WO2002069972A2 - Triazole compounds and the use thereof in the prophylaxis and therapy of neurodegenerative diseases, cerebral trauma and cerebral ischemia - Google Patents
Triazole compounds and the use thereof in the prophylaxis and therapy of neurodegenerative diseases, cerebral trauma and cerebral ischemia Download PDFInfo
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- WO2002069972A2 WO2002069972A2 PCT/EP2002/002202 EP0202202W WO02069972A2 WO 2002069972 A2 WO2002069972 A2 WO 2002069972A2 EP 0202202 W EP0202202 W EP 0202202W WO 02069972 A2 WO02069972 A2 WO 02069972A2
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- Prior art keywords
- phenyl
- alkyl
- use according
- methyl
- compounds
- Prior art date
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- -1 Triazole compounds Chemical class 0.000 title claims abstract description 164
- 238000011321 prophylaxis Methods 0.000 title claims abstract description 11
- 238000002560 therapeutic procedure Methods 0.000 title claims abstract description 11
- 206010008118 cerebral infarction Diseases 0.000 title claims abstract description 9
- 201000006474 Brain Ischemia Diseases 0.000 title claims abstract description 8
- 206010008120 Cerebral ischaemia Diseases 0.000 title claims abstract description 8
- 230000004770 neurodegeneration Effects 0.000 title claims abstract description 8
- 208000015122 neurodegenerative disease Diseases 0.000 title claims abstract description 7
- 230000002490 cerebral effect Effects 0.000 title abstract description 4
- 208000014674 injury Diseases 0.000 title abstract 2
- 230000008733 trauma Effects 0.000 title abstract 2
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
- 208000006011 Stroke Diseases 0.000 claims abstract description 9
- 208000037921 secondary disease Diseases 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 57
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000002947 alkylene group Chemical group 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
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- 125000001424 substituent group Chemical group 0.000 claims description 9
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
- QVWDCTQRORVHHT-UHFFFAOYSA-N tropone Chemical compound O=C1C=CC=CC=C1 QVWDCTQRORVHHT-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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
- C07D401/12—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 chain containing hetero atoms as chain links
-
- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K31/495—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
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- 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
- A61P25/28—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
-
- 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
- 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
- C07D401/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- 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
Definitions
- the invention relates to triazole compounds and their use for the prophylaxis and therapy of neurodegenerative diseases, brain trauma and cerebral ischemia, in particular stroke, and the secondary diseases caused by these diseases.
- Neurodegenerative diseases such as multiple sclerosis and Alzheimer's, brain trauma and cerebral ischemic events, especially stroke, and their complications are serious diseases that are currently difficult to treat with medication.
- WO 99/02503 describes triazole compounds and their use for the treatment of diseases of the central nervous system.
- the compounds described there are selective dopamine D 3 receptor ligands.
- Ar 1 represents phenyl, naphthyl, a 5- or 6-membered heteroaromatic ring with 1, 2, 3 or 4 heteroatoms, which are selected independently of one another from 0, S and N, indolyl, benzofuranyl or benzothienyl, where Ar 1 optionally has 1 or 2 substituents which are independently selected from C !
- -C 6 alkyl which is optionally substituted by fluorine or phenyl, hydroxy, Cx-Ce alkoxy, C 2 -c 6 alkenyl, C 3 -C 6 cycloalkyl, halogen, CN, COOR 2 , NR 3 R 4 , N0 2 , S0 2 R 5 , S0 2 NR 3 R 4 and phenyl, optionally by Ci-C ⁇ -alkyl, Ci-C ⁇ - alkoxy, Ci-C 6 -alkoxy-C ⁇ -C 6 -alkyl, CN, CF 3 , CHF, or halogen is substituted;
- R 1 represents H, C 3 -C 6 cycloalkyl or Ci-Cg-alkyl, which is optionally substituted by OH, Ci-Cg-alkoxy, fluorine or phenyl;
- R 2 , R 3 , R 4 and R 5 which may be the same or different, for H or Ci-Ce-alkyl, which may be replaced by OH,
- OCi-Cs-alkyl or phenyl is substituted, or two radicals R 3 , R 4 together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered nitrogen heterocycle, which may contain an NH-, N- -C ⁇ - C-alkyl group or an oxygen tom can have as ring member, where R 5 can also mean phenyl or tolyl;
- Ar 2 represents naphthyl, azanaphthyl or diazanaphthyl, which may be hydrogenated in the condensed ring which is not bonded to X and which may contain 1, 2, 3 or 4 substituents. ten, selected from OH, Ci-C ö alkyl, Cx-C ß alkoxy, phenoxy, Ci-C ⁇ -haloalkyl, halogen, CN, and N0 2 ;
- the invention thus relates to the use of triazole compounds of the formula I defined above and of their salts with physiologically tolerated acids for the prophylaxis and therapy of neurodegeneration, brain trauma, cerebral ischemia, in particular stroke, and the secondary diseases caused by these diseases.
- the invention also relates to the manufacture of a medicament for the therapy and prophylaxis of these diseases.
- At least one compound of the general formula I with the meanings mentioned at the outset is used to treat the above-mentioned indications.
- the compounds of the formula I have one or more centers of asymmetry, it is also possible to use enantiomer mixtures, in particular racemates, diastereomer mixtures, tautomer mixtures, but preferably the respective essentially pure enantiomers, diastereomers and tautomers.
- Physiologically tolerable salts of the compounds of the formula I can also be used.
- suitable physiologically acceptable organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid or benzoic acid. Further usable acids are described in advances in drug research, volume 10, pages 224 ff., Birkhäuser Verlag, Basel and Stuttgart, 1966.
- halogen includes a fluorine, chlorine, bromine or iodine atom and in particular a fluorine or chlorine atom.
- Terms such as C n -C m alkyl, C n -C m alkoxy, etc. include straight-chain or branched hydrocarbon groups, the prefix C n -C m each indicating the possible number of carbon atoms in the group. For example:
- -CC 4 alkyl for: methyl, ethyl, n-propyl, isopropyl, n-butyl,
- Ci-Cg-alkyl e.g. for: -C-C-alkyl as mentioned above, such as e.g. n-pentyl, 2-pentyl, 2-methylbutyl, 3-methylbutyl,
- C ⁇ -C 4 alkoxy for: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, iso-butoxy or ter-butoxy, preferably for methoxy, ethoxy or isopropoxy;
- Ci-C ö alkoxy for example for: C ⁇ -C alkoxy as mentioned above, and for example n-pentyloxy, 2-pentyloxy, 2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, n -Hexoxy, 1, 1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy , 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1, 1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1 -Ethyl-l-methylpropoxy or l-ethyl-2-methylpropoxy, preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-but
- alkyl, alkoxy, etc. include in particular:
- Ci-Cg-alkyl (Ci-Cg-haloalkyl) partially or completely substituted by fluorine, chlorine, bromine and / or iodine, e.g. one of the radicals mentioned under C 1 -C -haloalkyl and for 5-fluoro-1-pentyl, 5-chloro-1-pentyl, 5-bromo-1-pentyl, 5-iodo-1-pentyl, 5.5, 5 Trichloro-1-pentyl, undecafluoropentyl, 6-fluoro-1-hexyl, 6-chloro-1-hexyl, 6-bromo-1-hexyl, 6-iodo-1-hexyl, 6,6, 6-trichloro l-hexyl or tridecafluorohexyl;
- alkyl which is preferably monosubstituted by phenyl, for example: benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylprop-1-yl, 2-phenylprop-l-yl, 3-phenylprop-l-yl, 1-phenylbut-l-yl, 2-phenylbut-l-yl, 3-phenylbut-l-yl, 4-phenylbut-l-yl, l-phenylbut-2-yl, 2-phenylbut-2- yl, 3-phenyl-but-2-yl, 4-phenylbut-2-yl, l- (phenylmethyl) -eth-l-yl, l- (phenylmethyl) -l- (methyl) -eth-l-yl or 1- (phenylmethyl) prop-l-yl, preferably benzyl or 2-phenylethyl.
- cycloalkyl encompasses mono- or polycyclic saturated hydrocarbon groups with - unless otherwise stated - preferably 3 to 6 and in particular 5 or 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
- alkylene basically includes straight-chain or branched radicals, such as methylene, eth-1,1-ylene, eth-1,2-ylene, prop-1,1-ylene, prop-1,2-ylene, prop-1 , 3-ylene, prop-2, 2-ylene, but-1, 1-ylene, but-1, 2-ylene, but-1, 3-ylene, but-l, 4-ylene, but-2,2 -ylene, 2-methylprop-l, 3-ylene, pent-1, 1-ylene, pent-1,2-ylene, pent-l, 3-ylene, pent-l, 4-ylene, pent-1,5 -ylene, pent-2,2-ylene, pent-2,3-ylene, pent-2, 4-ylene, pent-3,3-ylene, 1-methyl-but-l, 4-ylene, 2-methylbut -l, 4-ylene, etc., preferably with - unless stated otherwise - 1 to 18, in particular 2 to 10 and particularly preferably 3 to 8 carbon atoms
- the two binding sites of the alkylene chain are preferably not on the same atom but instead, optionally together with the at least one group Z, form an at least three-membered and preferably at least four-membered chain which separates the triazole ring from the nitrogen atom of the (part ) separates saturated nitrogen heterocycle by at least 4 and preferably by at least 5 bonds.
- the saturated bonds in alkenylene can be replaced by unsaturated bonds (alkenylene; alkynylene). This may result in straight-chain or branched unsaturated radicals whose number and arrangement of the carbon atoms corresponds to that of the alkylene radicals mentioned above, but one or several single bonds through corresponding unsaturated double or Triple bonds are replaced.
- the alkylene group in A comprises at least one of the groups Z, this can be arranged anywhere in the alkylene chain or in position 1 or 2 of group A (as viewed from the rest of Ar 1 ).
- Z is preferably in position 1, ie Z is bonded to the triazole ring.
- the CONR 3 and COO radicals are preferably arranged such that the carbonyl group is bonded to the triazole ring.
- Examples of "5- or 6-membered aromatic heterocyclic radicals which have 1, 2, 3 or 4 heteroatoms selected from 0, S and N" are, in particular, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, pyrrolyl, Pyrazolyl, thienyl, furanyl, oxazolyl, thiazolyl, isoxazolyl, tetrazolyl, thiadiazolyl and triazolyl. These can have 1 or 2 of the abovementioned substituents on the nitrogen atoms and on the carbon atoms. If one of the substituents is hydroxy, the radicals can also be in a tautomeric form with a carbonyl group.
- Azanaphthyl is synonymous with quinolinyl (1-azanaphthyl), isoquinolinyl (2-azanaphthyl) and 4H-quinolizinyl.
- Diazanaphthyl is synonymous with quinazolinyl, quinoxalinyl, cinnolinyl and 1,8-naphthyridinyl.
- Partially hydrogenated naphthyl, azanaphthyl and diazanaphthyl residues are the di- and tetrahydro derivatives, whereby in the compounds according to the invention only the ring not bound to X can be hydrogenated.
- the (partially) hydrogenated ring preferably does not have a nitrogen atom as a ring member, as in 5,6, 7, 8-tetrahydro naphthyl, 5, 6, 7, 8-tetrahydroquinolinyl, 5, 6, 7, 8-tetrahydroisoquinolinyl, 5 , 6,7,8-tetrahydroquinazolinyl.
- the naphthyl, azanaphthyl and diazanaphthyl radicals are preferably bonded to X via the ⁇ position (i.e. via the 1-, 4-, 5- or 8-position).
- Preferred substituents on Ar 1 are CN, CH 3 , OH, 0CH 3 , halogen, phenyl and tert. Butyl.
- Ar 1 is unsubstituted or has one or two substituents, for example a methyl group, one or two methoxy groups.
- Ar 1 represents phenyl, pyrrolyl, especially 2-pyrrolyl, 1-methylpyrrolyl, especially l-methylpyrrol-2-yl, thienyl, especially 2-thienyl, indolyl, especially 2-indolyl, pyridinyl, pyrazinyl or pyrimidinyl ;
- Z preferably stands for 0, SO or S0 2 and in particular for S.
- a very particularly preferably stands for S- (CH 2 ) k with k 2, 3, 4 or 5 and in which S is bonded to the triazole radical.
- R 1 is hydrogen, Ci-Cg-alkyl, C 3 -C 6 cycloalkyl, in particular Ci-Cö-alkyl and especially methyl;
- R 2 are hydrogen, C alkyl, hydroxy-C ⁇ -C4 alkyl, methoxy C ⁇ -C 4 -alkyl, phenyl-C 1 -C 4 alkyl;
- R 3 is hydrogen, C 1 -C 4 alkyl
- R 4 is hydrogen, -CC alkyl, or R 3 and R 4 together with the nitrogen atom to which they are attached form a pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl radical;
- R 5 -CC 4 alkyl, phenyl or tolyl Particularly preferred are the compounds of the general formulas I-Al, I-A2, I-Bl, I-B2, I-Cl and I-C2, in which Ar 1 , R 1 , Z, X and Y are those mentioned above, in particular those mentioned as being preferred meanings a 'is C 2 -C ⁇ o- and in particular C 3 -C 6 -alkylene -Al- and a "is C 3 -C ⁇ o- and in particular C 4 -CG -alkylene, wherein alkylene is a double bond can have and in particular is saturated.
- Z in particular represents sulfur.
- the compounds I can in principle be prepared analogously to known processes of the prior art, as are already described in WO 99/02503. Processes i) to v) described below are particularly suitable for preparing the compounds (I).
- Y 1 represents a conventional leaving group such as halogen, for example bromine or iodine, alkanesulfonyloxy, arylsulfonyloxy or the like, with a compound of the general formula (III)
- Y 1 has the meaning given above and A 2 represents C 2 -C ⁇ o-alkylene, wherein A 1 and A 2 together have 3 to 10 C-Ato e and A 1 and / or A 2 optionally comprise at least one group Z. ; or
- Z 2 represents CO or a methylene group and Z 2 and A 2 together have 4 to 8 carbon atoms, or
- Y 2 represents a phosphorane or a phosphonic acid ester
- customary methods as described, for example, in Houben Weyl "Manual of Organic Chemistry” 4th edition, Thieme Verlag Stuttgart, volume V / lb p. 383 ff or volume V / lc p .575 ff is implemented.
- the compounds of the formulas II, IV, VI and VIII and residues of Tv p Ar 1 and Ar 2 are known from the prior art, for example from WO 99/02503 or can be prepared by known processes, for example as described in S. Kubota et al. Chem. Pharm. Bull 1975, 23, 955 or AR Katritzky, CW Rees (ed.) "Comprehensive Heterocyclic Chemistry", Pergamon Press, or "The Chemistry of Heterocyclic Compounds"'J. Wiley & Sons Inc. NY and the literature cited therein.
- the compounds of formula (III) are starting compounds for the preparation of compounds of formulas (V) and (VII) and are by standard methods, such as. B. described in JA Kiristy et al., J. Med. Chem. 1978, 21, 1303 or CB Pollard, J. Am. Chem. Soc. 1934, 56, 2199, or by making
- Q is H or a common amino protecting group, e.g. B. butyloxycarbonyl, benzyl or methyl
- Y 3 is a leaving group, for. B. triflate, Sn (butyl) 3 , B (0H) 2 , B (0R ') 2 or halogen, with a compound of the general formula (XIV)
- Y 4 for a boronic acid or boronic ester residue e.g. for B (0H) 2 , B (0R ') 2 or a metal-containing leaving group, e.g. B.
- SnR 3 (R butyl or phenyl) or zinc halide when Y 3 is halogen or trifluoromethylsulfonyloxy or Y 4 is halogen or trifluoromethylsulfonyloxy when Y 3 is a boronic acid or boronic ester radical such as B (0H) 2 , B ( 0R ') 2 or for a metal-containing leaving group, e.g. B.
- Any subsequent elimination can be carried out using strong acids, preferably thionyl chloride or polyphosphoric acid.
- the subsequent elimination is generally carried out at temperatures in the range from 0 to 80 ° C. and expediently in an inert organic solvent, in particular a halogenated hydrocarbon, or without a solvent.
- Some special compounds of formula I which have a sulfinyl or sulfonyl grouping at A, are prepared from the underlying final stages of formula I by specific oxidation methods of suitable precursors, e.g. by oxidation with methachloroperbenzoic acid or with chlorine water.
- the reactions described above are generally carried out in a solvent at temperatures between room temperature and the boiling point of the solvent used.
- Usable solvents are, for example, esters, such as ethyl acetate, ethers, such as diethyl ether or tetrahydrofuran, dimethyl formate, dimethyl sulfoxide, dimethoxyethane, toluene, xylene, ketones, such as acetone or methyl ethyl ketone, or alcohols, such as ethanol or butanol.
- Suitable acid-binding agents are inorganic bases, such as sodium or potassium carbonate, sodium or potassium hydrogen carbonate, sodium ethylate, sodium hydride or organometallic compounds, such as butyllithium or alkylmagnesium compounds, or organic bases, such as triethylamine or pyridine. The latter can also serve as solvents.
- the reactions are optionally carried out using a catalyst, e.g. Transition metals and their salts or complexes, e.g. Tetrakis [triphenylphosphine] palladium, bis [triphenylphosphine] palladium (II) chloride, palladium acetate or tetrakis [tri- o-tolylphosphine] palladium, and / or a phase transfer catalyst, e.g. Tetrabutylammonium chloride or Tetrapropyla monium bromide.
- a catalyst e.g. Transition metals and their salts or complexes, e.g. Tetrakis [triphenylphosphine] palladium, bis [triphenylphosphine] palladium (II) chloride, palladium acetate or tetrakis [tri- o-tolylphosphine] palladium, and / or a phase transfer catalyst, e.g. Te
- the crude product is isolated in the customary manner, for example by filtration, distilling off the solvent or extraction from the reaction mixture etc.
- the compounds obtained can be purified in the customary manner, for example by recrystallization from a solvent, chromatography or conversion into an acid addition compound.
- the acid addition salts are in a conventional manner by mixing the free base with the corresponding acid, optionally in solution in an organic solvent, for example a lower alcohol, such as methanol, ethanol or propanol, an ether, such as methyl t-butyl ether, a ketone, such as Acetone or methyl ethyl ketone or an ester such as ethyl acetate.
- 5-HT A receptors those which have a high affinity for 5-HT A receptors are particularly advantageous according to the invention.
- particular preference is given to compounds which have in vitro Ki values of less than 100 nM, in particular less than 10 nM and in particular less than 5 nM.
- Suitable test methods for selecting these compounds are known to the person skilled in the art.
- binding affinities for 5-HTi A receptors can be determined in receptor binding studies via the displacement of 3 H-8-OH-DPAT.
- test systems described above and other similarly suitable test systems can form the basis for in vitro screening methods, preferably for primary screening, with which the compounds described can be selected which are special with regard to the use according to the invention Offer advantages.
- This can be automated. Screening robots are used for the efficient evaluation of the individual assays, which are preferably arranged on microtiter plates.
- Kits and components for performing this assay can be obtained commercially, for example from Amersham Pharmacia Biotech.
- FlashPlate technology known in the field of active substance screening.
- Kits and components for performing this assay can be obtained commercially, for example from NEN Life Science Products.
- This principle is also based on microtiter plates (96 or 384), which are coated with scintillation substance.
- test methods which are particularly suitable for secondary screening are based on in-vitro and in-vivo models for indications to be treated according to the invention.
- Suitable in vivo models in the field of the above indications are known, for example the induced ones cerebral ischemia in mammals such as rats and determining the extent of affected tissue as described below.
- the use of the compounds described according to the invention includes a method in the context of the treatment.
- An effective amount of one or more compounds, generally formulated in accordance with pharmaceutical and veterinary practice, is administered to the individual to be treated, preferably a mammal, in particular a human, useful or domestic animal. Whether such treatment is indicated and in what form it must be carried out depends on the individual case and is subject to a medical assessment (diagnosis), the existing signs, • symptoms and / or malfunctions, risks, certain signs, symptoms and / or malfunctions develop, and include other factors.
- the treatment is usually given as a single or repeated daily administration, optionally together with or alternating with other active substances or preparations containing active substances, the dosage depending on the age, condition and weight of the patient and on the type of application.
- the administration takes place in an amount such that a daily dose of approximately 10 to 1000 mg / kg body weight is administered to an individual to be treated, preferably from approximately 1 to 500 mg / kg body weight when administered parenterally.
- the invention also relates to pharmaceutical compositions for the treatment of an individual, preferably a mammal, in particular a human, useful or domestic animal, and their production.
- the active compounds according to the invention are usually administered in the form of pharmaceutical compositions which comprise a pharmaceutically acceptable excipient with at least one ligand according to the invention and optionally further active compounds.
- These compositions can be administered, for example, by the oral, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal routes.
- suitable pharmaceutical formulations are solid pharmaceutical forms, such as powders, powders, granules, tablets, in particular film-coated tablets, pastilles, sachets, cachets, coated tablets, capsules such as hard and soft gelatin capsules, suppositories or vaginal pharmaceutical forms, semi-solid pharmaceutical forms such as ointments, creams, Hydrogels, pastes or plasters, and liquid pharmaceutical forms, such as solutions, emulsions, in particular oil-in-water emulsions, suspensions, for example lotions, injection and infusion preparations, eye and ear drops.
- Implanted delivery devices can also be used to administer active substances according to the invention be used. Liposomes or microspheres can also be used.
- active compounds according to the invention are usually mixed or diluted with an excipient.
- Excipients can be solid, semi-solid or liquid materials that serve as vehicles, carriers or media for the active ingredient.
- the formulations can be pharmaceutically acceptable carriers or customary auxiliaries, such as lubricants; Wetting agents; emulsifying and suspending agents; preservatives; antioxidants; Antiirritatives; chelating agents; Coating aids; Emulsion stabilizers; film formers; gelling agents; Odor masking agents; masking flavors; resins; Hydrocoloid; Solvents; Solubilizing agents; Neutralizing agents; permeation; pigments; quaternary ammonium compounds; Refatting and overfatting agents; Ointment, cream or oil base materials; Silicone derivatives; spreading aids; stabilizers; Sterilanzien; suppository bases; Tablet excipients such as binders, fillers, lubricants, disintegrants or coatings; Propellant; Desiccant; Opacifiers; Thickener; waxes; plasticizers; Include white oils.
- auxiliaries such as lubricants; Wetting agents; emulsifying and suspending agents; preserv
- a design in this regard is based on expert knowledge, as is shown, for example, in Fiedler, H.P., Lexicon of auxiliaries for pharmacy, cosmetics and related areas, 4th edition, Aulendorf: ECV-Editio-Cantor-Verlag, 1996. (cf. H. Sucker et al., Pharmaceutical 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.
- the compounds of the present invention have a surprisingly high affinity for the 5-HT- A receptor, as shown by binding studies with cloned human 5-HT- A receptors.
- Example 3 1- (4- ⁇ 3- [(4-Methyl-5- (3-pyridinyl) -427-l, 2,4-triazol-3-yl) sulfanyl] propyl ⁇ -l-piperazinyl) isoquinoline
- Example 7 1- [4- (2- ⁇ [4-methyl-5- (3-pyrazinyl) -4jj-l, 2,4-triazol-3-yl] sulfanyl ⁇ ethyl) -l-piperazinyl] isoquinoline M.p. : 159-161 ° C (Fu arat)
- Example 8 1- [4- (2- ⁇ [4-methyl-5- (1-methyl-1H-pyrrol-2-yl) -4H-1,2,4-triazol-3-yl] sulfanyl ⁇ ethyl) -1-piperazi- 5 nyl] isoquinoline
- Example 10 1- [4- (3 - ⁇ [5- (2,4-dimethoxyphenyl) -4-methyl-4i ⁇ -l, 2,4-triazol-3-yl] sulfanyl ⁇ propyl) -1- piperazinyl] isoquinoline 15
- Example 11 1- ⁇ 4- [3- ( ⁇ 4-Methyl-5- [4- (tri-luoromethy1) henyl] -4H-l, 2,4-triazol-3-yl ⁇ sulfanyl) propyl] -l- piperazinyl ⁇ isoquinoline
- Example 12 1- [- (3- ⁇ [4-Methyl-5- (4-methyl-l, 3-thia-25 zol-5-yl) -4i ⁇ -l, 2,4-triazol-3-yl ] sulfanyl ⁇ propyl) -1-piperazinyl] isoquinoline
- Example 13 8- (4- ⁇ 3- [(4-Methyl-5-phenyl-4iT-1,2,4,4-triazol-3-yl) sulfanyl] propyl ⁇ -1-piperazinyl) quinoline
- Example 14 1- ⁇ 3- [(4-Methyl-5-phenyl-4i ⁇ -l, 2,4-triazol-3-yl) sulfanyl] propyl ⁇ -4- (1-naphthyl) -1,2 , 3, 6-tetrahydropyridine
- Example 15 1- ⁇ 3- [(4-Methyl-5-phenyl-4H-1,2, triazol-3-yl) sulfanyl] propyl ⁇ -4- (1-naphthyl) iperidine.
- Example 16 1- ⁇ 4- [2- ( ⁇ 4-Methyl-5- [3-pyrazinyl] -4 # -1, 2,4-triazol-3-yl ⁇ sulfanyl) ethyl] -1-piperazinyl ⁇ isoquinoline m.p .: 190-192 ° C (hydrochloride)
- Example 17 1- ⁇ 4- [2- ( ⁇ 4-Methyl-5- [3-pyrazinyl] -4H-1,2,4,4-triazol-3-yl ⁇ sulfanyl) ethyl] -1-piperazinyl ⁇ isoquinoline m.p .: 58-60 ° C
- Example 18 1- ⁇ 4- [3- ( ⁇ 4-Methyl-5- [4-pyridinyl] -4i ⁇ -l, 2,4-triazol-3-yl ⁇ sulfanyl) propyl] -1-piperazinyl ⁇ isoquinoline m.p .: 124-126 ° C
- Example 19 1- ⁇ 4- [3- ( ⁇ 4-Methyl-5- [2-thiophenyl] -4i ⁇ -l, 2,4-triazol-3-yl ⁇ sulfanyl) propyl] -1-piperazinyl ⁇ isoquinoline m.p .: 213-215 ° C (hydrochloride)
- Example 20 1- ⁇ 4- [3- ( ⁇ 4-Methyl-5- [3-thiophenyl] -4i ⁇ -l, 2,4-triazol-3-yl ⁇ sulfanyl) propyl] -1-piperazinyl ⁇ isoquinoline mp: 217 ° C (hydrochloride)
- Example 21 8- (4- ⁇ 3- [(4-Methyl-5- (li ⁇ -pyrrol-2-yl) -4i ⁇ -l, 2,4,4-triazol-3-yl) sulfanyl] propyl ⁇ - l-piperazinyl) quinoline M.p .: 162-164 ° C (hydrochloride)
- Example 22 8- (4- ⁇ 3- [(4-Methyl-5- (3-pyridinyl) ⁇ 4i7-l, 2,4-triazol-3-yl) sulfanyl] propyl ⁇ -l-piperazinyl) -quinoline mp .: 206-208 ° C (hydrochloride)
- Example 23 8- (4- ⁇ 3- [(4-Methyl-5- (3-pyrazinyl) -4H-1,2,4,4-triazol-3-yl) sulfanyl] propyl ⁇ -l-piperazinyl) -quinoline mp .: 158-160 ° C (hydrochloride)
- Example 24 1- ⁇ 2- [(4-Methyl-5- (3-pyridinyl) -4ü " -1, 2,4-triazol-3-yl) sulfanyl] ethyl ⁇ -4- (1-naphthyl ) -1,2,3,6-tetrahydropyridine MS (m / z): 429 [M + H] +
- Example 25 1- ⁇ 3- [(4-Methyl-5- (3-pyridinyl) -4H-1,2,4-triazol-3-yl) sulfanyl] propyl ⁇ -4- (1-naphthyl) -1, 2, 3, 6-tetrahydropyridine MS (m / z): 443 [M + H] +
- Example 26 1- ⁇ 2- [(4-methyl-5- (1-methyl-li ⁇ -pyrrol-2-yl) -4 # -l, 2,4-triazol-3-yl) sulfanyl] ethyl ⁇ -4- (1-naphthyl) -l, 2, 3, 6-tetrahydropyridine MS (m / z): 431 [M + H] +
- Example 27 1- ⁇ 4- [2- ( ⁇ 4-Methyl-5- [3-thiophenyl] -4i ⁇ -l, 2,4-triazol-3-yl ⁇ sulfanyl) ethyl] -l-piperazinyl ⁇ isoquinoline m.p .: 168-170 ° C (hydrochloride)
- Example 28 1- ⁇ 4- [2- ( ⁇ 4-Methyl-5- [2-thiophenyl] -4H-1,2,4-triazol-3-yl ⁇ sulfanyl) ethyl] -l-piperazinyl ⁇ isoquinoline m.p .: 170-172 ° C (hydrochloride)
- Example 29 1- ⁇ 4- [3- ( ⁇ 4-Methyl-5- [3-pyrazinyl] -4J ⁇ -l, 2,4-triazol-3-yl ⁇ sulfanyl) propyl] -1-piperazinyl ⁇ isoquinoline mp: 207 ° C (hydrochloride)
- Example 30 1- ⁇ 4- [2- ( ⁇ 4-Methyl-5- [2-pyridinyl] -4i ⁇ -l, 2,4-triazol-3-yl ⁇ sulfanyl) ethyl] -1-piperazinyl ⁇ isoquinoline m.p .: 125-127 ° C (hydrochloride)
- Example 31 1- ⁇ 4- [3- ( ⁇ 4-Methyl-5- [2-pyridinyl] -4J ⁇ -l, 2,4-triazol-3-yl ⁇ sulfanyl) propyl] -1-piperazinyl ⁇ isoquinoline m.p .: 209-212 ° C (hydrochloride)
- Example 32 1- ⁇ 4- [3 - ( ⁇ 4-Methyl-5- [2-indolyl] -4F-l, 2,4-triazol-3-yl ⁇ sulfane l) propyl] -1-piperazinyl ⁇ isoquinoline -4 m.p. : 192-195 ° C
- Example 33 1- ⁇ 4- [2- ( ⁇ 4-Methyl-5- [4-pyridinyl] -4i ⁇ -l, 2,4-triazol-3-yl ⁇ sulfanyl) ethyl] -l-piperazinyl ⁇ isoquinoline m.p .: 210-212 ° C (hydrochloride)
- Example 34 1- ⁇ 3- [(4-Methyl-5- (4-pyridinyl) -4i ⁇ -l, 2,4-triazol-3-yl) sulfanyl] propyl ⁇ -4- (1-naphthyl) -1, 2, 3, 6-tetrahydropyridine din .: 184-186 ° C (hydrochloride)
- Example 35 1- ⁇ 3- [(4-Methyl-5- (3-pyrazinyl) -4J ⁇ -l, 2,4-triazol-3-yl) sulfanyl] propyl ⁇ -4- (1-naphthyl) -1, 2, 3, 6-tetrahydropyridine din .: 180-182 ° C (hydrochloride)
- Example 36 1- (4- ⁇ 3- [(5-phenyl-4iT-l, 2,4-triazol-3-yl) sulfanyl] propyl ⁇ -l-piperazinyl) isoquinoline mp: 230-232 ° C (hydrochloride)
- Example 37 1- (4- ⁇ 4- [(4-methyl-5-phenyl-4i ⁇ -l, 2,4-triazol-3-yl) sulfanyl] butyl ⁇ -l-piperazinyl) isoquinoline MS (m / z): 460 [M + H] +
- Example 38 1- (4- ⁇ 4- [(4-methyl-5- ⁇ 2-thiophenyl ⁇ -4-1,2,4,4-triazol-3-yl) sulfanyl] butyl ⁇ -l-piperazinyl) isoquinoline MS (m / z): 466 [M + H] +
- the compounds of the present invention have a surprisingly high affinity for the 5-HT ⁇ A ⁇ receptor, as binding studies with cloned human 5-HT ⁇ receptors show.
- 5-HT iA receptor-expressing HEK293 cells are in RPMI / Glutamax medium (RPMI 1640, 25 mM Hepes, 2 M Glutamax, 10% FCS, 2 mM glutamine, penicillin / streptomycin (100 IU / l each), geneticin ( G-418) sulfates 400 mg / 1, NaHC0 3 1.2 g / 1) cultivated in culture bottles (TripleFlasks T - 175) in a 5% C0 2 atmosphere at 37 ° C. After confluence is reached, the medium is removed and the bottles are filled with 15 ml sterile PBS (phosphate buffered saline).
- RPMI 1640 25 mM Hepes, 2 M Glutamax, 10% FCS, 2 mM glutamine, penicillin / streptomycin (100 IU / l each), geneticin ( G-418) sulfates 400 mg / 1, NaHC0 3 1.2 g / 1
- the cells are incubated for 10 minutes (incubator, 37 ° C.) with a trypsin solution (0.05% trypsin, 0.0004% EDTA, 0.02% EGTA, 2.682 mM KC1, 1.47 mM KH 2 P0 4 , 6.46 mM Na 2 HP0, 136.89 mM NaCl).
- the detachment of the cells is promoted by tapping the bottom of the bottle. After transferring them into 50 ml tubes (Greiner), the cells are centrifuged at 250 xg at room temperature. The supernatant is discarded and the cells are resuspended in 10 ml of medium.
- the cells are again distributed on culture flasks and cultivated for a further 5 to 6 days until the membranes are prepared.
- the supernatants from the cells are removed and the culture bottles are filled with PBS.
- the cells are then incubated for 10 minutes with a trypsin solution (for composition, see above).
- the detachment of the cells is promoted by tapping the bottom of the bottle.
- the cell suspension is removed and the remaining cells are also taken up in PBS by washing the culture bottles twice with PBS.
- the collected cell suspension is distributed into 150 ml Falcon tubes and centrifuged for 10 minutes at 250 x g at 4 ° C. The supernatants are discarded and the cells in the pellet are discarded
- the frozen membranes are thawed at 37 ° C, centrifuged at 48000 * g (20 minutes), and resuspended in binding buffer (50 mM Tris-HCl pH 7.4, 5 mM CaCl 2 ).
- binding buffer 50 mM Tris-HCl pH 7.4, 5 mM CaCl 2 .
- the non-specific binding is determined in the presence of 10 -5 M 5-carboxamidotryptamine. After incubation at 22 ° C.
- the bound and free ligand is separated from one another by filtration through GF / B filters and subsequent washing with 5 to 9 ml of ice-cold binding buffer.
- the GF / B filters are in front Use treated with 0.3% polyethyleneimine for at least 2 hours. After filtration, the filters are mixed with 3 to 4 ml Packard Ultima Gold XR and the radioactivity is determined by liquid scintillation counting in the Packard Tricarb.
- the displacement curves are analyzed by nonlinear regression using a modified version of the "Ligand” program by Munson & Rodbard (Anal. Biochem., 107, 220 (1980)).
- the value for the theoretical non-specific binding is estimated as the theoretical radioligand binding with an infinitely high ligand concentration.
- the measured values for the non-specific binding are treated as data points of the displacement curve, which correspond to measuring points at an infinitely high ligand concentration.
- mice Male Long Evans rats deflated the day before are used as test animals.
- the weight of the animals should be between 280 and 320 g on the day of fasting. They are pre-anesthetized with 4% halothane in 30% oxygen and 70% N 2 0 in the desiccator and treated ip with 0.1 mg / kg atropine. For the operation, the halothane concentration is reduced to 1.5% and the test animal is connected to the temperature controller (37 ° C).
- the jugular vein is dissected for the venous catheter.
- MCA A. cerebri edia
- the rat is placed on the left side and fixed.
- a scalpel With a scalpel, a vertical incision is made at the height between the eye and ear, and the surgical site is kept open with a wound spreader.
- the skull bone is exposed and then milled with a hand drill so that it can be lifted off with tweezers and the MCA underneath becomes visible.
- the freed-up MCA is permanently tied with a thread below the lowest visible branch to the right. The rat is then connected to the infusion.
- the rat receives 0.1 ml of IV heparin.
- a femoral artery is prepared for blood collection and the rectal temperature is measured.
- the first blood sample is used to determine the blood gases, the second is centrifuged and used to determine glucose.
- the brain is cut into 2 mm thick slices, which are then incubated in a 2% TTC solution at 37 ° C for 30 min.
- the treated sections are stored in 3.8% formalin.
- the infarct volume is determined using a computerized image processing system.
- the effect of the test substance is determined using appropriate statistical methods.
- test animals The treatment of the test animals with the test substance began 90 minutes after the MCA occlusion with a bolus injection of 2 mg / kg iv. The subsequent continuous infusion of 1 mg / kg / h iv was over 20.5 until the end of the test Maintain hours (dosage scheme "2 + 1"). The following percentage infarction reductions (based on the control animals treated with empty solution) were achieved:
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Cited By (5)
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WO2008097640A3 (en) * | 2007-02-08 | 2008-10-02 | Synta Pharmaceuticals Corp | Triazole compounds that are useful in the treatment of proliferative disorders, such as cancer |
US7662813B2 (en) | 2005-08-18 | 2010-02-16 | Synta Pharmaceuticals Corp. | Triazole compounds that modulate HSP90 activity |
US7825244B2 (en) | 2005-06-10 | 2010-11-02 | Janssen Pharmaceutica Nv | Intermediates useful in the synthesis of alkylquinoline and alkylquinazoline kinase modulators, and related methods of synthesis |
US8071768B2 (en) | 2005-06-10 | 2011-12-06 | Janssen Pharmaceutica, N.V. | Alkylquinoline and alkylquinazoline kinase modulators |
US8222238B2 (en) | 2003-03-25 | 2012-07-17 | Vasopharm Biotech Gmbh | Use of pteridine derivatives for the treatment of increased intracranial pressure, secondary ischemia, and disorders associated with an increased level of cytotoxic reactive oxygen species |
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- 2001-03-01 DE DE10109866A patent/DE10109866A1/en not_active Withdrawn
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US8222238B2 (en) | 2003-03-25 | 2012-07-17 | Vasopharm Biotech Gmbh | Use of pteridine derivatives for the treatment of increased intracranial pressure, secondary ischemia, and disorders associated with an increased level of cytotoxic reactive oxygen species |
US9382252B2 (en) | 2003-03-25 | 2016-07-05 | Vasopharm Gmbh | Use of pteridine derivatives for the treatment of increased intracranial pressure, secondary ischemia, and disorders associated with an increased level of cytotoxic reactive oxygen species |
US9422289B2 (en) | 2003-03-25 | 2016-08-23 | Vasopharm Gmbh | Use of pteridine derivatives for the treatment of increased intracranial pressure, secondary ischemia, and disorders associated with an increased level of cytotoxic reactive oxygen species |
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