WO2003072043A2 - Procede de reduction des effets secondaires d'agents anticancereux - Google Patents

Procede de reduction des effets secondaires d'agents anticancereux Download PDF

Info

Publication number
WO2003072043A2
WO2003072043A2 PCT/US2003/005482 US0305482W WO03072043A2 WO 2003072043 A2 WO2003072043 A2 WO 2003072043A2 US 0305482 W US0305482 W US 0305482W WO 03072043 A2 WO03072043 A2 WO 03072043A2
Authority
WO
WIPO (PCT)
Prior art keywords
inhibitor
pde
agents
cisplatin
treatment
Prior art date
Application number
PCT/US2003/005482
Other languages
English (en)
Other versions
WO2003072043A3 (fr
Inventor
Hideo Kikkawa
Mine Kinoshita
Mariko Maeda
Akiko Mizukami
Kazunori Ozawa
Original Assignee
Smithkline Beecham Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to AU2003217669A priority Critical patent/AU2003217669A1/en
Publication of WO2003072043A2 publication Critical patent/WO2003072043A2/fr
Publication of WO2003072043A3 publication Critical patent/WO2003072043A3/fr

Links

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide

Definitions

  • the present invention relates to a method of reducing nephrotoxicity and diarrhea caused by anti-neoplastic agents in a mammal using an inhibitor of phosphodiesterase 4 (PDE 4) .
  • Cisplatin cis-diaminedichloroplatinum
  • cisplatin cis-diaminedichloroplatinum
  • cisplatin is a heavy metal complex with a central platinum atom surrounded by two ammonia molecules and two chlorine atoms in the cis position.
  • Cisplatin is typically used as a secondary therapy in combination with other chemotherapeutic agents for metastatic testicular tumors and metastatic ovarian tumors in the patients who have already received appropriate surgical or radiotherapeutic treatment.
  • Cisplatin is also used as a single agent in treating patients with transitional cell bladder cancer, which is not suited for surgical, or radiotherapeutic treatment.
  • Other uses of cisplatin include treating epithelial malignancies as well as cancers of the head and neck, the esophagus, and the lung.
  • cisplatin The major dose-limiting toxicity of cisplatin is cumulative renal insufficiency, which has been associated with renal tubular damage. Renal toxicity becomes more prolonged and more severe with repeated cisplatin treatments. Electrolyte disturbances are often secondary effects of renal damage. Hydration and diuresis are used to reduce renal toxicity, but renal damage often occurs even if these measures are taken. Other side effects of cisplatin include gastrointestinal effects such as nausea and vomiting.
  • Intracellular concentrations of cAMP can be elevated by several mechanisms, including activating surface receptors which are G-protein coupled to the cAMP generating enzyme adenylate cyclase; increasing cAMP levels by directly stimulating adenylate cyclase; by treating with a stable analog of cAMP (e.g., dibutyl cAMP or 8-bromo cAMP), or by inhibiting cyclic nucleotide phosphodiesterases (PDEs), which decreases the rate at which cAMP is catabolized to AMP.
  • a stable analog of cAMP e.g., dibutyl cAMP or 8-bromo cAMP
  • PDEs cyclic nucleotide phosphodiesterases
  • Phosphodiesterases comprise a large, divergent family of enzymes that catalyze the catabolism of cAMP and cGMP to AMP and GMP, respectively. Eleven members of this family have been identified to date based on substrate specificity, kinetic properties, sensitivity to specific inhibitors, tissue distribution, and primary sequences (Manganiello, VC et al., Arch Biochem Biophvs, 322 (1 ): 1 -1 3, (1995); Fawcett, L et al., Proc Natl Acad Sci USA. 97(7): 3702-3707 (2000)). Recognition of these differences has greatly stimulated interest in PDEs as drug targets.
  • PDE4 cAMP specific PDE
  • a method reducing nephrotoxicity and/or diarrhea side effects caused by anti-neoplastic agents in a mammal being treated with the same comprising: administering an amount effective for reducing said side effects with a phosphodiesterase 4 (PDE4 or PDEIV) inhibitor.
  • PDE4 or PDEIV phosphodiesterase 4
  • a PDE4 inhibitor in the preparation of a medicament for the reduction of nephrotoxicity and/or diarrhea caused by anti-neoplastic agents in a mammal being treated with the same anti-neoplastic agents.
  • a pharmaceutical formulation comprising a PDE4 inhibitor in an amount effective to reduce anti-neoplastic agent induced nephrotoxicity and/or diarrhea in a mammal being treated with the same anti- neoplastic agents.
  • alkyl refers to a straight or branched chain hydrocarbon having from one to twelve carbon atoms, optionally substituted with substituents selected from the group which includes, but is not limited to, Ci-C ⁇ alkyl, CI -C ⁇ alkoxy, Ci -C ⁇ alkylsulfanyl, Ci-C ⁇ alkylsulfenyl, Ci -C ⁇ alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by a substituent selected from the group including alkyl, nitro, cyano, halogen and lower perfluoroalkyi, multiple degrees of substitution being allowed.
  • substituents selected from the group which includes, but is not limited to, Ci-C ⁇ alkyl, CI -C ⁇ alkoxy, Ci -C ⁇ alkylsulfanyl, Ci-C ⁇
  • alkoxy refers to the group R a O-, where R a is alkyl.
  • aryl refers to a 6 to 10 carbon aromatic moiety.
  • examples of "aryl” as used herein include, but are not limited to, phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazyl, and triazyl.
  • aryloxy refers to the group R a O-, where R a is aryl.
  • halogen refers to the group fluorine, chlorine, bromine, and iodine.
  • neoplasm refers to an abnormal growth of cells or tissue and is understood to include benign, i.e., non-cancerous growths, and malignant, i.e., cancerous growths.
  • neoplastic means of or related to a neoplasm.
  • the term "agent” is understood to mean a substance that produces a desired effect in a tissue, system, animal, mammal (in particular human), or other subject.
  • anti-neoplastic agent is understood to mean a substance producing an anti-neoplastic effect in a tissue, system, animal, mammal (in particular human), or other subject.
  • an “agent” may be a single compound or a combination or composition of two or more compounds.
  • Some of the typical anti-neoplastic 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.
  • alkylating agents such as melphalan, chlorambucil, cyclophosphamide, mechlorethamine, hexamethylmelamine, busulfan, carmustine, lomus
  • 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, human, or other subject that is being sought by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder, and also includes amounts effective to enhance normal physiological function.
  • anti-neoplastic agents for which the present PDE4 inhibitors are useful for reducing nephrotoxicity and diahrrea 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 ⁇ -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 ⁇ ,20-epoxy-l ,2 ⁇ ,4,7 ⁇ ,10 ⁇ ,l 3 ⁇ -hexa-hydroxytax- 1 1 -en-9-one 4,10-diacetate 2-benzoate 1 3-ester with (2R,3S)-N- benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Tax us brevifolia and is commercially available as an iniectable solution TAXOL®. It is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. I. 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 lournal of Biology and Medicine. 64:583, 1991 ; McGuire et al., Ann. Intern. Med.. 1 1 1 :273.1 989) and for the treatment of breast cancer (Holmes et al., I. Nat. Cancer Inst.. 83:1 797,1 991 .) It is a potential candidate for treatment of neoplasms in the skin (Einzig et. al., Proc. Am. Soc. Gin. Oncol.. 20:46) and head and neck carcinomas (Forastire et. al., Sem. Oncol..
  • the compound also shows potential for the treatment of polycystic kidney disease (Woo et al., Nature. 368:750. 1 994), 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. 1 998) related to the duration of dosing above a threshold concentration (50nM) (Kearns, CM. et. al., Seminars in Oncology. 3(6) p.16-23, 1 995).
  • a threshold concentration 50nM
  • Docetaxel (2R,3S)- N-carboxy-3-phenylisoserine,N-fe/T- butyl ester, 1 3-ester with 5 ⁇ -20-epoxy-l ,2 ,4,7 ⁇ ,1 0 ⁇ ,l 3 ⁇ - hexahydroxytax-1 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 anti-neoplastic 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
  • VELBAN® an injectable solution.
  • testicular cancer and various lymphomas including Hodgkin's Disease; lymphocytic and histiocytic lymphomas.
  • 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 anti-neoplastic 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 anti- neoplastic 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.
  • antimetabolite anti-neoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine and thioguanine. 5-fluorouracil, 5-fluoro-2,4- (1 H.3H) pyrimidinedione, is commercially available as fluorouracil.
  • 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 (1 H)- pyrimidinone is commercially available as CYTOSAR-U® and is commonly known as Ara-C.
  • 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'-difluorodeoxycytidine (gemcitabine).
  • 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. Myelosuppresion and gastrointestinal mucositis are expected side effects of mercaptopurine at high doses.
  • 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)-l 0,1 1 -ethylenedioxy-20- camptothecin.
  • 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 : irintecan 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 HCI are myelosuppression, including neutropenia, and Gl 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: known by the chemical name "7-(4-methylpiperazino-methylene)- 1 0,1 1 -ethylenedioxy-20(R,S)-camptothecin (racemic mixture) or "7- (4-methylpiperazino-methylene)-l 0,1 1 -ethylenedioxy-20(R)- camptothecin (R enantiomer) or "7-(4-methylpiperazino-methylene)- 1 0,1 1 -ethylenedioxy-20(S)-camptothecin (S enantiomer).
  • the method of the present invention includes administering a specific PDE4 inhibitor agent.
  • PDE4 inhibitor agents include, but are not limited to, rolipram and rolipram derivatives; and fused ring compounds such as benzopyrazoles, benzimidazoles, benzofurans, diazepinio-indoles, quinolines, quinolones, nitraquazone derivatives, purines and xanthines, and losartan analogues.
  • PDE4 inhibitors are described, for instance, in "PDE4 inhibitors 1 998", Norman, Peter; Exp. Opin. Ther.
  • Ri is -(CR 4 Rs)n C(O)O(CR 4 R 5 )m Re, -(CR 4 Rs)n C(0)NR 4 (CR 4 Rs)m Re, -(CR 4 Rs)n O(CR 4 Rs)m Re, or — (CR 4 Rs)r Re wherein the alkyl moieties may be optionally substituted with one or more halogens; m is 0 to 2; n is 0 to 4; r is 0 to 6;
  • R 4 and R$ are independently selected from hydrogen or a C1-2 alkyl
  • R ⁇ is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxy C1-3 alkyl, halo substituted aryloxy C1-3 alkyl, indanyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl group; provided that: when Re is hydroxyl, then m is 2; or when Re is hydroxyl, then r is 2 to 6; or when Re is 2-tetrahydropyranyl, 2-tetrahydr
  • X is YR2, halogen, nitro, NR 4 Rs, or formyl amine; Y is O or S(O)m '; m' is 0, 1 , or 2; X 2 is O or NR 8 ; X3 is hydrogen or X; X 4 is
  • X 5 is H, R 9 , ORs, CN, C(O)R 8 , C(O)OR 8 , C(O)NR 8 Rs, or NR 8 Rs ;
  • R2 is independently selected from the group consisting of — CH3 and — CH2 CH3 optionally substituted by 1 or more halogens;
  • R2' is a hydrogen, halogen, or OR17;
  • s is 0 to 4;
  • R 3 ' and R 4 ' are each independently -(CH2) t Xe; t is 0, 1 , 2, or 3;
  • v is 0, 1 , 2, or 3;
  • X ⁇ is a mono- or bicyclic aryl group optionally containing one or more heteroatoms selected from sulfur, oxygen, or nitrogen;
  • R' and Re are each independently hydrogen or an optionally substituted alkyl
  • CRsC(O)ORs CRsC(O)ONR 8 Rs, C(-CN)NO , C(-CN)C(O)OR 9 , C(- CN)C(O)NR 8 R 8 ;
  • Z is C(Y')R 14 , C(O)ORi4, C(Y')NR ⁇ o Ri4, C(NR ⁇ o)NR 10 Ri4, CN, C(NOR 8 )Ri4, C(O)NRs NR 8 C(O)R 8 , C(0)NR 8 NR10 Ri4, C(NOR 14 )R8, C(NR 8 )NR ⁇ o Ri4, C(NR ⁇ 4 )NR 8 Rs C(NCN)NR ⁇ o Ri4, C(NCN)SRg, (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl[l ,2,3]), (3- or 5-triazolyl[l ,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5- isoxazolyl), (3- or 5-oxadiazolyl[l ,2,4]), (2oxadiazolyl[l ,3,4]), (2- thiadiazolyl[
  • R7 is — (CR 4 R5)q R12 or C ⁇ -6 alkyl wherein the Ri2 or C1-6 alkyl group is optionally substituted one or more times by C ⁇ -2 alkyl optionally substituted by one to three fluorines, — F, — Br, — Cl, — NO2, — NR10 R11 , — C(O)R 8 , — C(O)OR 8 , —ORs, — CN, — C(O)NR ⁇ o Rn , - -OC(O)NR ⁇ o Rn , — OC(O)R 8 , — NR10 C(O)NR ⁇ o Rn , — NRio C(O)R 1 1 ( — NRio C (0)OR 9 , — NRio C(O)R 13 , — C(NR 10 )NR 10 Rn , — C(NCN)NR ⁇ o Rn , — C(NCN)SRg, --NRio C
  • R12 is C3 -C7 -cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1 - or 2-imidazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), (4- or 5-thiazolyl), quinolinyl, naphthyl, or phenyl; R 8 is independently selected from hydrogen or R9 ;
  • Rg is C1-4 alkyl optionally substituted by one to three fluorines
  • Rn is hydrogen, or C1-4 alkyl optionally substituted by one to three fluorines; or when Rio and Rn are as NRio Rn they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O/N/or S;
  • Ri3 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two C1-2 alkyl groups;
  • Ri4 is hydrogen or R7 ; or when Rio and R14 are as NRio R14 they may together with the nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from O, N, or S;
  • Ri5 is optionally substituted pyridyl, pyrazinyl, pyrimidinyl, isoxazolyl; or an N-oxide thereof; or a optionally substituted phenyl, wherein s optional substituents are one or more selected from the group consisting of halogen, haloalkyi, aryl, arylalkyi, alkoxy, aryloxy, alkylthio, arylthio, alkoxycarbonyl, alkanoyl, aroyl, alkylsulphonyl, arylsulphonyl, alkylsulphinyl, arylsulphinyl, hydroxy, hydroxyalkyl, formyl, alkanoylamino, aroylamino, cyano, and nitro;
  • Ri6 is amino, Ci-Ce alkylamino, arylamino, Ci-C ⁇ alkoxy, or aryloxy;
  • R17 is hydrogen, or optionally substituted alkyl, alkenyl, alkoxyalkyl, or alkanoyl, or a formyl, carboxamido, or thiocarboxamido;
  • PDEIV inhibitors of Formula I are c/ -4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-l - carboxylic acid and 4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l -one (SB 200473) and salt thereof.
  • the first compound compound has the trademark of ARIFLO, represented by Figure 9(a) of WO 01 /93909.
  • the second compound is described in Example 1 of US 5,643,946.
  • Other compounds within the scope of Formula I are also described in WO 01 /93909 and/or US5,643,946.
  • Still another group of Formula I PDE4 inhibitor compounds that can be usefully employed in the process of the present invention includes (+/-)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl) ⁇ 2- phenylethyl]pyridine (CDP-840), represented by Figure 10(b) of WO 01 /93909, and related compounds. These compounds are described, as well as the synthesis thereof, in International Patent Applications WO 94/14742; 97/23460; 97/23461 ; 97/38976; 97/421 72; and 98/1 21 78.
  • PDE4 inhibitors which can be utilized in the present invention include: (i) nitroquazone, depicted in Figure 1 1 (a) of WO 01 /93909, and nitraquazone derivatives, such compounds being described in WO 93/07146 including the synthesis thereof;
  • the PDE4 inhibitor agent is a compound of Formula I
  • the PDE4 inhibitor is c/s-4-cyano- 4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-l -carboxylic acid or salt thereof; N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4- methoxybenzamide; 1 -[3-cyclopentyloxy)-4-methoxyphenyl] ethanone (E)-O- ⁇ aminocarbonyl ⁇ oxime; (+/-)-4-[2-(3- cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine; SB200473; or rofluminast.
  • the preferred PDEIV inhibitors of the present invention are PDEIV specific inhibitors.
  • PDEIV specific inhibitors they are meant that activities of inhibitors against PDE IV enzyme is at least 400 times or more potent in terms of ICso as compared to activities against other PDE isoenzymes, e.g. PDE I, II, III, or V.
  • activities of rofluminast, rolipram and cilomilast (ARIFLO) against PDE IV are more than 400 times potent against PDE I, II, III and V. ( see: J Pharmacol Exp Ther 2001 Apr;297(l ):267-79).
  • PDE4 inhibitors to reduce anti-neoplastic agents induced sides effects are not only limited to the human use, but to a veterinary use as well. However, it is well understood that the effectiveness of a particular PDE4 inhibitor in a particular species is limited, such as, by its bioavailability in that species. Which PDE4 inhibitor is more effective in a particular species can be readily ascertained by conventional pharmacological methods.
  • the anti-neoplastic agent and the PDE4 inhibitor may be employed in combination in accordance with the invention by administration concomitantly in (1 ) a unitary pharmaceutical composition including both compounds or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein the PDE4 inhibitor or anti-neoplastic agent is administered first and the other second. Such sequential administration may be close in time or remote in time.
  • the PDE4 inhibitor is administered first and the anti-neoplastic agent is subsequently administered within a time period suitable to achieve the desired therapeutic effect.
  • the present method of using PDEIV inhibitors to reduce anti- neoplastic agent induced diarrhea and nephrotoxicity is applicable in any situations when anti-neoplastic agents are being administered to treat cancers or tumors.
  • tumors or cancers being treated are those of solid malignancies, notably those of the bladder, cervix, lung, ovary, and testis such as testicular tumor; bladder cancer; ureterpyelonephritic tumor; prostatic cancer; ovarian cancer; head and neck cancer; non-small-cell lung cancer; esophageal cancer; cervical cancer; neuroblastoma; gastric cancer; small cell lung cancer; bone cancer; non-Hodgkin's lymphomas; tumours of brain, endometrium, upper gastrointestinal tract, head and neck, and thymus; neuroblastoma; and sarcoma of bone and soft tissue.
  • the PDE4 inhibitor of the present invention may be administered by any appropriate route. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intraveneous, intradermal, intrathecal, and epidural). It will be appreciated that the preferred route may vary with, for example, the condition of the recipient.
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non- aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
  • Capsules are made by preparing a powder mixture as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be combined with free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided.
  • Dyestuffs can be added to these coatings to distinguish different unit dosages.
  • Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a non- toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding paniculate material in polymers, wax or the like.
  • the agents for use according to the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 31 8 (1 986).
  • compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting a free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base.
  • a pharmaceutical combination including an anti-neoplastic agent and a PDE4 inhibitor.
  • the therapeutically effective amount of a PDE4 inhibitor of the present invention will depend upon a number of factors including, for example, the age and weight of the mammal, the precise condition requiring treatment, the severity of the condition, the nature of the formulation, and the route of administration. Ultimately, the therapeutically effective amount will be at the discretion of the attendant physician or veterinarian.
  • the anti-neoplastic agent will be given in the range of 0.1 to 1 00 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 1 0 mg/kg body weight per day.
  • Acceptable daily dosages of the PDE4 inhibitor for preventing/reducing the severity of side effects induced by administration of a phase specific anti-neoplastic agent may be from about 0.1 to about 1000 mg/day, and preferably from about 0.2 to about 1 00 mg/day.
  • PDE4 inhibitors PDE4 inhibitors, rolipram (TOCRIS, USA), roflumilast (and SB200473, were suspended in 1 % CMC-Na/water solution with a sonicator and utilized in the following examples.
  • Cisplatin-induced nephrotoxicity was assessed by both rise in serum creatinine and BUN levels that reflect renal dysfunction and increased excretion of urinary LDH and ⁇ -GTP that exhibit renal tissue damage. Prevention of cisplatin-induced nephrotoxicity was shown by suppression of such increase in those serum and urinary parameters. Prevention of diarrhea caused by cisplatin treatment was inhibition of diarrheal fecal condition. Intraperitoneal treatment of the mice with 1 5 mg/kg of cisplatin induced rises in serum creatinine and BUN levels and urinary LDH and ⁇ -GTP excretion. At the same time, cisplatin treatment also caused diarrhea. In Examples 2 and 3, PDE4 inhibitors were tested for their ability to inhibit cisplatin-induced nephrotoxicity and diarrhea, respectively.
  • mice Male BALB/c mice, 5 weeks of age, were used for the experiment. PDE4 inhibitors suspended in ⁇ % CMC-Na/water (vehicle) were orally administered to the mice at the doses of 1 -10 mg/kg (rolipram and roflumilast) or 30-300 mg/kg (SB200473) 1 hour prior to the cisplatin treatment. The control group was administered with the vehicle. Then, the mice were intraperitoneally treated with cisplatin at 1 5 mg/kg (Day 0). The urine was collected on Day 3 for analysis of urinary parameters.
  • PDE4 inhibitors suspended in ⁇ % CMC-Na/water were orally administered to the mice at the doses of 1 -10 mg/kg (rolipram and roflumilast) or 30-300 mg/kg (SB200473) 1 hour prior to the cisplatin treatment.
  • the control group was administered with the vehicle. Then, the mice were intraperitoneally treated with cisplatin at 1
  • mice On Day 4, the mice were bled from the abdominal vein under anesthesia for analysis of serum parameters. Urinary LDH, ⁇ -GTP and creatinine levels and the concentrations of serum BUN and creatinine were determined with a biochemical auto- analyzer for assessment of the tissue damage and dysfunction of kidney. All the groups consisted of 6 animals (Ishikawa, M. et al., (1 993), Biol. Farm. Bull 1 6:1 104-1 1 07).
  • **p ⁇ 0.01 compared with Vehicle (Dunnett's multiple comparison test).
  • mice Male BALB/c mice, 5 weeks of age, were used for the experiment.
  • PDE4 inhibitors suspended in ⁇ % CMC-Na/water (vehicle) was orally administered to the mice at at the doses of 1 -10 mg/kg (rolipram and roflumilast) or 30-300 mg/kg (SB200473) 1 hour prior to the cisplatin treatment.
  • the control group was administered with the vehicle.
  • the mice were intraperitoneally treated with cisplatin at 1 5 mg/kg (Day 0).
  • mice Oral treatment of the mice with PDE4 inhibitors dose- dependently prevented cisplatin-induced diarrhea (Table 3 and 4).
  • Table 3 Effects of rolipram and roflumilast on cisplatin-induced diarrhea in mice.

Abstract

L'invention concerne un procédé de réduction de la néphrotoxicité et des diarrhées causées, chez un mammifère, par des agents anticancéreux, à l'aide d'un inhibiteur de phosphodiestérase 4 (PDE4).
PCT/US2003/005482 2002-02-25 2003-02-21 Procede de reduction des effets secondaires d'agents anticancereux WO2003072043A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003217669A AU2003217669A1 (en) 2002-02-25 2003-02-21 A method of recuding anti-neoplastic agent induced side effects

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US35934602P 2002-02-25 2002-02-25
US60/359,346 2002-02-25

Publications (2)

Publication Number Publication Date
WO2003072043A2 true WO2003072043A2 (fr) 2003-09-04
WO2003072043A3 WO2003072043A3 (fr) 2004-03-04

Family

ID=27766068

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2003/005482 WO2003072043A2 (fr) 2002-02-25 2003-02-21 Procede de reduction des effets secondaires d'agents anticancereux

Country Status (2)

Country Link
AU (1) AU2003217669A1 (fr)
WO (1) WO2003072043A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2114147A2 (fr) * 2007-02-12 2009-11-11 DMI Biosciences, Inc. Réduction des effets secondaires du tramadol
CN109908139A (zh) * 2018-12-28 2019-06-21 南京市儿童医院 西洛司特在制备用于治疗急性肾损伤相关病症的药物中的用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6156753A (en) * 1997-10-28 2000-12-05 Vivus, Inc. Local administration of type III phosphodiesterase inhibitors for the treatment of erectile dysfunction

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6156753A (en) * 1997-10-28 2000-12-05 Vivus, Inc. Local administration of type III phosphodiesterase inhibitors for the treatment of erectile dysfunction

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2114147A2 (fr) * 2007-02-12 2009-11-11 DMI Biosciences, Inc. Réduction des effets secondaires du tramadol
EP2114147A4 (fr) * 2007-02-12 2010-04-07 Dmi Biosciences Inc Réduction des effets secondaires du tramadol
EP2486921A1 (fr) * 2007-02-12 2012-08-15 DMI Biosciences, Inc. Réduciton Des Effets Secondaires Du Tramadol
CN109908139A (zh) * 2018-12-28 2019-06-21 南京市儿童医院 西洛司特在制备用于治疗急性肾损伤相关病症的药物中的用途

Also Published As

Publication number Publication date
AU2003217669A8 (en) 2003-09-09
AU2003217669A1 (en) 2003-09-09
WO2003072043A3 (fr) 2004-03-04

Similar Documents

Publication Publication Date Title
JP6621501B2 (ja) 新規癌治療法としてのアリール炭化水素受容体（ＡｈＲ）改変物質
AU2002210993B2 (en) Medicinal compositions for concominant use as anticancer agents
CN103997894B (zh) 乳癌的治疗
JP2020521741A (ja) がんの処置のための化合物およびその使用の方法
JP2022088616A (ja) 再発性神経膠腫および進行性の二次性脳腫瘍からなる群から選択される悪性腫瘍の治療に使用するための薬剤の調製方法
EP1289557B1 (fr) Composition pour le traitement du cancer comprenant un agent anti-neoplastique et un inhibiteur de pde4
TW201306842A (zh) 使用ｐｉ３ｋ／ｍｔｏｒ吡啶並嘧啶酮抑制劑及苯達莫司汀及／或利妥昔單抗治療惡性血液疾病之組合療法
TW201210592A (en) Substituted 5-fluoro-1H-pyrazolopyridines and their use
EA020589B1 (ru) Противораковая комбинация
TW200803842A (en) Antineoplastic combinations of temsirolimus and sunitinib malate
US11795160B2 (en) Kinase inhibitors
EP1968981B1 (fr) Azaxanthones et leurs utilisations dans le traitement de tumeurs
TW202133856A (zh) 涉及二芳基巨環化合物之組合療法
WO2002045717A1 (fr) Polytherapie a base de lometrexol
KR101797415B1 (ko) 암의 치료를 위한 아푸레세르팁과 조합된 엔잘루타미드
TW202023563A (zh) 新穎喹唑啉egfr抑制劑
JP2014534238A (ja) 癌を治療するためのビス（チオヒドラジドアミド）化合物の投与
US20090203719A1 (en) Enhancing treatment of mdr cancer with adenosine a3 antagonists
MXPA06014477A (es) Agente antitumor, fortificador de efecto antitumor y metodo de terapia para cancer.
WO2003072043A2 (fr) Procede de reduction des effets secondaires d'agents anticancereux
US20030171306A1 (en) Cancer treatment method
US10624897B2 (en) Chlorobenzene substituted azaaryl compounds
US8410096B2 (en) Antitumor agent, kit and method of treating cancer
WO2005034873A2 (fr) Methode de diminution des effets secondaires induits par un agent anti-neoplasique
Sands et al. Preclinical activity of an iv formulation of rubitecan in IDD-P™ against human solid tumor xenografts

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

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

AL Designated countries for regional patents

Kind code of ref document: A2

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

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

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP