CN1336910A - 新的1,2-二苯基-2-丙烯-1-酮衍生物 - Google Patents
新的1,2-二苯基-2-丙烯-1-酮衍生物 Download PDFInfo
- Publication number
- CN1336910A CN1336910A CN00802868A CN00802868A CN1336910A CN 1336910 A CN1336910 A CN 1336910A CN 00802868 A CN00802868 A CN 00802868A CN 00802868 A CN00802868 A CN 00802868A CN 1336910 A CN1336910 A CN 1336910A
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- Prior art keywords
- compound
- phenyl
- salt
- hydrogen
- group
- Prior art date
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- ZTKPNSXSOUTJFJ-UHFFFAOYSA-N 1,2-diphenylprop-2-en-1-one Chemical class C=1C=CC=CC=1C(=C)C(=O)C1=CC=CC=C1 ZTKPNSXSOUTJFJ-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 138
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 15
- 239000001257 hydrogen Substances 0.000 claims abstract description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 10
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 7
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 7
- 230000004410 intraocular pressure Effects 0.000 claims abstract description 7
- -1 4Be hydrogen Chemical class 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 4
- 230000000994 depressogenic effect Effects 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 abstract description 11
- 230000004660 morphological change Effects 0.000 abstract description 10
- 210000001585 trabecular meshwork Anatomy 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 32
- 239000000243 solution Substances 0.000 description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 239000003814 drug Substances 0.000 description 18
- 238000000034 method Methods 0.000 description 15
- 230000000694 effects Effects 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- AVOLMBLBETYQHX-UHFFFAOYSA-N etacrynic acid Chemical compound CCC(=C)C(=O)C1=CC=C(OCC(O)=O)C(Cl)=C1Cl AVOLMBLBETYQHX-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 239000012141 concentrate Substances 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- NQBWNECTZUOWID-UHFFFAOYSA-N (E)-cinnamyl (E)-cinnamate Natural products C=1C=CC=CC=1C=CC(=O)OCC=CC1=CC=CC=C1 NQBWNECTZUOWID-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 5
- NQBWNECTZUOWID-QSYVVUFSSA-N cinnamyl cinnamate Chemical compound C=1C=CC=CC=1\C=C/C(=O)OC\C=C\C1=CC=CC=C1 NQBWNECTZUOWID-QSYVVUFSSA-N 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000003889 eye drop Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- APEJMQOBVMLION-VOTSOKGWSA-N trans-cinnamamide Chemical compound NC(=O)\C=C\C1=CC=CC=C1 APEJMQOBVMLION-VOTSOKGWSA-N 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000003810 ethyl acetate extraction Methods 0.000 description 4
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 4
- 229940012356 eye drops Drugs 0.000 description 4
- 238000010191 image analysis Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 208000010412 Glaucoma Diseases 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- KBEBGUQPQBELIU-UHFFFAOYSA-N cinnamic acid ethyl ester Natural products CCOC(=O)C=CC1=CC=CC=C1 KBEBGUQPQBELIU-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 235000011167 hydrochloric acid Nutrition 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000004062 sedimentation Methods 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- KBEBGUQPQBELIU-CMDGGOBGSA-N Ethyl cinnamate Chemical compound CCOC(=O)\C=C\C1=CC=CC=C1 KBEBGUQPQBELIU-CMDGGOBGSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 2
- 229930182566 Gentamicin Natural products 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 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 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 2
- 229960003942 amphotericin b Drugs 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 238000013475 authorization Methods 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
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- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 2
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
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- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical group O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 2
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- JENANTGGBLOTIB-UHFFFAOYSA-N 1,5-diphenylpentan-3-one Chemical compound C=1C=CC=CC=1CCC(=O)CCC1=CC=CC=C1 JENANTGGBLOTIB-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 1
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- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
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Abstract
本发明提供通式(I)表示的化合物或其盐,该化合物可通过导致小梁网细胞中的形态学改变而降低眼内压。在通式中,R1代表H,低级烷基,羟基,低级烷氧基或卤素,R2,R3和R4每个代表H或低级烷基,且…代表单键或双键,条件是,当R3和/或R4为氢时,则氨基可以被保护。
Description
技术领域
本发明涉及用作青光眼治疗剂的新化合物。
背景技术
通常青光眼为一种由眼內压升高而引起的视觉功能障碍的疾病。水状液流出与眼内压的升高密切相关。当水状液流出受到干扰时,眼内压升高。水状液主要由小梁网通过眼球外的巩膜静脉窦流出。水状液流出可通过减少在这种小梁网中的水状液流出的阻力而增加。形成小梁网的细胞(小梁网细胞)具有巯基基团。现已报道了一种降低眼內压的方法,其中给予一种可与巯基反应的化合物以产生小梁网细胞的形态学改变,并增加水状液的流出率。(日本审定专利公开号13013/1995)。该专利公开了苯氧乙酸衍生物,优选利尿酸作为能和巯基反应的化合物。
通过导致小梁网细胞的形态学改变而降低眼內压的方法作为一种治疗青光眼的方法是十分引人关注的。但是,还没有研究出具有该功能机理的药物。在青光眼的治疗剂的开发中创制新药的研究是非常令人关注的课题
本发明公开
由于注意到利尿酸,即一种具有α,β-不饱和羰基的苯氧乙酸衍生物,具有导致小梁网细胞中的形态学改变和降低眼内压的作用,本发明人合成了各种新颖的化合物,并研究了它们对小梁网细胞的形态学的作用。结果,本发明人发现了新的1,2-二苯基-2-丙烯-1-酮衍生物,即具有以1,2-二苯基-2-丙烯-1-酮结构为基本结构,而在其苯环的1位侧链上引入氨基的化合物,它们具有出色的效果。因此,本发明得以完成。
本发明涉及由下面的通式[I]代表的化合物及其盐(此后在没有前提的情况下指“本发明化合物”),及含有它们作为活性组分的药物组合物:
其中,R1为氢,低级烷基,羟基,低级烷氧基或卤素,R2,R3和R4相同或不同,为氢成低级基,且
…为单键或双键。
上面定义的基团在下面详细描述。
低级烷基为具有一到八个碳原子的直链或支链烷基,例如甲基,乙基,丙基,丁基,己基,异丙基,异丁基,异戊基,异己基,叔丁基或3,3-二甲基丁基。
低级烷氧基为具有一到八个碳原子的直链或支链烷氧基,例如甲氧基,乙氧基,丙氧基,丁氧基,己氧基,异丙氧基或叔丁氧基。
卤素为氟。氯。溴或碘。
当本发明的化合物中R3和/或R4为氢时,氨基可用保护基保护。氨基的保护基为通用的氨基保护基,例如酰基,酯基,取代的低级烷基或取代的磺酰基。详细地说,保护基的实例为酰基,例如甲酰基,低级烷酰基,卤代低级烷酰基或苯基碳酰基;酯基例如低级烷氧羰基,取代的低级烷氧羰基或苯氧羰基;取代的低级烷基例如烯丙基,苯基-低级烷基或苯甲酰基-低级烷基;和取代的磺酰基例如低级烷基磺酰基或苯基磺酰基。上述所提到的苯基碳酰基,苯氧羰基,苯基-低级烷基,苯甲酰基-低级烷基和苯基磺酰基中的每一个苯基环都可以被卤素,低级烷基,低级烷氧基或硝基取代。
优选的氨基保护基的具体实列为酰基,例如甲酰基,乙酰基,三氯乙酰基,三氟乙酰基或苯甲酰基;酯基例如甲氧羰基,异丁氧羰基,叔丁氧羰基,烯丙氧羰基,2,2,2-三氯乙氧羰基,苄氧羰基,二苯基甲氧羰基或苯氧羰基;取代的烷基例如烯丙基,苄基,三苯基甲基或(4-甲氧基苯基)二苯基甲基;和取代的磺酰基,例如苯磺酰基,2,4,6-三甲基苯磺酰基或甲苯磺酰基。
当R1为羟基时,羟基可被类似于氨基保护的通用的保护基保护。
本发明中的盐是指任何药学可接受的盐,例如与诸如盐酸,硝酸或硫酸的无机酸所形成的盐,与诸如乙酸,富马酸,马来酸,柠檬酸或酒石酸等的有机酸所形成的盐。当本发明的化合物存在几何异构体或旋光异构体时,这些异构体也包括在本发明中。
本发明的化合物也可以以溶剂化物例如水合物的形式存在
本发明的化合物的优选的实例为其中的基团为通式[I]所代表的化合物或其盐中的基团的那些化合物:
(1a)R1为选自氢。低级烷基卤素的基团;和/或
(2a)R2为氢;和/或
(3a)R3和R4都为低级烷基。
即
·用上述的(1a)定义的通式[I]所代表的化合物或其盐中的化合物,
·用上述的(2a)定义的通式[I]所代表的化合物或其盐中的化合物,
·用上述的(3a)定义的通式[I]所代表的化合物或其盐中的化合物,及
·用两个或多个上述的(1a),(2a)和(3a)的组合定义的通式[I]所代表的化合物或其盐中的化合物。
本发明化合物的更优选的实例为下面的化合物及其盐。
1)1-[4-[(E)-2-(二甲基氨基)-1-丙烯基]苯基-2-苯基-2-丙烯-1-酮2)1-[4-[3-(二甲基氨基)丙基]苯基-2-苯基-2-丙烯-1-酮
本发明还涉及下面的通式[IV]所代表的化合物及其盐,该化合物为上面所述通式[I]所代表的化合物的合成中间件:
其中,R1,R2,R3和R4和
…与上述的定义相同,而且>X为>CHOH或>C=O。当R3和/或R4为氢时,氨基可被保护基保护。
本发明化合物[1]的典型的合成路线如下所示:
上述的合成路线并不代表所有方法,仅仅是一个典型的例子。具体的合成方法将在后面的实施例中详细描述。
上述的合成路线的合成方法如下所详述。
在氧化试剂(例如,二甲亚砜(DMSO))的存在下处理氨基醇[II](通式[IV]所代表的化合物及其盐中,其中>X为>CHOH的化合物),得到通式[III]所代表的羰基化合物(通式[IV]所代表的化合物及其盐中,其中>X为>C=O的化合物)。而后,化合物[III]在仲胺的存在下通过曼尼期反应与多聚甲醛缩合,而后通过消去反应得到本发明化合物[I]。
当上述的合成方法中反应物的分子中有羟基或氨基时,该基团可任选地被适当的保护基保护,该保护基也可在反应后用常规的方法除去。
本发明的化合物为文献中所未知的新化合物,其特征在于本发明的化合物具有1,2-二苯基-2-丙烯-1-酮结构,即,这些化合物具有被两个苯环取代的α,β-不饱和羰基基团为基本结构,且氨基是在苯环的1-位侧链上引入的。
如在“背景技术”部分所描述的,已经有人报导了利尿酸具有通过使小梁网细胞中的形态学改变和提高水状液流出的速率而降低眼內压的作用(见日本审定专利公报No.13013/1995)。利尿酸为具有α,β-不饱和羰基基团的苯氧乙酸衍生物。通过集中研究利尿酸的该化学结构,本发明人发现在利尿酸的α-位引入一个苯环并在另一个苯环的侧链上引入氨基基团而得到显示出更高活性的新化合物。
给药方法可以是一种以活性化合物本身给药的方法,或一种以在体內分解和转化为活性化合物的形式,即以前药的形式给药的方法。两种方法都是广泛使用的方法。当本发明化合物在其分子中具有为适当的保护基所保护的羟基或氨基时,本发明化合物可以以被保护基保护的羟基或氨基形式给药。本发明化合物也可以在除去保护基而将被护基转变为羟基或氨基后给药。
为了研究本发明化合物的用途,对本发明化合物对小梁网细胞形态学的影响进行了研究。详细情况在后面的“药理学实验”部分加以描述,加入本发明化合物后小梁网细胞的形态学改变通过图象分析加以研究。结果,本发明化合物对小梁网细胞显示出卓越的形态学改变作用。因此,可认为本发明化合物具有卓越的眼內压降低作用。
本发明化合物主要以非肠道方式给药,也可以口服给药。剂型的例子为滴眼剂,注射剂,片剂,胶囊剂,颗粒剂等。本发明化合物可按常规方法制成制剂。例如,滴眼剂可通过可选地使用下列物质加以制备:等渗剂例如氯化钠或浓甘油;缓冲液例如磷酸钠或乙酸钠;表面活性剂例如聚氧乙烯山梨醇单油酸酯,硬脂酸-40-聚烃氧基酯,或聚氧乙烯氢化蓖麻油;稳定剂例如柠檬酸钠或乙二胺四乙酸二钠盐;防腐剂例如苯扎氯铵或对羟基苯甲酸酯;等。pH值可在眼药制剂允许的范围,优选在4到8的范围。口服剂例如片剂,胶囊剂和颗粒剂的制备,可选的可通过使用稀释剂例如乳糖,淀粉,结晶纤维素或植物油;润滑剂例如硬酯酸镁或滑石粉;粘合剂例如羟丙基纤维素或聚乙烯吡咯烷酮;绷解剂例如羧甲基纤维素钙;包衣剂例如羟丙基甲基纤维素,大粒凝胶(macrogol)或硅氧烷树脂;或明胶成膜试剂加以制备。
本发明化合物的剂量可根据症状,年龄,剂型等加以适当选择。在滴眼液的情况下,可使用它们的浓度为0.001到3%(w/v)的溶液每天滴注一次到多次,对于口服制剂,通常每天的剂量为1到1000毫克,可以给予单剂量或多个均分剂量。
本发明化合物的制备,制剂和药理实验结果如下所示。这些实施例并不限制本发明的范围,而是使人们更清楚的理解本发明。
本发明的最好实施方式化合物制备:参考实施例1:4-(苯基乙酰基)肉桂酸(参考化合物No.1-1)
1)向4-羧基肉桂酸乙酯(2.0g)的氯仿(4ml)溶液中,在氮气氛下滴加亚硫酰氯(3.3ml),而后向其中加入一滴二甲基甲酰胺,将混合物回流30分钟。反应混合物在减压下浓缩,得到相应酰基氯的残余物。将残余物在氮气氛下溶于四氢呋喃(30ml)中,溶液用干冰冷却。向其中滴加苄基氯化镁在四氢呋喃(4.5ml)的2.0M溶液。滴加完成十二分钟后,向用干冰冷却的反应混合物中加入10%的柠檬酸水溶液,而后升温至室温,而后全部用乙醚提取。有机层用水和饱和盐水依次洗涤,用无水硫酸镁干燥,并减压浓缩。得到的残余物用硅胶柱色谱法提纯,得到结晶的4-(苯基乙酰基)肉桂酸乙酯(675mg)。
熔点110.5℃~111.3℃
IR(KBr,cm-1)2986,1690,1410,1330,1206,970,704
2)在氮气氛下,向4-(苯基乙酰基)肉桂酸乙酯(675mg)在乙醇(6ml)-四氢呋喃(6ml)的溶液中加入1N氢氧化钠水溶液(2.3ml)和水(4ml),将混合物在室温下搅拌6.5小时。向反应混合物中加入1N盐酸将其酸化,反应液整体用乙酸乙酯提取。有权层用饱和盐水洗涤,用无水硫酸镁干燥,并在减压下浓缩。将得到的沉淀过滤,得到标题化合物(参考化合物No.1-1)的结晶。
(参考化合物No.1-1)
熔点232℃~236℃(分解)
IR(KBr,cm-1)3036,2589,1684,1630,1337,1230,993
下面的化合物可按与参考实施例1类似的方法制备得到。
·4-[(4-甲苯基)乙酰基]肉桂酸(参考化合物No.1-2)
·4-[(4-氟苯基)乙酰基]肉桂酸(参考化合物No.1-3)
1)在冰浴冷却下向无水氯化铝(4.27g)的1,2-二氯乙烷(30ml)溶液中加入苯基乙酰氯(3.4ml),而后向其中滴加3-苯基丙酸乙酯(5.1g)的无水1,2-二氯乙烷(5ml)溶液。将混合物在冰冷却下搅拌20分钟,并在室温下过夜。将反应混合物一点一点地加入到含有冰(100g)的饱和碳酸氢钠水溶液(150ml)中。将得到的沉淀过滤除去。向滤液中加入乙醚。有机层用饱和碳酸氢钠水溶液和饱和盐水依次洗涤,用无水硫酸镁干燥,并减压浓缩。得到的残余物用硅胶柱色谱法提纯,得到结晶的3-[4-(苯基乙酰基)苯基]丙酸乙酯。
熔点50.5℃~52.5℃
IR(KBr,cm-1)3059,2977,2921,1735,1682,1605,1479,1455,1437,1357,1316,1181,822
2)向3-[4-(苯基乙酰基)苯基]丙酸乙酯(700mg)在乙醇(6ml)-四氢呋喃(3ml)的溶液中加入1N氢氧化钠水溶液(3.1ml),将混合物在室温下搅拌两小时。向反应混合物中加入10%柠檬酸水溶液将其酸化,反应液整体用乙酸乙酯提取。有机层用水和饱和盐水依次洗涤,用无水硫酸钠干燥,并在减压下浓缩。得到的沉淀过滤,得到标题化合物(参考化合物No.2-1)的结晶。
(参考化合物No.2-1)
熔点132℃~137℃
IR(KBr,cm-1)3497,3028,1680,1607,1498,1455,1348,1221,1182,992,826
参考实施例3:
N,N-二甲基-4-(苯基乙酰基)肉桂酰胺(参考化合物No.3-1)
向4-(苯基乙酰基)肉桂酸(参考化合物No.1-1,3.23g)在无水四氢呋喃(120ml)-氯仿(20ml)中的溶液中加入1-羟基苯并三唑(1.64g),二甲基胺盐酸盐(1.19g),N-甲基吗啉(3.1ml)和1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺盐酸盐(2.56g),将混合物在室温下搅拌5小时。反应混合物在减压下浓缩,向浓缩液中加入10%柠檬酸水溶液,整个用乙酸乙酯提取。有机层用水,饱和碳酸氢钠水溶液,水,饱和盐水依次洗涤,用无水硫酸镁干燥,并在减压下浓缩。过滤得到的沉淀,得到标题化合物(参考化合物No.3-1,3.00g)的结晶。
(参考化合物No.3-1)
熔点:138.5℃~141.5℃
IR(KBr,cm-1)3030,1684,1653,1604,1498,1413,1328,1205,992,967
下面化合物是按照与参考实施例3类似的方法得到的。
·N,N-二甲基-3-[4-(苯基乙酰基)苯基]丙酰胺(参考化合物No.3-2)
熔点:125℃~131℃
IR(KBr,cm-1)3028,2908,1684,1640,1604,1495,1452,1407,1141
·N,N-二甲基-4-[(4-甲苯基)乙酰基]肉桂酰胺(参考化合物No.3-3)
·N,N-二甲基-4-[(4-氟苯基)乙酰基]肉桂酰胺(参考化合物No.3-4)
·4-[(4-氯苯基)乙酰基]-N,N-二甲基肉桂酰胺(参考化合物No.3-5)
·4-(苯基乙酰基)肉桂酰胺(参考化合物No.3-6)
实施例1:
在冰冷却下,氮气氛下,将N,N-二甲基-4-(苯基乙酰基)肉桂酰胺(参考化合物No.3-1,3.00g)在无水四氢呋喃(72ml)中的溶液,滴加到氢化铝锂(0.58g)在无水四氢呋喃(30ml)中的悬浊液中。全部加完后,混合物在室温下搅拌20分钟。
向反应混合物中加入无水硫酸钠,并在搅拌下向其中滴加水。过滤除去得到的不溶性物质,滤液在减压下浓缩。得到的残余物通过硅胶柱色谱提纯,并溶解在4.0N氯化氢的乙酸乙酯溶液中。真空浓缩后,过滤得到的沉淀,得到标题化合物(化合物No.1-1,0.80g)结晶。
(化合物No.1-1)
熔点:152℃~164℃
IR(KBr,cm-1)3334,2954,2664,1650,1418,1161,1034,984,752,708
下面的化合物可通过与实施例1类似的方法得到。
·1-[4-[3-(二甲基氨基)丙基]苯基]-2-苯基-1-乙醇(化合物No.1-2)
IR(膜,cm-1)3026,2941,2860,2778,1495,1454,1042
·1-[4-[(E)-3-(二甲基氨基)-1-丙烯基]苯基]-2-(4-甲苯基)-1-乙醇(化合物No.1-3)
·1-[4-[(E)-3-(二甲基氨基)-1-丙烯基]苯基]-2-(4-氟苯基)-1-乙醇(化合物No.1-4)
·2-(4-氯苯基)-1-[4-[(E)-3-(二甲基氨基)-1-丙烯基]苯基]-1-乙醇(化合物No.1-5)
·1-[4-[(E)-3-氨基-1-丙烯基]苯基]-2-苯基-1-乙醇(化合物No.1-6)
实施例2:
用乙酸酐在吡啶中处理1-[4-[(E)-3-氨基-1-丙烯基]苯基]-2-苯基-1-乙醇(化合物No.1-6)得到标题化合物(化合物No.2-1)。
实施例3:
在室温搅拌下向1-[4-[(E)-3-(二甲基氨基)-1-丙烯基]苯基]-2-苯基-1-乙醇盐酸盐(化合物No.1-1,800mg)的二甲亚砜(15ml)溶液中加入三乙胺(2.1ml),而后向其中进一步滴加三氧化硫-吡啶复合物(1.6g)的二甲亚砜(10ml)溶液。将混合物在室温下搅拌三小时,向反应混合物中加入0.1N氢氧化钠水溶液,整体用乙醚提取。有机层用饱和盐水洗涤,用无水硫酸镁干燥,并在减压下浓缩。得到的残余物用硅胶柱色谱提纯得到标题化合物(化合物No.3-1,270mg)结晶。
(化合物No.3-1)
IR(KBr,cm-1)2767,1682,1599,1452,1408,1332,1219,1175,975,726,697
下面的化合物可通过与实施例3类似的方法得到。
·1-[4-[3-(二甲基氨基)丙基]苯基]-2-苯基-1-乙酮(化合物No.3-2)
熔点:37.8℃~40.0℃
IR(KBr,cm-1)2809,2758,1682,1601,1565,1493,1453,1409
·1-[4-[(E)-3-(二甲基氨基)-1-丙烯基]苯基]-2-(4-甲苯基)-1-乙酮(化合物No.3-3)
·1-[4-[(E)-3-(二甲基氨基)-1-丙烯基]苯基]-2-(4-氟苯基)-1-乙酮(化合物No.3-4)
·2-(4-氯苯基)-1-[4-[(E)-3-(二甲基氨基)-1-丙烯基]苯基]-1-乙酮(化合物No.3-5)
·1-[4-[(E)-3-(乙酰氨基)-1-丙烯基]苯基]-2-苯基-1-乙酮(化合物No.3-6)
实施例4:
1-[4-[(E)-3-(二甲基氨基)-1-丙烯基]苯基]-2-苯基-2-丙烯-1-酮(化合物No.4-1)
将1-[4-[(E)-3-(二甲基氨基)-1-丙烯基]苯基]-2-苯基-1-乙酮(化合物No.3-1,200mg)的二噁烷(10ml)溶液导入压力管中。向该溶液中加入多聚甲醛(86mg),二甲胺盐酸盐(233mg),乙酸(一滴)和无水硫酸镁(1g),将混合物加热到120℃搅拌过夜。在冰冷却下向反应混合物中加入饱和碳酸氢钠水溶液进行碱化,整体用乙酸乙酯提取。有机层用饱和盐水洗涤,用无水硫酸镁干燥,并在减压下浓缩。得到的残余物用硅胶柱色谱提纯得到标题化合物(化合物No.4-1,145mg)。
(化合物No.4-1)
IR(膜,cm-1)2941,2771,1664,1601,1412,1217,1175,980,700
下面的化合物可通过类似于实施例4的方法得到
·1-[4-[3-(二甲基氨基)丙基]苯基]-2-苯基-2-丙烯-1-酮(化合物No.4-2)
IR(KBr,cm-1)3416,3027,2942,2814,2765,1665,1604,1465,1415,981,915
·1-[4-[(E)-3-(二甲基氨基)-1-丙烯基]苯基]-2-(4-甲苯基)-2-丙烯-1-酮(化合物No.4-3)
·1-[4-[(E)-3-(二甲基氨基)-1-丙烯基]苯基]-2-(4-氟苯基)-2-丙烯-1-酮(化合物No.4-4)
·2-(4-氯苯基)-1-[4-[(E)-3-(二甲基氨基)-1-丙烯基]苯基]-2-丙烯-1-酮(化合物No.4-5)
·1-[4-[(E)-3-(乙酰氨基)-1-丙烯基]苯基]-2-苯基-2-丙烯-1-酮(化合物No.4-6)
制剂:
使用本发明化合物制备滴眼剂和口服制剂的制剂实施例如下所示。
1)滴眼剂
在10ml中
本发明化合物 1mg
浓缩的甘油 250mg
聚山梨酯80 200mg
二水合磷酸二氢钠 20mg
1N氢氧化钠 适量
1N盐酸 适量
无菌纯化水 足量
2)片剂
在100mg中
本发明化合物 1mg
乳糖 66.4mg
玉米淀粉 20mg
羧甲基纤维素钙 6mg
羟丙基纤维素 6mg
硬脂酸镁 0.6mg
药理实验:
为了研究本发明化合物在青光眼中的用途,研究了本发明化合物对小梁网细胞形态的影响。
1)对小梁网细胞形态的作用
已经有人报道了以下可能性,即具有提高水性液体流出作用的药物可通过评价药物对培养的小梁网细胞的形态的作用而发现(Invest.Ophthalmol.Vis.Sci.,33,2631-2640(1992))。因此,按照上述文献所描述的相似方法研究本发明化合物对培养的牛小梁网细胞形态的作用。
实验方法:
通过图像分析,对在培养的牛小梁网细胞中加入本发明化合物而造成的形态学改变加以定量评价。
细胞的制备:
在用于哺乳动物细胞培养的基础培养基D-MEM(Dulbecco’s修饰的伊格尔氏培养基,由Gibco Co.,Ltd.制造)中进行牛小梁网细胞(传代数2到5)的培养,该培养基含有胎牛血清(10%),两性霉素B(2.5μg/ml)和庆大霉素(50μg/ml),在随后的药品处理的24小时之前用胰蛋白酶-EDTA溶液(0.05%胰蛋白酶,0.53mM EDTA·4Na)处理,并接种在24-孔板中(104个细胞/孔)。在随后的药品处理12小时之前,将细胞用磷酸缓冲的生理盐水洗涤,而后将培养基换成含有两性霉素B(2.5μg/ml)和庆大霉素(50μg/ml)的D-MEM(在下文中称为“培养基A”)。在随后的药品处理的一小时之前,从上述制备的细胞中筛选出互相不接触的细胞并用于实验。
试验化合物溶液的制备:
将试验化合物溶于二甲亚砜(DMSO)中,向溶液中加入培养基A,而后通过过滤将溶液灭菌。而后再将培养基A加入而将其稀释到指定浓度。该稀释的溶液在随后的药品处理的一小时前,在37℃在5%二氧化碳气氛下,保持等温状态一小时,以制备试验化合物溶液。
测定方法:
首先,在药品处理前一小时,用孔扫描仪对细胞拍照。接着,将细胞培养基用试验化合物溶液替换,将细胞用药品处理,并在37℃在5%二氧化碳气氛下培养3小时。而后,将与用药品处理一小时之前拍过照的细胞相同的细胞用孔扫描仪拍照。
图像分析:
用CCD照相机(由HAMAMATU Co.,Ltd.公司制造)将拍摄的细胞图像从照片插入到图像分析系统中。描绘插入的细胞图像轮廓,并测定面积。由试验化合物造成的小梁网细胞形态学改变的程度通过下面的面积的改变率(%)表示。
面积的改变率(%)=[(A-B)/A]×100
A:药品处理前的细胞面积
B:药品处理后的细胞面积
结果:
表1显示减少小梁网细胞的细胞面积的50%所需的浓度,即EC50值,作为测试结果的实例。表1也显示了使用利尿酸作为对照药品的结果。
表1
试验化合物 | EC50(M) |
化合物No.4-1 | 5.8×10-7 |
化合物No.4-2 | 8.4×10-7 |
利尿酸 | 6.2×10-5 |
表1显示本发明化合物对小梁网细胞具有出色的细胞形态学的改变作用。这些作用大大地高于已知的用于比较的对照药物利尿酸的作用。
上述的结果表明本发明化合物具有出色的细胞形态学改变作用,可用作眼内压降低剂,即可作为青光眼的治疗剂。
工业实用性:
本发明提供了通过导致小梁网细胞的形态学改变而降低眼内压的化合物。这些化合物可用作青光眼的治疗剂。
Claims (8)
2.如权利要求1的化合物或其盐,其中R3和/或R4为氢,而且氨基被保护基保护。
3.如权利要求1的化合物或其盐,其中:
1)R1为选自氢。低级烷基和卤素的基团;和/或
2)R2为氢;和/或
3)R3和R4都为低级烷基。
4.一种选自下面一组的化合物:1-[4-[(E)-3-(二甲基氨基)-1-丙烯基]苯基-2-苯基-2-丙烯-1-酮和1-[4-[3-(二甲基氨基)丙基]苯基-2-苯基-2-丙烯-1-酮或其盐。
5.一种药物组合物,包含权利要求1所要求的化合物或其盐作为活性组分。
6.一种水状液流出改进剂,包含权利要求1所要求的化合物或其盐作为活性组分。
7.一种眼内压降低剂,包含权利要求1所要求的化合物或其盐作为活性组分。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP893799 | 1999-01-18 | ||
JP8937/1999 | 1999-01-18 |
Publications (2)
Publication Number | Publication Date |
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CN1336910A true CN1336910A (zh) | 2002-02-20 |
CN1179940C CN1179940C (zh) | 2004-12-15 |
Family
ID=11706593
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB008028680A Expired - Fee Related CN1179940C (zh) | 1999-01-18 | 2000-01-12 | 1,2-二苯基-2-丙烯-1-酮衍生物 |
Country Status (8)
Country | Link |
---|---|
US (1) | US6395932B1 (zh) |
EP (1) | EP1142865B1 (zh) |
KR (1) | KR20010101535A (zh) |
CN (1) | CN1179940C (zh) |
AT (1) | ATE243187T1 (zh) |
CA (1) | CA2359470A1 (zh) |
DE (1) | DE60003386D1 (zh) |
WO (1) | WO2000041993A1 (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2375522T3 (es) * | 2006-12-26 | 2012-03-01 | Santen Pharmaceutical Co., Ltd | Nuevo derivado de n-(2-aminofenil)benzamida con estructura urea. |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0074005B1 (de) * | 1981-08-29 | 1985-05-02 | BASF Aktiengesellschaft | Phenylpropylammoniumsalz enthaltende Fungizide und Verfahren zur Bekämpfung von Pilzen |
EP0228415B1 (en) * | 1985-06-14 | 1993-05-26 | MASSACHUSETTS EYE & EAR INFIRMARY | Increasing aqueous humor outflow |
JPH0713013A (ja) | 1993-06-29 | 1995-01-17 | Casio Comput Co Ltd | カラーフィルタとブラックマスクの形成方法 |
-
2000
- 2000-01-12 KR KR1020017008918A patent/KR20010101535A/ko not_active Application Discontinuation
- 2000-01-12 DE DE60003386T patent/DE60003386D1/de not_active Expired - Lifetime
- 2000-01-12 CA CA002359470A patent/CA2359470A1/en not_active Abandoned
- 2000-01-12 WO PCT/JP2000/000094 patent/WO2000041993A1/ja not_active Application Discontinuation
- 2000-01-12 CN CNB008028680A patent/CN1179940C/zh not_active Expired - Fee Related
- 2000-01-12 EP EP00900335A patent/EP1142865B1/en not_active Expired - Lifetime
- 2000-01-12 AT AT00900335T patent/ATE243187T1/de not_active IP Right Cessation
- 2000-01-12 US US09/889,140 patent/US6395932B1/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
US6395932B1 (en) | 2002-05-28 |
ATE243187T1 (de) | 2003-07-15 |
DE60003386D1 (de) | 2003-07-24 |
CN1179940C (zh) | 2004-12-15 |
EP1142865B1 (en) | 2003-06-18 |
KR20010101535A (ko) | 2001-11-14 |
EP1142865A1 (en) | 2001-10-10 |
EP1142865A4 (en) | 2002-07-03 |
CA2359470A1 (en) | 2000-07-20 |
WO2000041993A1 (fr) | 2000-07-20 |
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