WO2005018531A2 - Compositions pharmaceutiques, composes azo-heterocycliques et procedes de fabrication et d'utilisation correspondants - Google Patents

Compositions pharmaceutiques, composes azo-heterocycliques et procedes de fabrication et d'utilisation correspondants Download PDF

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Publication number
WO2005018531A2
WO2005018531A2 PCT/RU2004/000331 RU2004000331W WO2005018531A2 WO 2005018531 A2 WO2005018531 A2 WO 2005018531A2 RU 2004000331 W RU2004000331 W RU 2004000331W WO 2005018531 A2 WO2005018531 A2 WO 2005018531A2
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Prior art keywords
acid
dihydrogen
indole
sulfonyl
dioxo
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PCT/RU2004/000331
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English (en)
Russian (ru)
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WO2005018531A3 (fr
Inventor
Alexander Vasilievich Ivashchenko
Alexey Petrovich Ilyin
Vladimir Vasilievich Kobak
Dmitri Vladimirovich Kravchenko
Alexander Viktorovich Khvat
Sergey Yevgenievich Tkachenko
Ilya Matusovich Okun
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'chemical Diversity Research Institute' Ltd
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'chemical Diversity Research Institute' Ltd
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Priority claimed from RU2003125936/04A external-priority patent/RU2248978C1/ru
Priority claimed from RU2003125938/04A external-priority patent/RU2259999C2/ru
Priority claimed from RU2003126299/04A external-priority patent/RU2251546C1/ru
Application filed by 'chemical Diversity Research Institute' Ltd filed Critical 'chemical Diversity Research Institute' Ltd
Publication of WO2005018531A2 publication Critical patent/WO2005018531A2/fr
Publication of WO2005018531A3 publication Critical patent/WO2005018531A3/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines 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 to carbon atoms of the hetero ring
    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/12—Heterocyclic compounds containing pteridine ring systems containing pteridine ring systems condensed with carbocyclic rings or ring systems
    • C07D475/14—Benz [g] pteridines, e.g. riboflavin

Definitions

  • Sazruze-3 ⁇ ⁇
  • ge ⁇ a ⁇ e ⁇ v [ ⁇ ze ⁇ t ⁇ ⁇ .; ⁇ a ⁇ ⁇ .; ⁇ a ⁇ az ⁇ .; ⁇ ⁇ .; ⁇ 1e ⁇ Ua ⁇ e ⁇ t ⁇ ⁇ .; ⁇ izi ⁇ ⁇ .; ⁇ i ⁇ es- ⁇ 7e ⁇ zk ⁇ ⁇ .; ⁇ agteg, ⁇ .
  • SIGNIFICANT FOX (DR. 26) 25 Ethyl ether 4 - [[3- (2,4- ⁇ 2001002394 ⁇ 1, dioxo-5-thiazolidinyl-2001 den) -2,3-dihydrogen-2-oxo- ⁇ ' -indole-1-yl] - sulfonyl] -3- acid acid
  • the more recent invention is subject to a new pharmaceutical composition containing inactive active substances new inherent in the form of active substances; and ⁇ ayu ⁇ e ⁇ s ⁇ s ⁇ bu its ⁇ lucheniya and s ⁇ s ⁇ bu its ⁇ imeneniya for the treatment and ⁇ edu ⁇ ezhdeniya ⁇ azvi ⁇ iya ⁇ azlichny ⁇ zab ⁇ levany, svyazanny ⁇ with ⁇ vyshenn ⁇ y a ⁇ ivatsiey a ⁇ za, na ⁇ ime ⁇ , ⁇ s ⁇ ye ishemiches ⁇ ie ⁇ azheniya (na ⁇ ime ⁇ , insul ⁇ , in ⁇ a ⁇ mi ⁇ a ⁇ da) ney ⁇ degene ⁇ a ⁇ ivnye (na ⁇ ime ⁇ , b ⁇ lezni Pa ⁇ ins ⁇ na and ⁇ ltsgeyme ⁇ a) vi ⁇ usnye zab ⁇ levaniya (for example, he
  • the invention is also available for the new 3-oxo-1,2,3,4-tetrahydroxynosalines and 1-sulfonyl-1,3-dihydrogen-1I-indole-2-onam.
  • the following terms are used below for the terminology that are used in the description of the invention.
  • Lead Compound means a compound with an outstanding activity of a related disease.
  • “Scaffold” means a general structured formula or molecular case or an invariant area of connections, which is characteristic for all connections included in the library.
  • “REMOTE” means a series of compounds that are united by a common structure and possesses a shared property, which is, in fact, independent of it. To be honest, for example, the “new potassium channel activity assay”, or the “known inhibitory potency assay”, and so on. Generally, the presence of a common business unit in the compounds in the framework of a single technology is an unavailable and unavailable condition for unavailability.
  • Substitute means a chemical radical that is quickly connected to a synthesized process or synthesized product in the process of synthesis.
  • ⁇ As a substituent, it can be used as a halogen, hydroxyl group, carboxylic acid group, large group, or amalgamate group.
  • Preferred “inert substitutes” are C] - C 7 alkyl, C 2 - C 7 alkenyl, C 2 - C 7 alkynyl, C ⁇ - C 7 alkoxy, C 7 - C] 2 aralkyl, ⁇ 7 - ⁇ 2 alkaryl, ⁇ 3 - ⁇ cycloalkyl, ⁇ 3 - ⁇ ] 0 cycloalkenyl, phenyl, substituted phenyl, ( ⁇ 2 ) t -0- ( ⁇ - ⁇ 7 alkyl), - ( ⁇ 2 ) t - ⁇ ( ⁇ - ⁇ 7 alkyl) ⁇ , aryl, substituted aryl, heterocyclic and substituted heterocyclyl.
  • substituted alkyl means alkyl, at one or several substituents, for example, hydroxylalkyl or methyl-2-amino, amethyl a substituted amine group means an amine group, one or two substitutes, for example, acylamine group, ⁇ , ⁇ -dialkylamine group, ⁇ -acyl- ⁇ 10
  • substituted phenyl means phenyl, at one or several substitutes, for example 2-methoxyphenylphenyl, 4-amine-3-methoxyphenylphenyl, 3,4-diamine.
  • Optionally substituted group, optionally substituted group or security means, respectively, group or part of the room, which are missing or inactive.
  • “Uril” means a carbon-aromatic cycle. “Erroneous” may be a constituent person, for example, like phthaline, or an uncompensated one, for example, like a phenyl. “Substituted aryl” has one or several “non-interfering” substitutes. “Condensed system” means the presence of a condensed system, for example, such as benzimidazole, acridine or tetralin. “Condensed Cycle” or “annihilated Cycle” means the presence of a bi- or poli-cyclic system, in a cyclic “condensed” Cycle and (poli) Cycle, with a Cycle
  • aromatic cycles are benzene, naphthalene, anthracene and t. ⁇ .
  • heterogeneous cycles in the system of participation, ⁇ -electrics and ⁇ -electrics are received, their total number is also equal to 2 (4).
  • Examples of such cycles are pyridine, thiophene, pyrupul, furuan, thiazole and ⁇ . ⁇ .
  • “Optionally aromatic cycle” means the presence of a cycle, which can be somewhat aromatic, such as antacids, and non-aromatic, for example.
  • Particle means the presence of a multi- or political system, which is made up of only a large number of carbohydrates.
  • Pharmaceuticals can be aromatic, alike, and alicyclic. PERSONAL POLICY MAY HAVE ONE AND MORE THAN COMMON ATHLETES.
  • the cycles can be “saturated”, for example, like cyclohexane, or “partially saturated”, for example, like thetaline.
  • Heteril means a heterogeneous cycle, which can be a short-circuited system, for example, like a chinoline, or an undeniable one.
  • a “substitute geteril” has one or more substitutes.
  • Heterocycle means one or several saturated, partially saturated or aromatic cycles with 5, 6 or 7 atoms, which is the only one that is used. The preferred hetero- thems are sulfur, acid and nitrogen.
  • “Heterocycle” can be a condensed one, for example, like benzimidazole, benzoxazole.
  • benzothiazole quinoline, or non-condensed, such as bipyridyl.
  • Start up means a heterocycle, including, at the very least, one atom of nitrogen, for example, like benzimidazole, benzoxazole, benzothiazole, chinoline.
  • Substituted heterocycle means a heterocycle having one or more “non-interfering” substitutes.
  • Halogen means a phthorepus, cold, bromine or iodine.
  • Parallel synthesis means the method of carrying out a chemical synthesis of a combined library of individual compounds.
  • the purpose of the present invention is the creation of a new pharmaceutical compound, which has an inhibitory effect on the treatment of a serous drug, (treatment), in the case of a medication
  • treatment in the case of a medication
  • the stated goal is achieved by the pharmaceutical pharmaceutical composition, which is an active substance of the pharmaceutical industry, and is of a
  • ⁇ 1 and ⁇ 2 are independent of each other; they supply water or a non-hazardous substitute; ⁇ ⁇ , ⁇ 7, 8 and ⁇ ⁇ 9 nezavisim ⁇ d ⁇ ug ⁇ d ⁇ uga ⁇ eds ⁇ avlyayu ⁇ : a ⁇ m v ⁇ d ⁇ da, a ⁇ m gal ⁇ gena, cF 3 S ⁇ , ine ⁇ ny zames ⁇ i ⁇ el, vyb ⁇ anny of g ⁇ u ⁇ y v ⁇ lyuchayuschey niz ⁇ - or ne ⁇ ea ⁇ tsi ⁇ nn ⁇ - s ⁇ s ⁇ bny ne ⁇ byaza ⁇ eln ⁇ substituted ⁇ adi ⁇ al, ⁇ a ⁇ y ⁇ a ⁇ C 7 C alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 7 alkoxy, C 7 -C 12 aralkyl, C 7 -C ]
  • X represents an acid or a sulfur atom; S ⁇ glasn ⁇ iz ⁇ b ⁇ e ⁇ eniyu b ⁇ lee ⁇ ed ⁇ ch ⁇ i ⁇ eln ⁇ y ⁇ a ⁇ matsev ⁇ iches ⁇ y ⁇ m ⁇ zitsiey, ⁇ bladayuschey ingibi ⁇ uyuschim deys ⁇ viem in ⁇ n ⁇ shenii se ⁇ in ⁇ vy ⁇ ⁇ eaz ( ⁇ as ⁇ az) yavlyae ⁇ sya ⁇ a ⁇ zhe ⁇ m ⁇ zitsiya, s ⁇ de ⁇ zhaschaya in ⁇ aches ⁇ ve a ⁇ ivn ⁇ y subs ⁇ antsii ⁇ a ⁇ matsev ⁇ iches ⁇ i e ⁇ e ⁇ ivn ⁇ e ⁇ liches ⁇ v ⁇ zameschenny ⁇ 8 amin ⁇
  • ⁇ 10 and ⁇ 11 are independent of each other and supply hydrogen, an inert substituent, and an optionally substituted Hydroxy 1 . 6 alkyl group, optionally substituted with amino C; a radical group, optionally substituted with C].
  • b alkil-karuboksi. 6 alkaline group optionally substituted by ⁇ . 6 alkyl group, optionally substituted with group group, substituted with group group; or
  • ⁇ 10 and ⁇ 11 together with the nitrogen they are disconnected, they are optionally replaced and optionally have a non-hazardous battery, they are 3-, or ⁇ 10 and ⁇ 11 together with nitrogen, they are disconnected, they are equipped with a non-hazardous, non-hazardous and non-hazardous product.
  • ⁇ 12 and ⁇ 13 are independent of each other and supply hydrogen or an inert substitute.
  • ⁇ 14 and ⁇ 15 independently of each other, they are supplied with hydrogen, an inert substituent, optionally substituted with a hydroxy- 5 alkyl group, and an optionally substituted amine 7 .
  • ⁇ 1 , ⁇ 2 , ⁇ 6 and ⁇ 7 have the above meaning
  • ⁇ 16 represents a substituted sulphanyl group, a substituted sulphinyl group or a substituted sulphonyl group. According to the invention, a more preferable pharmaceutical company,
  • a pharmaceutical pharmaceutical component which is a component of an active pharmaceutical ingredient, 1.1, 2.1, 2.1, 2.1, 2.1
  • the purpose of the present invention is also a new method of manufacturing a pharmaceutical composition by mixing an active substance with an inert solvent, a diluent and / or a separator.
  • ⁇ 4 provides optionally substituted alkyl, optionally substituted cyclic, optionally substituted aryl, optionally substituted heterocyclic; ⁇ 5 It provides an acid or a carbohydrate that is excluded from a slightly hazardous, slightly substituted, and non-hazardous substance that does not X represents an acid or a sulfur atom;
  • ⁇ 1 , ⁇ 2 , ⁇ 6 , ⁇ 7 and ⁇ 16 have the above meaning.
  • the goal is also achieved by replacing 3-oxo-1,2,3,4-tetrahydroxyhydroxaline-acid and their derivative of general formula 2.1.1
  • ⁇ 17 Provides an optionally substituted, large group, an optionally substituted, large group, an optionally substituted aromatic group, or a non-essential group.
  • the purpose of the present invention is also the creation of new 1-sulfonyl-1,3-dihydrogen-1 I-indole-2-ammonia. The stated goal is achieved by the substituted 1-sulfonyl-1,3-dihydrogen-1 ⁇ -indole-2-ones of the general formula 3.1
  • ⁇ 4 , ⁇ 6 and ⁇ 7 have the above meaning, with the exception of: 1-methylsulfonyl-Sh-indole-2,3-dione, 1-benzylsulfonyl-Sh-indole-2,3-dione, 5-brom-1 -benzenesulfonyl- Sh-indole-2,3-dione, 1 - (2-nitro-benzene sulphonyl) - 1Ya-indole-2,3 - dione, 1 - (toluene-4-sulfonyl) - Sh-indole-2,3 -Dione, 5-methyl- 1 - (toluol-4-sulfonyl) -SH-indol-2,3-dione, 5-cool-1- (toluol-4-sulfonyl) -Sh-indol-2,3-di , 5-methoxy-1- (tolu)-
  • ⁇ 4 , ⁇ 6 , ⁇ 7 and X have the above meaning; ⁇ 18 It provides water or a non-hazardous substituent, excluding: 1- (phenylsulfonyl) -1,3-dihydrogen-3- (4-oxy-2-tioxo-5-thiazolidinylidene-2-I-2-I- 2,5-dichloro-phenyl) sulfonyl] -1,3-dihydro-3- (4-octo-2-thioco-5-thiazolidinylidene-2H-indole-2-one, 1 - [(2,4,5- ⁇ ihylo ⁇ phenyl) sulfonyl] -1,3-dihydrogen-3- (4- oxycod-2-tioxo-5-thiazolidinylidene-2-indole-2-one, 1- (phenylsulfonyl)
  • Table 2 lists some 2,3-dihydrogen-1 ⁇ -benzo [ ⁇ ] synthesized 4-compounds of general formula 1.1, which are obtained above. Table 2. The well-known 2,3-dihydrogen-Sh-benzo [ ⁇ ] p-teridine-4-one of the general formula 1.2.
  • 1-sulfonyl-1J-indole-2,3-diodes 3.1.1 may be obtained from the procedures described in table 1 for the known 1-sulfonyl-1J-indole-2,3-diodes; Production of 1- sulfonyl-3- (4-oxo-thiazolidin-5-ylidene) -1, 3-dihydrogen-1I-indole-2-compounds 3.1.2, it is possible to carry out the procedures described in [ ⁇ . ⁇ 08092248, 1994], proceeding from the compounds
  • Nanocarboxylic acid (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benz [ ⁇ ] p-teridin-8-yl) - amide 1.1 ⁇ 22 ⁇ ; ⁇ - (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydride-benzo [ ⁇ ] p-teridin-8-yl) benzamide 1 ⁇ 23 ⁇ ;
  • Nanocarboxylic acid (1,3,7- ⁇ -methyl-2,4-dioxo-1,2,3,4-tetrahydride-benz [ ⁇ ] p-teridin-8-yl) - amide 1.1 ⁇ 36 ⁇ ;
  • Nanocarboxylic acid (1,3,9- ⁇ -methyl-2,4-dioxo-1,2,3,4-tetrahydride-benz [ ⁇ ] p-teridin-8-yl) - amide 1.1 ⁇ 45 ⁇ ;
  • Heptanoic acid (3-allyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydride-benz [ ⁇ ] n-teridin-8-yl) -amide 1.1 ⁇ 62 ⁇ ;
  • Nanocarboxylic acid (3-butyl-2,4-dioxo-1,2,3,4-tetrahydride-benz [ ⁇ ] n-teridin-8-yl) -amide
  • Heptanoic acid (3-hydroxyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydride-benz [ ⁇ ] n-teridin-8-yl) -amide 1.1 ⁇ 92 ⁇ ;
  • Nanocarboxylic acid (3-cyclohexyl-2,4-dioxo-1,2,3,4-tetrahydride-benz [ ⁇ ] sawridin-8-yl) - amide 1.1 ⁇ 5 ⁇ ;
  • Nanocarboxylic acid (3-cyclohexyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydroxybenzo [ ⁇ ] n-teridin-8-yl) -amide 1.1 ⁇ 706 " ⁇ ;
  • Nanocarboxylic acid (3-benzyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydride-benz [ ⁇ ] sawridin-8-yl) -amide 1.1 ⁇ 775 ⁇ ;
  • Nanocarboxylic acid (7-methyl-2,4-dioxo-1,2,3,4-tetrahydride-benz [ ⁇ ] n-teridin-8-yl) -amide
  • the reactive mixture is heated at 80-90 ° C and with constant stirring for 2-12 hours.
  • the dry mass is gradually cooled by stirring at 10 ° C and acidified with 2% salted acid. 5.
  • the resulting product is dried and washed with 100 ml of oil. Receive acid 14, which is used for further synthesis without additional calculation. ⁇ Pond 85-95%.
  • the reactive mixture is heated at 80-90 ° C and with continuous stirring for 8-14 hours.
  • the resulting product is separated, washed 5 times with 100 ml of water and dried. Receive acid 16, which is used in the future synthesis without additional calculation. ⁇ Pond 70-90%.
  • the obtained plant dries over a five-phase powder for a constant weight, 2.1 is obtained with an output of 70-80%, including: 2- (3-bromo-phenylmethanesulphin-4-tet-3-tet-3-t-ith-3-t-ith-3-t - ⁇ bonic acid 2 ⁇ ⁇ 24 ⁇ : ⁇ - ⁇ ( ⁇ -êt? 6 ) ⁇ - ⁇ ⁇ 3.38 (t, W, ⁇ - ⁇ 2-502); 3.71 ( ⁇ , W, C ⁇ -
  • 2-Benzylsulfonylmet has - 7-trifluoromeths-3-oxy-1,2,3,4-tetrahydroxylin 2.1 ⁇ 37 ⁇ : Cor. weight 384.38, IX ⁇ , t / ⁇ 385 ( ⁇ + 1).
  • Example 4 The general method for the synthesis of substituted amides of Z-oxo-1, 2,3,4-tetrahydroxin-7-carboxylic acid 2.1.1.
  • the inactive mass is diluted with 2 ml of water, the precipitate is filtered off, dried in a vacuum, washed with ethanol or ethyl acetate. After drying, the combined library of famous and new 1-sulphonyl-1 ⁇ -indol-2-nov 3.1.1: 0 1-Nomadul-S-indol-2,3-din 3.1.1 (1): weight 225.22.
  • Table 5 shows the activity of two of the tested 1-sulfonyl-1,3-dihydrogen-indole-2-inones 3.1.2 (3 ⁇ and 3.1.2 (4 ⁇ , and in FIG. 3 it is shown ⁇ The increased dependence of inhibition of the concentration of 3. Table 3.
  • Example 10 Example of a table. Mix 1600 mg of starch, 1600 mg of crushed lactose, 400 mg of talc and 1000 mg of 2,2,2- ⁇ r ⁇ ⁇ ⁇ ⁇ -(- (7-methyl-4-- ⁇ ⁇ ⁇ 2- Wunsch ⁇ ⁇ ⁇ -1,2 1,2,3,4- Canal ⁇ ⁇ ⁇ ⁇ Provision ⁇ benzene [ ⁇ ] n-theteridin-8-yl) -acetamide 1.1 ⁇ 75 ⁇ , and then is transferred to a bead. The resulting strand is crushed into granules and sifted through a sieve, collecting granules with a size of 14-16 mesh. Received granules are tested in the form of tablets with a weight of 560 mg each.
  • EXAMPLE 11 EXAMPLE OF CAPSULES ⁇ a ⁇ suly s ⁇ de ⁇ zhaschie s ⁇ edineniya 200 mg 1.1 (75 ⁇ ⁇ luchayu ⁇ ⁇ scha ⁇ elnym mixing s ⁇ edineniya 1.1 (75 ⁇ with ⁇ sh ⁇ m la ⁇ zy s ⁇ n ⁇ shenii in 2: 1 mixture P ⁇ luchennuyu ⁇ sh ⁇ b ⁇ aznuyu u ⁇ a ⁇ vyvayu ⁇ ⁇ 300 mg zhela ⁇ in ⁇ vye ⁇ a ⁇ suly ⁇ d ⁇ dyascheg ⁇ ⁇ azme ⁇ a P ⁇ ime ⁇ 12.
  • Injection It is obtained by mixing 500 mg of an active ingredient with a suitable solution, for example, hydrochloride compound 1.1 (75 ⁇ , with a dose of 100 mg of a drug, 2 ml It is just 1 ml in ampoules, which are sealed and sterilized in an autoclave.
  • the invention can be used in medicine, veterinary medicine, biochemistry, and general chemistry.
  • Example 10 Example of a table. Mix 1600 mg of starch, 1600 mg of crushed lactose, 400 mg of talc and 1000 mg of 2,2,2- ⁇ r conducted ⁇ ⁇ -(- (7-methyl-4--vic-2- conducted ⁇ ⁇ -1,2 1,2 1,2 ⁇ Provision ⁇ ⁇ Provision ⁇ ⁇ Provision ⁇ benzene [ ⁇ ] ertteridin-8-yl) -acetamide 1.1 (75 ⁇ , and then it is pulverized. The resulting bead is crushed into granules and is electrically charged; Each Example 11.

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Abstract

La composition pharmaceutique de l'invention manifeste une activité inhibitrice par rapport à la sérine protéinase (Kaspaz) et comprend un principe actif ayant la forme d'une quantité pharmaceutiquement acceptable d'un composé azo-hétérocyclique ayant la formule générale 1, 2 et 3, ou de leur sel, avec un acide, un hydrate ou un N-oxyde pharmaceutiquement acceptable.
PCT/RU2004/000331 2003-08-26 2004-08-25 Compositions pharmaceutiques, composes azo-heterocycliques et procedes de fabrication et d'utilisation correspondants Ceased WO2005018531A2 (fr)

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RU2003125936/04A RU2248978C1 (ru) 2003-08-26 2003-08-26 Фармацевтические композиции, способ их получения и применения
RU2003125938 2003-08-26
RU2003125938/04A RU2259999C2 (ru) 2003-08-26 2003-08-26 1-сульфонил-1,3-дигидроиндол-2-оны, фармацевтические композиции (варианты), способ их получения и применения
RU2003125936 2003-08-26
RU2003126299/04A RU2251546C1 (ru) 2003-08-29 2003-08-29 Замещенные 3-оксо-1,2,3,4-тетрагидрохиноксалины, фармацевтические композиции (варианты), способ их получения и применения
RU2003126299 2003-08-29

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US9351974B2 (en) 2011-11-10 2016-05-31 OSI Pharmaceuticals, LLC Substituted pteridinones for the treatment of cancer

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PT509398E (pt) * 1991-04-15 2002-02-28 Aventis Pharma Gmbh Quinoxalinas processo para a sua preparacao e sua utilizacao
DE4342024A1 (de) * 1993-12-09 1995-06-14 Hoechst Ag Kombinationspräparate, enthaltend ein Chinoxalin und ein Nukleosid
DE4437406A1 (de) * 1994-10-19 1996-04-25 Hoechst Ag Chinoxaline, Verfahren zu ihrer Herstellung und ihre Verwendung
ATE243034T1 (de) * 1996-01-17 2003-07-15 Taiho Pharmaceutical Co Ltd Intimale verdickungsinhibitoren
AU6062900A (en) * 1999-07-01 2001-01-22 Geron Corporation Substituted indole compounds and their use for the treatment of cancer
FR2827604B1 (fr) * 2001-07-17 2003-09-19 Sanofi Synthelabo Nouveaux derives de 1-phenylsulfonyl-1,3-dihydro-2h-indol-2- one, un procede pour leur preparation et les compositions pharmaceutiques en contenant

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US9351974B2 (en) 2011-11-10 2016-05-31 OSI Pharmaceuticals, LLC Substituted pteridinones for the treatment of cancer

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