EP1140099A1 - Verwendung von 2-substituierten 1,2-benzisothiazol-derivaten und von 3-substituierten tetrahydropyridopyrimidinon-derivaten zur prophylaxe und therapie der zerebralen ischämie - Google Patents

Verwendung von 2-substituierten 1,2-benzisothiazol-derivaten und von 3-substituierten tetrahydropyridopyrimidinon-derivaten zur prophylaxe und therapie der zerebralen ischämie

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Publication number
EP1140099A1
EP1140099A1 EP99966990A EP99966990A EP1140099A1 EP 1140099 A1 EP1140099 A1 EP 1140099A1 EP 99966990 A EP99966990 A EP 99966990A EP 99966990 A EP99966990 A EP 99966990A EP 1140099 A1 EP1140099 A1 EP 1140099A1
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European Patent Office
Prior art keywords
alkyl
branched
unbranched
substituted
mmol
Prior art date
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EP99966990A
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German (de)
English (en)
French (fr)
Inventor
Gerd Steiner
Kurt Schellhaas
Wilfried Lubisch
Uta Holzenkamp
Dorothea Starck
Laszlo Szabo
Franz Emling
Francisco Javier Garcia-Ladona
Hans-Peter Hofmann
Liliane Unger
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BASF SE
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BASF SE
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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
    • A61K31/495—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
    • A61K31/435—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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • 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
    • 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 compounds of formula I for the prophylaxis and therapy of cerebral ischemia
  • R 1 for hydrogen, (C ⁇ _ 6 ) Al yl branched or unbranched, CO- (C ⁇ _ 4 ) alkyl, C0 2 tBu, CO-aryl and a phenylalkyl- C 1 -C 4 -R.es, which in turn on the aromatic F, Cl, Br, I, 5 1 -C alkyl, C 1 -C 4 alkoxy, trifluoroethyl, hydroxy, amino, cyano or nitro may be substituted,
  • A is branched or unbranched (C ⁇ - ⁇ o) -alkylene or straight-chain or branched (C2 10) -alkylene which 0 comprises at least one group Z which is selected from 0, S, MR2, cyclopropyl, CHOH, a double or a triple bond,
  • R 2 represents hydrogen and C 1 -C 4 alkyl, 5
  • B stands for 4-piperidine, 4-tetrahydro-l, 2, 3, 6 pyridine, 4-piperazine and the corresponding ring compounds enlarged by a methylene group, the linkage to A taking place via an N atom of B and 0
  • Ar for phenyl which may be branched or unbranched by (C ⁇ _ 6 ) alkyl, O- (C ⁇ _ 6 ) alkyl branched or unbranched, OH, F, Cl, Br, I, trifluoromethyl, NR 2 2 , C0 2 R 2 , cyano or substituted phenyl, tetralin, indane, more highly condensed 5 aromatics such as naphthalene, which is optionally substituted by (C ⁇ ) alkyl or 0 (C ⁇ -) alkyl, anthracene or 5- or 6-membered aromatic heterocycles with 1 to 2 hetero - ato en, which are independently selected from O and N, which can be fused with other aromatic radicals.
  • A, X and Y have the meaning given above and Q represents a cleavable group (for example Cl, Br, I, alkanesulfonyloxy or arylsulfonyloxy), with a compound of the formula III,
  • B 1 is piperazine or homopiperazine and W is hydrogen or one of the usual amino protecting groups (such as Boc or Cbz), with a compound of general formula VIII
  • P is B (OH) 2 , SnR 3 , OTf, Br, Cl, or I and R is iC 4 -Al yl, in a known manner; or
  • B2 is 4-tetrahydro-l, 2, 3, 6-pyridine and the corresponding ring compounds enlarged by a methylene group and Pi is Cl, Br, I, SnR 3 - where R is C 1 -C 4 -alkyl, OTf with a compound of the general formula X
  • B 3 represents piperidines linked in the 1,4-position and the corresponding ring compounds enlarged by a methylene group
  • the hydrochloride was precipitated from the solution of the residue in ethyl acetate by adding 30% isopropanol / HCl solution, which was dried in a vacuum drying cabinet at 40 ° C. after suction. 17 g (67%) of substance were obtained. Mp ..- 200 ° C.
  • the aqueous phase was filtered, made alkaline and extracted with dichloromethane. After drying over sodium sulfate and extensive removal of the solvent, the mixture was diluted with diethyl ether and the hydrochloride was precipitated with ethereal hydrochloric acid. 3.2 g (67%) of the product were obtained. (Mp: 293 ° C).
  • R 1 , R 2 independently of one another represent (C ⁇ - ⁇ ) alkyl
  • R 3 , R 4 independently of one another for hydrogen, (C ⁇ _ 6 ) alkyl branched or unbranched, OH, 0- (C ⁇ - 6 ) alkyl branched or unbranched, F, Cl, Br, I, trifluoromethyl, NR 5 R 6 , C0 2 R 7 , nitro, cyano, pyrrole, for a phenylalkyl C 1 -C 4 radical, which in turn is aromatic on F, Cl, Br, I, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, trifluoromethyl , Hydroxy, amino, cyano or nitro can be substituted,
  • R 5 , R 6 independently of one another for hydrogen, (C ⁇ - 6 ) alkyl branched or unbranched, COPh, C0 2 tBu, CO- (C ⁇ _ 4 ) alkyl or together for a 5- or 6-membered ring which may optionally be a second N contains (e.g. piperazine),
  • R 7 represents hydrogen and (C ⁇ _g) alkyl branched or unbranched
  • A represents branched or unbranched (C ⁇ _ ⁇ o) alkylene or straight-chain or branched (C_ ⁇ o) alkylene which comprises at least one group Z which is selected from 0, S, NR 7 , cyclopropyl, CHOH, a double or a triple bond,
  • B represents 4-piperidine, 4-tetrahydro-l, 2, 3, 6 pyridine, 4-piperazine and the corresponding ring compounds enlarged by a methylene group, the linkage to A taking place via an N atom of B and
  • Ar for phenyl which is optionally branched or unbranched by (Ci- ⁇ ) alkyl, 0- (Ci- ⁇ ) alkyl branched or unbranched, OH, F, Cl, Br, I, trifluoromethyl, NR 5 R 6 , C0 2 R 7, cyano or phenyl, tetralin, indan, highly condensed aromatics such as naphthalene, which is optionally substituted by (C 1 - 4) alkyl or 0 (C ⁇ _ 4) is substituted alkyl, anthracene or 5- or 6-membered aromatic heterocycles having 1 up to 2 heteroatoms, which are independently selected from 0 and N, and those with others aromatic residues can be fused, for example quinoline, isoquinoline, phthalazine, indole and quinazoline, which in turn can be substituted with phenyl,
  • R 1 to R 4 and A have the meaning given above and Q represents a cleavable group (for example Cl, Br, I, alkanesulfonyloxy or arylsulfonyloxy), with a secondary amine of the formula III,
  • B 1 is piperazine or homopiperazine and W is hydrogen or one of the usual amino protecting groups (such as Boc or Cbz), with a compound of general formula VIII
  • P is B (OH) 2 , SnR 3 , OTf, Br, Cl, or I and R is C 1 -C 4 -alkyl, in a known manner; or
  • B 3 represents piperidines linked in the 1,4-position and the corresponding ring compounds enlarged by a methylene group;
  • Example 2 3, 3-Dimethyl-2- [3- (4- (2-phenylquinazoline-4-yl) piperazin-1-yl) prop-1-yl] -2, 3-dihydro-l, 2-benzisothiazole-1,1-dioxide (mp: 269 ° C., hydrochloride).
  • Example 3 3, 3-Dimethyl-2- [3- (4-quinolin-2-yl-piperazine-l-yl) prop-1-yl] -2, 3-dihydro-l, 2-benzisothiazole- l, 1-dioxide (mp: 63 ° C).
  • Example 4 3, 3-Dimethyl-2- [3- (4-naphth-l-yl-l, 4-diazapan-l-yl) prop-l-yl] -2, 3-dihydro-l, 2-benzisothiazole-l, 1-dioxide (mp: 126 ° C, hydrochloride).
  • Example 5 3,3-dimethyl-2- [3- (4- (4-chlorophthalazin-l-yl) piperazin-1-yl) eth-l-yl] -2, 3-dihydro-l, 2-benzisothiazole-l, l-dioxide (mp: 190 ° C.).
  • Example 6 3, 3-Dimethyl-2- [3- (4-naphth-l-yl-piperazine-l-yl) -2-methylene prop-l-yl] -2, 3-dihydro-1,2 -benzisothiazole-l, l-dioxide (mp: 193 ° C).
  • Example 7 3, 3-Dimethyl-2- [2- (4-quinazolin-4-yl-piperazine-1-yl) eth-1-yl] -2, 3-dihydro-1, 2-benzisothiazole- l, 1-dioxide (mp: 178 ° C, hydrochloride).
  • Example 8 3, 3-Dimethyl-2- [2- (4-naphth-l-yl-piperazine-l-yl) eth-l-yl] -2, 3-dihydro-l, 2-benzisothiazole- l, 1-dioxide (mp: 282 ° C, hydrochloride).
  • Example 9 3, 3-Dimethyl-2- [2- (4-isoquinolin-4-yl) piperazin-1-yl) eth-l-yl] -2, 3-dihydro-l, 2-benziso - thiazole-1,1-dioxide (mp: 243 ° C, hydrochloride).
  • Example 10 3,3-Diethyl-2- [2- (4-naphth-l-yl-piperazine-l-yl) eth-l-yl] -2, 3-dihydro-l, 2-benzisothiazole- l, 1-dioxide (oil).
  • Example 11 3,3-Dimethyl-2- [3- (4-naphth-l-yl-piperazine-l-yl) prop-1-yl] -6-pyrrole-l-yl-2,3- dihydro-l, 2-benzisothiazole-l, l-dioxide (mp: 269 ° C., hydrochloride).
  • the pyrrole ring was formed by reacting 3, 3-dimethyl-2- [3- (4-naphth-l-yl-piperazine-l-yl) prop-l-yl] -6-amino-2, 3-dihydro -l, 2-benzisothiazole-1, 1-dioxide with 2, 5-dimethoxytetrahydrofuran in glacial acetic acid at 100 ° C (1 h) in 86% yield.
  • Example 12 3, 3-Dimethyl-2- [3- (4-naphth-l-yl-piperazine-l-yl) prop-l-yl] -6-benzoylamido-2, 3-dihydro-l, 2-benzisothiazole-1,1-dioxide (mp: 127 ° C.).
  • Example 13 3, 3-Dimethyl-2- [3- (4-naphth-1-yl-piperazine-1-yl) prop-1-yl] -6-nitro-2, 3-dihydro-1, 2-benzisothiazole-1,1-dioxide (mp: 203 ° C.).
  • Example 14 3,3-Dimethyl-2- [2- (4- (2,3-dimethylphenyl) piperazin-1-yl) eth-l-yl] -2,3-dihydro-1,2 benzisothiazole-l, l-dioxide (mp: 291 ° C., hydrochloride).
  • Example 15 3, 3-Dimethyl-2- [2- (4-indan-4-yl-piperazine-1-yl) eth-1-yl] -2, 3-dihydro-1, 2-benzisothiazole- l, 1-dioxide (mp: 271 ° C, hydrochloride).
  • Example 16 3, 3-Dimethyl-2- [3- (4- (4-chloro-naphth-1-yl) piperazin-1-yl) prop-1-yl] -2, 3-dihydro-l, 2-benzisothiazole-l, l-dioxide (mp: 151 ° C.).
  • Example 17 3, 3-Dimethyl-2- [3- (4-pyrimidin-2-yl-piperazine-l-yl) prop-l-yl] -2, 3-dihydro-l, 2-benzisothiazole- l, 1-dioxide (mp: 263 ° C, hydrochloride).
  • Example 18 3,3-Dimethyl-2- [2- (4- (4-methoxyphenyl) piperazin-l-yl) eth-l-yl] -2, 3-dihydro-l, 2-benzoiso- thiazole-1,1-dioxide (mp: 207 ° C, hydrochloride).
  • Example 19 3,3-Dimethyl-2- [3- (4- (2-methoxyphenyl) piperazin-1-yl) -2-hydroxy-prop-l-yl] -2, 3-dihydro -l, 2-benzisothiazole-l, 1-dioxide (mp: 160 ° C).
  • Example 20 3,3-diethyl-2- [3- (4-naphth-l-yl-piperazine-l-yl) prop-l-yl] -2, 3-dihydro-l, 2-benzisothiazole- l, 1-dioxide (mp: 179 ° C).
  • Example 21 3,3-Dimethyl-2- [3- (4- (2,5-dimethylphenyl) piperazin-1-yl) prop-1-yl] -2,3-dihydro-1,2 benzisothiazole-1,1-dioxide (mp: 218 ° C., hydrochloride).
  • Example 22 3,3-Dimethyl-2- [2- (4- (2-cyano-phenyl) -piperazin-1-yl) -eth-1-yl] -2, 3-dihydro-1,2-benziso - thiazole-1,1-dioxide (mp: 228 ° C, hydrochloride).
  • 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 medicines can be used in common galenical forms of application in solid or liquid form, for example 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.
  • 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 branched or unbranched (C ⁇ _ 10 ) alkylene or straight-chain or branched (C 2 - ⁇ o) alkylene which comprises at least one group Z which is selected from 0, S, NRs, cyclopropyl, C0 2 , CHOH , a double or a triple bond,
  • B represents 4-piperidine, 4-tetrahydro-l, 2, 3, 6 pyridine, 4-piperazine or the corresponding ring compounds enlarged by a methylene group, the linkage to A taking place via an N atom of B and
  • Ar for phenyl which is branched or unbranched by (C ⁇ _ 5 ) alkyl, O- (Ci_ 6 ) alkyl branched or unbranched, OH, F, Cl, Br, I, trifluoromethyl, NR 2 2 , C0 2 R 2 , cyano or substituted phenyl, tetralin, indane, more highly condensed aromatics such as naphthalene, which is optionally substituted by (C ⁇ ) alkyl or 0 (C ⁇ _- ⁇ ) alkyl, anthracene or 5- or 6-membered aromatic heterocycles having 1 to 2 heteroatoms, the are independently selected from O and N, which can also be fused with other aromatic radicals,
  • R ⁇ R 2 independently of one another are -CC 6 alkyl
  • R 3 , R 4 independently of one another for hydrogen, (C ⁇ _ 6 ) alkyl branched or unbranched, OH, O- (C ⁇ - 6 ) alkyl branched or unbranched, F, Cl, Br, I, trifluoromethyl, NR 5 R 6 , C0R 7 , nitro, cyano, pyrrole, for a phenylalkyl C 1 -C 4 radical, which in turn is aromatic on F, Cl, Br, I, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, trifluoromethyl, hydroxy, amino , Cyano or nitro may be substituted, R 5 , R 6 independently of one another for hydrogen, (C ⁇ _ 6 ) alkyl branched or unbranched, COPh, C0 2 tBu, CO- (C 1 -. 4 ) alkyl or together for a 5- or 6-membered ring which optionally contains a second N (for example piperazine),
  • R 7 represents hydrogen and (C ⁇ _ 6 ) alkyl branched or unbranched
  • R 8 represents hydrogen and C 1 -C 4 alkyl
  • R 9 for hydrogen, (C ⁇ _ 6 ) alkyl branched or unbranched, CO- (C 1 -) alkyl, C0 2 tBu, CO-aryl and a phenylalkyl -C-C 4 radical, which in turn on the aromatic through F, Cl, Br, I, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, trifluoromethyl, hydroxy, amino, cyano or nitro can be substituted,
  • One use according to the invention also relates to neuroprotection.
  • the preparation as a medicament is carried out with a compound of the formula I or its pharmacologically acceptable acid addition salt as an active ingredient, together with customary carrier and diluent.
  • a compound of the formula I or its pharmacologically acceptable acid addition salt as an active ingredient, together with customary carrier and diluent.
  • 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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EP99966990A 1999-01-11 1999-12-22 Verwendung von 2-substituierten 1,2-benzisothiazol-derivaten und von 3-substituierten tetrahydropyridopyrimidinon-derivaten zur prophylaxe und therapie der zerebralen ischämie Withdrawn EP1140099A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19900544A DE19900544A1 (de) 1999-01-11 1999-01-11 Verwendung von Verbindungen der Formel I zur Prophylaxe und Therapie der zerebralen Ischämie
DE19900544 1999-01-11
PCT/EP1999/010275 WO2000041697A1 (de) 1999-01-11 1999-12-22 Verwendung von 2-substituierten 1,2-benzisothiazol-derivaten und von 3-substituierten tetrahydropyridopyrimidinon-derivaten zur prophylaxe und therapie der zerebralen ischämie

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EP1140099A1 true EP1140099A1 (de) 2001-10-10

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JP (1) JP2002534467A (hu)
KR (1) KR20010101440A (hu)
CN (1) CN1333685A (hu)
AR (1) AR029741A1 (hu)
AU (1) AU2285100A (hu)
BG (1) BG105688A (hu)
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CA (1) CA2359390A1 (hu)
DE (1) DE19900544A1 (hu)
HU (1) HUP0200520A3 (hu)
IL (1) IL144145A0 (hu)
MX (1) MXPA01006966A (hu)
NO (1) NO20013408L (hu)
PL (1) PL348916A1 (hu)
SK (1) SK9682001A3 (hu)
TR (1) TR200102009T2 (hu)
WO (1) WO2000041697A1 (hu)
ZA (1) ZA200105473B (hu)

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WO2004041210A2 (en) 2002-11-05 2004-05-21 Smithkline Beecham Corporation Antibacterial agents
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HUP0200520A3 (en) 2003-04-28
CA2359390A1 (en) 2000-07-20
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KR20010101440A (ko) 2001-11-14
NO20013408D0 (no) 2001-07-10
PL348916A1 (en) 2002-06-17
SK9682001A3 (en) 2002-03-05
IL144145A0 (en) 2002-05-23
MXPA01006966A (es) 2002-04-10
AU2285100A (en) 2000-08-01
AR029741A1 (es) 2003-07-16
HUP0200520A2 (hu) 2002-07-29
NO20013408L (no) 2001-08-21
WO2000041697A1 (de) 2000-07-20
BR9916888A (pt) 2001-11-20
ZA200105473B (en) 2002-10-03
JP2002534467A (ja) 2002-10-15
BG105688A (en) 2002-02-28
DE19900544A1 (de) 2000-07-13

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