CN1561336A - 作为血清素再摄取抑制剂的苯基哌嗪衍生物 - Google Patents
作为血清素再摄取抑制剂的苯基哌嗪衍生物 Download PDFInfo
- Publication number
- CN1561336A CN1561336A CNA028190254A CN02819025A CN1561336A CN 1561336 A CN1561336 A CN 1561336A CN A028190254 A CNA028190254 A CN A028190254A CN 02819025 A CN02819025 A CN 02819025A CN 1561336 A CN1561336 A CN 1561336A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- piperazine
- alkyl
- sulfenyl
- alkynyl
- 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.)
- Granted
Links
- 239000003772 serotonin uptake inhibitor Substances 0.000 title description 10
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical class C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 73
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 15
- 208000017194 Affective disease Diseases 0.000 claims abstract description 6
- 208000019022 Mood disease Diseases 0.000 claims abstract description 6
- 208000019906 panic disease Diseases 0.000 claims abstract description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 79
- 125000000304 alkynyl group Chemical group 0.000 claims description 59
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 59
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 48
- 238000000034 method Methods 0.000 claims description 28
- 229910052760 oxygen Inorganic materials 0.000 claims description 26
- 239000001301 oxygen Substances 0.000 claims description 22
- 150000001336 alkenes Chemical class 0.000 claims description 17
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 9
- 208000024732 dysthymic disease Diseases 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 6
- VAXHGPCUAFNAQS-UHFFFAOYSA-N 1-(2-phenoxyphenyl)piperazine Chemical compound C1CNCCN1C1=CC=CC=C1OC1=CC=CC=C1 VAXHGPCUAFNAQS-UHFFFAOYSA-N 0.000 claims description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- JOMNTHCQHJPVAZ-UHFFFAOYSA-N 2-methylpiperazine Chemical compound CC1CNCCN1 JOMNTHCQHJPVAZ-UHFFFAOYSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- JYVRCNMQFCWSGB-UHFFFAOYSA-N 1-[2-(4-bromophenyl)sulfanylphenyl]piperazine Chemical compound C1=CC(Br)=CC=C1SC1=CC=CC=C1N1CCNCC1 JYVRCNMQFCWSGB-UHFFFAOYSA-N 0.000 claims description 3
- NGQQPARRDBDNPB-UHFFFAOYSA-N 1-[2-(4-chlorophenyl)sulfanylphenyl]piperazine Chemical compound C1=CC(Cl)=CC=C1SC1=CC=CC=C1N1CCNCC1 NGQQPARRDBDNPB-UHFFFAOYSA-N 0.000 claims description 3
- VZGBPMFEQIPRPQ-UHFFFAOYSA-N 1-[2-(4-methylsulfanylphenyl)sulfanylphenyl]piperazine Chemical compound C1=CC(SC)=CC=C1SC1=CC=CC=C1N1CCNCC1 VZGBPMFEQIPRPQ-UHFFFAOYSA-N 0.000 claims description 3
- QPCFHMMOSPLACK-UHFFFAOYSA-N 4-(2-piperazin-1-ylphenyl)sulfanylphenol Chemical compound C1=CC(O)=CC=C1SC1=CC=CC=C1N1CCNCC1 QPCFHMMOSPLACK-UHFFFAOYSA-N 0.000 claims description 3
- NGFUOELUUCTJQU-UHFFFAOYSA-N FC1=CC=C(C=C1)SC1=C(C=C(C=C1)CN)N1CCNCC1 Chemical compound FC1=CC=C(C=C1)SC1=C(C=C(C=C1)CN)N1CCNCC1 NGFUOELUUCTJQU-UHFFFAOYSA-N 0.000 claims description 3
- YRLCROOFFQBDRN-UHFFFAOYSA-N NCC1=CC=C(C=C1)SC1=C(C=CC=C1)C=1CCNCC1 Chemical compound NCC1=CC=C(C=C1)SC1=C(C=CC=C1)C=1CCNCC1 YRLCROOFFQBDRN-UHFFFAOYSA-N 0.000 claims description 3
- NBKHHMUSDIMHQX-UHFFFAOYSA-N NCC1=CC=C(C=C1)SC1=C(C=CC=C1)N1CCNCC1 Chemical compound NCC1=CC=C(C=C1)SC1=C(C=CC=C1)N1CCNCC1 NBKHHMUSDIMHQX-UHFFFAOYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- ADCOZQWLQPONRQ-UHFFFAOYSA-N 1-[2-(3-chlorophenoxy)phenyl]piperazine Chemical compound ClC1=CC=CC(OC=2C(=CC=CC=2)N2CCNCC2)=C1 ADCOZQWLQPONRQ-UHFFFAOYSA-N 0.000 claims description 2
- XOBCMDJXBRDTER-UHFFFAOYSA-N 1-[2-(3-methylphenoxy)phenyl]piperazine Chemical compound CC1=CC=CC(OC=2C(=CC=CC=2)N2CCNCC2)=C1 XOBCMDJXBRDTER-UHFFFAOYSA-N 0.000 claims description 2
- JLTRKMBOLGQAPN-UHFFFAOYSA-N 1-[2-(4-butylphenoxy)phenyl]piperazine Chemical compound C1=CC(CCCC)=CC=C1OC1=CC=CC=C1N1CCNCC1 JLTRKMBOLGQAPN-UHFFFAOYSA-N 0.000 claims description 2
- GYSBNDJHYWWUMO-UHFFFAOYSA-N 1-[2-(4-methylphenoxy)phenyl]piperazine Chemical compound C1=CC(C)=CC=C1OC1=CC=CC=C1N1CCNCC1 GYSBNDJHYWWUMO-UHFFFAOYSA-N 0.000 claims description 2
- 241001465754 Metazoa Species 0.000 claims description 2
- 229910021386 carbon form Inorganic materials 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 8
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 35
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 33
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 32
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 25
- -1 1-piperazinyl Chemical group 0.000 description 24
- 238000000105 evaporative light scattering detection Methods 0.000 description 24
- 239000000243 solution Substances 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- 239000011347 resin Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 229920005989 resin Polymers 0.000 description 15
- 239000000203 mixture Substances 0.000 description 14
- 230000000694 effects Effects 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- 229940093499 ethyl acetate Drugs 0.000 description 11
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 239000000376 reactant Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000004793 Polystyrene Substances 0.000 description 10
- 229920002223 polystyrene Polymers 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
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- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
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- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 5
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
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- 229910052786 argon Inorganic materials 0.000 description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
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- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical class [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 description 3
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- 229910001510 metal chloride Inorganic materials 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000004050 mood stabilizer Substances 0.000 description 1
- 229940127237 mood stabilizer Drugs 0.000 description 1
- 125000005322 morpholin-1-yl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- CYJAWBVQRMVFEO-UHFFFAOYSA-N piperazine-2,6-dione Chemical class O=C1CNCC(=O)N1 CYJAWBVQRMVFEO-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 230000036647 reaction Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- 239000003727 serotonin 1A antagonist Substances 0.000 description 1
- 208000012201 sexual and gender identity disease Diseases 0.000 description 1
- 208000015891 sexual disease Diseases 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- RZWQDAUIUBVCDD-UHFFFAOYSA-M sodium;benzenethiolate Chemical compound [Na+].[S-]C1=CC=CC=C1 RZWQDAUIUBVCDD-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- FWBIXSBYPKNQIE-UHFFFAOYSA-N tert-butyl 4-[2-(4-chlorophenyl)sulfanylphenyl]-3,5-dioxopiperazine-1-carboxylate Chemical compound O=C1CN(C(=O)OC(C)(C)C)CC(=O)N1C1=CC=CC=C1SC1=CC=C(Cl)C=C1 FWBIXSBYPKNQIE-UHFFFAOYSA-N 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
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
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- 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
- C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
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- C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—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 one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
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Abstract
本发明提供通式I化合物,其中取代基定义在申请书中。盐用于制备治疗情感障碍,如抑郁症,包括一般的焦虑疾病和恐慌疾病的焦虑疾病以及强迫性的强制的疾病的药物的用途。
Description
技术领域
本发明涉及作为血清素再摄取抑制剂的新的化合物,该化合物在例如抑郁和焦虑症的治疗中效果显著。
背景技术
因为与传统三环抗忧郁药相比,选择性的血清素再摄取抑制剂(以下简称为SSRIs)效果显著,耐受性好以及具有良好的安全曲线,所以它们已经成为治疗抑郁症,某些形式的焦虑和社交恐怖症的首选药物。
但是,抑郁症的临床研究显示,SSRIs的疗效基本上为零,至多30%。另外的,人们常常忽视抗抑郁剂治疗中的顺应性,它对患者连续药物治疗的激励具有相当深的影响。
首先,SSRIs治疗的作用有迟延。有时在治疗的第一周症状甚至恶化。其次,所有的SSRIs都有性功能紊乱的副作用。不考虑这些问题不可能实现真正的抑郁和焦虑症的药物治疗。
为了对付无药理反应,精神病学家有时使用增进作用策略。抗抑郁剂治疗的增进作用可以通过情绪稳定剂如碳酸锂或三碘甲(状)腺原氨酸(triiodothyronin)共同给药或通过利用电休克完成。
抑制血清素再摄取的化合物和5-HT1A受体拮抗剂合并给药的效果已经在几项研究中被评价(Innis et al.Eur.J.Pharmacol.1987,143,1095-204和Gartside Br.J.Pharmacol.1995,115,1064-1070,Blier et al.Trends in Pharmacol.Science 1994,15,220)。在这些研究中,现已发现5-HT1A受体拮抗剂将会消除对血清素再摄取抑制剂导致的5-HT神经传递的最初的阻碍,产生5-HT传输的快速增加以及速效的治疗作用。
已经有若干包括通过利用5-HT1A拮抗剂和血清素再摄取抑制剂的结合治疗抑郁症的专利申请被提出(参见例如EP-A2-687472和EP-A2-714663)。
另外通过阻断5HT1B自身受体也可能增强末端5-HT。大鼠微量渗析试验的确已经显示通过西酞普兰产生的海马体5-HT的增加是通过GMC2-29,实验的5-HT1B受体拮抗剂增强的。
包括SSRI和5-HT1B拮抗剂或部分激动剂的若干专利申请也已经被提出(WO 97/28141,WO 96/03400,EP-A-701819和WO 99/13877)。
以前已经发现,按照微量渗析实验测定血清素再摄取抑制剂与具有5-HT2C拮抗或相反的竞争作用的化合物(在5-HT2C受体具有阴性效果的化合物)结合提供终端区域5-HT的浓度相当多的增加(WO01/41701)。这暗示抗抑郁剂临床作用的迅速的开始以及血清素再摄取抑制剂(SRI)治疗效果的增进或增强。
本发明提供作为血清素再摄取抑制剂用于治疗情感障碍如抑郁症,包括一般的焦虑疾病和恐慌疾病的焦虑疾病以及强迫性的强制疾病的化合物。一些化合物也具有血清素再摄取抑制的综合作用和5HT2C受体调节作用,按照WO 01/41701暗示,兴奋剂活性加快产生。
一些本发明化合物以前已经被公开于WO 01/49681和WO02/59108。但是,WO 01/49681没有公开任何治疗或生物活性。WO02/59108公开的化合物为合成不同于本发明具有黑色素皮质素受体拮抗剂治疗活性的化合物的化合物的合成中间体。本发明的一个化合物,1-(2-苯氧基苯基)哌嗪,公开于US 4,064,245,用于治疗代谢失调。
发明概述
本发明提供通式I化合物
其中
Y为N,C或CH;
X表示O或S;
m为1或2;
p为0,1,2,3,4,5,6,7或8;
q为0,1,2,3或4;
s为0,1,2,3,4或5;
虚线表示可以存在的键;
各R1独立地选自C1-6-烷基,或两个R1连接于同一个碳原子形成3-6-元螺旋连接的环烷基;
各R2独立地选自卤素,氰基,硝基,C1-6烷基(烯基/炔基)基,C1-6烷基(烯基/炔基)氧基,C1-6烷基(烯基/炔基)硫基(sulfanyl),羟基,羟基-C1-6-烷基(烯基/炔基)基,卤素-C1-6-烷基(烯基/炔基)基,卤素-C1-6-烷基(烯基/炔基)氧基,C3-8-环烷(烯)基,C3-8-环烷(烯)基-C1-6-烷基(烯基/炔基)基,酰基,C1-6-烷基(烯基/炔基)氧羰基,C1-6-烷基(烯基/炔基)磺酰基,或-NRxRy;
各R3独立地选自卤素,氰基,硝基,C1-6烷基(烯基/炔基)基,C1-6烷基(烯基/炔基)氧基,C1-6烷基(烯基/炔基)硫基(sulfanyl),羟基,羟基-C1-6-烷基(烯基/炔基)基,卤素-C1-6-烷基(烯基/炔基)基,卤素-C1-6-烷基(烯基/炔基)氧基,C3-8-环烷(烯)基,C3-8-环(烯)烷基-C1-6-烷基(烯基/炔基)基,C1-6-烷基(烯基/炔基)磺酰基,芳基,C1-6-烷基(烯基/炔基)氧羰基,酰基,-NRxCO-C1-6-烷基(烯基/炔基),CONRxRy或NRxRy;
或两个相邻的R3取代基一起形成与苯基稠合的选自如下的杂环
其中W为O或S,以及R′和R″为氢或C1-6-烷基;
或两个相邻的R3取代基一起形成含一个,两个或三个杂原子的稠合杂芳基系统,
其中各Rx和Ry独立地选自氢,C1-6-烷基(烯基/炔基)基,C3-8-环烷(烯)基,C3-8-环烷(烯)基-C1-6-烷基(烯基/炔基)基,或芳基;或Rx和Ry与连接它们的氮一起形成非强制性地含一个另外的杂原子的3-7元环;
或其酸加成盐。
本发明也提供上述化合物,条件是该不是1-(2-苯氧基苯基)-哌嗪;
本发明也提供上述化合物,条件是该化合物不是1-[2-(2-甲氧基苯氧基)苯基]哌嗪,1-[2-(2,6-二甲氧基苯氧基)苯基]-[1,4]-二氮杂,1-{2-[3-(二甲氨基)苯氧基]苯基}哌嗪,1-[2-(4-甲基苯氧基)苯基]哌嗪,1-[2-(3-甲基苯氧基)苯基]哌嗪,1-[2-(3-氯苯氧基)苯基]哌嗪,1-[2-(3-甲氧基苯氧基)苯基]哌嗪和1-(2-苯氧基苯基)-哌嗪;
本发明提供上述用作药物的化合物。
本发明提供包含上述化合物或其药学上可接受的酸加成盐和至少一种药学上可接受的载体或稀释剂。
本发明提供上述化合物或其药学上可接受的酸加成盐用于制备治疗情感障碍,如抑郁症,包括一般的焦虑疾病和恐慌疾病的焦虑疾病以及强迫性的强制的疾病的药物的用途。
本发明提供一种用于治疗活的动物体,包括人类的情感障碍,包括抑郁症,包括一般的焦虑疾病和恐慌疾病的焦虑疾病以及强迫性的强制的疾病的方法,其中包含使用治疗有效量的上述化合物或其药学上可接受的酸加成盐。
发明详述
本发明优选方案中p为0;
本发明优选方案中m为1或2;
本发明的优选方案中R2为三氟甲基,或C1-6-烷基;
本发明优选方案中R3选自卤素,C1-6-烷氧基,C1-6-硫基(sulfanyl),C1-6-烷基,羟基或三氟甲基;
本发明特别优选方案中包括任何下列本发明化合物:
1-[2-(2-三氟甲基苯基硫基)苯基]哌嗪,
1-[2-(4-溴苯基硫基)苯基]哌嗪,
1-{2-[4-(甲基硫基)苯基硫基]苯基}哌嗪,
1-[2-(4-羟基苯基硫基)苯基]哌嗪,
1-[2-(2,4-二甲基苯基硫基)苯基]哌嗪,
1-[2-(3,5-二甲基苯基硫基)苯基]哌嗪,
1-[2-(2,6-二甲基苯基硫基)苯基]哌嗪,
1-[2-(2,5-二甲基苯基硫基)苯基]哌嗪,
1-[2-(2-三氟甲基苯基硫基)苯基][1,4]二氮杂,
1-[2-(3-甲基苯基硫基)苯基]-[1,4]-二氮杂,
1-[2-(4-丁基苯基硫基)苯基]哌嗪,
1-[2-(4-甲氧基苯氧基)苯基]哌嗪,
2-(4-甲基苯基硫基)苯基-1-哌嗪,
1-[2-(4-氯苯基硫基)苯基]-哌嗪,
1-[2-(4-甲氧基苯基硫基)-4-氯苯基]哌嗪,
1-[2-(4-甲氧基苯基硫基)-4-甲基苯基]哌嗪,
1-[2-(4-甲氧基苯基硫基)-5-甲基苯基]哌嗪,
1-[2-(4-氟苯基硫基)-5-甲基苯基]哌嗪,
1-[2-(4-甲氧基苯基硫基)-5-三氟甲基苯基]哌嗪,
1-[2-(4-氯苯基硫基)苯基]-3-甲基哌嗪,
1-[2-(4-氯苯基硫基)苯基]-3,5-二甲基哌嗪,
4-[2-(4-甲基苯基硫基)苯基]-3,6-二氢-2H-吡啶,
4-[2-(4-甲氧基苯基硫基)苯基]-3,6-二氢-2H-吡啶或
4-[2-(4-甲基苯基硫基)苯基]哌嗪
或其药学上可接受的酸加成盐。
取代基定义
卤素表示氟,氯,溴或碘。
词语C1-6-烷基(烯基/炔基)表示C1-6-烷基,C2-6-链烯基或C2-6-炔基。词语C3-8-环烷(烯)基表示C3-8-环烷基或环烯基。
术语C1-6-烷基指具有一到六个碳原子的支链或直链烷基,包括而不限于甲基,乙基,1-丙基,2-丙基,1-丁基,2-丁基,2-甲基-2-丙基和2-甲基-1-丙基。
同样地,C2-6-链烯基和C2-6-炔基分别表示具有二到六个碳原子,分别包含一个双键和一个三键的此类基团,包括而不限于乙烯基,丙烯基,丁烯基,乙炔基,丙炔基和丁炔基。
术语C3-8环烷基指具有三到八个C原子的单环或二环碳环,包括而不限于环丙基,环戊基,环己基,等。
术语C3-8-环烯基表示具有三到八个C原子并且包括一个双键的单环或二环碳环。
术语C3-8-环烷(烯)基-C1-6-烷基(烯基/炔基)中的C3-8-环烷(烯)基和C1-6-烷基(烯基/炔基)定义如上。
术语C1-6-烷基(烯基/炔基)氧基,C1-6-烷基(烯基/炔基)硫基,羟基-C1-6-烷基(烯基/炔基),卤素-C1-6-烷基(烯基/炔基),卤素C1-6-烷基(烯基/炔基)氧基,C1-6-烷基(烯基/炔基)磺酰基,等中的C1-6-烷基(烯基/炔基)定义如上。
本申请使用的术语C1-6-烷基(烯基/炔基)氧羰基指C1-6-烷基(烯基/炔基)-O-CO-,其中C1-6-烷基(烯基/炔基)定义如上。
本申请使用的术语酰基指甲酰基,C1-6-烷基(烯基/炔基)羰基,芳基羰基,芳基-C1-6-烷基(烯基/炔基)羰基,C3-8-环烷(烯)基羰基或C3-8-环烷(烯)基-C1-6-烷基(烯基/炔基)羰基。
本申请使用的术语非强制性地包含一个另外的杂原子的3-7元环指如1-吗啉基,1-哌啶基,1-氮杂基,1-哌嗪基,1-高哌嗪基,1-咪唑基,1-吡咯基或吡唑基的环状系统,它们都可以进一步被C1-6-烷基取代。
由两个相邻的R3取代基形成和与母体环稠合的杂环可以一起形成如下的环,如5-元单环如3H-1,2,3-噁噻唑,1,3,2-噁噻唑,1,3,2-二噁唑,3H-1,2,3-二噻唑,1,3,2-二噻唑,1,2,3-噁二唑,1,2,3-噻二唑,1H-1,2,3-三唑,异噁唑,噁唑,异噻唑,噻唑,1H-咪唑,1H-吡唑,1H-吡咯,呋喃或噻吩和6-单环如1,2,3-噁噻嗪,1,2,4-噁噻嗪,1,2,5-噁噻嗪,1,4,2-噁噻嗪,1,4,3-噁噻嗪,1,2,3-二噁嗪,1,2,4-二噁嗪,4H-1,3,2-二噁嗪,1,4,2-二噁嗪,2H-1,5,2-二噁嗪,1,2,3-二噻嗪,1,2,4-二噻嗪,4H-1,3,2-二噻嗪,1,4,2-二噻嗪,2H-1,5,2-二噻嗪,2H-1,2,3-噁二嗪,2H-1,2,4-噁二嗪,2H-1,2,5-噁二嗪,2H-1,2,6-噁二嗪,2H-1,3,4-噁二嗪,2H-1,2,3-噻二嗪,2H-1,2,4-噻二嗪,2H-1,2,5-噻二嗪,2H-1,2,6-噻二嗪,2H-1,3,4-噻二嗪,1,2,3-三嗪,1,2,4-三嗪,2H-1,2-噁嗪,2H-1,3-噁嗪,2H-1,4-噁嗪,2H-1,2-噻嗪,2H-1,3-噻嗪,2H-1,4-噻嗪,吡嗪,哒嗪,嘧啶,4H-1,3-氧硫杂环己二烯,1,4-氧硫杂环己二烯,4H-1,3-二噁英,1,4-二噁英,4H-1,3-二噻英(dithiin),1,4-二噻英,吡啶2H-吡喃或2H-噻英。
术语芳基指碳环的,芳香的系统如苯基和萘基。
本发明的酸加成盐优选本化合物和无毒的酸形成的药学上可接受的盐。这样的有机盐的例子为马来酸盐,富马酸盐,苯甲酸盐,抗坏血酸盐,琥珀酸盐,草酸盐,二亚甲基水杨酸盐,甲磺酸盐,乙二磺酸盐,乙酸盐,丙酸盐,酒石酸盐,水杨酸盐,柠檬酸盐,葡萄糖酸盐,乳酸盐,苹果酸盐,扁桃酸盐,肉桂酸盐,柠康酸盐,天冬氨酸盐,硬脂酸盐,棕榈酸盐,衣康酸盐,乙醇酸盐,对氨基苯甲酸盐,谷氨酸盐,苯磺酸盐和二甲基黄嘌呤乙酸,以及8-卤二甲基黄嘌呤盐,例如8-溴二甲基黄嘌呤盐。这样的无机盐的例子为盐酸盐,氢溴酸盐,磷酸盐,氨基磺酸盐,磷酸盐和硝酸盐。
另外,本发明化合物可以无溶剂的形式存在以及与药学上可接受的溶剂如水,乙醇等形成溶剂化物。一般说来,用于本发明目的的溶剂化物形式被认为相当于无溶剂的形式。
一些本发明化合物包含手性中心,这样的化合物存在异构体(即对映体)形式。本发明包括所有这类异构体和其混合物,包括外消旋混合物。
外消旋形式可以通过已知的方法分解为旋光对映体,例如,使用旋光活性酸分离非对映体盐,用碱处理释放旋光活性的胺化合物。另外的解析外消旋物成为旋光对映体的方法基于旋光活性基质上的层析法。本发明外消旋化合物还可以通过d或1-(酒石酸,苦杏仁酸或樟脑磺酸)盐分级结晶被分解为它们的旋光对映体。本发明化合物也可以通过形成非对映体衍生物分解。
可以使用本领域技术人员已知的用于解析旋光异构体的其他方法。这样的方法包括J.Jaques,A.Collet和S.Wilen在“对映体,外消旋物,和解析”,John Wiley and Sons,New York(1981)论述的方法。
旋光性化合物还可以从旋光活性原料制备。
药物组合物
发明的药物制剂可以通过本领域中的常规方法制备。例如:使活性成分与普通辅助剂和/或稀释剂混合,随后在常规的压片机中压缩该混合物可以制备片剂。辅助剂或稀释剂的例子包括:玉米淀粉,马铃薯淀粉,滑石,硬脂酸镁,明胶,乳糖,树胶,等。使用任何其他的辅助剂或添加剂的目的通常为染色,调味,防腐等等,条件是它们与活性成分不矛盾。
注射剂溶液可以通过将活性成分和可能的添加剂溶于一部分注射剂溶剂,优选无菌水,调节该溶液到需要的体积,灭菌并且填充在合适的安瓿或管形瓶中而制备。可以加入任何通常用于本领域的合适的添加剂,如张力调节剂,防腐剂,抗氧化剂,等。
本发明药物组合物或按照本发明生产的药物组合物可以通过任何合适的途径给药,例如以片剂形式口服,胶囊,粉末,糖浆,等等,或以注射液形式胃肠外给药。可以使用本领域众所周知的方法制备这样的组合物,并且可以使用通常用于本领域的任何药学上可接受的载体,稀释剂,赋形剂或其他添加剂。
方便地,本发明化合物以单位剂型给药,其中包含约0.01到100毫克量的该化合物。总日剂量的范围通常为约0.05到500毫克,最优选约0.1到50毫克本发明活性化合物。
本发明化合物通过以下一般方法制备:
a)由式II化合物的聚合物载体脱保护或裂解
其中Z表示
以及R1,R2,R3,m,p,q,s,X,Y和虚线如上所述,并且R为叔丁基,甲基,乙基,烯丙基或苄基或ROCO2为氨基甲酸酯基团载体,如基于氨基甲酸酯衔接物的王氏树脂。
b)式II化合物的化学转变
R1,R2,m,p,q,Y和虚线如上所述,成为相应的重氮化合物,并且随后与化合物HXZ反应,其中X和Z定义如上。
c)使式IV化合物
其中R2,R3,X,s和q如上所述,与式(C1-(CH2)m+1)NH(CH2)2Cl或(Br-(CH2)m+1)NH(CH2)2Br反应,其中m定义如上。
d)使式IV化合物
其中R2,R3,X,s和q如上所述以及G为溴或碘原子,与式VI化合物反应
其中R1,m和p定义如上。
e)使式VII化合物脱水以及同时非强制性地脱保护
其中R1,R2,R3,X,m,p,q和s如上所述,R为氢原子或BOC基团。
f)氢化式VIII化合物中的双键
其中R1,R2,R3,X,m,p,q和s如上所述。
方法a)的脱保护按照本领域的专业人员已知的标准技术以及教科书“有机合成中的保护基(Protective Groups in OrganicSynthesis)”T.W.Greene and P.G.M.Wuts,Wiley Interscience,(1991)ISBN 0471623016详细描述的进行。
其中R=tert-Bu的原料式II化合物按照下文所述方法制备。按照Sawyer et al.J.Org.Chem.1998,63,6338的方法,使氟硝基苯衍生物与苯酚或苯硫酚反应,接着使用本领域的专业人员已知的标准方法还原。它包括在醇溶剂中使用与钯碳催化剂结合的金属氢化物盐如氢化硼钠还原成相应的苯胺或使用金属氯化物盐如氯化锌或氯化锡还原。然后按照Kruse et al.Recl.Trav.Chim.Pays-Bas 1998,107,303的改进方法使用N-丁氧羰基亚氨基二乙酸将所得苯胺变为适当地取代的3,5-环缩二氨酸。然后使用例如甲硼烷将3,5-环缩二氨酸衍生物还原为相应的BOC保护的哌嗪,然后将其就地脱保护成为哌嗪。
其中Y=CH以及非强制的双键被还原的式II所示的化合物,由它们的其中R为BOC基团的叔醇前体VII,通过与Hansen et al.Synthesis1999,1925-1930所述相似的改进的Barton还原,制备。中间体叔醇由相应的适当地取代的1-溴-苯基硫基苯或其相应的醚,通过金属-卤素交换,接着按与Palmer et al.J.Med.Chem.1997,40,1982-1989所述类似方式,加入适当的式IX亲电子试剂,制备。适当取代的1-溴苯基硫基苯按与文献所述类似方式,通过适当地取代的苯硫酚与适当地取代的芳基碘按照Schopfer and Schlapbach Tetrahedron2001,57,3069-3073,Bates et al.,Org.Lett.2002,4,2803-2806以及Kwong et al.Org.Lett.2002,4(in press)所述的方法反应,制备。相应的取代的1-溴-苯氧基苯可以按照Buck etal.Org.Lett.2002,4,1623-1626描述的方法制备。
按照方法a)的由聚合物载体,如基于氨基甲酸酯衔接物的王氏树脂的裂解,按照文献已知的方法进行(Zaragoza TetrahedronLett.1995,36,8677-8678以及Conti et al.TetrahedronLett.1997,38,2915-2918)。
式II原料也可以按照专利申请WO 01/49681描述的方法制备。二胺或者可从市场上买到或者通过本领域化学家已知的方法人工合成。铁配合物,像η6-1,2-二氯苯-η5-环戊二烯铁(II)六氟磷酸盐和取代的类似物按照文献已知的方法(Pearson et al.J.Org.Chem.1996,61,1297-1305)人工合成或者通过本领域化学家已知的方法人工合成。
按照方法b)接着通过与化合物HXZ反应的重氮化,通过在苯硫酚钠盐溶液或者铜含水悬浮剂中的苯酚中加入相应的苯胺的重氮盐进行。氟硝基苯衍生物在包含有机碱如三乙胺的溶剂如DMF,NMP或其他偶极非质子溶剂中与哌嗪衍生物起反应,得到邻硝基苯基哌嗪衍生物。随后使用如上所述的标准方法还原中间体邻硝基苯基哌嗪,得到式III原料。
IV化合物与其中m定义如上的式(Cl-(CH2)m+1)NH(CH2)2Cl或(Br-(CH2)m+1)NH(CH2)2Br烷化剂的氢溴酸盐或盐酸盐的反应按Sircar et al.J.Med.Chem.1992,35,4442-4449所述的类似方法进行。如上所述,式IV原料由式II原料制备。
方法d)中的式V化合物与式VI二胺的反应按Nishiyama etal.Tetrahedron Lett.1998,39,617-620所述类似方法进行。式V原料按Schopfer et al.Tetrahedron 2001,57,3069-3073所述类似方法制备。
方法e)中的式VII化合物的脱水反应和非强制的同时发生的脱保护按Palmer et al J.Med.Chem.1997,40,1982-1989所述类似方法进行。其中R=H的原料通过在甲醇中使用盐酸脱保护由其中R为BOC基团(参见上文)的式VII化合物制备。其中R=BOC的式VII化合物可以按Palmer et al.J.Med.Chem.1997.40,1982-1989所述制备。
方法f)的双键还原通常通过在低压力(<3atm.)的Parr装置中通过催化氢化进行,或通过使用还原剂如乙硼烷或在三氟乙酸中由NaBH4就地产生的氢硼衍生物在惰性溶剂如四氢呋喃(THF),二氧六环,或乙醚中进行。式VIII原料按方法a)所述由II制备。
实施例
分析LC-MS数据由装有lonSpray source和Shimadzu LC LC-8A/SLC-10A LC系统的PE Sciex API 150EX仪器得到。柱:30×4.6mmWaters Symmmetry C18柱;粒度:3.5μm;溶剂系统:A=水/三氟乙酸(100∶0.05)和B=水/乙腈/三氟乙酸(5∶95∶0.03);方法:使用90%A到100%B在4分钟内线性梯度洗脱,流速2毫升/分钟。通过UV(254纳米)和ELSD痕迹测定纯度。保留时间(RT)用分钟表示。制备LC-MS-纯化在相同仪器上进行。柱:50×20毫米YMC ODS-A;粒度5μm;方法:80%A到100%B在7分钟内线性梯度洗脱;流速22.7毫升/分钟。通过split-flow MS检测进行流分收集。
1H NMR光谱在Bruker Avance DRX500仪器的500.13MHz记录,或在Bruker AC 250仪器的250.13MHz记录。氘化二氯甲烷(99.8%D),氯仿(99.8%D)或二甲亚砜(99.8%D)用作溶剂。TMS用作内标。化学位移值用ppm值表示。以下缩写用于许多NMR信号:s=单峰,d=双峰,t=三重峰,q=四重峰,qui=五重峰,h=七重峰,dd=双双重峰,dt=双三重峰,dq=双四重峰,tt=三三重峰,m=多重峰以及b=宽单峰。
离子交换层析使用以下物资:SCX-柱(1g)Varian Mega BondElutChrompack cat.No.220776。在前使用的SCX-柱的前置条件为10%乙酸在甲醇(3毫升)中的溶液。对于光照脱络合作用,使用Philipps紫外灯(300W)。用于固相合成的原料聚合物载体使用Wang-树脂(1.03毫摩尔/克,Rapp-Polymere,Tuebingen,Germany)。
中间体的制备
η6-1,2-二氯苯-η5-环戊二烯基铁(II)六氟磷酸盐将二茂铁(167克),无水三氯化铝(238克)和粉末铝(24克)悬浮在1,2-二氯苯(500毫升)中并且在氮气氛及强烈搅拌下在90℃加热5小时。将该混合物冷却室温,冰浴冷却下少量分批地小心地加入水(1000毫升)。加入庚烷(500毫升)和二乙醚(500毫升),将该混合物在室温下搅拌30分钟。用二乙醚(3×300毫升)萃取该混合物。过滤水相,在搅拌下少量分批地加入六氟磷酸铵(60克,在50毫升水中)。在室温下沉淀产物。3小时后,滤过沉淀,用水强烈地洗涤并且真空(50℃)干燥,得到81克(21%)淡黄色粉末状标题化合物。
1H NMR(D6-DMSO):5.29(s,5H);6.48(m,2H);7.07(m,2H)。
结合胺的聚苯乙烯的制备
4-[(哌嗪-1-基)羰基氧甲基]苯氧基甲基聚苯乙烯
将4-[(4-硝基苯氧基)羰基氧甲基]苯氧基甲基聚苯乙烯(267克,235毫摩尔)悬浮在无水的N,N-二甲基甲酰胺(2L)中。加入N-甲基吗啉(238.0克,2.35摩尔)和哌嗪(102.0克,1.17摩尔)并且将该混合物在室温下搅拌16小时。将该树脂滤过并且用N,N-二甲基甲酰胺(2×1L),四氢呋喃(2×1L),水(1×500毫升),甲醇(2×1L),四氢呋喃(2×1L)和甲醇(1×1L)洗涤。最后,用二氯甲烷(3×500毫升)洗涤该树脂并且真空(25℃,36小时)干燥,得到几乎无色的树脂(240.0克)。
类似地制备下列结合二胺的聚苯乙烯:
4-[(1,4-二氮杂-1-基)羰基氧甲基]苯氧基甲基聚苯乙烯结合η6-芳基-η5-环戊二烯基铁(II)六氟磷酸盐的树脂制备4-({4-[η6-(2-氯苯基)-η5-环戊二烯基铁(II)]哌嗪-1-基}羰基氧甲基)苯氧基甲基聚苯乙烯六氟磷酸盐(1a-1h和1k-11的中间体)
将4-[(哌嗪-1-基)羰基氧甲基]苯氧基甲基聚苯乙烯(115.1克,92毫摩尔)悬浮在无水的四氢呋喃(1.6L)中,加入η6-1,2-二氯苯-η5-环戊二烯基铁(II)六氟磷酸盐(76.0克,184毫摩尔),接着加入碳酸钾(50.9克,368毫摩尔)。将反应混合物在60℃搅拌16小时。冷却到室温后,将该树脂滤过并且用四氢呋喃(2×500毫升),水(2×250毫升),四氢呋喃(2×500毫升),水(2×250毫升),甲醇(2×250毫升),二氯甲烷(2×250毫升)和甲醇(2×250毫升)洗涤。最后,用二氯甲烷(3×500毫升)洗涤该树脂并且真空(25℃,36小时)干燥,得到暗橙色树脂(142克)。
类似地制备下列结合铁-配合物的聚苯乙烯:
4-({4-[η6-(2-氯苯基)-η5-环戊二烯基铁(II)]-[1,4]-二氮杂-1-基}羰基氧甲基)苯氧基甲基聚苯乙烯六氟磷酸盐(1i和1j的中间体)
另外的中间体的制备
1-叔丁氧羰基-4-[2-(甲基苯基硫基)苯基]哌啶-4-醇
将在-78℃氩气氛下BuLi溶液(2.5M,己烷中,12.0毫升,30毫摩尔)慢慢地加入搅拌的1-溴-2-(4-甲基苯基硫基)苯(30毫摩尔)在无水THF(75毫升)中的溶液中。将该溶液搅拌10分钟,一批加入4-氧-哌啶-1-羧酸叔丁酯(5.98克,30毫摩尔)。使该溶液达到室温,然后搅拌3小时。加入NH4Cl(150毫升)饱和溶液,用乙酸乙酯萃取该溶液(150毫升)。将有机相用盐水,无水的(硫酸镁)洗涤并且真空蒸发溶剂。粗品1通过硅胶闪式层析法纯化(洗脱液乙酸乙酯/庚烷20∶80),产生该靶子化合物的白色泡沫LC/MS(m/z)399.3(MH+);RT=3.82;纯度(UV,ELSD):98%,100%;产率:5.02克(42%)。
1-叔丁氧羰基-4-[2-(4-甲基苯基硫基)苯基]-3,5-二氧代哌嗪(2a的)中间体
将2-(4-甲基苯基硫基)苯胺(2.9克,13.5毫摩尔)溶于无水的四氢呋喃(200毫升)并且在氮气氛下放置。加入N-(叔丁氧羰基)亚氨基二乙酸(4.7克,20.2毫摩尔)和羰基二咪唑(4.2克,40.4毫摩尔)并且将反应物回流60小时。将该反应混合物冷却到室温并且加入乙酸乙酯(500毫升)。然后用2N碳酸氢钠(2×200毫升),2NHCl(2×200毫升)和饱和氯化钠溶液(100毫升)洗涤并且真空蒸发溶剂。产率6.0克,107%。
1H NMR(CDCl3)1.5(s,9H);2.32(s,3H);4.4-4.6(m,4H);7.02-7.18(m,3H);7.2-7.45(m,5H)。
以类似的方式制备下列3,5二酮哌嗪衍生物:
1-叔丁氧羰基-4-[2-(4-氯苯基硫基)苯基]-3,5-二氧代哌嗪(2b的中间体)
1-叔丁氧羰基-4-[2-(4-甲氧基苯基硫基)-4-氯苯基]-3,5-二氧代哌嗪(2c的中间体)
1-叔丁氧羰基-4-[2-(4-甲氧基苯基硫基)-4-甲基苯基]-3,5-二氧代哌嗪(2d的中间体)
1-叔丁氧羰基-4-[2-(4-甲氧基苯基硫基)-5-甲基苯基]-3,5-二氧代哌嗪(2e的中间体)
1-叔丁氧羰基-4-[2-(4-氟苯基硫基)-5-甲基苯基]-3,5-二氧代哌嗪(2f的中间体)
1-叔丁氧羰基-4-[2-(4-甲氧基苯基硫基)-5-三氟甲基苯基]-3,5-二氧代哌嗪(2g的中间体)2-(3-甲基哌嗪-1-基)苯胺(3a的中间体)
将氟硝基苯(7.1克,50毫摩尔)溶于包含三乙胺(10克,100毫摩尔)的DMF(100毫升)并且在氮气氛下放置。在该溶液中加入2-甲基哌嗪(5.5克,55毫摩尔)。将反应物在80℃加热16小时。使反应物冷却到室温,然后真空蒸发溶剂为半体积。在该溶液中加入乙酸乙酯(200毫升)和冰-水(250)并且用乙醚(2×200毫升)萃取产物。将水相用氯化钠饱和,用乙酸乙酯(2×200毫升)萃取。合并有机相,用饱和盐水洗涤,用硫酸镁干燥,过滤,真空浓缩滤液。将产物(10.5克)溶于乙醇(250毫升)。加入钯炭催化剂(10%w/w,2.2克),在3巴的Parr装置中将该溶液氢化3小时。过滤并且真空蒸发该溶液,得到苯胺产物。产率(8.0,83%)
以类似的方式制备下列中间体:
2-(3,5-二甲基哌嗪-1-基)苯胺(3b的中间体)
本发明化合物:
实施例1
1a,1-[2-(2-三氟甲基苯基硫基)苯基]哌嗪
在室温下在2-三氟甲基硫代苯酚(1.75克,9.8毫摩尔)在四氢呋喃/二甲基甲酰胺1∶1混合物(30毫升)中的溶液中小心地加入氢化钠(7.4毫摩尔,60%,在矿物油中的)(警告:产生氢)。将该混合物搅拌另外的30分钟后氢产生停止。随后加入4-({4-[η6-(2-氯-苯基)-η5-环戊二烯基铁(II)]哌嗪-1-基}羰基氧甲基)苯氧基甲基聚苯乙烯六氟磷酸盐(3.5克,2.45毫摩尔),将该混合物在55℃搅拌12小时。冷却到室温后,滤过该树脂并且用四氢呋喃(2×50毫升),四氢呋喃/水(1∶1)(2×50毫升),N,N-二甲基甲酰胺(2×50毫升),水(2×50毫升),甲醇(3×50毫升),四氢呋喃(3×50毫升)洗涤,并且随后用甲醇和四氢呋喃(各50毫升,5循环)洗涤。最后,将该树脂用二氯甲烷(3×50毫升)洗涤并且真空干燥(25℃,12小时),得到暗橙色树脂。因此得到的树脂和0.5M 1,10-菲酮在吡啶/水3∶1混合物(20毫升)中的溶液置于光线-透明反应器试管。将该悬浮液在可见光光照下旋转搅拌12小时。过滤树脂并且用甲醇(2×25毫升),水(2×25毫升)和四氢呋喃(3×25毫升)洗涤,直到洗涤液为无色(近5个循环),光照步骤重复直到解络作用完全(近5个循环)。解络作用完成后,将该树脂用二氯甲烷(3×25毫升)洗涤,真空干燥(25℃,12小时),得到浅棕色树脂。将100毫克(77毫摩尔)因此得到的树脂悬浮在三氟乙酸和二氯甲烷1∶1混合物(2毫升)中,在室温下搅拌2小时。滤过树脂并且用甲醇(1×0.5毫升)和二氯甲烷(1×0.5毫升)洗涤。收集滤液并且真空蒸发挥发性溶剂。通过制备LC-MS纯化,随后通过离子交换层析纯化粗产品。LC/MS(m/z)339(MH+);RT=2.39;纯度(UV,ELSD):92%,100%;总产量:1毫克(4%)。
类似地制备下列芳基哌嗪和芳基[1,4]二氮杂:
1b,1-[2-(4-溴苯基硫基)苯基]哌嗪:LC/MS(m/z)350(MN+);RT=2.46;纯度(UV,ELSD):75%,92%;产率:2毫克(7%)。
1c,1-{2-[4-(甲基硫基)苯基硫基]苯基}哌嗪:LC/MS(m/z)317(MN+);RT=2.39;纯度(UV,ELSD):91%,100%;产率:2毫克(8%)。
1d,1-[2-(4-羟基苯基硫基)苯基]哌嗪:LC/MS(m/z)287(MN+);RT=1.83;纯度(UV,ELSD):84%,100%;产率:3毫克(13%)。
1e,1-[2-(2,4-二甲基苯基硫基)苯基]哌嗪:LC/MS(m/z)299(MN+);RT=2.48;纯度(UV,ELSD):95%,100%;产率:4毫克(17%)。
1f,1-[2-(3,5-二甲基苯基硫基)苯基]哌嗪:LC/MS(m/z)299(MN+);RT=2.51;纯度(UV,ELSD):96%,100%;产率:5毫克(21%)。
1g,1-[2-(2,6-二甲基苯基硫基)苯基]哌嗪:LC/MS(m/z)299(MN+);RT=2.42;纯度(UV,ELSD):97%,100%;产率:4毫克(17%)。
1h,1-[2-(2,5-二甲基苯基硫基)苯基]哌嗪:LC/MS(m/z)299(MN+);RT=2.46;纯度(UV,ELSD):97%,100%;产率:1毫克(4%)。
1i,1-[2-(2-三氟甲基苯基硫基)苯基]-[1,4]-二氮杂:LC/MS(m/z)353(MN+);RT=2.46;纯度(UV,ELSD):70%,96%;产率:1毫克(4%)。
1j,1-[2-(3-甲基苯基硫基)苯基]-[1,4]-二氮杂:LC/MS(m/z)299(MN+);RT=2.44;纯度(UV,ELSD):76%,93%;产率:1毫克(4%)。
1k,1-[2-(4-丁基苯氧基)苯基]哌嗪:LC/MS(m/z)311(MN+);RT=2.77;纯度(UV,ELSD):91%,100%;产率:4毫克(17%)。
11,1-[2-(4-甲氧基苯氧基)苯基]哌嗪:LC/MS(m/z)285(MN+);RT=2.08;纯度(UV,ELSD):93%,100%;产率:4毫克(18%)。
实施例2
2a,2-(4-甲基苯基硫基)苯基-1-哌嗪盐酸盐
将1-叔丁氧羰基-4-[2-(4-甲基苯基硫基)苯基]-3,5-二氧代哌嗪(5.5克,13毫摩尔)溶于无水的四氢呋喃(50毫升)并且在氮气氛下放置。加入四氢呋喃中的甲硼烷四氢呋喃配合物(50毫摩尔,1.0M),反应物回流十分钟。通过加入过量乙酸乙酯猝灭过量甲硼烷,反应物回流另外的20分钟。使反应物冷却室温,然后加入溶于甲醇的氯化氢(50毫升,4M)并且将反应物回流4.5小时。使反应物冷却室温,真空浓缩反应物。通过加入醚/甲醇溶液使化合物从树脂残渣结晶。将结晶固体过滤并且用醚/甲醇(1∶1)洗涤,得到白色结晶固体。产率(2.0克,47%)。
1H NMR(D6-DMSO)2.35(s,3H);3.18(brs,8H);6.68(d,2H);7.02(m,1H);7.18(m,1H);7.3-7.5(m,4H);MS(MH+)285。
以类似的方式制备下列化合物:
2b,1-[2-(4-氯苯基硫基)苯基]哌嗪:LC/MS(m/z)305.1(MN+);RT=2.46;纯度(UV,ELSD):71%,91%;产率:0.096克,100%
2c,1-[2-(4-甲氧基苯基硫基)-4-氯苯基]哌嗪:LC/MS(m/z)335.2(MN+);RT=2.38;纯度(UV,ELSD):98%,100%;产率:0.22克,62%
2d,1-[2-(4-甲氧基苯基硫基)-4-甲基苯基]哌嗪:LC/MS(m/z)315.1(MN+);RT=2.33;纯度(UV,ELSD):97%,100%;产率:0.21克,56%
2e,1-[2-(4-甲氧基苯基硫基)-5-甲基苯基]哌嗪:LC/MS(m/z)315.2(MN+);RT=2.38;纯度(UV,ELSD):98%,100%;产率:2.3克,58%
2f,1-[2-(4-氟苯基硫基)-5-甲基苯基]哌嗪:LC/MS(m/z)303.2(MN+);RT=2.46;纯度(UV,ELSD):98%产率:2.1克(62%)。
2g,1-[2-(4-甲氧基苯基硫基)-5-三氟甲基苯基]哌嗪:LC/MS(m/z)(MN+)369RT=2.50(UV,ELSD):96%,100%;产率:0.54克,31%
实施例3
3a,1-[2-(4-氯苯基硫基)苯基]-3-甲基哌嗪
将2-(3-甲基哌嗪-1-基)苯胺(0.96克,5毫摩尔)溶于包含硫酸(0.28毫升,5.2毫摩尔)的30毫升水中并且将该溶液冷却到0℃,加入(0.36克,5.2毫摩尔)。将反应物搅拌30分钟,然后用乙酸钠将反应物的pH值调节为pH 7。在4-氯硫代苯酚铜(0.3克,5毫摩尔)的2MNaOH(4毫升)悬浮液中形成的溶液中滴入重氮盐溶液。将反应混合物在60℃加热30分钟,然后冷却到室温,加入乙酸乙酯(10毫升)。过滤反应混合物并且分层。水层用乙酸乙酯(2×10毫升)萃取。将合并的有机相干燥(硫酸镁)真空蒸发挥发性的溶剂。通过硅胶闪式层析法纯化粗产品,用乙酸乙酯/甲醇/氨96∶3∶1洗脱。分离的纯产物为无色的油状物。产率(0.18克,11%)。
1H NMR(CDCl3,500MHz)1.12(d,3H);2.6-2.72(brm,2H);3.0-3.15(m,5H);6.9(m,2H);7.08(d,1H);7.15(m,1H);7.25-7.35(m,4H);MS(MH+)319.1。
以类似的方式制备下列化合物:
3b,1-[2-(4-氯苯基硫基)苯基]-3,5-二甲基哌嗪:LC/MS(m/z)(MN)+333.1RT=2.29;纯度(UV,ELSD):83%,100%;产率:0.54克,31%
实施例4
4a,4-[2-(4-甲基苯基硫基)苯基]-3,6-二氢-2H-吡啶
将浓盐酸(10毫升)加入搅拌的1-叔丁氧羰基-4-[2-(4-甲基苯基硫基)苯基]哌啶-4-醇(0.84克,2.1毫摩尔)在乙酸(30毫升)中的溶液。将该溶液沸腾回流过夜,冷却到室温,然后在冰浴中搅拌。慢慢地加入NaOH水溶液(9.1M,40毫升),用乙酸乙酯(2×40毫升)萃取不透明的溶液。将合并的有机相干燥(硫酸镁),真空蒸发溶剂。将粗品物质(0.48克)在50℃溶于乙酸乙酯(3.2毫升),慢慢地加入草酸(0.11克)在EtOH(3.2毫升)中的溶液。收集目标化合物的白色草酸盐。
1H(DMSO-d6)δ7.3-7.2(m,7H);7.15(m,1H);7.00(m,1H);5.6(d,1H);3.7(d,2H);3.25(t,2H);2.6(m,2H);2.3(s,3H).LC/MS(m/z)282.2(MH+);RT=2.24;纯度(UV,ELSD):99%,100%;产率:0.31g(40%)。
类似地制备下列衍生物:
4b,4-[2-(4-甲氧基苯基硫基)苯基]-3,6-二氢-2H-哌啶:LC/MS(m/z)298(MN+);RT=2.00;纯度(UV,ELSD):97%,100%;产率:0.28克,(30%)
实施例5
5a,4-[2-(4-甲基苯基硫基)苯基]哌嗪
在0℃氩气氛下,将氯-氧代-乙酸甲酯(1.37克,11.25毫摩尔)加入搅拌的1-叔丁氧羰基-4-[2-(4-甲基苯基硫基)苯基]哌啶-4-醇(3.00克,7.5毫摩尔)和4-(二甲氨基)吡啶(1.65克,13.5毫摩尔)在无水CH3CN(24毫升)和CHCl3(12毫升)的混合物中的溶液。使反应混合物达到室温,然后搅拌2小时。加入乙酸乙酯(140毫升),通过硅藻土过滤除去某些盐。将有机相用饱和碳酸氢钠(140毫升),盐水(140毫升)洗涤并且干燥(硫酸镁)。真空蒸发溶剂,真空干燥粗品物质。在氩气气氛下将该物质溶于无水甲苯(48毫升)。加入Bu3SnH(3.27克,11.25毫摩尔)和AIBN(0.31克,1.88毫摩尔)。在90℃氩气氛下将该溶液搅拌2.5小时。真空蒸发溶剂,通过硅胶闪式层析法纯化粗品物质(洗脱液∶乙酸乙酯在庚烷中的分级梯度为10∶90到20∶80),得到4-[2-(4-甲基苯基硫基)苯基]-哌啶-1-羧酸叔丁基酯的澄清油状物(1.94克,67%)。将该油状物溶于甲醇(9.2毫升)在0℃加入乙醚中的HCl(2.0M)。使反应混合物温热到室温并且搅拌过夜。收集目标化合物的盐酸盐。
M.p 229-231℃.元素分析计算值C18H21NS.HCl:C 67.58;H 6.63;N4.38.实测值:C 67.33;H 6.97;N 4.31.LC/MS(m/z)284(MH+);RT=2.12;纯度(UV,ELSD):96%,100%;产率:0.26g(46%)。
大鼠大脑突触体整体摄取[3H]血清素的抑制
通过测量试验化合物体外抑制大鼠大脑突触体整体摄取[3H]血清素的能力试验它们的抑制5-HT再摄取的作用。该测定按照HyttelPsychopharmacology 1978,60,13描述的进行。
通过荧光计确定的5-HT2c受体效果
通过荧光成像阅读器(FLIPR)分析确定试验化合物的5-HT2C受体表达的的CHO细胞(Euroscreen)上的效果。该测定按照MolecularDevices Inc.关于它们的FLIPR钙测定试剂盒的说明书以及Porteret al.British Journal of Pharmacology 1999,128,13的改进进行。
在以上测定中,优选的本发明化合物显示低于200nM(IC50)血清素再摄取抑制浓度。更优选的化合物显示低于100nM的抑制浓度,最优选的化合物显示低于50nM的抑制浓度,特别令人感兴趣的化合物显示低于10nM的血清素再摄取抑制浓度。
Claims (15)
1.一种通式I表示的化合物或其药学上可接受的酸加成盐
其中
Y为N,C或CH;
X表示O或S;
m为1或2;
p为0,1,2,3,4,5,6,7或8;
q为0,1,2,3或4;
s为0,1,2,3,4或5;
虚线表示可以存在的键;
各R1独立地选自C1-6-烷基,或两个R1连接于同一个碳原子形成3-6-元螺旋连接的环烷基;
各R2独立地选自卤素,氰基,硝基,C1-6烷基(烯基/炔基),C1-6烷基(烯基/炔基)氧基,C1-6烷基(烯基/炔基)硫基(sulfanyl),羟基,羟基-C1-6-烷基(烯基/炔基),卤素-C1-6-烷基(烯基/炔基),卤素-C1-6-烷基(烯基/炔基)氧基,C3-8-环烷(烯)基,C3-8-环(烯)烷基-C1-6-烷基(烯基/炔基),酰基,C1-6-烷基(烯基/炔基)氧羰基,C1-6-烷基(烯基/炔基)基磺酰基,或-NRxRy;-NRxCO-C1-6-烷基(烯基/炔基);
各R3独立地选自卤素,氰基,硝基,C1-6烷基(烯基/炔基)基,C1-6烷基(烯基/炔基)氧基,C1-6烷基(烯基/炔基)硫基(sulfanyl),羟基,羟基-C1-6-烷基(烯基/炔基)基,卤素-C1-6-烷基(烯基/炔基)基,卤素-C1-6-烷基(烯基/炔基)氧基,C3-8-环烷(烯)基,C3-8-环(烯)基-C1-6-烷基(烯基/炔基)基,C1-6-烷基(烯基/炔基)磺酰基,芳基,C1-6-烷基(烯基/炔基)氧羰基,酰基,-NRxCO-C1-6-烷基(烯基/炔基)基,CONRxRy或NRxRy;
或两个相邻的R3取代基一起形成与苯基稠合的选自如下的杂环
其中W为O或S,以及R′和R″为氢或C1-6-烷基;
或两个相邻的R3取代基一起形成含一个,两个或三个杂原子的稠合杂芳基系统,
其中各Rx和Ry独立地选自氢,C1-6-烷基(烯基/炔基),C3-8-环烷(烯)基,C3-8-环烷(烯)基-C1-6-烷基(烯基/炔基)基,或芳基;或Rx和Ry与连接它们的氮一起形成非强制性地含一个另外的杂原子的3-7元环。
2.按照权利要求1的化合物,条件是该化合物不是1-(2-苯氧基苯基)哌嗪
3.按照权利要求1的化合物,条件是该化合物不是1-[2-(2-甲氧基苯氧基)苯基]哌嗪,1-[2-(2,6-二甲氧基苯氧基)苯基]-[1,4]-二氮杂,1-{2-[3-(二甲氨基)苯氧基]苯基)哌嗪,1-[2-(4-甲基苯氧基)苯基]哌嗪,1-[2-(3-甲基苯氧基)苯基]哌嗪,1-[2-(3-氯苯氧基)苯基]哌嗪,1-[2-(3-甲氧基苯氧基)苯基]哌嗪和1-(2-苯氧基苯基)-哌嗪。
4.按照权利要求1-3中任何一项的化合物,其中p为0,1或2。
5.按照权利要求1-4中任何一项的化合物,其中R1为C1-6-烷基。
6.按照权利要求1-5中任何一项的化合物,其中m为1或2。
7.按照权利要求1-6中任何一项的化合物,其中q为0,1或2。
8.按照权利要求1-7中任何一项的化合物,其中R2为三氟甲基,或C1-6-烷基。
9.按照权利要求1-8中任何一项的化合物,其中s为1或2。
10.按照权利要求1-9中任何一项的化合物,其中R3选自卤素,C1-6-烷氧基,C1-6-硫基(sulfanyl),C1-6-烷基,羟基或三氟甲基。
11.按照上述任何权利要求的,该化合物为
1-[2-(2-三氟甲基苯基硫基)苯基]哌嗪,
1-[2-(4-溴苯基硫基)苯基]哌嗪,
1-{2-[4-(甲基硫基)苯基硫基]苯基}哌嗪,
1-[2-(4-羟基苯基硫基)苯基]哌嗪,
1-[2-(2,4-二甲基苯基硫基)苯基]哌嗪,
1-[2-(3,5-二甲基苯基硫基)苯基]哌嗪,
1-[2-(2,6-二甲基苯基硫基)苯基]哌嗪,
1-[2-(2,5-二甲基苯基硫基)苯基]哌嗪,
1-[2-(2-三氟甲基苯基硫基)苯基][1,4]二氮杂,
1-[2-(3-甲基苯基硫基)苯基]-[1,4]-二氮杂,
1-[2-(4-丁基苯氧基)苯基]哌嗪,
1-[2-(4-甲氧基苯氧基)苯基]哌嗪,
2-(4-甲基苯基硫基)苯基-1-哌嗪,
1-[2-(4-氯苯基硫基)苯基]-哌嗪,
1-[2-(4-甲氧基苯基硫基)-4-氯苯基]哌嗪,
1-[2-(4-甲氧基苯基硫基)-4-甲基苯基]哌嗪,
1-[2-(4-甲氧基苯基硫基)-5-甲基苯基]哌嗪,
1-[2-(4-氟苯基硫基)-5-甲基苯基]哌嗪,
1-[2-(4-甲氧基苯基硫基)-5-三氟甲基苯基]哌嗪,
1-[2-(4-氯苯基硫基)苯基]-3-甲基哌嗪,
1-[2-(4-氯苯基硫基)苯基]-3,5-二甲基哌嗪,
4-[2-(4-甲基苯基硫基)苯基]-3,6-二氢-2H-吡啶,
4-[2-(4-甲氧基苯基硫基)苯基]-3,6-二氢-2H-吡啶或
4-[2-(4-甲基苯基硫基)苯基]哌嗪
或其药学上可接受的酸加成盐。
12.一种药物组合物,其中包含按照权利要求1-11的化合物或其药学上可接受的酸加成盐和至少一种药学上可接受的载体或稀释剂。
13.按照权利要求1到11的化合物或其药学上可接受的酸加成盐用于制备治疗情感障碍,如抑郁症,包括一般的焦虑疾病和恐慌疾病的焦虑疾病以及强迫性的强制的疾病的药物中的用途。
14.一种用于治疗活的动物体,包括人类的情感障碍,包括抑郁症,包括一般的焦虑疾病和恐慌疾病的焦虑疾病以及强迫性的强制的疾病的方法,其中包括使用治疗有效量的权利要求1-11化合物或其药学上可接受的酸加成盐。
15.用作药物的按照权利要求1-11的化合物。
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- 2014-05-13 NO NO2014011C patent/NO2014011I2/no not_active IP Right Cessation
- 2014-06-03 BE BE2014C036C patent/BE2014C036I2/nl unknown
- 2014-06-11 CY CY2014022C patent/CY2014022I2/el unknown
-
2015
- 2015-06-19 US US14/744,197 patent/US9708280B2/en not_active Expired - Lifetime
-
2017
- 2017-06-15 US US15/624,417 patent/US10844029B2/en not_active Expired - Lifetime
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2020
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