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
  • A61K31/40—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
  • A61K31/4025—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 not condensed and containing further heterocyclic rings, e.g. cromakalim
• • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• This invention relates to organic compounds, in particular to pharmaceutical compositions for use for the delay of progression or treatment of a proliferative disease, especially a disease associated with a PAX/FKHR translocation, especially a Sarcoma, especially Alveolar Rhabdomyosarcoma.
• Esterified hydroxy is preferably lower alkanoyloxy or C ⁇ -C ⁇ arylcarbonyloxy, such as benzoyloxy.
• An aliphatic carbohydrate radical R 3 , R 4 , R 8 or R 10 with up to 29 carbon atoms which is substituted by acyclic substituents and preferably has a maximum of 18, especially a maximum of 12, and as a rule not more than 7 carbon atoms, may be saturated or unsaturated and is especially an unsubstituted or a straight-chain or branched lower alkyl, lower alkenyl, lower alkadienyl, or lower alkinyl radical substituted by acyclic substituents.
• the hydrocarbyl (hydrocarbon radical) R 0 is an acyclic (aliphatic), carbocyclic, or carbocyclic-acyclic hydrocarbon radical, with up to 29 carbon atoms each, especially up to 18, and preferably up to 12 carbon atoms, and is saturated or unsaturated, unsubstituted or substituted. Instead of one, two, or more carbon atoms, it may contain identical or different heteroatoms, such as especially oxygen, sulfur, and nitrogen in the acyclic and/or cyclic part; in the latter case, it is described as a heterocyclic radical (heterocyclyl radical) or a hetero- cyclic-acyclic radical.
• Cycloalkyl R 0 has most especially from 3 up to and including 10 carbon atoms and is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, as well as bicyclo[2,2,2]octyl, 2-bicyclo[2,2,1]heptyl, and adamantyl, which may also be substituted by 1 , 2, or more, for example lower, alkyl radicals, especially methyl radicals; cycloalkenyl is for example one of the monocyclic cycloalkyl radicals already named which carries a double bond in the 1-, 2-, or 3 position.
• An acyl derived from a phosphoric acid, esterified if necessary, which is designated Ac 3 , is especially one with the subformula R°O(R°O)P( O)-, wherein the radicals R 0 are, independently of one another, as defined in the general and specific meanings indicated above.
• Preferred acyl radicals Ac 1 are acyl radicals of a carboxylic acid which are characterised by the subformula R°-CO-, wherein R 0 has one of the above general and preferred meanings of the hydrocarbyl radical R 0 .
• Especially preferred radicals R 0 here are lower alkyl, especially methyl or ethyl, amino-lower alkyl, wherein the amino group is unprotected or protected by a conventional amino protecting group, especially by lower al- koxycarbonyl, typically tert-lower alkoxycarbonyl, for example tert-butoxycarbonyl, e.g.
• a further preferred Acyl Ac 1 is derived from monoesters of carbonic acid and is characterised by the subformula R°-O-CO-.
• the lower alkyl radicals, especially tert-butyl, are especially preferred hydrocarbyl radicals R 0 in these derivatives.
• the compounds of the invention may also be present in the form of pharmaceutically, i.e. physiologically, acceptable salts, provided they contain salt-forming groups.
• pharmaceutically unacceptable salts may also be used.
• therapeutic use only pharmaceutically acceptable salts are used, and these salts are preferred.
• compounds of formula I having free acid groups for example a free sulfo, phosphoryl or carboxyl group, may exist as a salt, preferably as a physiologically acceptable salt with a salt-forming basic component.
• R 3 , R 4 , R 8 , R 1O are independently of each other hydrogen, lower alkyl, lower alkenyl or lower alkadienyl, which are each unsubstituted or monosubstituted or polysubsituted, preferably monosubstituted or disubstituted by a substituent independently selected from lower alkyl; hydroxy; lower alkoxy, which may be unsubstituted or mono-, di-, or trisubstituted by (i) heterocyclyl with 4 to 12 ring atoms, which may be unsaturated, wholly saturated, or partly saturated, is monocyclic or bicyclic and may contain up to three heteroatoms selected from nitrogen, oxygen and sulfur, and is most especially pyrrolyl, for example 2-pyrrolyl or 3-pyrrolyl, pyridyl, for example 2-, 3- or 4-pyridyl, or in a broader sense also thienyl, for example 2- or 3-thienyl, or
• the invention provides a package comprising a compound of formula I (or pharmaceutically acceptable salt or prodrug ester thereof) together with instructions for the use for the treatment of a proliferative disease, especially a sarcoma, more especially aRMS.
• solid tumor disease comprises, but is not restricted to glioma, thyroid cancer, breast cancer, ovarian cancer, cancer of the colon and generally the Gl tract, cervix cancer, lung cancer, in particular small-cell lung cancer, and non-small-cell lung cancer, head and neck cancer, bladder cancer, cancer of the prostate, or a sarcoma such as Kaposi's sarcoma or Alveolar Rhabdomyosarcoma.
• the tumor disease to be treated is Alveolar Rhabdomyosarcoma, glioma, cancer of the prostate or thyroid cancer.
• the present composition inhibits the growth of solid tumors, but also liquid tumors. Furthermore, depending on the tumor type and the particular composition used, a decrease of the tumor volume can be obtained.
• the composition disclosed herein is also suited to prevent the metastatic spread of tumors and the growth or development of micrometastases.
• Composition B [00182]
• Antidiarrheal agents suitable for use in the inventive methods and compositions include, but are not limited to, natural opiods, such as tincture of opium, paregoric, and codeine, synthetic opioids, such as diphenoxylate, difenoxin and loperamide, bismuth subsalicylate, octreotide (e.g. available as SANDO- STATINTM), motilin antagonists and traditional antidiarrheal remedies, such as kaolin, pectin, berberine and muscarinic agents.
• natural opiods such as tincture of opium, paregoric, and codeine
• synthetic opioids such as diphenoxylate, difenoxin and loperamide, bismuth subsalicylate, octreotide (e.g. available as SANDO- STATINTM)
• motilin antagonists e.g. available as SANDO- STATINTM

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• Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Epidemiology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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• 2006
  • 2006-11-13 JP JP2008539452A patent/JP5308820B2/ja not_active Expired - Fee Related
  • 2006-11-13 WO PCT/EP2006/068410 patent/WO2007054579A1/en not_active Ceased
  • 2006-11-13 BR BRPI0618571-1A patent/BRPI0618571A2/pt not_active IP Right Cessation
  • 2006-11-13 CN CNA2006800384359A patent/CN101304749A/zh active Pending
  • 2006-11-13 CA CA2629478A patent/CA2629478C/en not_active Expired - Fee Related
  • 2006-11-13 AU AU2006313724A patent/AU2006313724B2/en not_active Ceased
  • 2006-11-13 EP EP06829981A patent/EP1951255A1/en not_active Withdrawn
  • 2006-11-13 RU RU2008123382/15A patent/RU2443421C2/ru not_active IP Right Cessation
  • 2006-11-13 KR KR1020087011406A patent/KR20080067654A/ko not_active Ceased
  • 2006-11-13 US US12/090,626 patent/US7973032B2/en not_active Expired - Fee Related

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