Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
• • 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
• • 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

• the invention relates to the use of pyrimidine derivatives for the prophylaxis and therapy of cerebral ischemia
• R 1 is a hydrogen atom, a Ci-C-alkyl group, an acetyl or benzoyl group, a phenylalkyl C __- C_ radical, the aromatic optionally by halogen, Ci-C 4 alkyl, trifluoromethyl, hydroxy, C ⁇ -C 4th Alkoxy, amino, cyano or mitro groups is substituted, a naphthylalkyl C ⁇ C radical, a phenylalkanone C -C 3 radical or a phenylcarbamoylalkyl C 2 radical, where the phenyl group can be substituted by halogen,
• R 2 is optionally mono, di- or tri-substituted by halogen atoms, -CC alkyl, trifluoromethyl, trifluoromethoxy, hydroxy, C ⁇ -C alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups
• C represents hydrogen, methyl or hydroxy
• X represents a nitrogen atom
• Y is CH 2 , CH 2 -CH 2 , CH 2 -CH 2 -CH 2 or CH 2 -CH,
• Z represents a nitrogen atom, carbon atom or CH, where the bond between Y and Z can also be a double bond,
• n represents the number 2, 3 or 4.
• R 3 represents a cyano group or a C ⁇ _ 3 alkyl-carboxylic acid ester group
• R 4 represents C ⁇ - 3 alkyl
• C represents hydrogen, methyl or hydroxy, with a primary amine of the formula III
• R 2 and B has the meaning given above, and the compound thus obtained is optionally converted into the acid addition salt of a physiologically acceptable acid.
• reaction is conveniently carried out in an inert organic compound
• Solvents in particular a lower alcohol, for example methanol or ethanol, or a cyclic saturated ether, in particular tetrahydrofuran or dioxane, or without a solvent.
• the reaction is usually carried out at from 20 to 190 ° C., in particular from 60 to 90 ° C., and is generally completed within 1 to 10 hours.
• R 3 represents a cyano group or a C ⁇ - 3 alkyl-carboxylic acid ester group
• R 4 represents C ⁇ - 3 alkyl
• C represents hydrogen, methyl or hydroxy, with a primary amine of the formula IV
• halogenating agent e.g.
• the compounds of the formula I according to the invention can either be recrystallized by recrystallization from the customary organic solvents, preferably from a lower alcohol, such as ethanol, or purified by column chromatography.
• the free 3-substituted pyrido [4 ', 3': 4,5] thieno [2,3-d] pyrimidine derivatives of the formula I can in the usual way in the acid addition salts of a solution with the stoichiometric amount of the corresponding acid.
• Pharmaceutically acceptable acids are, for example, hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, amidosulfonic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid or citric acid.
• the aqueous phase was extracted again with methylene chloride and the combined organic phases were concentrated after drying.
• the crude product was purified by column chromatography (silica gel, mobile phase acetone). 2.3 g (72%) of product were isolated, which was dissolved in 100 ml of ethyl acetate and converted into the hydrochloride with a melting point of 233-235 ° C. using HCl / ethyl acetate solution.
• the aqueous phase was extracted again with methylene chloride and the combined organic phases were concentrated after drying.
• the crude product was purified by column chromatography (silica gel, mobile phase acetone). 1.0 g (25%) of the product was isolated, which was dissolved in 100 ml of ethyl acetate and converted into the hydrochloride having a melting point of 190-192 ° C. (decomp.) Using HCl / ethyl acetate solution.
• disorders and dysthymia This also includes anxiety such as generalized anxiety, panic attacks, sociophobia, obsessive-compulsive disorders and post-traumatic stress symptoms, memory disorders including dementia, amnesias and age-related memory.
• Q shrinkage and psychogenic eating disorders such as anorexia nervosa and bulimia nervosa.
• R 1 is a hydrogen atom, a C 1 -C 4 alkyl group, an acetyl group, a phenylalkyl C 1 -C 4 radical, the aromatic optionally being replaced by halogen, C 1 -C 4 alkyl, trifluoromethyl, hydroxy, C 1 -C 4 alkoxy, Amino, cyano or nitro groups are substituted or a carboxylic acid -C 3 -C 3 alkyl ester radical,
• R 2 is optionally mono- or disubstituted by halogen atoms, C 1 -C 4 -alkyl, trifluoromethyl, trifluoromethoxy, hydroxy, C 1 -C 4 alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups
• Phenyl, pyridyl, pyrimidinyl or pyrazinyl group optionally with a benzene nucleus, optionally by halogen atoms, C 1 -C 4 alkyl, hydroxy, trifluoromethyl, C 1 -C 4 alkoxy, amino, Cyano or nitro groups can be mono- or disubstituted and can optionally contain 1 nitrogen atom, or can be fused with a 5- or 6-membered ring which can contain 1-2 oxygen atoms,
• A represents NH or an oxygen atom
• Z represents a nitrogen atom, carbon atom or CH, where the bond between Y and Z can also be a double bond,
• R 3 represents a cyano group or a C ⁇ _-alkyl-carboxylic acid ester grouping and R 4 C ⁇ _ 3 alkyl, with a primary amine of formula III
• R 2 has the meaning given above, and the compound thus obtained is optionally converted into the acid addition salt of a physiologically acceptable acid.
• reaction is conveniently carried out in an inert organic solvent, especially a lower alcohol, e.g. Methanol or ethanol, or a cyclic saturated ether, especially tetrahydrofuran or dioxane.
• a lower alcohol e.g. Methanol or ethanol
• a cyclic saturated ether especially tetrahydrofuran or dioxane.
• the reaction is usually carried out at from 20 to 110 ° C., in particular from 60 to 90 ° C., and is generally completed within 1 to 10 hours.
• R 3 represents a cyano group or a C ⁇ _ 3 -alkyl-carboxylic acid ester group and R 4 means C ⁇ _ 3 -alkyl, with a primary amino alcohol of the formula IV
• the compounds of the formula I according to the invention can either be recrystallized by recrystallization from the customary organic solvents, preferably from a lower alcohol, such as ethanol, or purified by column chromatography.
• [3 ', 4': 4,5] thieno [2, 3-d] pyrimidine derivatives of the formula I can in the usual way in the acid addition salts of a solution with the stoichiometric amount of the corresponding acid.
• Pharmaceutically acceptable acids are, for example, hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, amidosulfonic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid or citric acid.
• the following examples serve to illustrate the invention:
• the cells were grown in RPMI 1640 medium (Life Technologies), which additionally contained 10% fetal calf serum (FCS), 2 mmol / 1 L-glutamine and 400 mg / 1 Geneticin G 418. The cells were kept until a closed, single-layer
• 35-day cell layer (“monolayer") in a so-called “tub stack” in an air / 5% CO 2 incubator incubated at 37 ° C.
• the cells were then detached from the culture vessels using a buffer of the following composition: (data per liter) trypsin 10 mg; EDTA 4 mg; EGTA 200 mg; KC1 200 mg; KH 2 P0 4
• the compounds according to the invention have a high affinity (K; 30 30 nM) for human 5-HT, 5-HT 3 and 5-HT ID receptor types which are expressed in cloned cell lines.
• radioligand solution [ 3 H] 5-carboxamidotryptamine (5-CT) for h5HTlB and h5HTlD receptors or [ 3 H] 8-hydroxy-di-propylaminotetralin (8-OH-DPAT) for h5HTlA receptors.
• the final concentrations the radioligands were set to 3 nmol / 1 and 0.3 nmol / 1, respectively.
• the assay mixture was incubated at 25 ° C. for 30 minutes and then filtered through fiberglass filters (Whatman GF / B) using a cell harvester (Skatron) and the filters were washed with 5 to 9 ml of cold buffer.
• the filters were combined in scintillation vials with 5 ml Ultima GoldxR liquid scintillator (Packard), shaken for 1 hour and then the radioactivity was determined in a beta counter (Wallac).
• the measurement data were determined by means of an iterative non-linear regression analysis using the "Statistical Analysis System (SAS), that described by Munson and Rodbard (Anal. Biochem: 107, 220 (1980))
• Disorders and dysthymia This includes anxiety such as generalized anxiety, panic attacks, sociophobia, obsessive-compulsive disorder and post-traumatic stress symptoms, memory disorders including dementia, amnesias and age-related memory loss as well as psychogenic eating disorders such as anorexia nervosa and bulimia nervosa.
• R 1 and R 2 represent a hydrogen atom or a -CC alkyl group
• R 3 is an optionally mono- or disubstituted phenyl by halogen atoms, C 1 -C 4 -alkyl, trifluoromethyl, trifluoromethoxy, hydroxy, C 1 -C 4 alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups -, pyridyl, pyrimidinyl or
• Pyrazinyl group optionally with a benzene nucleus, which may optionally be mono- or disubstituted by halogen atoms, -CC alkyl, hydroxy, trif luormethyl, -C-alkoxy, amino, cyano or nitro groups and if necessary 1
• A represents NH or an oxygen atom
• Z represents a nitrogen atom, carbon tom or CH, where the bond between Y and Z can also be a double bond,
• R 3 represents a cyano group or a C ⁇ _-alkyl-carboxylic acid ester group and R 4 C ⁇ _ 3 alkyl, with a primary amine of formula III
• reaction is conveniently carried out in an inert organic solvent, especially a lower alcohol, e.g. Methanol or ethanol, or a cyclic saturated ether, especially tetrahydrofuran or dioxane.
• a lower alcohol e.g. Methanol or ethanol
• a cyclic saturated ether especially tetrahydrofuran or dioxane.
• the reaction is usually carried out at from 30 ° to 110 ° C., in particular from 60 to 90 ° C., and is generally completed within 1 to 10 hours.
• R 1 has the meaning given above
• R 3 represents a cyano group or a C 1 -C 8 -alkyl-carboxylic acid ester group
• R 4 denotes C 3 -C 3 -alkyl, with a primary amino alcohol of the formula IV
• halogenating agent e.g.
• the compounds of the formula I according to the invention can either be recrystallized by recrystallization from the customary organic solvents, preferably from a lower alcohol, such as ethanol, or purified by column chromatography.
• the free 3-substituted pyrido [3 ', 4': 4,5] thieno [2,3-d] pyrimidine derivatives of the formula I can in the usual way in the acid addition salts of a solution with the stoichiometric amount of the corresponding acid.
• Pharmaceutically acceptable acids are for example hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, amidosulfonic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid or citric acid.
• R 1 is a hydrogen atom, a C 1 -C 4 -alkyl group, an acetyl group, a phenylalkyl C 1 ⁇ C radical, the aromatic optionally being replaced by halogen, C 1 -C 4 -alkyl, trifluoromethyl, hydroxyl, C 1 -C 4 -alkoxy, Amino, cyano or nitro groups is substituted or represents a phenylalkanone radical, where the phenyl group can be substituted by halogen,
• R 2 is an optionally mono- or disubstituted phenyl by halogen atoms, -C ⁇ C alkyl, trifluoromethyl, trifluoromethoxy, hydroxy, C ⁇ -C 4 alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups -, Pyridyl, pyrimidinyl or pyrazinyl group, optionally with a benzene nucleus, optionally by halogen atoms, -CC alkyl, hydroxy, trifluoromethyl, C ⁇ -C alkoxy, amino, cyano - or nitro groups can be mono- or disubstituted and can optionally contain 1 nitrogen atom, or can be fused with a 5- or 6-membered ring which can contain 1-2 oxygen atoms,
• A represents NH or an oxygen fatom
• Z represents a nitrogen atom, carbon atom or CH, where the bond between Y and Z can also be a double bond,
• n represents the number 2, 3 or 4.
• R 3 represents a cyano group or a C ⁇ _ 3 -alkyl-carboxylic acid ester group and R 4 means C ⁇ _ 3 -alkyl, with a primary amine of the formula III
• R 2 has the meaning given above, and the compound thus obtained is optionally converted into the acid addition salt of a physiologically acceptable acid.
• reaction is conveniently carried out in an inert organic solvent, especially a lower alcohol, e.g. Methanol or ethanol, or a cyclic saturated ether, especially tetrahydrofuran or dioxane.
• a lower alcohol e.g. Methanol or ethanol
• a cyclic saturated ether especially tetrahydrofuran or dioxane.
• the reaction is usually carried out at from 20 to 110 ° C., in particular from 60 to 90 ° C., and is generally completed within 1 to 10 hours.
• R 3 represents a cyano group or a C ⁇ _ 3 alkyl-carboxylic acid ester group and R 4 means C ⁇ _ 3 alkyl, with a primary amino alcohol of the formula IV
• halogenating agent e.g.
• the compounds of the formula I according to the invention can either be recrystallized by recrystallization from the customary organic solvents, preferably from a lower alcohol, such as ethanol, or purified by column chromatography.
• the free 3-substituted pyrido [3 ', 4': 4,5] thieno [2,3-d] pyrimidine derivatives of the formula I can in the usual way in the acid addition salts of a solution with the stoichiometric amount of the corresponding acid.
• Pharmaceutically acceptable acids are, for example, hydrochloric acid, phosphoric acid, sulfuric acid, methane sulfonic acid, amidosulfonic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid or citric acid.
• the 6-position acetyl group can be analogous to DE 19 636 769.7 with 10 percent. Hydrochloric acid are cleaved under reflux to the corresponding 30 secondary amines. The alkylations on N-6 to the 6-alkyl derivatives can also be carried out as described in DE 19 636 769.7.
• central nervous disorders such as seasonal mood disorders and dysthymia.
• anxiety such as generalized anxiety, panic attacks, sociophobia, obsessive-compulsive disorders and post-traumatic stress symptoms, memory disorders including dementia, amnesias and age-related memory loss as well as psychogenic eating disorders such as anorexia nervosa and bulimia nervosa.
• A represents NH or an oxygen atom
• C represents hydrogen, methyl or hydroxy
• E - C - NR 3 R 4 means or
• X represents a nitrogen atom
• Y is CH 2 , CH 2 -CH 2 , CH 2 -CH 2 -CH 2 or CH 2 -CH,
• Z represents a nitrogen atom, carbon atom or CH, where the bond between Y and Z can also be a double bond,
• R 1 is a hydrogen atom, a C 1 -C 4 alkyl group, an acetyl or benzoyl group, a phenylalkyl C ⁇ -C 4 radical or phenylalkoxy C 2 -C 5 radical, the aromatic optionally by halogen, C] .- C -Alkyl-, trifluoromethyl, hydroxy, C ⁇ -C -alkoxy, amino, cyano or nitro groups is substituted, a naphthylalkyl C] _- C 3 radical, a phenylalkanone C -C radical or a phenyl or Pyridylcarbamoylalkyl means C 2 radical, where the phenyl or pyridyl group can be substituted by halogen, a C ⁇ -C alkyl group, a methoxy group and by a nitro or amino group,
• R 2 is an optionally mono, di- or tri-substituted phenyl by halogen atoms, -CC alkyl, trifluoromethyl, trifluoromethoxy, hydroxy, C ⁇ C alkoxy, amino, monomethyl ino, dimethylamino, cyano or nitro groups -, pyridyl,
• Pyrimidinyl or pyrazinyl group which optionally with a benzene nucleus, optionally mono- or disubstituted by halogen atoms, -CC 4 alkyl, hydroxy, trifluoromethyl, -C 4 alkoxy, amino, cyano or nitro groups can be and optionally contain 1 nitrogen atom, or can be fused with a 5- or 6-membered ring, which can contain 1-2 oxygen atoms, or by a phenyl-C ⁇ -C 2 alkyl or. alkoxy group may be substituted, where the phenyl radical may be substituted by halogen, a methyl, trifluoromethyl or methoxy group,
• R 3 and R 4 independently of one another represent a hydrogen atom or a C 1 -C 4 -alkyl group
• One use according to the invention also relates to neuroprotection.
• the use according to the invention can take place in the usual way orally or parenterally, intravenously or intramuscularly.
• the dosage depends on the age, condition and weight of the patient and on the type of application.
• the daily dose of active substance is between approximately 1 and 100 mg / kg body weight when administered orally and between 0.1 and 10 mg / kg body weight when administered parenterally.
• the drugs can be used in common galenical forms of administration, solid or liquid, e.g. as tablets, film-coated tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, creams or sprays. These are manufactured in the usual way.
• the active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (see H. Sucker et. Al: Pharmaceuticals Technology, Thieme-Verlag, Stuttgart, 1978).
• the administration forms obtained in this way normally contain the active ingredient in an amount of 1 to 99% by weight.

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