CN1414946A - 衍生于(rr,ss)-3-(2-二甲基氨甲基-1-羟基环己基)苯基2-羟基苯甲酸酯的新酯 - Google Patents
衍生于(rr,ss)-3-(2-二甲基氨甲基-1-羟基环己基)苯基2-羟基苯甲酸酯的新酯 Download PDFInfo
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- 150000002148 esters Chemical class 0.000 title abstract description 4
- -1 3-(2-dimethylaminomethyl-1-hydroxy cyclohexyl) phenyl Chemical group 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
- 239000012442 inert solvent Substances 0.000 claims description 3
- YJGSDSMGARCJEM-UHFFFAOYSA-N CCN(CC)CC.C1=CC=CC2=NNN=C21.CC1=CC=C(S(O)(=O)=O)C=C1 Chemical compound CCN(CC)CC.C1=CC=CC2=NNN=C21.CC1=CC=C(S(O)(=O)=O)C=C1 YJGSDSMGARCJEM-UHFFFAOYSA-N 0.000 claims description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical class CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- VCKCXBLOUSAWRC-UHFFFAOYSA-N n,n-diethylethanamine;ethyl carbonochloridate Chemical compound CCOC(Cl)=O.CCN(CC)CC VCKCXBLOUSAWRC-UHFFFAOYSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims 1
- 230000003287 optical effect Effects 0.000 claims 1
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 abstract description 20
- 229960004380 tramadol Drugs 0.000 abstract description 17
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 abstract description 17
- 230000000202 analgesic effect Effects 0.000 abstract description 10
- ZQBAKBUEJOMQEX-UHFFFAOYSA-N phenyl salicylate Chemical compound OC1=CC=CC=C1C(=O)OC1=CC=CC=C1 ZQBAKBUEJOMQEX-UHFFFAOYSA-N 0.000 abstract 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 206010022998 Irritability Diseases 0.000 description 6
- 230000001186 cumulative effect Effects 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- UWJUQVWARXYRCG-UHFFFAOYSA-N o-desmethyltramadol Chemical compound CN(C)CC1CCCCC1(O)C1=CC=CC(O)=C1 UWJUQVWARXYRCG-UHFFFAOYSA-N 0.000 description 6
- 239000008896 Opium Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000006260 foam Substances 0.000 description 5
- 229960001027 opium Drugs 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000010520 demethylation reaction Methods 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000017858 demethylation Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 3
- 231100000027 toxicology Toxicity 0.000 description 3
- 206010010774 Constipation Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 230000029058 respiratory gaseous exchange Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- XVMIKRZPDSXBTP-UHFFFAOYSA-N 1,3-dibromobutan-2-one Chemical compound CC(Br)C(=O)CBr XVMIKRZPDSXBTP-UHFFFAOYSA-N 0.000 description 1
- RMWVZGDJPAKBDE-UHFFFAOYSA-N 2-acetyloxy-4-(trifluoromethyl)benzoic acid Chemical compound CC(=O)OC1=CC(C(F)(F)F)=CC=C1C(O)=O RMWVZGDJPAKBDE-UHFFFAOYSA-N 0.000 description 1
- LWXFCZXRFBUOOR-UHFFFAOYSA-N 4-chloro-2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1O LWXFCZXRFBUOOR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 229920005372 Plexiglas® Polymers 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000026781 habituation Effects 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000009191 jumping Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/26—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C219/28—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton having amino groups bound to acyclic carbon atoms of the carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明涉及衍生于(RR,SS)-3-(2-二甲基氨甲基-1-羟基环己基)苯基2-羟基苯甲酸酯的新酯,一种曲马朵的类似物,制备它们的方法和这些化合物在制备具有镇痛性质的药剂中的用途。这些通式(I)的新产品显示高于曲马朵的镇痛活性。
Description
发明领域
本发明涉及衍生于(RR,SS)-3-(2-二甲基氨甲基-1-羟基环己基)苯基2-羟基苯甲酸酯的新酯,一种曲马朵的类似物。所得的化合物显示高于曲马朵的镇痛活性。
发明背景
疼痛的治疗在医学领域具有第一重要性。目前用于疼痛治疗的药理学制剂主要地包括两大组:鸦片类化合物和非甾体抗炎药物(NSAIDs)。NSAIDs仅仅用于轻度至中度疼痛的情形;严重疼痛传统上以鸦片类化合物治疗。然而,所述鸦片类化合物存在一系列不希望的副作用,例如便秘、呼吸抑制和耐受性及成瘾性。
美国专利3652589介绍了一类具有取代环烷醇苯酚酯结构的镇痛化合物,它在环烷基环上具有碱性特征的氨基基团。它们中,化合物(1R,2R或1S,2S)-2-[(二甲氨基)甲基]-1-(3-甲氧苯基)环己醇、通称为曲马朵可以用于缓解,并且在所述的专利中专门要求保护它。
曲马朵
荷兰专利NL6610022中公开了一系列衍生于先前类的产品,其中在环烷醇环中出现脱水和在苯环发生3-甲氧基脱甲基作用,产品结构如下:
此专利也介绍了衍生于前述美国专利的那些化合物的产品,其中苯环3-位的甲氧基被脱甲基即,具有如下结构的产品:
在此专利介绍的产品中包括邻-脱甲曲马朵,该化合物已被描述为曲马朵脱甲基产品的一种(Von W.Lintz和col.Arzneim-Forsch(Drug Res)31(II);1932-43(1981)。其(+)异构体是曲马朵镇痛活性的起因(Lars Poulsen和col.Clin.Pharmacol.Ther(St.Louis)1996,60(6),636-644)。虽然如此,尚无代谢物邻-脱甲曲马朵临床用途的数据。
最近,EP753506中描述了新的邻-脱甲基取代的、1-卤代和/或3-环己基取代的曲马朵衍生物。
曲马朵具有鸦片类兴奋作用。然而,曲马朵的临床实践表明,尽管这种事实,它并不具有某些鸦片类激动剂的典型副作用,例如呼吸抑制(W.Vogel和col.Arzneim.Forsch(Drug Res)28(I),183(1978))、便秘(I.Arend和col.,Arzneim.Forsch(Drug Res)28(I),199(1978)、耐受性(L.Flohe等,Arzneim.Forsch(Drug Res)28(I),213(1978)、滥用可能性(T.Yenagita等,Arzneim.Forsch(Drug Res)28(I),158(1978))。已发现了当其静脉内途径(i.v.)迅速注射时引起的曲马朵的一些特定的副作用,例如窒息和出汗。
由曲马朵显示的另外的缺点是其作用持续时间短(T.Matthiesen,T.Wohrmann,T.P.Coogan,H.Uragg.“The experimental toxicology ofTramadol:an overview”,《毒理学通报》(Toxicology letters),95,63-71,(1998))。
由于先前的背景,我们关心具有改善镇痛活性的新化合物。
发明的说明
本发明涉及衍生于(RR,SS)-3-(2-二甲基氨甲基-1-羟基环己基)苯基2-羟基苯甲酸酯的新的衍生物,一种曲马朵的类似物。
已证明这些化合物的镇痛活性高于曲马朵的活性。
尤其,本发明描述和要求保护了通式(I)的产品、它们的盐和旋光异构体,以及它们的制备方法。本发明也涉及这些化合物在制备用于治疗疼痛的药物上的用途。
*表示不对称碳的可能性
其中:
-R1是卤素、任意取代的C1-C6烷基、OR3、NO2或者任意取代的芳基,这里R3是C1-C6烷基。
-R2是H或CH3CO-。
优选地,R1是卤素,例如F、Cl、Br、卤素取代的苯基或氢化(C1-C6氟代烷基)。
特别地,本发明优选的化合物是:
-(RR-SS)-2-乙酸基-4-三氟甲基-苯甲酸3-(2-二甲氨基甲基-1-羟基-环己基)-苯基酯
-(RR-SS)-2-羟基-4-三氟甲基-苯甲酸3-(2-二甲氨基甲基-1-羟基-环己基)-苯基酯
-(RR-SS)-4-氯-2-羟基-苯甲酸3-(2-二甲氨基甲基-1-羟基-环己基)-苯基酯
-(RR-SS)-2-羟基-4-甲基-苯甲酸3-(2-二甲氨基甲基-1-羟基-环己基)-苯基酯
-(RR-SS)-2-羟基-4-甲氧基-苯甲酸3-(2-二甲氨基甲基-1-羟基-环己基)-苯基酯
-(RR-SS)-2-羟基-5-硝基-苯甲酸3-(2-二甲氨基甲基-1-羟基-环己基)-苯基酯
-(RR-SS)-2′,4′-二氟-3-羟基-联苯基-4-羧酸3-(2-二甲氨基甲基-1-羟基-环己基)-苯基酯
通式(I)的化合物可以通过下列亦在本发明范围之内的步骤得到。
方法的说明
方法A
本发明通式(I)的化合物可通过特征在于将式(II)的化合物和相应的通式(III)的酸或酸衍生物反应的通常方法得到:其中R1和R2具有以上定义的含义,并且L=OH、卤素、
O-R4或-CO-R5,这里
R4=C1-C6烷基、苯基、任意取代的苯基,
和
R5=烷基、被一个或多个取代基任意取代的苯环或被一个或多个取代基任意取代的杂环。
优选地,L是OH或卤素。
反应在惰性溶剂中进行,例如二氯甲烷、四氢呋喃、乙腈、1,2-二氯乙烷、乙酸乙酯、二甲氧基乙烷或二噁烷,优选二氯甲烷或四氢呋喃,温度为-20℃至120℃,优选0℃至35℃,得到高纯度的化合物,并且优选在缩合促进剂存在的条件下加速反应,例如羰基二咪唑、二环己基碳化二亚胺、三乙胺乙基氯甲酸酯、三乙胺苯并三唑甲苯磺酸酯或二乙基氯代磷酸盐,优选羰基二咪唑或二环己基碳化二亚胺。
按照文献(NL6610022或Flick等,Arzneim.Forsch/Drug Res.(1978),28(I),107-113)描述的方法得到式(II)的化合物。
方法B
(R2=CH3CO) (R2=H)
其中R1具有以上定义的含义。
下一步,描述用于确定化合物的药理学活性的方法。
镇痛活性测试
热板法
采用的方法是Eddy N.B.和Leimbach D.介绍的(J.Pharm.Exp.Ther.107:385-393,1953)。产品的镇痛作用通过分析动物在保持为55℃±1℃的热表面上的行为进行评估。
采用重20-25g的雄性瑞士小鼠。开始试验1小时之前,通过口服途径给予试验化合物。
此方法包括将动物放在热板上,同时置于25cm直径和21cm高的有机玻璃(Plexiglas)圆筒内,测定它们跳离热表面需要的时间。在试验开始之前选择动物,以使超过10秒仍然未跳的那些不包括在接受治疗组内。
给予研究的产品之后,重复试验,再测量在热板上的最大持久时间。从板上移去60秒后仍不跳跃的动物以便避免对动物的损害,将它们作为被100%保护。
结果表示为跳跃时间(t)的百分比增量,按如下计算:
本发明的目的之一是采用通式(I)的化合物制备用于疼痛治疗的药物。同样,本发明的又一项目的是用于治疗疼痛的药物组合物,它包括所述的通式(I)的化合物和药学上可接受的赋形剂。
实验
下一步,阐述下列举例说明性实施例,但是它们并不构成本发明范围的限制:
合成实施例
实施例N°1
(RR-SS)-2-乙酸基-4-三氟甲基-苯甲酸3-(2-二甲氨基甲基-1-羟基-环己基)-苯基酯
在室温和惰性空气下,向15.0g(60.5mmol)4-三氟甲基乙酰基水杨酸的150ml无水四氢呋喃溶液中加入9.3g(57.4mmol)羰基二咪唑。三十分钟之后,加入13.1g(52.6mmol)3-(2-二甲氨基甲基-1-羟基环己基)苯酚。所得的溶液在室温保持3天。将混合物加入到pH8的NaHCO3水溶液中,并以二氯甲烷萃取(3×50ml)。经Na2SO4干燥合并的有机萃取物、过滤和减压浓缩得到残余物,该残余物通过硅胶柱色谱纯化(洗脱剂:9∶1二氯甲烷/丙酮和渐增量的丙酮),由此得到20g油状标题化合物。
1H-NMR(CDCl3):1.20-2.25(m,16H)包括2.15(s,6H);2.30(s,3H);2.45(dd,1H);7.08(m,1H);7.15-7.50(m,5H);8,35(m,1H)。
实施例N°2
(RR-SS)-2-羟基-4-三氟甲基-苯甲酸3-(2-二甲氨基甲基-1-羟基-环己基)-苯基酯
将实施例1的化合物溶于600ml异丙醇和25ml 35%盐酸中。将所得溶液40℃搅拌16小时。蒸发异丙醇,令残余物溶于100ml二氯甲烷,并加入pH8的100mlNaHCO3水溶液。进行产物的萃取,水相以新鲜二氯甲烷部分洗涤(2×50ml)。经Na2SO4干燥合并的有机萃取物,然后过滤和减压浓缩。将所得的粗产物通过硅胶柱色谱纯化(洗脱剂:9∶1二氯甲烷/丙酮和渐增量的丙酮),由此得到12.4g(57%)白色泡沫状标题化合物。
1H-NMR(CDCl3):1.20-2.30(m,16H)包括2.15(s,6H);2.45(dd,1H);7.08(m,1H);7.15-7.35(m,2H);7.45(m,3H);8.20(m,1H);10.50(br.s,1H)。
实施例N°3
(RR-SS)-4-氯-2-羟基-苯甲酸3-(2-二甲氨基甲基-1-羟基-环己基)-苯基酯
在室温和惰性空气下,向10.0g(58.0mmol)4-氯水杨酸的150ml无水四氢呋喃溶液中加入8.9g(54.9mmol)羰基二咪唑。三十分钟之后,加入12.6g(50.6mmol)3-(2-二甲氨基甲基-1-羟基环己基)苯酚。所得的溶液在室温保持3天。将混合物加入pH8的NaHCO3水溶液中,并以二氯甲烷萃取(3×50mml)。经Na2SO4干燥合并的有机萃取物,接着过滤和减压浓缩。所得的残余物通过硅胶柱色谱纯化(洗脱剂:9∶1二氯甲烷/丙酮和渐增量的丙酮),由此得到12.2g(66%)白色泡沫状标题化合物。
1H-NMR(CDCl3):1.20-2.20(m,16H)包括2.12(s,6H);2.45(dd,1H);6.95(dd,1H);7.05(m,2H);7.43(m,3H);8.05(d,1H);10.60(br.s,1H)。
实施例N°4
以与描述的制备实施例3的化合物相同的方法操作,从10.0g(65.7mmol)4-甲基水杨酸、10.0g(61.7mmol)羰基二咪唑、14.3g(57.4mmol)3-(2-二甲氨基甲基-1-羟基环己基)苯酚和165ml无水四氢呋喃开始,并且在硅胶柱色谱之后(洗脱剂:9∶1二氯甲烷/丙酮和渐增量的丙酮),得到14.6g(66%)白色泡沫状标题化合物。
1H-NMR(CDCl3):1.20-2.60(m,20H)包括2.15(s,6H)和2.20(s,3H);6.80(m,2H);7.05(m,1H);7.45(m,3H);7.95(d,1H);10.55(s,1H)。
实施例N°5
以与描述的制备实施例3的化合物相同的方法操作,从10.0g(59.5mmol)4-甲氧基水杨酸、9.1g(56.2mmol)羰基二咪唑、12.9g(51.8mmol)3-(2-二甲氨基甲基-1-羟基环己基)苯酚和150ml无水四氢呋喃开始,并且在硅胶柱色谱之后(洗脱剂:9∶1二氯甲烷/丙酮和渐增量的丙酮),得到13.7g(66%)白色泡沫状标题化合物。
1H-NMR(CDCl3):1.20-2.30(m,16H)包括2.15(s,6H);2.45(dd,1H);3.85(s,3H);6.55(m,2H);7.07(m,1H);7.40(m,3H);7.95(d,1H);10.75(s,1H)。
实施例N°6
(RR-SS)-2-羟基-5-硝基-苯甲酸3-(2-二甲氨基甲基-1-羟基-环己基)-苯基酯
以与描述的制备实施例3的化合物相同的方法操作,从10.0g(54.6mmol)5-硝基水杨酸、8.3g(51.2mmol)羰基二咪唑、11.9g(47.8mmol)3-(2-二甲氨基甲基-1-羟基环己基)苯酚和135ml无水四氢呋喃开始,并且在硅胶柱色谱之后(洗脱剂:1∶1二氯甲烷/丙酮和渐增量的丙酮),得到326mg(2%)黄色固体状标题化合物。
1H-NMR(CDCl3):1.20-2.30(m,16H)包括2.15(s,6H);2.45(dd,1H);7.00-7.25(m,2H);7.45(m,3H);8.40(d,1H);9.05(d,1H)。
实施例N°7
(RR-SS)-2′,4′-二氟-3-羟基-联苯基-4-羧酸3-(2-二甲氨基甲基-1-羟基-环己基)-苯基酯
以与描述的制备实施例3的化合物相同的方法操作,从5.0g 2′,4′-二氟-3-羟基-联苯基-4-羧酸、3.5g羰基二咪唑、5.0g 3-(2-二甲氨基甲基-1-羟基环己基)苯酚和50ml无水四氢呋喃开始,并且在硅胶柱色谱之后,得到4.1g白色泡沫状标题化合物。
1H-NMR(CDCl3):1.20-2.30(m,16H)包括2.15(s,6H);2.45(dd,1H);6.85-7.55(m,9H);7.70(m,1H);8.22(d,1H);10.60(br.s,1H)。
药理结果
下表1中显示了本发明几个产品实施例以及曲马朵的药理活性结果。结果以热板试验反应时间的增量百分比表示。
由其可看出,本发明的化合物活性高达曲马朵活性的三倍。
产品在小鼠热板实验中的镇痛活性
表1
产品80μmol/kg p.o. | 反应时间增量百分比 |
曲马朵 | 218 |
实施例1 | 710 |
实施例2 | 724 |
实施例3 | 400 |
实施例4 | 525 |
实施例5 | 688 |
实施例6 | 661 |
实施例7 | 686 |
Claims (10)
1.通式(I)的化合物及其盐和光学异构体:
其中:
-R1是卤素、任意取代的C1-C6烷基、OR3、NO2或者任意取代的芳基,这里R3是C1-C6烷基。
-R2是H或CH3CO-。
2.权利要求1的化合物,其特征在于R1是卤素,例如F、Cl、Br、卤素取代的苯基或氢化(C1-C6氟代烷基)。
3.权利要求1的化合物,其特征在于它选自以下的一种:
-(RR-SS)-2-乙酸基-4-三氟甲基-苯甲酸3-(2-二甲氨基甲基-1-羟基-环己基)-苯基酯
-(RR-SS)-2-羟基-4-三氟甲基-苯甲酸3-(2-二甲氨基甲基-1-羟基-环己基)-苯基酯
-(RR-SS)-4-氯-2-羟基-苯甲酸3-(2-二甲氨基甲基-1-羟基-环己基)-苯基酯
-(RR-SS)-2-羟基-4-甲基-苯甲酸3-(2-二甲氨基甲基-1-羟基-环己基)-苯基酯
-(RR-SS)-2-羟基-4-甲氧基-苯甲酸3-(2-二甲氨基甲基-1-羟基-环己基)-苯基酯
-(RR-SS)-2-羟基-5-硝基-苯甲酸3-(2-二甲氨基甲基-1-羟基-环己基)-苯基酯
-(RR-SS)-2′,4′-二氟-3-羟基-联苯基-4-羧酸3-(2-二甲氨基甲基-1-羟基-环己基)-苯基酯。
5.按照权利要求4的方法,其特征在于加入缩合促进剂。
6.按照权利要求4的方法,其特征在于所述惰性溶剂选自二氯甲烷、四氢呋喃、乙腈、1,2-二氯乙烷、乙酸乙酯、二甲氧基乙烷或二噁烷,优选二氯甲烷或四氢呋喃。
7.按照权利要求5的方法,其特征在于所述缩合促进剂选自羰基二咪唑、二环己基碳化二亚胺、三乙胺乙基氯甲酸酯、三乙胺苯并三唑甲苯磺酸酯或二乙基氯代磷酸盐,优选羰基二咪唑或二环己基碳化二亚胺。
8.按照权利要求4的方法,其特征在于所述温度范围是0℃至35℃。
9.按照权利要求1至3的任何通式(I)化合物在制备治疗疼痛的药物中的用途。
10.一种用于治疗疼痛的药物组合物,包括按照权利要求1至3的任何通式(I)化合物和药学上可接受的赋形剂。
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ES200000060A ES2160534B1 (es) | 1999-12-30 | 1999-12-30 | Nuevos esteres derivados de (rr,ss)-2-hidroxibenzoato de 3-(2-dimetilaminometil-1-hidroxiciclohexil) fenilo. |
ESP200000060 | 1999-12-30 |
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