WO2003037898A1 - Derives de pyrimido [4,5-b] indole - Google Patents

Derives de pyrimido [4,5-b] indole Download PDF

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WO2003037898A1
WO2003037898A1 PCT/EP2002/012057 EP0212057W WO03037898A1 WO 2003037898 A1 WO2003037898 A1 WO 2003037898A1 EP 0212057 W EP0212057 W EP 0212057W WO 03037898 A1 WO03037898 A1 WO 03037898A1
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Prior art keywords
pyrimido
indole
carbamoyl
amino
alkyl
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PCT/EP2002/012057
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English (en)
Inventor
Timothy Lowinger
Makoto Shimazaki
Hiroki Sato
Kazuho Tanaka
Naoki Tsuno
Karsten Marx
Masaru Yamamoto
Klaus Urbahns
Florian Gantner
Hiromi Okigami
Kosuke Nakashima
Keisuke Takeshita
Kevin B. Bacon
Hiroshi Komura
Nagahiro Yoshida
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Bayer Healthcare Ag
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Priority claimed from JP2001334662A external-priority patent/JP2003137886A/ja
Priority claimed from GB0214544A external-priority patent/GB2390090A/en
Application filed by Bayer Healthcare Ag filed Critical Bayer Healthcare Ag
Priority to CA002464934A priority Critical patent/CA2464934A1/fr
Priority to MXPA04004019A priority patent/MXPA04004019A/es
Priority to EP02777332A priority patent/EP1442039A1/fr
Priority to JP2003540179A priority patent/JP2005515173A/ja
Publication of WO2003037898A1 publication Critical patent/WO2003037898A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • A61P37/08—Antiallergic agents
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • inhibitory activity can be used for the prophylaxis and treatment of diseases associated with MKK7 and MKK4 activity.
  • the compounds of the present invention are also useful for treatment of ischemia, myocardial injury, pulmonary hypertension, renal failure, Huntington's chorea and cardiac hypertrophy, as well as neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and focal ischemia, since the diseases also relate to MKK7 and/or MKK4.
  • the mitogen-activated protein kinases are a family of serine/threonine kinases involved in the transduction of signals from the cell membrane to the nucleus in response to various types of stimuli such as lipopolysaccharide (LPS), tumor necrosis factor- ⁇ (TNF- ), interleukins, CD40 and others. These kinases participate in a wide variety of signaling cascades controlling cellular events such as cell growth, differentiation, activation, apoptosis, stress responses, and transformation.
  • LPS lipopolysaccharide
  • TNF- tumor necrosis factor- ⁇
  • CD40 interleukins
  • SAPK/JNKs regulate the activation and proliferation of T and B lymphocytes, activation of mast cells
  • MKK stress kinase mitogen-activated protein kinase kinase
  • MAPKs themselves require dual phosphorylation of both threonine and tyrosine at their so-called Thr-X-Tyr motif, wliich is brought upon by the upstream regulators MAPK kinases (MKKs).
  • MKK1-MKK7 MEK1, MEK2,
  • MKK3, MKK4, MEK5, MKK6, and MKK7 are known to date with MKK7 being the most recently identified (Tournier C, Whitmarsh J., Cavanagh J., Barrett T.,
  • p38 controls the release of IL-12 and IFN ⁇ and in B cells, CD40 cross-linking leads to rapid p38 activation and thus controls proliferation, and adhesion molecule expression.
  • p38 MAPK are activated by hypoxia and, by controlling the transcription factor ATF2, play a role in neuronal development and survival (Lee JC, Kumar S., Griswold DE., Underwood DC, Notta BJ., Adams JL. Inhibition of p38 MAP kinase as a therapeutic strategy. Immunopharmacology, Al: 185-201, 2000).
  • inhibitors should also have therapeutic potential for the treatment of renal failure, Huntington's chorea, cardiac hypertrophy and neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and focal ischemia (Xia XG., Harding T., Weller M., Bieneman A., Uney JB., Schulz JB. Gene transfer of the JNK interacting protein- 1 protects dopaminergic neurons in the MPTP model of Parkinson's disease. Proc Natl Acad Sci USA, 98: 10433-10438, 2001).
  • WO 9842708 discloses anti-asthma agent represented by the general formula:
  • WO 9626941 discloses pharmaceutical agents represented by the general formula:
  • R lc , R 2c , R 3c , R 4c , R 5c and R 6c are defined in the specification.
  • WO 9320078 discloses pharmaceutically active compound represented by the formula:
  • IN 157280 discloses the method for preparing anti hypertension agents represented by the formula:
  • WO 97/02266 discloses anti-hyperproliferative disease agents represented by the general formula:
  • R is hydrogen, amino, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C -6 )alkynyl, halogen substituted (C 1-6 ) alkyl, cyano, cyano(C 1-6 )alkyl, (C -8 )cycloalkyl, nitro, nitro(C 1 .. 6 )alkyl or fluoro;
  • R 2 and R 3 independently represent hydrogen, (C 2 - 6 )alkenyl, (C 2-6 )alkynyl,
  • R 2 and R 3 are taken together with the attached nitrogen atom to form a 3-8 membered saturated ring optionally interrupted by one or two atoms selected from the group consisting of oxygen, sulfur and nitrogen,
  • said saturated ring is optionally fused by benzene or 3-8 membered saturated ring having 0 to 3 nitrogen atoms,
  • said saturated ring is optionally having substituents independently selected from the group consisting of halogen, hydroxy, carbamoyl, carboxy, amino, oxo, pyrrolidino, (C 1-6 )alkoxy, (C 2-6 )alkenyl, (C 2-6 )- alkynyl, (C 3-8 )cycloalkyl, (C 1-6 )alkylcarbonyl, (C 1-6 )alkylsulfonyl, arylsulfonyl, (C 1-6 )alkyl, hydroxy(C 1-6 )alkyl, (C 1-6 )alkoxy(C 1-6 )alkyl, (C 1-6 )alkoxycarbonyl, (C 1-6 )alkoxycarbonyl(C ⁇ -6 )alkyl, (C 3- )cyclo- alkyl(C 1-6 )alkyl, aryl(C 1-6 )alkyl, carbamoyl(C 1-6
  • spiro ring is optionally interrupted by 0 to 3 nitrogen or oxygen atoms
  • R 4 is halogen, hydroxy, (C 1-6 )alkyl, amino (C 1-6 )alkyl, (C 1-6 )alkoxy, cyano, carboxy, (C 1-6 )alkoxycarbony, or carbamoyl;
  • R 5 is hydrogen, or (C 1-6 )alkyl.
  • Alkoxy illustratively and preferably represents methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • Alkanoyl illustratively and preferably represents acetyl and propanoyl.
  • Alkylamino represents an alkylamino radical having one or two (independently selected) alkyl substituents, illustratively and preferably representing methylamino, ethylainino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n- hexyl-amino, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N- methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, N-t-butyl-N-methylamino, N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino.
  • Alkylaminocarbonyl or alkylcarbamoyl represents an alkylammocarbonyl radical having one or two (independently selected) alkyl substituents, illustratively and preferably representing methylaminocarbonyl, ethylaminocarbonyl, n-propylamino- carbonyl, isopropylamino-carbonyl, tert-butylaminocarbonyl, n-pentylamino- carbonyl, n-hexylaminocarbonyl, N,N-dimethylaminocarbonyl, N,N-diethylamino- carbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-n-propylaminocarbonyl, N- isopropyl-N-n-propylaminocarbonyl, N-t-butyl-N-methylaminocarbonyl, N-ethyl-N- n-
  • Alkylaminosulphonyl represents an alkylaminosulphonyl radical having one or two (independently selected) alkyl substituents, illustratively and preferably representing methylaminosulphonyl, ethylaminosulphonyl, n-propylaminosulphonyl, isopropyl- aminosulphonyl, tert-butylaminosulphonyl, n-pentylaminosulphonyl, n-hexyl-amino- sulphonyl, N,N-dimethylaminosulphonyl, N,N-diethylaminosulphonyl, N-ethyl-N- methylamino-sulphonyl, N-methyl-N-n-propylaminosulphonyl, N-isopropyl-N-n-propylaminosulphonyl, N-t-butyl-N-methylaminosulphonyl, N-ethy
  • Alkylsulphonylamino illustratively and preferably represents methylsulphonylamino, ethylsulphonylamino, n-propylsulphonylamino, isopropylsulphonylamino, tert-butyl- sulphonylamino, n-pentylsulphonylamino and n-hexylsulphonylamino.
  • Alkoxycarbonyl illustratively and preferably represents methoxycarbonyl, ethoxy- carbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxy- carbonyl and n-hexoxycarbonyl.
  • Alkoxycarbonylamino illustratively and preferably represents methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, tert-butoxycarbonylamino, n-pentoxycarbonylamino and n-hexoxycarbonylamino .
  • Alkanoylamino illustratively and preferably represents acetylamino and ethyl- carbonylamino.
  • Cycloalkyl per se and in cycloalkylamino and in cycloalkylcarbonyl represents a cycloalkyl group having generally 3 to 8 and preferably 5 to 7 carbon atoms, illustratively and preferably representing cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Aryl per se and in arylamino and in arylcarbonyl represents a mono- to tricyclic aromatic carbocyclic radical having generally 6 to 14 carbon atoms, illustratively and preferably representing phenyl, naphthyl and phenanthrenyl.
  • Arylamino represents an arylamino radical having one or two (independently selected) aryl substituents, illustratively and preferably representing phenylamino, diphenylamino and naphthylamino.
  • Arylcarbonyl illustratively and preferably represents phenylcarbonyl and naphthyl- carbonyl.
  • Heteroarylamino represents an heteroarylamino radical having one or two (independently selected) heteroaryl substituents, illustratively and preferably representing thienylamino, furylamino, pyrrolylamino, thiazolylamino, oxazolylamino, imidazolyl-amino, pyridylamino, pyrimidylamino, pyridazinylamino, indolylamino, indazolylamino, benzofuranylamino, benzothiophenylamino, quinolinyl-amino, isoquinolinylamino .
  • Heteroarylcarbonyl illustratively and preferably represents thienylcarbonyl, furyl- carbonyl, pyrrolylcarbonyl, thiazolylcarbonyl, oxazolylcarbonyl, imidazolyl- carbonyl, pyridylcarbonyl, pyrimidylcarbonyl, pyridazinylcarbonyl, indolylcarbonyl, indazolylcarbonyl, benzofiiranylcarbonyl, benzothiophenylcarbonyl, quinolinyl- carbonyl, isoquinolinylcarbonyl.
  • Heterocyclyl per se and in heterocyclylcarbonyl represents a mono- or polycyclic, preferably mono- or bicyclic, nonaromatic heterocyclic radical having generally 4 to 10 and preferably 5 to 8 ring atoms and up to 3 and preferably up to 2 hetero atoms and or hetero groups selected from the group consisting of N, O, S, SO and SO 2 .
  • the heterocyclyl radicals can be saturated or partially unsaturated.
  • the compounds of the present invention surprisingly show excellent MKK7 and/or MKK4 inhibitory activity. They are, therefore, suitable for the production of medicament or medical composition, which may be useful to treat MKK7 and/or MKK4 related diseases.
  • the compounds of the present invention are also useful for treatment of ischemia, myocardial injury, pulmonary hypertension, renal failure, Huntington's chorea and cardiac hypertrophy, as well as neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and focal ischemia, since the diseases also relate to MKK7 and/or MKK4.
  • the compounds of formula (I) are those wherein:
  • R 1 is amino
  • R 2 is pyrrolidyl(C 1-6 )alkyl, saturated(C 3-8 )cycloalkyl or benzyl, and
  • R 3 is hydrogen, (C 1-6 )alkyl, or benzyl
  • R 2 and R 3 are taken together with the attached nitrogen atom to form
  • the compounds of formula (I) are those wherein:
  • R 1 is amino
  • R is carbamoyl or amino (C 1-6 )alkyl
  • R 5 is hydrogen or (C ⁇ -6 )alkyl.
  • the compounds of formula (I) are those wherein:
  • R 4 is carbamoyl
  • R 5 is hydrogen
  • the compounds of formula (I) are those wherein:
  • R 1 is hydrogen, methyl or amino
  • R 4 is carbamoyl
  • R is hydrogen
  • (C 3-8 )cycloalkyl optionally substituted by hydroxy or hydroxy (C 1-6 )alkyl, benzyl, or 5-7 membered saturated heterocyclic ring interrupted by one or two oxygen atoms;
  • R 2 and R 3 are taken together with the attached nitrogen atom to form a saturated heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, piperazino, homopiperidino, and morpholino
  • heterocyclic ring is optionally fused by benzene or saturated(C 3-8 )- cycloalkyl
  • R is carbamoyl or amino(C ⁇ -6 )alkyl
  • R 5 is hydrogen
  • the compounds of formula (I) are those wherein:
  • R 1 is hydrogen, methyl or amino
  • R 2 and R 3 independently represent hydrogen, (C 1-6 )alkyl optionally substituted by amino, hydroxy, methoxy, imidazolyl, (C ⁇ -6 )alkoxy or (C -8 )cycloalkyl optionally substituted by hydroxy or hydroxy (C 1-6 )alkyl, benzyl, or 5-7 membered saturated heterocyclic ring interrupted by one or two oxygen atoms;
  • R 2 and R 3 are taken together with the attached nitrogen atom to form a saturated heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, piperazino, homopiperidino, and morpholino
  • heterocyclic ring is optionally substituted by amino, methylamino, acetamido, hydroxy, oxo, carbamoyl, benzyl, bromo, carboxy, pyrrolidino, or (C 1-6 )alkyl optionally substituted by hydroxy, amino or carboxy,
  • heterocyclic ring is optionally fused by benzene or saturated(C 3-8 )- cycloalkyl
  • R 5 is hydrogen
  • the compounds of formula (I) are those wherein:
  • R 1 is amino
  • R 2 is saturated(C 3-8 )cycloalkyl or benzyl;
  • R 3 is hydrogen, or (C 1-6 )alkyl,
  • heterocyclic ring is selected from the group consisting of pyrrolidino, piperidino, piperazino, homopiperidino, and morpholino,
  • R is hydrogen
  • the compounds of formula (I) are those wherein:6- Carbamoyl-4-( 1 -piperidinyl)-9H-pyrimido [4,5 -bjindole,
  • 6-Carbamoyl-4 (4-hydroxy-l-piperidinyl)-9H-pyrimido[4,5-b]indole, 6-Carbamoyl-4- (cycloheptylamino)-9H-pyrimido[4,5-b]indole, 6-Carbamoyl-4- ⁇ (4-methyl- 1 -piperidinyl)-9H-pyrimido [4,5 -b]indole, 6-Carbamoyl-4 (3-methyl-l-piperidinyl)-9H-pyrimido[4,5-b]indole, 6-Carbamoyl-4 (3,5-dimethyl-l-pi ⁇ eridinyl)-9H-pyrimido[4,5-b]indole,
  • 6-Carbamoyl-4 [2-(hydroxymethyl)-l-pi ⁇ eridinyl]-9H-pyrimido[4,5-b]indole, 6-Carbamoyl-4- (cyclo ⁇ entylamino)-9H-pyrimido[4,5-b]indole, 6-Carbamoyl-4- -(l-azepanyl)-9H-pyrimido[4,5-b]indole,
  • the present invention provides a medicament which include one of the compounds described above and optionally pharmaceutically acceptable excipient.
  • the compound of the formula (I) of the present invention can be, but not limited to be, prepared by combining various known methods.
  • one or more of the substituents, such as amino group, carboxyl group, and hydroxyl group of the compounds used as starting materials or intermediates are advantageously protected by a protecting group known to those skilled in the art. Examples of the protecting groups are described in "Protective Groups in Organic Synthesis (2nd Edition)" by Greene and Wuts.
  • the compound of the formula (I) of the present invention can be, but not limited to be, prepared by the method [A] below.
  • This reaction can be carried out without solvent or in a solvent including, for instance, alcohol such as methanol and ethanol; ethers, such as dioxane, diethyl ether, and tetrahydrofuran (THF); aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as dimethylformamide (DMF) and dimethylacetamide; sulfoxides such as dimethyl sulfoxide, and others.
  • a solvent including, for instance, alcohol such as methanol and ethanol; ethers, such as dioxane, diethyl ether, and tetrahydrofuran (THF); aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as dimethylformamide (DMF) and dimethylacetamide; sulfoxides such as dimethyl sul
  • the reaction temperature can be optionally set depending on the compounds to be reacted.
  • the reaction temperature is usually, but not limited to, about 10°C to 200°C and preferably about 20°C to 100°C
  • the reaction may be conducted for, usually, 30 mins to 48 hrs and preferably 1 hr to 24 hrs.
  • the reaction can be advantageously conducted in the presence of a base.
  • a base examples include an alkali metal hydride such as sodium hydride or potassium hydride; alkali metal alkoxide such as sodium methoxide or sodium ethoxide; alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; carbonates such as sodium carbonate or potassium carbonate, and bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; organic amines such as triethylamine.
  • the amine (III) are commercially available or can be synthesized by conventional methods. If required, R 1 , R 2 , R 3 , R 4 and R 5 can be optionally protected during the reaction and deprotected afterward.
  • the compound of the formula (I-a) can be, but not limited to be, prepared by the methods [B] or [C] below. Method [B]
  • R 2 , R 3 and R 5 are the same as defined above, and X represents hydrogen or (C 1-6 )- alkyl) and ammonia.
  • the reaction can be carried out without solvent or in a solvent including, for instance, alcohols such as methanol and ethanol, 1 -propanol, isopropanol and tert-butanol; water; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; amides such as N, N-dimethylformamide (DMF), N, N-dimethyl- acetamide; sulfoxides such as dimethyl sulfoxide, and others.
  • a solvent including, for instance, alcohols such as methanol and ethanol, 1 -propanol, isopropanol and tert-butanol; water; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydro
  • the reaction temperature can be optionally set depending on the compounds to be reacted.
  • the reaction temperature is usually, but not limited to, about 0°C to 60°C
  • the reaction may be conducted for, usually, 30 mins to 48 hrs and preferably 1 hr to 24 hrs.
  • the reaction can be advantageously carried out using coupling agent including, for instance, carbo- diimides such as N, N-dicyclohexylcarbodiimide and l-(3-dimethylaminopropyl)-3- ethylcarbodiimide; carbonyldiazoles such as l,l'-carbonyldi(l,3-imiazole)(CDI) and l,l'-carbonyldi(l,2,4-triazole)(CDT), and others.
  • coupling agent including, for instance, carbo- diimides such as N, N-dicyclohexylcarbodiimide and l-(3-dimethylaminopropyl)-3- ethylcarbodiimide; carbonyldiazoles such as l,l'-carbonyldi(l,3-imiazole)(CDI) and l,l'-carbonyldi(l,2,4-triazole)(CD
  • the reaction can be carried out in a solvent including, for instance, alcohols such as methanol and ethanol, 1 -propanol, isopropanol, n-butanol and tert-butanol; water; ketone such as acetone; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide, and others.
  • a solvent including, for instance, alcohols such as methanol and ethanol, 1 -propanol, isopropanol, n-butanol and tert-butanol; water; ketone such as acetone; ethers such as diethyl ether, isopropyl ether
  • the reaction temperature can be optionally set depending on the compounds to be reacted.
  • the reaction temperature is usually, but not limited to, about 0°C to 60°C
  • the reaction may be conducted for, usually, 30 mins to 48 hrs and preferably 1 hr to 24 hrs.
  • the reaction can be advantageously conducted in the presence of a base, including, for instance, an alkali metal alkoxide such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal phosphate such as sodium phosphate, and others.
  • a base including, for instance, an alkali metal alkoxide such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal phosphate such as sodium phosphate, and others.
  • the reaction can be advantageously conducted in the presence of oxidating agent, for instance, hydrogen peroxide, manganese dioxide, dimethyl dioxirane, sodium percarbonate, sodium perborate, oxone, and the others.
  • oxidating agent for instance, hydrogen peroxide, manganese dioxide, dimethyl dioxirane, sodium percarbonate, sodium perborate, oxone, and the others.
  • the reaction can be advantageously conducted in the presence of an acid including, for instance, trifluoroacetic acid, hydrochloric acid and sulfonic acid, and others.
  • an acid including, for instance, trifluoroacetic acid, hydrochloric acid and sulfonic acid, and others.
  • compound 2 can be prepared by the reaction of compound 1 (wherein L' represents leaving group including, for instance, halogen atom such as chlorine, bromine, or iodine atom; C 6-10 arylsulfonyloxy group such as benzenesulfonyloxy or p-toluenesulfonyloxy; C 1-4 alkylsulfonyloxy group such as methanesulfonyloxy; and halogen substituted C 1- alkylsulfonyloxy group such as trifluoromethanesulfonyloxy and the like, and R and R 5 are the same as defined above) with ethyl cyanoacetate using a base, for instance, sodium hydride.
  • L' represents leaving group including, for instance, halogen atom such as chlorine, bromine, or iodine atom
  • C 6-10 arylsulfonyloxy group such as benzenesulfonyloxy or p
  • the reaction may be carried out in a solvent including, for instance, ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2- dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N- methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO); alcohols such as methanol, ethanol, 1 -propanol, isopropanol and tert-butanol,; and others.
  • a solvent including, for instance, ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2- dimethoxyethane; aromatic hydrocarbons such as benzene, tolu
  • the reaction may be carried out without solvent or in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2- dichloroethane;such as ethers such as dioxane and tetrahydrofuran (THF) and 1,2- dimethoxyethane; aromatic hydrocarbons such as benzene, toluene, and xylene, and others.
  • halogenated hydrocarbons such as dichloromethane, chloroform and 1,2- dichloroethane
  • ethers such as dioxane and tetrahydrofuran (THF) and 1,2- dimethoxyethane
  • aromatic hydrocarbons such as benzene, toluene, and xylene, and others.
  • two or more of the solvents selected from the listed above can be mixed and used.
  • the carrier may serve as a diluent, which may be solid, semi-solid, or liquid material wliich acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • a diluent which may be solid, semi-solid, or liquid material wliich acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powder
  • the resulting GST-MKK4 was purified with the use of glutathione column (Amersham Pharmacia Biotech AB, Uppsala, Sweden) according to the manufacturer's instruction. The purity of the protein was confirmed to be more than 90% by SDS-PAGE.
  • huPBMC Human peripheral blood mononucleated cells isolated using mono-poly resolving medium were either directly used for experiments (lxl 0s cells per well in 200 ⁇ l medium) or differentiated to dendritic cells (DC) in the presence of GM-SCF
  • TNF- ⁇ and IL-12 released from cell cultures were determined by commercially available ELISA (Genzyme Tech., Minneapolis, US) according to the manufacturer's instructions.
  • mice Male Balb/c mice (20-25 g body weight) were in injected with agonistic anti-CD3 Ab (Pharmingen, San Diego, US; 10 ⁇ g/mouse; clone 145-2C11) i.v. 5 minutes after compound application (i.v. in 10 % . 2 hrs post-challenge, mice were sacrificed and the serum cytokines IL-2, IL-4 and IFN- ⁇ were determined by ELISA (Genzyme Tech., Minneapolis, US) according to the manufacturer's instruction. Data represent mean values ⁇ SD of 5-6 animals each. * p ⁇ 0.05, ** p ⁇ 0.01 vs. vehicle control (V); Dunnett's test was used to detect differences among groups and statistics were performed using one-sided ANONA or Student's t-test if applicable.
  • MKK 7 kinase assay MKK 7 kinase assay
  • MKK4 kinase assay MKK4 kinase assay
  • NBS N-bromosuccinimide
  • benzoyl peroxide 0.45 g
  • the reaction mixture was passed through a filter paper to remove resulting precipitates, that were washed with chloroform (50 ml). The filtrates were combined and washed with saturated sodium thiosulfite water solution and brine, successively.
  • Example 6-2 to 6-16 as shown in Table 6 were synthesized.

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Abstract

L'invention porte sur des pyrimido[4,5-b]indoles utiles en tant que principe actif de compositions pharmaceutiques. Les pyrimido[4,5-b]indoles de la présente invention ont une activité inhibitrice sur MKK7 et MKK4 et peuvent s'utiliser dans la prévention et le traitement des maladies associées à l'activité des MKK7 et MKK4. Ces maladies comprennent des troubles inflammatoires et immunorégulateurs et des maladies telles que l'asthme, la dermatite atopique, la rhinite, la rhinite allergique, les maladies allergiques, la BPCO, le choc septique, l'arthrite, les maladies des articulations et les accidents du myocarde ainsi que des pathologies auto-immunes telles que la polyarthrite rhumatoïde, la maladie de Graves et l'athérosclérose. Les composés de la présente invention sont aussi utiles dans le traitement de l'ischémie, de la lésion myocardique, de l'hypertension pulmonaire, de l'insuffisance rénale, de la chorée de Huntington et de l'hypertrophie cardiaque ainsi que de maladies neurodégénératives telles que la maladie de Parkinson, la maladie d'Alzheimer et l'ischémie focale.
PCT/EP2002/012057 2001-10-31 2002-10-29 Derives de pyrimido [4,5-b] indole WO2003037898A1 (fr)

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WO2004058764A1 (fr) * 2002-12-27 2004-07-15 Bayer Healthcare Ag Derives 4-phenyl-pyrimido [4,5-b]indoles
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EP2200437A1 (fr) * 2007-08-27 2010-06-30 Duquesne University of the Holy Ghost Composés tricycliques ayant une activité cytostatique et/ou cytotoxique et leurs procédés d'utilisation
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EP2310014A1 (fr) * 2008-07-10 2011-04-20 Duquesne University of the Holy Ghost Composés tricycliques ayant une activité antimitotique et/ou antitumorale et leurs procédés d'utilisation
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WO2013110198A1 (fr) 2012-01-27 2013-08-01 Université de Montréal Dérivés de pyrimido[4,5-b]indole et leur utilisation dans l'expansion des cellules souches hématopoïétiques
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US9399647B2 (en) 2012-01-25 2016-07-26 Proteostasis Therapeutics, Inc. Proteasome activity modulating compounds
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RU2625316C1 (ru) * 2016-04-13 2017-07-13 Федеральное государственное бюджетное учреждение науки Институт элементоорганических соединений им. А.Н. Несмеянова Российской академии наук (ИНЭОС РАН) 2-АМИНОЗАМЕЩЕННЫЕ 6-МЕТОКСИ-4-ТРИФТОРМЕТИЛ-9Н-ПИРИМИДО[4,5b]ИНДОЛЫ, СПОСОБ ИХ ПОЛУЧЕНИЯ, ПРИМЕНЕНИЕ И ПРЕДШЕСТВЕННИКИ
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US10618887B2 (en) 2012-06-08 2020-04-14 Sunesis Pharmaceuticals, Inc. Pyrimidinyl tyrosine kinase inhibitors
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WO2021018820A1 (fr) * 2019-07-29 2021-02-04 Heparegenix Gmbh Inhibiteurs de protéine kinase de pyrazolo-pyridine substitués par hétéroaryle pour favoriser la régénération du foie ou réduire ou prévenir la mort des hépatocytes
US11174243B2 (en) 2016-07-21 2021-11-16 Sunesis Pharmaceuticals, Inc. Succinate forms and compositions of Bruton's tyrosine kinase inhibitors
EP2247558B1 (fr) 2008-02-14 2022-02-02 Eli Lilly and Company Nouveaux agents d'imagerie pour la détection d'une dysfonction neurologique
US11485734B2 (en) 2018-10-02 2022-11-01 Northwestern University Beta-carbolines as positive allosteric modulators of the human serotonin receptor 2C (5-HT2C)
US11731968B2 (en) 2018-06-21 2023-08-22 Heparegenix Gmbh Tricyclic protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
US11858927B2 (en) 2018-01-31 2024-01-02 Heparegenix Gmbh Protein kinase MKK4 inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
US11912701B2 (en) 2018-07-16 2024-02-27 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
US11945818B1 (en) 2023-09-06 2024-04-02 King Faisal University Pyrrolo[3,2-c]quinoline compounds as CK2 inhibitors
US11964981B1 (en) 2023-09-18 2024-04-23 King Faisal University Substituted pyrimido[4,5-b]indoles as CK2 inhibitors
US12011460B2 (en) 2018-02-20 2024-06-18 Universite De Montreal Expansion of NK and DC cells in vivo mediating immune response
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995019970A1 (fr) * 1994-01-25 1995-07-27 Warner-Lambert Company Composes tricycliques pouvant inhiber les tyrosines kinases de la famille des recepteurs du facteur de croissance epidermique
WO1996026941A1 (fr) * 1995-03-02 1996-09-06 Pharmacia & Upjohn Company PYRIMIDO[4,5-b]INDOLES
WO1998042708A2 (fr) * 1997-01-08 1998-10-01 Pharmacia & Upjohn Company Amines tricycliques pharmaceutiquement actives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995019970A1 (fr) * 1994-01-25 1995-07-27 Warner-Lambert Company Composes tricycliques pouvant inhiber les tyrosines kinases de la famille des recepteurs du facteur de croissance epidermique
WO1996026941A1 (fr) * 1995-03-02 1996-09-06 Pharmacia & Upjohn Company PYRIMIDO[4,5-b]INDOLES
WO1998042708A2 (fr) * 1997-01-08 1998-10-01 Pharmacia & Upjohn Company Amines tricycliques pharmaceutiquement actives

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WO2004058764A1 (fr) * 2002-12-27 2004-07-15 Bayer Healthcare Ag Derives 4-phenyl-pyrimido [4,5-b]indoles
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WO2021018820A1 (fr) * 2019-07-29 2021-02-04 Heparegenix Gmbh Inhibiteurs de protéine kinase de pyrazolo-pyridine substitués par hétéroaryle pour favoriser la régénération du foie ou réduire ou prévenir la mort des hépatocytes
WO2024233776A1 (fr) * 2023-05-09 2024-11-14 Merck Sharp & Dohme Llc Inhibiteurs à petites molécules de mutant kras g12d
US11945818B1 (en) 2023-09-06 2024-04-02 King Faisal University Pyrrolo[3,2-c]quinoline compounds as CK2 inhibitors
US11958851B1 (en) 2023-09-06 2024-04-16 King Faisal University Pyrrolo[3,2-c]quinoline compounds as CK2 inhibitors
US11970496B1 (en) 2023-09-06 2024-04-30 King Faisal University Pyrrolo[3,2-c]quinoline compounds as CK2 inhibitors
US11964981B1 (en) 2023-09-18 2024-04-23 King Faisal University Substituted pyrimido[4,5-b]indoles as CK2 inhibitors
US12180218B1 (en) 2023-09-18 2024-12-31 King Faisal University Substituted pyrimido[4,5-b]indoles as CK2 inhibitors

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CA2464934A1 (fr) 2003-05-08

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