CN115232134A - Vardenafil analogue and synthetic method and application thereof - Google Patents
Vardenafil analogue and synthetic method and application thereof Download PDFInfo
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
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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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
Abstract
The invention belongs to the technical field of drug synthesis, and discloses a vardenafil hydrochloride structural analogue which has a brand-new compound structure, is similar to a vardenafil hydrochloride structure, has the effect of inhibiting phosphodiesterase type 5 (PDE 5) through activity test, and can be used for treating male penile Erection Dysfunction (ED) and treating diseases such as pulmonary hypertension, heart failure and the like.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a vardenafil analogue and a synthesis method and application thereof.
Background
Vardenafil Hydrochloride, named as Vardenafil Hydrochloride in English and Levitra in Chinese, is an inhibitor of phosphodiesterase type 5 (PDE 5), is mainly used for treating male penile Erection Dysfunction (ED) and is one of the mainstream medicaments for treating ED at present. Vardenafil hydrochloride was developed by Bayer (Bayer) corporation and approved for marketing in the european union and the united states in 2003 and subsequently in japan, china, russia, australia, etc. in many countries and regions. The mesocultural 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] triazin-4-one, and the hydrochloride trihydrate has the structural formula shown in the specification. At present, the marketed specification of vardenafil hydrochloride tablets is 5mg, 10mg and 20mg, and the specification of 2.5mg is removed.
Due to the obvious first-pass effect of the vardenafil hydrochloride tablet, the average absolute bioavailability of the vardenafil hydrochloride tablet after oral administration is about 15%, and the absorption of the drug is seriously influenced.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to disclose a vardenafil analogue which shows an inhibiting effect on type 5 phosphodiesterase through an enzyme bioactivity test and can be used as a phosphodiesterase inhibitor for metabolizing cGMP (cyclic Gomp-like protein) for preventing or treating diseases such as erectile dysfunction, pulmonary hypertension, arrhythmia and the like.
The purpose of the invention is realized by adopting the following technical scheme:
a vardenafil analog having the formula I:
in the formula I, R 1 Is a hydroxyl group,
R 2 Is methoxy or ethoxy.
Further, the vardenafil analogue has a structural formula shown in any one of formulas II to VII:
further, the vardenafil analog has a structural formula shown in formula II:
the purpose of the invention is realized by adopting the following technical scheme:
a method for synthesizing vardenafil analogs, comprising the steps of: reacting the first reaction raw material with hydrazine hydrate, and then performing ring closure reaction with the compound 2 to generate a compound 3; compound 3 in acid solvent, POCl 3 Under the action of the intermediate 4, the intermediate is generated through a ring closure reaction; the intermediate 4 reacts with chlorosulfonic acid to generate a 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-ethoxy formamidine hydrochloride or 2-methoxy formamidine 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 formula IX, the structural formula of the intermediate 4 is shown as formula X, and the structural formula of the intermediate 5 is shown as formula XI:
further, the method comprises the following steps: reacting 2-ethoxyformamidine hydrochloride with hydrazine hydrateThen, carrying out ring closure reaction with the compound 2 to generate a compound 3; compound 3 in acid solvent, POCl 3 Generating an intermediate 4 through ring closure reaction under the action; the intermediate 4 reacts with chlorosulfonic acid to generate a sulfonyl chloride intermediate 5; the sulfonyl chloride intermediate 5 reacts with N-ethylpiperazine to generate a target product vardenafil analogue, wherein the structural formula is shown as a formula II:
further, when the structural formula of the target product vardenafil analogue is shown as formula II, the reaction flow is as follows:
the invention also provides application of the vardenafil analogue, the prodrug thereof or the pharmaceutically acceptable salt thereof in preparing medicaments for treating male penile erection dysfunction, medicaments for treating pulmonary hypertension and medicaments for treating heart failure.
The application of the invention in pharmacy is realized by adopting the following technical scheme:
the active ingredient of the drug for treating male penile erectile dysfunction is the vardenafil analogue, the prodrug thereof or the pharmaceutically acceptable salt thereof.
The active ingredient of the drug for treating pulmonary hypertension is the vardenafil analogue, the prodrug or the pharmaceutically acceptable salt thereof.
The active ingredient of the drug for treating heart failure is the vardenafil analogue, the prodrug thereof or the pharmaceutically acceptable salt thereof.
Compared with the prior art, the invention has the beneficial effects that:
(1) The vardenafil analog provided by the invention is a brand-new vardenafil hydrochloride analog, has a novel compound structure, has the characteristics of definite structure and high chemical purity, and is proved to have 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 hypertension, heart failure and other diseases.
(2) The vardenafil analogue provided by the invention can improve the relative bioavailability of the vardenafil analogue and improve the absorption of medicaments by improving the first-pass effect, and is applied to the treatment of male penile erectile dysfunction, pulmonary arterial hypertension and heart failure.
Detailed Description
The present invention is further described below with reference to specific embodiments, and it should be noted that, without conflict, various embodiments or technical features described below may be arbitrarily combined to form a new embodiment. The raw materials, equipments and the like used in the following examples are commercially available unless otherwise specified.
A vardenafil analog having the formula I:
in the formula I, R 1 Is a hydroxyl group,
R 2 Is methoxy or ethoxy.
As a further embodiment, the vardenafil analog has a structural formula as shown in any one of formulas II-VII:
as a further embodiment, the vardenafil analog has the structural formula shown in formula II, wherein 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 "analog CJ-003" to represent the analog shown in formula II:
the vardenafil analogue (shown in any formula II to VII) provided by the embodiment of the invention has a structure similar to vardenafil hydrochloride, has the effect of inhibiting phosphodiesterase type 5 (PDE 5), and can be used for treating male penile Erectile Dysfunction (ED), pulmonary hypertension, heart failure and other diseases.
The vardenafil analogue (shown in any formula II-VII), the prodrug thereof or the pharmaceutically acceptable salt thereof provided by the embodiment of the invention can be used for preparing a medicament for treating male penile erectile dysfunction, or a medicament for treating pulmonary hypertension, or a medicament for treating heart failure.
A method for synthesizing vardenafil analogs, comprising the steps of: reacting the first reaction raw material with hydrazine hydrate, and then performing ring closure reaction with the compound 2 to generate a compound 3; compound 3 in acid solvent, POCl 3 Generating an intermediate 4 through ring closure reaction under the action; the intermediate 4 reacts with chlorosulfonic acid to generate a 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-ethoxy formamidine hydrochloride or 2-methoxy formamidine hydrochloride; the second reaction raw material is N-ethyl piperazine, N-methyl piperazine or water; the structural formula of the compound 2 is shown as the formula VIII:
as a further embodiment, when the target vardenafil analog has the structural formula shown in formula II (analog CJ-003), the synthesis method comprises the following steps: after reacting commercially available 2-ethoxy formamidine hydrochloride (compound 1) with hydrazine hydrate, performing ring closure reaction with compound 2 to generate compound 3; compound 3 in acetic acid solvent, POCl 3 The ring closure reaction is carried out under the action to generate an intermediate 4(ii) a The intermediate 4 reacts with chlorosulfonic acid to generate a sulfonyl chloride intermediate 5; the sulfonyl chloride intermediate 5 reacts with N-ethylpiperazine (compound 6) to generate the target product vardenafil analogue CJ-003, and the reaction flow is as follows:
example 1
Synthesis of intermediate (Compound 3) of vardenafil analog CJ-003 (formula II), scheme and procedure were as follows:
adding EtOH (300 mL) and 2-ethoxy formamidine hydrochloride (compound 1, 30g,149.50mmol, 1eq) into a 500mL three-necked flask, cooling to 0 ℃ in an ice-water bath, and dropwise adding hydrazine hydrate NH into the system 2 NH 2 .H 2 O (8.23g, 164.45mmol,7.99mL, 1.1eq) and stirring was maintained at 0 ℃ for 0.5 h. The temperature is automatically returned to the room temperature of 20 ℃, the mixture is stirred for 1 hour (until the raw materials disappear), the compound 2 (41.83g, 194.35mmol, 1.3eq) is added into the system, the temperature is raised to 45 ℃, and N is added 2 The reaction was carried out for 12 hours under protection, and TLC (petroleum ether/ethyl acetate =1/1, rf = 0.30) monitored that the intermediate reaction was complete and a new spot was formed. The reaction was cooled to room temperature and then concentrated, water (100 mL) and dichloromethane (100 mL) were added, ammonia was added dropwise with stirring to adjust pH =9-10, the organic phase was separated, the aqueous phase was washed with dichloromethane (80mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried 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 subjected to Pre-HPLC purification (column: agela DuraShell C18250: 80mm 10um mobile phase: [ water (10 mm NH4HCO3) -ACN](ii) a B%:15% -45%,20 min) to give 9g of a yellow solid product, denoted as compound 3.
The structure of compound 3 obtained in example 1 was confirmed by nuclear magnetic 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, scheme and method of vardenafil analog CJ-003 intermediate 4 are as follows:
adding compound 3 (2.5g, 7.57mmol, 1eq) to a 500mL three-necked flask at 25 ℃, adding AcOH (25 mL), stirring for dissolution, cooling to 0 ℃ in an ice water bath, and slowly adding POCl dropwise 3 (5.79g, 37.76mmol, 4.99eq), heating to 100 ℃ after completion of dropwise addition, reacting for 12 hours, TLC (petroleum ether/ethyl acetate =0/1, R) f = 0.29) monitoring that the reaction is complete, a new spot is formed. The reaction was cooled to room temperature and then quenched into water (20 mL), concentrated to remove AcOH, adjusted to pH =7-8 by the addition of 1M aqueous potassium hydroxide at 10 ℃, followed by sequential extractions with dichloromethane (20mL x 3), combined organic phases, washed with saturated brine (20 mL), separated organic phase, dried over anhydrous sodium sulfate, filtered, concentrated filtrate to 3.5g crude product, purified by column chromatography (ethyl acetate/petroleum ether = 10/1-0/1) to give 1.71g solid product, denoted as intermediate 4.
The structure of the intermediate 4 obtained in example 2 was confirmed by LCMS and nuclear magnetic hydrogen spectroscopy, and the results were as follows:
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 synthesis, scheme and method are as follows:
methylene chloride (100 mL) and intermediate 4 (6.2 g,19.85mmol, 1eq) were charged into a 250mL three-necked flask, and a solution of chlorosulfonic acid (22.74g, 195.11mmol, 9.83eq) in methylene chloride (10 mL) was added dropwise to the reaction mixture at 25 ℃ to react 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 spot was formed. The reaction was quenched by slowly pouring into saturated aqueous sodium bicarbonate (100 mL) with stirring, extracted with dichloromethane (100mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to give 8g of crude product. The crude product was directly subjected to the next reaction without further purification and was designated as intermediate 5.
The structure of the intermediate 5 obtained in example 3 was confirmed by nuclear magnetic hydrogen spectroscopy, 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 method for synthesizing vardenafil analog CJ-003 comprises the following steps:
dichloromethane (40 mL) and intermediate 5 (4 g,9.74mmol, 1eq) were added to a 100mL single-neck flask, the temperature was reduced to 0 ℃ in an ice-water bath, and N-ethylpiperazine (compound 6,2.22g,19.47mmol,2.47mL, 2eq), N, was added dropwise to the system 2 Stirring at 0 deg.C for 0.5 hr under protection, automatically heating to 25 deg.C, and stirring for 11.5 hr. TLC (petroleum ether/ethyl acetate =0/1,r f = 0.15) monitoring, the reaction of the raw materials is finished. Water (40 mL) was added to the reaction mixture) And dichloromethane (40 mL), the organic phase was separated, the aqueous phase was extracted with dichloromethane (40mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and spun dry to give 5.5g of crude product. The crude product was isolated by column chromatography (petroleum ether/ethyl acetate = 10/1-0/1) to yield 3.5g of a white solid product designated as analog CJ-003 (formula ii).
The analogue CJ-003 obtained in example 4 was structurally confirmed by LCMS and nuclear magnetic hydrogen spectroscopy, 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 method for synthesizing vardenafil analogue IV, a flow scheme and a method are as follows:
MeCN (20 mL), H was added to a 100mL single-neck flask 2 O (40 mL) and compound 5 (4 g,9.74mmol, 1eq), stirred at 25 ℃ for 12 hours, detected by LCMS, after the reaction of the starting materials, the reaction solution was filtered, rinsed twice with acetonitrile (30 mL), and the filter cake was concentrated to give the 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, a compound of formula IV.
The analog obtained in example 5, formula IV, was structurally confirmed by LCMS and nuclear magnetic hydrogen spectroscopy as follows:
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) comprises the following steps:
methylene chloride (40 mL) and intermediate 5 (4 g,9.74mmol, 1eq) were added to a 100mL single-neck flask, the temperature was reduced to 0 ℃ in an ice-water bath, and N-methylpiperazine (compound 7,1.95g,19.47mmol,2.47mL, 2eq), N-methylpiperazine (compound 7,1.95g,19.47mmol,2.47mL, 2eq) was added dropwise to the system 2 Stirring at 0 deg.C for 0.5 hr under protection, automatically heating to 25 deg.C, and stirring for 12 hr. TLC (petroleum ether/ethyl acetate =0/1,r f = 0.15) monitoring, the reaction of the raw materials is finished. The reaction was added to water (40 mL) and dichloromethane (40 mL), the organic phase was separated, the aqueous phase was extracted with dichloromethane (40mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and spun dry to give 4.3g of crude product. The crude product was subjected to column chromatography (petroleum ether/ethyl acetate = 10/1-0/1) to afford 2.7g of a white solid product, designated as analog formula III.
The analogue obtained in example 6, formula III, was structurally confirmed by LCMS and nuclear magnetic hydrogen spectroscopy as follows:
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, scheme and method of vardenafil analog (formula V) intermediate (compound 9) is as follows:
adding EtOH (300 mL) and 2-methoxy formamidine hydrochloride (compound 8, 30g,160.73mmol, 1eq) into a 500mL three-necked bottle, cooling to 0 ℃ in an ice-water bath, and dropwise adding hydrazine hydrate NH into the system 2 NH 2 .H 2 O (10.6g, 176.8mmol, 1.1eq) and stirring was maintained at 0 ℃ for 0.5 h. The temperature is automatically returned to the room temperature of 20 ℃, the mixture is stirred for 1 hour (till the raw materials disappear), the compound 2 (41.83g, 194.35mmol, 1.3eq) is added into the system, the temperature is raised to 45 ℃, and N is added 2 The reaction was carried out for 12 hours under protection, and TLC (petroleum ether/ethyl acetate =1/1, rf = 0.30) monitored that the intermediate reaction was complete and a new spot was formed. The reaction was cooled to room temperature and then concentrated, water (100 mL) and dichloromethane (100 mL) were added, ammonia was added dropwise with stirring to adjust pH =9-10, the organic phase was separated, the aqueous phase was washed with dichloromethane (80mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to give 25g of crude 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 subjected to Pre-HPLC purification (column: agela DuraShell C18250 × 80mm 1 um mobile phase: [ water (10 mM NH4HCO3) -ACN](ii) a B%:15% -45%,20 min) to give 9.3g of a yellow solid product, which is designated as compound 9.
The structure of compound 9 obtained in example 7 was confirmed by nuclear magnetic 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, scheme and method of vardenafil analog (formula V) intermediate 10 is as follows:
at 25 deg.CCompound 9 (2.4g, 7.57mmol, 1eq) was added to a 500mL three-necked flask, followed by addition of AcOH (25 mL) and dissolution with stirring, cooling to 0 ℃ in an ice water bath, and POCl was slowly added dropwise 3 (5.8g, 37.85mmol, 5.0eq), after completion of dropwise addition, the temperature was raised to 100 ℃ to conduct reaction for 12 hours, and TLC (petroleum ether/ethyl acetate =0/1, R) f = 0.29) monitor reaction completion, new spot formation. The reaction was cooled to room temperature and then quenched into water (20 mL), concentrated to remove AcOH, adjusted to pH =7-8 by the addition of 1M aqueous potassium hydroxide at 10 ℃, followed by sequential extractions with dichloromethane (20mL x 3), combined organic phases, washed with saturated brine (20 mL), separated organic phase, dried over anhydrous sodium sulfate, filtered, concentrated filtrate to 3.4g crude, purified by column chromatography (ethyl acetate/petroleum ether = 10/1-0/1) to give 1.5g solid product, denoted as intermediate 10.
The structure of intermediate 10 obtained in example 8 was confirmed by LCMS, and the results were as follows:
LCMS:m/z＝299.1[M+1] +
example 9
Vardenafil analog (formula V) intermediate 11 was synthesized as follows:
a250 mL three-necked flask was charged with dichloromethane (100 mL) and intermediate 10 (5.92g, 19.85mmol, 1eq), and a solution of chlorosulfonic acid (22.74g, 195.11mmol, 9.83eq) in dichloromethane (10 mL) was added dropwise to the reaction mixture at 25 ℃ to react 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 spot was formed. The reaction was quenched by slowly pouring into saturated aqueous sodium bicarbonate (100 mL) with stirring, extracted with dichloromethane (100mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to give 8g of crude product. The crude product was taken directly to the next reaction without further purification and was designated as intermediate 11.
Example 10
A synthetic method of vardenafil analogue (formula V), the process and method are as follows:
a100 mL single-neck flask was charged with dichloromethane (40 mL) and intermediate 11 (3.87g, 9.74mmol, 1eq), cooled to 0 ℃ in an ice-water bath, and N-ethylpiperazine (compound 6,2.22g,19.47mmol,2.47mL, 2eq), N-ethylpiperazine (compound 6,2.22g,19.47mmol,2.47mL, 2eq) was added dropwise to the system 2 Stirring at 0 deg.C for 0.5 hr under protection, automatically heating to 25 deg.C, and stirring for 11.5 hr. TLC (petroleum ether/ethyl acetate =0/1,r) f = 0.15) monitoring, the reaction of the raw materials is finished. The reaction was added to water (40 mL) and dichloromethane (40 mL), the organic phase was separated, the aqueous phase was extracted with dichloromethane (40mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and spun dry to give 4.5g of crude product. The crude product was subjected to column chromatography (petroleum ether/ethyl acetate = 10/1-0/1) to afford 3.7g of a white solid product, designated as analog V.
The structure of the analog V obtained in example 10 was confirmed by LCMS and nuclear magnetic hydrogen spectroscopy, and the results were as follows:
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 synthetic method of vardenafil analogue VII comprises the following steps:
MeCN (20 mL), H was added to a 100mL single-neck flask 2 O (40 mL) and Compound 11 (3.87g, 9.74mmol, 1eq) were stirred at 25 ℃ for 12 hours, LCMS detected, the starting material reacted, the reaction was filtered and the filtrate was washed with ethyl acetateNitrile (30 mL) was washed twice and the filter cake was concentrated to give the 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, a compound represented by formula VII.
The structure of the analogue VII obtained in example 11 was confirmed by LCMS and nuclear magnetic hydrogen spectroscopy, and the results were 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 are as follows:
dichloromethane (40 mL) and intermediate 11 (3.87g, 9.74mmol, 1eq) were added to a 100mL single-neck flask, the temperature was reduced to 0 ℃ in an ice-water bath, and N-methylpiperazine (compound 7,1.95g,19.47mmol,2.47mL, 2eq), N, was added dropwise to the system 2 Stirring at 0 deg.C for 0.5 hr under protection, automatically heating to 25 deg.C, and stirring for 12 hr. TLC (petroleum ether/ethyl acetate =0/1,r) f = 0.15) monitoring, the reaction of the raw materials is finished. The reaction was added to water (40 mL) and dichloromethane (40 mL), the organic phase was separated, the aqueous phase was extracted with dichloromethane (40mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and spun dry to give 3.8g of crude product. The crude product was subjected to column chromatography (petroleum ether/ethyl acetate = 10/1-0/1) to afford 2.3g of a white solid product, designated as analog formula VI.
The analog obtained in example 5, formula VI, was structurally confirmed by LCMS and nuclear magnetic hydrogen spectroscopy as follows:
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 assay of Compounds II-VII
The experimental method comprises the following steps:
1 preparation of reaction buffer solution and reaction stop solution
1.11 times of reaction buffer
IMAP reaction buffer containing 0.1% BSA (5 ×) (IMAP FP IPP Explorer Kit) diluted to 1 times reaction buffer containing 1mM DTT.
1.2 reaction stop solution
IMAP modified binding buffer A (5X), IMAP modified binding buffer B (5X), and IMAP modified binding reagent (available from IMAP FP IPP Explorer Kit) were prepared according to the instructions.
2 preparation of the Compound
2.1 dilution of the Compound
Solutions with 100-fold final concentration for compound detection were prepared. The compounds were diluted in gradient to the number of concentration points set using an automated micropore pipettor (Precision PRC 384U) as follows: add 50. Mu.l of the starting concentration of compound DMSO solution to A2 wells on an Echo 384-well plate, 30. Mu.l of 100% DMSO was added to each of A3-A11 as A3-fold dilution; taking 15 mu l of compound from the A2 hole, adding the compound into the A3 hole, uniformly mixing, sequentially diluting by 3 times downwards, and diluting by 10 concentration points; add 30. Mu.l of 100% DMSO to A1 and A12 wells.
2.2 transfer of Compounds to 384 reaction plates
200nl of compound was transferred from the above-diluted Echo 384-well plates to 384-well reaction plates using an Echo550 apparatus, and 200nl of 100% DMSO was transferred into each of the negative control and the positive control.
3 enzymatic reaction
3.1 preparation of 2-fold enzyme solution
PDE5A1 was added to A1 fold reaction buffer to form a2 fold enzyme solution.
3.2 preparation of 2-fold substrate solution
For the enzyme PDE5A1, FAM-labeled cGMP was added to A1-fold reaction buffer to form a 2-fold substrate solution.
3.3 addition of enzyme solution to 384-well plates
Mu.l of a 2-fold enzyme solution was added to a 384-well reaction plate well. For the no enzyme control wells, the enzyme solution was replaced with 10. Mu.l of 1-fold reaction buffer. Centrifuge at 1000rpm for 1min and incubate at room temperature for 15 min.
3.4 addition of substrate solution to 384-well plates to initiate enzymatic reactions
To each well of a 384-well reaction plate, 10. Mu.l of a 2-fold substrate solution was added. Centrifuge at 1000rpm for 1min. The reaction was carried out at 25 ℃ for 20 minutes.
3.5 termination of the enzymatic reaction
The reaction was terminated by adding 60. Mu.l of the reaction terminator to each well of the 384-well reaction plate, and incubated for 60 minutes at room temperature by shaking at 600rpm with a shaker and protecting from light.
4 EnVision read data and data computation
EnVision readings were used.
5 inhibition calculation and IC50 curve fitting
Data were replicated from EnVision, where the maximum refers to the reading of the DMSO control and the minimum refers to the reading of the no enzyme live control. Suppression rate (%) = (maximum value-sample value)/(maximum value-minimum value) × 100%.
Importing the data into MS Excel and fitting an IC50 value by using 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 for the results of the PDE5 enzyme inhibition activity test
Note: CJ-003 (the compound of formula II) was the compound prepared in example 4.
The above experimental data show that the vardenafil hydrochloride analogue disclosed by the invention has stronger inhibition effect on phosphodiesterase type 5 (PDE 5), wherein the inhibition activity of the compounds in the formula II, the formula III and the formula V is not inferior to that of the marketed drugs of sildenafil and tadalafil.
Furthermore, the literature (Wang Z, et al, the Selectivity and the tension of the New PDE5 Inhibitor TPN729MA. J Sex Med.2013 Nov;10 (11): 2790-7) reports the PDE5 enzyme inhibitory activity IC50:5.22nM of sildenafil, the literature (Block MA, et al, binding of transcribed sildenafil, tadalafil, or vardenafil to the phosphorus dioxide-5 catalytic site displacement capacity, specificity, homology, cGMP stimulation. Mol Pharmacol.2004 Jul 66 (1): 144-52) reports the PDE5 enzyme inhibitory activity IC50:1.8nM of tadalafil. The inhibitory activity of the compounds of formula II, III and V of the present invention is further verified in combination with the above literature records as being not inferior to that of the marketed drugs sildenafil and tadalafil.
The compounds II to VII provided by the embodiment of the invention have the effect of inhibiting phosphodiesterase type 5 (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 hypertension, heart failure and the like.
The above embodiments are only preferred embodiments of the present invention, and the scope of the present invention should not be limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are intended to be covered by the claims.
Claims (9)
1. A vardenafil analog having the formula I:
in the formula I, R 1 Is a hydroxyl group,
R 2 Is methoxy or ethoxy.
2. The vardenafil analog of claim 1, wherein the vardenafil analog has the formula of any one of formulas ii to VII:
3. the vardenafil analog of claim 2 wherein the vardenafil analog has the formula ii:
4. a method of synthesizing vardenafil analogues according to any of claims 1-3 comprising the steps of: reacting the first reaction raw material with hydrazine hydrate, and then performing ring closure reaction with the compound 2 to generate a compound 3; compound 3 in acid solvent, POCl 3 Under the action of the intermediate 4, the intermediate is generated through a ring closure reaction; the intermediate 4 reacts with chlorosulfonic acid to generate a 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-ethoxy formamidine hydrochloride or 2-methoxy formamidine 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:
5. a method of synthesizing vardenafil analog as claimed in claim 4, wherein: the structural formula of the compound 3 is shown as formula IX, the structural formula of the intermediate 4 is shown as formula X, and the structural formula of the intermediate 5 is shown as formula XI:
6. the method of synthesizing vardenafil analog according to claim 4, comprising the steps of: reacting 2-ethoxy formamidine hydrochloride with hydrazine hydrate, and then performing ring closure reaction with a compound 2 to generate a compound 3; compound 3 in acid solvent, POCl 3 Under the action of the intermediate 4, the intermediate is generated through a ring closure reaction; the intermediate 4 reacts with chlorosulfonic acid to generate a sulfonyl chloride intermediate 5; the sulfonyl chloride intermediate 5 reacts with N-ethylpiperazine to generate a target product vardenafil analogue, wherein the structural formula is shown as a formula II:
7. the method for synthesizing vardenafil analog as claimed in claim 6, wherein when the structural formula of the target vardenafil analog is shown in formula II, the reaction flow is shown as follows:
8. use of vardenafil analogue or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 for the manufacture of a medicament for the treatment of male penile erectile dysfunction, for the manufacture of a medicament for the treatment of pulmonary arterial hypertension, for the manufacture of a medicament for the treatment of heart failure.
9. A drug for treating male penile erectile dysfunction, characterized in that the active ingredient thereof is the vardenafil analog or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3.
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