MXPA06005965A - Preventive and/or therapeutic agent for higher brain dysfunction - Google Patents
Preventive and/or therapeutic agent for higher brain dysfunctionInfo
- Publication number
- MXPA06005965A MXPA06005965A MXPA/A/2006/005965A MXPA06005965A MXPA06005965A MX PA06005965 A MXPA06005965 A MX PA06005965A MX PA06005965 A MXPA06005965 A MX PA06005965A MX PA06005965 A MXPA06005965 A MX PA06005965A
- Authority
- MX
- Mexico
- Prior art keywords
- cerebral dysfunction
- agent
- preventing
- high cerebral
- treating high
- Prior art date
Links
- 210000004556 Brain Anatomy 0.000 title abstract description 15
- 230000004064 dysfunction Effects 0.000 title abstract description 12
- 239000003814 drug Substances 0.000 title abstract description 3
- 230000003449 preventive Effects 0.000 title abstract 2
- 239000011780 sodium chloride Substances 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 239000004480 active ingredient Substances 0.000 claims abstract description 9
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 9
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 claims abstract description 9
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 5
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 5
- 208000009025 Nervous System Disease Diseases 0.000 claims description 53
- 239000003795 chemical substances by application Substances 0.000 claims description 37
- 208000001183 Brain Injury Diseases 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 231100000874 brain damage Toxicity 0.000 claims description 10
- LRFVTYWOQMYALW-UHFFFAOYSA-N Xanthine Chemical class O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 230000002490 cerebral Effects 0.000 claims description 8
- 206010003062 Apraxia Diseases 0.000 claims description 7
- 230000032683 aging Effects 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 208000006888 Agnosia Diseases 0.000 claims description 6
- 241001047040 Agnosia Species 0.000 claims description 6
- 125000004430 oxygen atoms Chemical group O* 0.000 claims description 6
- 208000000044 Amnesia Diseases 0.000 claims description 4
- 206010001954 Amnestic disease Diseases 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000004434 sulfur atoms Chemical group 0.000 claims description 4
- 208000008208 Craniocerebral Trauma Diseases 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- 239000001301 oxygen Substances 0.000 abstract 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 abstract 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract 1
- 239000011593 sulfur Substances 0.000 abstract 1
- 241000700159 Rattus Species 0.000 description 56
- 150000001875 compounds Chemical class 0.000 description 46
- -1 4-pentenyl Chemical group 0.000 description 19
- 239000002904 solvent Substances 0.000 description 15
- 230000006399 behavior Effects 0.000 description 13
- 239000000203 mixture Substances 0.000 description 11
- 239000007924 injection Substances 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 9
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 9
- STECJAGHUSJQJN-FWXGHANASA-N Scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 9
- 238000007792 addition Methods 0.000 description 9
- 239000002775 capsule Substances 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 229960002646 scopolamine Drugs 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 210000003027 Ear, Inner Anatomy 0.000 description 8
- 210000004080 Milk Anatomy 0.000 description 7
- 238000007796 conventional method Methods 0.000 description 7
- 239000012153 distilled water Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 235000013336 milk Nutrition 0.000 description 7
- 239000008267 milk Substances 0.000 description 7
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2R,3R,4S,5R,6S)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2R,3R,4S,5R,6R)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 6
- 208000006011 Stroke Diseases 0.000 description 6
- 201000007201 aphasia Diseases 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 229920000609 methyl cellulose Polymers 0.000 description 6
- 239000001923 methylcellulose Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 125000003282 alkyl amino group Chemical group 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 239000004033 plastic Substances 0.000 description 5
- 229920003023 plastic Polymers 0.000 description 5
- 210000001168 Carotid Artery, Common Anatomy 0.000 description 4
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K Tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- 238000009811 bilateral tubal ligation Methods 0.000 description 4
- 235000005911 diet Nutrition 0.000 description 4
- 230000037213 diet Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 3
- 206010027175 Memory impairment Diseases 0.000 description 3
- 210000003739 Neck Anatomy 0.000 description 3
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 description 3
- 125000005153 alkyl sulfamoyl group Chemical group 0.000 description 3
- 125000003435 aroyl group Chemical group 0.000 description 3
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 3
- 230000003925 brain function Effects 0.000 description 3
- 230000003247 decreasing Effects 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 239000003549 soybean oil Substances 0.000 description 3
- 235000012424 soybean oil Nutrition 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
- 208000007848 Alcoholism Diseases 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 206010068346 Anosognosia Diseases 0.000 description 2
- 210000001367 Arteries Anatomy 0.000 description 2
- 206010003816 Autoimmune disease Diseases 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- 208000007774 Broca Aphasia Diseases 0.000 description 2
- 206010008118 Cerebral infarction Diseases 0.000 description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 description 2
- 208000008313 Contusions Diseases 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 206010013654 Drug abuse Diseases 0.000 description 2
- 210000002969 Egg Yolk Anatomy 0.000 description 2
- 206010014599 Encephalitis Diseases 0.000 description 2
- 206010015769 Extradural haematoma Diseases 0.000 description 2
- BJHIKXHVCXFQLS-UYFOZJQFSA-N Fructose Natural products OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-UYFOZJQFSA-N 0.000 description 2
- 206010070511 Hypoxic-ischaemic encephalopathy Diseases 0.000 description 2
- 208000002262 Ideomotor Apraxia Diseases 0.000 description 2
- 229940067606 Lecithin Drugs 0.000 description 2
- 208000009433 Moyamoya Disease Diseases 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N Pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 229960001412 Pentobarbital Drugs 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- 206010042316 Subarachnoid haemorrhage Diseases 0.000 description 2
- 208000002667 Subdural Hematoma Diseases 0.000 description 2
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 2
- 208000002579 Wernicke Aphasia Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 201000007930 alcohol dependence Diseases 0.000 description 2
- 125000005138 alkoxysulfonyl group Chemical group 0.000 description 2
- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 125000005333 aroyloxy group Chemical group 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 125000004429 atoms Chemical group 0.000 description 2
- 201000008098 auditory agnosia Diseases 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000002146 bilateral Effects 0.000 description 2
- 125000001589 carboacyl group Chemical group 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000000546 chi-square test Methods 0.000 description 2
- 230000001143 conditioned Effects 0.000 description 2
- 201000009910 diseases by infectious agent Diseases 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000002996 emotional Effects 0.000 description 2
- 230000001747 exhibiting Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 201000006470 prosopagnosia Diseases 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 230000002588 toxic Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 235000019798 tripotassium phosphate Nutrition 0.000 description 2
- 201000008148 visual agnosia Diseases 0.000 description 2
- CRPTXKKKIGGDBX-UHFFFAOYSA-N (Z)-but-2-ene Chemical group [CH2]C=CC CRPTXKKKIGGDBX-UHFFFAOYSA-N 0.000 description 1
- 125000005871 1,3-benzodioxolyl group Chemical group 0.000 description 1
- 125000005877 1,4-benzodioxanyl group Chemical group 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- YZYQQJHFYIVWPS-UHFFFAOYSA-N 3,4,5,6-tetradehydrothiopyran Chemical group [CH]1SC#CC#C1 YZYQQJHFYIVWPS-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- 206010065040 AIDS dementia complex Diseases 0.000 description 1
- 206010000565 Acquired immunodeficiency syndrome Diseases 0.000 description 1
- 102000000506 Adenosine A2 Receptors Human genes 0.000 description 1
- 108010041368 Adenosine A2 Receptors Proteins 0.000 description 1
- 206010002855 Anxiety Diseases 0.000 description 1
- 206010057666 Anxiety disease Diseases 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 208000008581 Brain Disease Diseases 0.000 description 1
- 208000001408 Carbon Monoxide Poisoning Diseases 0.000 description 1
- 206010051290 Central nervous system lesion Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010014623 Encephalopathy Diseases 0.000 description 1
- 206010014625 Encephalopathy Diseases 0.000 description 1
- 206010070246 Executive dysfunction Diseases 0.000 description 1
- 235000016623 Fragaria vesca Nutrition 0.000 description 1
- 240000009088 Fragaria x ananassa Species 0.000 description 1
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 210000003128 Head Anatomy 0.000 description 1
- 206010022114 Injury Diseases 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- 206010025135 Lupus erythematosus Diseases 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 229960005190 Phenylalanine Drugs 0.000 description 1
- 229940023488 Pill Drugs 0.000 description 1
- 208000005374 Poisoning Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 229940005550 Sodium alginate Drugs 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 206010069776 Thrombocytosis Diseases 0.000 description 1
- 208000005485 Thrombocytosis Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000000240 adjuvant Effects 0.000 description 1
- 229940053550 agents used for ADHD and nootropics psychostimulants Xanthine derivatives Drugs 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical class [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 230000003042 antagnostic Effects 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000001088 anti-asthma Effects 0.000 description 1
- 230000001430 anti-depressive Effects 0.000 description 1
- 230000000648 anti-parkinson Effects 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000000939 antiparkinson agent Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000003542 behavioural Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000003292 diminished Effects 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000002218 hypoglycaemic Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N iodine atom Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- 230000003902 lesions Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940083747 low-ceiling diuretics Xanthine derivatives Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical compound [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000005641 methacryl group Chemical group 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000008368 mint flavor Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- 150000002780 morpholines Chemical class 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003287 optical Effects 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 230000000607 poisoning Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 230000035812 respiration Effects 0.000 description 1
- 230000000241 respiratory Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- BZHJMEDXRYGGRV-UHFFFAOYSA-N vinyl chloride Chemical compound ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000016776 visual perception Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Abstract
A preventive and/or therapeutic agent for higher brain dysfunctions which contains as an active ingredient a xanthane derivative represented, for example, by the following formula (I) or a pharmacologically acceptable salt thereof:(I) (II) wherein R1, R2, and R3 are the same or different and each represents hydrogen, lower alkyl, lower alkenyl, or lower alkynyl;R4 represents cycloalkyl, -(CH2)n-R5, or the formula (II) given above;and X1 and X2 are the same or different and each represents oxygen or sulfur.
Description
AGENTS TO PREVENT AND / OR TREAT HIGH BRAIN DYSFUNCTIONS
FIELD OF THE INVENTION The present invention generally relates to agents for preventing and / or treating high cerebral dysfunctions comprising, as an active ingredient, a xanthine derivative or a pharmaceutically acceptable salt thereof.
Background of the invention
The high cerebral dysfunctions in general mean that high cerebral functions to execute the daily life, such as memory, thought, recognition, action, learning, language and attention, are harmed by cerebral deteriorations due to several causes. Examples of these include brain dysfunction caused by brain impairment due to illness, accident or aging, such as (1) hemispatial negligence (visual perception defects characterized by deterioration to be noticed in the middle of the space while patients are aware of observing the total space); (2) aphasia (Wernicke's aphasia (fluent aphasia), Brocka's aphasia (non-fluent aphasia), defect or loss of language function that includes "speech, hearing, learning or
Ref.:173034 writing "relative to the comprehension or expression of words; (3) apraxia (ideokinetic apraxia, ideomotor apraxia; impairments characterized by difficulties in executing the deliberate movement and action, or the movement of accusation and action even though their hands and legs can be moved); (4) agnosia (asomatognosia (anosognosia); imbalances in the recognition of the body, for example, in which the patient does not recognize their own body parts, considering parts of the body lost, or not recognizing positively the event of paralysis, visual agnosia, prosopagnosia, auditory agnosia, a loss of ability to recognize which is the object despite the ability to identify it visually, auditory or tactile elements), (5) memory impairments (amnesia, impairments characterized by difficulties in memory and learning (particularly difficulty in memory of new things)); (6) executive dysfunction (impairment) characterized by difficulties in carrying out activities, that is, information arrangements, planning, consideration of a process and practice); (7) aprosexia (decreased attention and ability to concentrate); (8) emotional behavior and impairments (referring to states such as excitement in insignificant things and acting impulsively, panic in an attack of surprising anxiety, and decreasing spontaneity in reverse) [see; Merck Manual, 17th edition, section 169, Total Rehabilitation, vol.11, p. 605-608 (1983); Shin Seirikagaku taipei (A Survey of New Physiological Science) 12, p.1-5 (1988), edited by Toshio Suzuki, Igaku-Shoin Ltd.]. Diseases that cause lesions in the brain which are causes of high brain dysfunctions, for example, trauma to the head (eg, extradural hematoma, subdural hematoma, cerebral contusion, intracerebral hemorrhage, etc.), cerebrovascular accidents (eg. ., intracerebral hemorrhage, cerebral infarction, cerebral apoplexy, hypoxic encephalopathy, subarachnoid hemorrhage, moyamoya disease, etc.), infections (eg, encephalitis, AIDS encephalopathy, etc.), autoimmune diseases (eg systemic lupus erythematosus, nervous disease from Beh? et, etc.), toxic diseases (eg, alcoholism, carbon monoxide poisoning, drug abuse, etc.) brain tumor, and the like. On the other hand, many of the xanthine derivatives including the compound represented by the formula (I) which will be described later have been known to have, for example, anti-Parkinsonian action, exciting action of the central nerve, suppressive action in neurodegeneration, and similar (referring to Japanese Examined Publication of Patent Application No. 26,516 / 1972; Japanese Unexamined Publication of Patent Application No. 211,856 / 1994;
Japanese Unexamined Publication of Patent Application No. 239,862 / 1994; Japanese Unexamined Publication of Patent Application No. 016,559 / 1994; WO 99/12546 etc.). They are also known to have antagonistic action towards the adenosine A2 receptor, antidepressant action, anti-asthma action, surprising action for bone resorption, hypoglycemic action, suppressive action towards thrombocytosis, and the like [WO92 / 06976, WO94 / 01114, W095 / 23165 , W099 / 35147; Journal of Medicinal Chemistry (J.Med.Chem.), Vol.34, p.1431 (1991); Journal of Medicinal Chemistry (J.Med.Chem.), Vol.36, p.1333 (1993)].
BRIEF DESCRIPTION OF THE INVENTION
An object of the present invention is to provide agents for preventing and / or treating high cerebral dysfunction comprising, as an active ingredient, for example, a xanthine derivative or a pharmaceutically acceptable salt thereof, and the like. The present invention relates to the following (1) to (14). (1) An agent for preventing and / or treating high cerebral dysfunction comprising, as an active ingredient, a xanthine derivative represented by the formula (I): [wherein R1, R2 and R3 are the same or different, and represent a hydrogen atom, lower alkyl, lower alkenyl or lower alkynyl; R4 represents cycloalkyl, - (CH2) n -R5 (in which R5 represents substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic group, and n represents an integer from 0 to 4) or a group represented by formula (II) :
(in which Y1 and Y2 are the same or different, and represent a hydrogen atom, halogen or lower alkyl); and Z represents substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group); X1 and X2 are the same or different, and represent an oxygen atom or a sulfur atom] or a pharmaceutically acceptable salt thereof. (2) The agent for preventing and / or treating high cerebral dysfunction according to the above (1), in which X1 and X2 each is an oxygen atom. (3) The agent for preventing and / or treating high cerebral dysfunction according to that of above (1) or (2), wherein R4 is a group represented by formula (II):
(in which Y1, Y2 and Z each have the same meanings as defined above). (4) The agent for preventing and / or treating high cerebral dysfunction according to the above (3), in which Y1 and Y2 are both hydrogen atoms. (5) The agent for preventing and / or treating high dysfunction according to those above (3) or (4), wherein Z is substituted or unsubstituted aryl or a group represented by the formula (III):
(in which R6 represents a hydrogen atom, hydroxy, lower alkyl, lower alkoxy, halogen, nitro or amino, and m represents an integer from 1 to 3). (6) The agent for preventing and / or treating high cerebral dysfunction according to any of the above (1) to (5), in which the cerebral dysfunction is a high cerebral dysfunction caused by brain damage. (7) The agent for preventing and / or treating high cerebral dysfunction according to the above (6), in which the brain damage is brain damage due to aging. (8) The agent for preventing and / or treating high cerebral dysfunction according to the above (6), in which the brain damage is brain damage due to disorder selected from the group consisting of head trauma and stroke . (9) The agent for preventing and / or treating high cerebral dysfunction according to any of the above (1) to (8), in which the high cerebral dysfunction is a deterioration of the high brain function selected from the group which consists of memory, thought, recognition, action and learning. (10) The agent for preventing and / or treating high cerebral dysfunction according to any of the above (1) to (8), in which the high cerebral dysfunction is a cerebral dysfunction selected from the group consisting of agnosia, amnesia and apraxia. (11) The agent to prevent and / or treat high cerebral dysfunction according to any of the above (1) to (8), in which the high cerebral dysfunction is a deterioration in memory. (12) The agent for preventing and / or treating high cerebral dysfunction according to any of the above (1) to (8), in which the high cerebral dysfunction is a deterioration in learning. (13) A method for preventing and / or treating high cerebral dysfunction which comprises administering an effective amount of xanthine derivative represented by formula (I):
[wherein R1, R2, R3, R4, X1 and X2 each have the same meanings as defined above] or a pharmaceutically acceptable salt thereof. (14) Use of a xanthine derivative represented by the formula (I):
[wherein R1, R2, R3, R ^ X1 and X2 each have the same meanings as defined above] or a pharmaceutically acceptable salt for the preparation of an agent to prevent and / or treat high cerebral dysfunction. In the present invention, "high cerebral dysfunctions" means that "high cerebral dysfunctions to develop daily life, such as memory, thinking, recognition, action, learning, language and attention, are damaged by brain injuries due to various causes". In particular, examples of those that include "high brain dysfunction" caused by "brain deterioration" due to illness, accident or aging. More especially, examples of those that include high brain dysfunction caused by brain deterioration due to illness, accident or aging, such as (1) hemispatial negligence; (2) aphasia (Wernicke's aphasia
(fluent aphasia), Broca's aphasia (non-fluent aphasia) and the like); (3) apraxia; (4) agnosia (somatagnosia
(anosognosia), visual agnosia, prosopagnosia, auditory agnosia and the like); (5) memory impairments (amnesia and the like); (6) dysfunctions to perform activities; (7) aprosexia; and (8) emotional and behavioral impairments. Diseases that cause "brain injuries" which are causes of these brain dysfunctions including, for example, head trauma (eg, extradural hematoma, subdural hematoma, cerebral contusion, intracerebral hemorrhage, etc.), cerebrovascular accidents ( eg, intracerebral hemorrhage, cerebral infarction, cerebral apoplexy, hypoxic encephalopathy, subarachnoid hemorrhage, moyamoya disease, etc.), infections (eg, encephalitis, encephalopathy AIDS, etc.), autoimmune diseases (eg, lupus erythematosus) systemic, Beh? et nerve disease, etc.), toxic diseases (eg, alcoholism, carbon dioxide poisoning, drug abuse, etc.), brain tumor, and the like. In particular, "impairments of high cerebral functions" which can be prevented and / or treated in an appropriate manner by agents to prevent and / or treat high cerebral dysfunctions of the present invention include, for example, impairments of memory, thinking, action, learning and the like, and functions combined with one or more of them, that is, recognition, knowledge, execution and the like. Among them, one or more of the impairments of high brain functions selected from impairments of memory, thought, action, learning, recognition, knowledge and execution may be preventable and / or treated.
In addition, in particular, the "high cerebral dysfunctions", which can be prevented and / or adequately treated by agents to prevent and / or treat high cerebral dysfunctions of the present invention, including "high cerebral dysfunctions" caused by "brain lesions" due to illness, accident or aging as described above. Among them, hemispatial negligence, apraxia, agnosia, deterioration in memory, impairments in learning, dysfunctions to perform activities and they can be adequately prevented and / or treated. In the definition of each group in the formula
(I): Examples of lower alkyl and the lower alkyl portion of lower alkoxy include straight or branched chain alkenyl groups having from 1 to 6 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl. Examples of lower alkenyl include straight or branched chain alkenyl groups having from 2 to 6 carbons, such as vinyl, allyl, methacryl, crotyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 2-hexenyl and 5-hexenyl.
Examples of lower alkynyl include straight chain alkenyls or branched chain groups having from 2 to 6 carbons, such as ethynyl, propargyl, 2-butynyl, 3-butynyl, 2-pentynyl, 4-pentynyl, 2-hexynyl, 5- Hexynyl and 4-methyl-2-pentynyl. Examples of cycloalkyl include cycloalkyl groups having from 3 to 8 carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Halogen means a fluorine, chlorine, bromine and iodine atom. Examples of aryl include those having 6 to 14 carbons, such as phenyl, naphthyl and anthryl. Examples of the heterocyclic group include 5- or 6-membered monocyclic heterocyclic groups containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom; bicyclic or tricyclic fused ring heterocyclic groups containing at least one atom selected from a nitrogen atom, - an oxygen atom and a sulfur atom in which 3- to 8-membered rings are fused and the like. Specific examples of these include, in particular, furyl, thienyl, pyrrolyl, pyranyl, thiopyranyl, pyridyl, pyrimidinyl, triazinyl, purinyl, pyrazinyl, pyridazinyl, benzimidazolyl, 2-oxobenzozidazolyl, benzotriazolyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, 1, 3 -benzodioxolyl, 1,4-benzodioxanyl, 3,4-dihydro-2H-1, 5-benzodioxepinyl, indazolyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, naft iridinyl, quinoxalinyl, pyrazolyl, quinazolinyl, cinnolinyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothizaolyl, dihydroisoquinolyl, tetrahydroquinolyl and hydrobenzopyranyl. The substituted aryl and the substituted heterocyclic group have from 1 to 3 substituents which are the same or different, such as lower alkyl, lower alkenyl, lower alkynyl, hydroxy, substituted or unsubstituted lower alkoxy, halogen, nitro, amino, lower alkylamino , di-lower alkylamino, trifluoromethyl, trifluoromethoxy, aralkyl, aralkyloxy, aryl, aryloxy, lower alkanoyl, lower alkanoyloxy, aroyl, aroyloxy, arylalkyloxyloxy, carboxy, lower alkoxycarbonyl, lower alkylcarbamoyl, lower di-alkylcarbamoyl, sulfo, lower alkoxysulfonyl, lower alkylsulfamoyl and di-lower alkylsulfamoyl. The lower alkyl portion of the lower alkyl described above, lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl, lower alkanoyloxy, lower alkoxycarbonyl, lower alkylcarbamoyl, lower di-alkylcarbamoyl, lower alkoxysulfonyl, lower alkylsulfamoyl, and lower di-alkylsulfamoyl have the same meaning as described above of lower alkyl. Halogen, lower alkenyl and lower alkynyl have the same meanings as described above in this regard. Two lower alkyl portions of di-lower alkylamino, the lower di-alkylcarbamoyl and the lower di-alkylsulfamoyl may be the same or different. A portion of the aryl of the aryl and the aryloxy is the same as the aryl described above, and examples of the aralkyl portion of the aralkyl and the aralkyloxy include benzyl, phenethyl and the like. Examples of an aroyl portion in the aroyl and the aroyloxy include benzoyl, naphthoyl and the like. Examples of an arylalkyl portion of arylalkyloxy are benzyl, phenethyl and the like. Examples of the substituent (s) in the substituted alkoxy include hydroxy, lower alkoxy, halogen, amino, azido, carboxy, lower alkoxycarbonyl, and the like. In this, a lower alkyl portion of the lower alkoxy and the lower alkoxycarbonyl has the same meaning as the lower alkyl described above, and the halogen has the same meaning as described above. After this, a compound represented by the formula (I) will be referred to as Compound (I). Examples of the pharmaceutically acceptable salt of Compound (I) are acceptable pharmaceutical salts with addition of acid, metal salt, ammonium salt, salt with addition of organic amine, salt with addition of amino acid and the like. Examples of acceptable pharmaceutical salts with addition of compound (I) include an inorganic acid salt such as chloride, sulfate and phosphate; and an organic acid salt such as acetate, maleate, fumarate, tartrate, citrate and methanesulfonate. Examples of the pharmaceutically acceptable metal salts include an alkali metal salt such as sodium salt and potassium salt; alkaline earth metal salt such as magnesium salt and calcium salt; aluminum salt; zinc salt and the like. Examples of acceptable pharmaceutical ammonium salts include ammonium and tetramethylammonium. Examples of the pharmaceutically acceptable salt with addition of organic mine include an addition of morpholine salt or piperidine. Examples of acceptable pharmaceutical salts with addition of amino acid include an addition of lysine, glycine or phenylalanine. The compound (I) is capable of being produced by a process disclosed in Japanese Publication
Examined from Patent Application No. 26,516 / 1972;
Journal of Medicinal Chemistry (J. Med. Chem.), Vol.34, p.1431 (1991); Journal of Medicinal
(J.Med.Chem.), Vol.36, p. 1333 (1993); WO 92/06976; Japanese Unexamined Publication of Patent Application No. 211, 856/1994; Japanese Unexamined Publication of Patent Application No. 211,856 / 1994; WO 95/23165; Japanese Unexamined Publication of Patent Application No. 16559/1994; WO 94/01114; WO 99/12546; WO 99/35147 and the like, or by a process similar to this. The desired compound in each production process can be isolated and purified by a purification method which has been commonly used in synthetic organic chemistry such as filtration, extraction, washing, drying, concentration, recrystallization and various chromatographies. When it is desired to obtain a salt of Compound (I), in the case in which Compound (I) is produced in the salt form, it can be purified like this, but in which it is produced in its free form, This can be converted into a salt, after being dissolved or suspended in an appropriate solvent followed by the addition of an appropriate acid or base. In addition, Compound (I) and acceptable pharmaceutical salts thereof may exist in the form of adducts with water or various solvents, and these adducts are also used as the agents for preventing and / or treating high cerebral dysfunctions of the present invention. For some Compounds (I), optical isomers and the like may exist, and all possible isomers including them and mixtures thereof may be used as the agents for preventing and / or treating high cerebral dysfunctions of the present invention. Specific examples of Compound (I) are shown in Table 1.
Table 1
Compound No,
The effect of the present invention will be explained by the following Test Examples.
Test Example 1: Test for active avoidance learning The experiment was carried out using 10 SD male rats
(body weight: 220-280 gr) for a group. Using a transfer box apparatus consisting of two boxes (TK-401s; Unicom), the rats were prepared to learn and train (escape training) behavior conditioned to avoidance. In a test in the escape training, an alarm stimulus for light and ringing sound as a conditioned stimulus was given to the rats for 8 seconds. When the rat does not move inside to the next box in 4 seconds from the start of the alarm stimulus (avoidance behavior by alarm stimulus), an unconditioned stimulus was given to the rat by an electric current flow of 3 mA in the floor grid for 4 seconds (reinforcement learning factor). The test is repeated at time intervals of 5 seconds, and the escape training was repeated 50 tests / l training / 1 day p.or - 10 days. The test compound was used as a suspension in injectable distilled water containing 0.3% Tween-80 (by Otsuka Pharmaceutical Co., Ltd., solution 0.3% Tween-80) and orally administered to each of the rats at a time. dose of 10 mL / kg 1 hour before the test (Group administered with the test compound). Separately, a 0.3% T een-80 solution was administered orally to each of the rats at a dose of 10 mL / kg 1 hour before the test (group administered with solvent). For analysis of the results of the test, several parameters were entered into a personal computer (NEC, PC-982lXe) and the avoidance speed (%) (average in 10 rats, the rats which took avoidance behavior by a stimulus of alarm was observed as a successful escape, the avoidance speed when the rat is successful in escaping all 50 tests was observed as 100%) and the reaction timeout change (the time required for completion of the total test ) were compared with those of the group administered with solvent. The analysis was carried out by a resolution test. Table 2 shows the results. Table 2
Resolution test: * ~ p < 0.05; ** = p < 0.01 From the results above, the following ones become clear. In the group administered with compound, the avoidance avoidance speed was greater than the group administered with solvent (90.8%). In addition, in Compound 2 (3.0 mg / kg) of the administered group, the rate of withdrawal increased significantly (p <0.01, resolution test). On the other hand, in the group administered with Compound-2, the total test was completed within a shorter period of time than that of the group administered with solvent (99.1 seconds). In the group administered with compound 1 (0.3 mg / kg) and the group administered with Compound 1 (3.0 mg / kg), the time required for the completion of the total tests was significantly reduced (p <0.05 and p < 0.01, in this respect, resolution test). Test Example 2: Passive avoidance learning test The experiment was carried out using 32 female albino rats (body weight: around 100 gr) for a group. Test for passive avoidance learning was conducted in a test box (40 cm x 31 cm x 29 cm) in which a stainless steel grid was extended on the floor in such a way that an electrical shock of 1.1 mA was given in a manner random In the test box, a plastic tray (15 cm x 5 cm) of 0.5 cm thickness was placed in a corner to cover the floor; and the test box comprises a mechanism that when a rat placed on the plate walks on the floor grid, the rat receives an electric shock. Normally, the rat that receives an immediate electric shock gets from the plastic tray but leaves the tray; then the rat is again given an electric shock. Normally, the rat gradually changes its behavior with repetition of the shock (learning and training), and at the end it remains in the plastic tray (passive avoidance behavior). After the training and learning, the rats that maintained the memory were selected and used for the test based on memory maintenance test as mentioned above. Each of the rats was placed in the plastic tray, and from this time as in the initial point, (1) in the case that the rat left the tray in 60 seconds and (2) in the case in which the rat did not resist to leave by delicate thrust after a lapse of 60 seconds, the rat was judged not to maintain learning memory for passive avoidance behavior. The test compound was used as a suspension thereof in distilled water containing 0.3% T een-80; A scopolamine was used as a solution thereof in distilled water (by Sigma). For each of the rats which learned the passive avoidance behavior, immediately after the learning, 1 mgr / kgr (2 mL / kgr volume) of scopolamine (subcutaneous administration) was administered simultaneously (group administered with the test compound ); and 2 hours after administration, the rats were evaluated if they maintained the learning memory of passive avoidance behavior. Separately, each of the rats that learned the passive avoidance behavior, immediately after learning, 2 mL / kg of solution volume 0.3% Tween-80 was only administered orally, and the rats were referred to as a group administered with solvent; while in the same way, each of the rats administered with 1 mgr / kg of scopolamine (2mL / kg volume) subcutaneously, were referred to a group of scopolamine administered. The results of the test were analyzed by means of the two-tailed Chi-square test comparing the speed of the rats exhibiting the passive avoidance behavior with that of the group administered with scopolamine. Table 3 shows the results. . Table 3
Two square test washings Chi; * = p < 0.05
From the results above, the following is clear. In a group administered with scopolamine whose damage to the memory process was caused by administration of scopolamine, the speed of the rats showing the passive avoidance behavior was markedly diminished in comparison with that of the group administered with solvent. On the other hand, in the group to which Compound 2 was simultaneously supplied with scopolamine (group administered with test compound), the speed of the rats exhibiting passive, avoidance behavior was increased significantly compared to that of the administered group with scopolamine (p <0.05: two-tailed Chi-square test).
Example test 3: Labyrinth learning test in rats prepared by bilateral ligation of the common carotid arteries
The test was carried out according to the methods described in the following references. (1) Minutes. Neuropathol. 87, p.484-492 (1994) (2) Brain Res., Vol. 729, p.55-65 (1996) (3) Neuroscience, vol. 79, p. 1039-1050 (1997) (4) Nicho-yakuri-shi, vol.113, p.85-95 (1999) (5) Stroke, vol.26, p.1415-1422 (1995) (6) Non-shinkei , vol.49, p.639-644 (1997) (7) Jpn. J. Pharmacol., Vol. 75, p.443-446 (1997)
The experiment was carried out using 10 female Wistar rats (body weight 210-310 gr) per group. Under anesthesia with pentobarbital, the necks of the rats were cut and the common carotid bilateral arteries were ligated (bound rats). Separately, the necks of the rats were cut but the common carotid bilateral arteries were not ligated (sham operation of rats). Under anesthesia with pentobarbital, the rat was placed in an apparatus to fix the brain of the rat (Nasishige; SR-6). Hydrogen electrodes (Unique Medical; UHE-100, IS needle type) were inserted into a brain coordinate (A2.0, L2.0, D-2.0). Indifferent hydrogen electrode (Unique Medical) was placed in the neck of the rats. Artificial respiration was applied to the rat through a respiratory device (Shinano Seisakusyo; SN-480-7), through which about 40 L of hydrogen gas was inhaled by force 2 or 3 times at intervals of about 15 minutes. In the labyrinth learning test, a grayish radial labyrinth of vinyl chloride was used. The labyrinth was placed 50 cm above the floor and constituted of 8 radially extended paths (12 cm x 60 cm) and a central platform, in which a hole (3 cm in diameter, 1 cm deep) was placed in each end of the path and milk was placed as a reward. The run the maze learning test was developed twice. In the first run, the reward milk was placed in all the gaps of the 8 lanes, among which 4 lanes were blocked by blocks in such a way that the rat did not enter the lanes. In the first run, the rat was able to enter the labyrinth freely. When the rat returned to the platform after obtaining 4 milk holes it was restricted by a cylinder placed on the platform, during which the blocks on the 4 paths were removed. Ten seconds after the rat was restrained, the cylinder was removed and the second run was developed. In the second run, the rat was able to obtain milk placed in the hollows of the 4 remaining paths. At the same time, the frequency of the selection of the paths required to obtain the 4 milk hollows was registered until the run 16 of the selection was completed. The labyrinth learning test was initiated 4 weeks after bilateral ligation of the common carotid arteries. The first run and the second run were conducted as a single test; and the training of 2 tests was done at intervals of around 15 minutes and for 10 consecutive days. The average frequency of selection in the first and second tests was observed as a learning result. The paths in which the blocks were placed in the first run were determined according to each rat and were kept constant during the test period. The test compound was used as a suspension thereof in distilled water for injection with 0.5% methylcellulose (MC) (Otsuka Pharmaceutical Co.) and was administered orally for each of the rats bound at a dose of 10 mL / kgr. volume one hour before the start of the first test (group administered with the test compound). Separately, to each of the rats with operation
In contrast, each of the bound rats, 0.5% MC solution alone, was administered orally at a dose of 10 mL / kg volume one hour before the start of the first test., respectively, and were referred for fake operation of group and group of administered with solvent, respectively. The results of the tests were analyzed by Bonferroni-type multiple test procedures by comparing the frequency of path selection (Frequency of path selection) required to obtain 4 milk gaps in the second run of the learning test of labyrinth in the group administered with solvent. Figure 1 shows the results. From the above mentioned results, the following is clear. In the group administered with solvent, the path selection frequency increased significantly compared to the group with fake operation, indicating a decrease in the learning result (p <; 0.01; Bonferroni type multiple test procedures). In the group administered with the compound to which Compound 1 was administered (1 mg / kg) and Compound 1 (3 mg / kg) respectively, decreased learning results caused by bilateral ligation of the common carotid arteries improved significantly , respectively (p < 0.025 &p <
0. 005; Multiple test procedures type
Bonferroni).
Test Example 4: Test for learning of an alternate problem postponed (non-corresponding to sample)
The test was carried out in a manner similar to the method as described in Drug Dev. Res., 35, p.83-95 (1996).
The experiment was carried out using 10 male Wistar rats (Han) (body weight 200-250 gr) for a group. We used a Skinner box (30 cm x 25 cm x 30 cm) equipped with 3 effort-type levers (center, left and right sides) connected to a feeding container (supplying 45 mgr of diet pellets). The control of the test condition and the accumulation of data were automatically conducted when connecting to a MED program system. PC Each rat received learning and effort lever training, and from there on learning and training the alternative problem postponed. In the learning and training of the effort lever, the rat learned and was trained in such a way that the diet could be obtained by pushing from any center, left and right effort type levers. In the subsequent learning and training of the postponed alternate problem, the rat learned and was trained so that the diet could be obtained by thrusting first of any left and right lever, and then the pushed lever was removed; then, 5 seconds later, both levers left and right were presented, but the diet was only provided when the opposite side of the push lever was pushed forward. The time of presentation of each lever was set at 20 seconds, and if the rat did not push the lever within the time, the lever was removed, and the subsequent test started 10 seconds after it. The test compound was used as a suspension thereof in distilled injectable water containing 0.5% methylcellulose (MC) (Outsuka Pharmaceutical Co.) And was administered orally for each of the rats that learned and trained the lever by pushing a dose of 10 mL / kgr volume once a day from the beginning of learning and training of an alternative problem postponed continuously for a week (group administered with the test compound). Separately, to each of the rats which learned and trained the pushed lever, 0.5% MC of solution alone was administered orally at a dose of 10 mL / kgr volume once a day from the beginning of the learning and training of an alternate problem postponed continuously for 1 week, and the rats were referred to as a group administered with solvent. The accuracy of the speed for the reaction was indicated by the speed (%) of the left and right lever selected correctly (average of 10 rats), and the results of the test were analyzed by an ANOVA student test manner. Table 4 shows the results. Table 4
Student test: NS = not significant; * = p < 0.05; ++ = p < 0.01 Of the above mentioned results, the following is clear. In the postponed alternate problem test, the accuracy of the rate for the reaction of the group administered with compound-2 increased significantly compared to that of the group administered with solvent. The speed accuracy for the reaction after one week (Speed accuracy for the speed reaction in one week) increased significantly to 50.6 ± 1.5 (%) in contrast to the group administered with solvent 45.4 + 1.6 (%). From the results of the Test examples of Examples 1 to 4 as mentioned above, it was elucidated that compounds (I) or pharmaceutically acceptable salts thereof have effects of improvement and / or increase in high brain functions such as memory , learning, thinking, action, cognition, recognition and execution. In other words, it was shown that compounds (I) or pharmaceutically acceptable salts thereof are useful as agents for preventing and / or treating high cerebral dysfunctions (e.g., hemiespatial negligence, apraxia, agnosia, memory impairment, learning impairment, dysfunctions to perform activities and the like, caused by brain injuries due to diseases, accidents or aging). Compound (I) or a pharmaceutically acceptable salt thereof can be used as is or in various pharmaceutical dosage forms. The pharmaceutical composition of the present invention can be worked up by a uniform mixing of Compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient in an effective dose with a pharmaceutically acceptable carrier. It is preferred in such a way that a pharmaceutically acceptable composition is in a convenient unit dosage form for administration such as rectal or oral administration or parenteral administration (including subcutaneous, intravenous and intramuscular). In the preparation of a composition in an orally administered form, any pharmaceutically acceptable useful carrier can be used. In the case of an oral liquid preparation such as a suspension and syrup, it can be made using water, saccharide such as sucrose, sorbitol and fructose, glycol such as polyethylene glycol and propylene glycol, oil such as sesame oil, olive oil and soybean oil, antiseptic agent such as p-hydroxybenzoate, flavoring such as strawberry and mint flavor, etc. In the case of diluted powder, pill, capsule and tablet, this can be prepared using excipient such as lactose, glucose, sucrose and mannitol, disintegrating agent such as starch and sodium alginate, lubricant such as magnesium stearate and talc, binders such such as polyvinyl alcohol, hydroxypropyl cellulose and gelatin, surfactant such as fatty acid ester, plasticizers such as glycillin, and the like. Tablets and capsules are the most useful agents being administered per os because their administration is easy. In the manufacture of tablets and capsules, a solid pharmaceutical carrier is used.
Injection preparations can be prepared using a carrier comprising distilled water, salt solution, glucose solution or a mixture of brine and glucose solution, or the like. In this case, it is prepared as a solution, suspension or dispersion using an appropriate adjuvant according to the conventional method. The compound (I) or a pharmaceutically acceptable salt thereof can be administered orally in the pharmaceutical dosage form described above or parenterally as injections. Although the effective dose and frequency of administration of this varies depending on the form of administration, age and body weight of a patient, symptom, etc., this is appropriate to administer 1 to 100 mg / 60 kg / day or, preferably , 1 to 20 mg / 60 kgr / day once a day or several times a day. Brief description of the figures
Fig. 1 shows the effect of compound 1 on the labyrinth learning test in rats prepared by bilateral ligation of the common carotid arteries. The ordinate indicates the frequency of the path selection
(Frequency selection of the lanes) required to obtain the 4 milk gaps in the second run in the maze learning test. The abscissa indicates the number of days elapsed (days) after the start of the test. Each path in the graph has the following meanings. ~: Feigned operation group -0-: Group administered with solvent -? - .- (1 mgr / kgr) -group administered with Compound 1 -D-: (3 mg / kg) -group administered with Compound 1
Best method for carrying out the invention
The embodiments of the present invention are illustrated in detail below referring to the examples. Example 1: Tablets Tablets comprising the following composition are prepared by a conventional method. Compound 1 (40 gr), 286.8 gr of lactose and
60 g of potato starch are mixed and 120 g of 10% of an aqueous solution of hydroxypropyl cellulose is added to it. The mixture is kneaded by a conventional method, granulated, dried and subjected to selection of particle size to give granules for processing into tablets. Magnesium stearate (1.2 g) is added to it and mixed together and subjected to rattling using a tabletting machine (RT-15 made by Kikushisha) that has drills with 8 mm diameter to make tablets (each tablet contains 20 mgr of ingredient active) .
Prescription Compound 1 20 mgr Lactose 143.3 mgr Potato starch 30 mgr Hydroxypropyl cellulose 6 mgr Magnesium stearate 0.6 mgr 200 mgr
Example 2: Capsule preparations Capsule preparations comprising the following composition are prepared by a conventional method. Compound 2 (200 g), 995 g of Avicel and 5 g of magnesium stearate are mixed by a conventional method. The mixture is filled into hard capsules No. 4 (capacity of one capsule is 120 mgr) using a capsule filling machine (type LZ-64, manufactured by Zanasi) to prepare capsule preparations (each capsule containing 20 mgr of the active ingredient ).
Prescription Compound 2 20 mgr Avicel 99.5 mgr Magnesium stearate 0.5 mgr 120 mgr Example 3: Injection preparations The injection preparations comprising the following composition are prepared by a conventional method. Compound 3 (1 g) is dissolved in 100 g of pure soybean oil and 12 g of pure yolk lecithin and 25 g of glycerol for injection are added to it. The mixture is made using 1000 mL of distilled water for injection by a conventional method followed by kneading and emulsification. The resulting dispersion is subjected to an aseptic filtration using a membrane filter of a disposable 0.2 μm type and each 2 mL of this is aseptically filled into a glass jar to prepare injection preparations (each vial contains 2 mgr of the ingredient active) .
Prescription Compound 3 2 mgr Pure soybean oil 200 mgr Pure yolk lecithin 24 mgr Glycerol for injection 50 mgr Distilled water for injection 1.72 mgL 2.00 mL Example 4: Anal suppositories A preparation for rectal administration comprising the following composition is prepared by a method conventional Witepsol ™ H15 (produced by Dynamite Nobel) (678.8 gr) and 290.9 gr of Witepsol ™ E75 (produced by Dynamite Nobel) are melted at 40 to 50 ° C. Compound 4 (2.5 gr), 13.6 g of primary potassium phosphate and 14.2 g of secondary sodium phosphate are mixed uniformly with the above mentioned and dispersed. After that, the mixed / dispersed product is filled into suppository molds made of plastic followed by gradual cooling to prepare anal suppositories (each preparation contains 2.5 mgr of the active ingredient).
Prescription Compound 4 2.5 mgr Witespol ™ H15 678.8 mgr Witespol ™ E75 290.9 mgr Primary potassium phosphate 13.6 mgr Second sodium phosphate 14.2 mgr 1,000 mg
Industrial Applicability The present invention provides agents for preventing and / or treating high cerebral dysfunctions comprising, as an active ingredient, for example, a xanthine derivative or a pharmaceutically acceptable salt thereof. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Claims (13)
- Y2 (in which Y1 and Y2 are the same or different, and represent a hydrogen atom, halogen or lower alkyl, and Z represents substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group); X1 and X2 are the same or different, and represent an oxygen atom or a sulfur atom] or a pharmaceutically acceptable salt thereof.
- 2. The agent for preventing and / or treating high cerebral dysfunction according to claim 1, characterized in that X1 and X2 each is an oxygen atom.
- 3. The agent for preventing and / or treating high cerebral dysfunction according to claim 1 or 2, characterized in that R4 is a group represented by the formula (II): (in which Y1, Y2 and Z each have the same meanings as defined above).
- 4. The agent for preventing and / or treating high cerebral dysfunction according to claim 3, characterized in that Y1 and Y2 are both hydrogen atoms.
- 5. The agent for preventing and / or treating high cerebral dysfunction according to claim 3 or 4, characterized in that Z is unsubstituted or substituted aryl or a group represented by the formula (III): (in which R6 represents a hydrogen atom, hydroxy, lower alkyl, lower alkoxy, halogen, nitro or amino, and m represents an integer from 1 to 3).
- 6. The agent for preventing and / or treating high cerebral dysfunction according to any of claims 1 to 5, characterized in that the cerebral dysfunction is a high cerebral dysfunction caused by brain damage.
- 7. The agent for preventing and / or treating high cerebral dysfunction according to claim 6, characterized in that the brain damage is brain damage due to aging.
- 8. - The agent for preventing and / or treating high cerebral dysfunction according to claim 6, characterized in that the brain damage is brain damage due to disorder selected from the group consisting of head trauma and stroke.
- 9. - The agent for preventing and / or treating high cerebral dysfunction according to any of claims 1 to 8, characterized in that the high cerebral dysfunction is a deterioration of the high cerebral function selected from the group consisting of memory, thought, recognition, action and learning.
- 10. The agent for preventing and / or treating high cerebral dysfunction according to any of claims 1 to 8, characterized in that the high cerebral dysfunction is a cerebral dysfunction selected from the group consisting of agnosia, amnesia and apraxia.
- 11. - The agent for preventing and / or treating high cerebral dysfunction according to any of claims 1 to 8, characterized in that the high cerebral dysfunction is a deterioration in memory.
- 12. The agent for preventing and / or treating high cerebral dysfunction according to any of claims 1 to 8, characterized in that the high cerebral dysfunction is a deterioration in learning.
- 13. - The use of a xanthine derivative represented by the formula (I): [wherein R- ^ R, R, R, X and X each have the same meanings as defined above] or a pharmaceutically acceptable salt thereof for the preparation of an agent for preventing and / or treating high cerebral dysfunction.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2003-410432 | 2003-12-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA06005965A true MXPA06005965A (en) | 2006-10-17 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7851478B2 (en) | Agent for preventing and/or treating movement disorder | |
EP1738766A1 (en) | Preventive and/or therapeutic agent for disease accompanied by chronic muscle/skeleton pain | |
CN106999462A (en) | Include selective S1P1The pharmaceutical composition of receptor stimulating agent | |
WO2005115471A2 (en) | Methods and compositions for treatment of nicotine dependence and dementias | |
EP2705841A1 (en) | Combinations of nootropic agents for treating cognitive dysfunctions | |
CN114478450A (en) | Benzyloxybelphthalide compound, preparation method and application thereof | |
EP0667349B1 (en) | Depression remedy | |
TW544311B (en) | Therapeutic or preventive agent for intractable epilepsies | |
MXPA06005965A (en) | Preventive and/or therapeutic agent for higher brain dysfunction | |
EP1709966A1 (en) | Preventive and/or therapeutic agent for higher brain dysfunction | |
CA2554426C (en) | Agents for treating migraine | |
JP5188066B2 (en) | Agents for preventing and / or treating drug addiction | |
EP1640007A1 (en) | Antiepileptic agent | |
JP2009143929A (en) | Preventive or treating agent for sleep disorder | |
EP1581163A2 (en) | Use of istradefylline (kw-6002) for the treatment of behavioral disorders | |
EP3122187A1 (en) | Treatment of rett syndrome | |
JPH0624968A (en) | Therapeutic agent for disturbance of consciousness | |
JPH0541603B2 (en) |