CN1090480C - 用于治疗多巴胺系统紊乱疾病的苯氧哌嗪衍生物 - Google Patents
用于治疗多巴胺系统紊乱疾病的苯氧哌嗪衍生物 Download PDFInfo
- Publication number
- CN1090480C CN1090480C CN96194666A CN96194666A CN1090480C CN 1090480 C CN1090480 C CN 1090480C CN 96194666 A CN96194666 A CN 96194666A CN 96194666 A CN96194666 A CN 96194666A CN 1090480 C CN1090480 C CN 1090480C
- Authority
- CN
- China
- Prior art keywords
- amino
- halogen
- carbonyl
- alkyl group
- expression hydrogen
- 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.)
- Expired - Fee Related
Links
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 229960003638 dopamine Drugs 0.000 title claims abstract description 8
- IFKOXBOKMDXHAH-UHFFFAOYSA-N 1-phenoxypiperazine Chemical class C1CNCCN1OC1=CC=CC=C1 IFKOXBOKMDXHAH-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 239000001257 hydrogen Substances 0.000 claims abstract description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 22
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 17
- 150000002367 halogens Chemical class 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 11
- -1 furan-2-yl-carbonyl-amino Chemical group 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000003118 aryl group Chemical group 0.000 claims abstract description 4
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims abstract description 3
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 3
- 150000002431 hydrogen Chemical class 0.000 claims abstract 13
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 6
- 208000035475 disorder Diseases 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 201000000980 schizophrenia Diseases 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000005091 alkenylcarbonylamino group Chemical group 0.000 claims description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 2
- 206010025482 malaise Diseases 0.000 claims 1
- 230000003340 mental effect Effects 0.000 claims 1
- 230000002265 prevention Effects 0.000 abstract description 2
- 125000001769 aryl amino group Chemical group 0.000 abstract 1
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 abstract 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 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 229940099112 cornstarch Drugs 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 2
- 101100230376 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) celI gene Proteins 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N 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
- 229930006000 Sucrose Natural products 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229960003878 haloperidol Drugs 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- ZZJYIKPMDIWRSN-TZBSWOFLSA-N (+)-butaclamol Chemical compound C12=CC=CC=C2CCC2=CC=CC3=C2[C@@H]1CN1CC[C@@](C(C)(C)C)(O)C[C@@H]13 ZZJYIKPMDIWRSN-TZBSWOFLSA-N 0.000 description 1
- WICKLEOONJPMEQ-UHFFFAOYSA-N 1-(2-methylphenyl)piperazine Chemical compound CC1=CC=CC=C1N1CCNCC1 WICKLEOONJPMEQ-UHFFFAOYSA-N 0.000 description 1
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 235000019737 Animal fat Nutrition 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 229920000180 alkyd Polymers 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 150000008378 aryl ethers Chemical class 0.000 description 1
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-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
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 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
- 239000004202 carbamide Substances 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([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
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 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
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- XIPFMBOWZXULIA-UHFFFAOYSA-N pivalamide Chemical compound CC(C)(C)C(N)=O XIPFMBOWZXULIA-UHFFFAOYSA-N 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000002265 sensory receptor cell Anatomy 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及通式I所示的化合物的应用,其中:R1和R3分别独立地表示氢,芳基,氨基甲酰基,低级烷基羰基,低级烷基,卤素,低级烷基羰氨基,低级链烯基羰基,氨基,芳氨基,芳氧基,硝基,芳乙酰基,低级链烷酰基低级烷基,烷基磺酰氨基,脲基或呋喃-2-羰氨基,和R2表示氢,低级烷基,三氟甲基,卤素,低级烷氧基,低级烷羰基或低级烷基羰氨基;或R1和R2共同表示-OCH2O-,-O(CH2)2O-或-O(CH2)3-;R4表示氢,卤素,羟基,低级烷基,低级烷氧基或硝基;R5表示氢,卤素或低级烷氧基;R6表示氢,低级烷基,卤素,羟基,氨基,低级烷氧基,三氟甲基,硝基或低级烷基羰氨基和R7表示氢,低级烷基羰基。也包括其在药剂学上可接受的盐的应用。这些化合物可以用以控制和阻止由于多巴胺系统紊乱所引起的疾病,也可以用于生产相应药物。
Description
低级烷基,卤素,低级烷基羰氨基,低级链烯基羰氨基,
氨基,芳氨基,芳氧基,硝基,芳乙酰基,低级链烷酰基
低级烷基,烷基磺酰氨基,脲基或呋喃-2-羰胺基,和R2 表示氢,低级烷基,三氟甲基,卤素,低级烷氧基,低级
烷基羰基或低级烷基羰氨基,或R1和R2 可以在一起表示
-OCH2O-,-O(CH2)2O-或-(CH2)3-,R4 可以是氢,卤素,羟基,低级烷基,低级烷氧基或硝基R5 表示氢,卤素或低级烷氧基,R6 表示氢,低级烷基,卤素,羟基,氨基,低级烷氧基,三
氟甲基,硝基或低级烷基羰氨基以及R7 表示氢,低级烷基羰基。
这些化合物和它们的盐是已知的。它们的制备和它们作为抗高血压剂的应用已在DE-OS 1964423中描述过。
在本文中,“低级烷基”表示直链或支链的1~6个碳原子的低级烷基,如,甲基、乙基、异丙基、丁基、戊基以及类似基团。“低级烷氧基”表示低级烷基醚基团,其中低级烷基如前所述。例如,甲氧基、乙氧基、异丙氧基以及类似基团。“卤素”指氯,溴、氟和碘。在上述卤素原子中,优选氟和氯。
如有要求,氨基基团可被有1-6个碳原子的低级烷基基团取代,如甲基-,乙基-,丙基-,丁基-或戊-氨基等。“低级链烯基”表示直链或支链的烯型的2-6个碳原子的不饱和碳氢基团。“芳基”表示苯基或含有1-4个碳原子的低级烷基的苯基。其中,优选对-甲苯基。
目前,人们惊奇地发现这些化合物可以用以控制和防止由于多巴胺系统紊乱所引起的疾病。此时它们属于精神病治疗药物,如用于精神分裂症。本发明的目的是分子式I的化合物用于治疗和抑制由多巴胺系统紊乱所引发的疾病的用途和这些化合物作为有效成分用于生产上述治疗的药物的应用以及包含这些化合物的药物。
这些化合物的新型药理学性质是由于对神经受体有高度选择性亲和力,特别是对多巴胺D4受体。因此,当使用它们时,人们可以期望它们比已知的传统的中枢抗精神病药如氟哌啶醇有更为轻微的副作用。氟哌啶醇是公认地结合于D2和D3受体的药物。人们发现它在治疗精神分裂症时,D2和D3受体浓度增加大约10%,而与此同时D4受体浓度的增加大于600%(TiPS,July 1994,vol.15,p.264-70)。试验说明
这些化合物以结合D4受体的能力来定义其特征。
此外,相对于D2受体活性,这些化合物可期望有好的结合于D4受体的选择性。
在实验中使用的是CHO细胞(中国仓鼠卵巢细胞)。
用超速离心法从D4-CHO和D2-CHO细胞分离到粗制的膜,储存在-80℃。在解冻后与缓冲液(50mM Tris,1mM EDTA,5nM KCl,1.5mM CaCl2,4mMMgCl2,PH7.4)匀浆化,在室温下与200pM[3H]-史匹哌酮和浓度逐渐增加的受试化合物(1×10-11M-1×10-4M)共孵90分钟,非特异的结合通过与1×10-5M(+)-布他拉莫共孵来建立。用一个GF/C玻璃过滤器过滤掉未结合的配体,结合物的放射活性在Parkard TopCount液闪计数器中通过闪烁作用来测得。
表一所示为特定的活性化合物,它们是下列化合物:1 1-苯氧基-3-(4-苯基哌嗪-1-基)-丙-2-醇2 1-(2-氨基苯氧基)-3-(4-苯基哌嗪-1-基)-丙-2-醇3 1-[2-[2-羟基-3-(4-苯基哌嗪-1-基)-丙氧基]-苯基]-乙酮4 2-[2-羟基-3-(4-苯基哌嗪-1-基)-丙氧基]-苯甲酰胺5 1-[4-(4-氯苯基)-哌嗪-1-基]-3-(3-三氟甲基苯氧基)-丙-2-醇6 N-[2-[2-羟基-3-(4-邻-甲苯基哌嗪-1-基)-丙氧基]-苯基]-乙酰胺7 N-[2-[2-羟基-3-[4-(2-三氟甲基苯基)-哌嗪-1-基]-丙氧基]-苯
基]-乙酰胺8 N-[2-[2-羟基-3-(4-(2-羟基苯基)-哌嗪-1-基)-丙氧基]-苯基]-乙
酰胺9 [+]-1-(2-氨基苯氧基)-3-[4-(2-甲氧基苯基)-哌嗪-1-基]-丙-2-醇10 N-[2-[2-羟基-3-[4-(2-甲氧基苯基)-哌嗪-1-基]-丙氧基]-苯基]乙
酰胺11 [+]-N-[2-[2-羟基-3-[4-(2-甲氧基苯基)-哌嗪-1-基]-丙氧基]-苯
基]乙酰胺12 [-]-N-[2-[2-羟基-3-[4-(2-甲氧基苯基)-哌嗪-1-基]-丙氧基]-苯
基]乙酰胺13 N-[2-[2-羟基-3-[4-(2-甲氧基苯基)-哌嗪-1-基]-丙氧基]-苯基]丙
酰胺14 己酸[2-[2-羟基-3-[4-(2-甲氧基苯基)-哌嗪-1-基]-丙氧基]-苯
基]-酰胺15 N-[2-[2-羟基-3-[4-(2-甲氧基苯基)-哌嗪-1-基]-丙氧基]-苯基]-
2,2-二甲基-丙酰胺16 [+]-(E)-丁-2-烯醇酸[2-[2-羟基-3-[4-(2-甲氧基苯基)-哌嗪-1-
基]-丙氧基]-苯基]-酰胺17 呋喃-2-羧酸[2-[2-羟基-3-[4-(2-甲氧基-苯基)-哌嗪-1-基]-丙氧
基]-苯基]-酰胺18 [2-[2-羟基-3-[4-(2-甲氧基苯基)-哌嗪-1-基]-丙氧基]-苯基]-脲19 N-[2-[2-羟基-3-[4-(2-甲氧基-苯基)-哌嗪-1-基]-丙氧基]-5-甲基
-苯基]-乙酰胺20 N-[2-[2-羟基-3-[4-(2-甲氧基苯基)-哌嗪-1-基]-丙氧基]-4-甲基-
苯基]-乙酰胺21 N-[2-[3-[4-(2-乙氧基苯基)-哌嗪-1-基]-2-羟基-丙氧基]-苯基]-
丙酰胺22 1-(2-氨基苯氧基)-3-[4-(2-硝基苯基)-哌嗪-1-基]-丙-2-醇30 2-(2-乙酰氨基苯氧基)-1-[4-(2-甲氧基-苯基)-哌嗪-1-基-甲基]-
乙酸乙酯31 [+]-2-(2-乙酰氨基苯氧基)-1-[4-(2-甲氧基苯基)-哌嗪-1-基-甲
基]-乙酸乙酯
下表2清楚地表明了一些化合物对D2受体的选择性,以D4受体和D2受体的Ki比值来表示。
表2
化合物号 | R1 | R2 | R3 | R4 | R5 | R6 | R7 | Kiat D4[nM] | 选择性,对D2 |
23242526272829 | HHHHNO2HH | CH3HHHHBrH | H-NHCOCH2CH3-NHCOCH3-NHSO2CH3-NHCOCH3-NHCOCH3-NHCOCH3 | HHOHHHHH | HHHHHHH | HH-OCH3-OCH3-OCH3-OCH3NO2 | HHHHHHH | 9.62910.23.2155.88.7 | 3002331370177112135360 |
式I的化合物及其在药剂学上可接受的盐可以作为药物使用。例如,以药物制剂的形式。药物制剂可以是口服的,如片剂,包衣片剂,糖丸,硬和软明胶胶囊,溶液剂,乳剂或混浮剂。此外,也可以直肠给药,如以栓剂的方式给药,或可以是经肠外给药,如以注射液的方式给药。
可以在生产符合分子式I的化合物和其在药剂学上可接受的盐的药物制剂时使用药剂学惰性的、无机的或有机的载体。如乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或硬脂酸盐等可以用作为片剂、包衣片剂、糖丸和硬明胶胶囊的赋形剂。软明胶胶囊的合适的赋形剂是,比如,植物油,蜡,动物脂肪,半固态和液态多元醇等;然而取决于活性成分的性质。通常制做软胶囊时不需要载体。生产溶液剂和糖浆剂的赋形剂有如,水,多元醇,蔗糖,转化蔗糖,葡萄糖等。制备分子式I中的化合物的水溶性的盐的水性注射液时可以应用乙醇,多元醇,甘油,植物油等辅料。但是这并不是一个既定的规则。栓剂的适合的赋形剂,如天然的或硬化油,蜡,动物油脂,半固态和液态多元醇等。
此外,药学制剂还可以含有防腐剂,增溶剂,稳定剂,湿润剂,乳化剂,甜味剂,着色剂,增香剂,改变渗透压的盐,缓冲液,包衣剂或抗氧化剂。还可以含有其他有治疗价值的物质。
如前所述,本发明的目的还是含有符合分子式I的化合物或其在药剂学上可接受的盐和在治疗上为惰性的赋形剂的药剂,以及生产上述药剂的方法,该方法包括符合分子式I的一种或多种化合物或其在药剂学上可接受的盐以及如果必要,与一种或多种有治疗价值的物质组成复方,并含有一种或多种治疗惰性的载体。剂量可以在很宽的范围内进行变化,并根据各个具体情况而变化。总之,每日1-1000mg左右的剂量应是适宜的。
最后,如前所述,本发明的目的还在于采用符合分子式I的化合物及其在药剂学上可以接受的盐生产药物,特别是用于控制和预防由于多巴胺系统紊乱引起的疾病的药物的用途。
实施例A
以通用的方式生产包含下列成分的片剂:
mg/片活性成分 100乳糖粉末 95白色玉米淀粉 35聚乙烯吡咯烷 8羧甲基淀粉钠 10硬脂酸镁 2
片重250
实施例B
以通用的方式生产包含下列成分的片剂:
mg/片活性成分 200乳糖粉末 100白色玉米淀粉 64聚乙烯吡咯烷酮 12羧甲基淀粉钠 20硬脂酸镁 4
片重400
实施例C
制备包含下列成分的胶囊剂:
mg/片活性成分 50乳糖结晶 60微晶纤维素 34滑石 5硬脂酸镁 1
胶囊全重150颗粒尺寸合适的活性成分,结晶乳糖和微晶纤维素,混合均匀,过筛后,加入滑石和硬脂酸镁混匀,最后将混合物填入合适尺寸的硬胶囊制成。
Claims (4)
级烷基,卤素,低级烷基羰氨基,低级链烯基羰氨基,氨基,
芳氨基,芳氧基,硝基,芳乙酰基,低级链烷酰基低级烷基,
烷基磺酰氨基,脲基或呋喃-2-羰氨基,和R2 表示氢,低级烷基,三氟甲基,卤素,低级烷氧基,低级烷
羰基或低级烷基羰氨基;或R1和R2 共同表示
-OCH2O-,-O(CH2)2O-或-(CH2)3-;R4 表示氢,卤素,羟基,低级烷基,低级烷氧基或硝基;R5 表示氢,卤素或低级烷氧基;R6 表示氢,低级烷基,卤素,羟基,氨基,低级烷氧基,三氟
甲基,硝基或低级烷基羰氨基和R7 表示氢,低级烷基羰基。
2.根据权利要求1的符合通式I的化合物的用途,其中R1表示氢或甲基,R2表示氢,三氟甲基或甲基,R4表示氢,羟基或卤素,R5表示氢,R3、R6和R7与权利要求1中的相同。
3.根据权利要求1或2的用途,其用在精神疾病方面。
4.根据权利要求3的用途,其用在抗精神分裂症方面。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH1703/954 | 1995-06-09 | ||
CH170395 | 1995-06-09 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1187128A CN1187128A (zh) | 1998-07-08 |
CN1090480C true CN1090480C (zh) | 2002-09-11 |
Family
ID=4216630
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN96194666A Expired - Fee Related CN1090480C (zh) | 1995-06-09 | 1996-06-04 | 用于治疗多巴胺系统紊乱疾病的苯氧哌嗪衍生物 |
Country Status (9)
Country | Link |
---|---|
US (1) | US5614526A (zh) |
EP (1) | EP0833639A1 (zh) |
JP (1) | JP3076065B2 (zh) |
CN (1) | CN1090480C (zh) |
AU (1) | AU6222096A (zh) |
BR (1) | BR9608938A (zh) |
CA (1) | CA2222225A1 (zh) |
TR (1) | TR199701580T1 (zh) |
WO (1) | WO1996041630A1 (zh) |
Families Citing this family (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1172919C (zh) | 2002-06-03 | 2004-10-27 | 上海医药工业研究院 | 芳烷醇哌嗪衍生物及其在制备抗抑郁症药物中的应用 |
US7071204B2 (en) * | 2003-06-30 | 2006-07-04 | Research Triangle Institute | Camptothecin analogs having an E-ring ketone |
CN102131790A (zh) * | 2008-06-27 | 2011-07-20 | H.隆德贝克有限公司 | 新型苯酚型和儿茶酚型胺及其前药 |
US8673920B2 (en) | 2009-05-06 | 2014-03-18 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
US9073882B2 (en) | 2010-10-27 | 2015-07-07 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
WO2012058134A1 (en) | 2010-10-29 | 2012-05-03 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
BR112014003801A2 (pt) | 2011-08-19 | 2017-03-07 | Merck Sharp & Dohme | composto, composição farmacêutica, e, métodos para a inibição de romk, para a provocação de diurese, natriurese ou ambas, e para o tratamento ou a profilaxia de um ou mais distúrbios |
WO2013039802A1 (en) | 2011-09-16 | 2013-03-21 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
US8999990B2 (en) | 2011-10-25 | 2015-04-07 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
US8999991B2 (en) | 2011-10-25 | 2015-04-07 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
EP2773351B1 (en) | 2011-10-31 | 2017-08-23 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
US9139585B2 (en) | 2011-10-31 | 2015-09-22 | Merck Sharp & Dohme Corp. | Inhibitors of the Renal Outer Medullary Potassium channel |
WO2013066717A1 (en) | 2011-10-31 | 2013-05-10 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
US9206199B2 (en) | 2011-12-16 | 2015-12-08 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
AR092031A1 (es) | 2012-07-26 | 2015-03-18 | Merck Sharp & Dohme | Inhibidores del canal de potasio medular externo renal |
WO2014085210A1 (en) | 2012-11-29 | 2014-06-05 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
EP2934533B1 (en) | 2012-12-19 | 2017-11-15 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
US9604998B2 (en) | 2013-02-18 | 2017-03-28 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
EP2968288B1 (en) | 2013-03-15 | 2018-07-04 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
EP3027625B1 (en) | 2013-07-31 | 2018-05-30 | Merck Sharp & Dohme Corp. | Spiro-fused derivatives of piperidine useful for the treatment of inter alia hypertension and acute or chronic heart failure |
US9951052B2 (en) | 2013-10-31 | 2018-04-24 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
WO2016127358A1 (en) | 2015-02-12 | 2016-08-18 | Merck Sharp & Dohme Corp. | Inhibitors of renal outer medullary potassium channel |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA967965A (en) * | 1968-12-24 | 1975-05-20 | Hoffmann-La Roche Limited | Aromatic ethers and process for the manufacture thereof |
-
1996
- 1996-04-29 US US08/639,384 patent/US5614526A/en not_active Expired - Fee Related
- 1996-06-04 BR BR9608938A patent/BR9608938A/pt not_active Application Discontinuation
- 1996-06-04 CN CN96194666A patent/CN1090480C/zh not_active Expired - Fee Related
- 1996-06-04 TR TR97/01580T patent/TR199701580T1/xx unknown
- 1996-06-04 CA CA002222225A patent/CA2222225A1/en not_active Abandoned
- 1996-06-04 EP EP96920789A patent/EP0833639A1/en not_active Withdrawn
- 1996-06-04 WO PCT/EP1996/002428 patent/WO1996041630A1/en not_active Application Discontinuation
- 1996-06-04 AU AU62220/96A patent/AU6222096A/en not_active Abandoned
- 1996-06-04 JP JP09502584A patent/JP3076065B2/ja not_active Expired - Lifetime
Non-Patent Citations (1)
Title |
---|
EUR,J.PHARMACOL.VOL,205,NO.1 1991.1.31 H.O.BORBE it Al S-HT/a-agonistic proper-ties of naftopidic.anael antihyper tensive hrah * |
Also Published As
Publication number | Publication date |
---|---|
TR199701580T1 (xx) | 1998-03-21 |
AU6222096A (en) | 1997-01-09 |
JPH10507777A (ja) | 1998-07-28 |
US5614526A (en) | 1997-03-25 |
MX9709396A (es) | 1998-07-31 |
BR9608938A (pt) | 1999-06-29 |
JP3076065B2 (ja) | 2000-08-14 |
WO1996041630A1 (en) | 1996-12-27 |
CA2222225A1 (en) | 1996-12-27 |
EP0833639A1 (en) | 1998-04-08 |
CN1187128A (zh) | 1998-07-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1090480C (zh) | 用于治疗多巴胺系统紊乱疾病的苯氧哌嗪衍生物 | |
KR100283709B1 (ko) | 안정한 서방성 경구 투여 조성물 | |
US6030642A (en) | Extended release clonidine formulation (capsule) | |
EP0320051A1 (en) | Controlled release combination of carbidopa/levodopa | |
US20070218135A1 (en) | Sustained release matrix pharmaceutical composition | |
JPH07509456A (ja) | 2型糖尿病および肥満の治療および予防のための1,3−ジシクロプロピメチル−8−アミノ−キサンチンの使用 | |
CN1237905A (zh) | 应用Sibutramine类似物预防糖尿病的发展 | |
CN1069191A (zh) | 药用组合制剂 | |
EA004311B1 (ru) | Таблетированная фармацевтическая композиция непролонгированного действия | |
JPH05186346A (ja) | 経口投与後のインダパミドの徐放性マトリックス錠剤 | |
CA2211325C (en) | Extended release clonidine formulation | |
CN109431966A (zh) | 依达拉奉药物组合物 | |
JPWO2004066998A1 (ja) | 安定な経口用固形医薬組成物 | |
JP2021001221A (ja) | 精神障害の治療における使用のためのイロペリドン代謝物 | |
KR20120055313A (ko) | 레베티라세탐 또는 이의 약학적으로 허용되는 염을 포함하는 용출 안정성이 개선된 서방형 약학 조성물 및 이의 제조방법 | |
JPH04360833A (ja) | 1,4−ジヒドロピリジン誘導体を含有する製剤 | |
US20060159752A1 (en) | Extended release matrix tablets | |
SK15472001A3 (sk) | Použitie saredutantu a jeho farmaceuticky prijateľných solí na prípravu liečiva použiteľného na liečenie alebo prevenciu porúch nálady, porúch adaptácie alebo stavov úzkosti a depresie | |
JPH0840906A (ja) | 過血糖症を治療するための薬剤学的製剤 | |
CN1334081A (zh) | 含有星形细胞功能改进剂作为活性组分的帕金森氏病治疗剂 | |
JPH08325145A (ja) | 安定なイソプロピルアンチピリン含有製剤 | |
JP4983750B2 (ja) | 経口投与用製剤 | |
CN1187124A (zh) | 苯氧基哌啶衍生物用于治疗多巴胺系统紊乱所造成的疾病的用途 | |
JPS6150915A (ja) | 抗アンギナ医薬組成物 | |
JP3004732B2 (ja) | ドーパミン系の障害によって引き起こされる疾患の処置のためのフェノキシピリジン誘導体の用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C19 | Lapse of patent right due to non-payment of the annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |