CN115232134B - Vardenafil analogue and synthesis method and application thereof - Google Patents
Vardenafil analogue and synthesis method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicine synthesis, and discloses a vardenafil hydrochloride structural analogue which has a brand new compound structure, is similar to the vardenafil hydrochloride structure, has the effect of inhibiting type 5 phosphodiesterase (PDE 5) through an activity test, and can be used for treating male penile Erectile Dysfunction (ED), pulmonary arterial hypertension, heart failure and other diseases.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a vardenafil analogue, and a synthesis method and application thereof.
Background
Vardenafil hydrochloride, with the english name Vardenafil Hydrochloride, the trade name Levitra, and the chinese name Ai Lida, is a type 5 phosphodiesterase (PDE 5) inhibitor, is mainly used for treating male penile Erectile Dysfunction (ED), and is one of the currently mainstream drugs for treating ED. Vardenafil hydrochloride was developed by Bayer (Bayer) corporation, marketed in the european union and united states in 2003, and subsequently marketed in various countries and regions such as japan, china, russia, australia, etc. The Chinese culture name of vardenafil hydrochloride is 2- [ 2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl ] -5-methyl-7-propyl-3H-imidazo [5,1-f ] [1,2,4] triazine-4-one, and hydrochloride trihydrate, and the structural formula is shown as follows. The current marketed specifications of vardenafil hydrochloride tablets are 5mg, 10mg and 20mg,2.5mg of which have been removed.
Due to the significant first pass effect of vardenafil hydrochloride tablets, the average absolute bioavailability of vardenafil hydrochloride tablets after oral administration is about 15%, severely affecting the absorption of the drug.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to disclose a vardenafil analogue, and the compound shows an inhibition effect on type 5 phosphodiesterase through enzyme biological activity test, can be used as a phosphodiesterase inhibitor for metabolism of cGMP and is used for preventing or treating diseases such as erectile dysfunction, pulmonary arterial hypertension, arrhythmia and the like.
The invention adopts the following technical scheme:
a vardenafil analogue has a structural formula shown in a formula I:
in the formula I, R 1 Is hydroxy group,
R 2 Methoxy or ethoxy.
Further, the vardenafil analog has a structural formula shown in any one of formulas II to VII:
further, the vardenafil analog has a structural formula shown in a formula II:
the invention adopts the following technical scheme:
a method for synthesizing vardenafil analog, comprising the steps of: the first reaction raw material reacts with hydrazine hydrate and then reacts with compound 2 in a ring closing way to generate compound 3; compound 3 inPOCl in acid solvent 3 The ring closing reaction is carried out under the action to generate an intermediate 4; intermediate 4 reacts with chlorosulfonic acid to form sulfonyl chloride intermediate 5; the sulfonyl chloride intermediate 5 reacts with a second reaction raw material to generate a target product vardenafil analogue; the first reaction raw material is 2-ethoxyformamidine hydrochloride or 2-methoxyformamidine hydrochloride; the second reaction raw material is N-ethylpiperazine, N-methylpiperazine or water; the structural formula of the compound 2 is shown as a formula VIII:
further: the structural formula of the compound 3 is shown as a formula IX, the structural formula of the intermediate 4 is shown as a formula X, and the structural formula of the intermediate 5 is shown as a formula XI:
further, the method comprises the following steps: 2-ethoxyformamidine hydrochloride reacts with hydrazine hydrate and then reacts with compound 2 in a ring closing way to generate compound 3; compound 3 in acid solvent, POCl 3 The ring closing reaction is carried out under the action to generate an intermediate 4; intermediate 4 reacts with chlorosulfonic acid to form sulfonyl chloride intermediate 5; the sulfonyl chloride intermediate 5 reacts with N-ethylpiperazine to generate a target product vardenafil analogue, and the structural formula is shown as a formula II:
further, when the structural formula of the target product vardenafil analog is shown as formula II, the reaction flow is shown as follows:
the invention also provides application of the vardenafil analog, the prodrug or the pharmaceutically acceptable salt thereof in preparing medicines for treating male penile erection dysfunction, preparing medicines for treating pulmonary arterial hypertension and preparing medicines for treating heart failure.
The pharmaceutical application of the invention is realized by adopting the following technical scheme:
a medicine for treating male penile erection dysfunction contains vardenafil analogue, prodrug or pharmaceutically acceptable salt thereof as an active ingredient.
The active ingredient of the medicine for treating pulmonary arterial hypertension is vardenafil analog, prodrug or pharmaceutically acceptable salt thereof.
The active ingredient of the drug for treating heart failure is vardenafil analogue, prodrug or pharmaceutically acceptable salt thereof.
Compared with the prior art, the invention has the beneficial effects that:
(1) The vardenafil analogue provided by the invention is a brand-new vardenafil hydrochloride analogue, has a novel compound structure, has the characteristics of definite structure and high chemical purity, and has the effect of inhibiting type 5 phosphodiesterase (PDE 5) through biological activity tests, and can be used for treating male penile Erectile Dysfunction (ED), pulmonary arterial hypertension, heart failure and other diseases.
(2) The vardenafil analog provided by the invention can improve the relative bioavailability of the vardenafil analog by improving the first pass effect, improves the absorption of medicines, and is applied to the treatment of male penile erectile dysfunction, pulmonary arterial hypertension and heart failure.
Detailed Description
The present invention will be further described with reference to the following specific embodiments, and it should be noted that, on the premise of no conflict, new embodiments may be formed by any combination of the embodiments or technical features described below. The raw materials, equipment and the like used in the examples described below are commercially available except for special restrictions.
A vardenafil analogue has a structural formula shown in a formula I:
in the formula I, R 1 Is hydroxy group,
R 2 Methoxy or ethoxy.
As a further embodiment, the vardenafil analog has the structural formula shown in any one of formulas ii to VII:
as a further embodiment, vardenafil analogues have the structural formula shown in formula II, the name of the compound shown in formula II is 4- { 2-ethoxy-5- [ (4-ethylpiperazin-1-yl) sulfonyl ] phenyl } -8-methyl-6-propyl-imidazo [1,5-d ] [1,2,4] triazin-1 (2H) -one, and the invention uses the code "analogue CJ-003" to represent the analogue shown in formula II:
the vardenafil analogue (shown in any one of the formulas II to VII) provided by the embodiment of the invention has a structure similar to vardenafil hydrochloride, has the effect of inhibiting type 5 phosphodiesterase (PDE 5), and can be used for treating male penile Erectile Dysfunction (ED), pulmonary arterial hypertension, heart failure and other diseases.
The vardenafil analog (shown in any one of formulas II to VII), the prodrug or the pharmaceutically acceptable salt thereof provided by the embodiment of the invention can be used for preparing medicines for treating male penile erectile dysfunction, medicines for treating pulmonary arterial hypertension or medicines for treating heart failure.
Synthesis method of vardenafil analogueThe method comprises the following steps: the first reaction raw material reacts with hydrazine hydrate and then reacts with compound 2 in a ring closing way to generate compound 3; compound 3 in acid solvent, POCl 3 The ring closing reaction is carried out under the action to generate an intermediate 4; intermediate 4 reacts with chlorosulfonic acid to form sulfonyl chloride intermediate 5; the sulfonyl chloride intermediate 5 reacts with a second reaction raw material to generate a target product vardenafil analogue; the first reaction raw material is 2-ethoxyformamidine hydrochloride or 2-methoxyformamidine hydrochloride; the second reaction raw material is N-ethylpiperazine, N-methylpiperazine or water; the structural formula of the compound 2 is shown as a formula VIII:
as a further embodiment, when the structural formula of the vardenafil analog as the target product is shown in formula II (analog CJ-003), the synthesis method comprises the following steps: commercially available 2-ethoxyformamidine hydrochloride (compound 1) reacts with hydrazine hydrate and then reacts with compound 2 in a ring closing way to generate compound 3; POCl of Compound 3 in acetic acid solvent 3 The ring closing reaction is carried out under the action to generate an intermediate 4; intermediate 4 reacts with chlorosulfonic acid to form sulfonyl chloride intermediate 5; the sulfonyl chloride intermediate 5 is reacted with N-ethylpiperazine (compound 6) to form the desired product vardenafil analog CJ-003, the reaction scheme is shown below:
example 1
The synthesis of vardenafil analog CJ-003 (formula ii) intermediate (compound 3) is performed as follows:
into a 500mL three-necked flask, etOH (300 mL) and 2-ethoxyformamidine hydrochloride (Compound 1, 30g,149.50mmol,1 eq) were added, the ice-water bath was cooled to 0℃and hydrazine hydrate NH was added dropwise to the system 2 NH 2 .H 2 O (8.23 g,164.45mmol,7.99mL,1.1 eq) and maintained at 0deg.C for 0.5 hours. Automatically heating to 20deg.C, stirring for 1 hr (until the material disappears), adding compound 2 (41.83 g,194.35mmol,1.3 eq) to the system, heating to 45deg.C, N 2 The reaction was allowed to proceed for 12 hours under protection, and TLC (petroleum ether/ethyl acetate=1/1, rf=0.30) monitored the intermediate reaction to completion with a new point. The reaction solution was cooled to room temperature and then concentrated, water (100 mL) and methylene chloride (100 mL) were added, aqueous ammonia was added dropwise with stirring to adjust ph=9-10, the organic phase was separated, the aqueous phase was extracted with methylene chloride (80 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin-drying to give 25g of crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=10/1-0/1) to give 15g of crude product, which was purified by Pre-HPLC (column: agela DuraShell C18250. Times. 80mm*10um;mobile phase: [ water (10 mM NH4HCO 3) -ACN)]The method comprises the steps of carrying out a first treatment on the surface of the B%:15% -45%,20 min) to give 9g of a yellow solid product, designated compound 3.
The structure of the compound 3 obtained in example 1 was confirmed by nuclear magnetic resonance hydrogen spectroscopy, and the results were as follows:
1 H NMR:(400MHz,CDCl 3 ),δ11.85(br s,1H),7.62(br d,J＝7.5Hz,1H),7.43(brt,J＝7.8Hz,1H),7.09-6.99(m,2H),6.80(br d,J＝7.5Hz,1H),5.52(q,J＝7.1Hz,1H),4.13(q,J＝7.0Hz,2H),2.22(t,J＝7.5Hz,2H),1.69(qd,J＝7.3,14.7Hz,2H),1.56(d,J＝6.8Hz,3H),1.38(t,J＝7.0Hz,3H),0.95(t,J＝7.3Hz,3H)。
example 2
The synthesis of vardenafil analog CJ-003 intermediate 4 is carried out according to the following scheme and method:
compound 3 (2.5 g,7.57mmol,1 eq) was added to a 500mL three-necked flask at 25℃followed by AcOH (25 mL) with stirring to dissolve, the ice-water bath was cooled to 0℃and POCl was slowly added dropwise 3 (5.79 g,37.76mmol,4.99 eq.) and reaction at 100℃for 12 hours after completion of the dropwise addition, TLC (Petroleum ether/ethyl acetate=0/1, R) f =0.29) to monitor the completion of the reaction, a new spot was generated. The reaction solution was cooled to room temperature and then poured into water (20 mL) to quench it, concentrated to remove AcOH, added with 1M aqueous potassium hydroxide solution at 10 ℃ to adjust ph=7-8, then extracted with dichloromethane (20 ml×3) in sequence, the organic phases were combined, washed with saturated brine (20 mL), the organic phases were separated, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated to 3.5g of crude product, and purified by column chromatography (ethyl acetate/petroleum ether=10/1-0/1) to give 1.71g of solid product, which was noted as intermediate 4.
Intermediate 4 obtained in example 2 was structurally confirmed using LCMS and nuclear magnetic hydrogen spectroscopy, with the following results:
LCMS:m/z＝313.0[M+1] +
1 H NMR:(400MHz,CDCl 3 )δ9.53(br s,1H),7.53(t,J＝7.9Hz,1H),7.42(d,J＝7.5Hz,1H),7.09(t,J＝7.5Hz,1H),6.98(d,J＝8.3Hz,1H),4.12-3.96(m,2H),2.69(s,3H),2.29(ddd,J＝6.2,9.4,15.2Hz,1H),2.05(ddd,J＝6.1,9.5,15.5Hz,1H),1.58-1.34(m,2H),1.21(t,J＝6.9Hz,3H),0.63(t,J＝7.2Hz,3H)
example 3
Vardenafil analog CJ-003 intermediate 5 was synthesized as follows:
to a 250mL three-necked flask were added dichloromethane (100 mL) and intermediate 4 (6.2 g,19.85mmol,1 eq), and a solution of chlorosulfonic acid (22.74 g,195.11mmol,9.83 eq) in dichloromethane (10 mL) was added dropwise to the reaction solution at 25℃and reacted at 25℃for 12 hours. TLC (petroleum ether/ethyl acetate=1/1, r f =0.43), the reaction of the starting materials was complete and a new point was generated. The reaction was slowly poured into saturated aqueous sodium bicarbonate (100 mL) with stirring, extracted with dichloromethane (100 mL x 3), the combined organic phases dried over anhydrous sodium sulfate, filtered and the filtrate was dried by spin-drying to give 8g of crude product. The crude product was directly subjected to the next reaction without further purification, and the crude product was designated as intermediate 5.
The intermediate 5 obtained in example 3 was subjected to structural confirmation by using nuclear magnetic resonance hydrogen spectrum, and the results were as follows:
1 H NMR:(400MHz,CDCl 3 )δ9.74(s,1H),8.24(dd,J＝2.4,8.9Hz,1H),8.16(d,J＝2.4Hz,1H),7.17(d,J＝8.9Hz,1H),4.25-4.14(m,2H),2.70(s,3H),2.35(ddd,J＝6.0,9.6,15.4Hz,1H),2.02(ddd,J＝5.9,9.4,15.3Hz,1H),1.60-1.37(m,2H),1.30(t,J＝7.0Hz,3H),0.67(t,J＝7.4Hz,3H)
example 4
A synthesis method of vardenafil analogue CJ-003 comprises the following steps:
to a 100mL single-necked flask, methylene chloride (40 mL) and intermediate 5 (4 g,9.74mmol,1 eq) were added, the temperature was lowered to 0℃in an ice-water bath, and N-ethylpiperazine (Compound 6,2.22g,19.47mmol,2.47mL,2 eq), N were added dropwise to the system 2 Stirring at 0deg.C for 0.5 hr under protection, automatically heating to 25deg.C, and stirring for 11.5 hr. TLC (petroleum ether/ethyl acetate=0/1, r f =0.15) was monitored, and the starting material was reacted. The reaction solution was added to water (40 mL) and methylene chloride (40 mL), the organic phase was separated, the aqueous phase was extracted with methylene chloride (40 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried by spin-drying to give 5.5g of crude product. Column chromatography (petroleum ether/ethyl acetate=10/1-0/1) of the crude product gave 3.5g of a white solid product, designated as analogue CJ-003 (formula ii).
The analogue CJ-003 obtained in example 4 was structurally confirmed by LCMS and nuclear magnetic resonance spectroscopy, and the results were as follows:
ExactMass:488.22,LCMS:m/z＝489.1[M+1] + ,m/z＝245.1[M/2+1] +
1 HNMR:(400MHz,CDCl 3 )δ9.58(s,1H),7.93(dd,J＝2.2,8.8Hz,1H),7.84(d,J＝2.4Hz,1H),7.09(d,J＝8.6Hz,1H),4.22-4.03(m,2H),3.09(m,4H),2.69(s,3H),2.55(br t,J＝4.5Hz,4H),2.42(q,J＝7.2Hz,2H),2.27(ddd,J＝6.2,9.3,15.4Hz,1H),2.07-1.99(m,1H),1.63-1.39(m,2H),1.26(t,J＝7.1Hz,3H),1.04(t,J＝7.2Hz,3H),0.67(t,J＝7.4Hz,3H)。
example 5
A synthesis method of vardenafil analog IV comprises the following steps:
MeCN (20 mL), H, was added to a 100mL single-necked flask 2 O (40 mL) and compound 5 (4 g,9.74mmol,1 eq) were stirred at 25℃for 12 hours, LCMS detection, reaction of the starting material was complete, the reaction was filtered, washed twice with acetonitrile (30 mL) and the filter cake concentrated to give crude product. The crude product was dispersed in water (30 mL) and stirred for 1 hour, filtered, and the filter cake was stirred in water (30 mL) for 1 hour and filtered. The filter cake was concentrated to give 3.16g of a white solid product of the compound of formula IV.
The structural confirmation of the analogue of formula IV obtained in example 5 was performed using LCMS and nuclear magnetic hydrogen spectroscopy, with the following results:
ExactMass:392.12,LCMS:m/z＝393.0(M+1) + ,m/z＝785.0(2M+1) +
1 H NMR:(400MHz,DMSO-d 6 )δ12.03(s,1H),7.79(dd,J＝2.1,8.6Hz,1H),7.71(d,J＝2.1Hz,1H),7.13(d,J＝8.7Hz,1H),4.15-3.98(m,2H),2.56(s,3H),2.27-2.15(m,1H),2.09(m,J＝7.0Hz,1H),1.48-1.34(m,2H),1.10(t,J＝7.0Hz,3H),0.59(t,J＝7.3Hz,3H)。
example 6
A method for synthesizing vardenafil analog (formula III), the synthesis equation and method being as follows:
to a 100mL single-necked flask, methylene chloride (40 mL) and intermediate 5 (4 g,9.74mmol,1 eq) were added, the temperature was lowered to 0℃in an ice-water bath, and N-methylpiperazine (Compound 7,1.95g,19.47mmol,2.47mL,2 eq), N were added dropwise to the system 2 Stirring at 0deg.C for 0.5 hr under protection, automatically heating to 25deg.C, and stirring for 12 hr. TLC (petroleum ether/ethyl acetate=0/1, r f =0.15) was monitored, and the starting material was reacted.The reaction solution was added to water (40 mL) and methylene chloride (40 mL), the organic phase was separated, the aqueous phase was extracted with methylene chloride (40 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried by spin-drying to give 4.3g of crude product. Column chromatography (petroleum ether/ethyl acetate=10/1-0/1) of the crude product afforded 2.7g of the product as a white solid, noted as analogue of formula III.
The structural confirmation of the analogue of formula III obtained in example 6 was performed using LCMS and nuclear magnetic hydrogen spectroscopy, with the following results:
ExactMass:474.22,LCMS:m/z＝475.1[M+1] +
1 HNMR:(400MHz,CDCl 3 )δ9.58(s,1H),7.93(dd,J＝2.2,8.8Hz,1H),7.84(d,J＝2.4Hz,1H),7.09(d,J＝8.6Hz,1H),4.22-4.03(m,2H),3.09(m,4H),2.69(s,3H),2.55(br t,J＝4.5Hz,4H),2.49(s,3H),2.27(ddd,J＝6.2,9.3,15.4Hz,1H),2.07-1.99(m,1H),1.63-1.39(m,2H),1.04(t,J＝7.2Hz,3H),0.67(t,J＝7.4Hz,3H)。
example 7
The synthesis of vardenafil analog (formula V) intermediate (compound 9), scheme and method is as follows:
into a 500mL three-necked flask, etOH (300 mL) and 2-methoxyformamidine hydrochloride (Compound 8, 30g,160.73mmol,1 eq) were added, the ice-water bath was cooled to 0℃and hydrazine hydrate NH was added dropwise to the system 2 NH 2 .H 2 O (10.6 g,176.8mmol,1.1 eq) and maintained at 0deg.C for 0.5 hours. Automatically heating to 20deg.C, stirring for 1 hr (until the material disappears), adding compound 2 (41.83 g,194.35mmol,1.3 eq) to the system, heating to 45deg.C, N 2 The reaction was allowed to proceed for 12 hours under protection, and TLC (petroleum ether/ethyl acetate=1/1, rf=0.30) monitored the intermediate reaction to completion with a new point. The reaction solution was cooled to room temperature and then concentrated, water (100 mL) and methylene chloride (100 mL) were added, aqueous ammonia was added dropwise with stirring to adjust ph=9-10, the organic phase was separated, the aqueous phase was extracted with methylene chloride (80 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin-drying to give 25gCrude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=10/1-0/1) to give 18g of crude product, which was purified by Pre-HPLC (column: agela DuraShell C18250 80mm 10um; mobile phase: [ water (10 mm nh4hco 3) -ACN)]The method comprises the steps of carrying out a first treatment on the surface of the B%:15% -45%,20 min) to give 9.3g of a yellow solid product, designated compound 9.
The structure of the compound 9 obtained in example 7 was confirmed by nuclear magnetic resonance hydrogen spectroscopy, and the results were as follows:
1 H NMR:(400MHz,CDCl 3 ),δ11.85(br s,1H),7.62(br d,J＝7.5Hz,1H),7.43(brt,J＝7.8Hz,1H),7.09-6.99(m,2H),6.80(br d,J＝7.5Hz,1H),5.52(q,J＝7.1Hz,1H),4.15(s,3H),2.22(t,J＝7.5Hz,2H),1.69(m,2H),1.56(d,J＝6.8Hz,3H),0.95(t,J＝7.3Hz,3H)。
example 8
The synthesis of vardenafil analog (formula V) intermediate 10, procedure and method are as follows:
compound 9 (2.4 g,7.57mmol,1 eq) was added to a 500mL three-necked flask at 25℃followed by AcOH (25 mL) with stirring to dissolve, the ice-water bath was cooled to 0℃and POCl was slowly added dropwise 3 (5.8 g,37.85mmol,5.0 eq.) and reaction at 100℃for 12 hours after completion of the dropwise addition, TLC (Petroleum ether/ethyl acetate=0/1, R) f =0.29) to monitor the completion of the reaction, a new spot was generated. The reaction solution was cooled to room temperature and then poured into water (20 mL) to quench it, concentrated to remove AcOH, added with 1M aqueous potassium hydroxide solution at 10 ℃ to adjust ph=7-8, then extracted with dichloromethane (20 ml×3) in sequence, the organic phases were combined, washed with saturated brine (20 mL), the organic phases were separated, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated to 3.4g of crude product, and purified by column chromatography (ethyl acetate/petroleum ether=10/1-0/1) to give 1.5g of solid product, which was noted as intermediate 10.
Intermediate 10 obtained in example 8 was structurally confirmed by LCMS and the results were as follows:
LCMS:m/z＝299.1[M+1] +
example 9
Vardenafil analog (formula V) intermediate 11 is synthesized as follows:
to a 250mL three-necked flask were added dichloromethane (100 mL) and intermediate 10 (5.92 g,19.85mmol,1 eq), and a solution of chlorosulfonic acid (22.74 g,195.11mmol,9.83 eq) in dichloromethane (10 mL) was added dropwise to the reaction solution at 25℃and reacted at 25℃for 12 hours. TLC (petroleum ether/ethyl acetate=1/1, r f =0.43), the reaction of the starting materials was complete and a new point was generated. The reaction was slowly poured into saturated aqueous sodium bicarbonate (100 mL) with stirring, extracted with dichloromethane (100 mL x 3), the combined organic phases dried over anhydrous sodium sulfate, filtered and the filtrate was dried by spin-drying to give 8g of crude product. The crude product was directly subjected to the next reaction without further purification, and the crude product was designated as intermediate 11.
Example 10
A synthesis method of vardenafil analog (formula V) comprises the following steps:
to a 100mL single-necked flask, methylene chloride (40 mL) and intermediate 11 (3.87 g,9.74mmol,1 eq) were added, the temperature was lowered to 0℃in an ice-water bath, and N-ethylpiperazine (Compound 6,2.22g,19.47mmol,2.47mL,2 eq) was added dropwise to the system, N 2 Stirring at 0deg.C for 0.5 hr under protection, automatically heating to 25deg.C, and stirring for 11.5 hr. TLC (petroleum ether/ethyl acetate=0/1, r f =0.15) was monitored, and the starting material was reacted. The reaction solution was added to water (40 mL) and methylene chloride (40 mL), the organic phase was separated, the aqueous phase was extracted with methylene chloride (40 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried by spin-drying to give 4.5g of crude product. Column chromatography (petroleum ether/ethyl acetate=10/1-0/1) of the crude product gave 3.7g of a white solid product, designated as analogue V.
Analogue V obtained in example 10 was structurally confirmed using LCMS and nuclear magnetic hydrogen spectroscopy, with the following results:
ExactMass:474.20,LCMS:m/z＝475.2[M+1] + ,m/z＝238.1[M/2+1] +
1 HNMR:(400MHz,CDCl 3 )δ9.57(s,1H),7.92(dd,J＝2.2,8.8Hz,1H),7.84(d,J＝2.4Hz,1H),7.09(d,J＝8.6Hz,1H),4.17(s,3H),3.09(m,4H),2.69(s,3H),2.55(br t,J＝4.5Hz,4H),2.42(q,J＝7.2Hz,2H),2.27(ddd,J＝6.2,9.3,15.4Hz,1H),2.07-1.99(m,1H),1.63-1.39(m,2H),1.04(t,J＝7.2Hz,3H),0.67(t,J＝7.4Hz,3H)。
example 11
A synthesis method of vardenafil analog VII comprises the following steps:
MeCN (20 mL), H, was added to a 100mL single-necked flask 2 O (40 mL) and compound 11 (3.87 g,9.74mmol,1 eq) were stirred at 25℃for 12 hours, and the reaction was completed by LCMS, the reaction solution was filtered, washed twice with acetonitrile (30 mL) and the filter cake was concentrated to give crude product. The crude product was dispersed in water (30 mL) and stirred for 1 hour, filtered, and the filter cake was stirred in water (30 mL) for 1 hour and filtered. The filter cake was concentrated to give 2.79g of a white solid product of the compound of formula VII.
The structure of analogue VII obtained in example 11 was confirmed by LCMS and nuclear magnetic hydrogen spectroscopy, as follows:
ExactMass:378.1,LCMS:m/z＝379.0(M+1) +
1 H NMR:(400MHz,DMSO-d 6 )δ12.03(s,1H),7.79(dd,J＝2.1,8.6Hz,1H),7.71(d,J＝2.1Hz,1H),7.13(d,J＝8.7Hz,1H),4.13(s,3H),2.56(s,3H),2.27-2.15(m,1H),2.09(m,J＝7.0Hz,1H),1.48-1.34(m,2H),0.59(t,J＝7.3Hz,3H)。
example 12
A method for synthesizing vardenafil analog (formula VI), the synthesis equation and method being as follows:
to a 100mL single-necked flask, methylene chloride (40 mL) and intermediate 11 (3.87 g,9.74mmol,1 eq) were added, the temperature was lowered to 0℃in an ice-water bath, and N-methylpiperazine (Compound 7,1.95g,19.47mmol,2.47mL,2 eq) was added dropwise to the system 2 Stirring at 0deg.C for 0.5 hr under protection, automatically heating to 25deg.C, and stirring for 12 hr. TLC (petroleum ether/ethyl acetate=0/1, r f =0.15) was monitored, and the starting material was reacted. The reaction solution was added to water (40 mL) and methylene chloride (40 mL), the organic phase was separated, the aqueous phase was extracted with methylene chloride (40 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried by spin-drying to give 3.8g of crude product. Column chromatography (petroleum ether/ethyl acetate=10/1-0/1) of the crude product afforded 2.3g of the product as a white solid, noted as analogue of formula VI.
The structural confirmation of the analogue of formula VI obtained in example 5 was performed using LCMS and nuclear magnetic hydrogen spectroscopy, with the following results:
ExactMass:460.22,LCMS:m/z＝461.1[M+1] +
1 HNMR:(400MHz,CDCl 3 )δ9.56(s,1H),7.91(dd,J＝2.2,8.8Hz,1H),7.83(d,J＝2.4Hz,1H),7.08(d,J＝8.6Hz,1H),4.20(s,3H),3.09(m,4H),2.65(s,3H),2.55(br t,J＝4.5Hz,4H),2.48(s,3H),2.25(ddd,J＝6.2,9.3,15.4Hz,1H),2.08–2.00(m,1H),1.65-1.40(m,2H),0.65(t,J＝7.4Hz,3H)。
effect verification
1. PDE5 enzyme inhibition Activity test of Compounds II-VII
The experimental method comprises the following steps:
1 preparation of reaction buffer and reaction termination solution
1.11 times reaction buffer
IMAP reaction buffer was diluted with 0.1% BSA (5X) (IMAP FP IPP Explorer Kit) to 1-fold reaction buffer containing 1mM DTT.
1.2 reaction termination liquid
IMAP modified binding buffer A (5X), IMAP modified binding buffer B (5X), IMAP modified binding reagent (IMAP FP IPP Explorer Kit) was prepared according to the instructions for use.
2 preparation of Compounds
2.1 dilution of Compounds
Solutions were formulated to detect 100-fold concentrations of the compound. The compounds were diluted in gradient to the set number of concentration spots using an automated microwell pipette (Precision PRC 384U) as follows: if A3-fold dilution is performed, 50. Mu.l of a starting concentration of compound DMSO solution is added to A2 wells on an Echo384 well plate, and 30. Mu.l of 100% DMSO is added to each of A3-A11; taking 15 μl of the compound from the A2 hole, adding the compound into the A3 hole, uniformly mixing, and sequentially diluting the compound by 3 times to 10 concentration points; 30 μl of 100% DMSO was added to wells A1 and A12.
2.2 transfer of Compounds to 384 reaction plates
200nl of compound was transferred from the diluted Echo384 well plates to 384 well reaction plates using an Echo550 instrument, and both negative and positive controls were transferred into 200nl of 100% DMSO.
3 enzymatic reaction
3.1 preparation of 2-fold enzyme solution
PDE5A1 was added to the 1-fold reaction buffer to form a 2-fold enzyme solution.
3.2 preparation of 2-fold substrate solution
For enzyme PDE5A1, FAM-labeled cGMP was added to the 1-fold reaction buffer to form a 2-fold substrate solution.
3.3 addition of enzyme solution to 384 well plates
To 384-well wells 10. Mu.l of 2-fold enzyme solution was added. For the no enzyme activity control wells, 10. Mu.l of 1-fold reaction buffer was used instead of enzyme solution. Centrifuge at 1000rpm for 1min and incubate at room temperature for 15 min.
3.4 addition of substrate solution to 384 well plates initiates enzymatic reactions
To 384 well reaction plates 10 μl of 2-fold substrate solution was added per well. Centrifuge at 1000rpm for 1min. The reaction was carried out at 25℃for 20 minutes.
3.5 termination of the enzymatic reaction
To 384-well reaction plates, 60. Mu.l of reaction stop solution was added to each well to stop the reaction, and the plates were incubated at room temperature under shaking at 600rpm for 60 minutes in the dark.
4 EnVision read data and data computation
Read with EnVision.
5 inhibition calculation and IC50 curve fitting
Data were replicated from EnVision, where maximum refers to DMSO control reads and minimum refers to no enzyme activity control reads. Inhibition ratio (%) = (maximum value-sample value)/(maximum value-minimum value) ×100%.
Data were imported into MS Excel and IC50 values were fitted with XLFIT Excel add-in version 5.4.0.8;
fitting formula: y=bottom+ (Top-Bottom)/(1+ (IC 50/X)/(HillSlope)
The test results are shown in table 1:
TABLE 1 Table 1 results of test for PDE5 enzyme inhibition activity
Note that: CJ-003 (compound of formula II) is the compound prepared in example 4.
The experimental data show that the vardenafil hydrochloride analog disclosed by the invention has a strong inhibition effect on type 5 phosphodiesterase (PDE 5), wherein the inhibition activity of the compounds in the formulas II, III and V is not inferior to that of the marketed medicines sildenafil and tadalafil.
Furthermore, literature (Wang Z, et al, the Selectivity and Potency of the New PDE5 Inhibitor TPN729MA J Sex Med.2013 Nov;10 (11): 2790-7) reports PDE5 enzyme inhibitory activity of sildenafil IC50:5.22nM, literature (count MA, et al, binding oftritiated sildenafil, tadalafil, or vardenafil to the phosphodiesterase-5 catalytic site displays potency,specificity,heterogeneity,and cGMP stimulation.Mol Pharmacol.2004 Jul;66 (1): 144-52) reports PDE5 enzyme inhibitory activity of tadalafil IC50:1.8nM. In combination with the above reported results, it was further verified that the compounds of formula II, formula III and formula V according to the present invention have inhibitory activity comparable to that of the marketed drugs sildenafil and tadalafil.
The compounds II-VII provided by the embodiment of the invention have the effect of inhibiting type 5 phosphodiesterase (PDE 5), have similar pharmacological activities with sildenafil, tadalafil and vardenafil, and can be used for treating diseases such as male penile Erectile Dysfunction (ED), pulmonary arterial hypertension, heart failure and the like.
The above embodiments are only preferred embodiments of the present invention, and the scope of the present invention is not limited thereto, but any insubstantial changes and substitutions made by those skilled in the art on the basis of the present invention are intended to be within the scope of the present invention as claimed.
Claims (8)
1. The vardenafil analogue is characterized in that the structural formula is shown as formula I:
in the formula I, R 1 Is hydroxy group,
R 2 Methoxy or ethoxy.
2. The vardenafil analog of claim 1, wherein the vardenafil analog has a structural formula as shown in any one of formulas ii-VII:
3. the vardenafil analog of claim 2, wherein the vardenafil analog has a structural formula shown in formula ii:
4. a method of synthesizing a vardenafil analog according to any one of claims 1-3, comprising the steps of: the first reaction raw material reacts with hydrazine hydrate and then reacts with compound 2 in a ring closing way to generate compound 3; compound 3 in acid solvent, POCl 3 The ring closing reaction is carried out under the action to generate an intermediate 4; intermediate 4 reacts with chlorosulfonic acid to form sulfonyl chloride intermediate 5; the sulfonyl chloride intermediate 5 reacts with a second reaction raw material to generate a target product vardenafil analogue; the first reaction raw material is 2-ethoxyformamidine hydrochloride or 2-methoxyformamidine hydrochloride; the second reaction raw material is N-ethylpiperazine, N-methylpiperazine or water; the structural formula of the compound 2 is shown as a formula VIII:
the structural formula of the compound 3 is shown as a formula IX, the structural formula of the intermediate 4 is shown as a formula X, and the structural formula of the intermediate 5 is shown as a formula XI:
5. the method for synthesizing vardenafil analog according to claim 4, comprising the steps of: 2-ethoxyformamidine hydrochloride reacts with hydrazine hydrate and then reacts with compound 2 in a ring closing way to generate compound 3; compound 3 in acid solvent, POCl 3 The ring closing reaction is carried out under the action to generate an intermediate 4; intermediate 4 reacts with chlorosulfonic acid to form sulfonyl chloride intermediate 5; the sulfonyl chloride intermediate 5 reacts with N-ethylpiperazine to generate a target product vardenafil analogue, the structural formula of which is shown as the formula II：
6. The method for synthesizing vardenafil analog according to claim 5, wherein when the structural formula of the target product vardenafil analog is shown in formula ii, the reaction flow is as follows:
7. use of a vardenafil analog or a pharmaceutically acceptable salt thereof according to any one of claims 1-3 for the preparation of a medicament for the treatment of male penile erectile dysfunction, for the preparation of a medicament for the treatment of pulmonary arterial hypertension, for the preparation of a medicament for the treatment of heart failure.
8. A medicament for treating male penile erectile dysfunction, characterized in that an active ingredient thereof is the vardenafil analogue or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3.
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