EP1140838A1 - Derives de 1,4-piperazine agissant sur le recepteur de 5ht1a - Google Patents
Derives de 1,4-piperazine agissant sur le recepteur de 5ht1aInfo
- Publication number
- EP1140838A1 EP1140838A1 EP99965282A EP99965282A EP1140838A1 EP 1140838 A1 EP1140838 A1 EP 1140838A1 EP 99965282 A EP99965282 A EP 99965282A EP 99965282 A EP99965282 A EP 99965282A EP 1140838 A1 EP1140838 A1 EP 1140838A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- phenyl
- compound
- piperidin
- ylmethyl
- methoxy
- 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.)
- Withdrawn
Links
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 title description 12
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 title description 10
- 230000000694 effects Effects 0.000 title description 7
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical class C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 53
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 13
- 208000035475 disorder Diseases 0.000 claims abstract description 13
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 6
- 210000003169 central nervous system Anatomy 0.000 claims abstract description 6
- 230000036506 anxiety Effects 0.000 claims abstract description 5
- 208000007848 Alcoholism Diseases 0.000 claims abstract description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 4
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- 201000001880 Sexual dysfunction Diseases 0.000 claims abstract description 4
- 206010013663 drug dependence Diseases 0.000 claims abstract description 4
- 231100000872 sexual dysfunction Toxicity 0.000 claims abstract description 4
- 208000019116 sleep disease Diseases 0.000 claims abstract description 4
- 208000011117 substance-related disease Diseases 0.000 claims abstract description 3
- 208000010877 cognitive disease Diseases 0.000 claims abstract 2
- 150000003839 salts Chemical class 0.000 claims description 19
- -1 2-pyrimidyl Chemical group 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 101100295738 Gallus gallus COR3 gene Proteins 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 4
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
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- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 claims description 2
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 claims description 2
- HJVPMOBGEDSBBT-UHFFFAOYSA-N [3-[[4-(2-methoxyphenyl)piperazin-1-yl]methyl]piperidin-1-yl]-phenylmethanone Chemical compound COC1=CC=CC=C1N1CCN(CC2CN(CCC2)C(=O)C=2C=CC=CC=2)CC1 HJVPMOBGEDSBBT-UHFFFAOYSA-N 0.000 claims description 2
- 229960004038 fluvoxamine Drugs 0.000 claims description 2
- CJOFXWAVKWHTFT-XSFVSMFZSA-N fluvoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 CJOFXWAVKWHTFT-XSFVSMFZSA-N 0.000 claims description 2
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- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 claims description 2
- 229960004688 venlafaxine Drugs 0.000 claims description 2
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 claims description 2
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- ADJGWYBDBDPFIQ-UHFFFAOYSA-N 3-[2-[3-[[4-(2-methoxyphenyl)piperazin-1-yl]methyl]piperidin-1-yl]ethyl]-1h-indole Chemical compound COC1=CC=CC=C1N1CCN(CC2CN(CCC=3C4=CC=CC=C4NC=3)CCC2)CC1 ADJGWYBDBDPFIQ-UHFFFAOYSA-N 0.000 claims 1
- MQEIOMUYEJXEPC-UHFFFAOYSA-N 4-[4-[(1-methylpiperidin-4-yl)methyl]piperazin-1-yl]-1h-indole Chemical compound C1CN(C)CCC1CN1CCN(C=2C=3C=CNC=3C=CC=2)CC1 MQEIOMUYEJXEPC-UHFFFAOYSA-N 0.000 claims 1
- 102000012306 5-Hydroxytryptamine 1A receptors Human genes 0.000 claims 1
- 108050002825 5-Hydroxytryptamine 1A receptors Proteins 0.000 claims 1
- AWEGTIINADHCLD-UHFFFAOYSA-N [4-(1h-indol-4-yl)piperazin-1-yl]-piperidin-4-ylmethanone Chemical compound C1CN(C=2C=3C=CNC=3C=CC=2)CCN1C(=O)C1CCNCC1 AWEGTIINADHCLD-UHFFFAOYSA-N 0.000 claims 1
- RKEUQGOWWNIJDN-UHFFFAOYSA-N [4-[[4-(2-methoxyphenyl)piperazin-1-yl]methyl]piperidin-1-yl]-phenylmethanone Chemical compound COC1=CC=CC=C1N1CCN(CC2CCN(CC2)C(=O)C=2C=CC=CC=2)CC1 RKEUQGOWWNIJDN-UHFFFAOYSA-N 0.000 claims 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 claims 1
- PRPORFQJMQKDME-UHFFFAOYSA-N cyclohexyl-[3-[[4-(2-methoxyphenyl)piperazin-1-yl]methyl]piperidin-1-yl]methanone Chemical compound COC1=CC=CC=C1N1CCN(CC2CN(CCC2)C(=O)C2CCCCC2)CC1 PRPORFQJMQKDME-UHFFFAOYSA-N 0.000 claims 1
- PFNLCLQZPCGTKH-UHFFFAOYSA-N cyclohexyl-[4-[[4-(2-methoxyphenyl)piperazin-1-yl]methyl]piperidin-1-yl]methanone Chemical compound COC1=CC=CC=C1N1CCN(CC2CCN(CC2)C(=O)C2CCCCC2)CC1 PFNLCLQZPCGTKH-UHFFFAOYSA-N 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 208000020685 sleep-wake disease Diseases 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 239000000047 product Substances 0.000 description 40
- 239000000203 mixture Substances 0.000 description 25
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 239000007787 solid Substances 0.000 description 20
- 238000001914 filtration Methods 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 238000000921 elemental analysis Methods 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000012267 brine Substances 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 239000001530 fumaric acid Substances 0.000 description 8
- 229960005141 piperazine Drugs 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 8
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 7
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
- 125000002950 monocyclic group Chemical group 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 5
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 5
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- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 4
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
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- DDMVHGULHRJOEC-UHFFFAOYSA-N 1-(2-methoxyphenyl)piperazin-1-ium;chloride Chemical compound Cl.COC1=CC=CC=C1N1CCNCC1 DDMVHGULHRJOEC-UHFFFAOYSA-N 0.000 description 2
- VNZLQLYBRIOLFZ-UHFFFAOYSA-N 1-(2-methoxyphenyl)piperazine Chemical compound COC1=CC=CC=C1N1CCNCC1 VNZLQLYBRIOLFZ-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
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- LNAANGYWIDUDRG-UHFFFAOYSA-N 1-butoxycarbonylpiperidine-4-carboxylic acid Chemical compound CCCCOC(=O)N1CCC(C(O)=O)CC1 LNAANGYWIDUDRG-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
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- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
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- NTLAICDKHHQUGC-UHFFFAOYSA-N 3-(2-bromoethyl)-1h-indole Chemical compound C1=CC=C2C(CCBr)=CNC2=C1 NTLAICDKHHQUGC-UHFFFAOYSA-N 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
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- YZKSXUIOKWQABW-UHFFFAOYSA-N 4-piperazin-1-yl-1h-indole Chemical compound C1CNCCN1C1=CC=CC2=C1C=CN2 YZKSXUIOKWQABW-UHFFFAOYSA-N 0.000 description 1
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- 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
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- 239000004202 carbamide Substances 0.000 description 1
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
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- 125000004663 dialkyl amino group Chemical group 0.000 description 1
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
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- 238000002474 experimental method Methods 0.000 description 1
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- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- 235000003599 food sweetener Nutrition 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
- 150000002334 glycols Chemical class 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
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
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- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical class OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- FTQWRYSLUYAIRQ-UHFFFAOYSA-N n-[(octadecanoylamino)methyl]octadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)NCNC(=O)CCCCCCCCCCCCCCCCC FTQWRYSLUYAIRQ-UHFFFAOYSA-N 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
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- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
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- 229960001779 pargyline Drugs 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
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- 125000003226 pyrazolyl group Chemical group 0.000 description 1
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- 102000005962 receptors Human genes 0.000 description 1
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- 238000010561 standard procedure Methods 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
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- 125000003107 substituted aryl group Chemical group 0.000 description 1
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- 235000012222 talc Nutrition 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
- 229960000278 theophylline Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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- 239000001993 wax Substances 0.000 description 1
- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical class N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- 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
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/20—Hypnotics; Sedatives
-
- 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
- A61P25/22—Anxiolytics
-
- 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
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
Definitions
- novel arylpiperidine derivatives which are agonists and antagonists of the 5HT1A receptor subtype.
- compounds of the present invention are useful for the treatment of central nervous system (CNS) disorders such as depression, anxiety, panic. OCD. sleep disorders, sexual dysfunction, alcohol and drug addiction, cognition enhancement, Alzheimer's disease. Parkinson's disease, obesity and migraine.
- CNS central nervous system
- R ] is aryl or heteroaryl:
- A is NR 2 or CH 2 and B is NR 2 or CH 2 , provided that A is not equal to B;
- R is hydrogen, alkyl, cycloalkyl. alkylcycloalkyl, heterocycloalkyl, alkylhetero- cycloalkyl, aryl, aralkyl. heteroaryl, alkylheteroaryl or COR3;
- R3 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl. aryl or heteroaryl; n is an integer from 0 to 2. or a pharmaceutical salt thereof.
- R ] is phenyl; 2-, 3- or 4-pyridyl; 2-pyrimidyl; benzodioxan-5-yl; indol-4-yl; 3-thienyl; l-, or 2-naphthyl.
- R ] is phenyl or indol-4-yl.
- R 2 is aralkyl, alkylheterocycloalkyl or COR3.
- Alkyl' as used herein means a branched or straight chain having from 1 to 6 carbon atoms and more preferably from 1 to 4 carbon atoms.
- exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
- Lower alkyl refers to alkyl having from 1 to 6 carbon atoms.
- Alkoxy' * as used herein means an alkyl-O group in which the alkyl group is as previously described.
- exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and t-butoxy.
- Aryl' as used herein means mono or bicyclic aromatic ring having from 6 to 10 carbon atoms. Monocyclic rings preferably have 6 members and bicyclic rings preferably have 8, 9 or 10 membered ring structures.
- Exemplary aryl groups include phenyl, naphthyl, and biphenyl. In some preferred embodiments aryl is phenyl, 1-naphthyl or 2-naphthyl. In still more preferred embodiments aryl is phenyl.
- the aryl group may be substituted with one or more substituents. Substituted aryl groups preferably have one to three substituents.
- Cycloalkyl as used herein means a monocyclic alkyl group having from 3 to 8 carbon atoms. In some preferred embodiments cycloalkyl may be substituted with from 1 to 3 substituents.
- Heterocycloalkyl as used herein means a monocyclic alkyl group having from
- heterocycloalkyl groups include piperidinyl, piperazinyl and morpholino.
- heterocycloalkyl groups may be substituted with from 1 to 3 substituents.
- Halogen as used herein means fluorine, chlorine, iodine and bromine.
- Heteroaryl means 5 to 10 membered mono or bicyclic aromatic ring having from 1 to 3 heteroatoms selected from N, O and S. Monocyclic rings preferably have 5 or 6 members and bicyclic rings preferably have 8, 9 or 10 membered ring structures. Exemplary heteroaryls include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, benzopyranyl and benzodioxanyl.
- Preferred heteroaryl groups include thienyl, pyridyl, furyl, indolyl and benzodioxanyl. More preferred are heteroaryl groups including 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 3-indolyl, indol-4-yl and benzodiox- 5-yl.
- the heteroaryl group may be substituted with one or more substituents. Substituted heteroaryl groups preferably have from 1 to 3 substituents.
- Suitable substituents include halogen, alkyl, hydroxy, alkoxy, amino, amido, nitro, alkylamino, alkylamido, perhaloalkyl, carboxyalkyl, carboxy, carbamide, dialkylamino and aryl.
- Carbon number refers to the number of carbons in the carbon backbone and does not include carbon atoms occurring in substituents such as an alkyl or alkoxy substituents.
- alkylcycloalkyl is an alkyl-cycloalkyl group in which alkyl and cycloalkyl are as previously described.
- Pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, and the like.
- a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, and the like.
- the compounds of this invention contain a chiral center, providing for various seteroisomeric forms of the compounds such as racemic mixtures as well as the individual optical isomers.
- the individual isomers can be prepared directly or by asymmetric or stereospecific synthesis or by conventional separation of optical isomers from the racemic mixture.
- a tert-butyl carbamate is an example of a suitable protection group (P) which can be removed by the action of acid.
- P protection group
- Deprotection to the amine, and subsequent reduction of the amide using lithium aluminum hydride or borane-tetrahydrofuran complex can afford the required unsubstituted product A.
- the product may be alkylated with alkyl halides under the influence of a base such as sodium hydride or potassium carbonate to afford further derivatives, or alternatively may be acylated with carboxylic acid derivatives and the amide subsequently reduced under the above noted conditions to afford further derivatives.
- 4-nipecotamide 4-(2-Methoxyphenyl)piperazine hydrochloride (5.0 g, 21.8 mmol) was added to a mixture of DAEC (4.18 g, 21.8 mmol), HOBT (1.3 equivalents, 3.83 g, 28.3 mmol) and N-t-butoxycarbonyl nipecotic acid (5 g, 21.8 mmol) in DMF (35 mL), and the resulting solution was treated with NMM (2.5 equivalents, 6.0 mL, 54.5 mmol) and stirred at ()°C for 16 hours.
- Benzoyl chloride (0.49 g, 3.5 mmol) was added to a solution of l-(2- methoxyphenyl)-4-piperidin-4-ylmethyl-piperazine (1.0 g, 3.5 mmol) from example 1 and triethylamine (2 equivalents, 1 mL) in CH 2 C1 2 (30 mL) and the solution stirred under N 2 at ()°C for 16 hours.
- the mixture was concentrated under vacuum, water (50 mL) added and the product extracted into ethyl acetate (3 x 25 mL). The combined organics were washed with water (25 mL), saturated sodium bicarbonate (20 mL) and brine (25 mL).
- Example 6 l-(2-Methoxy-phenyl)-4-piperidin-3-ylmethyl-piperazine A solution of the amide from intermediate 4 (7.4 g, 21.8 mmol) and triethylamine (6 mL) in THF (100 mL) was treated with the dropwise addition of borane-THF (1.0 M, 76 mL) at 0°C under nitrogen. The mixture was refluxed for 16 hours and after cooling to 0°C, the reaction was terminated by the addition of 2N-HC1 (50 mL). After stirring for 1 hour, the solution was made basic with NaOH and the product extracted into ethyl acetate (3 x 35 mL).
- Benzoyl chloride (0.49 g, 3.5 mmol) was added to a solution of l-(2- methoxyphenyl)-4-piperidin-3-ylmethyl-piperazine ( 1.0 g, 3.5 mmol) from example 6 and triethylamine (2 equivalents, 1 mL) in CH C1, (30 mL) and the solution stirred under N, at 0°C for 16 hours.
- the mixture was concentrated under vacuum, water (50 mL) added and the product extracted into ethyl acetate (3 x 25 mL). The combined organics were washed with water (25 mL), saturated sodium bicarbonate (20 mL) and brine (25 mL).
- Compounds of the present invention bind with very high affinity to the 5-HT1A receptor and consequently, they are useful for the treatment of central nervous system disorders such as depression, anxiety, sleep disorders, sexual dysfunction, alcohol and cocaine addiction, cognition enhancement and related problems in addition to the treatment of Alzheimer's disease, Parkinson's disease, obesity and migraine.
- High affinity for the serotonin 5-HTIA receptor was established by testing the claimed compound's ability to displace [ 3 H] 8-OH-DPAT binding in CHO cells stably transfected with the human 5HT1A receptor.
- Stably transfected CHO cells are grown in DMEM containing 10% heat inactivated FBS and non-essential amino acids. Cells are scraped off the plate, transferred to centrifuge tubes, and washed twice by centrifugation (2000 rpm for 10 min.. 4"C) in buffer (50 mM Tris pH 7.5). The resulting pellets are aliquoted and placed at -8()"C. On the day of assay, the cells are thawed on ice and resuspended in buffer.
- the binding assay is performed in a 96 well microtiter plate in a total volume of 250 ⁇ L. Non-specific binding is determined in the presence of 10 mM 5-HT, final ligand concentration is 1.5 nM. Following a 30 minute incubation at room temperature, the reaction is terminated by the addition of ice cold buffer and rapid filtration through a GF/B filter presoaked for 30 minutes in 0.5% PEL Compounds are initially tested in a single point assay to determine percent inhibition at 1, 0.1 , and 0.01 mM, and Ki values are determined for the active compounds.
- 5-HT1A Receptor Intrinsic Activity Assay is performed in a 96 well microtiter plate in a total volume of 250 ⁇ L. Non-specific binding is determined in the presence of 10 mM 5-HT, final ligand concentration is 1.5 nM. Following a 30 minute incubation at room temperature, the reaction is terminated by the addition of ice cold buffer and rapid filtration through a GF/B filter presoaked for 30 minutes in
- the intrinsic activity of compounds of the present invention was established by testing the claimed compounds ability to reverse the stimulation of cyclic adenosinemonophosphate (cAMP) in CHO cells stably transfected with the human 5-HT 1 A receptor.
- cAMP cyclic adenosinemonophosphate
- Stably transfected CHO cells were grown in DMEM containing 10% heat inactivated FBS and non-essential amino acids. The cells are plated at a density of xl() 6 cells per well in a 24 well plate and incubated for 2 days in a CO 2 incubator. On the second day, the media is replaced with 0.5 mL treatment buffer (DMEM + 25 mM HEPES, 5 mM theophylline, 10 ⁇ M pargyline) and incubated for 10 minutes at 37°C. Wells are treated with forskolin (1 ⁇ M final concentration) followed immediately by the test compound (0.1 and 1 ⁇ M for initial screen) and incubated for an additional 10 minutes at 37°C.
- DMEM + 25 mM HEPES 5 mM theophylline, 10 ⁇ M pargyline
- compounds of the present invention exhibit high affinity for the 5HT1 A receptor subtype and exhibit intrinsic activity as evidenced by their ability to reverse stimulation of cyclic adenosinemonophosphate (cAMP). Accordingly, compounds of the present invention are useful for treatment of disorders of the central nervous system and may be administered to a patient suffering from one or more of said disorders. Treatment, as used herein, refers to the alleviation or amelioration of symptoms of a particular disorder in a patient. In addition, compounds of the present invention may be administered as part of a treatment regime that includes other agents which act on the central nervous system. In some preferred embodiments, compounds of the present invention are part of a combination therapy including a serotonin rcuptakc inhibitor.
- Serotonin reuptake inhibitors useful in combination therapies of the present invention fluoxetine, fluvoxamine, paroxetine, sertraline and venlafaxine. Said agents may be administered at the same time, where they may be combined into a single dosage form, or at a different time, as compounds of the present invention, while still being part of the regime of the combination therapy. Compounds of the invention may be administered to a patient either neat or with a convention pharmaceutical carrier.
- Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material.
- the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
- the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
- the powders and tablets preferably contain up to 99% of the active ingredient.
- Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine. low melting waxes and ion exchange resins.
- Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
- the active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
- the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
- suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g.
- cellulose derivatives preferably sodium carboxymethyl cellulose solution
- alcohols including monohydric alcohols and polyhydric alcohols e.g. glycols
- oils e.g. fractionated coconut oil and arachis oil
- the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
- Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
- the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules.
- the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
- the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
- the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
- the therapeutically effective dosage to be used in the treatment of a specific psychosis must be subjectively determined by the attending physician.
- the variables involved include the specific psychosis or state of anxiety and the size, age and response pattern of the patient.
- the novel method of the invention for treating conditions related to or are affected by the 5-HT 1 A receptor comprise administering to warm-blooded animals, including humans, an effective amount of at least one compound of Formula A and its non-toxic, pharmaceutically acceptable addition salts.
- the compounds may be administered orally, rectally, parenterally or topically to the skin and mucosa.
- the usual daily dose is depending on the specific compound, method of treatment and condition treated.
- the usual daily dose is 0.01 - 1000 mg/Kg for oral application, preferably 0.5 - 500 mg/Kg, and 0.1 - 100 mg/Kg for parenteral application, preferably 0.5 - 50 mg/Kg.
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Abstract
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US21347098A | 1998-12-17 | 1998-12-17 | |
US213470 | 1998-12-17 | ||
PCT/US1999/029881 WO2000035878A1 (fr) | 1998-12-17 | 1999-12-16 | Derives de 1,4-piperazine agissant sur le recepteur de 5ht1a |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1140838A1 true EP1140838A1 (fr) | 2001-10-10 |
Family
ID=22795242
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP99965282A Withdrawn EP1140838A1 (fr) | 1998-12-17 | 1999-12-16 | Derives de 1,4-piperazine agissant sur le recepteur de 5ht1a |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP1140838A1 (fr) |
JP (1) | JP2002532473A (fr) |
AU (1) | AU3123100A (fr) |
BR (1) | BR9916185A (fr) |
CA (1) | CA2351859A1 (fr) |
WO (1) | WO2000035878A1 (fr) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8106074B2 (en) | 2001-07-13 | 2012-01-31 | Pierre Fabre Medicament | Pyridin-2-yl-methylamine derivatives for treating opiate dependence |
CA2470808A1 (fr) * | 2001-12-21 | 2003-07-03 | Taisho Pharmaceutical Co., Ltd. | Derive de piperazine |
AR047759A1 (es) | 2003-09-26 | 2006-02-22 | Vertex Pharma | Derivados de fenil - piperazina como moduladores de receptores muscarnicos |
GB0525957D0 (en) * | 2005-12-21 | 2006-02-01 | Astrazeneca Ab | Methods |
WO2008117269A2 (fr) | 2007-03-28 | 2008-10-02 | Atir Holding S.A. | Composés hétérocycliques comme agents sérotoninergiques et dopaminergiques et leurs utilisations |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US5162523A (en) * | 1989-07-21 | 1992-11-10 | Hoffmann-La Roche Inc. | Cephalosporin antibacterial compounds |
FR2658823B1 (fr) * | 1990-02-27 | 1992-04-30 | Adir | Nouveaux derives d'aminomethylpiperidine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent . |
GB9715892D0 (en) * | 1997-07-29 | 1997-10-01 | Zeneca Ltd | Heterocyclic compounds |
-
1999
- 1999-12-16 CA CA002351859A patent/CA2351859A1/fr not_active Abandoned
- 1999-12-16 JP JP2000588140A patent/JP2002532473A/ja active Pending
- 1999-12-16 BR BR9916185-0A patent/BR9916185A/pt not_active IP Right Cessation
- 1999-12-16 EP EP99965282A patent/EP1140838A1/fr not_active Withdrawn
- 1999-12-16 AU AU31231/00A patent/AU3123100A/en not_active Abandoned
- 1999-12-16 WO PCT/US1999/029881 patent/WO2000035878A1/fr not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO0035878A1 * |
Also Published As
Publication number | Publication date |
---|---|
JP2002532473A (ja) | 2002-10-02 |
BR9916185A (pt) | 2001-09-04 |
WO2000035878A1 (fr) | 2000-06-22 |
AU3123100A (en) | 2000-07-03 |
CA2351859A1 (fr) | 2000-06-22 |
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