WO2006040281A1 - Thiazolyl-dihydro-indazole - Google Patents
Thiazolyl-dihydro-indazole Download PDFInfo
- Publication number
- WO2006040281A1 WO2006040281A1 PCT/EP2005/055021 EP2005055021W WO2006040281A1 WO 2006040281 A1 WO2006040281 A1 WO 2006040281A1 EP 2005055021 W EP2005055021 W EP 2005055021W WO 2006040281 A1 WO2006040281 A1 WO 2006040281A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- mmol
- membered
- group
- compounds
- alkyl
- Prior art date
Links
- IUKWKFSDLUSHFA-UHFFFAOYSA-N CC(N(C)c(cc1)ccc1NN)=O Chemical compound CC(N(C)c(cc1)ccc1NN)=O IUKWKFSDLUSHFA-UHFFFAOYSA-N 0.000 description 1
- JIROZRAFAWBHRQ-UHFFFAOYSA-N CC(Nc1nc(CCC(C(c2cnccc2)=O)C2=O)c2[s]1)=O Chemical compound CC(Nc1nc(CCC(C(c2cnccc2)=O)C2=O)c2[s]1)=O JIROZRAFAWBHRQ-UHFFFAOYSA-N 0.000 description 1
- GDSFAFQELMLXRK-UHFFFAOYSA-N CC(Nc1nc(CCc2c-3[n](-c(c(Cl)c4)ccc4C(O)=O)nc2-c2ccc[o]2)c-3[s]1)=O Chemical compound CC(Nc1nc(CCc2c-3[n](-c(c(Cl)c4)ccc4C(O)=O)nc2-c2ccc[o]2)c-3[s]1)=O GDSFAFQELMLXRK-UHFFFAOYSA-N 0.000 description 1
- ZCASTWZRGYZMMI-UHFFFAOYSA-N CC(Nc1nc(CCc2c-3[n](-c(c(Cl)c4)ccc4N)nc2-c2cnccc2)c-3[s]1)=O Chemical compound CC(Nc1nc(CCc2c-3[n](-c(c(Cl)c4)ccc4N)nc2-c2cnccc2)c-3[s]1)=O ZCASTWZRGYZMMI-UHFFFAOYSA-N 0.000 description 1
- BMOOANKYAHWFDG-UHFFFAOYSA-N CN(C)C(c(cc1F)ccc1-[n](c-1c2CCc3c-1[s]c(N)n3)nc2-c1cnccc1)=O Chemical compound CN(C)C(c(cc1F)ccc1-[n](c-1c2CCc3c-1[s]c(N)n3)nc2-c1cnccc1)=O BMOOANKYAHWFDG-UHFFFAOYSA-N 0.000 description 1
- FQRZYAIZMAZFMR-UHFFFAOYSA-N NNc1cc(I)ccc1 Chemical compound NNc1cc(I)ccc1 FQRZYAIZMAZFMR-UHFFFAOYSA-N 0.000 description 1
- MVXRYZFHCLZGSJ-UHFFFAOYSA-N NNc1ccc(CO)cc1Cl Chemical compound NNc1ccc(CO)cc1Cl MVXRYZFHCLZGSJ-UHFFFAOYSA-N 0.000 description 1
- QGLIRKPCVTUTII-AOOOYVTPSA-N OC([C@H](CC1)CC[C@H]1N1CCCC1)=O Chemical compound OC([C@H](CC1)CC[C@H]1N1CCCC1)=O QGLIRKPCVTUTII-AOOOYVTPSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/82—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/84—Naphthothiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Definitions
- the present invention relates to novel thiazolyl-dihydro-indazoles of the general formula (1)
- radicals R 1 to R 3 have the meanings mentioned in the claims and the description, their isomers, processes for the preparation of these thiazolyl-dihydro-indazoles and their use as medicaments.
- Phosphorylation of proteins and lipids is an important cellular regulatory mechanism involved in multiple biological processes, such as e.g. Cell proliferation, differentiation, apoptosis, metabolism, inflammation, immune responses and angiogenesis plays a role.
- kinases In the human genome over 500 kinases are encoded. Tyrosine protein kinases are generally transmitted through
- Serine / threonine protein kinases mostly phosphorylate proteins that cross-link and amplify intracellular signals. Lipid kinases are also important switches of intracellular signaling pathways linking diverse biological processes.
- Phosphatidylinositol-3 kinases are a subfamily of lipid kinases that catalyze the transfer of a phosphate moiety to the 3 'position of the inositol ring of phosphoinositides. They play an important role in numerous cellular processes such as cell growth and differentiation processes, the control of cytoskeletal changes and the regulation of intracellular transport processes.
- the PI3 kinases Due to their in vitro specificity for certain phosphoinositide substrates, the PI3 kinases can be divided into different classes.
- the PI3 kinase ⁇ , ⁇ and ⁇ are mainly activated by receptor tyrosine kinases (RTKs) or soluble tyrosine kinases.
- PI3 kinase ⁇ (class IB) is primarily activated by G ⁇ subunits released from heterotrimeric G proteins upon activation of heptahelical receptors. This different coupling to cell surface receptors in combination with a more or less restrictive expression inevitably results in very different tasks and functions of the 4 class I PI3 kinases in the intact organism.
- PI3 kinase activity was associated with the transforming activity of viral oncogenes, such as the middle T antigen of polyomaviruses, Src tyrosine kinases or activated growth factors (Workman, Biochem Soc Trans. 2004; 32 (Pt 2): 393-6 ).
- viral oncogenes such as the middle T antigen of polyomaviruses, Src tyrosine kinases or activated growth factors (Workman, Biochem Soc Trans. 2004; 32 (Pt 2): 393-6 ).
- tumors such as breast cancer, ovarian or pancreatic carcinoma one finds an overactivity of Akt / PKB, which is activated directly by the lipid products of class I PI3 kinases and thus passes the signals into the cell.
- the PIK3CA gene coding for the PI 10K subunit of PI3K ⁇ has a high mutation frequency in several tumor types, such as colon, mammary or lung carcinomas, some of which are representative as activating mutations (Samuels et al., Science 2004; 304 (5670): 554).
- tumor types such as colon, mammary or lung carcinomas, some of which are representative as activating mutations (Samuels et al., Science 2004; 304 (5670): 554).
- compounds of the general formula (1) in which the radicals R 1 to R 3 have the meanings mentioned below act as inhibitors of specific cell cycle kinases.
- the compounds of the present invention can be used to treat diseases related to the activity of specific cell cycle kinases and characterized by excessive or abnormal cell proliferation.
- the present invention relates to compounds of the general formula (1)
- R 1 is selected from the group consisting of -NHR C , -NHC (O) R 0 , -NHC (O) OR 0 , -NHC (O) NR 0 R 0, and -NHC (O) SR 0 ;
- R 2 is a radical optionally substituted with one or more R 4 selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl;
- R 3 is a radical optionally substituted by one or more R ° and / or R f radical selected from the group consisting of C 6-10 aryl and 5-10 membered heteroaryl;
- R 4 is a radical selected from the group consisting of R a , R b and R a substituted with one or more, identical or different R ° and / or R b ;
- each R a is independently selected from the group consisting of C 1-6 alkyl
- each R ° is independently hydrogen or a radical which is optionally substituted by one or more, identical or different R d and / or R ° selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl,
- each R d independently of one another represents hydrogen or a radical optionally substituted by one or more, identical or different R ° and / or R f, selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl,
- each R g is independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4 -14-membered heterocycloalkyl, 5-10 membered heteroaryl and 6- 16 membered heteroarylalkyl, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts.
- R 3 is a radical selected from the group consisting of phenyl, furyl, pyridyl, pyrimidinyl and pyrazinyl, optionally substituted with one or more R 4 .
- Another aspect of the invention are compounds of the general formula (1) wherein R 3 is pyridyl.
- Another aspect of the invention are compounds of the general formula (1) wherein R 1 is NHC (O) R 0 .
- Another aspect of the invention are compounds of general formula (1) wherein R 1 is -NHC (O) CH 3 .
- One aspect of the invention are compounds of the formula (A) in which
- X is -CH 3 , -OR 4 or -SR 4 and
- Y is phenyl, 5-10 membered heteroaryl or the group -C (O) O and R y is hydrogen, -NO 2 or C 1-6 alkyl and R 4 is as defined above.
- Another aspect of the invention are compounds of general formula (A) wherein R 4 is - C 1-6 alkyl.
- Another aspect of the invention is the use of compounds of formula (A) as synthesis intermediates.
- One aspect of the invention are compounds of the general formula (1), or their pharmaceutically active salts, as medicaments.
- One aspect of the invention is the use of compounds of general formula (1), or their pharmaceutically active salts, for the preparation of a medicament having an antiproliferative action.
- One aspect of the invention is a pharmaceutical preparation containing as active ingredient one or more compounds of general formula (1), or their physiologically tolerated salts, optionally in combination with customary excipients and / or carriers.
- Another aspect of the invention is the use of compounds of general formula (1) for the manufacture of a medicament for the treatment and / or prevention of cancer.
- One aspect of the invention is a pharmaceutical preparation comprising a compound of general formula (1) and at least one further cytostatic or cytotoxic active ingredient other than formula (1), optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures , and optionally their pharmacologically acceptable acid addition salts.
- Alkyl substituents are in each case saturated, unsaturated, straight-chain or branched aliphatic hydrocarbon radicals (alkyl radical) and include both saturated alkyl radicals and also unsaturated alkenyl and alkynyl radicals.
- Alkenyl substituents are each straight-chain or branched, unsaturated alkyl radicals which have at least one double bond.
- Alkynyl substituents are to be understood as meaning in each case straight-chain or branched, unsaturated alkyl radicals which have at least one triple bond.
- Heteroalkyl represents straight-chain or branched aliphatic hydrocarbon chains which are interrupted by 1 to 3 heteroatoms, wherein each of the available carbon and nitrogen atoms in the heteroalkyl chain may optionally each be independently substituted and the heteroatoms are each independently selected from the group consisting of O, N and S (e.g., dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminomethyl, diethylaminoethyl, diethylaminopropyl, 2-disopropylaminoethyl, bis-2-methoxyethylamino, [2- (dimethylaminoethyl) ethylamino] methyl, 3- [2 - (dimethylamino-ethyl) -ethyl-amino] -propyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, methoxy, ethoxy, prop
- Haloalkyl refers to alkyl radicals in which one or more hydrogen atoms are replaced by halogen atoms.
- Halogen refers to fluorine, chlorine, bromine and / or iodine atoms.
- Cycloalkyl is a monocyclic or bicyclic ring, it being possible for the ring system to be a saturated ring but also an unsaturated, nonaromatic ring which may optionally also contain double bonds, for example cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, Cyclohexyl, cyclohexenyl, norbornyl and norbornenyl.
- Cycloalkylalkyl includes a non-cyclic alkyl group in which a hydrogen atom bonded to a carbon atom, usually at a terminal carbon atom, is replaced by a cycloalkyl group.
- Aryl refers to monocyclic or bicyclic rings of 6-12 carbon atoms such as phenyl and naphthyl.
- Arylalkyl includes a non-cyclic alkyl group in which a hydrogen atom attached to a carbon atom, usually at a terminal C atom, is replaced by an aryl group.
- Heteroaryl is to be understood as meaning monocyclic or bicyclic rings which, instead of one or more carbon atoms, contain one or more identical or different heteroatoms, for example nitrogen, sulfur or oxygen atoms.
- Examples which may be mentioned are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and triazinyl.
- bicyclic heteroaryl radicals are indolyl, isoindolyl, benzo-furyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl and benzotriazinyl, indolizinyl, Oxazolopyridyl, imidazopyridyl, naphthyridinyl, indolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, IsobenzotetrahydroFuryl, Isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl,
- Triazolyl-iV-oxide Triazolyl-iV-oxide, tetrazolyl-iV-oxide, benzothiopyranyl-5-oxide and benzothiopyranyl- ⁇ S-dioxide.
- Heteroarylalkyl includes a non-cyclic alkyl group in which a hydrogen atom bonded to a carbon atom, usually at a terminal carbon atom, is replaced by a heteroaryl group.
- Heterocycloalkyl refers to saturated or unsaturated, non-aromatic, mono-, bicyclic or bridged bicyclic rings containing 3-12 carbon atoms which carry, instead of one or more carbon atoms, heteroatoms such as nitrogen, oxygen or sulfur.
- heterocycloalkyl radicals are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomethylholinyl-5'-oxide, thiomethylholinyl-5 ' , 1 S 'dioxide,
- Heterocycloalkylalkyl refers to a non-cyclic alkyl group in which a hydrogen atom bonded to a carbon atom, usually at a terminal carbon atom, is replaced by a heterocycloalkyl group.
- R-Ia (5 g, 18 mmol) is dissolved in 20 mL of JV, JV-dimethylacetamide and added to a suspension of sodium hydride (60% in paraffin oil, 0.8 g, 20 mmol) in 20 mL of JV, JV-dimethylacetamide at 37 ° C given so that the temperature does not exceed 48 ° C.
- methyl iodide (2.9 g, 20 mmol) is added and the mixture is stirred at RT for 10 min.
- the reaction mixture is treated with ethyl acetate and washed with water. Subsequently, the organic phase is treated with oxalic acid and washed with ethyl acetate.
- R-7a (34 g, 0.1 mol) is dissolved in 750 mL of morpholine, with a catalytic amount
- Methyl 4-amino-3-methyl-benzoate (10 g, 61 mmol) is combined with 50 mL conc. Hydrochloric acid and cooled to -15 ° C. A solution of sodium nitrite (6.3 g, 91 mmol) in 50 mL water is added dropwise so that the temperature does not exceed -5 ° C. After 4 h stirring at -10 ° C to the suspension, a solution of tin (II) chloride dihydrate in 50 mL conc. Hydrochloric acid added dropwise, the reaction temperature does not exceed -5 ° C. The viscous suspension is stirred for 15 h at RT, before being adjusted to pH 14 with 200 mL sodium hydroxide (10 N).
- the desired compound is obtained starting from 3-aminophenylacetic acid (2 g, 13.2 mmol), sodium nitrite (0.91 g, 13.2 mmol) and tin (II) chloride dihydrate (6.1 g, 26.4 mmol).
- Z-IO Analogously to the preparation of Z-7, 52 g of Z-IO are obtained from 40 g (190 mmol) of Z-6, 38 g (0.7 mol) of sodium methylate and 84 g (0.7 mol) of dimethyl oxalate.
- a solution of 1-8 (1.5 g, 3.3 mmol) in 150 ml of ammoniacal methanol is mixed with 20 mg of Raney nickel and stirred for 15 h under a hydrogen atmosphere (3.5 bar) at RT.
- the mixture is taken up in dichloromethane and filtered through silica gel. After removal of the solvent in vacuo, the residue is crystallized from diethyl ether / petroleum ether.
- Example 2.182 (1.37 g, 2.9 mmol) with 30 mL hydrochloric acid (37%) and 35 mL water and heated at 50 ° C for 12 h. After concentration in vacuo, the residue is taken up in water and treated with 4 N sodium hydroxide solution. The resulting precipitate is filtered and dried. Yield: 1.1 g
- Example 11-16 Analogously to the preparation of Example 11-16, starting from 1-46 (10.3 g, 24 mmol), 280 ml of hydrochloric acid (37%) in 330 ml of water, the desired product is obtained. Yield: 7.6 g
- HPLC Agilent 1100 Series
- MS 1100 Series LC / MSD (API-ES (+/- 3000V, quadrupole, G1946D); Mode: Scan pos 100-1000, neg 100-1000
- Solvent A: H 2 O desalted with 0.1% formic acid added
- Method AM2 HPLC Agilent Series 1100 (G1379A / G1310A converted to G1311A / G1313A / G1316A / G1948D / G1315B / G1946D) Mode: Scan pos 100-1000, neg 100-1000 Column: Agilent Zorbax SB-C8, 2.1x50 mm, 3.5 ⁇ m
- Solvent A: H 2 O desalted with 0.1% formic acid additive
- Solvent A H 2 O desalted with 0.1% formic acid added
- Range step 1.00 nm
- Threshold 4.00 mAU
- MS Positive and negative Mass ranks: 120 - 900 m / z Fragmentor: 120
- Range step 1.00 nm
- Threshold 4.00 mAU
- Solvent A H 2 O desalted with 0.1% formic acid added
- the carboxylic acid is first immobilized on a polymer.
- a polymer For this purpose, 1.2 g PL-TFP resin (1.25 mmol / g, 150-300 ⁇ m, Polymer Laboratories) are mixed with 12 mL dichloromethane and 5 minutes later the corresponding carboxylic acid (1.2 mmol in 6 mL DMF), DMAP (0.7 mmol in 6 mL dichloromethane) and 0.8 mL diisopropylcarbodiimide. The batch is allowed to stand at RT for 36 h.
- the resin is filtered through a glass frit (porosity 4) and washed 4 times with 15 mL DMF, 4 x with 20 mL dichloromethane, and 4 x with 20 mL THF, whereby the solvent drips through the glass frit without vacuum / pressure and is sucked dry before each new solvent task.
- the washed resin is dried for 2 d at RT and 0.2 mbar. Yield of dry resin: 2,204 g
- Example 2.18 the reaction of the carboxylic acid with (2-amino-cyclopropyl) -carbamic acid tert-butyl ester.
- the removal of the BOC protective group takes place with trifluoroacetic acid.
- a solution of 0.11 mmol thiocarbamate (or methyl carbamate) is mixed with 5 mL of the corresponding alcohol and stirred for 15 h at 80 ° C in a pressure tube.
- Example II-2 Analogously to the synthesis of Example II-2, the following compounds are prepared.
- HCTI 16 Cytotoxicity Test The test is based on the reduction of AlamarBlue (Biosource Int., USA) in live (metabolically active) cells to a fluorometrically detectable product. In the presence of cytotoxic substances, the substrate can not be reduced, so that no increase in fluorescence is measurable.
- HCTI 16 human colon carcinoma cell line
- the test substances are diluted in medium step by step and added to the cells so that the total volume is 200 ⁇ L / well.
- the controls used are cells which are mixed with medium but not with substance. After an incubation period of 4 to 6 days, add 20 ⁇ L / well of AlamarBlue and incubate the cells for a further 6-8 h at 37 ° C.
- fluorescence measurement is excited at a wavelength of 545 nm and measured at 590 nm, the emission.
- the substances of the present invention are PI3 kinase inhibitors. Because of their biological properties, the novel compounds of the general formula (1), their isomers and their physiologically tolerated salts are suitable for the treatment of diseases characterized by excessive or abnormal cell proliferation.
- Such diseases include, for example: viral infections (e.g., HIV and Kaposi sarcoma); Inflammation and autoimmune diseases (e.g., colitis, arthritis, Alzheimer's disease, glomerulonephritis, and wound healing); bacterial, fungal and / or parasitic infections; Leukemias, lymphomas and solid tumors; Skin disorders (e.g., psoriasis); Bone diseases; cardiovascular diseases
- the following cancers may be treated with compounds of the present invention: brain tumors such as acoustic neuroma, astrocytomas such as pilocytic astrocytomas, fibrillar astrocytoma, protoplasmic astrocytoma, gemocytic astrocytoma, anaplastic astrocytoma and glioblastoma, brain lymphoma, brain metastasis, pituitary tumor such as prolactinoma, HGH (human growth hormone) producing tumor and ACTH producing tumor (adrenocorticotropic hormone), craniopharyngioma,
- astrocytomas such as pilocytic astrocytomas, fibrillar astrocytoma, protoplasmic astrocytoma, gemocytic astrocytoma, anaplastic astrocytoma and glioblastoma
- brain lymphoma brain metastasis
- pituitary tumor such as prolactinoma, HGH (
- Nerve tumors such as tumors of the autonomic nervous system such as neuroblastoma sympathicum, ganglioneuroma, paraganglioma (pheochromocytoma, chromaffinoma) and carotid tumor, peripheral nervous system tumors such as amputation neuroma, neurofibroma, neuroma (neurilemmoma, schwannoma) and malignant schwannoma, and Tumors on the central nervous system as brain and spinal cord tumors; Colon cancer such as rectal cancer, colon carcinoma, anal carcinoma, small intestinal tumors and duodenal tumors; Eyelid tumors such as basal cell carcinoma or basal cell carcinoma; Pancreatic cancer or pancreatic carcinoma; Bladder cancer or bladder carcinoma; Lung cancer (bronchial carcinoma) such as small cell lung carcinoma (oat cell carcinoma) and non-small cell lung carcinoma such as squamous cell
- novel compounds may also be used, if appropriate, in combination with others for the prevention, short-term or long-term treatment of the abovementioned diseases "State-of-art” compounds, such as other anti-tumor substances, cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids or antibodies, can be used.
- Chemotherapeutics which may be administered in combination with the compounds of the present invention include, but are not limited to, hormones, hormone analogs and antihormones (eg tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, Buserelin acetate, fludrocortinson, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (eg, anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane,), LHRH agonists and antagonists (eg, gosereli
- goserelin eg, tamoxifen, toremifene, raloxifene, fulvestrant, me
- Anti-tumor antibiotics eg anthracyclines such as doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); Platinum derivatives (eg cisplatin, oxaliplatin, carboplatin); Alkylating agents (eg estramustine, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as carmustine and lomustine, thiotepa); antimitotic agents (eg vinca alkaloids such as vinblastine, vindesine, vinorelbine and vincristine; and
- Suitable application forms are, for example, tablets, capsules, suppositories, solutions, in particular solutions for injection (s.c., i.V., i.m.) and infusion, juices, emulsions or dispersible powders.
- the proportion of the pharmaceutically active compound (s) in each case in the range of 0.1 to 90 wt .-%, preferably 0.5 to 50 wt .-% of the total composition, that is, in amounts which are sufficient to those below reach the specified dosage range.
- the said doses may, if necessary, be given several times a day.
- Corresponding tablets can be prepared, for example, by mixing the active substance (s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants, such as
- Magnesium stearate or talc, and / or agents for obtaining the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate are obtained.
- the tablets can also consist of several layers.
- Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
- the core can also consist of several layers.
- the dragee wrapper to achieve a depot effect of several layers, wherein the above mentioned in the tablets excipients can be used.
- Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetener, such as saccharin, cyclamate, glycerol or sugar, and a taste-improving agent, for example flavorings, such as vanillin or orange extract.
- a sweetener such as saccharin, cyclamate, glycerol or sugar
- a taste-improving agent for example flavorings, such as vanillin or orange extract.
- Injection and infusion solutions are prepared in a conventional manner, e.g. with the addition of isotonic agents, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, optionally with the use of emulsifiers and / or dispersants, wherein, for example, when using water as a diluent organic solvents may optionally be used as solubilizers or auxiliary solvents , manufactured and filled into injection vials or ampoules or infusion bottles.
- isotonic agents e.g. with the addition of isotonic agents, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, optionally with the use of emulsifiers and / or dispersants, wherein, for example, when using water as a diluent organic solvents may optionally be used as
- the capsules containing one or more active ingredients or combinations of active substances can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules.
- inert carriers such as lactose or sorbitol
- Suitable suppositories can be prepared, for example, by mixing with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.
- adjuvants there may be mentioned, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g., petroleum fractions), oils of vegetable origin (e.g., peanut or sesame oil), mono- or polyfunctional alcohols (e.g., ethanol or glycerin), carriers such as e.g. ground natural minerals (e.g., kaolins, clays, talc, chalk), ground synthetic minerals (e.g., fumed silica and silicates), sugars (e.g., cane, dairy, and grape sugar), emulsifying agents (e.g., lignin,
- paraffins e.g., petroleum fractions
- oils of vegetable origin e.g., peanut or sesame oil
- mono- or polyfunctional alcohols e.g., ethanol or glycerin
- carriers such as e.g. ground natural minerals (e.g., kaolins, clays, talc, chalk), ground synthetic minerals (e.g.
- Sulfite liquors methyl cellulose, starch and polyvinyl pyrrolidone
- lubricants e.g., magnesium stearate, talc, stearic acid and sodium lauryl sulfate.
- the application is carried out in a customary manner, preferably orally or transdermally, particularly preferably orally.
- the tablets in addition to the carriers mentioned also additives, such as sodium citrate, Calcium carbonate and dicalcium phosphate together with various additives, such as starch, preferably potato starch, gelatin and the like.
- lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for tableting.
- the active ingredients may be added to the abovementioned excipients with various flavor enhancers or dyes.
- solutions of the active ingredients may be employed using suitable liquid carrier materials.
- the dosage for intravenous use is 1 - 1000 mg per hour, preferably between 5 - 500 mg per hour.
- the finely ground active ingredient, lactose and part of the corn starch are mixed together.
- the mixture is sieved, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated and dried.
- the granules, the remainder of the corn starch and the magnesium stearate are sieved and mixed together.
- the mixture is compressed into tablets of suitable shape and size.
- the finely ground active ingredient, a portion of corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture sieved and processed with the remainder of the corn starch and water to a granulate, which is dried and sieved.
- the active ingredient is dissolved in water at its own pH or optionally at pH 5.5-6.5 and treated with sodium chloride as isotonan.
- the resulting solution is filtered pyrogen-free and the filtrate filled under aseptic conditions in ampoules, which are then sterilized and sealed.
- the vials contain 5 mg, 25 mg and 50 mg active ingredient.
Abstract
Description
Claims
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP05792037A EP1799690B1 (de) | 2004-10-07 | 2005-10-05 | Thiazolyl-dihydro-indazole |
JP2007535166A JP5090914B2 (ja) | 2004-10-07 | 2005-10-05 | チアゾリルジヒドロインダゾール類 |
ES05792037T ES2304022T3 (es) | 2004-10-07 | 2005-10-05 | Tiazolil-dihidro-indazoles. |
DK05792037T DK1799690T3 (da) | 2004-10-07 | 2005-10-05 | Thiazolyl-dihydro-indazoler |
CA002579288A CA2579288A1 (en) | 2004-10-07 | 2005-10-05 | Thiazolyldihydroindazoles |
NZ554695A NZ554695A (en) | 2004-10-07 | 2005-10-05 | Thiazolyl-dihydro indazoles |
CN2005800343320A CN101035795B (zh) | 2004-10-07 | 2005-10-05 | 噻唑基二氢吲唑 |
DE502005003777T DE502005003777D1 (de) | 2004-10-07 | 2005-10-05 | Thiazolyl-dihydro-indazole |
MX2007003802A MX2007003802A (es) | 2004-10-07 | 2005-10-05 | Tiazolil-dihidro-indazoles. |
BRPI0518169-0A BRPI0518169A (pt) | 2004-10-07 | 2005-10-05 | tiazolil-dihidro-indazóis |
PL05792037T PL1799690T3 (pl) | 2004-10-07 | 2005-10-05 | Tiazolilo-dihydro-indazol |
AU2005293609A AU2005293609B2 (en) | 2004-10-07 | 2005-10-05 | Thiazolyl-dihydro indazoles |
IL182397A IL182397A (en) | 2004-10-07 | 2007-04-10 | Thiazolyldihydroindazole derivatives, pharmaceutical compositions containing them and tetrahydrobenzthiazoleacetamide intermediates for their preparation |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102004048877A DE102004048877A1 (de) | 2004-10-07 | 2004-10-07 | PI3-Kinasen |
DE102004048877.0 | 2004-10-07 | ||
DE102005005813A DE102005005813A1 (de) | 2005-02-09 | 2005-02-09 | PI3-Kinasen |
DE102005005813.2 | 2005-02-09 | ||
EP05107230.4 | 2005-08-05 | ||
EP05107230 | 2005-08-05 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2006040281A1 true WO2006040281A1 (de) | 2006-04-20 |
Family
ID=35448324
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2005/055021 WO2006040281A1 (de) | 2004-10-07 | 2005-10-05 | Thiazolyl-dihydro-indazole |
Country Status (23)
Country | Link |
---|---|
EP (1) | EP1799690B1 (de) |
JP (1) | JP5090914B2 (de) |
KR (1) | KR20070113188A (de) |
CN (1) | CN101035795B (de) |
AR (1) | AR051743A1 (de) |
AT (1) | ATE392425T1 (de) |
AU (1) | AU2005293609B2 (de) |
BR (1) | BRPI0518169A (de) |
CA (1) | CA2579288A1 (de) |
CY (1) | CY1108183T1 (de) |
DE (1) | DE502005003777D1 (de) |
DK (1) | DK1799690T3 (de) |
ES (1) | ES2304022T3 (de) |
IL (1) | IL182397A (de) |
MX (1) | MX2007003802A (de) |
NZ (1) | NZ554695A (de) |
PE (1) | PE20060583A1 (de) |
PL (1) | PL1799690T3 (de) |
PT (1) | PT1799690E (de) |
SI (1) | SI1799690T1 (de) |
TW (1) | TW200630374A (de) |
UY (1) | UY29149A1 (de) |
WO (1) | WO2006040281A1 (de) |
Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007113246A1 (de) * | 2006-04-06 | 2007-10-11 | Boehringer Ingelheim International Gmbh | Thiazolyldihydroindazol-derivate als proteinkinase- inhibitoren |
WO2007113245A1 (de) * | 2006-04-06 | 2007-10-11 | Boehringer Ingelheim International Gmbh | Thiazolyl-dihydro-indazole |
WO2007115933A1 (de) * | 2006-04-06 | 2007-10-18 | Boehringer Ingelheim International Gmbh | Thiazolyl-dihydro-indazole |
WO2007115929A1 (de) * | 2006-04-06 | 2007-10-18 | Boehringer Ingelheim International Gmbh | Thiazolyl-dihydro-quinazoline |
WO2007115930A1 (de) * | 2006-04-06 | 2007-10-18 | Boehringer Ingelheim International Gmbh | Thiazolyl-dihydro-indazole |
WO2008045371A2 (en) * | 2006-10-06 | 2008-04-17 | Wyeth | N-substituted-azacyclylamines as histamine-3 antagonists |
WO2009112565A1 (en) * | 2008-03-13 | 2009-09-17 | Boehringer Ingelheim International Gmbh | Thiazolyl-dihydro-indazoles |
WO2010007943A1 (ja) * | 2008-07-17 | 2010-01-21 | 旭化成ファーマ株式会社 | 含窒素複素環化合物 |
JP2010504913A (ja) * | 2006-09-26 | 2010-02-18 | シンタ ファーマシューティカルズ コーポレーション | 炎症及び免疫関連使用のための縮合環化合物 |
US7803825B2 (en) | 2007-07-16 | 2010-09-28 | Wyeth Llc | Aminoalkylazole derivatives as histamine-3 antagonists |
US7820825B2 (en) | 2006-03-15 | 2010-10-26 | Wyeth Llc | N-substituted-azacyclylamines as histamine-3 antagonists |
WO2010122091A1 (en) | 2009-04-22 | 2010-10-28 | Boehringer Ingelheim International Gmbh | Thia-triaza-as-indacenes as pi3-kinases inhibitors for the treatment of cancer |
WO2010122071A1 (en) | 2009-04-22 | 2010-10-28 | Boehringer Ingelheim International Gmbh | Thia-triaza-cyclopentazulenes as pi3-kinases inhibitors for the treatment of cancer |
US7842715B2 (en) | 2006-05-19 | 2010-11-30 | Wyeth Llc | N-benzoyl- and N-benzylpyrrolidin-3-ylamines as histamine-3 antagonists |
US8278313B2 (en) | 2008-03-11 | 2012-10-02 | Abbott Laboratories | Macrocyclic spiro pyrimidine derivatives |
US8354418B2 (en) | 2006-04-06 | 2013-01-15 | Boehringer Ingelheim International Gmbh | Thiazolyl-dihydro-quinazolines |
US8436005B2 (en) | 2008-04-03 | 2013-05-07 | Abbott Laboratories | Macrocyclic pyrimidine derivatives |
JP5258563B2 (ja) * | 2006-06-29 | 2013-08-07 | 日産化学工業株式会社 | αアミノ酸誘導体及びそれを有効成分として含む医薬 |
US8653097B2 (en) | 2008-10-17 | 2014-02-18 | Boehringer Ingelheim International Gmbh | Tetra-aza-heterocycles as phosphatidylinositol-3-kinases (P13-kinases) inhibitor |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7517995B2 (en) | 2006-04-06 | 2009-04-14 | Boehringer Ingelheim International Gmbh | Thiazolyl-dihydro-cyclopentapyrazole |
MX2012000178A (es) | 2009-07-02 | 2012-02-28 | Novartis Ag | 2-carboxamida-cicloamino-ureas utiles como inhibidores de pi3k. |
MX2013014887A (es) * | 2011-06-21 | 2014-02-17 | Novartis Ag | Polimorfos de 1- ({4-metil-5- [2- (2 ,2 ,2-trifluoro-1,1-dimetil-e til) piridin-4-il] - tiazol-2-il}-amida de 2-amida del acido (s) -pirrolidin-1,2-dicarboxilico. |
EP4013502A1 (de) * | 2019-08-16 | 2022-06-22 | Cyclacel Limited | Verfahren zur herstellung eines pyrimidino-diazepin-derivats |
CN112876503B (zh) * | 2021-03-18 | 2022-04-29 | 中国科学院兰州化学物理研究所 | 用于癌症硼中子俘获治疗药物的硼酸盐化合物及其制备 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020151544A1 (en) * | 2000-04-27 | 2002-10-17 | Masahiko Hayakawa | Fused heteroaryl derivatives |
WO2003035618A2 (en) * | 2001-10-24 | 2003-05-01 | Iconix Pharmaceuticals, Inc. | Modulators of phosphoinositide 3-kinase |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100423899B1 (ko) * | 2000-05-10 | 2004-03-24 | 주식회사 엘지생명과학 | 세포 증식 억제제로 유용한 1,1-디옥소이소티아졸리딘을갖는 인다졸 |
PE20030968A1 (es) * | 2002-02-28 | 2004-01-12 | Novartis Ag | Derivados de 5-feniltiazol como inhibidores de cinasas |
-
2005
- 2005-10-04 UY UY29149A patent/UY29149A1/es not_active Application Discontinuation
- 2005-10-05 ES ES05792037T patent/ES2304022T3/es active Active
- 2005-10-05 PL PL05792037T patent/PL1799690T3/pl unknown
- 2005-10-05 MX MX2007003802A patent/MX2007003802A/es active IP Right Grant
- 2005-10-05 NZ NZ554695A patent/NZ554695A/en not_active IP Right Cessation
- 2005-10-05 BR BRPI0518169-0A patent/BRPI0518169A/pt not_active IP Right Cessation
- 2005-10-05 CN CN2005800343320A patent/CN101035795B/zh not_active Expired - Fee Related
- 2005-10-05 AU AU2005293609A patent/AU2005293609B2/en not_active Ceased
- 2005-10-05 AT AT05792037T patent/ATE392425T1/de active
- 2005-10-05 PE PE2005001178A patent/PE20060583A1/es not_active Application Discontinuation
- 2005-10-05 SI SI200530249T patent/SI1799690T1/sl unknown
- 2005-10-05 CA CA002579288A patent/CA2579288A1/en not_active Abandoned
- 2005-10-05 DK DK05792037T patent/DK1799690T3/da active
- 2005-10-05 JP JP2007535166A patent/JP5090914B2/ja active Active
- 2005-10-05 WO PCT/EP2005/055021 patent/WO2006040281A1/de active IP Right Grant
- 2005-10-05 DE DE502005003777T patent/DE502005003777D1/de active Active
- 2005-10-05 KR KR1020077010385A patent/KR20070113188A/ko not_active Application Discontinuation
- 2005-10-05 EP EP05792037A patent/EP1799690B1/de active Active
- 2005-10-05 PT PT05792037T patent/PT1799690E/pt unknown
- 2005-10-06 TW TW094134894A patent/TW200630374A/zh unknown
- 2005-10-07 AR ARP050104226A patent/AR051743A1/es not_active Application Discontinuation
-
2007
- 2007-04-10 IL IL182397A patent/IL182397A/en not_active IP Right Cessation
-
2008
- 2008-07-09 CY CY20081100722T patent/CY1108183T1/el unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020151544A1 (en) * | 2000-04-27 | 2002-10-17 | Masahiko Hayakawa | Fused heteroaryl derivatives |
WO2003035618A2 (en) * | 2001-10-24 | 2003-05-01 | Iconix Pharmaceuticals, Inc. | Modulators of phosphoinositide 3-kinase |
Non-Patent Citations (2)
Title |
---|
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002359147, Database accession no. BRN: 791545 * |
GAZZETTA CHIMICA ITALIANA, vol. 103, 1973, pages 755 - 770 * |
Cited By (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7820825B2 (en) | 2006-03-15 | 2010-10-26 | Wyeth Llc | N-substituted-azacyclylamines as histamine-3 antagonists |
WO2007113246A1 (de) * | 2006-04-06 | 2007-10-11 | Boehringer Ingelheim International Gmbh | Thiazolyldihydroindazol-derivate als proteinkinase- inhibitoren |
US7902183B2 (en) | 2006-04-06 | 2011-03-08 | Boehringer Ingelheim International Gmbh | Thiazolyl-dihydro-indazole |
WO2007115929A1 (de) * | 2006-04-06 | 2007-10-18 | Boehringer Ingelheim International Gmbh | Thiazolyl-dihydro-quinazoline |
WO2007115930A1 (de) * | 2006-04-06 | 2007-10-18 | Boehringer Ingelheim International Gmbh | Thiazolyl-dihydro-indazole |
AU2007236043B2 (en) * | 2006-04-06 | 2012-09-13 | Boehringer Ingelheim International Gmbh | Thiazolyl-dihydroquinazolines |
WO2007113245A1 (de) * | 2006-04-06 | 2007-10-11 | Boehringer Ingelheim International Gmbh | Thiazolyl-dihydro-indazole |
US8354418B2 (en) | 2006-04-06 | 2013-01-15 | Boehringer Ingelheim International Gmbh | Thiazolyl-dihydro-quinazolines |
WO2007115933A1 (de) * | 2006-04-06 | 2007-10-18 | Boehringer Ingelheim International Gmbh | Thiazolyl-dihydro-indazole |
US7893049B2 (en) | 2006-04-06 | 2011-02-22 | Boehringer Ingelheim International Gmbh | Thiazolyl-dihydro-indazole |
US7691868B2 (en) | 2006-04-06 | 2010-04-06 | Boehringer Ingelheim International Gmbh | Thiazolyl-dihydro-quinazoline |
US8334378B2 (en) | 2006-04-06 | 2012-12-18 | Boehringer Ingelheim International Gmbh | Thiazolyl-dihydro-quinazoline compounds and processes for preparing same |
US7842715B2 (en) | 2006-05-19 | 2010-11-30 | Wyeth Llc | N-benzoyl- and N-benzylpyrrolidin-3-ylamines as histamine-3 antagonists |
JP5258563B2 (ja) * | 2006-06-29 | 2013-08-07 | 日産化学工業株式会社 | αアミノ酸誘導体及びそれを有効成分として含む医薬 |
US8779154B2 (en) | 2006-09-26 | 2014-07-15 | Qinglin Che | Fused ring compounds for inflammation and immune-related uses |
JP2010504913A (ja) * | 2006-09-26 | 2010-02-18 | シンタ ファーマシューティカルズ コーポレーション | 炎症及び免疫関連使用のための縮合環化合物 |
US7935719B2 (en) | 2006-10-06 | 2011-05-03 | Wyeth Llc | N-substituted-azacyclylamines as histamine-3 antagonists |
WO2008045371A3 (en) * | 2006-10-06 | 2008-06-19 | Wyeth Corp | N-substituted-azacyclylamines as histamine-3 antagonists |
WO2008045371A2 (en) * | 2006-10-06 | 2008-04-17 | Wyeth | N-substituted-azacyclylamines as histamine-3 antagonists |
US7803825B2 (en) | 2007-07-16 | 2010-09-28 | Wyeth Llc | Aminoalkylazole derivatives as histamine-3 antagonists |
US8278313B2 (en) | 2008-03-11 | 2012-10-02 | Abbott Laboratories | Macrocyclic spiro pyrimidine derivatives |
US8304556B2 (en) | 2008-03-13 | 2012-11-06 | Boehringer Ingelheim International Gmbh | Thiazolyl-dihydro-indazoles |
WO2009112565A1 (en) * | 2008-03-13 | 2009-09-17 | Boehringer Ingelheim International Gmbh | Thiazolyl-dihydro-indazoles |
JP2011513471A (ja) * | 2008-03-13 | 2011-04-28 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | チアゾリル−ジヒドロ−インダゾール |
US8436005B2 (en) | 2008-04-03 | 2013-05-07 | Abbott Laboratories | Macrocyclic pyrimidine derivatives |
EP2314587A1 (de) * | 2008-07-17 | 2011-04-27 | Asahi Kasei Pharma Corporation | Nitrogenierte heterocyclische verbindung |
EP2314587A4 (de) * | 2008-07-17 | 2012-01-25 | Asahi Kasei Pharma Corp | Nitrogenierte heterocyclische verbindung |
AU2009272033B2 (en) * | 2008-07-17 | 2011-10-13 | Asahi Kasei Pharma Corporation | Nitrogenated heterocyclic compound |
RU2477281C2 (ru) * | 2008-07-17 | 2013-03-10 | Асахи Касеи Фарма Корпорейшн | Азотсодержащие гетероциклические соединения |
WO2010007943A1 (ja) * | 2008-07-17 | 2010-01-21 | 旭化成ファーマ株式会社 | 含窒素複素環化合物 |
US8653097B2 (en) | 2008-10-17 | 2014-02-18 | Boehringer Ingelheim International Gmbh | Tetra-aza-heterocycles as phosphatidylinositol-3-kinases (P13-kinases) inhibitor |
JP2012524751A (ja) * | 2009-04-22 | 2012-10-18 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 癌の治療用pi3−キナーゼ阻害薬としてのチア−トリアザ−シクロペンタアズレン |
JP2012524756A (ja) * | 2009-04-22 | 2012-10-18 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 癌の治療用PI3−キナーゼ阻害薬としてのチア−トリアザ−as−インダセン |
US8288379B2 (en) | 2009-04-22 | 2012-10-16 | Boehringer Ingelheim International Gmbh | Thia-triaza-cyclopentazulenes |
WO2010122071A1 (en) | 2009-04-22 | 2010-10-28 | Boehringer Ingelheim International Gmbh | Thia-triaza-cyclopentazulenes as pi3-kinases inhibitors for the treatment of cancer |
WO2010122091A1 (en) | 2009-04-22 | 2010-10-28 | Boehringer Ingelheim International Gmbh | Thia-triaza-as-indacenes as pi3-kinases inhibitors for the treatment of cancer |
US9243000B2 (en) | 2009-04-22 | 2016-01-26 | Boehringer Ingelheim International Gmbh | Thia-triaza-indacenes |
Also Published As
Publication number | Publication date |
---|---|
AR051743A1 (es) | 2007-02-07 |
CN101035795A (zh) | 2007-09-12 |
BRPI0518169A (pt) | 2008-11-04 |
PL1799690T3 (pl) | 2008-09-30 |
UY29149A1 (es) | 2006-05-31 |
KR20070113188A (ko) | 2007-11-28 |
ES2304022T3 (es) | 2008-09-01 |
JP2008515854A (ja) | 2008-05-15 |
ATE392425T1 (de) | 2008-05-15 |
AU2005293609B2 (en) | 2011-11-24 |
EP1799690A1 (de) | 2007-06-27 |
EP1799690B1 (de) | 2008-04-16 |
CN101035795B (zh) | 2012-03-21 |
PE20060583A1 (es) | 2006-08-17 |
DE502005003777D1 (de) | 2008-05-29 |
PT1799690E (pt) | 2008-06-16 |
TW200630374A (en) | 2006-09-01 |
CA2579288A1 (en) | 2006-04-20 |
SI1799690T1 (sl) | 2008-08-31 |
MX2007003802A (es) | 2007-04-23 |
IL182397A (en) | 2011-11-30 |
CY1108183T1 (el) | 2014-02-12 |
NZ554695A (en) | 2010-12-24 |
IL182397A0 (en) | 2007-07-24 |
AU2005293609A1 (en) | 2006-04-20 |
JP5090914B2 (ja) | 2012-12-05 |
DK1799690T3 (da) | 2008-06-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1799690B1 (de) | Thiazolyl-dihydro-indazole | |
US8207349B2 (en) | Thiazolyl-dihydro-indazoles | |
JP5579724B2 (ja) | ホスファチジルイノシトール−3−キナーゼ(pi−3キナーゼ)阻害剤としてのテトラ−アザ−複素環 | |
CA2654670A1 (en) | New compounds | |
EP1751118A1 (de) | Pyrimidine als plk inhibitoren | |
WO2006131552A1 (de) | Alpha-carboline als cdk-1 inhibitoren | |
EP2007774B1 (de) | Thiazolyldihydroindazol-derivate als proteinkinase- inhibitoren | |
JP2010529161A (ja) | インドリノン誘導体及び癌等の症状を治療する際のそれらの使用 | |
EP2007773B1 (de) | Thiazolyl-dihydro-indazole |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV LY MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2007/01653 Country of ref document: ZA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2579288 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/a/2007/003802 Country of ref document: MX Ref document number: 2380/DELNP/2007 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12007500742 Country of ref document: PH |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2005293609 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2007535166 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 200580034332.0 Country of ref document: CN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 182397 Country of ref document: IL |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 554695 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2005792037 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2007116858 Country of ref document: RU Ref document number: 1020077010385 Country of ref document: KR |
|
WWP | Wipo information: published in national office |
Ref document number: 2005792037 Country of ref document: EP |
|
WWG | Wipo information: grant in national office |
Ref document number: 2005792037 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: PI0518169 Country of ref document: BR |