CN100383118C - 4-吡咯烷基-苯基-苄基醚衍生物 - Google Patents
4-吡咯烷基-苯基-苄基醚衍生物 Download PDFInfo
- Publication number
- CN100383118C CN100383118C CNB038219522A CN03821952A CN100383118C CN 100383118 C CN100383118 C CN 100383118C CN B038219522 A CNB038219522 A CN B038219522A CN 03821952 A CN03821952 A CN 03821952A CN 100383118 C CN100383118 C CN 100383118C
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- Prior art keywords
- phenyl
- benzyloxy
- oxo
- compound
- pyrrolidin
- 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.)
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- YOVMEQZKFWKEAI-UHFFFAOYSA-N 1-[4-[phenyl-[phenyl-(4-pyrrolidin-1-ylphenyl)methoxy]methyl]phenyl]pyrrolidine Chemical class C1CCCN1C1=CC=C(C(OC(C=2C=CC=CC=2)C=2C=CC(=CC=2)N2CCCC2)C=2C=CC=CC=2)C=C1 YOVMEQZKFWKEAI-UHFFFAOYSA-N 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 42
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- 229940052764 dopaminergic anti-parkinson drug mao b inhibitors Drugs 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 206010039966 Senile dementia Diseases 0.000 claims abstract description 4
- 230000001404 mediated effect Effects 0.000 claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims description 146
- 239000001257 hydrogen Substances 0.000 claims description 86
- 229910052739 hydrogen Inorganic materials 0.000 claims description 86
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 67
- 125000000217 alkyl group Chemical group 0.000 claims description 52
- -1 cyano, methoxy Chemical group 0.000 claims description 48
- 229910052736 halogen Inorganic materials 0.000 claims description 44
- 150000002367 halogens Chemical class 0.000 claims description 44
- 239000000203 mixture Substances 0.000 claims description 26
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
- 150000002431 hydrogen Chemical class 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 8
- 125000004970 halomethyl group Chemical group 0.000 claims description 7
- 239000012948 isocyanate Substances 0.000 claims description 7
- 150000002513 isocyanates Chemical class 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- UPUSESFNQZBPBZ-SFHVURJKSA-N n-[(3s)-2-oxo-1-(4-phenylmethoxyphenyl)pyrrolidin-3-yl]acetamide Chemical compound O=C1[C@@H](NC(=O)C)CCN1C(C=C1)=CC=C1OCC1=CC=CC=C1 UPUSESFNQZBPBZ-SFHVURJKSA-N 0.000 claims description 6
- CCJJUKMALAHICQ-UHFFFAOYSA-N 1-[4-[(3-fluorophenyl)methoxy]phenyl]-2-oxopyrrolidine-3-carboxamide Chemical compound O=C1C(C(=O)N)CCN1C(C=C1)=CC=C1OCC1=CC=CC(F)=C1 CCJJUKMALAHICQ-UHFFFAOYSA-N 0.000 claims description 5
- YYEXJVYKAMOYFG-UHFFFAOYSA-N 1-[4-[(3-fluorophenyl)methoxy]phenyl]-n-methyl-2-oxopyrrolidine-3-carboxamide Chemical compound O=C1C(C(=O)NC)CCN1C(C=C1)=CC=C1OCC1=CC=CC(F)=C1 YYEXJVYKAMOYFG-UHFFFAOYSA-N 0.000 claims description 5
- WADDKWIFTUCNLB-UHFFFAOYSA-N 1-[4-[(4-fluorophenyl)methoxy]phenyl]-2-oxopyrrolidine-3-carboxamide Chemical compound O=C1C(C(=O)N)CCN1C(C=C1)=CC=C1OCC1=CC=C(F)C=C1 WADDKWIFTUCNLB-UHFFFAOYSA-N 0.000 claims description 5
- ZPMTTZWHOJFZBS-UHFFFAOYSA-N 2-oxo-1-(4-phenylmethoxyphenyl)pyrrolidine-3-carbonitrile Chemical compound O=C1C(C#N)CCN1C(C=C1)=CC=C1OCC1=CC=CC=C1 ZPMTTZWHOJFZBS-UHFFFAOYSA-N 0.000 claims description 5
- HJFYUEPCZTUGRH-UHFFFAOYSA-N 2-oxo-1-[4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]pyrrolidine-3-carboxamide Chemical compound O=C1C(C(=O)N)CCN1C(C=C1)=CC=C1OCC1=CC=C(C(F)(F)F)C=C1 HJFYUEPCZTUGRH-UHFFFAOYSA-N 0.000 claims description 5
- OMEOUZIWEJNYTJ-KRWDZBQOSA-N n-[(3s)-2-oxo-1-(4-phenylmethoxyphenyl)pyrrolidin-3-yl]methanesulfonamide Chemical compound O=C1[C@@H](NS(=O)(=O)C)CCN1C(C=C1)=CC=C1OCC1=CC=CC=C1 OMEOUZIWEJNYTJ-KRWDZBQOSA-N 0.000 claims description 5
- DCKACKFSDYIGOR-UHFFFAOYSA-N 1-[4-[(4-fluorophenyl)methoxy]phenyl]-n-methyl-2-oxopyrrolidine-3-carboxamide Chemical compound O=C1C(C(=O)NC)CCN1C(C=C1)=CC=C1OCC1=CC=C(F)C=C1 DCKACKFSDYIGOR-UHFFFAOYSA-N 0.000 claims description 4
- ZHVAXEADTFDVRM-MRXNPFEDSA-N [(3r)-1-[4-[(3-fluorophenyl)methoxy]phenyl]-2-oxopyrrolidin-3-yl]urea Chemical compound O=C1[C@H](NC(=O)N)CCN1C(C=C1)=CC=C1OCC1=CC=CC(F)=C1 ZHVAXEADTFDVRM-MRXNPFEDSA-N 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- ZBAGLGKCDJXWMV-KRWDZBQOSA-N methyl n-[(3s)-1-[4-[(3-fluorophenyl)methoxy]phenyl]-2-oxopyrrolidin-3-yl]carbamate Chemical compound O=C1[C@@H](NC(=O)OC)CCN1C(C=C1)=CC=C1OCC1=CC=CC(F)=C1 ZBAGLGKCDJXWMV-KRWDZBQOSA-N 0.000 claims description 4
- STAHZHVJUPHDIP-GOSISDBHSA-N n-[(3r)-1-[4-[(3-fluorophenyl)methoxy]phenyl]-2-oxopyrrolidin-3-yl]acetamide Chemical compound O=C1[C@H](NC(=O)C)CCN1C(C=C1)=CC=C1OCC1=CC=CC(F)=C1 STAHZHVJUPHDIP-GOSISDBHSA-N 0.000 claims description 4
- PNYAWZSBCXQLPV-SFHVURJKSA-N n-[(3s)-1-[4-[(3,4-difluorophenyl)methoxy]phenyl]-2-oxopyrrolidin-3-yl]acetamide Chemical compound O=C1[C@@H](NC(=O)C)CCN1C(C=C1)=CC=C1OCC1=CC=C(F)C(F)=C1 PNYAWZSBCXQLPV-SFHVURJKSA-N 0.000 claims description 4
- STAHZHVJUPHDIP-SFHVURJKSA-N n-[(3s)-1-[4-[(3-fluorophenyl)methoxy]phenyl]-2-oxopyrrolidin-3-yl]acetamide Chemical compound O=C1[C@@H](NC(=O)C)CCN1C(C=C1)=CC=C1OCC1=CC=CC(F)=C1 STAHZHVJUPHDIP-SFHVURJKSA-N 0.000 claims description 4
- OJVZJPDLSQVWNL-UHFFFAOYSA-N n-methyl-2-oxo-1-[4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]pyrrolidine-3-carboxamide Chemical compound O=C1C(C(=O)NC)CCN1C(C=C1)=CC=C1OCC1=CC=C(C(F)(F)F)C=C1 OJVZJPDLSQVWNL-UHFFFAOYSA-N 0.000 claims description 4
- ZHVAXEADTFDVRM-INIZCTEOSA-N [(3s)-1-[4-[(3-fluorophenyl)methoxy]phenyl]-2-oxopyrrolidin-3-yl]urea Chemical compound O=C1[C@@H](NC(=O)N)CCN1C(C=C1)=CC=C1OCC1=CC=CC(F)=C1 ZHVAXEADTFDVRM-INIZCTEOSA-N 0.000 claims description 3
- 230000003213 activating effect Effects 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 150000008064 anhydrides Chemical class 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 230000006806 disease prevention Effects 0.000 claims description 3
- HDWWMMAGJHYCBH-QGZVFWFLSA-N n-[(3r)-1-[4-[(3-fluorophenyl)methoxy]phenyl]-2-oxopyrrolidin-3-yl]formamide Chemical compound FC1=CC=CC(COC=2C=CC(=CC=2)N2C([C@H](NC=O)CC2)=O)=C1 HDWWMMAGJHYCBH-QGZVFWFLSA-N 0.000 claims description 3
- BWQHYVTXCVOHTJ-QGZVFWFLSA-N n-[(3r)-1-[4-[(3-fluorophenyl)methoxy]phenyl]-2-oxopyrrolidin-3-yl]methanesulfonamide Chemical compound O=C1[C@H](NS(=O)(=O)C)CCN1C(C=C1)=CC=C1OCC1=CC=CC(F)=C1 BWQHYVTXCVOHTJ-QGZVFWFLSA-N 0.000 claims description 3
- HDWWMMAGJHYCBH-KRWDZBQOSA-N n-[(3s)-1-[4-[(3-fluorophenyl)methoxy]phenyl]-2-oxopyrrolidin-3-yl]formamide Chemical compound FC1=CC=CC(COC=2C=CC(=CC=2)N2C([C@@H](NC=O)CC2)=O)=C1 HDWWMMAGJHYCBH-KRWDZBQOSA-N 0.000 claims description 3
- BWQHYVTXCVOHTJ-KRWDZBQOSA-N n-[(3s)-1-[4-[(3-fluorophenyl)methoxy]phenyl]-2-oxopyrrolidin-3-yl]methanesulfonamide Chemical compound O=C1[C@@H](NS(=O)(=O)C)CCN1C(C=C1)=CC=C1OCC1=CC=CC(F)=C1 BWQHYVTXCVOHTJ-KRWDZBQOSA-N 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 6
- 230000002265 prevention Effects 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- 239000007787 solid Substances 0.000 description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 28
- 102000010909 Monoamine Oxidase Human genes 0.000 description 27
- 108010062431 Monoamine oxidase Proteins 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 239000000543 intermediate Substances 0.000 description 14
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
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- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
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- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
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- DZGWFCGJZKJUFP-UHFFFAOYSA-N tyramine Chemical compound NCCC1=CC=C(O)C=C1 DZGWFCGJZKJUFP-UHFFFAOYSA-N 0.000 description 6
- 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
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- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 5
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- 235000019359 magnesium stearate Nutrition 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
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- RASPWLYDBYZRCR-UHFFFAOYSA-N pyrrolidin-1-ium-2-one;chloride Chemical compound Cl.O=C1CCCN1 RASPWLYDBYZRCR-UHFFFAOYSA-N 0.000 description 4
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- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
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- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
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Abstract
本发明涉及外消旋或对映异构纯的式(I)的4-吡咯烷基衍生物、其制备方法、含有所述衍生物的药用组合物以及它们在预防和治疗疾病如由单胺氧化酶B抑制剂介导的疾病、特别是阿尔茨海默氏病或老年性痴呆中的用途。
Description
本发明涉及外消旋或对映异构纯的4-吡咯烷基衍生物、其制备方法、含有所述衍生物的药用组合物以及它们在预防和治疗疾病中的用途。
更具体地讲,本发明涉及式I化合物、其单一异构体、外消旋或非外消旋混合物:
其中:
X-Y为-CH2-CH2-、-CH=CH-或-CH2-O-;
R1、R1.1和R1.2彼此独立地选自氢、卤素、氰基、(C1-C6)-烷基、卤代-(C1-C6)-烷基、(C1-C6)-烷氧基和卤代-(C1-C6)-烷氧基;
R21、R22和R23彼此独立地选自氢和卤素;
R24为氢、卤素或甲基;
R3为氢;
R4为-CONHR5、-CN或-NHR6;
R5为氢或(C1-C3)-烷基;和
R6为-C(O)H、-C(O)-(C1-C6)-烷基、-C(O)-卤代-(C1-C3)烷基、-C(O)O(C1-C3)-烷基、-C(O)-NH2或-SO2-(C1-C6)-烷基。
甚至更具体地讲,本发明涉及式I*化合物、其单一异构体、外消旋或非外消旋混合物:
其中:
R1为卤素、卤代-(C1-C6)-烷基、氰基、(C1-C6)-烷氧基或卤代-(C1-C6)-烷氧基;
R21、R22、R23和R24彼此独立地选自氢和卤素;
R3为氢;
R4为-CONHR5、-CH2CN、-CN或-NHR6;
R5为氢或C1-C3-烷基;
R6为-CO-(C1-C6)-烷基或-SO2-(C1-C6)-烷基;和
n为0、1、2或3。
本发明还涉及药用组合物,该药用组合物含有本发明的化合物和药学上可接受的赋形剂。
申请人发现通式I和I*化合物及其单一异构体、外消旋或非外消旋混合物(下文称为活性化合物)是选择性单胺氧化酶B抑制剂。
单胺氧化酶(MAO,EC 1.4.3.4)是引起内源性单胺类神经递质如多巴胺、5-羟色胺、肾上腺素或去甲肾上腺素和痕量的胺如苯乙胺以及大量胺外源物的氧化脱氨作用的黄素酶。该酶以两种形式存在:MAO-A和MAO-B,这两种形式被不同的基因编码[BacH等人,Proc.Natl.Acad.Sci.USA 85:4934-4938(1988)],并且在组织分布、结构和底物专一性上有所不同。MAO-A对5-羟色胺、章鱼胺、肾上腺素和去甲肾上腺素的亲合力较高;而MAO-B的天然底物为苯乙胺和酪胺。多巴胺被认为可被这两种同种型所氧化。MAO-B广泛分布于包括脑在内的各种器官中[Cesura和Pletscher,Prog.Drug Research 38:171-297(1992)]。脑MAO-B的活性随年龄的增长而增加。已经将这种增加归因于与衰老相关的神经胶质增生[Fowler等人,J.Neural.Transm.49:1-20(1980)]。另外,MAO-B活性在阿尔茨海默氏病患者的脑中显著升高[Dostert等人,Biochem.Pharmacol.38:555-561(1989)],并且已经发现MAO-B活性在老年斑周围的星形胶质细胞中高度表达[Saura等人,Neuroscience 70:755-774(1994)]。在本文中,由于MAO对伯单胺的氧化脱氨作用产生了具有已确定或潜在毒性的物质NH3、醛和H2O2,因而提出了将选择性MAO-B抑制剂用于治疗痴呆和帕金森氏病的理论。抑制MAO-B可引起多巴胺的酶失活减少,并因此可延长神经递质在多巴胺能神经元中的有效性。与年龄相关的退化过程和阿尔茨海默氏病以及帕金森氏病还可以归因于氧化应激,所述的氧化应激由于MAO活性增加以及继而出现的由MAO-B形成的H2O2减少而引起。因此,MAO-B抑制剂可通过减少氧自由基的形成和增加单胺在脑中的水平而起作用。
鉴于MAO-B在上文提及的神经障碍中有所涉及,因此人们需要获得一种能够控制这种酶活性的有效和选择性的抑制剂。一些已知的MAO-B抑制剂的药理学例如由Bentué-Ferrer等人进行了讨论[CNS Drugs6:217-236(1996)]。然而,由于当饮食摄入酪胺时有诱发高血压危象的危险以及可能与其它药物疗法相互作用,该不可逆和非选择性MAO抑制剂活性的主要缺陷是需要遵守饮食预防措施[Gardner等人,J.Clin.Psychiatry57:99-104(1996)],这些不利因素与可逆性和选择性的MAO抑制剂、特别是MAO-B抑制剂的关联较少。因此,需要有一种具有高度选择性且没有有害的副作用的MAO-B抑制剂,所述的有害副作用是具有低酶选择性的不可逆性MAO抑制剂的特征。
不论所讨论的术语单独出现还是组合出现,此处使用的通用术语的下列定义均适用。必须指出的是,除非本文明确指出,说明书和所附的权利要求中所用的单数形式包括复数形式。
本申请中所使用的术语“(C1-C6)-烷基”意指含1-6个碳原子的直链或支链饱和烃基团,例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基和叔丁基等,优选含1-3个碳原子。因此,术语“(C1-C3)-烷基”意指含1-3个碳原子的直链或支链饱和烃基团。
术语“卤素”意指氟、氯、溴和碘。
“卤代-(C1-C6)-烷基”或“卤代-(C1-C6)-烷氧基”分别意指在其任意位置被一个或多个如此处所定义的卤素取代的低级烷基或低级烷氧基,所述的低级烷基或低级烷氧基如此处所定义。卤代烷基的实例包括但不局限于1,2-二氟丙基、1,2-二氯丙基、三氟甲基、2,2,2-三氟乙基、2,2,2-三氯乙基和3,3,3-三氟丙基等。“卤代烷氧基”包括三氟甲氧基。
“(C1-C6)-烷氧基”意指-O-R基团,其中R为如此处所定义的低级烷基。烷氧基的实例包括但不局限于甲氧基、乙氧基和异丙氧基等。
化合物的“药学上可接受的盐”意指通常是安全、无毒且既不是生物学也不是其它方面所不希望的在药学上可接受的盐,并且该盐具有所希望的母体化合物的药理学活性。这些盐衍生自无机或有机酸或碱。如果可能,可将式I化合物转化为药学上可接受的盐。应当理解的是,药学上可接受的盐也包括在本发明的范围内。
在另一实施方案中,本发明提供了如下定义的式I*化合物:其中R3为氢且R4选自-CONHR5、-CH2CN和-CN。
特别优选的是如下定义的式I*化合物:其中R4为-CONHR5且R5为氢或(C1-C3)-烷基。这类化合物的实例如下:
(RS)-1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酸甲基酰胺;
(RS)-1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酰胺;
(RS)-1-[4-(4-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酰胺;
(RS)-1-[4-(4-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酸甲基酰胺;
(RS)-2-氧代-1-[4-(4-三氟甲基-苄氧基)-苯基]-吡咯烷-3-甲酰胺;和
(RS)-2-氧代-1-[4-(4-三氟甲基-苄氧基)-苯基]-吡咯烷-3-甲酸甲基酰胺。
另一组优选的式I*化合物为其中R4为-CN的化合物。此类化合物的一个实例为(RS)-1-(4-苄氧基-苯基)-2-氧代-吡咯烷-3-甲腈。
还优选如下定义的式I*化合物:其中R3为氢,R4为-NHR6且R6为-CO-(C1-C6)-烷基或-SO2-(C1-C6)-烷基。这类化合物的实例为(S)-N-[1-(4-苄氧基-苯基)-2-氧代-吡咯烷-3-基]-乙酰胺和(S)-N-[1-(4-苄氧基-苯基)-2-氧代-吡咯烷-3-基]-甲磺酰胺。
式I*化合物可以被n个选自卤素、卤代-(C1-C6)-烷基、氰基、(C1-C6)-烷氧基和卤代-(C1-C6)-烷氧基的R1取代,其中n意指选自0、1、2和3的整数。优选n为1或2。优选的式I*化合物为其中R1是卤素或卤代-(C1-C6)-烷基的化合物。尤其优选的是其中R1为氟、氯或三氟甲基的式I*化合物。当式I*化合物被二个或三个R1取代时,每个R1可以相同或不同。
在一个实施方案中,本发明提供了其中-X-Y-为-CH2-O-的式I化合物。在另一实施方案中,本发明提供了其中-X-Y-为-CH2-CH2-或-CH=CH-的式I化合物。
在一个实施方案中,本发明提供了如下定义的式I化合物:其中R1、R1.1和R1.2彼此独立地选自氢、卤素、甲基、卤代甲基、氰基、甲氧基和卤代-甲氧基。在另一实施方案中,本发明提供了如下定义的式I化合物:其中R1、R1.1和R1.2为卤素如氟,例如2,4,6-三氟、2,4,5-三氟、2,3,6-三氟、2,3,4-三氟或3,4,5-三氟。在另一实施方案中,本发明还提供了如下定义的式I化合物:其中R1.2为氢,R1和R1.1彼此独立地选自氢、卤素、(C1-C6)-烷基、卤代-(C1-C6)-烷基、氰基、(C1-C6)-烷氧基和卤代-(C1-C6)-烷氧基。在另一实施方案中,本发明还提供了如下定义的式I化合物:其中R1.2为氢,R1和R1.1彼此独立地选自卤素和(C1-C6)-烷基。在另一实施方案中,本发明还提供了如下定义的式I化合物:其中R1.2为氢,R1.1为卤素以及R1为卤素或(C1-C6)-烷基。在另一实施方案中,本发明还提供了如下定义的式I化合物:其中R1.1和R1.2为氢,R1为卤素、(C1-C6)-烷基、卤代-(C1-C6)-烷基、氰基、(C1-C6)-烷氧基或卤代-(C1-C6)-烷氧基。在另一实施方案中,本发明还提供了如下定义的式I化合物:其中R1.1和R1.2为氢,R1为卤素、甲基、卤代甲基、氰基、甲氧基或卤代-甲氧基。在另一实施方案中,本发明还提供了如下定义的式I化合物:其中R1.1和R1.2为氢,R1为氟(如3-氟或4-氟)、氯(如3-氯)、卤代甲基(如3-三氟甲基或4-三氟甲基)、氰基、甲氧基(如2-甲氧基、3-甲氧基或4-甲氧基)或者卤代-甲氧基(如3-三氟甲氧基)。在另一实施方案中,本发明提供了其中R1、R1.1和R1.2为氢的式I化合物。
在一个实施方案中,本发明提供了式I化合物,其中R21、R22和R23为氢。
在一个实施方案中,本发明还提供了式I化合物,其中R24为氢。
在一个实施方案中,本发明还提供了式I化合物,其中R4为-CONHR5,其中R5为氢或(C1-C3)-烷基。在另一实施方案中,本发明提供了式I化合物,其中R4为-CONHR5,其中R5为氢或甲基。
在一个实施方案中,本发明提供了其中R4为-CN的式I化合物。
在一个实施方案中,本发明提供了式I化合物,其中R4为-NHR6,其中R6为-CO-H、-CO-(C1-C6)-烷基、-CO-卤代-(C1-C3)-烷基、-CO-O-(C1-C3)-烷基、-CO-NH2或-SO2-(C1-C6)-烷基。在另一实施方案中,本发明提供了式I化合物,其中R4为-NHR6,其中R6为-CO-H、-CO-(C1-C6)-烷基、-CO-O-(C1-C3)-烷基、-CO-NH2或-SO2-(C1-C6)-烷基。在另一实施方案中,本发明还提供了式I化合物,其中R4为-NHR6,其中R6为-CO-H、-CO-甲基、-CO-O-甲基、-CO-NH2或-SO2-甲基。
在一方面,本发明提供了具有(S)-构型的式I化合物。在一方面,本发明提供了具有(R)-构型的式I化合物。
在一个实施方案中,本发明提供了如下定义的式I化合物:其中X-Y为-CH2-O-;R1、R1.1和R1.2彼此独立地选自氢、卤素、甲基、卤代甲基、氰基、甲氧基和卤代-甲氧基;R21、R22和R23为氢;R24为氢且R4为-CONHR5,其中R5为氢或(C1-C3)-烷基。
在一个实施方案中,本发明提供了如下定义的式I化合物:其中X-Y为-CH2-O-;R1、R1.1和R1.2彼此独立地选自氢、卤素、甲基、卤代甲基、氰基、甲氧基和卤代-甲氧基;R21、R22和R23为氢;R24为氢且R4为-CN。
在一个实施方案中,本发明提供了如下定义的式I化合物:其中X-Y为-CH2-O-;R1、R1.1和R1.2彼此独立地选自氢、卤素、甲基、卤代甲基、氰基、甲氧基和卤代-甲氧基;R21、R22和R23为氢;R24为氢且R4为-NHR6,其中R6为-CO-H、-CO-(C1-C6)-烷基、-CO-卤代-(C1-C3)-烷基、-CO-O-(C1-C3)-烷基、-CO-NH2或-SO2-(C1-C6)-烷基。
在一个实施方案中,本发明提供了如下定义的式I化合物:其中X-Y为-CH2-O-;R1.2为氢且R1和R1.1彼此独立地选自氢、卤素、(C1-C6)-烷基、卤代-(C1-C6)-烷基、氰基、(C1-C6)-烷氧基和卤代-(C1-C6)-烷氧基;R21、R22和R23为氢;R24为氢;且R4为-CONHR5,其中R5为氢或(C1-C3)-烷基。
在一个实施方案中,本发明提供了如下定义的式I化合物:其中X-Y为-CH2-O-;R1.1和R1.2为氢且R1为卤素、(C1-C6)-烷基、卤代-(C1-C6)-烷基、氰基、(C1-C6)-烷氧基或卤代-(C1-C6)-烷氧基;R21、R22和R23为氢;R24为氢;且R4为-CONHR5,其中R5为氢或(C1-C3)-烷基。
在一个实施方案中,本发明提供了如下定义的式I化合物:其中X-Y为-CH2-O-;R1、R1.1和R1.2为氢;R21、R22和R23为氢;R24为氢;且R4为-CONHR5,其中R5为氢或(C1-C3)-烷基。
在一个实施方案中,本发明提供了如下定义的式I化合物:其中X-Y为-CH2-O-;R1.2为氢且R1和R1.1彼此独立地选自氢、卤素、(C1-C6)-烷基、卤代-(C1-C6)-烷基、氰基、(C1-C6)-烷氧基和卤代-(C1-C6)-烷氧基;R21、R22和R23为氢;R24为氢;且R4为-CN。
在一个实施方案中,本发明提供了如下定义的式I化合物:其中X-Y为-CH2-O-;R1.1和R1.2为氢且R1为卤素、(C1-C6)-烷基、卤代-(C1-C6)-烷基、氰基、(C1-C6)-烷氧基或卤代-(C1-C6)-烷氧基;R21、R22和R23为氢;R24为氢;且R4为-CN。
在一个实施方案中,本发明提供了如下定义的式I化合物:其中X-Y为-CH2-O-;R1、R1.1和R1.2为氢;R21、R22和R23为氢;R24为氢;且R4为-CN。
在一个实施方案中,本发明提供了如下定义的式I化合物:其中X-Y为-CH2-O-;R1.2为氢且R1和R1.1彼此独立地选自氢、卤素、(C1-C6)-烷基、卤代-(C1-C6)-烷基、氰基、(C1-C6)-烷氧基和卤代-(C1-C6)-烷氧基;R21、R22和R23为氢;R24为氢;且R4为-NHR6,其中R6为-CO-H、-CO-(C1-C6)-烷基、-CO-卤代-(C1-C3)-烷基、-CO-O-(C1-C3)-烷基、-CO-NH2或-SO2-(C1-C6)-烷基。
在一个实施方案中,本发明提供了如下定义的式I化合物:其中X-Y为-CH2-O-;R1.1和R1.2为氢且R1为卤素、(C1-C6)-烷基、卤代-(C1-C6)-烷基、氰基、(C1-C6)-烷氧基或卤代-(C1-C6)-烷氧基;R21、R22和R23为氢;R24为氢;且R4为-NHR6,其中R6为-CO-H、-CO-(C1-C6)-烷基、-CO-卤代-(C1-C3)-烷基、-CO-O-(C1-C3)-烷基、-CO-NH2或-SO2-(C1-C6)-烷基。
在一个实施方案中,本发明提供了如下定义的式I化合物:其中X-Y为-CH2-O-;R1、R1.1和R1.2为氢;R21、R22和R23为氢;R24为氢;且R4为-NHR6,其中R6为-CO-H、-CO-(C1-C6)-烷基、-CO-卤代-(C1-C3)-烷基、-CO-O-(C1-C3)-烷基、-CO-NH2或-SO2-(C1-C6)-烷基。
在一个实施方案中,本发明提供了如下定义的式I化合物:其中X-Y为-CH2-O-;R1.1和R1.2为氢且R1为卤素;R21、R22和R23为氢;R24为氢;且R4为-NHR6,其中R6为-CO-(C1-C6)-烷基。在另一实施方案中,本发明提供了如下定义的式I化合物:其中X-Y为-CH2-O-;R1.1、R1.2、R21、R22、R23和R24为氢;R1为卤素;且R4为-NHR6,其中R6为-CO-甲基。
式I化合物的实例包括:
(RS)-1-(4-苄氧基-苯基)-2-氧代-吡咯烷-3-甲腈,
(RS)-1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酸甲基酰胺,
(RS)-1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酰胺,
(RS)-1-[4-(4-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酰胺,
(RS)-1-[4-(4-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酸甲基酰胺,
(RS)-2-氧代-1-[4-(4-三氟甲基-苄氧基)-苯基]-吡咯烷-3-甲酰胺,
(RS)-2-氧代-1-[4-(4-三氟甲基-苄氧基)-苯基]-吡咯烷-3-甲酸甲基酰胺,
(S)-N-[1-(4-苄氧基-苯基)-2-氧代-吡咯烷-3-基]-乙酰胺,
(S)-N-[1-(4-苄氧基-苯基)-2-氧代-吡咯烷-3-基]-甲磺酰胺,
(S)-N-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-乙酰胺,
(R)-N-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-乙酰胺,
(R)-N-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-甲磺酰胺,
(S)-N-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-甲磺酰胺,
(S)-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-氨基甲酸甲酯,
(R)-N-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-甲酰胺,
(S)-N-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-甲酰胺,
(R)-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-脲,
(S)-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-脲,
(S)-N-{1-(S)-[4-(4-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-乙酰胺,
(S)-N-{1-(S)-[4-(2,6-二氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-乙酰胺,和
(S)-N-{1-[4-(3,4-二氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-乙酰胺。
在一个实施方案中,本发明提供了制备式I化合物的方法,其中:
(a)当R4为CONHR5时,
该方法包括使式II化合物:
其中R1、R1.1、R1.2、R21、R22、R23、R24、R3、X和Y如上文定义,R*为氢或(C1-C6)-烷基,
与式H2N-R5的胺反应,其中R5如上文定义;
(b)当R4为CN时,
该方法包括使式III化合物:
其中R1、R1.1、R1.2、R21、R22、R23、R24、R3、X和Y如上文定义,且Hal为卤素,
与氰盐反应;或者
(c)当R4为NHR6时,
该方法包括使式IV化合物:
其中R1、R1.1、R1.1、R21、R22、R23、R24、R3、X和Y如上文定义,
与式Z-CO-(C1-C6)-烷基、Z-CO-卤代-(C1-C3)-烷基、Z-CO-O-(C1-C3)-烷基或Z-SO2-(C1-C3)-烷基的酰基供体试剂(其中Z为活化基团如卤素或酐)反应或者与异氰酸酯/盐反应。
通式I*化合物可以采用下列方法制备:
使式II*化合物:
其中R1、R21、R22、R23、R24和n如上文定义,与式H2N-R5的胺反应,其中R5如上文定义,得到式Ia*化合物:
或者,将式II*化合物还原为相应的式III*的醇:
并使该化合物与氰盐反应,得到式Ib*化合物:
或者,
使其中X为卤素的式IV*化合物:
与氰盐反应,得到式Ic*化合物:
或者,使式V*化合物:
与式Y-CO-(C1-C6)-烷基或Y′-SO2-(C1-C6)-烷基的酰化剂反应,其中Y和Y′代表活化基团,如卤素,
得到式Id*化合物:
其中R6如上文定义。
根据本发明,流程图1显示了所有得自式V化合物的式I化合物的示范性合成路线。式V化合物与式VI化合物反应[Ikuta等,J.Med.Chem.30:1995(1987)]得到式IIIa中间体,该反应可以在惰性溶剂如二氯甲烷、乙酸乙酯或醚中、在碱如三乙胺或碳酸盐的存在下且温度为0℃至25℃下进行。中间体2,4-二卤代-N-酰基衍生物环化为吡咯烷酮IIIa可以在碱如氢氧化钠或氢氧化钾存在下、在惰性溶剂如二氯甲烷或醚中且温度为0℃至25℃下进行。其中R*为H的中间体II,即式IIa化合物,可以通过使式V化合物与6,6-二甲基-5,7-二氧杂-螺[2,5]辛烷-4,8-二酮反应而制备,如Danishefsky等人所述[J.Amer.Chem.Soc.97:3239(1975)]。
流程图1
在流程图1中,hal代表卤素。
另一制备式I化合物的方法包括使芳基锡烷[Lam等人,TetrahedronLett.43:3091(2002)]、芳基硼酸酯[Lam等人,Synlett 5:674(2000);Chan等人,Tetrahedron Lett.39:2933(1998)]或芳基卤化物[Buchwald等人,J.Amer.Chem.Soc.118:7215(1996)]与相应的吡咯烷酮进行交叉偶合反应(流程图2)。
流程图2
其中LG为卤素,如Cl、Br或I或SnR3或B(OH)2,cat.表示催化。
根据本发明,制备其中-X-Y-为-CH2-O-的通式V化合物,即式Va化合物的可能方法在流程图3中显示:式XII中间体可通过含对位取代的离去基团的式XI芳族硝基化合物与式X苄醇的亲核取代而获得。在对位的离去基团可例如是卤素(F、Cl、Br、I)、甲苯磺酸根、甲磺酸根或三氟甲磺酸根。这些取代反应可以在没有其它物质存在下进行或在惰性溶剂如甲苯或二甲苯中进行。反应温度优选在50℃至150℃之间。或者,式XII化合物可以通过Williamson-醚合成方法,采用式XIV的对硝基酚和式XIII的苄基卤化物、甲苯磺酸酯、甲磺酸酯或三氟甲磺酸酯制备。所用的碱可例如是醇化物或碳酸盐(碳酸钠、碳酸钾或碳酸铯)。溶剂实例包括低级醇、乙腈或低级酮,温度为20℃至回流温度。另一途径为苄醇与对硝基酚的Mitsunobu-偶合。该反应照例在惰性溶剂如乙醚或四氢呋喃中采用偶氮-二甲酸二烷基酯在膦(如三丁基膦或三苯膦)存在下进行。
式XII的关键中间体可以采用催化氢化反应还原为式Va的氨基化合物,例如采用铂炭作为催化剂在低级醇、乙酸乙酯或四氢呋喃中进行。另一可选择的方法是通过金属如铁、锡或锌在酸性介质如稀释的盐酸或乙酸中还原硝基。金属也可以被金属盐如氯化锡(II)替代。
流程图3
其中LG为离去基团,例如卤素和OTf或OH(对于Mitsunobu-偶合)。
根据本发明,制备式Vb(其中-X-Y-为-CH=CH-)和Vc(其中-X-Y-为-CH2-CH2-)中间体的可能方法在流程图4中显示:式XVII中间体可以通过将未取代或取代的式XV芳醛与式XVI的(4-硝基-苄基)-膦酸二烷基酯在碱如氢化钠的存在下进行烯化反应,生成相应的式XVII的硝基-烯烃而获得。
流程图4
在流程图4中,alkyl代表烷基。
式XVII的关键中间体可以采用催化氢化反应或者通过金属或金属盐如氯化锡(II)来选择性地还原为式Vb的氨基-烯烃,所述的催化氢化反应例如采用铂炭作为催化剂在作为溶剂的低级醇、乙酸乙酯或四氢呋喃中进行。式Vc的氨基衍生物可通过采用钯炭作为催化剂在作为溶剂的低级醇、乙酸乙酯或四氢呋喃中的氢化反应由式XVII的硝基衍生物或式Vb的氨基-烯烃直接得到。
采用标准方法将中间体II转化为式I化合物。酸II可以通过酰氯(亚硫酰氯或草酰氯)或用DCC或EDC等活化,随后与胺R5-NH2偶合。或者,通过式R5-NH2的胺的氨解作用将相应的烷基酯转化为中间体II。
中间体III可通过与氰化钠或氰化钾在溶剂如N,N-二甲基甲酰胺、丙酮或乙腈中且于20℃-140℃的温度下反应而转化为其中R4为CN的所需化合物I,即式Ib化合物。可以加入催化量的碘化钠或碘化钾以加速反应(流程图5)。
流程图5
式IV化合物可以以式II的酸衍生物为原料经由形成相应的异氰酸酯、通过碳原子至氮原子的亲核迁移如Hofmann或Curtius重排并将其用适宜的醇处理而获得,所述的醇可得到受保护的氨基基团,该方法本身可从文献中获知(流程图6)。为处理中间体异氰酸酯,选择可以得到典型的用作胺保护基团(如叔-丁氧羰基、苄氧羰基或芴基甲氧基羰基)的氨基羧酸酯的醇。将它们裂解为胺的方法可按照文献中众所周知的实验设计进行。进一步转化为式I化合物的步骤可以通过标准方法进行,例如通过与活化的酰基衍生物如酰基卤化物或酐反应,或者通过采用例如碳二亚胺作为缩合剂的酸缩合反应,或者通过与异氰酸酯/盐反应。
流程图6
其中PG为保护基团。
为制备式IV的对映纯的衍生物,也可以采用另外的途径(流程图7)。该方法主要采用Freidinger等所述的条件[J.Org.Chem.47:104-109(1982)],其中式V的苯胺衍生物通过缩合反应的标准条件、被外消旋或旋光活性的N-保护蛋氨酸衍生物酰化,得到式XIX化合物。于这些条件下、在惰性溶剂(例如THF、二氯甲烷或N,N-二甲基甲酰胺)中,用甲基碘或三甲基锍盐或三甲基氧化锍盐进行甲基化,并用碱(如氢化钠或双(三甲基甲硅烷基)氨化锂或钾)处理所得二甲基锍盐,得到环化N-保护的式XX产物。该环化方法的另一变体在EP 985,665中有描述,其涉及制备3-氨基-2-氧代-吡咯烷的方法。
流程图7
在其中-X-Y-为-CH2-O-的式I或XX化合物中,任选取代的苄基基团作为可经氢解裂除的过渡基团。然后将所得的式Id或Xxa酚在上文所述的条件下用不同的苄基再次烷基化。如本领域技术人员所熟知的,仅当在上文所述的反应条件下R6和PG对前述的氢解和烷基化反应的反应条件下稳定时该方法才是可能的。
通式I化合物还可以以光学纯的形式存在。可以以手性源的对映纯的化合物如(R)-或(S)-甲硫氨酸为原料。在其他情形下,可以根据本身已知的方法分离为对映体,或者优选在合成初期由式II化合物开始通过与光学活性的胺如(+)-或(-)-1-苯乙胺形成盐并分步结晶分离非对映的盐而进行分离,或者优选通过与手性助剂如(+)-或(-)-2-丁醇、(+)-或(-)-1-苯基乙醇或者(+)-或(-)-薄荷醇衍生并色谱和/或结晶分离非对映的产物、随后裂解与手性助剂结合的键而进行分离。为了确定所得吡咯烷酮衍生物的绝对构型,可通过常规的光谱法来分析纯的非对映的盐和衍生物,对单晶的X-射线光谱法是特别适宜的方法。
如上文已提及的,活性化合物为单胺氧化酶B抑制剂,并且可用于治疗或预防其中MAO-B抑制剂可能有用的疾病。所述疾病包括急性和慢性神经障碍、认知紊乱和记忆缺失。可治疗的神经障碍例如是神经系统的创伤性或慢性衰退过程,例如阿尔茨海默氏病、其它类型的痴呆、最低限度的认知缺失(minimal cognitive impairment)或帕金森氏病。其它适应症包括精神疾病如抑郁、焦虑、恐慌发作、社交恐慌、精神分裂症、饮食和代谢紊乱如肥胖症,以及对因滥用酒精、尼古丁和其它成瘾性药物而引起的戒断综合征的预防和治疗。其它可治疗的适应症可以是由癌症化疗(WO97/33,572)、奖励缺乏综合征(WO 01/34,172)或治疗多发性硬化症(WO96/40,095)而引起的外围神经病变和其它神经炎性疾病。
活性化合物可特别用于治疗和预防阿尔茨海默氏病和老年性痴呆。
这些化合物的药理学活性经下述方法测定:采用Schlaeger和Christensen所描述的操作方法[Cytotechnology 15:1-13(1998)],将编码人MAO-A和MAO-B的cDNA瞬时转染至EBNA细胞中。在转染后,用Polytron匀浆器将细胞在20mM Tris HCl缓冲液(pH 8.0)中匀浆,所述的缓冲液含有0.5mM EGTA和0.5mM苯甲磺酰氟。于45,000×g离心得到细胞膜,在用含0.SmM EGTA的20mM Tris HCl缓冲液(pH 8.0)漂洗两次后,最终将细胞膜重新悬浮于上述缓冲液中并将其等分试样贮存于-80℃备用。
采用由Zhou和Panchuk-Voloshina所描述的方法[AnalyticalBiochemistry 253:169-174(1997)]改良的分光光度测定法在96孔板中测定MAO-A和MAO-B的酶活性。简而言之,于37℃将细胞膜的等分试样在含不同浓度化合物的0.1M磷酸钾缓冲液(pH 7.4)中温育30分钟。在此过程后,通过加入MAO底物酪胺和1U/ml辣根过氧化酶(Roche Biochemicals)及80μM的N-乙酰基-3,7-二羟基吩噁嗪(Amplex Red,Molecular Probes)来引发酶反应。将样品于37℃以终体积为200μl再温育30分钟,然后使用SpectraMax读板仪(Molecular Devices)于570nm波长处测定吸收度。在10μM氯吉兰存在下测定MAO-A的本底(非特异性)吸收度,或者在10μM L-丙炔苯丙胺(deprenyl)存在下测定MAO-B的本底(非特异性)吸收度。由采用9个抑制剂浓度以一式两份得到的抑制曲线、通过使用计算机程序将数据拟合为四参数对数方程来测定IC50值。
本发明的化合物为特异性的MAO-B抑制剂。如在上述测定法中所测定的,优选活性化合物的IC50值为1μM或更低,优选为0.1μM或更低,更优选为0.02μM或更低。
活性化合物可例如以药物制剂的形式用作药物。该药物制剂可以经口服如以片剂、包衣片剂、糖锭剂、硬和软明胶胶囊剂、溶液剂、乳剂或混悬剂的形式给药。然而,还可经直肠(如以栓剂形式)或胃肠道外(如注射溶液的形式)进行给药。
活性化合物可与制药学惰性的无机或有机载体一起加工来生产药物制剂。可以使用乳糖、玉米淀粉或其衍生物、滑石粉、硬脂酸或其盐等来作为例如片剂、包衣片剂、糖锭剂和硬明胶胶囊的载体。适于软明胶胶囊的载体例如是植物油、蜡、脂肪、半固态和液态多元醇等;然而根据活性物质的性质,当为软明胶胶囊时通常不需要载体。适于生产溶液剂和糖浆剂的载体例如是水、多元醇、蔗糖、转化糖或葡萄糖等。辅料如醇、多元醇、甘油或植物油等可用于活性化合物的水溶性盐的注射水溶液,但通常不是必须的。适于栓剂的载体例如是天然油或硬化油、蜡、脂肪、半固态或液态多元醇等。
另外,该药物制剂可含有防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、矫味剂、调节渗透压的盐、缓冲剂、掩蔽剂或抗氧化剂。它们还可含有其它有治疗价值的物质。
如前文所提及的,含活性化合物和治疗惰性的赋形剂的药物也是本发明的目标,生产该药物的方法亦如此,所述方法包含将一种或多种活性化合物以及需要的一种或多种其它有治疗价值的物质与一种或多种治疗惰性的载体一起制成盖仑剂型。
剂量可在较宽范围内变化,并且在每个具体病例中当然应该适合于个体的需求。通常,对所有所述适应症而言,口服或胃肠道外给药的有效剂量为0.01-20mg/kg/天,优选剂量为0.1-10mg/kg/天。因此,对于体重为70kg的成人,每日剂量为0.7-1400mg/天,优选为7-700mg/天。
下列实施例用于说明本发明。它们不应当理解为对本发明范围的限制,而仅作为本发明范围的代表。缩写“RT”意指“室温”。
实施例1:(RS)-1-(4-苄氧基-苯基)-2-氧代-吡咯烷-3-甲腈
a)(RS)-N-(4-苄氧基-苯基)-2,4-二溴-丁酰胺
将12.8g(64.2mmol)4-苄氧基苯胺和9.74g(96.3mmol)三乙胺的125ml二氯甲烷溶液冷却至0℃。在45分钟内缓慢加入20.4g(77.1mmol)2,4-二溴丁酰氯[Ikuta等,J.Med.Chem.30:1995(1987)]。反应混合物另外搅拌15分钟,然后用100ml水水解。滤除不溶的沉淀,有机相顺次用饱和碳酸氢钠溶液和水洗涤。干燥并蒸发后,粗品产物经层析(硅胶,二氯甲烷),得到6.1g(22%)无色固体。Mp=139.5-142℃。
b)(RS)-1-(4-苄氧基-苯基)-3-溴-吡咯烷-2-酮
将6.1g(14.3mmol)(RS)-N-(4-苄氧基-苯基)-2,4-二溴-丁酰胺和0.1gDowex 2×10悬浮于50ml二氯甲烷中。于剧烈搅拌下缓慢加入7ml 50%氢氧化钠水溶液。于室温下,将所得反应混合物搅拌过夜,然后倾入25ml冷水中。分离有机相,干燥并蒸发。粗品物质自乙酸乙酯中重结晶,得到1.72g(35%)微棕色固体。Mp=125-126℃。
c)(RS)-1-(4-苄氧基-苯基)-2-氧代-吡咯烷-3-甲腈
将300mg(0.87mmol)(RS)-1-(4-苄氧基-苯基)-3-溴-吡咯烷-2-酮溶于5ml N,N-二甲基甲酰胺中。加入64mg(1.3mmol)氰化钠和13mg(0.09mmol)碘化钠,并于120℃搅拌悬浮液10分钟。用水处理反应混合物并用乙酸乙酯萃取,得到33mg(13%)无色固体。MS:m/e=293.3(M+H)+。
实施例2:(RS)-1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酸甲基酰胺
a)1-(4-苄氧基-苯基)-吡咯烷-2-酮
用3ml浓盐酸处理20.3g(101.9mmol)4-苄氧基苯胺和9.1ml(119.2mmol)γ-丁内酯。混合物于160℃加热20小时,然后于200℃加热5.5小时。冷却后,混合物用250ml乙酸乙酯萃取,用饱和碳酸氢钠水溶液洗涤并干燥。蒸发溶剂并于乙醚中重结晶,得到8.4g(31%)微棕色固体。MS:m/e=267(M+)。
b)1-(4-羟基-苯基)-吡咯烷-2-酮
将6.2g(23.2mmol)1-(4-苄氧基-苯基)-吡咯烷-2-酮溶于200ml THF中。加入3滴乙酸,于室温和常压下以及在0.62g 10%钯炭存在下将溶液氢化5小时。过滤并浓缩,得到半固体物质。经层析(硅胶,二氯甲烷/甲醇95∶5)得到2.73g(66%)微棕色固体。MS:m/e=175.9(M-H)。
c)1-[4-(3-氟-苄氧基)-苯基]-吡咯烷-2-酮
将2.73g(15.4mmol)1-(4-羟基-苯基)-吡咯烷-2-酮、3.2g(16.9mmol)3-氟苄基溴和4.26g(31mmol)碳酸钾在100ml 2-丁酮中的混合物于80℃加热18小时。冷却至室温后,反应混合物用水和乙酸乙酯处理。分离有机层,经硫酸镁干燥并减压蒸发。固体残留物于乙醚中结晶,得到3.86g(理论值的88%)1-[4-(3-氟-苄氧基)-苯基]-吡咯烷-2-酮,为无色固体。MS:m/e=286.0(M+H)+。
d)1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酸乙酯
将370mg(15.4mmol)氢化钠悬浮于20ml THF中,加入911mg(7.7mmol)碳酸二乙酯。加热悬浮液至回流温度。将2.0g(7.0mmol)1-[4-(3-氟-苄氧基)-苯基]-吡咯烷-2-酮的10ml THF溶液缓慢加至沸腾溶液中。混合物另外煮沸5小时,然后用冷水水解并依次用水、饱和碳酸氢钠溶液、水和饱和氯化钠溶液洗涤。经层析(硅胶,二氯甲烷/乙酸乙酯)得到1.3g(52%)微黄色半固体。MS:m/e=358.2(M+H)+。
e)(RS)-1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酸甲基酰胺
将300mg(0.84mmol)1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酸乙酯溶于2ml N,N-二甲基甲酰胺中。加入0.17ml(4.2mmol)33%甲胺的乙醇溶液。紧塞住反应容器并于120℃加热24小时。加入水沉淀出粗品物质。经层析(硅胶,二氯甲烷/甲醇)得到41mg(14%)微黄色固体。MS:m/e=343.2(M+H)+。
实施例3:(RS)-1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酰胺
a)1-(3-氟苄氧基)-4-硝基-苯
将5.04g(40mmol)3-氟苄醇和1.29g(4mmol)三-(二氧杂-3,6-庚基)胺的混合物用2.47g(44mmol)氢氧化钾处理。于室温下搅拌混合物10分钟,然后通过滴液漏斗缓慢加入5.55g(44mmol)4-氟-硝基苯。将混合物于80℃放置45分钟,冷却至室温并用约75ml水稀释。用乙酸乙酯萃取并用2M盐酸水溶液洗涤,得到微黄色有机相,将有机相干燥并蒸发。残留物自甲醇重结晶,得到6.07g(61%)标题化合物。黄色晶体,mp=104-105℃。
b)4-(3-氟-苄氧基)-苯胺
将3g(12.1mmol)1-(3-氟苄氧基)-4-硝基-苯溶于125ml甲醇中。加入150mg铂炭(5%)和并于常压下氢化约17小时。滤除催化剂并蒸发溶液得到2.51g(95%)粗品,为微褐色物质。MS:m/e=218.4(M+H)+。
c)(RS)-1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酸
将561mg(2.6mmol)4-(3-氟-苄氧基)-苯胺和448mg(2.6mmol)6,6-二甲基-5,7-二氧杂-螺[2,5]辛烷-4,8-二酮的2ml二氯甲烷溶液回流16小时。加入5ml乙醚并滤除沉淀,得到485mg(57%)无色固体。MS:m/e=330.2(M+H)+。
d)(RS)-1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酰胺
将300mg(0.91mmol)(RS)-1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酸溶于2ml二氯甲烷和2滴N,N-二甲基-甲酰胺中。溶液冷却至0℃并用173mg(1.37mmol)草酰氯处理。于0℃达1小时后,于室温下真空除去溶剂。残留物溶于1ml二氯甲烷中并缓慢加至2ml THF与5ml浓氨水的混合物中。于室温下持续搅拌1小时。蒸发溶剂并用水稀释,得到沉淀,将其滤除。用甲醇重结晶得到112mg(37%)无色固体。MS:m/e=329.2(M+H)+。
实施例4:(RS)-1-[4-(4-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酰胺
a)1-(4-氟苄氧基)-4-硝基-苯
类似于实施例3a),采用4-氟苄基醇和4-氟-硝基苯为原料制备标题化合物。收率:86%的微黄色固体。Mp=124-126℃。
b)4-(4-氟-苄氧基)-苯胺
类似于实施例3b),通过将1-(4-氟-苄氧基)-4-硝基-苯还原来制备标题化合物。收率:98%的红色固体。MS:m/e=218.3(M+H)+。
c)(RS)-1-[4-(4-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酸
类似于实施例3c),采用4-(4-氟-苄氧基)-苯胺和6,6-二甲基-5,7-二氧杂-螺[2,5]辛烷-4,8-二酮为原料制备标题化合物。收率:56%的无色固体。MS:m/e=284.1(M-CO2)。
d)(RS)-1-[4-(4-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酰胺
类似于实施例3d),采用(RS)-1-[4-(4-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酸和氨水为原料制备标题化合物。收率:18%的微棕色固体。MS:m/e=329.3(M++H)。
实施例5:(RS)-1-[4-(4-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酸甲基酰胺
类似于实施例3d),采用(RS)-1-[4-(4-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酸和甲胺作为原料制备标题化合物。收率:17%的无色固体。MS:m/e=343.2(M+H)+。
实施例6:(RS)-2-氧代-1-[4-(4-三氟甲基-苄氧基)-苯基]-吡咯烷-3-甲酰胺
a)1-(4-三氟甲基-苄氧基)-4-硝基-苯
类似于实施例3a),采用4-氟-硝基-苯和4-三氟甲基-苄基醇为原料制备标题化合物。收率82%的淡棕色固体。Mp.=80.5-81.5℃。
b)4-(4-三氟甲基-苄氧基)-苯胺
类似于实施例3b),通过将1-(4-三氟甲基-苄氧基)-4-硝基-苯还原来制备标题化合物。收率:91%的微黄色固体。MS:m/e=268.3(M+H)+。
c)(RS)-2-氧代-1-[4-(4-三氟甲基-苄氧基)-苯基]-吡咯烷-3-甲酸
类似于实施例3c),采用4-(4-三氟甲基-苄氧基)-苯胺和6,6-二甲基-5,7-二氧杂-螺[2,5]辛烷-4,8-二酮制备标题化合物。收率:37%的无色固体。MS:m/e=380.1(M+H)+。
d)(RS)-2-氧代-1-[4-(4-三氟甲基-苄氧基)-苯基]-吡咯烷-3-甲酰胺
将150mg(0.4mmol)(RS)-2-氧代-1-[4-(4-三氟甲基-苄氧基)-苯基]-吡咯烷-3-甲酸溶于4ml THF中。加入59mg(0.43mmol)1-羟基苯并三唑和80mg(0.42mmol)N-(3-二甲氨基丙基)-N’-乙基-碳二亚胺-盐酸盐,并将反应混合物于RT下搅拌30分钟。冷却至0℃后,加入4ml浓氨水,并将所得混合物于RT下搅拌1小时。用水稀释、萃取并经层析(硅胶,乙酸乙酯),得到15mg(10%的)无色固体。MS:m/e=379.2(M+H)+。
实施例7:(RS)-2-氧代-1-[4-(4-三氟甲基-苄氧基)-苯基]-吡咯烷-3-甲酸甲基酰胺
类似于实施例6d),采用(RS)-2-氧代-1-[4-(4-三氟甲基-苄氧基)-苯基]-吡咯烷-3-甲酸和甲胺作为原料制备标题化合物。收率:6%的无色固体。MS:m/e=393.2(M+H)+。
实施例8:(S)-N-[1-(4-苄氧基-苯基)-2-氧代-吡咯烷-3-基]-乙酰胺
a)(S)-[1-(4-苄氧基-苯基氨基甲酰基)-3-甲硫基-丙基]-氨基甲酸叔-丁酯
于室温下,将0.57g(2.3mmol)(S)-叔丁氧羰基-甲硫氨酸的5ml二氯甲烷溶液顺次用0.87g(2.3mmol)O-(苯并三唑-1-基)-N,N,N,,N’-四甲基脲鎓六氟磷酸盐(HBTU)、0.50g(2.1mmol)4-苄氧基-苯胺盐酸盐和0.98ml(5.7mmol)N-乙基-二异丙胺处理。于室温下,搅拌反应混合物1小时。对于后处理,反应混合物用二氯甲烷稀释并用20ml柠檬酸水溶液(10%)处理。水相用二氯甲烷再次萃取,合并有机相,经硫酸钠干燥并减压蒸发。将所得粗品物质经硅胶层析纯化,采用3∶1的正己烷和乙酸乙酯混合物为洗脱液。得到0.74g(理论值的82.5%)(S)-[1-(4-苄氧基-苯基氨基甲酰基)-3-甲硫基-丙基]-氨基甲酸叔-丁酯,为白色固体。MS:m/e=431(M+H)+。
b)(S)-[1-(4-苄氧基-苯基)-2-氧代-吡咯烷-3-基]-氨基甲酸叔-丁酯
于室温下,将0.35g(0.81mmol)(S)-[1-(4-苄氧基-苯基氨基甲酰基)-3-甲硫基-丙基]-氨基甲酸叔-丁酯和8.79g(62.0mmol)甲基碘的混合物搅拌3天。之后,蒸发甲基碘,中间体锍盐溶于15ml THF中,并于0℃用0.79ml(0.79ml)双-(三甲基甲硅烷基)氨化锂(1M的THF溶液)处理。于0℃搅拌2小时后,减压蒸发反应混合物,并将固态残留物直接经硅胶层析,洗脱液为2∶1的正己烷和乙酸乙酯混合物。得到0.175mg(理论值的56%)(S)-[1-(4-苄氧基-苯基)-2-氧代-吡咯烷-3-基]-氨基甲酸叔-丁酯,为白色固体。MS:m/e=383(M+H)+。
c)(S)-3-氨基-1-(4-苄氧基-苯基)-吡咯烷-2-酮盐酸盐
将137mg(0.36mmol)(S)-[1-(4-苄氧基-苯基)-2-氧代-吡咯烷-3-基]-氨基甲酸叔-丁酯的2ml二噁烷溶液用0.3ml盐酸(37%)处理。溶液于45℃温热1小时,形成白色悬浮液。对于后处理,减压蒸发反应混合物并将固态残留物用少量甲醇研磨。过滤和干燥后,得到94mg(S)-3-氨基-1-(4-苄氧基-苯基)-吡咯烷-2-酮盐酸盐(理论值的82%),为白色固体。MS:m/e=283(M+H)+。
d)(S)-N-[1-(4-苄氧基-苯基)-2-氧代-吡咯烷-3-基]-乙酰胺
将40mg(0.13mmol)(S)-3-氨基-1-(4-苄氧基-苯基)-吡咯烷-2-酮盐酸盐的2ml二氯甲烷溶液用38μl(0.28mmol)三乙胺处理,并冷却至0℃。向该溶液中加入10μl(0.14mmol)乙酰氯,并于0℃持续搅拌30分钟。对于后处理,反应混合物用2ml氢氧化铵溶液处理,分离有机相,之后经硫酸钠干燥并减压蒸发。为进行纯化,将所得物质经硅胶层析,洗脱液为95∶5的二氯甲烷和甲醇混合物。得到31mg(理论值的76%)(S)-N-[1-(4-苄氧基-苯基)-2-氧代-吡咯烷-3-基]-乙酰胺,为白色固体。MS:m/e=325(M+H)+。
实施例9:(S)-N-[1-(4-苄氧基-苯基)-2-氧代-吡咯烷-3-基]-甲磺酰胺
以类似于实施例8d)中所述的方法,在三乙胺存在下,使(S)-3-氨基-1-(4-苄氧基-苯基)-吡咯烷-2-酮盐酸盐与甲磺酰氯反应,得到(S)-N-[1-(4-苄氧基-苯基)-2-氧代-吡咯烷-3-基]-甲磺酰胺,为白色固体。MS:m/e=361(M+H)+。
实施例10:(S)-N-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-乙酰胺
a)以类似于实施例8a)至c)中所述的方法,得到(S)-3-氨基-1-[4-(3-氟-苄氧基)-苯基]-吡咯烷-2-酮盐酸盐:
将(S)-BOC-甲硫氨酸和4-(3-氟苄氧基)-苯胺[实施例3b)]通过HBTU缩合,得到(S)-{1-[4-(3-氟-苄氧基)-苯基氨基甲酰基]-3-甲硫基-丙基}-氨基甲酸叔-丁酯,为淡黄色固体;MS:m/e=449(M+H)+。随后经甲基化和结晶得到(S)-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-氨基甲酸叔-丁酯,为白色固体;MS:m/e=401(M+H)+。裂解BOC-基团得到(S)-3-氨基-1-[4-(3-氟-苄氧基)-苯基]-吡咯烷-2-酮盐酸盐,为白色固体;MS:m/e=301(M+H)+。
b)(S)-N-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-乙酰胺
以类似于实施例8d)中所述的方法,使(S)-3-氨基-1-[4-(3-氟-苄氧基)-苯基]-吡咯烷-2-酮盐酸盐乙酰化,得到标题化合物,为白色固体;MS:m/e=343(M+H)+。
实施例11:(R)-N-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-乙酰胺,
(R)-N-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-甲磺酰胺,
(S)-N-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-甲磺酰胺和
(S)-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-氨基甲酸甲酯
以类似于8d)实施例所述方法,使(R)-或(S)-3-氨基-1-[4-(3-氟-苄氧基)-苯基]-吡咯烷-2-酮盐酸盐酰化[(R)-异构体采用(R)-BOC-甲硫氨酸为原料、类似于如实施例10a)中所述的制备(S)-异构体的方法获得],得到下列化合物:
a)使(R)-3-氨基-1-[4-(3-氟-苄氧基)-苯基]-吡咯烷-2-酮盐酸盐与乙酰氯反应,得到(R)-N-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-乙酰胺,为白色固体;MS:m/e=343(M+H)+。
b)使(R)-3-氨基-1-[4-(3-氟-苄氧基)-苯基]-吡咯烷-2-酮盐酸盐与甲磺酰氯反应,得到(R)-N-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-甲磺酰胺,为白色固体;MS:m/e=377(M+H)+。
c)使(S)-3-氨基-1-[4-(3-氟-苄氧基)-苯基]-吡咯烷-2-酮盐酸盐与甲磺酰氯反应,得到(S)-N-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-甲磺酰胺,为白色固体;MS:m/e=377(M+H)+。
d)使(S)-3-氨基-1-[4-(3-氟-苄氧基)-苯基]-吡咯烷-2-酮盐酸盐与氯甲酸甲酯反应,得到(S)-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-氨基甲酸甲酯,为白色固体;MS:m/e=359(M+H)+。
实施例12:(R)-N-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-甲酰胺
于0℃制备188mg(18mmol)乙酸酐和107mg(23mmol)甲酸的混合物,之后于60℃加热2小时。冷却至室温后,混合物用1ml四氢呋喃稀释,然后加入213mg(7mmol)(R)-3-氨基-1-[4-(3-氟-苄氧基)-苯基]-吡咯烷-2-酮的2ml二氯甲烷溶液,该溶液由相应的盐酸盐通过用三乙胺处理而制备。在加入后形成白色悬浮液,将其于室温下搅拌1小时。对于后处理,反应混合物用二氯甲烷和水处理,然后分离有机层,经硫酸钠干燥并蒸发。得到215mg(理论值的92%)(R)-N-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-甲酰胺,为白色固体;MS:m/e=329(M+H)+。
实施例13:(S)-N-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-甲酰胺
类似于实施例12所述方法,使(S)-3-氨基-1-[4-(3-氟-苄氧基)-苯基}-吡咯烷-2-酮与乙酸酐和甲酸的混合物反应,得到标题化合物,为白色固体;MS:m/e=329(M+H)+。
实施例14:(R)-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-脲
将250mg(0.7mmol)(R)-3-氨基-1-[4-(3-氟-苄氧基)-苯基]-吡咯烷-2-酮盐酸盐和294mg(2.2mmol)N-乙基-二异丙胺的2ml N,N-二甲基甲酰胺溶液冷却至0℃并用267mg(2.2mol)异氰酸三甲酯处理。反应混合物温热至室温并持续搅拌2天。对于后处理,减压蒸发悬浮液。粗品产物用水研磨,然后再次在乙酸乙酯和饱和碳酸氢钠溶液的混合物中研磨所回收的固态物质。经过滤漏斗收集剩余固体,高真空干燥后得到155mg(理论值的61%)
(R)-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-脲,为白色固体;MS:m/e=344(M+H)+。
实施例15:(S)-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-脲
以类似于实施例14所述方法,使(S)-3-氨基-1-[4-(3-氟-苄氧基)-苯基]-吡咯烷-2-酮与异氰酸三甲酯反应,得到标题化合物,为白色固体;MS:m/e=344(M+H)+。
实施例16:(S)-N-{1-(S)-[4-(4-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-乙酰胺
a)(S)-[1-(4-羟基-苯基)-2-氧代-吡咯烷-3-基]-氨基甲酸叔-丁酯
以类似于实施例2b)中所述的方法,采用钯炭作为催化剂,氢解(S)-[1-(4-苄氧基-苯基)-2-氧代-吡咯烷-3-基]-氨基甲酸叔-丁酯[实施例8b)],以定量产率得到标题化合物,为白色固体;MS:m/e=291(M-H)+。
b)(S)-{1-[4-(4-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-氨基甲酸叔-丁酯
以类似于所述方法实施例2c),在碳酸钾存在下,用4-氟苄基溴使(S)-[1-(4-羟基-苯基)-2-氧代-吡咯烷-3-基]-氨基甲酸叔-丁酯烷基化,得到标题化合物,为白色固体;MS:m/e=401(M+H)+。
c)(S)-3-氨基-1-[4-(4-氟-苄氧基)-苯基]-吡咯烷-2-酮盐酸盐
以类似于实施例8c)中所述的方法,裂除(S)-{1-[4-(4-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-氨基甲酸叔-丁酯的BOC-基团,得到标题化合物,为白色固体;MS:m/e=301(M+H)+。
d)(S)-N-{1-[4-(4-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-乙酰胺
以类似于实施例8d)中所述的方法,使(S)-3-氨基-1-[4-(4-氟-苄氧基)-苯基]-吡咯烷-2-酮盐酸盐乙酰化,得到标题化合物,为白色固体;MS:m/e=343(M+H)+。
实施例17:(S)-N-{1-(S)-[4-(2,6-二氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-乙酰胺
21.(S)-{1-[4-(2,6-二氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-氨基甲酸叔-丁酯
以类似于实施例2c)中所述的方法,在碳酸钾存在下,用2,6-二氟苄基溴使(S)-[1-(4-羟基-苯基)-2-氧代-吡咯烷-3-基]-氨基甲酸叔-丁酯[实施例16a)]烷基化,得到标题化合物,为白色固体;MS:m/e=419(M+H)+。
b)(S)-3-氨基-1-[4-(2,6-二氟-苄氧基)-苯基]-吡咯烷-2-酮盐酸盐
以类似于实施例8c)中所述的方法,裂除(S)-{1-[4-(2,6-二氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-氨基甲酸叔-丁酯的BOC-基团,得到标题化合物,为白色固体。
c)(S)-N-{1-[4-(2,6-二氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-乙酰胺
以类似于实施例8d)中所述的方法,使(S)-3-氨基-1-[4-(2,6-二氟-苄氧基)-苯基]-吡咯烷-2-酮盐酸盐乙酰化,得到标题化合物,为白色固体;MS:m/e=361(M+H)+。
实施例18:(S)-N-{1-[4-(3,4-二氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-乙酰胺
a)(S)-{1-[4-(3,4-二氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-氨基甲酸叔-丁酯
以类似于实施例2c)中所述的方法,在碳酸钾存在下,用3,4-二氟苄基溴使(S)-[1-(4-羟基-苯基)-2-氧代-吡咯烷-3-基]-氨基甲酸叔-丁酯[实施例16a)]烷基化,得到标题化合物,为白色固体;MS:m/e=419(M+H)+。
b)(S)-3-氨基-1-[4-(3,4-二氟-苄氧基)-苯基]-吡咯烷-2-酮盐酸盐
以类似于实施例8c)中所述的方法,裂除(S)-{1-[4-(3,4-二氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-氨基甲酸叔-丁酯的BOC-基团,得到标题化合物,为白色固体;MS:m/e=319(M+H)+。
c)(S)-N-{1-[4-(3,4-二氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-乙酰胺
以类似于实施例8d)中所述的方法,使(S)-3-氨基-1-[4-(3,4-二氟-苄氧基)-苯基]-吡咯烷-2-酮盐酸盐乙酰化,得到标题化合物,为白色固体;MS:m/e=361(M+H)+。
实施例A:片剂
按照常规方法制备具有下述组成的片剂:
mg/片
活性成分 100
粉末状乳糖 95
白色玉米淀粉 35
聚乙烯吡咯烷酮 8
羧甲基淀粉钠 10
硬脂酸镁 2
片剂重量 250
实施例B:片剂
按照常规方法制备具有下述组成的片剂:
mg/片
活性成分 200
粉末状乳糖 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
片剂重量 400
实施例C:胶囊剂
制备具有下述组成的胶囊:
mg/胶囊
活性成分 50
晶体状乳糖 60
微晶纤维素 34
滑石粉 5
硬脂酸镁 1
胶囊填充重量 150
将具有适宜粒径的活性成分、晶体状乳糖和微晶纤维素相互均匀混合,过筛,随后混入滑石粉和硬脂酸镁。将最终混合物填充入具有适宜大小的硬明胶胶囊中。
实施例D:注射溶液
注射溶液可含有下述组成,并且可按照常规方法制备:
活性物质 1.0mg
1N HCl 20.0μl
乙酸 0.5mg
NaCl 8.0mg
苯酚 10.0mg
1N NaOH 适量至pH 5
H2O 适量至1ml
Claims (19)
1.式I化合物、其单一异构体、外消旋或非外消旋混合物:
其中:
X-Y为-CH2-CH2-、-CH=CH-或-CH2-O-;
R1、R1.1和R1.2彼此独立地选自氢、卤素、氰基、(C1-C6)-烷基、卤代-(C1-C6)-烷基、(C1-C6)-烷氧基和卤代-(C1-C6)-烷氧基;
R21、R22和R23彼此独立地选自氢和卤素;
R24为氢、卤素或甲基;
R3为氢;
R4为-CONHR5、-CN或-NHR6;
R5为氢或(C1-C3)-烷基;和
R6为-C(O)H、-C(O)-(C1-C6)-烷基、-C(O)-卤代-(C1-C3)烷基、-C(O)O(C1-C3)-烷基、-C(O)-NH2或-SO2-(C1-C6)-烷基。
2.权利要求1的化合物,其中X-Y为-CH2-O-。
3.权利要求1的化合物,其中R1、R1.1和R1.2彼此独立地选自氢、卤素、甲基、卤代甲基、氰基、甲氧基或卤代甲氧基。
4.权利要求1的化合物,其中R21、R22和R23为氢。
5.权利要求1的化合物,其中R24为氢。
6.权利要求1的化合物,其中R4为-CONHR5,其中R5为氢或(C1-C3)-烷基。
7.权利要求1的化合物,其中R4为-CN。
8.权利要求1的化合物,其中R4为-NHR6,其中R6为-CO-H、-CO-(C1-C6)-烷基、-CO-卤代-(C1-C3)-烷基、-CO-O-(C1-C3)-烷基、-CO-NH2或-SO2-(C1-C6)-烷基。
9.权利要求1的化合物,其中所述化合物具有(S)-构型。
10.权利要求1的化合物,其中所述化合物具有(R)-构型。
11.权利要求1的化合物,其中所述化合物选自:
(RS)-1-(4-苄氧基-苯基)-2-氧代-吡咯烷-3-甲腈,
(RS)-1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酸甲基酰胺,
(RS)-1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酰胺,
(RS)-1-[4-(4-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酰胺,
(RS)-1-[4-(4-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-甲酸甲基酰胺,
(RS)-2-氧代-1-[4-(4-三氟甲基-苄氧基)-苯基]-吡咯烷-3-甲酰胺,
(RS)-2-氧代-1-[4-(4-三氟甲基-苄氧基)-苯基]-吡咯烷-3-甲酸甲基酰胺,
(S)-N-[1-(4-苄氧基-苯基)-2-氧代-吡咯烷-3-基]-乙酰胺,
(S)-N-[1-(4-苄氧基-苯基)-2-氧代-吡咯烷-3-基]-甲磺酰胺,
(S)-N-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-乙酰胺,
(R)-N-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-乙酰胺,
(R)-N-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-甲磺酰胺,
(S)-N-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-甲磺酰胺,
(S)-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-氨基甲酸甲酯,
(R)-N-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-甲酰胺,
(S)-N-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-甲酰胺,
(R)-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-脲,
(S)-{1-[4-(3-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-脲,
(S)-N-{1-(S)-[4-(4-氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-乙酰胺,
(S)-N-{1-(S)-[4-(2,6-二氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-乙酰胺,和
(S)-N-{1-[4-(3,4-二氟-苄氧基)-苯基]-2-氧代-吡咯烷-3-基}-乙酰胺。
12.制备权利要求1的式I化合物的方法,其中:
(a)当R4为CONHR5时,
该方法包括使式II化合物:
其中R1、R1.1、R1.2、R21、R22、R23、R24、R3、X和Y如权利要求1中定义,R*为氢或(C1-C6)-烷基,
与式H2N-R5的胺反应,其中R5如权利要求1中定义;
(b)当R4为CN时,
该方法包括使式III化合物:
其中R1、R1.1、R1.2、R21、R22、R23、R24、R3、X和Y如权利要求1中定义,且Hal为卤素,
与氰盐反应;或者
(c)当R4为NHR6时,
该方法包括使式IV化合物:
其中R1、R1.1、R1.2、R21、R22、R23、R24、R3、X和Y如权利要求1中定义,
与其中Z为活化基团的式Z-CO-H、Z-CO-(C1-C6)-烷基、Z-CO-卤代-(C1-C3)-烷基、Z-CO-O-(C1-C3)-烷基或Z-SO2-(C1-C3)-烷基的酰基供体试剂反应或者与异氰酸酯/盐反应。
13.权利要求12的方法,其中(c)中的Z为卤素或酐。
15.药用组合物,该药用组合物含有权利要求1或14的化合物和药学上可接受的赋形剂。
16.权利要求15的药用组合物在制备用于治疗和预防由单胺氧化酶B抑制剂介导的疾病的药物中的用途。
17.权利要求16的用途,其中所述的疾病为阿尔茨海默氏病或老年性痴呆。
18.权利要求1或14的化合物及其药学上可接受的盐在制备用于治疗和预防由单胺氧化酶B抑制剂介导的疾病的药物中的用途。
19.权利要求18的用途,其中所述疾病为阿尔茨海默氏病或老年性痴呆。
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