidisable or hydrolysable to form a compound as defined above.
2. A compound according to claim 1 , wherein R1, R2 and R3 are each alkyl.
3. A compound according to claim 2, wherein R1 is methyl; R2 is methyl or ethyl, either of which is optionally substituted with hydroxy; and R3 is methyl or ethyl.
4. A compound according to claim 1 , wherein R1-Si-R2 taken together form heterocycloalkyl.
5. A compound according to claim 4, wherein R -Si-R2 form silacyclohexyl.
6. A compound according to claim 4 or claim 5, wherein R3 is alkyl.
7. A compound according to any preceding claim, wherein R4 is phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indanyl, indenyl or indolyl, any of which is optionally substituted.
8. A compound according to claim 7, wherein R4 is substituted with halogen or alkoxy.
9. A compound according to claim 7 or claim 8, wherein R4 is substituted with -Y-R5.
10. A compound according to claim 9, wherein Y is alkylene, alkenylene, -O- alkyl-, -S-alkyl- or -Si(R6)(R7)-alkyk
11. A compound according to claim 9 or claim 10, wherein R5 is morpholin-4- yl or thiomorpholin-4-yl, either of which is optionally substituted with alkyl or oxo.
12. A compound according to claim 9 or claim 10, wherein R5 is pyridin-4-yl, imidazolyl or pyridin-3-yl.
13. A compound according to any preceding claim, wherein W is pyrrolylene, pyrrolidinylene, pyrazolylene, imidazolylene, oxazolylene, thiazolylene, furanylene or thiophenylene, any of which is optionally substituted.
14. A compound according to claim 13, wherein W is pyrazolylene optionally substituted with aryl, heteroaryl, alkyl or cycloalkyl.
15. A compound according to any preceding claim, wherein X is oxygen.
16. A compound according to claim 1 , selected from 1-(4-chlorophenyl)-3-(2-p-tolyl-5-trimethylsilyl-2H-pyrazol-3-yl)-urea; 1-(4-methoxyphenyl)-3-(2-p-tolyl-5-trimethylsilyl-2H-pyrazol-3-yl)-urea; 1 -[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1 -yl]-3-(2-p-tolyl-5- trimethylsilyl-2H-pyrazol-3-yl)-urea;
1-[5-(ethyl-dimethyl-silyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-1 -yl]-urea;
1-(4-methoxy-naphthalen-1-yl)-3-(2-p-tolyl-5-trimethylsilyl-2H-pyrazol-3- yl)-urea;
1-indan-5-yl-3-(2-p-tolyl-5-trimethylsilyl-2H-pyrazol-3-yl)-urea; 1-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(2-p-tolyl-5-trimethylsilyl-2H- pyrazol-3-yl)-urea;
1 -[5-(1 -methyl-1 -silacyciohexyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea;
1 -[5-(1 -methyl-1 ~silacyclohexyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2- morpholin-4-yl-ethoxy)-phenyl]-urea;
1-[5-(hydroxymethyl-dimethyl-silyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea;
1-[2-(3-hydroxy-4-methyl-phenyl)-5-trimethylsilyl-2H-pyrazol-3-yl]-3-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea; 1 -{4-[2-(trans-2,6-dimethyl-morpholin-4-yl)-ethoxy]-naphthalen-1 -yl}-3-(2- p-tolyl-5-trimethylsilyl-2H-pyrazol-3-yl)-urea;
1-[5-(diethyl-methyl-silyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-1 -yl]-urea;
1-[2-(4-hydroxymethyl-phenyl)-5-trimethylsilyl-2H-pyrazol-3-yl]-3-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-1 -yl]-urea;
1-{4-[2-(3-oxo-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-3-(2-p-tolyl-5- trimethylsilyl-2H-pyrazol-3-yl)-urea;
1-{4-[2-(cis-2,6-dimethyl-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-3-(2-p- tolyl-5-trimethylsilyl-2H-pyrazol-3-yl)-urea; 1 -[4-(2-piperidin-1 -yl-ethoxy)-naphthalen-1 -yl]-3-(2-p~tolyl-5-trimethylsilyl-
2H-pyrazol-3-yl)-urea;
1-[4-(2-pyridin-4-yl-ethoxy)-naphthalen-1-yl]-3-(2-p-tolyl-5-trimethylsilyl- 2H-pyrazol-3-yl)-urea;
1-[2-(6-methyl-pyridin-3-yl)-5-trimethylsilyl-2H-pyrazol-3-yl]-3-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-1 -yl]-urea;
1-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-3-(2-phenyl-5- trimethylsilyl-2H-pyrazol-3-yl)-urea;
1-[4-(2-thiomorpholin-4-yl-ethoxy)-naphthalen-1-yl]-3-(2-p-tolyl-5- trimethylsilyl-2H-pyrazol-3-yl)-urea; 1 -{4-[2-(1 -oxo-thiomorpholin-4-yl)-ethoxy]-naphthalen-1 -yl}-3-(2-p-tolyl-5- trimethylsilyl-2H-pyrazol-3-yl)-urea;
1-[2-(6-methoxy-pyridin-3-yl)-5-trimethylsilyl-2H-pyrazol-3-yl]-3-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-1 -yl]-urea;
1 -(2-ethyl-5-trimethylsilyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-1 -yl]-urea;
1 -[4-(2-morpholin-4-yl-ethylsulphanyl)-naphthalen-1-yl]-3-(2-p-tolyl-5- trimethylsilyl-2H-pyrazol-3-yl)-urea;
1-(2-methyl-5-trimethylsilyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-1 -yl]-urea;
1 -(2-cyclopentyl-5-trimethylsilyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-1 -yl]-urea; 1 -[4-(2-thiomorpholin-4-yl-ethylsulphanyl)-naphthalen-1 -yl]-3-(2-p-tolyl-5- trimethylsilyl-2H-pyrazol-3-yl)-urea;
1 -{4-[d i methy l-(2-morphol i n-4-y l-ethy I )-silyl]-naphthalen-1 -yl}-3-(2-p-tolyl- 5-trimethylsilyl-2H-pyrazol-3-yl)-urea;
1 -[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1 -yl]-3-(2-p-tolyl-5- trimethylsilyl-1 H-pyrrol-3-yl)-urea;
1 -(3-(2-(pyridin-4-yl)ethyl)-1 H-indol-5-yl)-3-(1 -p-tolyl-3-(trimethylsilyl)-1 H- pyrazol-5-yl)urea;
(E)-1 -(3-(2-(pyridin-4-yl)vinyl)-1 H-indol-5-yl)-3-(1 -p-tolyl-3-(trimethylsilyl)- 1 H-pyrazol-5-yl)urea; 1 -(3-(2-(pyridin-3-yl)ethyl)-1 H-indol-5-yl)-3-(1 -p-tolyl-3-(trimethylsilyl)-1 H- pyrazol-5-yl)urea;
1 -(3-(2-(piperidin-4-yl)ethyl)-1 H-indol-5-yl)-3-(1 -p-tolyl-3-(trimethylsilyl)- 1 H-pyrazol-5-yl)urea;
1 -(3-(2-morpholinoethyl)-1 H-indol-5-yl)-3-(1 -p-tolyl-3-(trimethylsilyl)-1 H- pyrazol-5-yl)urea;
1 -(3-(2-(piperazin-1 -yl)ethyl)-1 H-indol-5-yl)-3-(1 -p-tolyl-3-(trimethylsilyl)- 1 H-pyrazol-5-yl)urea;
1 -(3-(2-morpholinoethyl)-1 H-pyrrolo[2,3-b]pyridin-5-yl)-3-(1 -p-tolyl-3- (trimethylsilyl)-1 H-pyrazol-5-yl)urea; 1 -(3-(2-(pyridin-4-yl)ethyl)-1 H-pyrrolo[2,3-b]pyridin-5-yl)-3-(1 -p-tolyl-3-
(trimethylsilyl)-1 H-pyrazol-5-yl)urea;
1-(3-(2-morpholinoethyl)-3H-benzo[d]imidazol-5-yl)-3-(1-p-tolyl-3- (trimethylsilyl)-1H-pyrazol-5-yl)urea;
1 -(1 -(2-morpholinoethyl)-1 H-indol-6-yl)-3-(1 -p-tolyl-3-(trimethylsilyl)-1 H- pyrazol-5-yl)urea;
1-(3-(2-(pyridin-4-yl)ethyl)-3H-benzo[d]imidazol-5-yl)-3-(1-p-tolyl-3- (trimethylsilyl)-l H-pyrazol-5-yl)urea; and
1-(1-(2-(pyridin-4-yl)ethyl)-1H-indol-6-yl)-3-(1-p-tolyl-3-(trimethylsilyl)-1H- pyrazol-5-yl)urea.
17. A compound according to claim 16, which is 1-[4-(2-morpholin-4-yl- ethoxy)-naphthalen-1-yl]-3-(2-p-tolyl-5-trimethylsilyl-2H-pyrazol-3-yl)-urea.
18. A compound according to claim 1 , selected from:
1 -(4-(2-(1 H-imidazol-1 -yl)ethoxy)naphthalen-1 -yl)-3-(2-p-tolyl-5- (trimethylsilyl)-2H-pyrazol-3-yl)urea;
1 -(4-(2-(1 H-imidazol-1 -yl)ethoxy)phenyl)-3-(2-p-tolyl-5-(trimethylsilyl)-2H- pyrazol-3-yl)urea; and 1 -(4-(2-(pyridin-3-yl)ethoxy)naphthalen-1 -yl)-3-(2-p-tolyl-5-(trimethylsilyl)-
2H-pyrazol-3-yl)urea.
19. A compound according to any preceding claim, which is in the form of a single enantiomer, diastereomer or tautomer.
20. A compound according to any preceding claim, for therapeutic use.
21. A pharmaceutical composition comprising a compound of any of claims 1 to 19 and a pharmaceutically acceptable diluent or carrier.
22. Use of a compound of any of claims 1 to 19, for the manufacture of a medicament for the treatment or prevention of an inflammatory disease.
23. Use according to claim 22, for the treatment or prevention of rheumatoid arthritis, multiple sclerosis, Guillain-Barre syndrome, Crohn's disease, ulcerative colitis, psoriasis, graft versus host disease, systemic lupus, erythematosus or insulin-dependent diabetes mellitus.
24. Use of a compound of any of claims 1 to 19, for the manufacture of a medicament for the treatment or prevention of an autoimmune disease.
25. Use according to claim 24, for the treatment or prevention of toxic shock syndrome, osteoarthritis, diabetes or inflammatory bowel disease.
26. Use of a compound of any of claims 1 to 19, for the manufacture of a medicament for the treatment or prevention of acute pain, chronic pain, neuropathic pain, contact dermatitis, atherosclerosis, glomerulonephritis, reperfusion injury, a bone resorption disease, asthma, stroke, myocardial infarction, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, dermatoses with acute inflammatory components, acute purulent meningitis, necrotising entrerocolitis, a syndrome associated with hemodialysis, septic shock, leukopherisis, granulocyte transfusion, acute or chronic inflammation of the lung caused by smoke inhalation, endometriosis, Behcet's disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme disease, restenosis following percutaneous transluminal coronary angioplasty, Alzheimer's disease, traumatic arthritis, sepsis, chronic obstructive pulmonary disease or congestive heart failure.
27. Use of a compound of any of claims 1 to 19, for the manufacture of a medicament for the treatment or prevention of osteoporosis, cachexia, Parkinson's disease, a periodontal disease, gout, an allergic disease, age- related macular degeneration, infection or cystic fibrosis.
28. Use of a compound of any of claims 1 to 19, for the manufacture of a medicament for the treatment or prevention of rheumatoid arthritis, psoriasis or chronic obstructive pulmonary disease.
29. Use according to claim 28, wherein the compound is 1 -[4-(2-morpholin-4- yl-ethoxy)-naphthalen-1-yl]-3-(2-p-tolyl-5-trimethylsilyl-2H-pyrazol-3-yl)-urea.
PCT/GB2004/002562 2003-06-19 2004-06-16 Silylated heterocyclylurea derivatives as cytokine-inhibitors WO2004113352A1 (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB0314292.4 2003-06-19
GB0314292A GB0314292D0 (en) 2003-06-19 2003-06-19 Compounds and their use
GB0328149.0 2003-12-04
GB0328149A GB0328149D0 (en) 2003-12-04 2003-12-04 Compounds and their use
GB0401244.9 2004-01-20
GB0401244A GB0401244D0 (en) 2004-01-20 2004-01-20 Compounds and their use

Publications (1)

Publication Number Publication Date
WO2004113352A1 true WO2004113352A1 (en) 2004-12-29

Family

ID=33544948

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2004/002562 WO2004113352A1 (en) 2003-06-19 2004-06-16 Silylated heterocyclylurea derivatives as cytokine-inhibitors

Country Status (1)

Country Link
WO (1) WO2004113352A1 (en)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7202257B2 (en) * 2003-12-24 2007-04-10 Deciphera Pharmaceuticals, Llc Anti-inflammatory medicaments
US7666895B2 (en) 2002-12-31 2010-02-23 Deciphera Pharmaceuticals, Llc Anti-inflammatory medicaments
US7777040B2 (en) * 2005-05-03 2010-08-17 Cgi Pharmaceuticals, Inc. Certain substituted ureas, as modulators of kinase activity
US7790756B2 (en) 2006-10-11 2010-09-07 Deciphera Pharmaceuticals, Llc Kinase inhibitors useful for the treatment of myleoproliferative diseases and other proliferative diseases
US8143293B2 (en) 2007-04-20 2012-03-27 Deciphera Pharmaceuticals, Llc Kinase inhibitors useful for the treatment of myleoprolific diseases and other proliferative diseases
WO2014033449A1 (en) * 2012-08-29 2014-03-06 Respivert Limited Kinase inhibitors
WO2014076484A1 (en) 2012-11-16 2014-05-22 Respivert Limited Kinase inhibitors
US8927563B2 (en) 2013-04-02 2015-01-06 Respivert Limited Kinase inhibitor
US8940756B2 (en) 2012-06-07 2015-01-27 Deciphera Pharmaceuticals, Llc Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
US9499486B2 (en) 2014-10-01 2016-11-22 Respivert Limited Kinase inhibitor
US9771353B2 (en) 2013-04-02 2017-09-26 Topivert Pharma Limited Kinase inhibitors based upon N-alkyl pyrazoles
US9790209B2 (en) 2012-08-29 2017-10-17 Respivert Limited Kinase inhibitors
US9796742B2 (en) 2012-08-29 2017-10-24 Respivert Limited Kinase inhibitors
US9890185B2 (en) 2013-12-20 2018-02-13 Respivert Limited Urea derivatives useful as kinase inhibitors
US10072034B2 (en) 2016-04-06 2018-09-11 Respivert Limited Kinase inhibitors
US10966966B2 (en) 2019-08-12 2021-04-06 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11185535B2 (en) 2019-12-30 2021-11-30 Deciphera Pharmaceuticals, Llc Amorphous kinase inhibitor formulations and methods of use thereof
US11266635B2 (en) 2019-08-12 2022-03-08 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11395818B2 (en) 2019-12-30 2022-07-26 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
US11779572B1 (en) 2022-09-02 2023-10-10 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998052558A1 (en) * 1997-05-23 1998-11-26 Bayer Corporation INHIBITION OF p38 KINASE ACTIVITY BY ARYL UREAS
WO2000043384A1 (en) * 1999-01-19 2000-07-27 Boehringer Ingelheim Pharmaceuticals, Inc. Aromatic heterocyclic compounds as antiinflammatory agents
WO2001004115A2 (en) * 1999-07-09 2001-01-18 Boehringer Ingelheim Pharmaceuticals, Inc. Novel process for synthesis of heteroaryl-substituted urea compounds
WO2003005999A2 (en) * 2001-07-11 2003-01-23 Boehringer Ingelheim Pharmaceuticals, Inc. Methods of treating cytokine mediated diseases

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998052558A1 (en) * 1997-05-23 1998-11-26 Bayer Corporation INHIBITION OF p38 KINASE ACTIVITY BY ARYL UREAS
WO2000043384A1 (en) * 1999-01-19 2000-07-27 Boehringer Ingelheim Pharmaceuticals, Inc. Aromatic heterocyclic compounds as antiinflammatory agents
WO2001004115A2 (en) * 1999-07-09 2001-01-18 Boehringer Ingelheim Pharmaceuticals, Inc. Novel process for synthesis of heteroaryl-substituted urea compounds
WO2003005999A2 (en) * 2001-07-11 2003-01-23 Boehringer Ingelheim Pharmaceuticals, Inc. Methods of treating cytokine mediated diseases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TAKCE R ET AL: "SILA-SUBSTITUTION - A USEFUL STRATEGY FOR DRUG DESIGN?", ENDEAVOUR, PERGAMON PRESS, OXFORD, GB, vol. 10, no. 4, 1986, pages 191 - 197, XP008002622, ISSN: 0160-9327 *

Cited By (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7342037B2 (en) 2002-12-31 2008-03-11 Deciphera Pharmaceuticals, Llc Anti-inflammatory medicaments
US7666895B2 (en) 2002-12-31 2010-02-23 Deciphera Pharmaceuticals, Llc Anti-inflammatory medicaments
US7737283B2 (en) 2002-12-31 2010-06-15 Deciphera Pharmaceuticals, Llc Anti-inflammatory medicaments
US7202257B2 (en) * 2003-12-24 2007-04-10 Deciphera Pharmaceuticals, Llc Anti-inflammatory medicaments
US7777040B2 (en) * 2005-05-03 2010-08-17 Cgi Pharmaceuticals, Inc. Certain substituted ureas, as modulators of kinase activity
US20100286190A1 (en) * 2005-05-03 2010-11-11 Cgi Pharmaceuticals, Inc. Certain substituted ureas, as modulators of kinase activity
US8222421B2 (en) * 2005-05-03 2012-07-17 Gilead Connecticut, Inc. Certain substituted ureas, as modulators of kinase activity
US7790756B2 (en) 2006-10-11 2010-09-07 Deciphera Pharmaceuticals, Llc Kinase inhibitors useful for the treatment of myleoproliferative diseases and other proliferative diseases
US8143293B2 (en) 2007-04-20 2012-03-27 Deciphera Pharmaceuticals, Llc Kinase inhibitors useful for the treatment of myleoprolific diseases and other proliferative diseases
US8940756B2 (en) 2012-06-07 2015-01-27 Deciphera Pharmaceuticals, Llc Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
USRE48731E1 (en) 2012-06-07 2021-09-14 Deciphera Pharmaceuticals, Llc Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
US9783556B2 (en) 2012-08-29 2017-10-10 Respivert Limited Kinase inhibitors
US20150225427A1 (en) * 2012-08-29 2015-08-13 Respivert Limited Kinase inhibitors
US9790209B2 (en) 2012-08-29 2017-10-17 Respivert Limited Kinase inhibitors
US9796742B2 (en) 2012-08-29 2017-10-24 Respivert Limited Kinase inhibitors
WO2014033449A1 (en) * 2012-08-29 2014-03-06 Respivert Limited Kinase inhibitors
US9732063B2 (en) 2012-11-16 2017-08-15 Respivert Limited Kinase inhibitors
WO2014076484A1 (en) 2012-11-16 2014-05-22 Respivert Limited Kinase inhibitors
US9481648B2 (en) 2013-04-02 2016-11-01 Respivert Limited Kinase inhibitors
US8927563B2 (en) 2013-04-02 2015-01-06 Respivert Limited Kinase inhibitor
US10435361B2 (en) 2013-04-02 2019-10-08 Topivert Pharma Limited Kinase inhibitors
US9771353B2 (en) 2013-04-02 2017-09-26 Topivert Pharma Limited Kinase inhibitors based upon N-alkyl pyrazoles
US9790174B2 (en) 2013-04-02 2017-10-17 Respivert Limited Kinase inhibitors
US9890185B2 (en) 2013-12-20 2018-02-13 Respivert Limited Urea derivatives useful as kinase inhibitors
US10392346B2 (en) 2014-10-01 2019-08-27 Topivert Pharma Limited Kinase inhibitors
US9499486B2 (en) 2014-10-01 2016-11-22 Respivert Limited Kinase inhibitor
US10125100B2 (en) 2014-10-01 2018-11-13 Respivert Limited Kinase inhibitors
US9822076B2 (en) 2014-10-01 2017-11-21 Respivert Limited Kinase inhibitor
US9751837B2 (en) 2014-10-01 2017-09-05 Respivert Limited Kinase inhibitors
US10941115B2 (en) 2014-10-01 2021-03-09 Oxular Acquisitions Limited Kinase inhibitors
US10442828B2 (en) 2016-04-06 2019-10-15 Topivert Pharma Limited Kinase inhibitors
US10072034B2 (en) 2016-04-06 2018-09-11 Respivert Limited Kinase inhibitors
US11529336B2 (en) 2019-08-12 2022-12-20 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11576904B2 (en) 2019-08-12 2023-02-14 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11266635B2 (en) 2019-08-12 2022-03-08 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11344536B1 (en) 2019-08-12 2022-05-31 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11813251B2 (en) 2019-08-12 2023-11-14 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11426390B2 (en) 2019-08-12 2022-08-30 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11433056B1 (en) 2019-08-12 2022-09-06 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US10966966B2 (en) 2019-08-12 2021-04-06 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11534432B2 (en) 2019-08-12 2022-12-27 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11612591B2 (en) 2019-12-30 2023-03-28 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
US11844788B1 (en) 2019-12-30 2023-12-19 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11185535B2 (en) 2019-12-30 2021-11-30 Deciphera Pharmaceuticals, Llc Amorphous kinase inhibitor formulations and methods of use thereof
US11918564B1 (en) 2019-12-30 2024-03-05 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11793795B2 (en) 2019-12-30 2023-10-24 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
US11801237B2 (en) 2019-12-30 2023-10-31 Deciphera Pharmaceuticals, Llc Amorphous kinase inhibitor formulations and methods of use thereof
US11395818B2 (en) 2019-12-30 2022-07-26 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
US11576903B2 (en) 2019-12-30 2023-02-14 Deciphera Pharmaceuticals, Llc Amorphous kinase inhibitor formulations and methods of use thereof
US11850240B1 (en) 2019-12-30 2023-12-26 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11850241B1 (en) 2019-12-30 2023-12-26 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11896585B2 (en) 2019-12-30 2024-02-13 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
US11903933B2 (en) 2019-12-30 2024-02-20 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11911370B1 (en) 2019-12-30 2024-02-27 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11779572B1 (en) 2022-09-02 2023-10-10 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors

Similar Documents

Publication Publication Date Title
WO2004113352A1 (en) Silylated heterocyclylurea derivatives as cytokine-inhibitors
JP4812745B2 (en) Aryl and heteroaryl piperidine carboxylic acid derivatives, their preparation and their use as FAAH enzyme inhibitors
US5180723A (en) Certain sulfonamide heterobicyclic platelet activating factor antagonists
KR910002583B1 (en) Piperazine derivative or its salt,process for producing the same and pharmaceutical composition comprsing the same as active ingredient
TW202304911A (en) Pyridinamide compound
JPH0649027A (en) Indole derivative
JP2002538157A (en) Pyrazolopyridine
JPH11508284A (en) Substituted indazole derivatives and inhibitors of phosphodiesterase (PDE) type IV and tumor necrosis factor (TNF) production
JP2006522065A (en) Compounds having 5-HT2C receptor activity and uses thereof
JP2007530648A (en) 3-((Hetero) arylsulfonyl) -8-((aminoalkyl) oxy) quinolines as 5-HT6 receptor antagonists for the treatment of CNS disorders
WO2000039097A1 (en) Imidazole compounds and medicinal use thereof
US5180724A (en) Carboxamide amino acid heterobicyclic paf antagonists
JP2007505075A (en) Quinoline compound and pharmaceutical composition containing the same
EA008801B1 (en) Aryl alkyl carbamate derivatives production and use thereof in therapy
JP3218243B2 (en) Benzimidazoles, their production and use
KR20050042000A (en) Silicon compounds
WO2005044825A1 (en) Silicon compounds and their use
EP0527817A1 (en) Gamma-butyrolactol ether derivatives
CN116670124A (en) Substituted piperidines and related methods of treatment
EP1439164B1 (en) Novel phenylethanolamine compounds having beta2-acceptor excitatory function and their preparation method
US8044066B2 (en) Derivatives of pyrrolopyridine-2-carboxamides, preparation thereof and therapeutic application thereof
US5852204A (en) Pyrrolo 3,2-b-!-carbazoles and 1H 1!benzothieno 2,3-f! indoles having anti-tumor activity
US5409937A (en) Hexahydrofuro(2,3-b)furans as PAF antagonists
US5866588A (en) Imidazopyridine derivatives
WO2005035541A1 (en) Silicon compounds and their use

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DPEN Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101)
122 Ep: pct application non-entry in european phase