Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
  • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems

Definitions

• the present invention relates to the use of 5-substituted pyridine and hexahydroquinoline-3-carboxylic acid derivatives for the production of medicaments, new active substances, a process for their preparation and their use, in particular for the treatment of diseases of the central nervous system.
• A represents aryl with 6 to 10 carbon atoms or pyridyl, which are optionally up to 3 times the same or different substituted by nitro, cyano, halogen, trifluoromethyl or by straight or branched alkyl, alkoxy or alkylthio having up to 6 carbon atoms ,
• R 1 represents hydrogen or straight-chain or branched alkyl with up to 8
• R 2 , R 3 and R 4 are the same or different and are hydrogen or methyl
• a is a number 0 or 1
• physiologically acceptable salts are preferred.
• Physiologically acceptable salts are generally salts of the invention
• Salts with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids such as, for example, acetic acid, maleic acid, fumaric acid, apple acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, are preferred,
• Ethanesulfonic acid phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid
• the compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
• the invention relates to both the antipodes and the racemic forms and the diastereomer mixtures
• A represents phenyl, naphthyl or pyridyl, optionally up to 3 times the same or different by nitro, cyano, fluorine, chlorine, bromine, iodine, trifluoromethyl or by straight-chain or branched alkyl, alkoxy or alkylthio with up to 4 carbon atoms are substituted,
• R 1 represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms
• R 2 , R 3 and R 4 are the same or different and are hydrogen or methyl
• a represents a number 0 or 1
• A represents phenyl or pyridyl, which are optionally substituted up to 2 times, identically or differently, by nitro, cyano, fluorine, chlorine, bromine, iodine, trifluoromethyl or by methyl, methoxy or methylthio,
• R 1 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
• R 2 , R 3 and R 4 are the same or different and are hydrogen or methyl
• a represents a number 0 or 1
• MID primary degenerative dementia
• PDD primary degenerative dementia
• pre-senile and senile dementia of the type of Alzheimer's disease
• HIV dementia HIV dementia and other forms of dementia
• AAMI age-related memory disorders
• They are suitable for prophylaxis, treatment and for combating the consequences of cerebral circulatory disorders such as cerebral ischemia, strokes, traumatic brain injuries and subarachnoid hemorrhages.
• They are valuable for the treatment of depression and psychoses, e.g. Schizo ⁇ phrenia. They are also suitable for the treatment of disorders of neuroendocrine secretion and of neurotransmitter secretion and related health disorders such as mania, alcoholism, drug abuse, addiction or pathological eating behavior. Other areas of application are the treatment of migraines, sleep disorders and neuropathies. They are also suitable as pain relievers.
• the active ingredients are also suitable for treating disorders of the immune system, in particular T lymphocyte proliferation and for influencing smooth muscles, in particular the uterus, urinary bladder and bronchial tract and for treating related diseases such as e.g. Asthma and urinary incontinence and used to treat hypertension, arrhythmia, angina and diabetes.
• the invention also relates to new compounds of the general formula (Ia)
• R 1 and A have the meaning given and
• R 5 represents C r C 4 alkyl
• Suitable solvents for the process are all inert organic solvents which do not change under the reaction conditions. These preferably include alcohols such as methanol, ethanol, propanol or isopropanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or diethylene glycol dimethyl ether, acetonitrile, or Amides such as hexamethylphosphoric triamide or dimethylformamide, or acetic acid or halogenated carbon Hydrogen such as methylene chloride, carbon tetrachloride or hydrocarbons such as benzene or toluene. It is also possible to use mixtures of the solvents mentioned. Isopropanol, ethanol, tetrahydrofuran, methanol, methylene chloride and dimethylformamide are particularly preferred.
• Suitable oxidizing agents are generally 2,3-dichloro-4,5-dicyan-p-benzoquinone and derivatives, pyridinium dichromate, elemental bromine, iodine and manganese dioxide. Manganese dioxide is preferred.
• the oxidizing agent is generally used in an amount of 1 mol to 20 mol, preferably 1 mol to 5 mol, in each case based on 1 mol of the dihydropyridines. In the case of MnO 2 , 5 to 20 times the amount by weight is added.
• solvents listed above are suitable as solvents for the oxidation, with methylene chloride being preferred.
• reaction temperatures can be varied over a wide range. Generally one works between + 10 ° C and + 150 ° C, preferably between + 20 ° C and + 100 ° C, especially at room temperature.
• the reactions can be carried out at normal pressure, but also at elevated or reduced pressure (e.g. 0.5 to 3 bar). Generally one works at normal pressure.
• the carboxylic acid esters are saponified by customary methods, by treating the esters with customary bases in inert solvents.
• reaction with hydrazine hydrate and the alkylation are carried out by customary methods.
• Rats C6-BUl glioma cells are used for this. From the through Data obtained from liquid scintillation is used to calculate the increase in Rb eflux caused by lonomycin over the Basalef lux and set as 100%. The stimulations in the presence of test substances are then related to this value.
• the present invention also includes pharmaceutical preparations which, in addition to inert, non-toxic, pharmaceutically suitable auxiliaries and excipients, contain one or more compounds of the general formulas (I) / (Ia) or which consist of one or more active compounds of the formulas ( I) and (Ia) exist, as well as processes for the preparation of these preparations.
• the active compounds of the formulas (I) / (Ia) should be present in these preparations in a concentration of 0.1 to 99.5% by weight, preferably 0.5 to 95% by weight, of the total mixture .
• the pharmaceutical preparations can also contain other pharmaceutical active ingredients.
• compositions listed above can be prepared in a customary manner by known methods, for example using the or the
• the active ingredient (s) / (Ia) in total amounts of from about 0.01 to about 100 mg / kg, preferably in total amounts of from about 1 mg / kg to 50 mg / kg Body weight per 24 hours, if necessary in the form of several single doses, to achieve the desired result.
• Running agent is advantageous to deviate from the amounts mentioned, depending on the type and body weight of the object being treated, on the individual behavior towards the medicament, the type and severity of the disease, the type of preparation and Application, as well as the time or interval at which the administration takes place.
• Running agent is advantageous to deviate from the amounts mentioned, depending on the type and body weight of the object being treated, on the individual behavior towards the medicament, the type and severity of the disease, the type of preparation and Application, as well as the time or interval at which the administration takes place.
• Example II Analogously to the procedure for Example I, 2.3 g (4.3 mmol) of the compound from Example II are oxidized by 10 g of manganese dioxide at RT for 1 h to 2.0 g (88% of theory) of the title compound.
• Example 1 1.5 g (3.92 mmol) l, 4,5,7-tetrahydro-4- (4-chlorophenyl) -2-methyl-7-oxo-furo [3,4-b] -pyridine-3-carboxylic acid methyl ester in 350 ml of methylene chloride with 7.5 g of manganese dioxide to 0.94 g (63% of theory) of the title compound.
• MS: 380 R j - 0.57 (methylene chloride / ethyl acetate 10 + 1)

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Psychiatry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Hospice & Palliative Care (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

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• 1994
  • 1994-08-29 DE DE4430639A patent/DE4430639A1/de not_active Withdrawn
• 1995
  • 1995-07-14 TW TW084107283A patent/TW401299B/zh not_active IP Right Cessation
  • 1995-08-16 JP JP8508446A patent/JPH10504831A/ja active Pending
  • 1995-08-16 WO PCT/EP1995/003235 patent/WO1996006610A1/de not_active Application Discontinuation
  • 1995-08-16 EP EP95929876A patent/EP0778769A1/de not_active Withdrawn
  • 1995-08-16 AU AU33460/95A patent/AU3346095A/en not_active Abandoned
  • 1995-08-16 CA CA002198495A patent/CA2198495A1/en not_active Abandoned
  • 1995-08-25 IL IL11507395A patent/IL115073A/xx not_active IP Right Cessation
  • 1995-08-28 ZA ZA957188A patent/ZA957188B/xx unknown
  • 1995-08-29 ID IDP951715A patent/ID17988A/id unknown
• 1999
  • 1999-01-28 US US09/238,569 patent/US6194428B1/en not_active Expired - Fee Related

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