WO2004113352A1 - Silylated heterocyclylurea derivatives as cytokine-inhibitors - Google Patents
Silylated heterocyclylurea derivatives as cytokine-inhibitors Download PDFInfo
- 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
Links
- 239000003112 inhibitor Substances 0.000 title description 5
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- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 8
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 8
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- XFOBMBPYICYBAD-UHFFFAOYSA-N 1-(2-ethyl-5-trimethylsilylpyrazol-3-yl)-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea Chemical compound CCN1N=C([Si](C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1OCCN1CCOCC1 XFOBMBPYICYBAD-UHFFFAOYSA-N 0.000 claims description 2
- AYCJEMNVOWAKCA-UHFFFAOYSA-N 1-(2-methyl-5-trimethylsilylpyrazol-3-yl)-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea Chemical compound CN1N=C([Si](C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1OCCN1CCOCC1 AYCJEMNVOWAKCA-UHFFFAOYSA-N 0.000 claims description 2
- CDGQLFLCPGMAQL-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-[2-(4-methylphenyl)-5-trimethylsilylpyrazol-3-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C=CC(Cl)=CC=2)=CC([Si](C)(C)C)=N1 CDGQLFLCPGMAQL-UHFFFAOYSA-N 0.000 claims description 2
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- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical class C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
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- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
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- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
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- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
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- 229940005550 sodium alginate Drugs 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
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- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960002703 undecylenic acid Drugs 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic 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
-
- 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.
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- Pain & Pain Management (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract
Description
Claims
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GB0314292A GB0314292D0 (en) | 2003-06-19 | 2003-06-19 | Compounds and their use |
GB0314292.4 | 2003-06-19 | ||
GB0328149.0 | 2003-12-04 | ||
GB0328149A GB0328149D0 (en) | 2003-12-04 | 2003-12-04 | Compounds and their use |
GB0401244A GB0401244D0 (en) | 2004-01-20 | 2004-01-20 | Compounds and their use |
GB0401244.9 | 2004-01-20 |
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