WO2018153212A1 - Dérivés de colchicine, leur procédé de préparation et leur utilisation médicale - Google Patents

Dérivés de colchicine, leur procédé de préparation et leur utilisation médicale Download PDF

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Publication number
WO2018153212A1
WO2018153212A1 PCT/CN2018/074283 CN2018074283W WO2018153212A1 WO 2018153212 A1 WO2018153212 A1 WO 2018153212A1 CN 2018074283 W CN2018074283 W CN 2018074283W WO 2018153212 A1 WO2018153212 A1 WO 2018153212A1
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acid
compound
group
pharmaceutically acceptable
mmol
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PCT/CN2018/074283
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English (en)
Chinese (zh)
Inventor
徐云根
何广卫
刘坤
储昭兴
朱启华
赵炎
刘为中
王奎
张陆勇
Original Assignee
中国药科大学
合肥医工医药有限公司
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Publication of WO2018153212A1 publication Critical patent/WO2018153212A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/14—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to acyclic carbon atoms
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/20—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/16—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings

Definitions

  • the invention belongs to the field of medicinal chemistry, and particularly relates to a class of colchicine derivatives, a preparation method thereof, and a pharmaceutical composition containing the same and the use thereof for treating lumbar disc herniation and liver fibrosis.
  • Lumbar disc herniation is a disease in which the degeneration of the lumbar disc progresses to the nucleus of the annulus causing stimulation of the nucleus pulposus or oppressing the blood vessels, cauda equina, and nerve roots of the patient and producing a sterile inflammatory response.
  • the main clinical manifestations are pain in the lower back and lower extremities. hemp.
  • More than 90% of the lumbar disc herniation occurs in the lumbar vertebrae L4-5 and L5-S1 segments, which are common in young adults aged 30-50 years.
  • the male incidence rate is about 6 times that of females. According to the survey, the incidence of lumbar disc herniation in the West is 15.2%-30%, and the incidence rate in China is about 18%.
  • Hepatic fibrosis is a pathophysiological process, which refers to the abnormal proliferation of connective tissue in the liver caused by various pathogenic factors.
  • a variety of cells and cytokines are involved in the formation of liver fibrosis.
  • In vitro infection and other factors can cause immune cells to release inflammatory factors such as TNF- ⁇ , monocyte chemoattractant protein-1 (MCP-1) and IL-1.
  • MCP-1 monocyte chemoattractant protein-1
  • ECM extracellular matrix
  • HSCs hepatic stellate cells
  • Liver fibrosis is a necessary stage for the development of chronic diseases such as chronic hepatitis, fatty liver and alcoholic liver to cirrhosis. Any liver injury has a process of liver fibrosis during liver healing and healing. Liver fibrosis is largely asymptomatic, it progressively worsens to cirrhosis and carries a high risk of morbidity and mortality. In digestive tract diseases, cirrhosis is the most common cause of non-neoplastic death. In the United States, 30,000 people die each year from the disease, and another 10,000 die from liver cancer caused by cirrhosis. The number of patients with hepatitis, fatty liver and alcoholic liver should be about 10 million in China.
  • liver fibrosis is the only way for various chronic liver diseases to lead to cirrhosis, anti-fibrosis treatment at this stage can block the occurrence of cirrhosis or slow the progression of cirrhosis. Even after liver cancer surgery, it is necessary to treat complicated cirrhosis by anti-liver fibrosis. However, there is currently no safe and effective drug for the treatment of liver fibrosis.
  • the present invention discloses a class of compounds of the formula (I) which have been shown by pharmacological experiments to have the effect of treating lumbar disc herniation and liver fibrosis.
  • R represents: hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 hydroxyalkyl, C 2-10 alkenyl, R 1 represents a methyl group, a methoxy group, an acetoxy group, a halogen, a nitro group or a cyano group, and R 1 is a mono-, di- or tri-substituted group.
  • R preferred R 1 represents a methyl group, a methoxy group, an acetoxy group, a halogen, a nitro group or a cyano group, and R 1 is a mono-, di- or tri-substituted group.
  • R is more preferred R 1 represents a methyl group, a methoxy group, an acetoxy group, a halogen, a nitro group or a cyano group, and R 1 may be a mono-, di- or tri-substituted group.
  • the compound of the formula (I) can form an acid addition salt with a pharmaceutically acceptable acid, wherein the acid used for the salt formation is: hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, carbonic acid, oxalic acid, citric acid, succinic acid, Tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.
  • the acid used for the salt formation is: hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, carbonic acid, oxalic acid, citric acid, succinic acid, Tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.
  • Preferred partial compounds of the invention are as follows:
  • the compound of the present invention and its pharmaceutically acceptable acid addition salt (I ⁇ A) can be produced by the following method:
  • the process for preparing compound IV by deacetylation of compound III is preferably sodium methoxide or sodium ethoxide, and the solvent is preferably methanol or ethanol.
  • the process for preparing compound V from compound IV by deprotection of a tert-butoxycarbonyl (Boc) group the reactant used is a mixed solution of trifluoroacetic acid or trifluoroacetic acid and dichloromethane, or a solution of saturated hydrogen chloride in ethyl acetate. .
  • the process for preparing Compound I from Compound V via Pinner reaction the reactant used is VI (ethyl imidate derivative or methyl imidate derivative), and the solvent is preferably ethanol or methanol.
  • the reactant (A) is hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, horse
  • the solvent is preferably methanol, ethanol, dichloromethane, acetone, ethyl acetate, toluene or tetrahydrofuran, or a mixed solvent of any of several.
  • the present invention also discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of the compound (I) of the present invention or a salt thereof (I ⁇ A) and a pharmaceutically acceptable carrier.
  • the compound of the present invention can be added into a pharmaceutically acceptable carrier to prepare common pharmaceutical preparations, such as tablets, capsules, powders, syrups, liquids, suspensions, freeze-dried powders, injections, and can be added to spices and sweets.
  • common pharmaceutical excipients such as flavoring agents, liquid or solid fillers or diluents.
  • the compound of the present invention can be administered in a clinical manner by oral administration or injection.
  • the present invention also includes stereoisomers, hydrates, solvates or crystals of the colchicine derivatives of the formula I, which have the same pharmacodynamics and can be used for the preparation of lumbar disc herniation and liver fibrosis.
  • Application in medicine Including the use of a compound of formula I, a stereoisomer, a hydrate, a solvate or a crystal of a compound having lumbar disc herniation or liver fibrosis or comprising a compound of the formula I, a stereoisomer, a hydrate, A solvate or a crystalline pharmaceutical composition to effectively alleviate the symptoms of the patient.
  • the therapeutic index (LD 50 /ED 50 ratio) of the compounds of the present invention was greater than that of colchicine, see Tables 6, 7 and 8.
  • the compounds of the invention have good clinical application prospects.
  • mice Male ICR mice, weighing 18-22 g, were randomly divided into control group, colchicine group (0.2 mg/kg), and 19 test compound groups (10 mg/kg). Each group was intragastrically administered 7 days before the onset of inflammation, and the blank control group was given the same volume of vehicle. Immediately after the last administration for 1 hour, the right ear was applied with 0.04 ml/x of xylene on both sides, and the left ear was control, with an interval of 1 hour. After the mouse cervical dislocation was sacrificed, the ears were cut along the baseline of the auricle, and the round ears were placed in the same position of the left and right ears with a punch of 8 mm in diameter, and the scale was weighed with an electronic balance.
  • SD rats were randomly divided into 4 experiments to complete the toxicity evaluation of 6 compounds and colchicine.
  • Each batch of animals was adapted for 7 days, and 50 rats were selected for each test drug.
  • the rats and the males were randomly divided into 5 groups, 10 in each group.
  • the rats were fasted for 12 hours before the administration.
  • the Dm and Dn determined according to the pre-experiment results were set to 5 dose groups, and the rats were given to the rats in turn.
  • After intragastric administration, the symptoms of poisoning, death, death time and body weight change were observed 14 days after administration.
  • the dead rats were immediately dissected, and the organs and pathological changes of the main lesions were recorded by naked eyes. Finally, according to each group.
  • the number of animal deaths was calculated by modified WeChat method.
  • the LD 50 and 95% confidence interval of the test drug administered by the rats were compared.
  • the rongeur bites the half-sided lamina and probes the right intervertebral foramen of L4 and L5.
  • the special silica gel sheet [2mm ⁇ 2mm ⁇ 1mm, the silicone sheet is disinfected in 75% alcohol solution for 2 hours, and then placed in the new Jieer In the middle of the preservation], the nerve compression model was created; the sham operation group only cut the skin and paravertebral muscles after anesthesia. After the operation, the gentamicin injection was partially washed, sutured layer by layer, and the chlortetracycline ointment was applied to the suture, and placed in the cage for observation.
  • Rats with neurological function of grade 1 or higher were selected according to the Siegal score from 24 hours to 48 hours after modeling, and intragastric administration was started. Each batch of experiments was divided into a sham operation group, a model group, and a test drug group.
  • the five doses of colchicine were intragastrically administered with 0.02mg/kg, 0.04mg/kg, 0.06mg/kg, 0.12mg/kg, 0.2mg/kg corresponding drugs (according to the pre-experimental dose).
  • the five doses of the test drugs I-1 ⁇ HCl, I-8 ⁇ HCl, I-11 ⁇ HCl, I-12 ⁇ HCl, I-14 ⁇ HCl, and I-17 ⁇ HCl were administered by intragastric administration of 2 mg/kg.
  • the administration time was 4 weeks. After 1 hour of the last administration, the neurological function score was performed, and the left hind limb pain threshold was measured by the YLS-3E electronic tenderness instrument.
  • the six-point method was determined using the neurological function recommended by Siegal, see Table 3, and observed twice daily.
  • the neurological function score ED 50 was compared with I-11 ⁇ HCl ⁇ I-8 ⁇ HCl ⁇ I-12 ⁇ HCl ⁇ I-14 ⁇ HCl ⁇ I-1 ⁇ HCI ⁇ I-17 ⁇ HCI; LD 50 /ED The ratio of 50 is greater than that of colchicine, and the ratio of I-11 ⁇ HCl is the highest, indicating that the therapeutic index of each compound is greater than that of colchicine, especially the therapeutic index of I-11 ⁇ HCl is more than twice that of colchicine. Good development prospects.
  • the results of pain threshold test showed that the ED 50 value of pain threshold in the left lower limb of rats was compared with I-11 ⁇ HCl ⁇ I-8 ⁇ HCl ⁇ I-12 ⁇ HCl ⁇ I-14 ⁇ HCl ⁇ I-1 ⁇ HCl ⁇ I-17 ⁇ HCl; LD 50 / ED 50 ratio is greater than colchicine, indicating that the therapeutic index of each compound is greater than colchicine, especially I-11 ⁇ HCl is more obvious.
  • Wistar rats were weighed 200 ⁇ 20g. Rats were randomly divided into blank group, model group and test drug group. The experiment was divided into 4 batches. Each batch of animals was adapted for 7 days and began to model. Except the blank group, the other groups of rats were subcutaneously injected with 5 ml/kg of peanut oil solution containing 40% CCl 4 , and then 3 ml/kg of peanut oil solution containing CCl 4 was injected every two days.
  • test drug group was intragastrically administered on the second day of the experiment, and the five doses of colchicine were intragastrically administered with 0.02 mg/kg, 0.04 mg/kg, 0.06 mg/kg, 0.12 mg/kg, and 0.2 mg/kg, respectively.
  • the test drugs I-1 ⁇ HCl, I-8 ⁇ HCl, I-11 ⁇ HCl, I-12 ⁇ HCl, I-14 ⁇ HCl, I- 17 ⁇ HCl 5 dose groups were intragastrically administered with 2mg/kg, 3.6mg/kg, 6.3mg/kg, 11.2mg/kg, 20mg/kg corresponding drugs (according to the dose of the previous rat lumbar disc herniation model).
  • rats in each group were anesthetized by intraperitoneal injection of 3% pentobarbital sodium.
  • Blood was taken from the abdominal aorta, serum was separated, ALT and AST contents were detected by ELISA kit, and the liver of the same part of each group was taken. After tissue and homogenization treatment, the ELISA kit was used to detect the content of PCIII in liver tissue, and the specific operation was carried out according to the kit instructions.
  • the ED 50 of the ALT and AST contents in the serum of rats inhibiting liver fibrosis was compared with I-11 ⁇ HCl ⁇ I-12 ⁇ HCl ⁇ I-8 ⁇ HCl ⁇ I-14 ⁇ HCl ⁇ I-1 ⁇ HCI. ⁇ I-17 ⁇ HCI; LD 50 /ED 50 ratio is greater than colchicine, indicating that the therapeutic index of each compound is greater than that of colchicine, and the ratio of I-11 ⁇ HCl is the highest, which has a good development prospect.
  • colchicine (10.0 g, 25.03 mmol), 4-dimethylaminopyridine (DMAP) (3.06 g, 25.03 mmol), and triethylamine were added in that order. 5.06g, 50.0mmol) and 100mL of tetrahydrofuran, heated to reflux with stirring, slowly adding a mixed solution of di-tert-butyl dicarbonate (Boc 2 O) (16.40g, 75.14mmol) and tetrahydrofuran (15mL), dripping, and continuing to reflux The reaction was carried out for 2 hours.
  • Boc 2 O di-tert-butyl dicarbonate

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention se rapporte au domaine technique de la chimie médicale, et concerne en particulier des dérivés de colchicine (I), leur procédé de préparation et des compositions pharmaceutiques comprenant les composés. Des expériences pharmacodynamiques prouvent que les composés de la présente invention ont des efficacités dans le traitement d'une hernie discale lombaire et d'une fibrose hépatique.
PCT/CN2018/074283 2017-02-22 2018-01-26 Dérivés de colchicine, leur procédé de préparation et leur utilisation médicale WO2018153212A1 (fr)

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CN201710095068.6 2017-02-22
CN201710095068.6A CN108456152B (zh) 2017-02-22 2017-02-22 秋水仙碱衍生物、其制备方法及医药用途

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CN108997420B (zh) * 2018-08-31 2020-11-13 湖北大学 氯化三苯基-n-(秋水仙碱酰胺基)丁基鏻化合物的合成方法及其在抗肿瘤药物中的应用
CN110305040A (zh) * 2019-07-15 2019-10-08 宁夏贝利特生物科技有限公司 一种乙亚胺酸乙酯盐酸盐的合成方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB935187A (en) * 1959-08-03 1963-08-28 Sandoz Ltd Improvements in or relating to thiocolchicine compounds
CN101284057A (zh) * 2007-04-13 2008-10-15 李毅 腰痛宁药物及其制备方法
CN101822659A (zh) * 2010-05-11 2010-09-08 中国药科大学 秋水仙碱在制备治疗胆汁淤积性肝病药物中的应用
WO2011021397A1 (fr) * 2009-08-20 2011-02-24 国立大学法人千葉大学 Dérivés de colchicine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB935187A (en) * 1959-08-03 1963-08-28 Sandoz Ltd Improvements in or relating to thiocolchicine compounds
CN101284057A (zh) * 2007-04-13 2008-10-15 李毅 腰痛宁药物及其制备方法
WO2011021397A1 (fr) * 2009-08-20 2011-02-24 国立大学法人千葉大学 Dérivés de colchicine
CN101822659A (zh) * 2010-05-11 2010-09-08 中国药科大学 秋水仙碱在制备治疗胆汁淤积性肝病药物中的应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HIROYUKI NISHIYAMA: "4-chlorocolchicine derivatives bearing a thiourea side chain at the C-7 position as potent anticancer agents", MEDCHEMCOMM, vol. 5, 7 February 2014 (2014-02-07), pages 452 - 458, XP055535096 *
LIN TAI-SHUN: "Synthesis and biological activities of chloroethylurea, methylurea, and nitrosourea analogues of N-deacetylme- thylthiocolchicine", JOURNAL OF MEDICINAL CHEMISTRY, 23 December 1980 (1980-12-23), pages 1440 - 1442 *

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