CN1177297A - 治疗强迫症、睡眠呼吸暂停、性功能障碍、呕吐和运动症的药物 - Google Patents
治疗强迫症、睡眠呼吸暂停、性功能障碍、呕吐和运动症的药物 Download PDFInfo
- Publication number
- CN1177297A CN1177297A CN96192286A CN96192286A CN1177297A CN 1177297 A CN1177297 A CN 1177297A CN 96192286 A CN96192286 A CN 96192286A CN 96192286 A CN96192286 A CN 96192286A CN 1177297 A CN1177297 A CN 1177297A
- Authority
- CN
- China
- Prior art keywords
- butyl
- piperazinyl
- pyrimidine radicals
- pyrazoles
- chloro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 201000002859 sleep apnea Diseases 0.000 title claims abstract description 18
- 239000003814 drug Substances 0.000 title claims abstract description 14
- 238000011282 treatment Methods 0.000 title claims abstract description 9
- 206010025482 malaise Diseases 0.000 title abstract description 3
- 230000001568 sexual effect Effects 0.000 title description 2
- 201000001880 Sexual dysfunction Diseases 0.000 claims abstract description 15
- 231100000872 sexual dysfunction Toxicity 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 55
- 150000001875 compounds Chemical class 0.000 claims description 18
- 206010047700 Vomiting Diseases 0.000 claims description 15
- 230000008673 vomiting Effects 0.000 claims description 13
- 206010029897 Obsessive thoughts Diseases 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- -1 piperidine-2-yl Chemical group 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 11
- 230000033001 locomotion Effects 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 claims 2
- 241000124008 Mammalia Species 0.000 claims 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N Carbazole Natural products C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 claims 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical class C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 34
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 238000005481 NMR spectroscopy Methods 0.000 description 22
- 239000000460 chlorine Substances 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- LTGPFZWZZNUIIK-LURJTMIESA-N Lysol Chemical compound NCCCC[C@H](N)CO LTGPFZWZZNUIIK-LURJTMIESA-N 0.000 description 15
- 230000000694 effects Effects 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 10
- 241000700159 Rattus Species 0.000 description 9
- 230000007958 sleep Effects 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 7
- 238000000034 method Methods 0.000 description 6
- 230000009329 sexual behaviour Effects 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- QWCRAEMEVRGPNT-UHFFFAOYSA-N buspirone Chemical compound C1C(=O)N(CCCCN2CCN(CC2)C=2N=CC=CN=2)C(=O)CC21CCCC2 QWCRAEMEVRGPNT-UHFFFAOYSA-N 0.000 description 5
- 229960002495 buspirone Drugs 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- 208000028017 Psychotic disease Diseases 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 4
- 229960004316 cisplatin Drugs 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 208000019901 Anxiety disease Diseases 0.000 description 3
- 206010003497 Asphyxia Diseases 0.000 description 3
- 241000282341 Mustela putorius furo Species 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 230000029058 respiratory gaseous exchange Effects 0.000 description 3
- TZJUVVIWVWFLCD-UHFFFAOYSA-N 1,1-dioxo-2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,2-benzothiazol-3-one Chemical compound O=S1(=O)C2=CC=CC=C2C(=O)N1CCCCN(CC1)CCN1C1=NC=CC=N1 TZJUVVIWVWFLCD-UHFFFAOYSA-N 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 230000008451 emotion Effects 0.000 description 2
- QOIGKGMMAGJZNZ-UHFFFAOYSA-N gepirone Chemical compound O=C1CC(C)(C)CC(=O)N1CCCCN1CCN(C=2N=CC=CN=2)CC1 QOIGKGMMAGJZNZ-UHFFFAOYSA-N 0.000 description 2
- 229960000647 gepirone Drugs 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 229950003599 ipsapirone Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- 230000000414 obstructive effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000036391 respiratory frequency Effects 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 238000009423 ventilation Methods 0.000 description 2
- DBGIVFWFUFKIQN-UHFFFAOYSA-N (+-)-Fenfluramine Chemical compound CCNC(C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-UHFFFAOYSA-N 0.000 description 1
- VHFVKMTVMIZMIK-UHFFFAOYSA-N 1-(3-chlorophenyl)piperazine Chemical compound ClC1=CC=CC(N2CCNCC2)=C1 VHFVKMTVMIZMIK-UHFFFAOYSA-N 0.000 description 1
- CJAWPFJGFFNXQI-UHFFFAOYSA-N 2-chloro-6-(1-piperazinyl)pyrazine Chemical compound ClC1=CN=CC(N2CCNCC2)=N1 CJAWPFJGFFNXQI-UHFFFAOYSA-N 0.000 description 1
- LDCYZAJDBXYCGN-VIFPVBQESA-N 5-hydroxy-L-tryptophan Chemical compound C1=C(O)C=C2C(C[C@H](N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-VIFPVBQESA-N 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- 229940000681 5-hydroxytryptophan Drugs 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 102000007527 Autoreceptors Human genes 0.000 description 1
- 108010071131 Autoreceptors Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010010219 Compulsions Diseases 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 102000014630 G protein-coupled serotonin receptor activity proteins Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 206010062519 Poor quality sleep Diseases 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical class C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- 206010038669 Respiratory arrest Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000003708 ampul Substances 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
- 230000036506 anxiety Effects 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229960001582 fenfluramine Drugs 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 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
- 239000001257 hydrogen Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- AHCPKWJUALHOPH-UHFFFAOYSA-N lesopitron Chemical compound C1=C(Cl)C=NN1CCCCN1CCN(C=2N=CC=CN=2)CC1 AHCPKWJUALHOPH-UHFFFAOYSA-N 0.000 description 1
- 229950001590 lesopitron Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 208000001797 obstructive sleep apnea Diseases 0.000 description 1
- LDCYZAJDBXYCGN-UHFFFAOYSA-N oxitriptan Natural products C1=C(O)C=C2C(CC(N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-UHFFFAOYSA-N 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 210000003899 penis Anatomy 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003169 respiratory stimulant agent Substances 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 238000011125 single therapy Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000007916 tablet composition Substances 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
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Reproductive Health (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Urology & Nephrology (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及1-{4-[4-芳基(或杂芳基)-1-哌嗪基]丁基}-1H-吡咯以其生理可接受盐在制备用于治疗强迫症、睡眠呼吸暂停、性功能障碍、呕吐和运动症的药物中的用途。
Description
本发明涉及1-{4-〔4-芳基(或杂芳基)-1-哌嗪基〕丁基}-1H-吡咯衍生物以及其生理可接受盐在制备用于治疗强迫症、睡眠呼吸暂停综合症、性功能障碍、呕吐和运动症(maldes transports)的药物中的用途。
本发明所涉及的化合物已在欧洲专利EP-0,382,637和EP-0,497,659中被描述,在欧洲专利EP-0,502,786中描述了芳基(或杂芳基)-哌嗪基-丁基-吡咯衍生物的制备方法。在专利EP-0,382,637和EP-0,497,659中,我们已要求了这些化合物治疗某些中枢神经系统疾病的用途。我们现发现芳基(或杂芳基)-哌嗪基-丁基-吡咯衍生物显示抗强迫症活性,防止睡眠呼吸暂停作用、促进性行为的作用、和抗呕吐抗恶心作用,它们从而可用于治疗和预防强迫症、睡眠呼吸暂停综合症性功能障碍和(尤其是)由细胞毒性治疗和/或化疗或运动引起的恶心和呕吐。这些化合物特别用于预防或治疗人和动物的忧郁、强迫症、睡眠呼吸暂停综合症、性功能障碍、呕吐和运动症。
其中
Ar代表含氮或不含氮的芳香基团,选自各种取代的芳基,各种取代的2-嘧啶,和3-(1,2-苯并异噻唑),
Z1代表氮原子或可用C-R1表示的取代或未取代的碳原子,
Z2代表氮原子或可用C-R2表示的取代或未取代的碳原子,
Z4代表氮原子或可用C-R4表示的取代或未取代的碳原子,
R1、R2、R3和R4,可相同或不同、也可以构成另一芳香或非芳香环的一部分,代表氢原子、卤原子、低级烷基、硝基、羟基、烷氧基、氰基、羧基、烷氧羰基、芳基或取代芳基、磺酸基、磺酰氨基、氨基上有取代或无取代的氨基羰基、氨基或取代氨基。
其中R7、R8和R9相同或不同,代表氢、卤原子、烷基、全卤代烷基、羟基、烷氧基或氰基。
本发明中的烷基应理解为低级烷基,优选直链或支链饱和或不饱和的C1-C6烷基,特别是甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基和其各种异构体。这一定义也适用于烷氧基中的烷基。
本发明中的卤原子优选指氟、氯、溴或碘。
本发明中的芳基特别指芳香基或杂芳基,特别是选自苯基、萘基、蒽基、菲基、吡啶基、嘧啶基等,优选苯基,这些芳基可被特别是选自下组的一个或多个基团取代或不取代:卤原子、低级烷基、硝基、羟基、烷氧基、氰基、羧基、烷氧羰基、芳基或取代芳基、磺酸基、磺酰氨基、氨基上有或没有取代的氨基羰基、和氨基或取代氨基。
氨基的取代基特别为烷基或芳基。
药用盐应理解为有机和无机酸的常规加成盐,如盐酸盐、二盐酸盐、甲磺酸盐或对甲苯磺酸盐。
下述实施例1-84中指出的化合物是按专利EO-0,382,637、EP-0,497,659和EP-0,502,786中描述的方法获得的,它们的鉴定数据详见表1。实施例1.1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}吡咯2.1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}咔唑3.1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}吲哚4.2,3-二苯基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}吲哚5.4-氨基甲酰基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑6.4-羧基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑7.3-甲基-5-三氟甲基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑8.4,5-二苯基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-咪唑9.2,4,5-三苯基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-咪唑10.4,5-二苯基-2-甲基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-咪唑11.4,5-二氯-2-甲基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-咪唑12.2-乙基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-咪唑13.2-苯基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-咪唑14.4-甲氧羰基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-咪唑15.4-苯基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-咪唑16.1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-苯并咪唑17.1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-3H-咪唑并[5,4-b]吡啶18.1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-咪唑并[4,5-b]吡啶19.1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-苯并三唑20.2-氯-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-苯并咪唑21.1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-1,2,4-三唑22.2-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-2H-苯并三唑23.2-甲基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-苯并咪唑24.5,6-二甲基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-苯并咪唑25.1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑26.3,5-二甲基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑27.3,5-二甲基-4-硝基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑28.4-甲基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑29.1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-咪唑30.4-溴-3,5-二甲基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑31.4-硝基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑32.4-氯-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑二盐酸盐33.4-乙氧羰基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑34.3-甲基-5-苯基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑35.4-溴-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑36.4-氰基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑37.4-氟-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑38.4-氨基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑39.4-甲磺酰氨基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑40.4-苯甲酰氨基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑41.4-乙酰氨基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑42.4-(2-丁基)氨基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑43.3-氯-4-氟-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑44.4-(4-甲氧基苯基)-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑45.4-(4-氯苯基)-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑46.4-(1-吡咯基)-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑47.4-苯基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑48.3,5-二苯基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑49.4-苯磺酰氨基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑50.4-(4-甲基苯)磺酰氨基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑51.4-丁基磺酰氨基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑52.4-丙基磺酰氨基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑53.4-乙基磺酰氨基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑54.3,5-二甲基-4-(N,N-二甲基磺酰氨基)-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑55.4-N-甲基磺酰氨基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑56.4-磺酸基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑57.1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1-咪唑58.2-甲基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-咪唑59.4,5-二氯-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-咪唑60.4-氯-1-{4-[4-(4-甲氧基苯基)-1-哌嗪基]丁基}-1H-吡唑61.4,5-二氯-2-甲基-1-{4-[4-(4-甲氧基苯基)-1-哌嗪基]丁基}-1H-咪唑62.4-氯-1-{4-[4-(2-甲氧基苯基)-1-哌嗪基]丁基}-1H-吡唑63.4,5-二氯-2-甲基-1-{4-[4-(2-甲氧基苯基)-1-哌嗪基]丁基}-1H-咪唑64.4-氯-1-{4-[4-(3-甲氧基苯基)-1-哌嗪基]丁基}-1H-吡唑65.1-{4-[4-(4-甲氧基苯基)-1-哌嗪基]丁基}吡咯66.1-{4-[4-(2-甲氧基苯基)-1-哌嗪基]丁基}吡咯67.1-{4-[4-(苯基)-1-哌嗪基]丁基}吡咯68.4-氯-1-{4-[4-(苯基)-1-哌嗪基]丁基}吡唑69.4,5-二氯-2-甲基-1-{4-[4-(苯基)-1-哌嗪基]丁基}-1H-咪唑70.4-氯-1-{4-[4-(2-氯苯基)-1-哌嗪基]丁基}吡唑71.4,5-二氯-2-甲基-1-{4-[4-(2-氯苯基)-1-哌嗪基]丁基}-1H-咪唑72.4-氯-1-{4-[4-(3-氯苯基)-1-哌嗪基]丁基}-1H-吡唑73.4,5-二氯-2-甲基-1-{4-[4-(2-氰基苯基)-1-哌嗪基]丁基}-1H-咪唑74.4,5-二氯-2-甲基-1-{4-[4-(2-氟苯基)-1-哌嗪基]丁基}-1H-咪唑75.4-氯-1-{4-[4-(2-氰基苯基)-1-哌嗪基]丁基}-1H-吡唑76.4,5-二氯-2-甲基-1-{4-[4-(3-三氟甲基苯基)-1-哌嗪基]丁基}-1H-咪唑77.4-氯-1-{4-[4-(3-三氟甲基苯基)-1-哌嗪基]丁基}-1H-吡唑78.4-氯-1-{4-[4-(2-氟苯基)-1-哌嗪基]丁基}-1H-吡唑79.4-氯-1-{4-[4-(1,2-苯并异噻唑-3-基)-1-哌嗪基]丁基}-1H-吡唑80.4,5-二氯-2-甲基-1-{4-[4-(1,2-苯并异噻唑-3-基)-1-哌嗪基]丁基}-1H-咪唑81.1-{4-[4-(1,2-苯并异噻唑-3-基)-1-哌嗪基]丁基}-1H-1,2,4-三唑82.1-{4-[4-(1,2-苯并异噻唑-3-基)-1-哌嗪基]丁基}-1H-苯并咪唑83.4-溴-1-{4-[4-(5-溴嘧啶-2-基)-1-哌嗪基]丁基}-1H-吡唑84.4-氯-1-{4-[4-(5-溴嘧啶-2-基)-1-哌嗪基]丁基}-1H-吡唑
表I
实施例 | Z1 | Z2 | Z4 | R3 | m.p. | IRcm-1 | NMR溶剂 | 1H-NMR(100 HHz),6,J=Hz |
1 | CH | CH | CH | H | oil | 2941,1585,1547,1500,1360,1260,983,724(膜) | CDCl3 | 1.55(m,2H);1.77(m,2H):2.25-2.55(a.c.6H);3.70-4.05(a.c.6H);6.13(t,J=2,0Hz,2H);6.47(t,J=4,7Hz,1H);6.65(t,J=2,0Hz,2H);8.29(d,J=4,7Hz,2H) |
2 | C-CH=CH-CH=CH-C | C-CH=CH-CH=CH~ | oil | 2941,1586,1547,1511,1404,1402,1359,1301,1260,983,750,723(膜) | CDCl3 | 1.6(m,2H)_;1.86(m,2H);2.27-2.45(a.c. 6H);3.78(t,J=5,2Hz,4H);4.30(t,J=1,1Hz,2H);6.43(t,J=4,7Hz,1H);7.12-7.46(a.c.6H);8.07(d,J=6,5Hz,2H);8.26(d,J=4,7Hz,2H) | ||
3 | C-CH=CH-CH=CH-C | CH | H | oil | 2940,1585,1547,1510,1446,1359,1259,983,741(膜) | CDCl3 | 1.54(m,2H);1.88(m,2H);2.37(a.c.6H);3.79(t,J=5Hz,4H),4.13(t,J=6,8Hz,2H);6.45(a.c.2H);6.9-7.1(a.c.5H);8.27(d,J=4,7Hz,2H) |
表I(续)
实施例 | Z1 | Z2 | Z4 | R3 | m.p. | IR cm-1 | NMR溶剂 | 1H-NMR(100 MHz),δ,J=Hz |
7 | N | CMe | CCF3 | H | 71-75℃ | 2937,2856,1586,1544,1496,1393,1228,1177,1125,981(KBr) | CDCl3 | 1.57(m,2H);1.89(m,2H);2.32(s,3H);2.30-2.55 (a.c.6H);3.82(t,J=5Hz,4H);4.10(t,J=7Hz,2H);6.25(s,1H);6.47(t,J=4,7Hz,1H);8.29(d,J=4,7Hz,2H) |
8 | CH | N | CPh | Ph | Oil | 2942,1585,1547,1505,1445,1360,1307,1260,983,774,754,700(膜) | CDCl3 | 1.55(m,4H);2.16-2.42(a.c.6H);3.71-3.89(a.c.6H);6.47(t,J=4,7Hz,1H);7.12-7.60(a.c.11H);8.27(d,J=4,7Hz,2H) |
9 | CPh | N | CPh | Ph | oil | 2942,1585,1546,1501,1445,1360,1260,983,698(膜) | CDCl3 | 1.55(m,4H);1.95-2.33(a.c.6H);3.69-4.07(a.c.6H);6.47(t,J=4,7Hz,1H);7.13-7.67(a.c.15H);8.26(d,J=4,7Hz,2H) |
表I(续)
实施例 | Z1 | Z2 | Z4 | R3 | m.p. | IR cm-1 | NMR溶剂 | 1H-NMR(100 MHz),δ,J=Hz |
10 | CMe | N | CPh | Ph | Oil | 2942,1585,1547,1500,1446,1393,1260,983,760,698(膜) | CDCl3 | 1.43(m,4H);2.18-2.47(a.c. 9H);3.72-3.76(a.c. 6H);6.47(t,J=4,7Hz,1H);7.09-7.39(a.c.10H);8.26(d,J=4,7Hz,2H) |
11 | CMe | N | CCl | Cl | oil | 2942,1586,1547,1500,1447,1359,1259,1245,983(膜) | CDCl3 | 1.45-1.84(a.c.4H);2.26-2.57(a.c.9H);3.74-4.05(a.c.6H);6.48(t,J=4,7Hz,1H);8.30(d,J=4,7Hz,2H) |
12 | CEt | N | CH | H | oil | 2938,1585,1547,1495,1446,1360,1260,983,638 (膜) | CDCl3 | 1.34(t,J=7,1,3H);1.66(m,4H);2.31-2.72(a.c. 8H);3.77-3.92(a.c. 6H);6.47(t,J=4,7Hz,1H);6.87(d,J=10Hz,2H);8.26(d,J=4,7Hz,2H) |
表I(续)
表I(续)
实施例 | Z1 | Z2 | Z4 | R3 | m.p. | IR cm-1 | NMR溶剂 | 1H-NMR(100 MHz),δ,J=Hz |
16 | CH | N | C-CH=CH-CH=CH- | 85-88℃ | 2944,1581,1542,1488,1466,1355,1259,741(KBr) | DMSO-d6 | 1.40(m,2H);1.82(m,2H);2.26-2.42(a.c.6H);3.62-3.71(a.c.4H);4.24(t,J=6,9Hz,2H);6.56(t,J=4,7Hz,1H);7.16-7.26(a.c.2H);7.55-7.70(a.c. 2H);8.22-8.34(a.c.3H) | |
17 | CH | N | C-N=CH-CH=CH- | 104℃ | 2935,1578,1545,1482,1443,1409,1357,1256,982,751(KBr) | DMSO-d6 | 1.45(m,2H);1.90(m,2H);2.23-2.50(a.c.6H);3.6(t,J=4,8Hz,4H);4.3(t,J=7,0Hz,2H);6.5(t,J=4,7Hz,1H);7.25(d.d,J=4,7Hz,1H);8.05(d,J=7,9Hz,1H);8.30-8.48(a.c.4H) | |
18 | CH | N | C-CH=CH-CH=N- | 134℃ | 2944,2828,1609,1582,1543,1487,1460,1355,1260,982,800 (KBr) | DMSO-d6 | 1.42(m,2H);1.84(m,2H);2.28-2.49(a.c.6H);3.60-3.69(a.c. 4H);4.03(t,J=7,0Hz,2H);6.5(t,J=4,7Hz,1H);7.28(dd,J=4,7Hz,1H);8.07(d,J=7,9Hz,1H);8.29-8.50(a.c. 4H) |
表I(续)
实施例 | Z1 | Z2 | Z4 | R3 | m.p. | IR cm-1 | NMR溶剂 | 1H-NMR(100 MHz),δ,J=Hz |
19 | N | N | C-CH=CH-CH=CH- | 89-90.5℃ | 2940,2818,1590,1544,1498,1360,1259,984,749(KBr) | DMSO-d6 | 1.43(m,2H);1.97(m,2H);2.24-2.53(a.c.6H);3.66(t,J=5,1Hz,4H);4.75(t,J=6,8Hz,2H);6.60(t,J=4,7Hz,1H);7,52(m,2 H);8.01(m,2H);8.31(s,1H);8.36(s,1H) | |
20 | CCl | N | C-CH=CH-CH=CH- | 153-145℃ | 2940,1583,1542,1491,1466,1443,1383,1264,1128,981,742(KBr) | DMSO-d6 | 1.50(m,2H);1.81(m,2H);2.20-2.42(a.c.6H);3.67(m,4H);4.28(t,J=7Hz,2H);6.58 (t,J=4,7Hz,1H);7.30(m,2H);7.60(m,2H);8.31(d,J=4,7Hz,2H) |
表I(续)
实施例 | Z1 | Z4 | R3 | Z2 | m.p. | IR cm-1 | 溶剂NMR | 1H-NMR 100 MHz),δ,J=Hz |
21 | CH | N | H | N | 69-71℃ | 2942,1582,1546,1458,1448,1360,1261,1138,1011,983,680(KBr) | CDCl3 | 1.55(m,2H);1.96(m,2H);2.32-2.51(a.c.6H);3.81(t,J=5,1Hz,4H);4.21(t,J=7,0Hz,2H);6.47(t,J=4,7Hz,1H);7.95(s,1H);8.09(s,1H);8.29(d,J=4,7Hz,2H) |
22 | N | N | -CH=CH-CH=CH-C | 97.4-98.2℃ | 2946,2863,2823,1585,1547,1483,1358,1256,982,799,761(KBr) | DMSO-d6 | 1.34-1.56(m,2H);1.97-2.13((m,2H);2.18-2.48(a.c.6H);3.65(t,J=5,3Hz,4H);4.75(t,J=6,8Hz,2H);6.56(t,J=4,7Hz,1H);7.40(dd,J=6,5Hz,J′=3,1Hz,2H);7.90(dd.,J= 6,6Hz,J′=3,3Hz,2H);8.28(s,1H);8.33(s,1H) |
表I(续)
实施例 | Z1 | Z2 | R3 | Z4 | m.p. | IR cm-1 | NMRs溶剂 | 1H-NMR(100 MHz),δ,J=Hz |
25 | N | CH | H | CH | Oil | 2942,2815,1586,1547,983(膜) | CDCl3 | 1.50(m,2H);1.90(m,2H);2.40(m,6H);3.80(m,4H);4.12(t,2H,J=6,9);6.20(t,1H,J=1,6);6.40(t,1H,J=4,7);7.42(dd,2H,J=4,7;J′=1.6);8.25(d,2H,J=4,7) |
26 | N | CMe | H | CMe | Oil | 1590,1550,1350,1260,980(膜) | CDCl3 | 1.58(m,2H);1.85(m,2H);2.20(s,3H);2.25(s,3H);2.44(m,6H);3.81(m,4H);3.97(t,2H,J=7,2);5.78(s,1H);6.43(t,1H,J=4,7);8.27(d,2H,J=4,7) |
27 | N | CMe | NO2 | CMe | Oil | 1590,1550,1350,1260,980(膜) | CDCl3 | 1.60(m,2H);1.90(m,2H);2.49(m,9H);2.63(s,3H);3.82(m,4H);4.09(t,2H,J=7);6.48(t,1H,J=4,7);8.29(d,2H,J=4,7) |
表I(续)
实施例 | Z1 | Z2 | R3 | Z4 | m.p. | IR cm-1 | NMRs溶剂t | 1H-NMR(100 MHz), δ,J=Hz |
28 | N | CH | Me | CH | Oil | 1590,1550,1500,1360,1260,980(膜) | CDCl3 | 1.52(m,2H);1.95(m,2H);2.05(s,3H);2.37(m,6H);3.81(m,4H);4.05(t,2H,J=6,8);6.41(t,1H,J=4,7);7.13(s,1H);7.27 (s,1H);8.25(d,2H,J=4,7) |
29 | N | CH | -CH=CH-CH=CH-C- | oil | 2930,1590,1550,1500,1360,1310,1260,980(膜) | CDCl3 | 1.51(m,2H);1.98(m,2H);2.36(m,6H);3.77(m,4H);4,39(t,2H,J=6,9);6.40(t,1H,J=4,7);7.0-7.7(m,4H);7.95(s,1H);8.25(d,2H,J=4,7) | |
30 | N | CMe | Br | CMe | oil | 2930,1590,1550,1500,1360,1310,1260,980(膜) | CDCl3 | 1.55(m,2H);1.81(m,2H);2.18(s,3H);2.20(s,3H);2.38(m,4H);3.80(m,4H);3.99(t,2H,J=6,9);6.42(t,1H,J=4,7);8.25(d,2H,J=4,7) |
表I(续)
实施例 | Z1 | Z2 | R3 | Z4 | m.p. | IR cm-1 | NMR溶剂 | 1H-NMR(100 MHz),δ,J=Hz |
31 | N | CH | NO2 | CH | 94-96℃ | 1584,1524,1480,1444,1406,1359,1305,819 ,(KBr) | CDCl3 | 1.5(m,2H);1.93(m,2H);2.38(m,6H);3.76(m,4H);4.15(t,2H,J=6,7);6.42(t,1H,J=4,7);8.01(s,1H);8.12(s,1H);8.24(d,2H,J=4,7) |
32 | N | CH | Cl | CH | 2HCl195-8℃ | 3429,2688,1636,1620,1346,1218,971 | DMSO-d6 | 1.69(m,2H);1.81(m,2H);2.98(m,2H);3.08(m,2H);3.39-3.53(m,4H);4.12(t,2h);4.67(d,2H);6.77(t,1H);7.53(d,1H);8.04(d,1H);8.45(d,2H) |
33 | N | CH | EtOOC- | CH | Oil | 1715,1586,1222,983(膜) | CDCl3 | 1.34(t,3H,J=7.1);1.54(m,2H);1.90(m,2H);2.46(m,6H);3.81(m,4H);4.25(m,4H);6.47(t,1H,J=4,7);7.90(s,2H);8.29(d,2H,J=4,7) |
表I(续)
实施例 | Z1 | Z2 | R3 | Z4 | m.p. | IR cm-1 | NMR溶剂 | 1H-NMR(100 MHz),δ,J=Hz |
34 | N | CMe | H | CPh | Oil | 1586,1547,1360,983(膜) | CDCl3 | 1.54(m,2H);1.85(m,2H);2.28(s,3H);2.45(m,6H);3.81(m,4H);4.07(t,2H,J=7);6.28(s,1H);6.43(t,1H,J=4,7);7.33(m,4H);7.75(m,2H);8.26(d,2H,J=4,7) |
35 | N | CH | Br | CH | oil | 1586,1547,1360,984(膜) | CDCl3 | 1.52(m,2H);1.89(m,2H);2.44(m,6H);3.62(m,4H);4.11(t,2H,J=6,7);6.46(t,1H,J=4,6);7.42(s,1H);7.45(s,1H);8.29(d,2H,J=4,6) |
36 | N | CH | C≡N | CH | 94-95℃ | 3076,2231,1587,1551,1258,982(KBr) | CDCl3 | 1.54(m,2H);1.96(m,2H);2.40(m,6H);3.81(m,4H);4.20(t,2H,J=6,9);6.48(t,1H,J=4,7);7.80(s,1H);7.83(s,1H);8.29(d,2H,J=4,7) |
表I(续)
实施例 | Z1 | Z2 | R3 | Z4 | m.p. | IR cm-1 | NMRs溶剂t | 1H-NMR(100 MHz),δ,J=Hz |
37 | N | CH | F | CH | Oil | 2944,1584,1546,1507,1359,1260,983(膜) | CDCl3 | 1.45(m,2H);1.96(m,2H);2.36(m,6H);3.77(m,4H);4.0(t,2H,J=6,9);6.47(t,1H,J=4,7);7.27(m,2H,J=4,8);8.29(d,2H,J=4,8) |
38 | CH | CH | H2N- | N | oil | 1586,1548,1360,984(膜) | CDCl3 | 1.50(m,2H);1.85(m,2H);2.43(m,6H);3.4(élargie 2H);3.8(m,6H);4.0(t,2H,J=6,4);6.46(t,1H,J=4,7);6.98(s,1H);7.10(s,1H);8.27(d,2H,J=4,7) |
39 | CH | CH | Me-SO2-NH- | N | 132℃ | 1582,1482,1360,1150,983(KBr) | CDCl3 | 1.58(m,2H);1.93(m,2H);2.45(m,6H);2.94(s,3H);3.8(m,4H);4.11(t,2H,J=6,9);6.45(t,1H,J=4,7);7.4(s,1H);7.5(s,1H);8.28(d,2H,J=4,7) |
表I(续)
实施例 | Z1 | Z2 | R3 | Z4 | m.p. | IR cm-1 | NMR溶剂 | 1H-NMR(100 MHz),δ,J=Hz |
40 | CH | CH | Ph-CO-NH- | N | 134-136℃ | 1646,1586,1542,1369(KBr) | CDCl3 | 1.55(m,2H);1.79(s,3H);1.88(m,2H);2.42(m,6H);3.80(m,4H);4.13(t,2H,J=6,8);6.51(t,1H,J=4,7);7.49(m,4H);7.83(m,2H);8.0(s,1H);8.11(s,1H);8.28 (d,2H,J=4,7) |
41 | CH | CH | Me-CO-NH- | N | 80-82℃ | 1650,1586,1454,1364,1261,983(KBr) | CDCl3 | 1.50(m,2H);1.88(m,2H);2.11(s,3H);2.43(m,6H);3.79(m,4H);4.8(t,2H,J=6,8);6.47(t,1H,J=4,7);7.36(s,1H);7.93(s,1H);8.28(d,2H,J=4,6);9.25(s,1H) |
表I(续)
表I(续)
实施例 | Z1 | Z2 | R3 | Z4 | m.p. | IR cm-1 | NMR溶剂 | 1H-NMR(100 MHz),δ,J=Hz |
51 | N | CH | n-Bu-SO2-NH- | CH | Oil | 2941,1586,1548,1448,1360,1146,984,755(膜) | CDCl3 | 0.91(t,3H,J=6,8);1,45(m,4H);1.85(m,4H);2.40(m,6H);3.0(m,2H);3.80(m,4H);4.11 (t,2H,J=6,5);6.5(t,1H,J=4,7);7.4(m,2H);7.5(s,1H);8.3(d,2H,J=4,7) |
52 | N | CH | n-Pr-SO2-NH- | CH | Oil | 2940,1586,1548,1447,1360,1146,984,755(膜) | CDCl3 | 1.0(t,3H,J=7,1);1.55(m,2H);1.9(m,4H);2.4 5(m,6H);3.0(t,2H,J=7,4);3.8(m,4H);4,1(t,2H,J=6,4);6,46(t,1H,J=4,7);7.35(m,2H);7.5(s,1H);8.3(d,2H,J=4,7) |
53 | N | CH | Et-SO2-NH- | CH | oil | 2943,1586,1548,1447,1360,1146,984,754(膜) | CDCl3 | 1.36(m,5H);1.9(m,2H);2.45(m,6H);3.0(m,2H);3.6(m,4H);4.1(t,2H,J=6,4);6.45(t,1H,J=4,7);7.39(s,1H);7.51(s,1H);8.3(d,2H,J=4,7) |
表I(续)
实施例 | Z1 | Z2 | R3 | Z4 | m.p. | IR cm-1 | NMR溶剂 | 1H-NMR(100 MHz),δ,J=Hz |
54 | N | CMe | -SO2-N-Me2 | CMe | Oil | 2939,1586,1547,1448,1360,1290,983,951,788(膜) | CDCl3 | 1.7(m,4H);2.3-3.0(abs.compl.18H);3.8(m,4H);4.0(t,2H,J=6,8);6.5(t,1H,J=4,7);8.2(d,2H,J=2,35) |
55 | N | CH | -SO2-N-Me2 | CH | 100-102℃ | 3135,2943,1586,1512,1357,1328,1156,982,728(KBr) | CDCl3 | 1.6(m,2H);1.9(m,2H);2.3-2.7(abs. compl.13H);3.8(m,4H);4.2(t,2H,J=6,8);6.4(t,1H,J=4,7);7.75(d,1H,J=4,4);8.28(d,2H,J=2,4) |
56 | N | CH | -SO3-H | CH | 230-235℃ | 3330,1590,1556,1449,1220,1178,1049,971,656(KBr) | D2O | 1.95(m,2H);3.3(m,6H);4.0(s,5H);4.27(t,2H,J=6,1);6.8(t,1H,J=4,8);7.8(s,1H);8.0(s,1H);8.43(d,2H,J=2,4) |
57 | CH | N | H | CH | oil | 2940,1585,1500,1360,1260,975(膜) | CDCl3 | 1.6(m,2H);1.8(m,2H);2.5(m,6H);3.80(m,6H);6.5(t,1H,J=4,7);6,9(s,1H);7.1(s,1H);7.5(s,1H);8.4(d,2H,J=4,7) |
表I(续)
实施例 | Z1 | Z2 | R3 | Z4 | m.p. | IR cm-1 | NMR溶剂 | 1H-NMR(100 MHz),δ,J=Hz |
58 | CMe | N | H | CH | Oil | 2941,1586,1547,1499,1359,1259,983(膜) | CDCl3 | 1.72(m,4H);2.37(s,3H);2.44(m,6H);3.80(m,6H); 6.45(t,1H,J=4,7);6.85(d,2H,J=4,5);8.27(d,2H,J=4,7) |
59 | CH | N | Cl | CCl | 69-71℃ | 2946,1584,1543,1492,1359,1254,983,797(KBr) | CDCl3 | 1.4-2.1(abs.compl.4H);2.46(m,6H);3.86(m,6H);6.47(t,1H,J=4,7);7.38(s,1H);8.29(d,2H,J=4,7) |
表I(续)
实施例 | Z1 | Z2 | R3 | Z4 | R7 | R8 | R9 | m.p. | IR cm-1 | NMR溶剂 | 1H-NMR(100 MHz),δ,J=Hz |
60 | N | CH | Cl | CH | H | H | MeO- | 76-77℃ | 2833,1511,1448,1247,1029,979,824(KBr) | DMSO-d6 | 1.43(m,2H);1.78(m,2H);1.71-2.48(a.c.6H);2.93-3.02(m,4H);3.67(s,3H);4.09(t,J=6,8Hz,2H);6.83(s,4H);7.52(s,1H);7.98(s,1H) |
61 | CMe | N | Cl | CCl | H | H | MeO- | 73-75℃ | 2940,2818,1512,1457,1245,1183,1036,826(KBr) | DMSO-d6 | 1.33-1.87(a.c.4H);2.32(s,3H);2.41-2.51(a.c.6H);2.82-3.0(m,4H);3.67(s,3H);3.93(t,J=7,2Hz,2H);6.83(s,4H); |
62 | N | CH | Cl | CH | MeO- | H | H | Oil | 2941,2816,1500,1450,1241,749(膜) | DMSO-d6 | 1.39(m,2H);1.77(m,2H);2.22-2.45(a.c6H);2.92(m,4H);3.76(s,3H);4.07(t,J=6,0Hz,2H);6.87(m,4H);7.51(s.1H);7.95(s,1H) |
表I(续)
实施例 | Z1 | Z2 | R3 | Z4 | R7 | R8 | R9 | m.p. | IR cm-1 | NMR溶剂 | 1H-NMR(100 MHz),δ,J=Hz |
63 | CMe | N | Cl | CCl | MeO- | H | H | 82-83℃ | 2943,2820,1502,1405,1241,1030,746(KBr) | DMSO-d6 | 1.43-1.60(a.c.4H);2.33(s,3H);2.40-2.50(a.c.6H);2.95(m,4H);3.76(s,3H);3.93(t,J=7,0Hz,2H);6.89(m,4H) |
64 | N | CH | Cl | CH | H | MeO- | H | Oil | 2943,2820,1601,1578,1496,1451,1203,1171,970(膜) | CDCl3 | 1.52(m,2H);1.85(m,2H);2.28-2.56(a.c.6H);3.16(m,4H);3.7(s,3H);4.05(t,J=7,0Hz,2H);6.4(m,3H);7.15(m,1H);7.34(s,1H);7.40(s,1H) |
65 | CH | CH | H | CH | H | H | MeO- | oil | 2943,2815,1512,1455,1244,1037,823,724(膜) | CDCl3 | 1.50-1.80(a.c.4H);2.31-2.61(a.c.6H);3.06(m,4H);3.74(s,3H);3.81(t,J=7.0Hz,2H);6.1(m,2H);6.6(m,2H);6.04(s,4H) |
表I(续)
实施例 | Z1 | Z2 | R3 | Z4 | R7 | R8 | R9 | m.p. | IR cm-1 | NMR溶剂 | 1H-NMR(100 MHz),δ,J=Hz |
66 | CH | CH | H | CH | MeO- | H | H | Oil | 2940,2814,1500,1451,1281,1241,1028,743,723(膜) | CDCl3 | 1.50-1.85(a.c.4H);2.33-2.66(a .c.6H);3.10(m,4H);3.84-3.96(a.c.5H);6.12(t,J=2Hz,2H);6.65(t,J=2Hz,2H);6.93(m,4H) |
67 | CH | CH | H | CH | H | H | H | oil | 2943,2817,1600,1501,1235,759,723, 692(膜) | CDCl3 | 1.41-1.89(a.c.4H);2.37(t,J=7,3Hz,2H);2.50-2.60(a.c.4H);3,18(m,4H);3.89(t,J=6,9Hz,2H);6.13(t,J=2,0Hz,2H);6.64(t,J=2,0Hz,2H);6.83-7.33(a.c.5H) |
表I(续)
实施例 | Z1 | Z2 | R3 | Z4 | R7 | R8 | R9 | m.p. | IR cm-1 | NMR溶剂 | 1H-NMR(100 MHz),δ,J=Hz |
68 | N | CH | Cl | CH | H | H | H | 58-61℃ | 2942,2819,1600,1500,1450,1881,1311,1240,1140,966,756(KBr) | CDCl3 | 1.47(m,2H);1.84(m,2H);2.35(t,J=7,2Hz,2H);2.52(m,4H);3.16(m,4H);4.04(t,J=6,8Hz,2H);6.75-6.94a.c.3H);7.16(s,H);7.23(s,1H);7.35(d,J=7,4Hz,2H) |
69 | CMe | N | Cl | CCl | H | H | H | Oil | 2944,2819,1600,1532,1503,1453,1404,1244,1143,759,692 (膜) | CDCl3 | 1.43-1.87(a.c.4H);2.33(s,3H);2.38-2.60(a.c.6H);3.17(m,H);3.83(t,J=7Hz,2H);6.9(a.c.3H);7.24(m,2H) |
70 | N | CH | CH | CH | Cl | H | H | oil | 2943,2817,1587,1480,1443,1231,1040,971,751, 612(膜)) | DMSO-d6 | 1.40 (m,2H);1.78(m,2H);2.2-2.6(a.c.6H);2.95(m,4H);4.08(t,J=6,5Hz,2H);6.95-7.41(a.c.4H);7.50(s,1H);7.97(s,1H) |
表I(续)
实施例 | Z1 | Z2 | R3 | Z4 | R7 | R8 | R9 | m.p. | IR cm-1 | NMR溶剂 | 1H-NMR(100 MHz),δ,J=Hz |
71 | CMe | N | Cl | CCl | Cl | H | H | 89-91℃ | 2936,2818,1587,1531,1480,1359,1243,1229,1036,1016,(KBr) | CDCl3 | 1.3-1.8(a.c.,4H);2.32(s,3H);2.35-2.70(a.c.6H);2.96(m,4H);3.94(t,J=7,2Hz,2H);6.90-7.50(a.c. aH) |
72 | N | CH | Cl | CH | H | Cl | H | Oil | 2944,2820,1594,1564,1487,1451,1433,1384,1239,987,980(膜) | CDCl3 | 1.3-1.70(m,2H);1.70-2.10(m,2H);2.39(t,J=7,4Hz,2H);2.59(m,4H);3.17(m,4H);4.09(t,J=4Hz,2H);6.6-6.9(a.c.3H);7.15(t,J=8,0Hz,1H);7.37(s,1H);7.4(s,1H) |
73 | CMe | N | Cl | CCl | CN | H | H | 80°(Dec) | 2956,2848,2219,1593,1488,1240,1232,1010,765(KBr) | CDCl3 | 1.45-1.80(a.c.4H);2.37(s,3H):2.20-2.70(a.c.6H);3.23(m,4H);3.88(t,J=7,1Hz,2H);6.90-7.06(a.c.2H);7.30-7.60(a.c.2H) |
表I(续)
实施例 | Z1 | Z2 | R3 | Z4 | R7 | R8 | R9 | m.p. | IR cm-1 | NMRs溶剂t | 1H-NMR(100 MHz),δ,J=Hz |
74 | CMe | N | Cl | CCl | F | H | H | Oil | 2944,2822,1501,1406,1241,1141,754(膜) | CDCl3 | 1.30-1.80(a.c.,4H);2.35(s,3H);2.20-2.70(a.c.6H);3.10(m,4H);3.87(t,J=7Hz,2H);6.70-7.07(a.c.4H) |
75 | N | CH | Cl | CH | CN | H | H | 59°(dec) | 2948,2823,2219,1596,1488,1447,1376,1231,971,762(膜) | CDCl3 | 1.50(m,2H);1.86(m,2H);2.43(t,J=7Hz,2H);2.63(m,4H);3.23(m,4H);4.11(t,J=6,8Hz,2H);6.80-7.10(a.c.2H);7.25-7.65(a.c.4H) |
76 | CMe | N | Cl | CCl | H | CF3 | H | oil | 2946,2821,1609,1450,1357,1319,1245,1163,1122,697(膜) | CDCl3 | 1.35-1.75(a.c.4H);2.35(s,3H);2.30-2.65(a.c.6H);3.22(m,4H);3.87(t,J=7,1Hz,2H);6.95-7.10(a.c.3H);7.32(m,1H) |
表I(续)
实施例 | Z1 | Z2 | R3 | Z4 | R7 | R8 | R9 | m.p. | IR cm-1 | NMR溶剂 | 1H-NMR(100 MHz),δ,J=Hz |
77 | N | CH | Cl | CH | H | CF3 | H | oil | 2947,2821,1610,1450,1357,1319,1163,1123,696(膜) | CDCl3 | 1.49(m,2H);1.89(m,2H);2.38(t,J=7,2Hz,2H);2.53(m,4H);3.21(m,4H);4.08(t,J=6,8Hz,2H);6.95-7.12(a.c.3H);7.20-7.45(m,3H(δ=7.36s,1H;δ=7.40s,1H)) |
78 | N | CH | Cl | CH | F | H | H | oil | 2944,2820,1501,1451,1239,971,753(膜) | CDCl3 | 1.50(m,2H);1.89(m,2H);2.41(t,J=7,2Hz,2H);2.59(m,4H);3.10(m,4H);4.09(t,J=6,9Hz);6.80-7.10(a.c.4H);7.37(s,1H);7.40(s,1H); |
下列实例证明本发明范围内几个衍生物的特性。
I.强迫症
因为据信5-羟色胺(5-HT)与情感疾病的病理生理有关,故大量使用了药理刺激模型来确定5-羟色胺在强迫症中的体内功能“动力学”。由于可能作为探测5-HT在数种情感疾病中中枢神经系统功能状态的工具,5-HT前体(α-色氨酸和5-羟基色氨酸)、5-HT吸收抑制剂和/或释放剂(DL-芬氟拉明)和直接作用于5-HT的激动剂(m-CPP、MK-212和丁螺环酮)引起了很大的关注,尽管对5-HT系统的总体特异性和对具体5-HT受体亚型的选择性都仍有争论(Murphy等:临床精神病杂志(J.Clin.Psychiatry)47:9-15,1986;Murphy等:英国精神病学杂志(Br.K.Psychiatry)155(补8):15-24,1989;Wan de Kar,S.D.:神经科学生物行为学综述(Neurosci,Biobehav.Rev)13:237-246,1989)。
另外,越来越清楚地看到,5-HT1A配体丁螺环酮、吉吡隆和伊沙匹隆是抗焦虑活性剂,可能具有抗强迫症特性,尽管它们的作用机制不十分清楚(Lesch等:生命科学(Life Sci.)46:1271-1277,1990)。
在5-HT1A受体亲合剂的抗焦虑作用的研究中,最有代表性的试验之一是测定小鼠在明/暗箱中逃避行为的试验,该箱有一个照得很亮的室和一个暗室(Costall等:J.Pharmacol.Exp.Ther.262(1):90-98,1992)。
将小鼠置于亮室中,小鼠变得厌恶亮室,从而激发一种焦虑状态。这引起小鼠偏向暗室的逃避反应,而这一点可与强迫行为相关联。所得结果(见表)说明来苏必通(Lesopitron)在所有试验剂量下延缓了小鼠向暗区运动这一强迫行为的出现,因为滞留时间明显延长。
处理 | 从亮区到暗区的通过滞留时间 |
对照(载体)来苏必通0.0001mg/kg,ip来苏必通0.01mg/kg,ip来苏必通0.5mg/kg,ip | 10秒15秒20秒24秒 |
II.睡眠呼吸暂停综合症
睡眠呼吸暂停综合症包括一系列严重程度不同的疾病。睡眠呼吸暂停分类为阻塞型、中枢型或混合型,取决于在气流停止期有还是没有呼吸努力。阻塞型和混合型呼吸暂停最常见,显示阻塞型睡眠呼吸暂停的综合症,在睡眠过程中可见上呼吸道周期性和偶发性的摺叠。完全摺叠时,嘴和鼻中没有空气循环,呼吸停止。通常结果是从睡眠中半醒过来并恢复正常呼吸。有时病人不记得这些呼吸暂停,但白天感到不明原因的疲倦和瞌睡。这种伴随血氧过少和睡眠不佳的呼吸暂停,重复发生会对神经和心脏造成严重后果。
迄今为止,睡眠呼吸暂停综合症的药物治疗没有取得什么成功。最近有少数出版物报道说5-HT1A激动剂丁螺环酮可能对睡眠呼吸暂停病有用(Mendelson等,临床精神病药理杂志(J.Clin,Psychopharmacol.)1991,11(1):71)。为了测定来苏必通对呼吸和睡眠的作用和该药剂在睡眠呼吸暂停综合症中的可能应用,按照对丁螺环酮进行的这方面工作(Mendelson等,美国呼吸疾病综述(Am.Rev.Respir.Dis)14(6):1527-1530,1990),研究了来苏必通对大鼠呼吸的影响。
所得结果证明,10和30mg/kg(i.v)剂量的来苏必通致使麻醉大鼠的呼吸频率以及肺通气显著提高。
来苏必通对乌拉坦麻醉大鼠的呼吸作用
来苏必通剂量(mg/kg,i.v.) | 肺通气(最大增长值) | 呼吸频率的提高(呼吸次数/分钟) |
0.3131030 | 10%20%20%22%44% | 915182023 |
大鼠睡眠的脑电描记法研究说明,5mg/kg的来苏必通显著提高睡眠潜伏期而同时减短了总的睡眠时间,即延长了清醒时间。
大鼠睡眠的脑电描记研究
组别 | 睡眠潜伏期(分) | 清醒时间(分) |
无REM | REM | ||
对照(载体)来 苏 必 通(5mg/kg,s.c.) | 32±371±4(*) | 62±6194±14(*) | 90±5130±4(*) |
综合所得结果,可以证实来苏必通是一种在睡眠过程中有持续作用的呼吸刺激剂,从而说明它可治疗睡眠呼吸暂停综合症。
III.性功能障碍
性功能障碍的病因可以包括心理因素、人与人之间的原因和环境原因、体质因素和药物的副作用。
鉴于性功能障碍可起因于从纯心理原因到纯体质原因的广泛因素,寄希望于单一治疗方式对所有病例都有效是不现实的。在通常临床实践中,处理性功能障碍的方法是确定切实原因并在可能时进行治疗。确定男人和女人性功能障碍的切实原因有时是非常复杂的,甚至不能确切断定。性功能障碍的心理药理治疗现在刚起步。治疗性功能障碍的药物应用没有取得什么成功,缺乏对该用途的被广泛接受和承认的疗法就反映了这一点。
因为8-OH-DPTA增加性交次数而降低了射精潜伏期,5-HT1A受体的活化似乎促进雄性大鼠的性行为(Murphy等:临床精神病杂志47:9-15,1986;Murphy等:英国精神病杂志155(补8):15-24,1989)。发现其他5-HT1A受体选择性物质如丁螺环酮、吉吡隆或伊沙匹隆也有相似作用。但不知5-HT1A激动剂对雄性和雌性大鼠性行为的作用是由这些物质对5-HT1A自身受体的刺激(这降低了5-HT的合成并造成血清素功能降低)而引起,还是由突触后受体的刺激所引合起的。
为了证明来苏必通改进性功能障碍的能力,评价了它对雄性大鼠性行为的作用。采用了M.M.Foreman等描述的方法(J.Pharmacol.Exp.Ther.270(3):1270-1281(1994))。用来评价这种作用的主要指标是EL(达到射精所需时间,或阴茎插入后的射精潜伏期)。
来苏必通剂量(mg/kg,皮下) | 与对照组相比射精潜期(EL)*的抑制率(%) |
0.1 | 40% |
1 | 60% |
10 | 70% |
*载体处理组的EL:745±30秒
用来苏必通所得结果证明该产物能促进大鼠的性行为。
IV.呕吐
按照Costall等描述的方法(神经药理,1986,25,959-961)在雪貂中研究了本发明化合物对呕吐的作用。
将两种性别的雪貂于21±1℃下单个关入笼中并正常饲养。然后经皮下途径给予实施例32的化合物或载体作为预处理,15分钟后给予顺铂(通过一固定的颈静脉插管,10mg/kg),从呕吐开始及此后240分钟内观察这些动物。呕吐以节律性腹部收缩为特征,或伴有固体或液体物排出(即呕吐),或不伴有固液物从口中通过(即恶心)。记录了恶心或呕吐的发作次数。
实施例32的化合物能够拮抗由顺铂诱发的呕吐(图1)。
图1:实施例32的化合物能够拮抗顺铂诱发的雪貂呕吐。动物在静脉接受顺铂(10mg/kg)后15分钟,接受载体(V,n=7)或各种剂量水平的实施例32化合物(0.05-0.5mg/kg s.c.,n=4)。观察动物240分钟。与V相比具有显著性差异,sP<0.05(Man n-Whithey U检验)。
用于人体治疗时,给药剂量虽然要根据所要治疗疾病的严重程度而变,一般在约5-100mg/天之间。本发明的衍生物例如将以片剂、胶囊形式或静脉途径给药。以下列举两种具体的药物形式。
片剂配方实例
实施例32的化合物 20mg
乳糖 50mg
微晶纤维素 20mg
聚乙烯吡咯烷酮 5mg
预凝胶化的淀粉 3mg
胶态二氧化硅 1mg
硬脂酸镁 1mg
片重 100mg
胶囊配方实例
实施例32的化合物 20mg
聚氧乙烯化甘油 125mg
正酸甘油酯 5mg
150mg
赋形剂:软胶囊q.s.
可注射安瓿配方实例
实施例32的化合物 4mg 8mg
氯化钠 15mg 30mg
注射用水c.s.p. 2ml 4ml
考虑到式I化合物的有利药理性质,本发明包括这些化合物作为药物的用途,含有它们的药物组合物,和它们在制备用于治疗强迫症、睡眠呼吸暂停、性功能障碍、呕吐和运动症的药物中的用途,尤其是用于制备抗强迫症药物、防止睡眠呼吸暂停的药物、改进性行为的药剂、镇吐和抗恶心的药物。
Claims (3)
1.通式1化合物和其药用盐在制备用于治疗哺乳动物(包括人)强迫症、睡眠呼吸暂停、性功能障碍、呕吐和运动症的药物中的用途:
2.根据权利要求1的用途,其特征在于式I化合物选自下组:1.1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}吡咯2.1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}咔唑3.1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}吲哚4.2,3-二苯基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}吲哚5.4-氨基甲酰基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑6.4-羧基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑7.3-甲基-5-三氟甲基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑8.4,5-二苯基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-咪唑9.2,4,5-三苯基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-咪唑10.4,5-二苯基-2-甲基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-咪唑11.4,5-二氯-2-甲基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-咪唑12.2-乙基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-咪唑13.2-苯基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-咪唑14.4-甲氧羰基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-咪唑15.4-苯基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-咪唑16.1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-苯并咪唑17.1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-3H-咪唑并[5,4-b]吡啶18.1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-咪唑并[4,5-b]吡啶19.1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-苯并三唑20.2-氯-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-苯并咪唑21.1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-1,2,4-三唑22.2-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-2H-苯并三唑23.2-甲基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-苯并咪唑24.5,6-二甲基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-苯并咪唑25.1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑26.3,5-二甲基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑27.3,5-二甲基-4-硝基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑28.4-甲基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑29.1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-咪唑30.4-溴-3,5-二甲基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑31.4-硝基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑32.4-氯-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑二盐酸盐33.4-乙氧羰基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑34.3-甲基-5-苯基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑35.4-溴-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑36.4-氰基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑37.4-氟-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑38.4-氨基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑39.4-甲磺酰氨基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑40.4-苯甲酰氨基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑41.4-乙酰氨基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑42.4-(2-丁基)氨基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑43.3-氯-4-氟-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑44.4-(4-甲氧基苯基)-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑45.4-(4-氯苯基)-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑46.4-(1-吡咯基)-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑47.4-苯基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑48.3,5-二苯基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑49.4-苯磺酰氨基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑50.4-(4-甲基苯)磺酰氨基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑51.4-丁基磺酰氨基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑52.4-丙基磺酰氨基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑53.4-乙基磺酰氨基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑54.3,5-二甲基-4-(N,N-二甲基磺酰氨基)-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑55.4-N-甲基磺酰氨基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑56.4-磺酸基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-吡唑57.1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1-咪唑58.2-甲基-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-咪唑59.4,5-二氯-1-{4-[4-(2-嘧啶基)-1-哌嗪基]丁基}-1H-咪唑60.4-氯-1-{4-[4-(4-甲氧基苯基)-1-哌嗪基]丁基}-1H-吡唑61.4,5-二氯-2-甲基-1-{4-[4-(4-甲氧基苯基)-1-哌嗪基]丁基}-1H-咪唑62.4-氯-1-{4-[4-(2-甲氧基苯基)-1-哌嗪基]丁基}-1H-吡唑63.4,5-二氯-2-甲基-1-{4-[4-(2-甲氧基苯基)-1-哌嗪基]丁基}-1H-咪唑64.4-氯-1-{4-[4-(3-甲氧基苯基)-1-哌嗪基]丁基}-1H-吡唑65.1-{4-[4-(4-甲氧基苯基)-1-哌嗪基]丁基}吡咯66.1-{4-[4-(2-甲氧基苯基)-1-哌嗪基]丁基}吡咯67.1-{4-[4-(苯基)-1-哌嗪基]丁基}吡咯68.4-氯-1-{4-[4-(苯基)-1-哌嗪基]丁基}吡唑69.4,5-二氯-2-甲基-1-{4-[4-(苯基)-1-哌嗪基]丁基}-1H-咪唑70.4-氯-1-{4-[4-(2-氯苯基)-1-哌嗪基]丁基}吡唑71.4,5-二氯-2-甲基-1-{4-[4-(2-氯苯基)-1-哌嗪基]丁基}-1H-咪唑72.4-氯-1-{4-[4-(3-氯苯基)-1-哌嗪基]丁基}-1H-吡唑73.4,5-二氯-2-甲基-1-{4-[4-(2-氰基苯基)-1-哌嗪基]丁基}-1H-咪唑74.4,5-二氯-2-甲基-1-{4-[4-(2-氟苯基)-1-哌嗪基]丁基}-1H-咪唑75.4-氯-1-{4-[4-(2-氰基苯基)-1-哌嗪基]丁基}-1H-吡唑76.4,5-二氯-2-甲基-1-{4-[4-(3-三氟甲基苯基)-1-哌嗪基]丁基}-1H-咪唑77.4-氯-1-{4-[4-(3-三氟甲基苯基)-1-哌嗪基]丁基}-1H-吡唑78.4-氯-1-{4-[4-(2-氟苯基)-1-哌嗪基]丁基}-1H-吡唑79.4-氯-1-{4-[4-(1,2-苯并异噻唑-3-基)-1-哌嗪基]丁基}-1H-吡唑80.4,5-二氯-2-甲基-1-{4-[4-(1,2-苯并异噻唑-3-基)-1-哌嗪基]丁基}-1H-咪唑81.1-{4-[4-(1,2-苯并异噻唑-3-基)-1-哌嗪基]丁基}-1H-1,2,4-三唑82.1-{4-[4-(1,2-苯并异噻唑-3-基)-1-哌嗪基]丁基}-1H-苯并咪唑83.4-溴-1-{4-[4-(5-溴嘧啶-2-基)-1-哌嗪基]丁基}-1H-吡唑84.4-氯-1-{4-[4-(5-溴嘧啶-2-基)-1-哌嗪基]丁基}-1H-吡唑
3.4-氯-1-{4-[4-(2-嘧啶基)-1-哌嗪基]-丁基}-1H-吡唑二盐酸盐在制备用于治疗哺乳动物(包括人)强迫症、睡眠呼吸暂停、性功能障碍、呕吐和运动症的药物中的用途。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9514690A FR2742052B1 (fr) | 1995-12-12 | 1995-12-12 | Utilisation des derives 1-(4-(4-aryl (ou heteroaryl)-1-piper azinyl)-buty)-1h-azole pour le traitement de la depression, des troubles obsessifs compulsifs, l'apnee du sommeil, les dysfonctions sexuelles, l'emese et le mal des transports |
FR95/14690 | 1995-12-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1177297A true CN1177297A (zh) | 1998-03-25 |
Family
ID=9485400
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN96192286A Pending CN1177297A (zh) | 1995-12-12 | 1996-12-11 | 治疗强迫症、睡眠呼吸暂停、性功能障碍、呕吐和运动症的药物 |
Country Status (16)
Country | Link |
---|---|
EP (1) | EP0808166A1 (zh) |
JP (1) | JPH11501051A (zh) |
CN (1) | CN1177297A (zh) |
AR (1) | AR004378A1 (zh) |
AU (1) | AU716665B2 (zh) |
CA (1) | CA2211161A1 (zh) |
CZ (1) | CZ255197A3 (zh) |
ES (1) | ES2134709B1 (zh) |
FR (1) | FR2742052B1 (zh) |
HU (1) | HUP9800198A2 (zh) |
IL (1) | IL121461A0 (zh) |
NO (1) | NO973589L (zh) |
PL (1) | PL321779A1 (zh) |
TR (1) | TR199700794T1 (zh) |
WO (1) | WO1997021439A1 (zh) |
ZA (1) | ZA9610457B (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101208314B (zh) * | 2005-04-26 | 2010-12-08 | 海普尼昂公司 | 苯并异*唑哌嗪化合物及其使用方法 |
CN115304590A (zh) * | 2022-09-19 | 2022-11-08 | 皮摩尔新药(辽宁)有限公司 | 2h-苯并三氮唑衍生物及其制备方法及含有它们的药物组合物 |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2763950B1 (fr) | 1997-06-02 | 2002-09-20 | Esteve Labor Dr | 2- {4- [4-(4,5-dichloro-2-methylimidazol-1-yl)butyl] -1- piperazinyl }-5-fluoropyrimidine, sa preparation et son utilisation therapeutique |
TW526202B (en) * | 1998-11-27 | 2003-04-01 | Shionogi & Amp Co | Broad spectrum cephem having benzo[4,5-b]pyridium methyl group of antibiotic activity |
US6046331A (en) * | 1998-12-17 | 2000-04-04 | Synaptic Pharmaceutical Corporation | Imidazolones and their use in treating benign prostatic hyperplasia and other disorders |
US7332494B2 (en) | 2000-08-14 | 2008-02-19 | Janssen Pharmaceutica, N.V. | Method for treating allergies using substituted pyrazoles |
PT1309592E (pt) | 2000-08-14 | 2006-07-31 | Ortho Mcneil Pharm Inc | Pirazoles substituidos |
RU2317988C2 (ru) | 2000-08-14 | 2008-02-27 | Орто-Макнейл Фармасьютикал, Инк. | Замещенные пиразолы, фармацевтическая композиция на их основе, применение фармацевтической композиции и способ ингибирования активности катепсина s |
PT1309591E (pt) | 2000-08-14 | 2007-04-30 | Ortho Mcneil Pharm Inc | Pirazoles substituídos |
CN1642973A (zh) | 2000-09-06 | 2005-07-20 | 奥索-麦克尼尔药品公司 | 治疗变态反应的方法 |
JP4964593B2 (ja) | 2003-09-25 | 2012-07-04 | セノメド バイオサイエンシーズ,エルエルシー | 神経学的病状の治療用のテトラヒドロインドロン誘導体 |
WO2005094827A1 (en) * | 2004-03-30 | 2005-10-13 | Kestrel Pharmaceuticals Inc. | Methods for treating sexual dysfunction |
BRPI0610258A2 (pt) | 2005-04-26 | 2012-09-25 | Hypnion Inc | composto ou um sal farmaceuticamente eficaz do mesmo, composição farmacêutica, e, uso de um composto |
GB2435827A (en) * | 2006-03-09 | 2007-09-12 | Del Dr Esteve S A Spain Lab | Use of substituted piperazine compounds for the treatment of food related disorders |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2672052B1 (fr) * | 1991-01-28 | 1995-05-24 | Esteve Labor Dr | Derives d'aryl (ou heteroaryl)-piperazinyl-alkyl-azoles, leur preparation et leur application en tant que medicaments. |
FR2723091B1 (fr) * | 1994-07-29 | 1996-11-08 | Esteve Labor Dr | Tetrahydropyridine-(6,4-hydroxypiperidine) alkylazoles |
-
1995
- 1995-12-12 FR FR9514690A patent/FR2742052B1/fr not_active Expired - Fee Related
-
1996
- 1996-12-11 EP EP96944029A patent/EP0808166A1/fr not_active Withdrawn
- 1996-12-11 JP JP9521756A patent/JPH11501051A/ja active Pending
- 1996-12-11 WO PCT/EP1996/005736 patent/WO1997021439A1/fr not_active Application Discontinuation
- 1996-12-11 IL IL12146196A patent/IL121461A0/xx unknown
- 1996-12-11 CA CA002211161A patent/CA2211161A1/fr not_active Abandoned
- 1996-12-11 CZ CZ972551A patent/CZ255197A3/cs unknown
- 1996-12-11 CN CN96192286A patent/CN1177297A/zh active Pending
- 1996-12-11 AU AU13764/97A patent/AU716665B2/en not_active Ceased
- 1996-12-11 HU HU9800198A patent/HUP9800198A2/hu unknown
- 1996-12-11 PL PL96321779A patent/PL321779A1/xx unknown
- 1996-12-11 TR TR97/00794T patent/TR199700794T1/xx unknown
- 1996-12-12 AR ARP960105644A patent/AR004378A1/es unknown
- 1996-12-12 ES ES009602700A patent/ES2134709B1/es not_active Expired - Lifetime
- 1996-12-12 ZA ZA9610457A patent/ZA9610457B/xx unknown
-
1997
- 1997-08-04 NO NO973589A patent/NO973589L/no not_active Application Discontinuation
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101208314B (zh) * | 2005-04-26 | 2010-12-08 | 海普尼昂公司 | 苯并异*唑哌嗪化合物及其使用方法 |
CN115304590A (zh) * | 2022-09-19 | 2022-11-08 | 皮摩尔新药(辽宁)有限公司 | 2h-苯并三氮唑衍生物及其制备方法及含有它们的药物组合物 |
WO2024060912A1 (zh) * | 2022-09-19 | 2024-03-28 | 原研药港生命科学研究(辽宁)有限公司 | 2h-苯并三氮唑衍生物及其制备方法及含有它们的药物组合物 |
CN115304590B (zh) * | 2022-09-19 | 2024-05-28 | 皮摩尔新药(辽宁)有限公司 | 2h-苯并三氮唑衍生物及其制备方法及含有它们的药物组合物 |
Also Published As
Publication number | Publication date |
---|---|
MX9706133A (es) | 1997-11-29 |
ES2134709A1 (es) | 1999-10-01 |
CZ255197A3 (cs) | 1998-01-14 |
ES2134709B1 (es) | 2000-05-16 |
ZA9610457B (en) | 1997-06-24 |
AU1376497A (en) | 1997-07-03 |
HUP9800198A2 (hu) | 1999-09-28 |
JPH11501051A (ja) | 1999-01-26 |
NO973589D0 (no) | 1997-08-04 |
EP0808166A1 (fr) | 1997-11-26 |
AU716665B2 (en) | 2000-03-02 |
FR2742052B1 (fr) | 1998-04-10 |
PL321779A1 (en) | 1997-12-22 |
WO1997021439A1 (fr) | 1997-06-19 |
IL121461A0 (en) | 1998-02-08 |
NO973589L (no) | 1997-10-08 |
TR199700794T1 (xx) | 1997-11-21 |
FR2742052A1 (fr) | 1997-06-13 |
AR004378A1 (es) | 1998-11-04 |
CA2211161A1 (fr) | 1997-06-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9592234B2 (en) | Methods and compositions for stimulating neurogenesis and inhibiting neuronal degeneration using isothiazolopyrimidinones | |
CN1177297A (zh) | 治疗强迫症、睡眠呼吸暂停、性功能障碍、呕吐和运动症的药物 | |
US20230348381A1 (en) | Composition comprising a benzoate salt of 5-methoxy-n,n-dimethyltryptamine | |
JP5907975B2 (ja) | 運動障害の治療のためのセロトニン受容体アゴニストの組み合わせ | |
CN1926136A (zh) | 作为缓激肽拮抗剂的氨基环丙烷羧酰胺衍生物 | |
CN110461853A (zh) | 苯并噻吩雌激素受体调节剂 | |
CN104520291A (zh) | 用于调节egfr活性的化合物和组合物 | |
TW201919612A (zh) | 包含帕博西尼(palbociclib)及6-(2,4-二氯苯基)-5-[4-[(3s)-1-(3-氟丙基)吡咯啶-3-基]氧基苯基]-8,9-二氫-7h-苯并[7]輪烯-2-甲酸的組合 | |
US20080234253A1 (en) | Methods and Compositons for Stimulating Neurogenesis and Inhibiting Neuronal Degeneration | |
CN102482272A (zh) | 情绪障碍治疗剂 | |
BR112021006033A2 (pt) | Uso de um inibidor de um transportador da família ent no tratamento de câncer e combinação do mesmo com um antagonista do receptor de adenosina | |
EP3096755A2 (en) | CYSTATHIONINE-(gamma)-LYASE (CSE) INHIBITORS FOR TREATING PAIN | |
TW200529833A (en) | Heteroaryl-hydrazone compounds | |
US20140221385A1 (en) | Combinations of serotonin receptor agonists for treatment of movement disorders | |
WO2004089410A1 (ja) | 神経因性疼痛の予防及び/または治療剤 | |
CN1072932C (zh) | 用四氢苯并[cd]吲哚-6-甲酰胺类化合物预防呕吐和治疗性机能障碍的方法 | |
CN103781771A (zh) | 苯并噻唑酮化合物 | |
CN1859913A (zh) | 改善肾功能损伤个体多尿症的方法 | |
US20150250798A1 (en) | Methods and Pharmaceutical Compositions For Treating Down Syndrome | |
CA3069462A1 (en) | Ambroxol to improve and/or extend healthspan, lifespan and/or mental acuity | |
US20110118317A1 (en) | Use of epothilones in the treatment of neuronal connectivity defects such as schizophrenia and autism | |
JP4390772B2 (ja) | ベンゾオキサゾール誘導体およびアデノシンレセプターリガンドとしてのその使用 | |
CN1711090A (zh) | 用于治疗慢性淋巴细胞白血病的氮芥类似物和甲磺酸依马替尼的组合 | |
US6333345B1 (en) | Methods of using and compositions comprising N-desmethylzolpidem | |
CN102317265A (zh) | 用于治疗炎性疾病的2,4-嘧啶二胺化合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |