CN117800938A - Hydroxy substituted beraprost derivative, synthesis method and application thereof - Google Patents

Hydroxy substituted beraprost derivative, synthesis method and application thereof Download PDF

Info

Publication number
CN117800938A
CN117800938A CN202311793574.4A CN202311793574A CN117800938A CN 117800938 A CN117800938 A CN 117800938A CN 202311793574 A CN202311793574 A CN 202311793574A CN 117800938 A CN117800938 A CN 117800938A
Authority
CN
China
Prior art keywords
beraprost
compound
substituted
chloroform
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202311793574.4A
Other languages
Chinese (zh)
Inventor
鲁卓敏
张宏峰
黄夏梦
陈滔彬
吴晓川
吴艳军
钟永健
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangzhou Kaishi Biotechnology Co ltd
Guangzhou Kaishi Pharmaceutical Co ltd
Original Assignee
Guangzhou Kaishi Biotechnology Co ltd
Guangzhou Kaishi Pharmaceutical Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guangzhou Kaishi Biotechnology Co ltd, Guangzhou Kaishi Pharmaceutical Co ltd filed Critical Guangzhou Kaishi Biotechnology Co ltd
Publication of CN117800938A publication Critical patent/CN117800938A/en
Pending legal-status Critical Current

Links

Abstract

The invention provides a hydroxyl substituted beraprost derivative, a synthesis method and application thereof, and belongs to the technical field of medicines. The compound is a coupling compound containing beraprost and a nitric oxide donor:

Description

Hydroxy substituted beraprost derivative, synthesis method and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a hydroxyl-substituted beraprost derivative, a synthesis method and application thereof.
Background
Pulmonary hypertension (Pulmonary Hypertension, PH, pulmonary arterial hypertension PulmonaryArterial Hypertension, PAH) is a group of diseases characterized by elevated pulmonary vascular resistance and right ventricular failure. The patient has high survival rate after being confirmed, and is a malignant disease.
There are three main classes of agents currently used clinically to treat pulmonary arterial hypertension, including 1) endothelin receptor antagonist pathways (e.g., bosentan, ambrisentan, macitentan); 2) Nitric oxide pathway such as phosphatase 5 inhibitors (e.g., nitric oxide, cetira, non-tadalafil), guanylate cyclase agonists (e.g., riocidine); 3) Prostaglandin pathways, such as prostacyclin analogs (e.g., sodium beraprost, epoprostenol, enoprostenol, treprostinil) and prostacyclin receptor agonists (e.g., selapage). The mechanism of action of these classes of drugs ultimately relaxes endothelial vascular smooth muscle through the final pathways of the second messengers cAMP and cGMP.
Among these drugs, prostaglandin analogues are the most effective and most classical drugs, and oral sodium beraprost (beraprost sudiam) is the preparation currently used mainly in clinical practice in China such as Indonesia, but because of its drug substitution defect, it needs to be administered several times daily, and thus researchers have made improvements in preparation (such as 60mcg sustained release tablet Careload of Torile Corp. In Japan, successfully marketed in Japan) and structure (the pre-shellfish optical body Esuberprost was developed by U.S. UT Corp. But three-phase clinical study was terminated).
Since Nitric Oxide (NO) plays an important role in pulmonary vascular smooth muscle relaxation, but is particularly fast and difficult to administer due to its gaseous character and metabolism, inhaled NO (iono) is difficult to deploy in practical PAH clinical therapeutic applications, although it is already approved for the market. Thus, the use of nitric oxide donor (NO donor) mode is a new attempt to develop new drugs, such as long-acting inhalants of liposome aerosols prepared using NO donors for the treatment of PAH (NaharK, et al, pharma res.2016); the latanoprost nitrate developed by Valeant Pharma consists of latanoprost butanediol mononitrate, and has a double action mechanism in treating glaucoma: latanoprost acid (a marketed drug) can act on the uveoscleral tract to promote drainage of aqueous humor; butanediol mononitrate (butanediol mononitrate) releases nitric oxide, NO, through the trabecular meshwork and Schlemm's canal, facilitating aqueous humor drainage. The new treatment method under double-tube alignment is verified in clinical trials: the nitrate ester of latanoprost is able to lower ocular tension more significantly than single administration of latanoprost, showing better clinical advantage, and this product was FDA approved for marketing in 2017 (trade name VYZULTA).
In addition to pulmonary hypertension, beraprost has been tried for the treatment of malignant tumor metastasis (developed by United states therapeutic corporation), atherosclerosis (developed by japanese scientific research Kaken Pharma), hypertension (developed by japanese scientific research Kaken Pharma and United states therapeutic corporation, respectively), diabetic neuropathy (developed by japanese scientific research Kaken Pharma), nephritis and renal failure, cerebrovascular dementia (CN 112691109 a), alcoholic fatty liver (HK 1219665A), and the like. NO donor drugs have also been used to develop treatments for a variety of diseases such as anti-inflammatory, cardiovascular diseases (MegsonIL & WebbDJ, expert Opin Investig Drugs,2002; knoxCD et al, MK5108, JAm HeartAssoc, 2016).
However, the sodium beraprost on the market has the defects of short elimination half-life, more times of single-day administration, saturated capping effect on curative effect, short rapid catabolism half-life of NO gas in solution and the like.
Disclosure of Invention
Aiming at the defects of short elimination half-life period, more single-day administration times, saturated capping effect in curative effect, short rapid catabolism half-life period of NO in solution and the like of the beraprost sodium, the invention provides a novel series of compounds of the beraprost sodium combined with an NO donor. The compound combined with the beraprost sodium NO donor can be applied to treatment medicaments for treating various diseases such as pulmonary arterial hypertension, respiratory distress syndrome, arterial occlusive diseases, organ fibrosis, nephropathy, ocular diseases (such as diabetic fundus lesions and the like), osteoporosis, thromboangiitis, myocardial infarction and the like.
The technical scheme of the invention is realized as follows:
the invention provides a hydroxyl substituted beraprost derivative, which has a structure shown in the following formula I:
R 1 、R 2 respectively selected from H,And R is 1 、R 2 Not simultaneously H; wherein R is 3 C being linear or branched 1 -C 10 Alkyl, C 5-7 Cycloalkyl or-C 1 -C 10 Alkyl-aromatic ring-, R 4 、R 5 C being linear or branched 1 -C 10 An alkyl group; wherein C is 1 -C 10 Alkyl, C 5-7 Cycloalkyl or aromatic rings may be substituted with one or more of the following substituents: halogen atoms, hydroxy, carboxyl, cyano or- (C) 1 -C 10 Alkyl) -ONO 2 。
As a further improvement of the present invention, the compound includes any one of the following structures:
the invention further provides a synthesis method of the hydroxyl-substituted beraprost derivative, which comprises the following steps:
s1, synthesizing a carboxylic acid nitrate intermediate B from a starting material A through substitution reaction;
s2, synthesizing the raw material C through esterification reaction to obtain an intermediate D;
s3, performing esterification reaction on the intermediate C and the intermediate B, and purifying and separating to obtain three types of substituted intermediates E, F or G;
s4, carrying out deprotection reaction on the intermediate E, F or G to obtain a product H, I or J.
Reagents for the S1 substitution reaction include, but are not limited to: silver nitrate, concentrated nitric acid, solvents used include, but are not limited to: acetonitrile, dichloromethane, chloroform, acetone, ethyl acetate, toluene, dioxane, etc.;
condensing agents used in the S2 esterification reaction include, but are not limited to: (1-ethyl-3 (3-dimethylpropylamine) carbodiimide), dicyclohexylcarbodiimide, trifluoromethanesulfonic anhydride, p-toluenesulfonic acid, using solvents including but not limited to: acetonitrile, dichloromethane, chloroform, acetone, ethyl acetate, toluene, dioxane, etc.;
condensing agents used in the S3 esterification reaction include, but are not limited to: (1-ethyl-3 (3-dimethylpropylamine) carbodiimide), dicyclohexylcarbodiimide, trifluoromethanesulfonic anhydride, p-toluenesulfonic acid, using solvents including but not limited to: acetonitrile, dichloromethane, chloroform, acetone, ethyl acetate, toluene, dioxane, etc.;
reagents used in the S4 deprotection reaction include, but are not limited to: trifluoroacetic acid, tetrabutylammonium fluoride, tetrabutylammonium iodide, hydrofluoric acid, hydrochloric acid, potassium hydroxide, sodium hydroxide, palladium carbon, and the like, using solvents including, but not limited to: acetonitrile, dichloromethane, chloroform, acetone, ethyl acetate, toluene, dioxane, methanol, ethanol, and the like.
The invention further protects the application of the hydroxyl-substituted beraprost derivative as prostacyclin analogue and nitric oxide coupling.
The invention further provides application of the hydroxyl-substituted beraprost derivative in preparing a medicament for treating pulmonary arterial hypertension, respiratory distress syndrome, arterial occlusive diseases, organ fibrosis, nephropathy, diabetic fundus lesions, osteoporosis, thromboangiitis and myocardial infarction.
The invention has the following beneficial effects: the invention relates to a series of medicines developed by compounds combining sodium beraprost and NO donors, which are decomposed into beraprost and generate nitric oxide NO after entering the body, and can generate double pharmacological actions, on one hand, the beraprost can be specifically combined with a prostatectoid receptor, and can play a role in dilating vascular smooth muscle through a cAMP (cyclic amp) way, and on the other hand, NO molecules which can be released by the compounds in the body can play a role in dilating blood vessels through an endothelial cell cGMP (cyclic gmp) way, so that the synergistic effect can be achieved.
The series of compounds can be used for treating pulmonary arterial hypertension, respiratory distress syndrome, arterial occlusive diseases, organ fibrosis, nephropathy, ocular diseases (such as diabetic fundus lesions and the like), osteoporosis, thromboangiitis, myocardial infarction and other diseases.
The invention provides a combination drug of beraprost sodium and NO donors, which solves the defects of short elimination half-life of beraprost sodium, multiple times of single-day administration, saturated capping effect in curative effect, short half-life of NO in rapid catabolism of gas in solution and the like, reduces dosage and administration frequency of the original beraprost, simultaneously utilizes the smooth muscle dilating effect caused by the compound releasing NO molecules in vivo, plays the synergistic effect of the two drugs through double effects, and improves the effectiveness and safety of the drugs.
Drawings
In order to more clearly illustrate the embodiments of the invention or the technical solutions of the prior art, the drawings which are used in the description of the embodiments or the prior art will be briefly described, it being obvious that the drawings in the description below are only some embodiments of the invention, and that other drawings can be obtained according to these drawings without inventive faculty for a person skilled in the art.
FIG. 1 is a graph showing in vitro NO release comparison of each group of compounds in the test examples.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1: preparation of Compound 1
The synthetic route is as follows:
the synthesis method comprises the following steps:
2-bromoacetic acid (5 mmol) was dissolved in acetonitrile, silver nitrate (8 mmol) was added under stirring, the reaction was carried out at 60℃for 4 hours, TLC was monitored to be complete, the solvent was dried by spin, dichloromethane was added, water was washed once, saturated brine was washed once, and column chromatography was carried out to obtain intermediate 1-B.
Beraprost (100 mg) was dissolved in 10mL of dichloromethane, 2, 4-dimethylbenzyl alcohol (65 mg), DMAP (25 mg) and edci.hcl (66 mg) were added in this order, and the mixture was stirred at room temperature for 14h, and the reaction was completely checked by tlc, diluted with ethyl acetate, washed once with 0.1M aqueous hydrochloric acid, washed once with saturated brine, and purified by column chromatography to give intermediate 1-D.
Intermediate 1-D (0.1 mmol), intermediate 1-B (0.15 mmol), EDCI.HCl (0.2 mmol) and HOBT (0.2 mmol) were dissolved in dichloromethane and stirred at room temperature for 4 hours, TLC monitored complete reaction, solvent was spun-dry, and column chromatography was performed to give intermediate 1-E.
Intermediate 1-E (0.1 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added and reacted at room temperature for 2 hours, after which the solvent was dried by spin-drying, and compound 1 was purified by HPLC to give 23% yield. 1 H NMR(500MHz,Chloroform-d)δ7.11–7.00(m,2H),6.96(dq,J＝7.7,1.0Hz,1H),5.84(dd,J＝15.6,7.0Hz,1H),5.72(dd,J＝15.6,6.4Hz,1H),5.08(td,J＝5.3,4.1Hz,1H),5.00(dt,J＝5.1,4.3Hz,1H),4.74–4.57(m,3H),4.17(qd,J＝6.4,1.1Hz,1H),3.47(dd,J＝5.7,4.2Hz,1H),3.00–2.87(m,1H),2.87–2.68(m,4H),2.42(dt,J＝14.6,4.2Hz,1H),2.38–2.27(m,3H),2.27–2.13(m,2H),2.01–1.81(m,3H),1.65(t,J＝2.0Hz,3H),1.02(d,J＝6.8Hz,3H)。
Example 2: preparation of Compound 2
The synthetic route is as follows:
referring to the synthesis method of the intermediate 1-B, the intermediate 2-B can be prepared.
Intermediate 1-D (0.1 mmol), intermediate 2-B (0.15 mmol), EDCI.HCl (0.2 mmol) and HOBT (0.2 mmol) were dissolved in dichloromethane and stirred at room temperature for 6 hours, TLC monitored complete reaction, solvent was spun-dry and purified by HPLC to give intermediate 2-C.
Referring to the synthetic method of example 1, compound 2 can be prepared by substituting 2-C for the starting material. 1 H NMR(500MHz,Chloroform-d)δ7.10–7.00(m,2H),6.94(ddt,J＝6.2,2.9,1.0Hz,1H),5.95–5.78(m,2H),5.12(td,J＝6.1,1.0Hz,1H),5.02–4.89(m,1H),4.32(t,J＝5.8Hz,2H),4.10(qd,J＝5.5,4.7Hz,1H),3.72(d,J＝5.3Hz,1H),3.40(dd,J＝5.7,4.2Hz,1H),2.76(ddddd,J＝6.5,5.1,4.2,3.2,1.1Hz,3H),2.44–2.28(m,4H),2.27–2.19(m,2H),2.18–1.98(m,3H),1.98–1.72(m,6H),1.65(t,J＝2.0Hz,3H),1.03(d,J＝6.8Hz,3H)。
Example 3: preparation of Compound 3
Referring to the synthesis of example 1, compound 3 can be prepared by substituting 4-bromobutyric acid for the starting material. 1 HNMR(500MHz,Chloroform-d)δ7.14–6.98(m,2H),6.96(dq,J＝7.7,1.0Hz,1H),5.84(dd,J＝15.6,7.0Hz,1H),5.72(dd,J＝15.6,6.4Hz,1H),5.09(td,J＝5.2,4.1Hz,1H),5.02(dt,J＝5.1,4.3Hz,1H),4.69(d,J＝6.2Hz,1H),4.43(qt,J＝10.4,6.1Hz,2H),4.17(qd,J＝6.4,1.1Hz,1H),3.47(dd,J＝5.7,4.2Hz,1H),2.94(dtd,J＝6.6,5.4,1.0Hz,1H),2.78(td,J＝6.4,1.0Hz,2H),2.61–2.47(m,2H),2.21(dp,J＝6.2,2.0Hz,2H),2.07(tt,J＝7.0,6.0Hz,2H),2.02–1.84(m,3H),1.65(t,J＝2.0Hz,3H),1.02(d,J＝6.8Hz,3H)。
Example 4: preparation of Compound 4
Referring to the synthetic method of example 2, compound 4 can be prepared by substituting 4-bromobutyric acid for the starting material. 1 HNMR(500MHz,Chloroform-d)δ7.21–6.99(m,2H),6.94(dq,J＝7.7,1.0Hz,1H),5.96–5.71(m,2H),5.09(td,J＝6.1,0.9Hz,1H),4.99–4.87(m,1H),4.54–4.37(m,2H),4.10(qd,J＝5.5,4.7Hz,1H),3.72(d,J＝5.3Hz,1H),3.40(dd,J＝5.7,4.2Hz,1H),2.88–2.66(m,3H),2.50(t,J＝7.0Hz,2H),2.35(t,J＝7.0Hz,2H),2.29–2.17(m,2H),2.17–2.01(m,5H),2.01–1.85(m,2H),1.65(t,J＝2.0Hz,3H),1.03(d,J＝6.7Hz,3H)。
Example 5: preparation of Compound 5
Referring to the synthetic method of example 2, compound 5 can be prepared by substituting 6-bromohexanoic acid for the starting material. 1 HNMR(500MHz,Chloroform-d)δ7.14–7.01(m,2H),6.94(ddt,J＝5.6,3.5,1.1Hz,1H),5.98–5.71(m,2H),5.12(td,J＝6.1,1.0Hz,1H),4.94(dt,J＝5.0,4.3Hz,1H),4.29(t,J＝6.0Hz,2H),4.10(qd,J＝5.6,4.7Hz,1H),3.72(d,J＝5.3Hz,1H),3.40(dd,J＝5.7,4.2Hz,1H),2.93–2.64(m,3H),2.32(td,J＝6.9,4.5Hz,4H),2.27–2.17(m,2H),2.17–1.98(m,3H),1.98–1.86(m,2H),1.86–1.73(m,2H),1.65(t,J＝2.0Hz,3H),1.62–1.44(m,4H),1.03(d,J＝6.8Hz,3H)。
Example 6: preparation of Compound 6
Referring to the synthetic method of example 1, compound 6 can be prepared by substituting 6-bromohexanoic acid for the starting material. . 1 H NMR(500MHz,Chloroform-d)δ7.11–6.99(m,2H),6.96(ddt,J＝7.5,1.8,0.9Hz,1H),5.83(dd,J＝15.7,6.9Hz,1H),5.72(dd,J＝15.6,6.4Hz,1H),5.03(ddt,J＝14.8,5.1,4.1Hz,2H),4.69(d,J＝6.2Hz,1H),4.32(t,J＝6.0Hz,2H),4.17(qd,J＝6.4,1.1Hz,1H),3.47(dd,J＝5.7,4.2Hz,1H),2.94(dtd,J＝6.6,5.5,1.0Hz,1H),2.87–2.69(m,4H),2.48–2.27(m,4H),2.21(dp,J＝6.2,2.0Hz,2H),2.06–1.71(m,7H),1.65(t,J＝2.0Hz,3H),1.02(d,J＝6.8Hz,3H)。
Example 7: preparation of Compound 7
Compound 7 can be prepared by substituting 7-bromoheptanoic acid for the starting material by the synthetic method of reference example 2. 1 H NMR(500MHz,Chloroform-d)δ7.15–7.01(m,2H),6.95(ddt,J＝5.5,3.3,0.9Hz,1H),5.94–5.73(m,2H),5.12(td,J＝6.1,1.0Hz,1H),4.94(dt,J＝5.0,4.3Hz,1H),4.29(t,J＝6.1Hz,2H),4.10(qd,J＝5.6,4.7Hz,1H),3.72(d,J＝5.3Hz,1H),3.40(dd,J＝5.5,4.2Hz,1H),2.86–2.63(m,3H),2.32(td,J＝7.0,2.7Hz,4H),2.31–2.18(m,3H),2.18–2.02(m,3H),1.97–1.84(m,2H),1.84–1.72(m,2H),1.65(t,J＝2.0Hz,3H),1.55–1.27(m,6H),1.03(d,J＝6.8Hz,3H)。
Example 8: preparation of Compound 8
Referring to the synthesis of example 1, compound 8 can be prepared by substituting 7-bromoheptanoic acid for the starting material. 1 H NMR(500MHz,Chloroform-d)δ7.25–6.99(m,2H),6.96(ddt,J＝7.0,2.2,1.1Hz,1H),5.83(dd,J＝15.6,6.9Hz,1H),5.73(dd,J＝15.6,6.4Hz,1H),5.16–4.94(m,2H),4.76(d,J＝6.2Hz,1H),4.29(t,J＝6.1Hz,2H),4.17(qd,J＝6.4,1.1Hz,1H),3.47(dd,J＝5.7,4.2Hz,1H),2.94(dtd,J＝6.6,5.5,1.0Hz,1H),2.78(td,J＝6.4,1.0Hz,2H),2.40(dt,J＝14.5,4.2Hz,1H),2.37–2.26(m,5H),2.21(dp,J＝6.2,2.0Hz,2H),2.02–1.85(m,3H),1.81(p,J＝6.3Hz,2H),1.65(t,J＝2.0Hz,3H),1.63–1.41(m,4H),1.02(d,J＝6.8Hz,3H)。
Example 9: preparation of Compound 9
The synthetic route is as follows:
intermediate 1-D (0.1 mmol), intermediate 1-B (0.3 mmol), EDCI.HCl (0.4 mmol) and HOBT (0.4 mmol) were dissolved in dichloromethane and stirred at room temperature for 6 hours, TLC monitored complete reaction, solvent was spun-dry and purified by HPLC to give intermediate 3-A. Referring to the synthetic method of example 1, compound 9 can be prepared. 1 H NMR(500MHz,Chloroform-d)δ7.15–7.00(m,2H),6.97(ddt,J＝6.2,2.9,1.1Hz,1H),5.99–5.72(m,2H),5.20–5.04(m,2H),4.99(dt,J＝5.1,4.2Hz,1H),4.63(q,J＝7.2Hz,4H),3.46(dd,J＝5.6,4.3Hz,1H),2.98–2.88(m,1H),2.88–2.70(m,6H),2.41(dt,J＝14.4,4.2Hz,1H),2.35–2.28(m,3H),2.24(dp,J＝6.1,2.0Hz,2H),2.10–1.86(m,3H),1.65(t,J＝2.0Hz,3H),1.03(d,J＝6.8Hz,3H)。
Example 10: preparation of Compound 10
Referring to the synthetic method of example 2, compound 10 can be prepared by substituting 8-bromooctanoic acid for the starting material. 1 H NMR(300MHz,Chloroform-d)δ7.16–7.02(m,2H),6.95(ddt,J＝6.0,2.7,0.9Hz,1H),5.93–5.61(m,4H),4.76–4.42(m,3H),4.29–4.04(m,2H),3.92(d,J＝5.5Hz,1H),3.43(dd,J＝5.5,4.2Hz,1H),2.96–
2.63(m,5H),2.45(td,J＝7.0,0.9Hz,2H),2.30–2.06(m,4H),2.06–1.84(m,3H),1.57(t,J＝2.0Hz,3H),1.00(d,J＝6.2Hz,3H)。
Example 11: preparation of Compound 11
Referring to the synthesis of example 2, compound 11 can be prepared by substituting 9-bromononanoic acid for the starting material. 1 H NMR(500MHz,Chloroform-d)δ7.19–7.02(m,2H),6.95(ddt,J＝7.1,2.0,0.9Hz,1H),5.97–5.71(m,2H),5.13(td,J＝6.1,1.0Hz,1H),4.94(dt,J＝5.0,4.3Hz,1H),4.29(t,J＝6.1Hz,2H),4.10(qd,J＝5.6,4.7Hz,1H),3.72(d,J＝5.3Hz,1H),3.39(dd,J＝5.6,4.3Hz,1H),2.87–2.63(m,3H),2.32(dt,J＝15.5,7.1Hz,4H),2.26–2.17(m,2H),2.17–1.98(m,3H),1.97–1.87(m,2H),1.86–1.73(m,2H),1.65(t,J＝2.0Hz,3H),1.56–1.41(m,4H),1.41–1.18(m,6H),1.03(d,J＝6.7Hz,3H)。
Example 12: preparation of Compound 12
Referring to the synthetic method of example 1, compound 12 can be prepared by substituting 7-bromoheptanoic acid for the starting material. 1 HNMR(500MHz,Chloroform-d)δ7.13–7.01(m,2H),6.97(ddt,J＝6.8,2.1,0.9Hz,1H),5.83(dd,J＝15.6,6.9Hz,1H),5.73(dd,J＝15.6,6.4Hz,1H),5.03(ddt,J＝11.3,5.1,4.3Hz,2H),4.76(d,J＝6.2Hz,1H),4.29(t,J＝6.1Hz,2H),4.17(qd,J＝6.4,1.1Hz,1H),3.47(dd,J＝5.7,4.2Hz,1H),2.94(dtd,J＝6.6,5.4,1.0Hz,1H),2.78(td,J＝6.4,1.0Hz,2H),2.40(dt,J＝14.5,4.2Hz,1H),2.36–2.24(m,5H),2.21(dp,J＝6.2,2.0Hz,2H),2.02–1.85(m,3H),1.85–1.71(m,2H),1.65(t,J＝2.0Hz,3H),1.55–1.31(m,6H),1.02(d,J＝6.8Hz,3H)。
Example 13: preparation of Compound 13
Referring to the synthetic method of example 2, compound 13 can be prepared by substituting 10-bromodecanoic acid for the starting material. 1 H NMR(500MHz,Chloroform-d)δ7.18–7.01(m,2H),6.95(ddt,J＝7.1,2.0,0.9Hz,1H),5.94–5.75(m,2H),5.13(td,J＝6.1,1.0Hz,1H),4.94(dt,J＝5.0,4.3Hz,1H),4.29(t,J＝6.1Hz,2H),4.10(qd,J＝5.5,4.7Hz,1H),3.95(d,J＝5.3Hz,1H),3.39(dd,J＝5.6,4.3Hz,1H),2.86–2.68(m,3H),2.32(dt,J＝12.1,7.1Hz,4H),2.27–2.18(m,2H),2.15–1.99(m,3H),1.95–1.86(m,2H),1.82–1.73(m,2H),1.65(t,J＝2.0Hz,3H),1.49(p,J＝6.9Hz,2H),1.46–1.38(m,2H),1.37–1.19(m,8H),1.03(d,J＝6.8Hz,3H)。
Example 14: preparation of Compound 14
Referring to the synthetic method of example 2, compound 14 can be prepared by substituting 6-bromohexanoic acid for the starting material. 1 H NMR(500MHz,Chloroform-d)δ7.15–7.02(m,2H),6.97(ddt,J＝6.6,2.0,1.0Hz,1H),5.92–5.73(m,2H),5.25–5.04(m,2H),4.99(dt,J＝5.1,4.2Hz,1H),4.29(t,J＝6.1Hz,4H),3.45(dd,J＝5.5,4.2Hz,1H),2.92(dtd,J＝6.6,5.4,1.0Hz,1H),2.86–2.63(m,2H),2.40(dt,J＝14.5,4.2Hz,1H),2.35–2.18(m,9H),2.08–1.85(m,3H),1.84–1.70(m,4H),1.64(t,J＝2.0Hz,3H),1.62–1.42(m,8H),1.03(d,J＝6.8Hz,3H)。
Example 15: preparation of Compound 15
Referring to the synthetic method of example 2, compound 15 can be prepared by substituting 4-bromocyclohexane-1-carboxylic acid for the starting material. 1 HNMR(500MHz,Chloroform-d)δ7.16–7.02(m,2H),6.95(ddt,J＝5.5,3.3,0.9Hz,1H),5.92–5.75(m,2H),5.13(td,J＝6.1,0.9Hz,1H),4.94(dt,J＝5.1,4.3Hz,1H),4.67(p,J＝5.4Hz,1H),4.10(qd,J＝5.6,4.7Hz,1H),3.72(d,J＝5.3Hz,1H),3.39(dd,J＝5.6,4.3Hz,1H),2.88–2.64(m,3H),2.40–2.29(m,3H),2.29–2.18(m,2H),2.15–2.02(m,3H),1.99–1.72(m,10H),1.65(t,J＝2.0Hz,3H),1.03(d,J＝6.7Hz,3H)。
Example 16: preparation of Compound 16
Referring to the synthetic method of example 1, compound 16 can be prepared by substituting 3-bromo-2-methylpropanoic acid for the starting material. 1 HNMR(500MHz,Chloroform-d)δ7.17–6.99(m,2H),6.96(dq,J＝7.7,1.0Hz,1H),5.84(dd,J＝15.6,7.0Hz,1H),5.72(dd,J＝15.6,6.4Hz,1H),5.10(td,J＝5.3,4.1Hz,1H),4.97(dt,J＝5.1,4.2Hz,1H),4.69(d,J＝6.2Hz,1H),4.38(d,J＝6.3Hz,2H),4.17(qd,J＝6.4,1.1Hz,1H),3.47(dd,J＝5.7,4.2Hz,1H),3.19–2.82(m,2H),2.78(td,J＝6.4,1.0Hz,2H),2.43(dt,J＝14.5,4.2Hz,1H),2.39–2.29(m,3H),2.26–2.12(m,2H),2.02–1.82(m,3H),1.65(t,J＝2.0Hz,3H),1.27(d,J＝7.3Hz,3H),1.02(d,J＝6.8Hz,3H)。
Example 17: preparation of Compound 17
Referring to the synthetic method of example 2, compound 17 can be prepared by substituting 2, 2-dibromoacetic acid for the starting material. 1 H NMR(500MHz,Chloroform-d)δ7.21–7.00(m,2H),6.95(ddt,J＝7.1,2.0,0.9Hz,1H),5.97–5.67(m,2H),5.17(td,J＝6.1,1.0Hz,1H),4.94(dt,J＝5.0,4.3Hz,1H),4.64(d,J＝6.4Hz,4H),4.10(qd,J＝5.5,4.6Hz,1H),3.72(d,J＝5.3Hz,1H),3.41(dd,J＝5.5,4.2Hz,1H),3.12(p,J＝6.5Hz,1H),2.91–2.61(m,3H),2.33(t,J＝7.1Hz,2H),2.24(dp,J＝6.0,2.0Hz,2H),2.18–1.97(m,3H),1.97–1.77(m,2H),1.65(t,J＝2.0Hz,3H),1.03(d,J＝6.8Hz,3H)。
Example 18: preparation of Compound 18
Referring to the synthetic method of example 2, compound 18 can be prepared by substituting 4-bromo-3-methylbutanoic acid for the starting material. 1 HNMR(500MHz,Chloroform-d)δ7.15–6.99(m,2H),6.94(ddt,J＝6.2,2.9,1.0Hz,1H),5.96–5.71(m,2H),5.10(td,J＝6.1,1.0Hz,1H),5.02–4.86(m,1H),4.32–4.16(m,2H),4.10(qd,J＝5.5,4.7Hz,1H),3.72(d,J＝5.3Hz,1H),3.40(dd,J＝5.7,4.2Hz,1H),2.87–2.66(m,3H),2.43–2.17(m,7H),2.17–2.01(m,3H),1.97–1.85(m,2H),1.65(t,J＝2.0Hz,3H),1.24(d,J＝6.7Hz,3H),1.03(d,J＝6.7Hz,3H)。
Example 19: preparation of Compound 19
The synthetic route is as follows:
the synthesis of intermediate 4-A can be obtained by reference to molecular, 2012,17,7556-7568.
Intermediate 1-D (0.1 mmol), intermediate 4-A, DMAP and TEA were dissolved in 2mL of anhydrous dichloromethane, stirred at room temperature for four hours, the reaction mixture was diluted with 3mL of dichloromethane, washed twice with 10% hydrochloric acid in sequence, washed once with saturated brine, filtered, the filtrate was concentrated, and HPLC purified to give intermediate 4-B.
Referring to the synthetic method of example 2, compound 19 can be produced. 1 HNMR(500MHz,Chloroform-d)δ7.91–7.80(m,2H),7.67–7.48(m,3H),7.15–7.01(m,2H),6.95(ddt,J＝7.3,1.9,0.9Hz,1H),6.12–5.99(m,2H),5.89–5.70(m,2H),5.14(td,J＝6.1,1.0Hz,1H),4.94(dt,J＝5.0,4.3Hz,1H),4.16–3.96(m,2H),3.57(s,2H),3.43(dd,J＝5.7,4.2Hz,1H),2.87–2.64(m,3H),2.33(t,J＝7.1Hz,2H),2.24(dp,J＝5.7,1.9Hz,2H),2.18–1.84(m,5H),1.65(t,J＝2.0Hz,3H),1.03(d,J＝6.7Hz,3H)。
Example 20: preparation of Compound 20
Compound 20 can be obtained by the synthesis method of reference example 19. 1 HNMR(500MHz,Chloroform-d)δ7.76–7.47(m,5H),7.18–7.04(m,2H),6.95(ddt,J＝7.3,1.9,1.0Hz,1H),6.04–5.66(m,2H),5.13(td,J＝6.0,1.1Hz,1H),4.94(dt,J＝5.0,4.3Hz,1H),4.70–4.58(m,2H),4.54(td,J＝6.2,0.8Hz,2H),4.21–3.92(m,2H),3.54(s,2H),3.43(dd,J＝5.7,4.2Hz,1H),2.93–2.69(m,3H),2.33(t,J＝7.0Hz,2H),2.27–2.17(m,2H),2.17–2.05(m,2H),2.05–1.85(m,3H),1.65(t,J＝2.0Hz,3H),1.03(d,J＝6.7Hz,3H)。
Example 21: preparation of Compound 21
Referring to the synthetic method of example 19, compound 21 can be prepared. 1 H NMR(500MHz,Chloroform-d)δ7.92–7.75(m,2H),7.68–7.43(m,3H),7.15–7.01(m,2H),6.95(ddt,J＝7.3,1.9,1.0Hz,1H),6.01–5.58(m,2H),5.14(td,J＝6.1,1.0Hz,1H),4.94(dt,J＝5.0,4.3Hz,1H),4.38(t,J＝6.1Hz,2H),4.21(t,J＝6.1Hz,2H),4.16–3.96(m,2H),3.54(s,2H),3.43(dd,J＝5.7,4.2Hz,1H),2.88–2.64(m,3H),2.33(t,J＝7.1Hz,2H),2.29–2.19(m,2H),2.19–1.86(m,7H),1.65(t,J＝2.0Hz,3H),1.03(d,J＝6.7Hz,3H)。
Test example 1, in vitro NO Release test
Test materials: blank solution was DMSO and PBS mixed; the Griess reagent is configured as follows: sulfonamide (4.0 g), N- (1-naphthyl) ethylenediamine dihydrochloride (0.2 g), and 10mL of 85% H 3 PO 4 Dissolving in 90mL distilled water, and stirring to obtain a clear solution; test compound (example compound 2, compound 5, compound 8, compound 10, compound 14 and compound 19) solution configuration: test compounds were precisely weighed, dissolved in DMSO and diluted in PBS to a concentration of 200 μm.
The test method comprises the following steps of (1) formulating a standard curve equation: preparing 0-100 mu mol/L sodium nitrite standard solution with blank solution respectively, mixing with Griess reagent uniformly, incubating in a shaking table at 37 ℃ for 30min, measuring absorbance at 540nm, subtracting the readings of the blank solution respectively, and regression to obtain standard curve equation.
Test: the test compound solution and the L-cysteine solution are mixed, incubated for 120min in a shaking table at a constant temperature of 37 ℃, then evenly mixed with Griess reagent, incubated for 30min in the shaking table at the constant temperature of 37 ℃, the absorbance at 540nm is measured, and the NO release amount is calculated according to a standard curve equation.
Some of the compound data are shown in fig. 1, which shows that the compound of the example has good NO release effect.
Test example 2, platelet aggregation inhibiting action
Experimental materials: ADP (adenosine diphosphate ), epinephrine, collagen, platelet aggregation function assay kit (cat# 5393).
The experimental method comprises the following steps: platelet rich plasma was prepared using a healthy human blood sample. The test was performed using the born's nephelometry. 225. Mu.L of platelet rich plasma was added to the reaction cup, 25. Mu.L of a test compound (compound of this patent example) solution prepared as a 1.8-1800nM solution (25 mM Tris-acetate and 120mM NaCl) was added, and after co-incubation at 37℃for 2min, platelet aggregation was induced by adding 2. Mu.M final concentration of ADP. The inhibition of ADP-induced platelet aggregation by the compounds was evaluated.
Test results: see table 1.
Table 1 example compounds inhibit ADP-induced platelet aggregation
From the above table, the compounds of examples have good effects of inhibiting ADP-induced platelet aggregation.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.

Claims (6)

1. A hydroxy-substituted beraprost derivative, which is characterized by having a structure shown in the following formula I:
wherein R is 1 、R 2 Respectively selected from H,And R is 1 、R 2 Not simultaneously H; wherein R is 3 C being linear or branched 1 -C 10 Alkyl, C 5-7 Cycloalkyl or-C 1 -C 10 Alkyl-aromatic ring-, R 4 、R 5 C being linear or branched 1 -C 10 An alkyl group; wherein C is 1 -C 10 Alkyl, C 5-7 Cycloalkyl or aromatic rings may be substituted with one or more of the following substituents: halogen atoms, hydroxy, carboxyl, cyano or- (C) 1 -C 10 Alkyl) -ONO 2 。
2. The hydroxy-substituted beraprost derivative according to claim 1, wherein the compound comprises any one of the following structures:
3. a method of synthesizing the hydroxy-substituted beraprost derivative according to claim 1 or 2, comprising the steps of:
wherein,
s1, synthesizing a carboxylic acid nitrate intermediate B from a starting material A through substitution reaction;
s2, synthesizing the raw material C through esterification reaction to obtain an intermediate D;
s3, performing esterification reaction on the intermediate C and the intermediate B, and purifying and separating to obtain three types of substituted intermediates E, F or G;
s4, carrying out deprotection reaction on the intermediate E, F or G to obtain a product H, I or J.
4. A process according to claim 3, wherein,
the reagent for S1 substitution reaction is selected from silver nitrate or concentrated nitric acid, and the solvent is selected from acetonitrile, dichloromethane, chloroform, acetone, ethyl acetate, toluene or dioxane;
the condensing agent used in the S2 esterification reaction is selected from (1-ethyl-3 (3-dimethylpropylamine) carbodiimide, dicyclohexylcarbodiimide, trifluoromethanesulfonic anhydride or p-toluenesulfonic acid, and the solvent used is selected from acetonitrile, dichloromethane, chloroform, acetone, ethyl acetate, toluene or dioxane;
the condensing agent used in the S3 esterification reaction is selected from (1-ethyl-3 (3-dimethylpropylamine) carbodiimide, dicyclohexylcarbodiimide, trifluoromethanesulfonic anhydride or p-toluenesulfonic acid, and the solvent used is selected from acetonitrile, dichloromethane, chloroform, acetone, ethyl acetate, toluene or dioxane;
the reagent used in the deprotection reaction of S4 is selected from trifluoroacetic acid, tetrabutylammonium fluoride, tetrabutylammonium iodide, hydrofluoric acid, hydrochloric acid, potassium hydroxide, sodium hydroxide or palladium carbon, and the solvent is selected from acetonitrile, dichloromethane, chloroform, acetone, ethyl acetate or toluene, dioxane, methanol or ethanol.
5. Use of a hydroxy-substituted beraprost derivative according to claim 1 or 2 as a prostacyclin analogue coupled with nitric oxide.
6. Use of a hydroxy-substituted beraprost derivative according to claim 1 or 2 for the manufacture of a medicament for the treatment of pulmonary hypertension, respiratory distress syndrome, arterial occlusive disease, organ fibrosis, kidney disease, diabetic fundus lesions, osteoporosis, thromboangiitis or myocardial infarction.
CN202311793574.4A 2023-03-28 2023-12-25 Hydroxy substituted beraprost derivative, synthesis method and application thereof Pending CN117800938A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202310312388 2023-03-28
CN2023103123888 2023-03-28

Publications (1)

Publication Number Publication Date
CN117800938A true CN117800938A (en) 2024-04-02

Family

ID=90424765

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202311793574.4A Pending CN117800938A (en) 2023-03-28 2023-12-25 Hydroxy substituted beraprost derivative, synthesis method and application thereof

Country Status (1)

Country Link
CN (1) CN117800938A (en)

Similar Documents

Publication Publication Date Title
ES2324746T3 (en) CYCLOPENTANE AND CYCLOPENTENE COMPOUNDS REPLACED USEFUL AS INHIBITORS OF NEURAMINIDASA.
CN108395443B (en) Cyclic compounds inhibiting programmed death receptor ligand 1 and uses thereof
JPH03204880A (en) Condensed purine derivative
JPH07502265A (en) Nucleophiles as nitric oxide donor prodrugs - oxygen-substituted derivatives of nitric oxide adducts
WO2013060258A1 (en) Clavatine a-c, preparation method thereof and pharmaceutical composition and use thereof
JPS63258841A (en) Tyrosine derivative and use thereof
JPH0326183B2 (en)
JP2009046486A (en) Analogue or derivative of quercetin (prodrug)
JPS6084221A (en) Benzothiophene derivative as antiasthmatic
TW202216705A (en) Substituted piperidine compound and application thereof
CN117800938A (en) Hydroxy substituted beraprost derivative, synthesis method and application thereof
EP0074411B1 (en) Ascorbic acid derivatives
JPS5919116B2 (en) Method for producing heterocyclic compounds
CN103819356A (en) Preparation method and use of kukoamine B analogue or medicinal salts thereof
US9266852B2 (en) Daidzein derivative, pharmaceutically acceptable salt and preparation method thereof, and pharmaceutical composition containing same
CN116003387B (en) Deuterated indazole propionamide compound, pharmaceutical composition and application
KR20000016565A (en) Polyol succinates and their pharmaceutical formulation
US6365611B1 (en) Pentaerythrite derivatives, the production and use thereof and intermediate products for the synthesis of the same
JPH0560478B2 (en)
CN114213381B (en) 4-chromanone derivative, preparation method and medical application thereof
BRPI0804764A2 (en) alpha-glycosity inhibitors, pharmaceutical compositions comprising them and process for their preparation
CN117800845A (en) Hydroxy-substituted treprostinil derivative, synthetic method and application thereof
JPH04368359A (en) Analgesic and vasodilator containing capsaicin derivative or its acid ester as effective component
JP3049284B2 (en) Hydantoin derivatives and preventive and therapeutic agents for diabetic complications and cardiovascular diseases using the same as active ingredients
CN117430614B (en) Isoquinoline derivative and synthetic method and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination