WO2005079192A2 - Novel treatment - Google Patents
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- WO2005079192A2 WO2005079192A2 PCT/US2004/030272 US2004030272W WO2005079192A2 WO 2005079192 A2 WO2005079192 A2 WO 2005079192A2 US 2004030272 W US2004030272 W US 2004030272W WO 2005079192 A2 WO2005079192 A2 WO 2005079192A2
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- treatment
- disorders
- renal dysfunction
- vanilloid receptor
- pharmaceutically acceptable
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
Definitions
- This invention relates to a novel treatment and in particular to a method for the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with diseases, such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure, as well as renal dysfunctions (or disorders) induced by drugs, including, but not limited, to antineoplastic agents, antibiotics, and immunosuppressants.
- diseases such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure
- renal dysfunctions or disorders induced by drugs, including, but not limited, to antineoplastic agents, antibiotics, and immunosuppressants.
- Nanilloids are a class of natural and synthetic compounds that are characterised by the presence of a vanillyl (4-hydroxy 3-methoxybenzyl) group or a functionally equivalent group.
- Vanilloid Receptor (VR-1) whose function is modulated by such compounds, has been widely studied and is extensively reviewed by Szallasi and Blumberg (The American Society for Pharmacology and Experimental Therapeutics, 1999, Vol. 51, No. 2.).
- a wide variety of vanilloid compounds of different structures are known in the art, for example those disclosed in European Patent Application Numbers, EP 0 347 000 and EP 0 401 903, UK Patent Application Number GB 2226313 and International Patent Application, Publication Number WO 92/09285.
- vanilloid compounds or vanilloid receptor modulators are capsaicin or trans 8-methyl-N-vanillyl-6-nonenamide which is isolated from the pepper plant, capsazepine ⁇ Tetrahedron, 53, 1997, 4791) and olvanil or - N-(4-hydroxy-3- methoxybenzyl)oleamide (J Med. Chem., 36, 1993, 2595).
- US Patent Numbers, US 3,424,760 and US 3,424,761 both describe a series of 3-Ureidopyrrolidines that are said to exhibit analgesic, central nervous system, and pyschopharmacological activities.
- International Patent Application, Publication Number WO 01/021577 discloses the preparation of a series of N-tetrahydronaphthalenyl derivatives, having biological activity as melanin-concentrating hormone antagonists.
- International Patent Application, Publication Number WO 02/08221 discloses diaryl piperazine and related compounds which bind with high selectivity and high affinity to vanilloid receptors, especially Type I vanilloid receptors, also known as capsaicin or VR-1 receptors. The compounds are said to be useful in the treatment of chronic and acute pain conditions, itch and urinary incontinence.
- compounds having activity as vanilloid receptor antagonists have activity in the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with diseases, such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure, as well as renal dysfunctions (or disorders) induced by drugs, including, but not limited to, antineoplastic agents, antibiotics, and immunosuppressants.
- the invention provides a method for the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with diseases, such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure, as well as renal dysfunctions (or disorders) induced by drugs, including, but not limited to, antineoplastic agents, antibiotics, and immunosuppressants, in humans or non-human mammals, which method comprises the administration of an effective, non-toxic and pharmaceutically acceptable amount of a vanilloid receptor antagonist.
- the invention provides a method for the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with diabetic nephropathy.
- the invention provides a method for the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with glomerular nephritis.
- the invention provides a method for the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with nephrosis.
- the invention provides a method for the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with congestive heart failure.
- the invention provides a method for the treatment and/or prophylaxis of renal dysfunction (or disorders) induced by antineoplastic agents.
- the invention provides a method for the treatment and/or prophylaxis of renal dysfunction (or disorders) induced by antibiotics.
- the invention provides a method for the treatment and/or prophylaxis of renal dysfunction (or disorders) induced by immunosuppressants.
- the vanilloid receptor antagonist is an antagonist of the vanilloid receptor- 1.
- the antagonist of the vanilloid receptor- 1 is N-(2-Bromophenyl)-N- [((R)- 1 -(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea.
- the invention in another aspect relates to a pharmaceutical composition for the treatment and or prophylaxis of renal dysfunction (or disorders) associated with diseases, such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure, as well as renal dysfunctions (or disorders) induced by drugs, including, but not limited to, antineoplastic agents, antibiotics, and immunosuppressants, which composition comprises a vanilloid antagonist, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier therefor.
- diseases such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure
- drugs including, but not limited to, antineoplastic agents, antibiotics, and immunosuppressants, which composition comprises a vanilloid antagonist, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier therefor.
- the invention relates to a vanilloid receptor antagonist or a pharmaceutically acceptable derivative thereof, for use in the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with diseases, such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure, as well as renal dysfunctions (or disorders) induced by drugs, including, but not limited to, antineoplastic agents, antibiotics, and immunosuppressants.
- diseases such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure
- drugs including, but not limited to, antineoplastic agents, antibiotics, and immunosuppressants.
- the invention also relates to a vanilloid receptor antagonist or a pharmaceutically acceptable derivative thereof, for use in the manufacture of a medicament for the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with diseases, such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure, as well as renal dysfunctions (or disorders) induced by drugs, including, but not limited to, antineoplastic agents, antibiotics, and immunosuppressants.
- diseases such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure
- drugs including, but not limited to, antineoplastic agents, antibiotics, and immunosuppressants.
- Suitable vanilloid receptor antagonists for use in accordance with the present invention include those disclosed in European Patent numbers EP 0 347 000 and EP 0 401 903 ; UK Patent Application Number GB 2226313 ; International Patent
- vanilloid receptor antagonists for use in accordance with the present invention include those disclosed in International Patent Applications, Publication Numbers WO 02/072536, WO 02/090326, WO 03/022809 and WO 03/053945; and International Patent Application Number PCT/GB03/00608.
- a particularly preferred vanilloid receptor antagonist for use in accordance with the present invention is a compound of formula (I), (IA) (IB), or (IC) as defined in the International Patent Application, Publication Number WO 03/022809, published March 20, 2003.
- vanilloid receptor antagonist for the present use is N-(2-Bromophenyl)-N-[((R)-l-(5-trifluoromethyl-2-pyridyl)pyrrolidin- 3-yl)]urea (hereafter referred to as "Compound A”), or a pharmaceutically acceptable derivative thereof.
- Compound A is disclosed at Example 1 of International Patent Application, Publication Number WO 03/022809. All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
- vanilloid receptor antagonists may exist in one of several tautomeric forms, all of which are encompassed by the present invention as individual tautomeric forms or as mixtures thereof. Where a vanilloid receptor antagonist contains a chiral carbon, and hence exists in one or more stereoisomeric forms or where one or more geometric isomers exist, it will be appreciated that the method of the present invention encompasses all of the said forms of the vanilloid receptor antagonists whether as individual isomers or as mixtures of isomers, including racemates.
- the term 'vanilloid receptor antagonist' relates to an antagonist, such as a small molecular weight antagonist, of the vanilloid receptor. It will be appreciated that the term also embraces suitable pharmaceutically acceptable derivatives thereof.
- Vanilloid receptor antagonist activity may be assessed by use of the methodologies disclosed in the above-mentioned patent applications, such as, WO 02/08221, WO 02/16317 and WO 02/090326.
- Suitable pharmaceutically acceptable derivatives of a vanilloid receptor antagonist are, for example, salts and solvates.
- Suitable pharmaceutically acceptable derivatives of any particular vanilloid receptor antagonist include those disclosed in the above-mentioned publications.
- Suitable pharmaceutically acceptable salts include salts derived from appropriate acids, such as acid addition salts, or bases.
- Suitable pharmaceutically acceptable salts include metal salts, such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl-b-phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine, quinine or quinoline.
- metal salts such as for example aluminium, alkali metal salts such as lithium, sodium or potassium,
- Suitable acid addition salts include pharmaceutically acceptable inorganic salts such as the sulfate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane-sulfonate, D-keto glutarate and D-glycerophosphate, especially the maleate salt.
- the vanilloid receptor antagonists referred to herein are conveniently prepared according to the methods disclosed in the above mentioned patent publications in which they are disclosed.
- the salts and/or solvates of the vanilloid receptor antagonists referred to herein may be prepared and isolated according to conventional procedures for example those disclosed in the above mentioned patent publications.
- the present invention also provides a vanilloid receptor antagonist or a pharmaceutically acceptable derivative thereof, for use in the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with diseases, such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure, as well as renal dysfunctions (or disorders) induced by drugs, including, but not limited to, antineoplastic agents, antibiotics, and immunosuppressants.
- diseases such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure
- drugs including, but not limited to, antineoplastic agents, antibiotics, and immunosuppressants.
- the present invention also provides a vanilloid receptor antagonist or a pharmaceutically acceptable derivative thereof, for use in the manufacture of a medicament for the the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with diseases, such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure, as well as renal dysfunctions (or disorders) induced by drugs, including, but not limited to, antineoplastic agents, antibiotics, and immunosuppressant.
- the vanilloid receptor antagonist may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
- the vanilloid receptor antagonist mentioned herein is formulated and administered in accordance with the methods disclosed in the above mentioned patent applications and patents.
- the preserit invention also provides a pharmaceutical composition for the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with diseases, such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure, and renal dysfunctions (or disorders) induced by drugs, including, but not limited to, antineoplastic agents, antibiotics, and immunosuppressants, which composition comprises a vanilloid antagonist, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier therefor.
- the term 'pharmaceutically acceptable' embraces compounds, compositions and ingredients for both human and veterinary use: for example the term
- composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use.
- anti-plastic agent is understood to mean a substance producing an antineoplastic effect in a tissue, system, animal, mammal (in particular human), or other subject. It is also to be understood that an “agent” may be a single compound or a combination or composition of two or more compounds.
- alkylating agents such as melphalan, chlorambucil, cyclophosphamide, mechlorethamine, hexamethylmelamine, busulfan, carmustine, lomustine, and dacarbazine
- antimetabolites such as 5-fluorouracil, methotrexate, cytarabine, mecaptopurine and thioguanine
- antimitotic agents such as paclitaxel, vinblastine, vincristine
- topoisomerase I inhibitors such as irinotecan, camptothecin and camptothecin derivatives
- topoisomerase II inhibitors such as doxorubicin
- platinum coordination complexes such as cisplatin and carboplatin.
- the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, mammal (in particular human), or other subject that is being sought by a researcher or clinician. More specifically typical antineoplastic agents for which the present vallinoid receptor antagonists are useful for the treatment and/or prophylaxis of renal dysfunction (or disorders) include, diterpenoids, vinca alkaloids, epipodophyllotoxins, antimetabolites, and camptothecins. Diterpenoids, which are derived from natural sources, are phase specific anti - cancer agents that operate at the G2/M phases of the cell cycle.
- diterpenoids stabilize the ⁇ -tubulin subunit of the microtubules, by binding with this protein. Disassembly of the protein appears then to be inhibited with mitosis being arrested and cell death following.
- diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.
- Paclitaxel 5 ⁇ ,20-epoxy- 1 ,2 ⁇ ,4,7 ⁇ , 1 O ⁇ , 13 ⁇ -hexa-hydroxytax- 11 -en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia and is commercially available as an injectable solution TAXOL®. It is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. J. Am. Chem, Soc, 93:2325.
- Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64:583, 1991 ; McGuire et al., Ann. Intern, Med., 111 :273,1989) and for the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83:1797,1991.) It is a potential candidate for treatment of neoplasms in the skin (Einzig et. al., Proc. Am. Soc. Clin.
- Docetaxel (2R,3S)- N-carboxy-3-phenylisoserine,N-tert-butyl ester, 13-ester with 5 ⁇ -20-e ⁇ oxy-l,2 ⁇ ,4,7 ⁇ ,10 ⁇ ,13 ⁇ -hexahydroxytax-l l-en-9-one 4-acetate 2- benzoate, trihydrate; is commercially available as an injectable solution as TAXOTERE®.
- Docetaxel is indicated for the treatment of breast cancer.
- Docetaxel is a semisynthetic derivative of paclitaxel q.v., prepared using a natural precursor, 10- deacetyl-baccatin III, extracted from the needle of the European Yew tree.
- Vinca alkaloids are phase specific antineoplastic agents derived from the periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is believed to be arrested in metaphase with cell death following. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine. Vinblastine, vincaleukoblastine sulfate, is commercially available as VELBAN® as an injectable solution.
- Vincristine vincaleukoblastine, 22-oxo-, sulfate
- ONCOVIN® an injectable solution.
- Vincristine is indicated for the treatment of acute leukemias and has also found use in treatment regimens for Hodgkin's and non- Hodgkin's malignant lymphomas.
- Vinorelbine 3',4'-didehydro -4'-deoxy-C'-norvincaleukoblastine [R-(R*,R*)- 2,3-dihydroxybutanedioate (1 :2)(salt)], commercially available as an injectable solution of vinorelbine tartrate (NAVELBINE®), is a semisynthetic vinca alkaloid.
- Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumours, particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers.
- Epipodophyllotoxins are phase specific antineoplastic agents derived from the mandrake plant.
- Epipodophyllotoxins typically affect cells in the S and G2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows.
- Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide. Etoposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R )-ethylidene- ⁇ -D- glucopyranoside], is commercially available as an injectable solution or capsules as VePESID® and is commonly known as VP-16.
- Etoposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of testicular and non-small cell lung cancers.
- Teniposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R )-thenylidene- ⁇ -D- glucopyranoside] is commercially available as an injectable solution as VUMON® and is commonly known as VM-26.
- Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children.
- Antimetabolite neoplastic agents are phase specific antineoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis.
- antimetabolite antineoplastic agents include, but are not limited to, 5-fluorouracil, methotrexate, cytarabine, mecaptopurine and thioguanine.
- 5-Fluorouracil, 5-fluoro-2,4- (1H,3H) pyrimidinedione, is commercially available as fluorouracil. Adminsitration of 5-fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result typically is cell death.
- 5-fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas.
- Other fluoropyrimidine analogs include 5-fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.
- Cytarabine 4-amino-l- ⁇ -D-arabinofuranosyl-2 (lH)-pyrimidinone, is commercially available as CYTOSAR-U® and is commonly known as Ara-C. It is believed that cytarabine exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporation of cytarabine into the growing DNA chain.
- Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia.
- Other cytidine analogs include 5- azacytidine and 2', 2 '-difluorodeoxy cytidine (gemcitabine).
- Mercaptopurine, 1 ,7-dihydro-6H-purine-6-thione monohydrate, is commercially available as PURINETHOL®.
- Mercaptopurine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism.
- Mercaptopurine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia.
- a useful mercaptopurine analog is azathioprine.
- Thioguanine 2-amino-l,7-dihydro-6H-purine-6-thione
- TABLOID® Thioguanine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism.
- Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia.
- Other purine analogs include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine.
- Methotrexate, N-[4[[(2,4-diamino-6-pteridinyl) methyl]methylamino] benzoyl]-L-glutamic acid is commercially available as methotrexate sodium.
- Methotrexate exhibits cell phase effects specifically at S-phase by inhibiting DNA synthesis, repair and/or replication through the inhibition of dyhydrofolic acid reductase which is required for synthesis of purine nucleotides and thymidylate.
- Methotrexate is indicated as a single agent or in combination with other chemotherapy agents in the treatment of choriocarconoma, meningeal leukemia, non-Hodgkin's lymphoma, and carcinomas of the breast, head, neck, ovary and bladder.
- Camptothecins, including, camptothecin and camptothecin derivatives are under development as Topoisomerase I inhibitors.
- Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity.
- camptothecins include, but are not limited to irinotecan and the various optical forms of 7-(4-methylpiperazino-methylene)- 10, 11 -ethylenedioxy-20-camptothecin.
- Irinotecan is a derivative of camptothecin which binds, along with its active metabolite SN-38, to the topoisomerase I - DNA complex.
- cytotoxicity occurs as a result of irreparable double strand breaks caused by interaction of the topoisomerase I : DNA : irinotecan or SN-38 ternary complex with replication enzymes.
- Irinotecan is indicated for treatment of metastatic cancer of the colon or rectum.
- the dose limiting side effects of irinotecan HC1 are myelosuppression, including neutropenia, and GI effects, including diarrhea.
- camptothecin derivative of formula II following, currently under development, including the racemic mixture (R,S) form as well as the R and S enantiomers:
- compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection and percutaneous absorption are also envisaged.
- Particularly suitable compositions for oral administration are unit dosage forms such as tablets and capsules.
- Other fixed unit dosage forms, such as powders presented in sachets, may also be used.
- the carrier may comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourant or other conventional adjuvant.
- Typical carriers include, for example, microcrystalline cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate, sodium lauryl sulphate or sucrose.
- Suitable dosages of the vanilloid receptor antagonist include the known doses for these compounds as described or referred to in reference texts such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31 st Edition page 341 and pages cited therein) or the above mentioned publications or doses which can be determined by standard procedures.
- the solid oral compositions may be prepared by conventional methods of blending, filling or tabletting.
- compositions employing large quantities of fillers may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art.
- the tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
- Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
- suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats
- emulsifying agents for example lecithin, sorbitan monooleate, or
- fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle.
- the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
- adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle.
- the composition can be frozen after filling into the vial and the water removed under vacuum.
- Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
- compositions may contain from 0.1 % to 99% by weight, preferably from
- compositions may, if desired, be in the form of a pack accompanied by written or printed instructions for use.
- the compositions are formulated according to conventional methods, such as those disclosed in standard reference texts, for example the British and US
- MC carboxymethylcellulose
- LDH lactate dehydrogenase
- ⁇ -GTP ⁇ -guanocin triphosphate
- BUN blood urea nitrogen
- Nephrotoxicity was induced by intraperitoneal administration of cisplatin at 15 mg/kg (Day 0). Evaluation of nephrotoxicity
- Each group consisted of 8 to 14 animals.
- Compound A was suspended in 1% MC solution.
- Compound A at 10 or 30 mg/kg or 1% MC solution was administered orally to mice 1 hour before the cisplatin treatment.
- the experimental groups were set up as follows: Intact* Vehicle (1% MC solution) + cisplatin Compound A (10 mg/kg) + cisplatin Compound A (30 mg/kg) + cisplatin * Mice without the cisplatin treatment.
- vanilloid antagonists in particular VR-1 antagonist of Compound A, are useful for the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with diseases, such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure, as well as renal dysfunctions (or disorders) induced by drugs, including, but not limited to, antinoeplastic agents, antibiotics, and immunosuppressants.
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Abstract
This invention relates to a novel treatment and in particular to a method for the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with diseases, such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure, as well as renal dysfunctions (~r disorders) induced by drugs, including, but not limited, to antineoplastic agents, antibiotics, and immunosuppressants.
Description
NOVEL TREATMENT
Field of Invention
This invention relates to a novel treatment and in particular to a method for the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with diseases, such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure, as well as renal dysfunctions (or disorders) induced by drugs, including, but not limited, to antineoplastic agents, antibiotics, and immunosuppressants.
Background of Invention
Nanilloids are a class of natural and synthetic compounds that are characterised by the presence of a vanillyl (4-hydroxy 3-methoxybenzyl) group or a functionally equivalent group. Vanilloid Receptor (VR-1), whose function is modulated by such compounds, has been widely studied and is extensively reviewed by Szallasi and Blumberg (The American Society for Pharmacology and Experimental Therapeutics, 1999, Vol. 51, No. 2.). A wide variety of vanilloid compounds of different structures are known in the art, for example those disclosed in European Patent Application Numbers, EP 0 347 000 and EP 0 401 903, UK Patent Application Number GB 2226313 and International Patent Application, Publication Number WO 92/09285. Particularly notable examples of vanilloid compounds or vanilloid receptor modulators are capsaicin or trans 8-methyl-N-vanillyl-6-nonenamide which is isolated from the pepper plant, capsazepine {Tetrahedron, 53, 1997, 4791) and olvanil or - N-(4-hydroxy-3- methoxybenzyl)oleamide (J Med. Chem., 36, 1993, 2595). US Patent Numbers, US 3,424,760 and US 3,424,761 both describe a series of 3-Ureidopyrrolidines that are said to exhibit analgesic, central nervous system, and pyschopharmacological activities. International Patent Application, Publication Number WO 01/021577 discloses the preparation of a series of N-tetrahydronaphthalenyl derivatives, having biological activity as melanin-concentrating hormone antagonists.
International Patent Application, Publication Number WO 02/08221 discloses diaryl piperazine and related compounds which bind with high selectivity and high affinity to vanilloid receptors, especially Type I vanilloid receptors, also known as capsaicin or VR-1 receptors. The compounds are said to be useful in the treatment of chronic and acute pain conditions, itch and urinary incontinence. International Patent Application, Publication Numbers WO 02/16317, WO 02/16318 and WO 02/16319 suggest that compounds having a high affinity for the vanilloid receptor are useful for treating stomach-duodenal ulcers. International Patent Applications, Publication Numbers WO 02/072536, WO 02/090326, WO 03/022809 and WO 03/053945; and International Patent Application Number PCT/GB03/00608 also describe a variety of compounds having activity as vanilloid receptor antagonists. It is now surprisingly indicated that compounds having activity as vanilloid receptor antagonists have activity in the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with diseases, such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure, as well as renal dysfunctions (or disorders) induced by drugs, including, but not limited to, antineoplastic agents, antibiotics, and immunosuppressants.
Summary of the Invention
The invention provides a method for the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with diseases, such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure, as well as renal dysfunctions (or disorders) induced by drugs, including, but not limited to, antineoplastic agents, antibiotics, and immunosuppressants, in humans or non-human mammals, which method comprises the administration of an effective, non-toxic and pharmaceutically acceptable amount of a vanilloid receptor antagonist. Suitably, the invention provides a method for the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with diabetic nephropathy. Suitably, the invention provides a method for the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with glomerular nephritis.
Suitably, the invention provides a method for the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with nephrosis. Suitably, the invention provides a method for the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with congestive heart failure. Suitably, the invention provides a method for the treatment and/or prophylaxis of renal dysfunction (or disorders) induced by antineoplastic agents. Suitably, the invention provides a method for the treatment and/or prophylaxis of renal dysfunction (or disorders) induced by antibiotics. Suitably, the invention provides a method for the treatment and/or prophylaxis of renal dysfunction (or disorders) induced by immunosuppressants. Suitably, the vanilloid receptor antagonist is an antagonist of the vanilloid receptor- 1. Suitably the antagonist of the vanilloid receptor- 1 is N-(2-Bromophenyl)-N- [((R)- 1 -(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea. In another aspect the invention relates to a pharmaceutical composition for the treatment and or prophylaxis of renal dysfunction (or disorders) associated with diseases, such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure, as well as renal dysfunctions (or disorders) induced by drugs, including, but not limited to, antineoplastic agents, antibiotics, and immunosuppressants, which composition comprises a vanilloid antagonist, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier therefor.
In further aspect, the invention relates to a vanilloid receptor antagonist or a pharmaceutically acceptable derivative thereof, for use in the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with diseases, such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure, as well as renal dysfunctions (or disorders) induced by drugs, including, but not limited to, antineoplastic agents, antibiotics, and immunosuppressants. Yet in another aspect, the invention also relates to a vanilloid receptor antagonist or a pharmaceutically acceptable derivative thereof, for use in the manufacture of a medicament for the treatment and/or prophylaxis of renal
dysfunction (or disorders) associated with diseases, such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure, as well as renal dysfunctions (or disorders) induced by drugs, including, but not limited to, antineoplastic agents, antibiotics, and immunosuppressants.
Specific Description of the Invention
Suitable vanilloid receptor antagonists for use in accordance with the present invention include those disclosed in European Patent numbers EP 0 347 000 and EP 0 401 903 ; UK Patent Application Number GB 2226313 ; International Patent
Applications, Publication Numbers WO 92/09285, WO 01/021577, WO 02/08221, WO 02/16317, WO 02/16318, WO 02/16319, WO 02/072536, WO 02/090326, WO2003055484, WO2003055848, WO 03/022809 and WO 03/053945; International Patent Application Number PCT/GB03/00608; and US Patent Numbers, US 3,424,760 and US 3,424,761. Preferred vanilloid receptor antagonists for use in accordance with the present invention include those disclosed in International Patent Applications, Publication Numbers WO 02/072536, WO 02/090326, WO 03/022809 and WO 03/053945; and International Patent Application Number PCT/GB03/00608. A particularly preferred vanilloid receptor antagonist for use in accordance with the present invention is a compound of formula (I), (IA) (IB), or (IC) as defined in the International Patent Application, Publication Number WO 03/022809, published March 20, 2003. Even more preferred vanilloid receptor antagonist for the present use is N-(2-Bromophenyl)-N-[((R)-l-(5-trifluoromethyl-2-pyridyl)pyrrolidin- 3-yl)]urea (hereafter referred to as "Compound A"), or a pharmaceutically acceptable derivative thereof. Compound A is disclosed at Example 1 of International Patent Application, Publication Number WO 03/022809. All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
Certain vanilloid receptor antagonists may exist in one of several tautomeric forms, all of which are encompassed by the present invention as individual tautomeric forms or as mixtures thereof. Where a vanilloid receptor antagonist contains a chiral carbon, and hence exists in one or more stereoisomeric forms or where one or more geometric isomers exist, it will be appreciated that the method of the present invention encompasses all of the said forms of the vanilloid receptor antagonists whether as individual isomers or as mixtures of isomers, including racemates. When used herein the term 'vanilloid receptor antagonist' relates to an antagonist, such as a small molecular weight antagonist, of the vanilloid receptor. It will be appreciated that the term also embraces suitable pharmaceutically acceptable derivatives thereof. Vanilloid receptor antagonist activity may be assessed by use of the methodologies disclosed in the above-mentioned patent applications, such as, WO 02/08221, WO 02/16317 and WO 02/090326. Suitable pharmaceutically acceptable derivatives of a vanilloid receptor antagonist are, for example, salts and solvates. Suitable pharmaceutically acceptable derivatives of any particular vanilloid receptor antagonist include those disclosed in the above-mentioned publications. Suitable pharmaceutically acceptable salts include salts derived from appropriate acids, such as acid addition salts, or bases. Suitable pharmaceutically acceptable salts include metal salts, such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl-b-phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine, quinine or quinoline. Suitable acid addition salts include pharmaceutically acceptable inorganic salts such as the sulfate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate,
maleate, citrate, succinate, benzoate, ascorbate, methane-sulfonate, D-keto glutarate and D-glycerophosphate, especially the maleate salt. The vanilloid receptor antagonists referred to herein are conveniently prepared according to the methods disclosed in the above mentioned patent publications in which they are disclosed. The salts and/or solvates of the vanilloid receptor antagonists referred to herein may be prepared and isolated according to conventional procedures for example those disclosed in the above mentioned patent publications. The present invention also provides a vanilloid receptor antagonist or a pharmaceutically acceptable derivative thereof, for use in the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with diseases, such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure, as well as renal dysfunctions (or disorders) induced by drugs, including, but not limited to, antineoplastic agents, antibiotics, and immunosuppressants. The present invention also provides a vanilloid receptor antagonist or a pharmaceutically acceptable derivative thereof, for use in the manufacture of a medicament for the the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with diseases, such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure, as well as renal dysfunctions (or disorders) induced by drugs, including, but not limited to, antineoplastic agents, antibiotics, and immunosuppressant. In the above-mentioned method the vanilloid receptor antagonist, may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier. In the treatment of the invention, the vanilloid receptor antagonist mentioned herein is formulated and administered in accordance with the methods disclosed in the above mentioned patent applications and patents. Accordingly, the preserit invention also provides a pharmaceutical composition for the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with diseases, such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure, and renal dysfunctions (or disorders) induced by drugs, including, but not limited to, antineoplastic agents, antibiotics, and
immunosuppressants, which composition comprises a vanilloid antagonist, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier therefor. As used herein the term 'pharmaceutically acceptable' embraces compounds, compositions and ingredients for both human and veterinary use: for example the term
'pharmaceutically acceptable salt' embraces a veterinarily acceptable salt. The composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use. The term "antineoplastic agent" is understood to mean a substance producing an antineoplastic effect in a tissue, system, animal, mammal (in particular human), or other subject. It is also to be understood that an "agent" may be a single compound or a combination or composition of two or more compounds.
Some of the typical antineoplastic agents include alkylating agents such as melphalan, chlorambucil, cyclophosphamide, mechlorethamine, hexamethylmelamine, busulfan, carmustine, lomustine, and dacarbazine; antimetabolites such as 5-fluorouracil, methotrexate, cytarabine, mecaptopurine and thioguanine; antimitotic agents such as paclitaxel, vinblastine, vincristine; topoisomerase I inhibitors such as irinotecan, camptothecin and camptothecin derivatives; topoisomerase II inhibitors such as doxorubicin; and platinum coordination complexes such as cisplatin and carboplatin. As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, mammal (in particular human), or other subject that is being sought by a researcher or clinician. More specifically typical antineoplastic agents for which the present vallinoid receptor antagonists are useful for the treatment and/or prophylaxis of renal dysfunction (or disorders) include, diterpenoids, vinca alkaloids, epipodophyllotoxins, antimetabolites, and camptothecins. Diterpenoids, which are derived from natural sources, are phase specific anti - cancer agents that operate at the G2/M phases of the cell cycle. It is believed that the diterpenoids stabilize the β-tubulin subunit of the microtubules, by binding with this protein. Disassembly of the protein appears then to be inhibited with mitosis being
arrested and cell death following. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel. Paclitaxel, 5 β,20-epoxy- 1 ,2α,4,7β, 1 Oβ, 13 α-hexa-hydroxytax- 11 -en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia and is commercially available as an injectable solution TAXOL®. It is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. J. Am. Chem, Soc, 93:2325. 1971), who characterized its structure by chemical and X-ray crystallographic methods. One mechanism for its activity relates to paclitaxel's capacity to bind tubulin, thereby inhibiting cancer cell growth. Schiff et al., Proc. Natl, Acad, Sci. USA, 77:1561-1565 (1980); Schiff et al., Nature, 277:665-667 (1979); Kumar, J. Biol, Chem, 256: 10435-10441 (1981). For a review of synthesis and anticancer activity of some paclitaxel derivatives see: D. G. I. Kingston et al., Studies in Organic Chemistry vol. 26, entitled "New trends in Natural Products Chemistry 1986", Attaur-Rahman, P.W. Le Quesne, Eds. (Elsevier, Amsterdam, 1986) pp 219-235. Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64:583, 1991 ; McGuire et al., Ann. Intern, Med., 111 :273,1989) and for the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83:1797,1991.) It is a potential candidate for treatment of neoplasms in the skin (Einzig et. al., Proc. Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas (Forastire et. al., Sem. Oncol., 20:56, 1990). The compound also shows potential for the treatment of polycystic kidney disease (Woo et al., Nature, 368:750. 1994), lung cancer and malaria. Treatment of patients with paclitaxel results in bone marrow suppression (multiple cell lineages, Ignoff, R.J. et. al, Cancer Chemotherapy Pocket Guide, 1998) related to the duration of dosing above a threshold concentration (50nM) (Kearns, CM. et. al., Seminars in Oncology, 3(6) p.16-23, 1995). Docetaxel, (2R,3S)- N-carboxy-3-phenylisoserine,N-tert-butyl ester, 13-ester with 5β-20-eρoxy-l,2α,4,7β,10β,13α-hexahydroxytax-l l-en-9-one 4-acetate 2- benzoate, trihydrate; is commercially available as an injectable solution as TAXOTERE®. Docetaxel is indicated for the treatment of breast cancer. Docetaxel
is a semisynthetic derivative of paclitaxel q.v., prepared using a natural precursor, 10- deacetyl-baccatin III, extracted from the needle of the European Yew tree. Vinca alkaloids are phase specific antineoplastic agents derived from the periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is believed to be arrested in metaphase with cell death following. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine. Vinblastine, vincaleukoblastine sulfate, is commercially available as VELBAN® as an injectable solution. Although, it has possible indication as a second line therapy of various solid tumors, it is primarily indicated in the treatment of testicular cancer and various lymphomas including Hodgkin's Disease; lymphocytic and histiocytic lymphomas. Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commercially available as ONCOVIN® as an injectable solution. Vincristine is indicated for the treatment of acute leukemias and has also found use in treatment regimens for Hodgkin's and non- Hodgkin's malignant lymphomas. Vinorelbine, 3',4'-didehydro -4'-deoxy-C'-norvincaleukoblastine [R-(R*,R*)- 2,3-dihydroxybutanedioate (1 :2)(salt)], commercially available as an injectable solution of vinorelbine tartrate (NAVELBINE®), is a semisynthetic vinca alkaloid. Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumours, particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers. Epipodophyllotoxins are phase specific antineoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide. Etoposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R )-ethylidene-β-D- glucopyranoside], is commercially available as an injectable solution or capsules as VePESID® and is commonly known as VP-16. Etoposide is indicated as a single
agent or in combination with other chemotherapy agents in the treatment of testicular and non-small cell lung cancers. Teniposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R )-thenylidene-β-D- glucopyranoside], is commercially available as an injectable solution as VUMON® and is commonly known as VM-26. Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children. Antimetabolite neoplastic agents are phase specific antineoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis.
Consequently, S phase does not proceed and cell death follows. Examples of antimetabolite antineoplastic agents include, but are not limited to, 5-fluorouracil, methotrexate, cytarabine, mecaptopurine and thioguanine. 5-Fluorouracil, 5-fluoro-2,4- (1H,3H) pyrimidinedione, is commercially available as fluorouracil. Adminsitration of 5-fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result typically is cell death. 5-fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas. Other fluoropyrimidine analogs include 5-fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate. Cytarabine, 4-amino-l-β-D-arabinofuranosyl-2 (lH)-pyrimidinone, is commercially available as CYTOSAR-U® and is commonly known as Ara-C. It is believed that cytarabine exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporation of cytarabine into the growing DNA chain. Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Other cytidine analogs include 5- azacytidine and 2', 2 '-difluorodeoxy cytidine (gemcitabine). Mercaptopurine, 1 ,7-dihydro-6H-purine-6-thione monohydrate, is commercially available as PURINETHOL®. Mercaptopurine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Mercaptopurine is indicated as a single agent or in combination with
other chemotherapy agents in the treatment of acute leukemia. A useful mercaptopurine analog is azathioprine. Thioguanine, 2-amino-l,7-dihydro-6H-purine-6-thione, is commercially available as TABLOID®. Thioguanine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Other purine analogs include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine. Methotrexate, N-[4[[(2,4-diamino-6-pteridinyl) methyl]methylamino] benzoyl]-L-glutamic acid, is commercially available as methotrexate sodium.
Methotrexate exhibits cell phase effects specifically at S-phase by inhibiting DNA synthesis, repair and/or replication through the inhibition of dyhydrofolic acid reductase which is required for synthesis of purine nucleotides and thymidylate. Methotrexate is indicated as a single agent or in combination with other chemotherapy agents in the treatment of choriocarconoma, meningeal leukemia, non-Hodgkin's lymphoma, and carcinomas of the breast, head, neck, ovary and bladder. Camptothecins, including, camptothecin and camptothecin derivatives are under development as Topoisomerase I inhibitors. Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity. Examples of camptothecins include, but are not limited to irinotecan and the various optical forms of 7-(4-methylpiperazino-methylene)- 10, 11 -ethylenedioxy-20-camptothecin. Irinotecan HC1, (4S)-4,1 l-diethyl-4-hydroxy-9-[(4-piperidinopiperidino) carbonyloxy]- 1 H-pyrano[3 ' ,4',6,7]indolizino[ 1 ,2-b]quinoline-3, 14(4H, 12H)-dione hydrochloride, is commercially available as the injectable solution CAMPTOSAR®. Irinotecan is a derivative of camptothecin which binds, along with its active metabolite SN-38, to the topoisomerase I - DNA complex. It is believed that cytotoxicity occurs as a result of irreparable double strand breaks caused by interaction of the topoisomerase I : DNA : irinotecan or SN-38 ternary complex with replication enzymes. Irinotecan is indicated for treatment of metastatic cancer of the colon or rectum. The dose limiting side effects of irinotecan HC1 are myelosuppression, including neutropenia, and GI effects, including diarrhea.
Also of interest, is the camptothecin derivative of formula II following, currently under development, including the racemic mixture (R,S) form as well as the R and S enantiomers:
known by the chemical name "7-(4-methylpiperazino-methylene)-10,l 1- ethylenedioxy-20(R,S)-camptothecin (racemic mixture) or "7-(4-methylpiperazino- methylene)-10,l l-ethylenedioxy-20(R)-camptothecin (R enantiomer) or "7-(4- methylpiperazino-methylene)- 10, 11 -ethylenedioxy-20(S)-camptothecin (S enantiomer). Such compound as well as related compounds are described, including methods of making, in U.S. Patent Nos. 6,063,923; 5,342,947; 5,559,235; 5,491,237 and pending U.S. patent Application No. 08/977,217 filed November 24, 1997. Usually the pharmaceutical compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection and percutaneous absorption are also envisaged. Particularly suitable compositions for oral administration are unit dosage forms such as tablets and capsules. Other fixed unit dosage forms, such as powders presented in sachets, may also be used. In accordance with conventional pharmaceutical practice the carrier may comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourant or other conventional adjuvant. Typical carriers include, for example, microcrystalline cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate, sodium lauryl sulphate or sucrose.
Suitable dosages of the vanilloid receptor antagonist include the known doses for these compounds as described or referred to in reference texts such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31 st Edition page 341 and pages cited therein) or the above mentioned publications or doses which can be determined by standard procedures. The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents. For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being
dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound. Compositions may contain from 0.1 % to 99% by weight, preferably from
10-60% by weight, of the active material, depending upon the method of administration. Compositions may, if desired, be in the form of a pack accompanied by written or printed instructions for use. The compositions are formulated according to conventional methods, such as those disclosed in standard reference texts, for example the British and US
Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.),
Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) and
Harry's Cosmeticology (Leonard Hill Books). No adverse toxicological effects are expected for the compositions or methods of the invention in the above mentioned dosage ranges.
EXAMPLES
The following abbreviations are used in the examples following as well as in other portions of the specification.
MC: carboxymethylcellulose LDH: lactate dehydrogenase γ-GTP: γ-guanocin triphosphate BUN: blood urea nitrogen
Method
Induction of nephrotoxicity Male, 5-week-old BALB/c mice (Charles River Japan) were used in this study.
Nephrotoxicity was induced by intraperitoneal administration of cisplatin at 15 mg/kg (Day 0).
Evaluation of nephrotoxicity
On Day 3, urine was collected for the analysis of urinary parameters. On Day 4, mice were bled from the abdominal aorta under anesthesia for the analysis of serum parameters. Urinary LDH, γ-GTP and creatinine levels, and serum creatinine and BUN levels were determined by the biochemical auto-analyzer for the assessment of tissue damage and dysfunction of kidney.
Experimental design
Each group consisted of 8 to 14 animals. Compound A was suspended in 1% MC solution. Compound A at 10 or 30 mg/kg or 1% MC solution was administered orally to mice 1 hour before the cisplatin treatment.
The experimental groups were set up as follows: Intact* Vehicle (1% MC solution) + cisplatin Compound A (10 mg/kg) + cisplatin Compound A (30 mg/kg) + cisplatin * Mice without the cisplatin treatment.
Results
Effects of Compound A on cisplatin-induced nephrotoxicity were shown in Table 1.
The results show that Compound A at 30 mg/kg significantly inhibited cisplatin- induced renal toxicity that was determined by the elevations of serum creatinine and BUN levels, while Compound A had no effect on the increases in urinary LDH and γ- GTP levels.
Table 1 Effects of Compound A on cisplatin-induced nephrotoxicity in mice.
Dose Route n Serum Serum Urinary Urinary γ - (mg kg) Creatinine BUN LDH GTP ( μ. mol/L) (mmol/L) (IU/g (IU/g creatinine) creatinine) Intact - - 13 7.3 8.2 128.6 345.8 -14 ±0.4 ±0.2 ± 11.9 ± 18.5 Vehicle - p.o. 13 84.9 124.3 2232.7 2052.0 -14 ± 12.4 *** ± 14.2 ±365.3 *** ±213.9 *** mm Compound 10 p.o. 8 58.9 95.1 2264.9 2465.7 A ± 13.2 ± 14.6 ±423.4 ±290.1 Compound 30 p.o. 14 45.5 78.3 2282.5 2429.2 A ±8.0 * ± 12.4 * ±367.1 ±211.6
Each data represents the mean ± SEM (n=8-14).
###p<0.001 : compared with the Intact group (Student's t-test).
*p<0.05: compared with the Vehicle group (Dunnett's multiple comparison test).
Utility of the Present Invention
The above biological data clearly shows that vanilloid antagonists, in particular VR-1 antagonist of Compound A, are useful for the treatment and/or prophylaxis of renal dysfunction (or disorders) associated with diseases, such as, diabetic nephropathy, glomerular nephritis, nephrosis, congestive heart failure, as well as renal dysfunctions (or disorders) induced by drugs, including, but not limited to, antinoeplastic agents, antibiotics, and immunosuppressants.
Claims
1. A method for the treatment and/or prophylaxis of renal dysfunction (or disorders) in humans or in non-human mammals, comprising administering an effective, non-toxic and pharmaceutically acceptable amount of a vanilloid receptor antagonist.
2. A method according to claim 1 in which the renal dysfunction is associated with diabetic nephropathy.
3. A method according to claim 1 in which the renal dysfunction is associated with glomerular nephritis.
4. A method according to claim 1 in which the renal dysfunction is associated with nephrosis.
5. A method according to claim 1 in which the renal dysfunction is associated with congestive heart failure.
6. A method according to claim 1 in which the renal dysfunction is induced by drugs.
7. A method according to claim 6 in which the drug is an antineoplastic agent.
8. A method according to claim 7 in which the antineoplastic agent is cisplatin.
9. A method according to claim 6 in which the drug is an antibiotics.
10. A method according to claim 6 in which the drug is an immunosuppressant.
11. A method according to claim 1 , wherein the vanilloid receptor antagonist is an antagonist of the vanilloid receptor- 1.
12. A method according to claim 11, wherein the vanilloid receptor- 1 antagonist is N-(2-Bromophenyl)-N '- [((R)- 1 -(5 -trifluoromethyl-2-pyridyl)pyrrolidin-3 - yl)]urea.
13. A pharmaceutical composition for the treatment and/or prophylaxis of renal dysfunction (or disorders) comprising a vanilloid antagonist, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier therefor.
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US20050004133A1 (en) * | 2003-06-05 | 2005-01-06 | Makings Lewis R. | Modulators of VR1 receptor |
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US20050004133A1 (en) * | 2003-06-05 | 2005-01-06 | Makings Lewis R. | Modulators of VR1 receptor |
Non-Patent Citations (4)
Title |
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GARCIA-MARTINEZ C. ET AL: 'Attenuation of thermal nociception and hyperalgesia by VR1 blockers' PNAS vol. 99, no. 4, 19 February 2002, pages 2374 - 2379, XP002295383 * |
GUNTHORPE M.J. ET AL: 'Identification and characterization of SB-366791, a potent selective vanilloid receptor (VR1/TRPVI) antagonist' NEUROPHARMACOLOGY vol. 46, no. 1, January 2004, pages 133 - 149, XP004639337 * |
NAGY I. ET AL: 'the role of the vanilloid (capsaicin) receptor (TRPVI) in physiology and pathology' EUROPEAN JOURNAL OF PHARMACOLOGY 500 01 October 2004, pages 351 - 369, XP004587649 * |
SZALLASI A.: 'Vanilloid Receptor Ligands: hopes and realities for the future' DRUS & AGING vol. 18, no. 8, 2001, pages 561 - 573, XP001105341 * |
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