WO2018141192A1 - 氘代化合物及其医药用途 - Google Patents

氘代化合物及其医药用途 Download PDF

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WO2018141192A1
WO2018141192A1 PCT/CN2018/000051 CN2018000051W WO2018141192A1 WO 2018141192 A1 WO2018141192 A1 WO 2018141192A1 CN 2018000051 W CN2018000051 W CN 2018000051W WO 2018141192 A1 WO2018141192 A1 WO 2018141192A1
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epoxy
pharmaceutically acceptable
methoxymorphinan
dissolved
ethylene
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PCT/CN2018/000051
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French (fr)
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仲伯华
王建明
杨家俊
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泰州华元医药科技有限公司
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Priority to US16/484,058 priority Critical patent/US10759809B2/en
Priority to JP2019542558A priority patent/JP7208635B2/ja
Publication of WO2018141192A1 publication Critical patent/WO2018141192A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/09—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems
    • C07D489/10—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems with a bridge between positions 6 and 14
    • C07D489/12—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems with a bridge between positions 6 and 14 the bridge containing only two carbon atoms
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to a novel deuterated N-cyclopropylmethyl-norpoxazone derivative having an analgesic effect, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound as an active ingredient, and the derivative Or a pharmaceutically acceptable salt thereof for use in the preparation of an analgesic.
  • Analgesics are one of the most commonly used drugs in the clinic.
  • potent analgesics such as morphine and dulantin have strong potential for dependence, and long-term use may cause addiction and tolerance; although non-narcotic analgesics do not rely on potential, the analgesic effect is weak and insufficient to relieve Severe pain in patients with cancer, trauma and surgery. Therefore, it is clinically necessary to provide an effective and safe analgesic new drug.
  • Buprenorphine is the most commonly used analgesic and detoxifying drug in clinical practice; ADP2 is a buprenorphine analogue that shows significantly higher analgesic activity and analgesic efficacy than buprenorphine (Master's thesis: Ding Synthesis of propofol analogues. 1999.6, graduate student: Wu Bo; instructor: Zhong Bohua).
  • both buprenorphine and ADP2 have certain addictive properties, and injection administration is effective, which limits its clinical application. Butylated propofol is continuously administered in the clinic, and there are side effects of constipation.
  • the present invention provides a compound represented by Structural Formula I and a non-toxic pharmaceutically acceptable salt thereof:
  • R1 is H, CH 3 or deuterated methyl (CD 3 );
  • R 2 is CH 3 or CH 2 CH 3 ;
  • R 3 , R 4 and R 5 are each independently H or ⁇ (D); when R 1 is H Or CH 3 , at least one of R3, R4 and R5 must be D.
  • the present invention provides a compound represented by Structural Formula I and a non-toxic pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound represented by Formula I and a non-toxic pharmaceutically acceptable salt thereof as an active ingredient, and a suitable excipient.
  • These pharmaceutical compositions may be solutions, tablets, capsules or injections; these pharmaceutical compositions may be administered by injection or orally.
  • the invention also provides the use of a compound represented by Formula I, and a non-toxic pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of pain.
  • the present invention provides the use of a compound represented by Formula I, and a non-toxic pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating a painful condition or for the preparation of a drug for detoxification.
  • the target compounds I 1-4 and I 8-11 can be prepared by the following synthetic route:
  • the target compounds of 18,19-diodes are prepared as follows:
  • magnesium powder 0.5 g was added to 10 ml of anhydrous diethyl ether, and a mixed solvent of 1.2 g of tert-butyl chloride (12 mmol) dissolved in 15 ml of anhydrous diethyl ether and 10 ml of anhydrous benzene was added dropwise with stirring to obtain a Grignard reagent; To the Grignard reagent, a solution of 4 g (10 mmol) of iii dissolved in 30 mL of diethyl ether-benzene (1:1) was added dropwise.
  • a Grignard reagent was prepared by replacing 2-butyl-2-methylbutane with tert-butyl chloride, and Grignard addition was carried out with iii to prepare (2S)-2-[(5R, 6R, 7R,14S)-N-methyl-4,5-epoxy-6,14-ethylidene-3-methoxy-6-methoxymorphinan-7-yl]-3,3-di Methyl pentan-2-ol (iv 2 ).
  • vi 2 was substituted for vi 1 and reacted with cyclopropionyl chloride to obtain (2S)-2-[(5R,6R,7R,14S)-N-cyclopropanoyl-4. 5-Epoxy-6,14-ethylidene-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol (vii 2 ).
  • vii 2 was used instead of vii 1 , and reacted with LiAlH 4 to obtain 20.58 g of ADP; ADP 2 was dissolved in ethanol, and hydrogen chloride diethyl ether solution was added thereto to pH 2, stirred, and the solid was precipitated, and after standing overnight, Filtration and washing with anhydrous diethyl ether afforded 0.43 g of ADP2 ⁇ HCl, m.p.
  • vii 1 was reacted with LiAlD 4 (%D: >98) to obtain I 1 ; I 1 was dissolved in ethanol, and salted with hydrogen chloride to obtain I 1 ⁇ HCl, melting point: > 200 ° C.
  • I 1 was used instead of buprenorphine to react with CD 3 I to obtain I 3 ;
  • I 3 was dissolved in ethanol and salted with hydrogen chloride to obtain I 3 ⁇ HCl, melting point: >200 ° C .
  • I 1 was used instead of buprenorphine to react with CH 3 I to obtain I 4 ;
  • I 4 was dissolved in ethanol and salted with hydrogen chloride to obtain I 4 ⁇ HCl, melting point: >200 ° C .
  • bromo reaction was carried out by using I 1 instead of buprenorphine to obtain (2S)-2-[(5R,6R,7R,14S)-1,2-dibromo-N-(cyclo).
  • I 6 is dissolved in ethanol and salted with hydrogen chloride to obtain I 6 ⁇ HCl, melting point: >200 ° C .
  • vi' was used instead of vi 1 to react with cyclopropionyl chloride to obtain (2S)-2-[(5R,6R,7R,14S)-N-cyclopropanoyl-4. 5-epoxy-6,14-dideuteroethylene-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylbutan-2-ol (vii') .
  • Example 2 ADP2 was used instead of buprenorphine to react with CD 3 I to obtain I 9 ; I 9 was dissolved in ethanol and salted with hydrogen chloride to obtain I 9 ⁇ HCl, melting point: >200 ° C.
  • I 8 was used instead of buprenorphine to react with CD 3 I to obtain I 10 ;
  • I 10 was dissolved in ethanol and salted with hydrogen chloride to obtain I 10 ⁇ HCl, melting point: >200 ° C .
  • I 8 was used instead of buprenorphine to react with CH 3 I to obtain I 11 ;
  • I 11 was dissolved in ethanol, and salted with hydrogen chloride to obtain I 11 ⁇ HCl, melting point: >200 ° C .
  • Example 5 replacing the buprenorphine with ADP2 and carrying out the bromination reaction to obtain (2S)-2-[(5R,6R,7R,14S)-1,2-dibromo-N-cyclopropane Methyl-4,5-epoxy-6,14-ethylidene-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol (viii 3 ); Deuteration reaction was carried out by using viii 3 instead of viii 1 to obtain I 12 ; I 12 was dissolved in ethanol, and salted with hydrogen chloride to obtain I 12 ⁇ HCl, melting point: >200 ° C.
  • Kunming mice male, placed on a hot plate at 55 °C, immediately timed, until the first occurrence of sputum or sputum hind paw, the time of arrival is the basic pain threshold before dosing; then random group, 10 animals per group After intragastric administration, the mice were placed on a hot plate at 55 ° C 1 hour after administration, and the time was up until the first occurrence of sputum or sputum hindrance. The time obtained was the post-dose pain threshold; There is no ankle or sputum hind foot for 100% analgesia. The percentage of analgesia was calculated by comparison before and after administration, and the formula was as follows:
  • SD rats Male, placed in the constant temperature water bath of 55 ° C, immediately timed, until the tip of the tail was removed from the water, this time is the basic pain threshold before administration. Then randomly grouped, 5 animals in each group; intragastric administration, 1 hour after the administration, the tip of the tail was placed in a constant temperature water bath at 55 ° C, and the time was immediately counted until the tip of the tail was removed from the water. Pain threshold after administration. In the 15s, no appendix is 100% analgesia. The percentage of analgesia was calculated by comparison before and after administration, and the formula was as follows:
  • SD rats male, weight 160-180 g were placed in a conditional position preference training box with the door open, and the rats were allowed to stay in each box within 15 min to determine the natural tendency of the rats. Rats were then randomized by white box residence time, 10 per group. The white box is used as the medicine box, and the black box is the non-medicine box.
  • the test compound was administered by intragastric administration at a dose of 3xED 50 (hot plate method), and the rats were immediately placed in a white box or a black box for 45 minutes, once a day for 9 consecutive days. On the 10th day, the rats were placed in a training box with the door open, and the residence time of the rats in the white box was measured within 15 minutes to evaluate the position preference effect of the rats.
  • Table 3 The experimental results are shown in Table 3:
  • mice Male and female, fasted 8 h before the experiment, free to drink water.
  • 3xED 50 dose (hot plate method) of the test compound was administered by gavage; suspension was prepared with 5% carbon powder and 10% methylcellulose, and the mice were given a dose of 0.2 ml/20 g 30 minutes after administration.
  • the stomach 15 minutes after gavage, was sacrificed by cervical dislocation.
  • the digestive tract was completely removed from the cardia to the end of the rectum, and the distance from the front end of the suspension was measured by flattening on a glass plate without traction, and the percentage of the length of the suspension to the total length of the intestine was calculated.
  • Ten animals are in a group. The percent inhibition of activated carbon excretion after administration was compared and compared by mean and standard deviation.

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Abstract

本发明涉及结构式（I）所代表的化合物及其非毒性药学上可接受的盐：式（I）中，R1为H，CH3或氘代甲基(CD3)；R2为CH3或CH2CH3；R3、R4和R5分别独立地为H或氘(D)；当R1为H或CH3时，R3、R4和R5必须至少有一个为D。

Description

氘代化合物及其医药用途 技术领域
本发明涉及具有镇痛作用的新的氘代N-环丙甲基-去甲东罂粟碱衍生物或其药学上可接受的盐，含有这些化合物作为活性成分的药物组合物，以及所述衍生物或其药学上可接受的盐用于制备镇痛类药物的用途。
背景技术
镇痛药是临床上最常用的药品之一。但是强效镇痛药如吗啡，杜冷丁等具有强大的致依赖潜能，长期使用易引起成瘾和耐受；非麻醉性镇痛药虽然没有依赖潜能，但镇痛作用较弱，不足以解除癌症，外伤和手术等病人的重度疼痛。因此，临床需要提供高效安全的镇痛新药。
丁丙喏啡(Buprenorphine)是临床最常用的镇痛及戒毒药物；ADP2为丁丙喏啡类似物，显示出显著高于丁丙喏啡的镇痛活性和镇痛效能(硕士学位论文：丁丙诺啡类似物的合成。1999.6，研究生：吴波；导师：仲伯华)。但是丁丙喏啡及ADP2均具有一定的成瘾性，而且注射给药才有效，限制了其临床应用。丁丙喏啡在临床连续用药，还有便秘的副作用。
Figure PCTCN2018000051-appb-000001
本发明的目的是提供口服有效、依赖潜能小的新的丁丙喏啡类似物。
发明内容
本发明提供由结构式I所代表的化合物及其非毒性药学上可接受的盐：
Figure PCTCN2018000051-appb-000002
式I中，R1为H，CH 3或氘代甲基(CD 3)；R2为CH 3或CH 2CH 3；R3、R4和R5分别独立地为H或氘(D)；当R1为H或CH 3时，R3、R4和R5必须至少有一个为D。
本发明提供由结构式I所代表的化合物及其非毒性药学上可接受的盐，选自如下结构：
Figure PCTCN2018000051-appb-000003
Figure PCTCN2018000051-appb-000004
Figure PCTCN2018000051-appb-000005
本发明还提供含有式I所代表的化合物及其非毒性药学上可接受的盐作为活性成分，以及适宜的赋型剂形成的药物组合物。这些药物组合物可以是溶液剂、片剂、胶囊或注射剂；这些药物组合物可以通过注射途径给药或口服给药。
本发明还提供含有式I所代表的化合物及其非毒性药学上可接受的盐，在制备治疗疼痛的药物中的用途。
进一步地，本发明还提供含有式I所代表的化合物及其非毒性药学上可接受的盐，在制备治疗疼痛疾病的药物或制备戒毒药物中的用途。
目标化合物I 1-4和I 8-11可通过以下合成路线来制备：
Figure PCTCN2018000051-appb-000006
18，19-二氘代的目标化合物如下制备：
Figure PCTCN2018000051-appb-000007
苯环上氘代的化合物可以如下制备：
Figure PCTCN2018000051-appb-000008
具体实施方式
通过下面的实施例可以对本发明进行进一步的描述，然而，本发明的范围并不限于下述实施例。本领域的专业人员能够理解，在不背离本发明的精神和范围的前提下，可以对本发明进行各种变化和修饰。
参考实施例1 (2S)-2-[(5R，6R，7R，14S)-N-环丙甲基-4，5-环氧基-6，14-亚乙基-3-羟基-6-甲氧基吗啡喃-7-基]-3，3-二甲基丁-2-醇(丁丙喏啡)的制备
1.1 7α-乙酰基-6，14-乙烯桥四氢蒂巴因(ii)的合成
在250ml反应瓶中加入50g蒂巴因(i)和80ml甲基乙烯酮，回流反应1小时；减压蒸除甲基乙烯酮，冷却后加入50ml甲醇，加热溶解，冷却，滤 集固体，用甲醇洗两次，干燥，得ii 51g，熔点118-121℃。
1.2 7α-乙酰基-6，14-乙基桥四氢蒂巴因(iii)的合成
将20g化合物ii，4g 10％的钯碳和200ml无水乙醇置于氢化釜中，通入氢气40-50kg/cm 2，于50-60℃氢化反应8-12小时，反应完毕，滤除催化剂，减压浓缩至1/3体积，冷却，滤集固体，用无水乙醇洗两次，干燥，得iii的固体17g，熔点134-137℃。
1.3 (2S)-2-[(5R，6R，7R，14S)-N-甲基-4，5-环氧基-6，14-亚乙基-3-甲氧基-6-甲氧基吗啡喃-7-基]-3，3-二甲基丁-2-醇(iv 1)的合成
将0.5g镁屑加于10ml无水乙醚中，搅拌下滴加1.2g特丁基氯(12mmol)溶于15ml无水乙醚和10ml无水苯的混合溶剂，制得格氏试剂；搅拌下，向格氏试剂中滴加4g(10mmol)iii溶于30mL乙醚-苯(1∶1)的溶液。加完后搅拌回流6小时；反应完毕于冰浴冷却下，滴加15mL饱合氯化铵溶液。过滤，将滤液静置，分出有机层；水层以乙醚提取(25ml×4)，合并有机相后以水洗至中性，用无水硫酸钠干燥过夜，减压蒸除溶剂，用硅胶柱层析分离，用二氯甲烷∶石油醚∶甲醇(2∶7∶1)混合溶剂洗脱，收集所需组分，减压蒸干，得淡黄色固体iv 1 3.7g。
1.4 (2S)-2-[(5R，6R，7R，14S)-N-氰基-4，5-环氧基-6，14-亚乙基-3-甲氧基-6-甲氧基吗啡喃-7-基]-3，3-二甲基丁-2-醇(v1)的合成
将溴化氰1.5g溶于15ml氯仿中，搅拌下滴加3.7g iv 1溶于25ml氯仿的溶液，回流反应12hr，反应完毕蒸除溶剂，以少量无水乙醇处理，得白色粉末v 1 3.8g。
1.5 (2S)-2-[(5R，6R，7R，14S)-4，5-环氧基-6，14-亚乙基-3-羟基-6-甲氧基吗啡喃-7-基]-3，3-二甲基丁-2-醇(vi 1)的合成
在25ml缩二甘醇中加入10g氢氧化钾，通氮气，搅拌加热至100℃；然后加入3.8g v 1，于190-200℃加热1小时，倾入冰水中。加入饱和氯化铵水溶液中和至pH 8-9，滤集固体，用硅胶柱层析分离，用二氯甲烷∶石油醚∶甲醇(2∶7∶1)混合溶剂洗脱，收集所需组分，减压蒸干，得vi 1 3.2克，熔点＞200℃。
1.6 (2S)-2-[(5R，6R，7R，14S)-N-环丙甲酰基-4，5-环氧基-6，14-亚乙基-3-羟基-6-甲氧基吗啡喃-7-基]-3，3-二甲基丁-2-醇(vii 1)的合成
在25ml无水二氯甲烷中加入3.2克(7.7mmol)vi 1，0.91g三乙胺，搅拌溶解；冰浴下滴加0.8g(7.7mmol)环丙甲酰氯。加完后，继续在冰浴中搅拌反应8小时，然后室温搅拌反应5小时。过滤，将滤液减压蒸干，用硅胶柱层析分离，用二氯甲烷∶石油醚∶甲醇(2∶7∶1)混合溶剂洗脱，收集所需组分，减压蒸干，得vii 1 1.7g.
1.7 丁丙喏啡的制备
将0.96g(2mmol)vii 1溶于5ml无水四氢呋喃中，搅拌下滴加2ml 2M的LiAlH 4的四氢呋喃溶液；加完后于室温下搅拌过夜；然后分批加入七水合硫酸镁，至无气体放出。过滤，将滤液减压蒸干，用硅胶柱层析分离，用石油醚∶二氯甲烷∶甲醇＝4∶1∶0.1洗脱，收集所需组分，用甲醇重结晶，得丁丙喏啡白色固体0.72g；将此固体用乙醇溶解，加入氯化氢乙醚溶液，至pH2，搅拌，析出固体，静置过夜后，过滤并以无水乙醚洗涤得丁丙喏啡·HCl 0.68g，熔点：＞200℃。 1H-NMR(400MHz，DMSO-d6)：9.65(br，1H)；9.40(br，1H)；6.74(d， 1H)；6.56(d，1H)；4.66(br，1H)；4.55(s，1H)；3.91(d，1H)；3.42(s，3H)；3.29(m，2H)；3.20(m，2H)；2.90m，1H)；2.80(m，2H)；2.29(m，1H)；1.95(m，2H)；1.83(m，2H)；1.71(m，1H)；1.45(m，1H)；1.34(m，1H)；1.31(s，3H)；1.02(s，9H)；0.68(m，2H)；0.61(m，2H)；0.40(m，1H).
参考实施例2 (2S)-2-[(5R，6R，7R，14S)-N-环丙甲基-4，5-环氧基-6，14-亚乙基-3-羟基-6-甲氧基吗啡喃-7-基]-3，3-二甲基戊-2-醇(ADP2)的制备
参照参考实施例1.3的方法，用2-氯-2-甲基丁烷代替特丁基氯制备格氏试剂，与iii进行格氏加成，制备(2S)-2-[(5R，6R，7R，14S)-N-甲基-4，5-环氧基-6，14-亚乙基-3-甲氧基-6-甲氧基吗啡喃-7-基]-3，3-二甲基戊-2-醇(iv 2)。
参照参考实施例1.4的方法，用iv 2代替iv 1，与溴化氰反应，制得(2S)-2-[(5R，6R，7R，14S)-N-氰基-4，5-环氧基-6，14-亚乙基-3-甲氧基-6-甲氧基吗啡喃-7-基]-3，3-二甲基戊-2-醇(v 2)。
参照参考实施例1.5的方法，用v 2代替v 1，与氢氧化钾反应，制得(2S)-2-[(5R，6R，7R，14S)-4，5-环氧基-6，14-亚乙基-3-羟基-6-甲氧基吗啡喃-7-基]-3，3-二甲基戊-2-醇(vi 2)。
参照参考实施例1.6的方法，用vi 2代替vi 1，与环丙甲酰氯反应，制得(2S)-2-[(5R，6R，7R，14S)-N-环丙甲酰基-4，5-环氧基-6，14-亚乙基-3-羟基-6-甲氧基吗啡喃-7-基]-3，3-二甲基戊-2-醇(vii 2)。
参照参考实施例1.7的方法，用vii 2代替vii 1，与LiAlH 4反应，制得ADP20.58g；将ADP2用乙醇溶解，加入氯化氢乙醚溶液，至pH2，搅拌，析出固体，静置过夜后，过滤并以无水乙醚洗涤得ADP2·HCl 0.43g，熔点：＞200℃。核磁共振氢谱： 1H-NMR(400MHz，DMSO-d6)：9.62(br，1H)；9.39(br，1H)；6.73(d， 1H)；6.55(d，1H)；4.64(br，1H)；4.54(s，1H)；3.90(d，1H)；3.41(s，3H)；3.28(m，2H)；3.20(m，2H)；2.88(m，1H)；2.79(m，2H)；2.28(m，1H)；1.96(m，2H)；1.82(m，2H)；1.70(m，1H)；1.47(m，1H)；1.35(m，1H)；1.30(s，3H)；1.23(q，2H)；1.03(s，6H)；0.98(t，3H)；0.67(m，2H)；0.60(m，2H)；0.39(m，1H).
实施例1 (2s)-2-[(5R，6R，7R，14S)-N-(环丙基-二氘代甲基)-4，5-环氧基-6，14-亚乙基-3-羟基-6-甲氧基吗啡喃-7-基]-3，3-二甲基丁-2-醇(I 1)的制备
Figure PCTCN2018000051-appb-000009
参照参考实施例1.7的方法，将vii 1与LiAlD 4(％D：＞98)反应，制得I 1；将I 1用乙醇溶解，与氯化氢成盐，制得I 1·HCl，熔点：＞200℃。 1H-NMR(400MHz，DMSO-d6)：9.70(br，1H)；9.43(br，1H)；6.75(d，1H)；6.58(d，1H)；4.71(br，1H)；4.53(s，1H)；3.92(d，1H)；3.42(s，3H)；3.29(m，2H)；2.90m，1H)；2.80(m，2H)；2.29(m，1H)；1.95(m，2H)；1.83(m，2H)；1.70(m，1H)；1.44(m，1H)；1.32(m，1H)；1.31(s，3H)；1.02(s，9H)；0.69(m，2H)；0.62(m，2H)；0.40(m，1H).
实施例2 (2S)-2-[(5R，6R，7R，14S)-N-环丙甲基-4，5-环氧基-6，14-亚乙基-3-三氘代甲基氧基-6-甲氧基吗啡喃-7-基]-3，3-二甲基丁-2-醇(I 2)的制备
Figure PCTCN2018000051-appb-000010
在5ml二甲基甲酰胺中，加入0.47g(1mmol)丁丙喏啡，搅拌溶解；然后加入280mg(2mmol)碳酸钾，搅拌下滴加290mg(％D：＞98，2mmol)CD 3I。将反应混合物于50℃搅拌反应15小时。滤去固体，将滤液减压蒸干。用硅胶柱层析分离，用二氯甲烷∶石油醚∶甲醇(2∶7∶1)混合溶剂洗脱，收集所需组分，减压蒸干，得I 2 430mg；将I 2用乙醇溶解，与氯化氢成盐，制得I 2·HCl，熔点：＞200℃。 1H-NMR(400MHz，DMSO-d6)：9.56(br，1H)；6.78(d，1H)；6.59(d，1H)；4.67(br，1H)；4.54(s，1H)；3.91(d，1H)；3.42(s，3H)；3.29(m，2H)；3.20(m，2H)；2.90m，1H)；2.80(m，2H)；2.29(m，1H)；1.95(m，2H)；1.83(m，2H)；1.71(m，1H)；1.45(m，1H)；1.34(m，1H)；1.30(s，3H)；1.01(s，9H)；0.67(m，2H)；0.60(m，2H)；0.39(m，1H).
实施例3 (2S)-2-[(5R，6R，7R，14S)-N-(环丙基-二氘代甲基)-4，5-环氧基-6，14-亚乙基-3-三氘代甲基氧基-6-甲氧基吗啡喃-7-基]-3，3-二甲基丁-2-醇(I 3)的制备
Figure PCTCN2018000051-appb-000011
参照实施例2的方法，用I 1代替丁丙喏啡与CD 3I反应，制得I 3；将I 3用乙醇溶解，与氯化氢成盐，制得I 3·HCl，熔点：＞200℃。 1H-NMR(400MHz，DMSO-d6)：9.60(br，1H)；6.79(d，1H)；6.60(d，1H)；4.68(br，1H)；4.56(s，1H)；3.92(d，1H)；3.42(s，3H)；3.29(m，2H)；2.90m，1H)；2.80(m，2H)；2.29(m，1H)；1.95(m，2H)；1.83(m，2H)；1.71(m，1H)；1.45(m，1H)；1.34(m，1H)；1.31(s，3H)；1.03(s，9H)；0.68(m，2H)；0.60(m，2H)；0.41(m，1H).
实施例4 (2S)-2-[(5R，6R，7R，14S)-N-(环丙基-二氘代甲基)-4，5-环氧基-6，14-亚乙基-3-甲氧基-6-甲氧基吗啡喃-7-基]-3，3-二甲基丁-2-醇(I 4)的制备
Figure PCTCN2018000051-appb-000012
参照实施例2的方法，用I 1代替丁丙喏啡与CH 3I反应，制得I 4；将I 4用乙醇溶解，与氯化氢成盐，制得I 4·HCl，熔点：＞200℃。 1H-NMR(400MHz，DMSO-d6)：9.58(br，1H)；6.77(d，1H)；6.59(d，1H)；4.82(br，1H)；4.55(s，1H)；3.91(d，1H)；3.85((s，3H)；3.42(s，3H)；3.26(m，2H)；2.87m，1H)；2.75(m，2H)；2.26(m，1H)；1.92(m，2H)；1.81(m，2H)；1.70(m，1H)；1.45(m，1H)；1.34(m，1H)；1.31(s，3H)；1.02(s，9H)；0.68(m，2H)；0.61(m，2H)；0.41(m，1H).
实施例5 (2S)-2-[(5R，6R，7R，14S)-1，2-二氘-N-环丙甲基-4，5-环氧基-6，14-亚乙基-3-羟基-6-甲氧基吗啡喃-7-基]-3，3-二甲基丁-2-醇(I 5)的制备
Figure PCTCN2018000051-appb-000013
在5ml二氯甲烷中，加入0.3g丁丙喏啡，搅拌溶解；冰浴冷却下滴加60μl溴于1ml二氯甲烷的溶液；加完后，升温至30℃，搅拌反应1小时。将反应液依次以水、饱和碳酸氢钠溶液洗；分出有机层，用无水硫酸钠干燥后，滤去固体，减压蒸干溶剂，用硅胶柱层析分离，用二氯甲烷∶石油醚∶甲醇(2∶7∶1)混合溶剂洗脱，收集所需组分，减压蒸干，得(2S)-2-[(5R，6R，7R，14S)-1，2-二溴-N-环丙甲基-4，5-环氧基-6，14-亚乙基-3-羟基-6-甲氧基吗啡喃-7-基]-3，3-二甲基丁-2-醇(viii 1)41mg。
将41mgviii 1用0.5ml无水四氢呋喃溶解，加入20μl无水三乙胺，20mg 10％Pd-C，将反应瓶连接于高真空系统，通氘气，常温搅拌反应24小时。滤去固体，减压蒸干，用硅胶柱层析分离，用二氯甲烷∶石油醚∶甲醇(2∶7∶1)混合溶剂洗脱，收集所需组分，减压蒸干，得I 5 19mg；将I 5用乙醇溶解，与氯化氢成盐，制得I 5·HCl，熔点：＞200℃。 1H-NMR(400MHz，DMSO-d6)：9.60(br，1H)；9.43(br，1H)；4.72(br，1H)；4.55(s，1H)；3.91(d，1H)；3.42(s，3H)；3.32(m，2H)；3.25(m，2H)；2.92m，1H)；2.83(m，2H)；2.31(m，1H)；1.97(m，2H)；1.86(m，2H)；1.74(m，1H)；1.46(m，1H)；1.34(m，1H)；1.31(s，3H)；1.00(s，9H)；0.69(m，2H)；0.61(m，2H)；0.40(m，1H).
实施例6 (2S)-2-[(5R，6R，7R，14S)-1，2-二氘代-N-(环丙基-二氘代甲基)-4，5-环氧基-6，14-亚乙基-3-羟基-6-甲氧基吗啡喃-7-基]-3，3-二甲基丁-2-醇(I 6)的制备
Figure PCTCN2018000051-appb-000014
参照实施例5的方法，用I 1代替丁丙喏啡进行溴代反应，制得(2S)-2-[(5R，6R，7R，14S)-1，2-二溴-N-(环丙基-二氘代甲基)-4，5-环氧基-6，14-亚乙基-3-羟基-6-甲氧基吗啡喃-7-基]-3，3-二甲基丁-2-醇(viii 2)；用viii 2代替viii 1进行氘代反应，制得I 6；将I 6用乙醇溶解，与氯化氢成盐，制得I 6·HCl，熔点：＞200℃。 1H-NMR(400MHz，DMSO-d6)：9.72(br，1H)；9.42(br，1H)；4.69(br，1H)；4.55(s，1H)；3.91(d，1H)；3.41(s，3H)；3.28(m，2H)；2.92m，1H)；2.83(m，2H)；2.32(m，1H)；1.98(m，2H)；1.86(m，2H)；1.73(m，1H)；1.47(m，1H)；1.35(m，1H)；1.31(s，3H)；1.01(s，9H)；0.68(m，2H)；0.61(m，2H)；0.40(m，1H).
实施例7 (2S)-2-[(5R，6R，7R，14S)--N-环甲基-4，5-环氧基-6，14-二氘代亚乙基-3-羟基-6-甲氧基吗啡喃-7-基]-3，3-二甲基丁-2-醇(I 7)的制备
Figure PCTCN2018000051-appb-000015
Figure PCTCN2018000051-appb-000016
参照参考实施例1.2的方法，用氘气代替氢气，将ii进行氘化加成反应，制得7α-乙酰基-6，14-二氘代乙基桥四氢蒂巴因(iii’)。
参照参考实施例1.3的方法，用iii’代替iii，与特丁基氯的格氏试剂进行格氏加成，制备(2S)-2-[(5R，6R，7R，14S)-N-甲基-4，5-环氧基-6，14-二氘代亚乙基-3-甲氧基-6-甲氧基吗啡喃-7-基]-3，3-二甲基丁-2-醇(iv’)。
参照参考实施例1.4的方法，用iv’代替iv 1，与溴化氰反应，制得(2S)-2-[(5R，6R，7R，14S)-N-氰基-4，5-环氧基-6，14-二氘代亚乙基-3-甲氧基-6-甲氧基吗啡喃-7-基]-3，3-二甲基丁-2-醇(v’)。
参照参考实施例1.5的方法，用v’代替v 1，与氢氧化钾反应，制得(2S)-2-[(5R，6R，7R，14S)-4，5-环氧基-6，14-二氘代亚乙基-3-羟基-6-甲氧基吗啡喃-7-基]-3，3-二甲基丁-2-醇(vi’)。
参照参考实施例1.6的方法，用vi’代替vi 1，与环丙甲酰氯反应，制得(2S)-2-[(5R，6R，7R，14S)-N-环丙甲酰基-4，5-环氧基-6，14-二氘代亚乙基-3-羟基-6-甲氧基吗啡喃-7-基]-3，3-二甲基丁-2-醇(vii’)。
参照参考实施例1.7的方法，用vii’代替vii 1，与LiAlH 4反应，制得I 7；将I 7用乙醇溶解，与氯化氢成盐，制得I 7·HCl，熔点：＞200℃。 1H-NMR(400MHz，DMSO-d6)：9.62(br，1H)；9.41(br，1H)；6.73(d，1H)；6.55(d，1H)；4.62(br，1H)；4.56(s，1H)；3.91(d，1H)；3.40(s，3H)；3.29(m，2H)；3.20(m，2H)；2.90m，1H)；2.80(m，2H)；2.29(m，1H)；1.83(m，2H)；1.71(m，1H)；1.30(s，3H)；1.03(s，9H)；0.68(m，2H)；0.61(m，2H)；0.40(m，1H).
实施例8 (2S)-2-[(5R，6R，7R，14S)-N-(环丙基-二氘代甲基)-4，5-环氧基-6，14-亚 乙基-3-羟基-6-甲氧基吗啡喃-7-基]-3，3-二甲基戊-2-醇(I 8)的制备
Figure PCTCN2018000051-appb-000017
参照参考实施例1.7的方法，将vii 2与LiAlD 4反应，制得I 8；将I 8用乙醇溶解，与氯化氢成盐，制得I 8·HCl，熔点：＞200℃。 1H-NMR(400MHz，DMSO-d6)：9.62(br，1H)；9.39(br，1H)；6.73(d，1H)；6.55(d，1H)；4.64(br，1H)；4.54(s，1H)；3.90(d，1H)；3.41(s，3H)；3.28(m，2H)；3.20(m，2H)；2.88(m，1H)；2.79(m，2H)；2.28(m，1H)；1.96(m，2H)；1.82(m，2H)；1.70(m，1H)；1.47(m，1H)；1.35(m，1H)；1.30(s，3H)；1.23(q，2H)；1.03(s，6H)；0.98(t，3H)；0.67(m，2H)；0.60(m，2H)；0.39(m，1H).
实施例9 (2S)-2-[(5R，6R，7R，14S)-N-环丙甲基-4，5-环氧基-6，14-亚乙基-3-三氘代甲基氧基-6-甲氧基吗啡喃-7-基]-3，3-二甲基戊-2-醇(I 9)的制备
Figure PCTCN2018000051-appb-000018
参照实施例2的方法，用ADP2代替丁丙喏啡与CD 3I反应，制得I 9；将I 9用乙醇溶解，与氯化氢成盐，制得I 9·HCl，熔点：＞200℃。 1H-NMR(400MHz， DMSO-d6)：9.51(br，1H)；6.78(d，1H)；6.59(d，1H)；4.65(br，1H)；4.54(s，1H)；3.90(d，1H)；3.41(s，3H)；3.31(m，2H)；3.24(m，2H)；2.90(m，1H)；2.82(m，2H)；2.29(m，1H)；1.99(m，2H)；1.82(m，2H)；1.70(m，1H)；1.47(m，1H)；1.35(m，1H)；1.30(s，3H)；1.23(q，2H)；1.06(s，6H)；0.98(t，3H)；0.67(m，2H)；0.60(m，2H)；0.39(m，1H).
实施例10 (2S)-2-[(5R，6R，7R，14S)-N-(环丙基-二氘代甲基)-4，5-环氧基-6，14-亚乙基-3-三氘代甲基氧基-6-甲氧基吗啡喃-7-基]-3，3-二甲基戊-2-醇(I 10)的制备
Figure PCTCN2018000051-appb-000019
参照实施例2的方法，用I 8代替丁丙喏啡与CD 3I反应，制得I 10；将I 10用乙醇溶解，与氯化氢成盐，制得I 10·HCl，熔点：＞200℃。 1H-NMR(400MHz，DMSO-d6)：9.40(br，1H)；6.78(d，1H)；6.58(d，1H)；4.69(br，1H)；4.54(s，1H)；3.90(d，1H)；3.40(s，3H)；3.25(m，2H)；2.86(m，1H)；2.77(m，2H)；2.26(m，1H)；1.956(m，2H)；1.82(m，2H)；1.70(m，1H)；1.47(m，1H)；1.31-1.30(m，4H)；1.24(q，2H)；1.05(s，6H)；0.97(t，3H)；0.67(m，2H)；0.61(m，2H)；0.42(m，1H).
实施例11 (2S)-2-[(5R，6R，7R，14S)-N-(环丙基-二氘代甲基)-4，5-环氧基-6，14-亚乙基-3-甲氧基-6-甲氧基吗啡喃-7-基]-3，3-二甲基戊-2-醇(I 11)的制备
Figure PCTCN2018000051-appb-000020
参照实施例2的方法，用I 8代替丁丙喏啡与CH 3I反应，制得I 11；将I 11用乙醇溶解，与氯化氢成盐，制得I 11·HCl，熔点：＞200℃。 1H-NMR(400MHz，DMSO-d6)：9.49(br，1H)；6.77(d，1H)；6.58(d，1H)；4.64(br，1H)；4.54(s，1H)；3.90(d，1H)；3.86(s，3H)；3.42(s，3H)；3.25(m，2H)；2.86(m，1H)；2.78(m，2H)；2.29(m，1H)；1.96(m，2H)；1.82(m，2H)；1.70(m，1H)；1.47(m，1H)；1.37(m，1H)；1.31(s，3H)；1.23(q，2H)；1.03(s，6H)；0.98(t，3H)；0.67(m，2H)；0.60(m，2H)；0.39(m，1H).
实施例12 (2S)-2-[(5R，6R，7R，14S)-1，2-二氘-N-环丙甲基-4，5-环氧基-6，14-亚乙基-3-羟基-6-甲氧基吗啡喃-7-基]-3，3-二甲基戊-2-醇(I 12)的制备
Figure PCTCN2018000051-appb-000021
参照实施例5的方法，用ADP2代替丁丙喏啡，进行溴代反应，制得(2S)-2-[(5R，6R，7R，14S)-1，2-二溴-N-环丙甲基-4，5-环氧基-6，14-亚乙基-3-羟基-6-甲氧基吗啡喃-7-基]-3，3-二甲基戊-2-醇(viii 3)；用viii 3代替viii 1进行氘代反应， 制得I 12；将I 12用乙醇溶解，与氯化氢成盐，制得I 12·HCl，熔点：＞200℃。 1H-NMR(400MHz，DMSO-d6)：9.62(br，1H)；9.39(br，1H)；4.64(br，1H)；4.54(s，1H)；3.90(d，1H)；3.43(s，3H)；3.26(m，2H)；3.17(m，2H)；2.86(m，1H)；2.79(m，2H)；2.28(m，1H)；1.96(m，2H)；1.82(m，2H)；1.70(m，1H)；1.47(m，1H)；1.35(m，1H)；1.32(s，3H)；1.23(q，2H)；1.01(s，6H)；0.99(t，3H)；0.68(m，2H)；0.62(m，2H)；0.40(m，1H).
实施例13 小鼠热板实验法测定镇痛活性
昆明种小鼠，雄性，置于55℃热板上，立刻计时，至第一次出现舔或跺后足时止，所得时间为给药前基础痛阈；然后随机分组，每组10只动物；灌胃给药，于给药后1小时，将小鼠置于55℃热板上，计时，至第一次出现舔或跺后足时止，所得时间为给药后痛阈；以60s内不出现舔足或跺后足为镇痛100％。以给药前后自身比较计算镇痛百分率，计算公式如下：
Figure PCTCN2018000051-appb-000022
采用bliss法计算ED 50值，结果见表1：
表1 小鼠热板实验法测定镇痛活性结果
Figure PCTCN2018000051-appb-000023
实施例14 大鼠热辐射甩尾实验测定镇痛活性
SD大鼠，雄性，将尾尖部放入55℃恒温水浴中，立即计时，至尾尖部从水中甩出止，该时间为给药前基础痛阈。然后随机分组，每组5只动物；灌胃给药，于给药后1小时，将尾尖部放入55℃恒温水浴中，立即计时，至尾尖部从水中甩出止，该时间为给药后痛阈。以15s内不甩尾为镇痛100％。以给药前后自身比较计算镇痛百分率，计算公式如下：
Figure PCTCN2018000051-appb-000024
采用bliss法计算ED 50值，结果见表2：
表2 大鼠热辐射甩尾实验测定镇痛活性结果
Figure PCTCN2018000051-appb-000025
实施例15 大鼠位置偏爱评价药物依赖性
SD大鼠(雄性，体重160-180g)，放入隔门打开的条件性位置偏爱训练箱内，测定大鼠15min内在各箱停留时间，以此判断大鼠的天然倾向性。然后按白箱停留时间将大鼠随机分组，每组10只。以白箱为伴药箱，黑箱为非伴药箱。灌胃给予3xED 50剂量(热板法)的待测化合物，立即将大鼠放入白箱或 黑箱内训练45分钟，每天1次，连续9天。第10天将大鼠放入隔门打开的训练箱内，测定15min内大鼠在白箱内停留时间，评价大鼠位置偏爱效应。实验结果见表3：
表3 药物诱导大鼠位置偏爱试验结果
Figure PCTCN2018000051-appb-000026
实施例16 小鼠灌胃活性炭排泄试验评价药物对胃肠蠕动的影响
小鼠，雌雄各半，实验前8h禁食，自由饮水。灌胃给予3xED 50剂量(热板法)的待测化合物；用5％炭末与10％甲基纤维素制成悬液，按0.2ml/20g的剂量在给药后30分钟给小鼠灌胃，灌胃后15min，用颈椎脱臼处死。立即剖腹将消化管自贲门至直肠末端完整地摘出，不加牵引地平铺于玻璃板上测量悬液前端距贲门的距离，计算其与肠道全长的百分比。10只动物为一组。比较给药后活性炭排泄的抑制百分率，以均值及标准差进行比较。
Figure PCTCN2018000051-appb-000027
实验结果见表4：
表4 药物对活性炭排泄的抑制作用
Figure PCTCN2018000051-appb-000028

Claims (5)

  1. 结构式I所代表的化合物及其非毒性药学上可接受的盐：
    Figure PCTCN2018000051-appb-100001
    式I中，R1为H，CH 3或氘代甲基(CD 3)；R2为CH 3或CH 2CH 3；R3、R4和R5分别独立地为H或氘(D)；当R1为H或CH 3时，R3、R4和R5必须至少有一个为D。
  2. 权利要求1的化合物，选自如下结构：
    Figure PCTCN2018000051-appb-100002
    Figure PCTCN2018000051-appb-100003
  3. 含有权利要求1-2中所述的任一化合物或其药学上可接受的盐作为活性成分，以及一种或多种药用载体或赋形剂的药物组合物。
  4. 权利要求1-2中所述的任一化合物或其药学上可接受的盐，或其药物组合物，在制备治疗疼痛疾病的药物中的用途。
  5. 权利要求1-2中所述的任一化合物或其药学上可接受的盐，或其药物组合物，在制备治疗成瘾性疾病的药物中的用途，所述的成瘾性疾病选自可卡因所致成瘾，甲基苯丙胺类毒品所致、阿片类毒品或药品所致成瘾、酒精性成瘾、吸烟所致成瘾或氯胺酮所致成瘾。
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