CN110357800B - Proline derivative and application thereof in preparing medicine for treating cardiovascular and cerebrovascular diseases - Google Patents
Proline derivative and application thereof in preparing medicine for treating cardiovascular and cerebrovascular diseases Download PDFInfo
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- CN110357800B CN110357800B CN201810312331.7A CN201810312331A CN110357800B CN 110357800 B CN110357800 B CN 110357800B CN 201810312331 A CN201810312331 A CN 201810312331A CN 110357800 B CN110357800 B CN 110357800B
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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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
The invention provides a proline derivative, a preparation method thereof and application thereof in preparing a medicament for treating cardiovascular and cerebrovascular diseases. The proline derivative has a structure of general formula (I); pharmacological experiments prove that the proline derivative provided by the invention has a remarkable nerve protection effect, can be used for preparing medicines for treating cardiovascular and cerebrovascular diseases, and is particularly used for preparing medicines for resisting cerebral arterial thrombosis.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a proline derivative, a preparation method thereof and application thereof in preparing medicines for treating cardiovascular and cerebrovascular diseases.
Background
Cerebral apoplexy is an intractable disease seriously endangering the life safety of human beings, and has the characteristics of high morbidity, high disability rate and high mortality. In the antecedent of death cause published by the ministry of health of China in 2008, cerebral apoplexy is the third cause of death in cities and the second cause of death in rural areas. Epidemiological investigations have shown that the incidence of stroke in young adults has been increasing in recent years, with stroke occurring in adults under the age of 45 years being reported in proportions of 5% and 13.44% in western and domestic countries, respectively. The cerebral apoplexy is divided into cerebral arterial thrombosis and hemorrhagic apoplexy according to the properties, wherein the cerebral arterial thrombosis accounts for 75 to 85 percent of the total number of stroke patients.
There are many treatment modes for treating cerebral arterial thrombosis, and drug therapy is one of the main treatment modes adopted for treating cerebral arterial thrombosis at present. The currently clinically used therapeutic drugs are mainly classified into the following categories: thrombolytic drugs, anti-platelet aggregation drugs, defibrotizing drugs, anticoagulant drugs, neuroprotective drugs, and the like. Through continuous efforts, great progress has been made in the research of drugs for treating ischemic stroke, but many problems remain unsolved. Such as the expanded application range of the thrombolysis 'time window', the drug selection and the combined use of the anticoagulation and the defibrination treatment, the clinical effectiveness and the safety of the neuroprotective drugs, and the like. With the deep research on the pathogenesis and the disease mechanism of the cerebral apoplexy, people gradually and clearly know the treatment target, which provides more research directions for the research and the clinical use of the cerebral apoplexy treatment medicament.
Herba Leonuri has bitter and pungent taste, slight cold, enters liver and pericardium channels, and has effects of promoting blood circulation, regulating menstruation, removing blood stasis, promoting tissue regeneration, inducing diuresis and relieving swelling. Mainly treats irregular menstruation, metrorrhagia, metrostaxis, dystocia, dysmenorrheal, postpartum stasis and other symptoms, and is called as 'Xue Jia Sheng medicine' and 'Jing Yuan Liang Yao'. Stachydrine (Stachydrine) and Leonurine (Leonurine) are one of the main effective components of traditional Chinese medicine motherwort. Animal studies show that stachydrine and leonurine both have anti-ischemic stroke activity in animal model groups, but the half-life of stachydrine is short, and the in vivo anti-ischemic stroke activity is poor. Leonurine is easy to generate glucuronidation in vivo and has low bioavailability.
The invention aims to combine the advantages of stachydrine and leonurine to develop a novel cardiovascular and cerebrovascular medicine with high efficiency.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a series of proline structure-based derivatives and application thereof in preparing medicaments for treating cardiovascular and cerebrovascular diseases. Pharmacological experiments prove that the proline structure-based derivative has a nerve protection effect and has a good treatment effect on cerebral arterial thrombosis and the like.
Another object of the present invention is to provide a process for producing the proline derivative.
In order to achieve the purpose, the technical scheme of the invention is as follows:
provided are a proline derivative and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the proline derivative has a structure shown in a formula (I):
wherein:
R 1 、R 2 、R 3 and R 4 Are each independently selected from O (CH) 2 ) n CH 3 Halogen atom, H, CF 3 、OCF 3 、OH、SH、NH 2 Carboxyl, ester group, sulfone group, sulfoxide group, sulfonic group, sulfonate group, sulfonamide group, ketone group, aldehyde group, nitro group, nitroso group, C 1-12 And C is a hydrocarbon group 1-12 Aryl of (a); n is 0 or a positive integer;
R 5 is H, CF 3 、OCF 3 、OH、C 1-12 Or C is a hydrocarbon group 1-12 Aryl of (2);
R 6 、R 7 and R 8 Each independently selected from halogen atoms, H, CF 3 、OCF 3 、OH、SH、NH 2 Carboxyl, ester group, sulfone group, sulfoxide group, sulfonic group, sulfonate group, sulfonamide group, ketone group, aldehyde group, nitro group, nitroso group, C 1-12 And C 1-12 Aryl of (2);
x is O or NH;
y is
R 9 A side chain selected from any one of natural amino acids, excluding proline;
R 10 is H, carboxyl, amido or ester group.
Preferably, the natural amino acid is glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, serine, tyrosine, cysteine, methionine, threonine, aspartic acid, asparagine, glutamine, glutamic acid, lysine, arginine, or histidine.
In a preferred embodiment, the proline derivative of the invention may have the structure shown in formula (II):
wherein R is 1 、R 2 、R 3 And R 4 Are each independently selected from O (CH) 2 ) n CH 3 H, CF, a halogen atom 3 、OCF 3 、OH、SH、NH 2 Carboxyl, ester group, sulfone group, sulfoxide group, sulfonic group, sulfonate group, sulfonamide group, ketone group, aldehyde group, nitro group, nitroso group, C 1-12 And C is a hydrocarbon group 1-12 N is 0 or a positive integer. Preferably, R is 1 、R 2 、R 3 And R 4 Are each independently selected from H and OCH 3 . More preferably, the proline derivative is selected from
In another preferred embodiment, the proline derivative of the invention has the structure shown in formula (III):
wherein X is O or NH;
y is
R 9 A side chain selected from any one of natural amino acids, excluding proline;
R 10 is H, carboxyl, amido or ester group.
Preferably, the natural amino acid is glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, serine, tyrosine, cysteine, methionine, threonine, aspartic acid, asparagine, glutamine, glutamic acid, lysine, arginine, or histidine.
The invention also provides the application of any proline derivative and stereoisomer thereof or pharmaceutically acceptable salt thereof in preparing medicaments for treating cardiovascular and cerebrovascular diseases; preferably, the cardiovascular and cerebrovascular diseases are selected from ischemic stroke, cerebral infarction, cerebral stroke or cerebral arteriosclerosis; most preferably, the cardiovascular and cerebrovascular disease is ischemic stroke.
The invention also provides a preparation method of the proline derivative, which comprises the following steps:
(1) carrying out hydrogenation reaction on the L-proline a and formaldehyde under the catalytic action of palladium carbon to obtain N-methyl-L-proline b:
(2) respectively carrying out condensation reaction on the N-methyl-L-proline b and a compound m under the action of dicyclohexylcarbodiimide to respectively prepare a proline derivative c, wherein the compound m is preferably anthranilic acid, gamma-aminobutanamide, glutamine or glycine;
(3) the proline derivative c and leonurine are subjected to condensation reaction under the action of dicyclohexylcarbodiimide to prepare the proline derivative shown in the formula (III).
Compared with the prior art, the proline derivative designed and synthesized by the invention has better activity than stachydrine and positive drugs in the aspects of neuroprotection, antioxidation, cytotoxicity inhibition, anticoagulation and the like, and has wide prospect of being developed into drugs for treating cardiovascular and cerebrovascular diseases.
Drawings
Figure 1 shows cerebral infarct sizes of different groups of rats in the rat arterial occlusion model of example 5.
Detailed Description
Unless otherwise defined, scientific and technical terms used herein shall have the meanings that are commonly understood by those of ordinary skill in the art.
The halogen atom in the invention comprises F, Cl, Br or I, and the alkyl comprises saturated or unsaturated open-chain alkyl and saturated or unsaturated cyclic alkyl.
The pharmaceutically acceptable salts of the present invention include salts derived from inorganic and organic acids. Preferably, the inorganic acid may be hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid; the organic acid may be methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid or mandelic acid. More preferably, the pharmaceutically acceptable salt is a hydrochloride salt.
The natural amino acid refers to amino acids capable of constituting protein, and includes glycine, alanine, leucine, isoleucine, valine, proline, phenylalanine, methionine, tryptophan, serine, glutamine, threonine, cysteine, asparagine, tyrosine, aspartic acid, glutamic acid, lysine, arginine and histidine. In addition to proline, these amino acids have the following general structure:
The proline derivative provided by the invention has the activities of neuroprotection, antioxidation, cytotoxicity inhibition, anticoagulation and the like, and can improve cerebral ischemia in an arterial occlusion cerebral ischemia model, so that the proline derivative can be used for developing a medicament for treating cardiovascular and cerebrovascular diseases and can also be developed into a neuroprotection and/or antioxidation and/or anticoagulation medicament. The proline derivative can be developed into a health product for treating cardiovascular and cerebrovascular diseases and/or resisting blood coagulation and/or oxidation and/or protecting nerves. The cardiovascular and cerebrovascular diseases of the invention include, but are not limited to, ischemic stroke, cerebral infarction, cerebral stroke and cerebral arteriosclerosis.
The following embodiments better illustrate the present disclosure. However, the present invention is not limited to the following examples.
Example 1: the synthetic route of N-methyl-L-proline b is as follows:
dissolving L-proline (4.0g,34.8mmol) in methanol (40mL), sequentially adding 40% formaldehyde aqueous solution (2.8mL, 38.2mmol) and 10% palladium-carbon (1g), adding, hydrogenating, reacting at room temperature for 24 hours, filtering after complete reaction, concentrating the mother liquor to obtain 4g of white solid, wherein the yield is 89%, namely N-methyl-L-proline (compound b). ESI-MS: (M/z,%) > 130[ M + H] + 。
Example 2: the synthetic route of compound B-4 is as follows:
adding dichloromethane (20mL) into the N-methyl-L-proline B (1.29g,10mmol), sequentially adding DCC (2.47g, 12mmol) and glycine (0.75g,10mmol), reacting at room temperature for 24 hours, filtering, and concentrating the mother liquor to obtain a white solid 1g, wherein the yield is 54%, and the compound B-4 is obtained. 1 H NMR(500MHz,CD 3 OD)δ＝4.14(t,J＝8.3,1H),4.00(s,2H),3.71(ddd,J＝11.4,7.7,4.1,1H),3.22(d,J＝11.1,1H),2.95(d,J＝10.5,3H),2.58(dd,J＝12.2,7.5,1H),2.24-2.02(m,3H)。
Example 3: the synthetic route of compound B-5 is as follows:
adding dichloromethane (20mL) into the B-4(1.86g,10mmol), sequentially adding DCC (2.47g, 12mmol) and Y5(3.1g,10mmol), reacting at room temperature for 24 hours, filtering, and concentrating the mother liquor to obtain colorless oil 1.4g, with the yield of 30%, namely the compound B-5. ESI-MS: (M/z,%) < 480[ M + H >] + 。 1 H NMR(500MHz,D 2 O)δ＝7.43(s,2H),4.49(d,J＝7.8Hz,2H),4.42(t,J＝6.5Hz,2H),4.31(t,J＝8.5Hz,1H),3.92(s,6H),3.85-3.80(m,1H),3.31-3.25(m,3H),2.99(s,3H),2.68-2.61(m,1H),2.32–2.04(m,3H),1.94-1.84(m,2H),1.80–1.73(m,2H)。
Example 4: the synthetic route of compound B-6 is as follows:
adding dichloromethane (20mL) into the B-4(1.86g,10mmol), sequentially adding DCC (2.47g, 12mmol) and Y6(3.1g,10mmol), reacting at room temperature for 24 hours, filtering, and concentrating the mother liquor to obtain colorless oil 1.2g, with a yield of 25%, which is the compound B-6. ESI-MS: (M/z,%) -479 [ M + H] + 。 1 H NMR(500MHz,CD 3 OD)δ＝7.33(s,2H),4.39(t,J＝6.5Hz,2H),4.13(s,2H),3.88(s,6H),3.34-3.3(m,2H),3.28(t,J＝7.0Hz,2H),2.71(m,1H),2.61(s,3H),2.36(m,1H),2.00-1.83(m,5H),1.79-1.73(m,2H)。
Example 5: determining the Effect of proline derivatives on glutamate-induced models of neuronal cell injury
Experimental grouping: blank control group, model group, positive drug group (MK-801), test compound 4 dose groups (1, 5, 10, 20 μmol).
Sample treatment: the samples were dissolved in DMSO and stored at low temperature, and the concentration of DMSO in the final system was controlled within a range that did not affect the assay activity (0.1%).
The experimental method comprises the following steps: the drug to be screened is added six days after the primary rat cerebellar granule nerve cells are cultured (1000-fold dilution is required when 96-well plates are added). Glutamic acid was added at a concentration of 200. mu.M on the seventh day. Cell viability was measured on day eight using MTT (final concentration should be 0.5mg/ml when added to 96-well plates). The results of the experiment are shown in table 1.
TABLE 1 detection of nerve cell survival rate
As can be seen from table 1: in a glutamic acid-induced nerve cell injury model, the compounds B-5(20uM) and B-6(10uM and 20uM) have significant difference compared with a glutamic acid model group, and are obviously superior to stachydrine, which indicates that the compounds B-5 and B-6 have neuroprotective effect.
Example 6: determination of the pharmacodynamic evaluation of proline derivatives on the model of arterial occlusion in rats
Grouping experiments: sham (sham), model (vehicle), B-6, 12-15 rats per group.
The experimental method comprises the following steps: SD male rats weighing 250-. The results of the experiments are shown in tables 2, 3 and fig. 1.
TABLE 2 cerebral infarction area (infarct size/total volume)
| Grouping | Concentration of | mean | SD | N |
| Artificial operation group | - | 0.000 | 0.000 | 8 |
| Model set | - | 32.294 | 4.638 | 8 |
| B6 | 1mg/kg | 9.957 | 2.679 | 8 |
TABLE 3 neuroethology score (points)
| Grouping | Concentration of | mean | SD | N |
| Artificial operation group | - | 0.000 | 0.000 | 8 |
| Model set | - | 2.625 | 0.518 | 8 |
| B6 | 1mg/kg | 1.500 | 0.535 | 8 |
The results show that: the compound B-6 can obviously reduce the cerebral infarction area caused by transient cerebral ischemia of rats and reduce the neurobehavioral score of the rats after the transient cerebral ischemia. The B-6 compound has obvious anti-ischemic cerebral apoplexy activity.
The acute toxicity test shows that the half lethal dose of B-6 to rats is 85mg/kg, and the active dose is 1mg/kg, so that the B-6 has a considerable treatment window.
The above examples are only intended to illustrate the technical solution of the present invention, and not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof; such modifications and substitutions do not depart from the spirit and scope of the corresponding claims.
Claims (3)
1. A proline derivative and its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: the proline derivative is selected from
2. Use of the proline derivatives and stereoisomers thereof or pharmaceutically acceptable salts thereof according to claim 1 for the preparation of a medicament for the treatment of cardiovascular and cerebrovascular diseases.
3. Use according to claim 2, characterized in that: the cardiovascular and cerebrovascular diseases are selected from cerebral apoplexy or cerebral arteriosclerosis.
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| CN201810312331.7A CN110357800B (en) | 2018-04-09 | 2018-04-09 | Proline derivative and application thereof in preparing medicine for treating cardiovascular and cerebrovascular diseases |
| PCT/CN2019/081913 WO2019196835A1 (en) | 2018-04-09 | 2019-04-09 | Proline derivative and application thereof in preparing drug for treating cardiovascular and cerebrovascular disease |
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| CN112552211B (en) * | 2020-12-30 | 2023-04-14 | 青岛海合生物科技有限公司 | Leonurine derivative and application thereof in preparation of medicines for preventing or treating ischemic cerebrovascular diseases |
| CN114796181A (en) * | 2021-01-27 | 2022-07-29 | 中国海洋大学 | Application of leonurine in preparation of medicine for preventing and treating non-vascular dementia or infectious central nerve injury |
| CN114507173A (en) * | 2022-03-08 | 2022-05-17 | 重庆医药高等专科学校 | Preparation method of 1-methylpyrrolidine-2-acrylic acid hydrochloride |
| CN114736146A (en) * | 2022-03-17 | 2022-07-12 | 重庆医药高等专科学校 | Preparation method of novel 1-methylpyrrolidine-2-acrylic acid |
| CN114874118A (en) * | 2022-04-18 | 2022-08-09 | 重庆医药高等专科学校 | Method for synthesizing N-methyl-D-prolinol by one-pot method |
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