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WO2009097709A1 - Pyrazolopyrimidinone-containing phenyl guanidine derivatives, pharmaceutical compositions containing them, process for their preparation and their use - Google Patents

Pyrazolopyrimidinone-containing phenyl guanidine derivatives, pharmaceutical compositions containing them, process for their preparation and their use Download PDF

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Publication number
WO2009097709A1
WO2009097709A1 PCT/CN2008/001995 CN2008001995W WO2009097709A1 WO 2009097709 A1 WO2009097709 A1 WO 2009097709A1 CN 2008001995 W CN2008001995 W CN 2008001995W WO 2009097709 A1 WO2009097709 A1 WO 2009097709A1
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WO
WIPO (PCT)
Prior art keywords
methyl
dihydro
pyrimidin
oxo
propylpyrazolo
Prior art date
Application number
PCT/CN2008/001995
Other languages
French (fr)
Chinese (zh)
Inventor
Zheng Liu
Guanghui Tian
Zhen Wang
Jie XIN
Jinfeng Zhang
Yi Zhu
Jingkang Shen
Jingshan Shen
Original Assignee
Topharman Shanghai Co., Ltd.
Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
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.)
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Publication date
Application filed by Topharman Shanghai Co., Ltd., Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences filed Critical Topharman Shanghai Co., Ltd.
Publication of WO2009097709A1 publication Critical patent/WO2009097709A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a phenylhydrazine derivative containing a pyrazolopyrimidinone, a pharmaceutically acceptable salt thereof or a solvate thereof, and to a pharmaceutical composition containing the compound and a process for preparing the same,
  • the compound of the present invention can effectively inhibit the V-type phosphodiesterase (PDE5), and can be applied to the treatment of various vascular disorders such as male erectile dysfunction.
  • PDE5 V-type phosphodiesterase
  • Sildenafil (WO94/28902) from Pfizer is the first oral PDE5 inhibitor for the treatment of male erectile dysfunction.
  • V-type phosphodiesterase By inhibiting the V-type phosphodiesterase in smooth muscle cells, it increases the cGMP level of the substrate of the enzyme, causing relaxation and vasodilation of smooth muscle, thereby increasing blood flow and causing erection.
  • W098/49166, W099/54333, WO 01/87888 discloses another series of pyrazolo[4,3-d]pyrimidin-7-one derivatives;
  • WO2004/096810 discloses a series of 5,7-diamine pyrazoles And [4,3-d]pyrimidine compounds;
  • WO2004/108726 discloses a series of ⁇ ' j dihydropyrrolo[2,3-d]pyrimidin-4-one compounds;
  • WO2004/101567 discloses a series of imidazo[1] , 5-a]-l,3,5-triazine 4(3H)-one compound;
  • WO2006/126081, WO2006/126083, WO2007/020521, CA02339677 discloses a series of pyridopyrazinone compounds;
  • WO2005089752 discloses A series of tetracyclic porphyrin compounds; WO2005/01
  • PDE5 inhibitors in development are also used for diabetic gastrointestinal symptoms, insulin resistance and hyperlipidemia.
  • sildenafil has achieved significant clinical efficacy, it also has different degrees of inhibition on other PDE isozymes other than PDE5, clinically showing headache, flushing, indigestion, and nasal congestion. , blurred vision, photosensitivity, light color and other toxic side effects.
  • these side effects are dose-related, so it is possible to reduce the dose and reduce the side effects by finding a stronger PDE5 inhibitor.
  • the symptom of visual disorder is sildenafil for type VI phosphate present in the retina.
  • Esterase (PDE6) also has the effect of inhibition, so increasing selectivity, especially relative to PDE6, is another goal in the search for new PDE5 inhibitors. Summary of the invention
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned pyrazolopyrimidinone-containing phenylhydrazine derivative, a pharmaceutically acceptable salt thereof or a solvate thereof;
  • Still another object of the present invention is to provide a process for producing the above phenyl hydrazine derivative containing a pyrazolopyrimidinone
  • Still another object of the present invention is to provide a pyridazopyrimidinone-containing phenylhydrazine derivative, a pharmaceutically acceptable salt thereof or a solvate thereof as a V-type phosphodiesterase inhibitor for the preparation of a male erectile dysfunction Use in medicines for a variety of vascular disorders.
  • the present inventors have designed and synthesized a series of novel phenyl hydrazine derivatives containing a pyrazolopyrimidinone as shown in the following formula I, pharmaceutically acceptable salts thereof or solvates thereof:
  • R 1 represents H, dC 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl, dC 3 haloalkyl or C 3 -C 6 cycloalkyl substituted dC 3 alkyl;
  • R 2 represents C 2 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl, dC 3 haloalkyl or C 3 -C 6 cycloalkyl substituted dC 3 alkyl;
  • R 3 represents QC 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 alkenyl, dC 3 haloalkyl, 3 ⁇ 4 QC 3 alkoxy substituted C r C 3 alkyl or by C 3 - C 6 cycloalkyl substituted C r C 3 alkyl;
  • R 4 and R 5 each independently represent H, aryl, C3 ⁇ 4R n, or a substituted or unsubstituted C r C 3 alkyl group, Wherein the substituent is selected from the group consisting of OH, dC 4 alkoxy and halogen;
  • R 6 and R 7 each independently represent: H, C r C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl, OH, OR 10 , CN, N0 2 , NR 8 R 9 , CONR 8 R 9 , COR 10 , aryl, Het or a substituted QC 3 alkyl group, the substituent being selected from the group consisting of OH, dC 4 alkoxy, C 3 -C 6 cycloalkyl, halogen And NR 8 R 9 , aryl and Het; an indenyl group which is unsubstituted or optionally substituted by one or more substituents selected from dC 6 alkyl, C 3 -C 6 cycloalkyl, The aryl group and Het; or R 6 and R 7 may form a 4-8 membered heterocyclic group together with the nitrogen atom to which they are attached, and the heterocyclic group is morpholinyl, thi
  • R 4 and R 6 or R 5 and R 6 together with two nitrogen atoms capable of forming a 5-7-membered ring
  • R 8 and R 9 each independently represent H, Ci-C 6 alkyl, aryl, Het or a QC 3 alkyl group substituted with a substituent selected from dC 4 alkoxy, C 3 -C 6 cycloalkyl, aryl and Het, or a nitrogen to which R 8 and R 9 may be attached Atoms together form azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl;
  • R 10 represents dC 6 alkyl, C 3 -C 4 alkenyl, C 3 -C 6 cycloalkyl, aryl, Het or dC 3 alkyl substituted with a substituent selected from OH, QC 4 alkoxy, C 3 -C 6 cycloalkyl, aryl and Het;
  • R 11 represents C r C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl or aryl;
  • Halogen represents F, Cl, Br or I
  • An aryl group represents a substituted or unsubstituted phenyl group, and the substitution is substituted with one or more substituents selected from the group consisting of halogen, dC 3 alkyl, QC 3 alkoxy, CF 3 , CN and NO 2 ;
  • Het represents an aromatic 5- to 6-membered heterocyclic group having 1 to 4 hetero atoms, the hetero atom is selected from N, S and 0, and the heterocyclic group may be optionally selected from halogen, dC 3 alkyl. Substituting one or more substituents of dC 3 alkoxy, CF 3 , CN and NO 2 .
  • dC 3 alkoxy, CF 3 , CN and NO 2 a preferred embodiment of the invention:
  • R 1 represents a Ci-C 4 alkyl group or a C 3 -C 6 cycloalkyl group
  • R 2 represents a C 2 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group
  • R 3 represents C r C 3 alkyl or C r C 3 alkyl substituted by C r C 3 alkoxy;
  • R 4 and R 5 each independently represent 11, aryl or C 3 ⁇ 4R n ;
  • R 6 and R 7 each independently represent: H, dC 6 alkyl, C 3 -C 6 cycloalkyl, aryl or dC 3 alkyl substituted by a substituent selected from OH, dC 4 Alkoxy, C 3 -C 6 cycloalkyl, NR 8 R 9 and aryl; substituted or unsubstituted fluorenyl, said substituent being selected from dC 4 alkyl, C 3 -C 6 cycloalkyl , NR 8 R 9 and aryl; or R 6 and R 7 may form a 4-8 membered heterocyclic group together with the nitrogen atom to which they are attached, the heterocyclic group being morpholinyl, thiomorpholinyl, piperidinyl, Pyrrolyl or piperazinyl;
  • R 8 and R 9 each independently represent H, Ci-C 6 alkyl, aryl, Het or a substituted QC 3 alkyl group, the substituent being selected from dC 4 alkoxy, C 3 -C 6 cycloalkyl, aryl and Het, or R 8 and R 9 may together with the nitrogen atom to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl;
  • R 11 represents dC 6 alkyl or phenyl
  • Het represents a pyridyl group.
  • R 1 represents a methyl group
  • R 2 represents an ethyl or n-propyl group
  • R 3 represents a methyl group, an ethyl group or a n-propyl group
  • 1 4 is 11, ethyl or benzyl
  • 1 5 is 11, ethyl or phenyl
  • R 6 and R 7 each independently represent: H, methyl, ethyl, phenyl, benzyl, 3-pyridylmethyl or C 2 -C 3 alkyl substituted with a substituent selected from the group consisting of Hydroxyl and anthracene, fluorenyl-dimethylamino; unsubstituted or substituted phenyl group; or when R 6 and R 7 are not simultaneously argon, R 6 and R 7 may be combined with the nitrogen atom to which they are attached Morpholinyl, piperidinyl, hydrazine-methylpiperazinyl or pyrrolidinyl;
  • the pyrazolopyrimidinone-containing phenylhydrazine derivative is selected from the group consisting of:
  • an alkyl group or alkoxy group having three or more carbon atoms may be straight-chain or branched unless otherwise specified.
  • the compounds of formula I may contain one or more chiral centers and thus stereoisomers, ie, enantiomers, diastereomers or mixtures thereof, may be present. If the compound of formula I contains an alkenyl or alkenylene group, cis ( ⁇ ) and trans ( ⁇ ) isomerism may also be present. Thus, the compounds of the invention may be individual isomers or mixtures of individual isomers. The cis/trans isomers can be separated by conventional techniques well known to those skilled in the art (e.g., chromatography and fractional crystallization).
  • racemate (or racemic precursor) can be reacted with a suitable optically active compound such as an alcohol, or in the case where the compound of formula I contains an acid moiety or a base moiety, Or an acid such as 1-phenylethylamine or tartaric acid.
  • a suitable optically active compound such as an alcohol, or in the case where the compound of formula I contains an acid moiety or a base moiety, Or an acid such as 1-phenylethylamine or tartaric acid.
  • the resulting diastereomeric mixture can be separated by chromatography and/or fractional crystallization, converting one or both of the diastereomers to the corresponding pure enantiomers by means well known to those skilled in the art. Structure.
  • the compounds of formula I may exist in the form of tautomers, and the invention includes mixtures thereof and single tautomers.
  • the invention includes radiolabeled derivatives of the compounds of formula I which are suitable for use in biological research.
  • the pyridylpyrimidinone-containing phenylhydrazine derivative represented by the formula I provided by the present invention contains a basic center, and thus the AT organism represented by the formula I can form an acid addition salt with an acid, for example, the AT organism.
  • a non-toxic acid addition salt with a mineral acid such as hydrochloric acid, hydrobromic acid, sulphuric acid or lithic acid, or with an organic carboxylic acid or an organic sulfonic acid.
  • Derivatives of formula I can also be reacted with a base to form pharmaceutically acceptable metal salts, especially non-toxic alkali metal salts (e.g., sodium and potassium salts;).
  • Preferred pharmaceutically acceptable salts are the methanesulfonate and the hydrochloride.
  • the invention includes any prodrug form of the compound of formula I.
  • the invention also includes pharmaceutically acceptable solvates (e.g., hydrates) of the compounds of formula I.
  • the invention also includes a plurality of crystalline forms of the compound of formula I and various salts.
  • the present invention provides a process for the preparation of compounds of formula I.
  • the invention also includes novel intermediates in the preparation process and preparation methods thereof, such as the following formula II,
  • the compounds of formula I can be divided into three different preparation methods: (i) compounds of formula I (R 6 and R 7 are not H, nor substituted or unsubstituted a phenylurea derivative of the pyrazolopyrimidinone of the formula II (wherein RR 2 , R 3 , R 4 , R 5 are as defined and preferred above) and a compound of the formula III (wherein R 6 , R 7 as defined above) is prepared by nucleophilic substitution reaction.
  • the compound of formula II usually at 50-150.
  • a suitable solvent preferably methanol, ethanol, acetonitrile, ethylene glycol monomethyl ether, hydrazine, hydrazine-dimethylformamide, fluorene-methylpyrrolidin-2-one, etc.
  • the reaction time is from 0.1 hour to 1 day, and a nucleophilic substitution reaction with a compound of the formula III is carried out in an amount of from 1 to 10 times to obtain a compound of the formula I.
  • a compound of formula IV usually at 0-50.
  • a suitable solvent preferably ethanol, butanol, acetonitrile, ethylene glycol monomethyl ether, hydrazine, hydrazine-dimethylformamide, hydrazine-methylpyrrolidin-2-one, dioxane, Dimethyl sulfoxide or water
  • an equimolar amount of an inorganic or organic acid preferably hydrochloric acid
  • the reaction time is from 1 hour to 2 days at C, and a compound of the formula I is obtained by a nucleophilic addition reaction with an equimolar amount of the compound of the formula V.
  • a suitable solvent preferably ethanol, butanol, acetonitrile, ethylene glycol monomethyl ether, hydrazine, hydrazine-dimethylformamide, hydrazine-methylpyrrolidin-2-one, dioxane, Dimethyl sulfoxide or water
  • an equimolar amount of an inorganic or organic acid preferably hydrochloric acid
  • the reaction time is 1 hour - 2 days, nucleophilic addition with an equimolar amount of sodium dicyanamide to obtain a compound of the formula VI;
  • the second step a compound of formula VI, is usually in the range of 50-200.
  • a suitable solvent preferably ethanol, butanol, acetonitrile, ethylene glycol monomethyl ether, hydrazine, hydrazine-dimethylformamide, hydrazine-methylpyrrolidin-2-one, dioxane
  • the reaction time is from 1 hour to 2 days, and is nucleophilicly added to an equimolar amount of an inorganic or organic acid (preferably hydrochloric acid) salt of the compound of the formula III to give a compound of the formula I.
  • the compound of formula VII usually at 0-80.
  • C in a suitable solvent (preferably dichloromethane, chloroform, methanol, ethanol, acetonitrile, ethylene glycol monomethyl ether, hydrazine, hydrazine-dimethylformamide, dioxane), reaction 0.1-12 hours , nucleophilic addition with methyl iodide to give a compound of formula II.
  • a suitable solvent preferably dichloromethane, chloroform, methanol, ethanol, acetonitrile, ethylene glycol monomethyl ether, hydrazine, hydrazine-dimethylformamide, dioxane
  • a compound of formula VII can be prepared from a compound of formula IV wherein RR 2 , R 3 , R 4 are as defined above.
  • a compound of formula IV usually at 0-120. C, in a suitable solvent (preferably water, methanol, ethanol, acetonitrile, dichloromethane, chloroform, ethylene glycol monomethyl ether, hydrazine, hydrazine-dimethylformamide, dioxane, dimethyl sulfoxide) , when R 5 is hydrazine, under acidic conditions (preferably acetic acid and acid), react with a compound of the formula VIII for 0.1 to 12 hours, and nucleophilic addition to obtain a compound of the formula VII;
  • a suitable solvent preferably water, methanol, ethanol, acetonitrile, dichloromethane, chloroform, ethylene glycol monomethyl ether, hydrazine, hydrazine-dimethylformamide, dioxane, dimethyl sulfoxide
  • a compound of formula IV can be prepared from a compound of formula IX wherein RR 2 , R 3 , R 4 are as defined above.
  • the invention also provides pharmaceutically acceptable compositions containing the compounds of formula I.
  • composition consists of one or more compounds of formula I (or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof) and at least one pharmaceutically acceptable adjuvant.
  • pharmaceutical excipients will vary depending on the route of administration and the nature of the action, and are usually fillers, diluents, binders, wetting agents, disintegrating agents, lubricants, emulsifiers, suspending agents and the like.
  • compositions of the invention may be administered orally, by injection (intravenous, intramuscular, subcutaneous and intracoronary), sublingual, buccal, rectal, transurethral, vaginal, nasal, inhalation or topical routes.
  • injection intravenous, intramuscular, subcutaneous and intracoronary
  • sublingual buccal
  • rectal transurethral
  • vaginal nasal
  • inhalation topical routes.
  • the preferred route is oral.
  • the proportion of the compound of the formula I in the above composition is from 0.1% to 99.9%, preferably from 1% to 99%, based on the total mass.
  • the invention also provides a process for the preparation of a pharmaceutically acceptable composition of a compound of formula I.
  • the compound of the formula I is usually mixed with a pharmaceutically acceptable adjuvant and prepared in a form suitable for administration by a conventional preparation method.
  • Dosage forms include tablets, capsules, granules, pills, solutions, suspensions, emulsions, ointments, films, creams, aerosols, injections, suppositories, and the like. Preferred are tablets and capsules.
  • composition of the tablet and the capsule may contain one or more compounds of the formula I, and one or more common excipients, such as starch, sucrose, lactose, glucose, microcrystalline cellulose, mannose and the like; Binders such as carboxymethyl cellulose, gelatin, alginate and polyvinylpyrrolidone; wetting agents such as glycerin; disintegrants such as agar, ethyl cellulose, sodium carboxymethyl starch, calcium carbonate; magnesium stearate , talc, polyethylene glycol and other lubricants.
  • common excipients such as starch, sucrose, lactose, glucose, microcrystalline cellulose, mannose and the like
  • Binders such as carboxymethyl cellulose, gelatin, alginate and polyvinylpyrrolidone
  • wetting agents such as glycerin
  • disintegrants such as agar, ethyl cellulose, sodium carboxymethyl starch, calcium carbonate; magnesium stearate ,
  • the compound of the present invention is usually administered in a dose of from 1 to 500 mg, preferably from 10 to 100 mg per day, in single or multiple doses. However, if necessary, the above doses may be appropriately deviated. Professionals can determine the optimal dose based on the specific situation and expertise. These conditions include the severity of the disease, individual differences in the patient, characteristics of the formulation, and route of administration.
  • the present invention provides the use of a compound of the formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable composition thereof, as a human medicament.
  • the invention further provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment or prevention of a condition in which a CGMP PDE5 inhibitor is required.
  • the invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable composition thereof, for use in the treatment or prevention of male erectile dysfunction, benign prostate Hyperplasia, female sexual dysfunction, premature labor, dysmenorrhea, bladder outlet obstruction, incontinence, unstable and variant Prinzmetal angina, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, stroke, peripheral vascular disease Uses in human medicines for Raynaud's disease, inflammatory diseases, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, and diseases characterized by intestinal motility disorders such as stress bowel syndrome.
  • the compound of formula I has a stronger PDE5 inhibitory activity than sildenafil and is more selective than PDE6 distributed in the retina. Therefore, the compounds provided by the present invention are expected to exhibit better safety and efficacy in clinical practice, and have broad clinical application prospects. Detailed ways
  • the compounds of Examples 2 to 7 were separately prepared by reacting the preparation compounds 15, 16, 17, 19, 20, 21 with a solution of the methylamine in the same manner as in Example 1.
  • Examples 9 to 15 were separately prepared by reacting the Preparation Compounds 15, 17, 19, 20, 21, 22, 23 with an ethanolamine solution in the same manner as in Example 8.
  • Examples 17 to 22 were separately prepared by reacting the Preparation Compounds 15, 16, 18, 19, 20, 22 with ethylenediamine in the same manner as in Example 16.
  • Examples 24 to 29 were separately prepared by reacting the Preparation Compounds 15, 16, 17, 18, 19, 20 with pyrrolidine in the same manner as in Example 23.
  • Example 42 From the preparation of the compounds of Examples 15, 16, 19, 20 and morphine The compounds of Examples 43 to 46 were prepared separately.
  • Examples 48 to 52 were separately prepared by the same procedures as in Example 47, from the preparation of Compounds 15, 17, 19, 20, 21 and benzylamine.
  • Example 56 The compounds of Examples 56-57 were prepared by the same procedure as in Example 55 from the preparation of Compounds 15 and 16 and 2-methylaminoethanol.
  • Example 58 The compounds of Examples 56-57 were prepared by the same procedure as in Example 55 from the preparation of Compounds 15 and 16 and 2-methylaminoethanol.
  • Example 58 Example 58
  • Example 59 The compound of Example 59 was prepared by the same procedure as in Example 58 from the preparation of compound 14 and 3-aminopyridylpyridine. ! H NMR (DMSO- 6) ⁇ : 8.63 (1 ⁇ , d), 8.55 (1 ⁇ , dd), 7.80 (3H m), 7.42-7.30 (2H, m), 7.17 (1H, d), 4.58 (2H, s), 4.26 (3H, s), 4.24 (2H, q), 2.86 (2H : t), 1.81 (2H, m), 1.51 (3H, t), 1.00 (3H, t).
  • Example 60 H NMR (DMSO- 6) ⁇ : 8.63 (1 ⁇ , d), 8.55 (1 ⁇ , dd), 7.80 (3H m), 7.42-7.30 (2H, m), 7.17 (1H, d), 4.58 (2H, s), 4.26 (3H, s), 4.24 (2H, q), 2.86 (2H : t), 1.81 (2H, m
  • Examples 65 to 66 were prepared by the same procedure as in Example 64 from the preparation of Compounds 15 and 19 and n-propanolamine.
  • the compound of Preparation 14 (150 mg, 0.28 mmol) was added to 20 ml of ethanol, and diethanolamine (84 mg, 0.8 mmol) was added and stirred at 70 ° C for 15 hours.
  • the cooled reaction solution was concentrated under reduced pressure.
  • the obtained paste solid was washed with 4 ml of ethyl acetate, and then dissolved in C3 ⁇ 4 C1 2 (100 ml), and washed with water (30 mlx2), 10% NaOH (20 ml) and saturated brine (40 ml).
  • the organic phase was dried over anhydrous Na 2 S0 4, and concentrated under reduced pressure. Recrystallization from ethyl acetate-methanol gave a white solid (75 mg).
  • Examples 71-72 were prepared by the same procedure as in Example 70 from the preparation of Compounds 15 and 16 and diethanolamine.
  • Phenylhydrazine derivative containing pyrazolopyrimidinone 20 Og
  • the enzyme used in the enzyme inhibition activity test was similar to that reported in the literature (Thrombosis Res. 1991, 62, 31 and J. Biol. Chem. 1997, 272, 2714), and different tissues were appropriately treated and separated by FPLC.
  • the enzyme required for the test Specifically, PDE5 is obtained from human platelets and PDE6 is isolated from the retina of cattle. Once the enzyme is isolated, the enzyme inhibition activity test is carried out.
  • the enzyme inhibition test is a direct detection of the AMP/GMP scintillation proximity assay using the TRKQ7100 and TRKQ7090 kits. This is roughly the case, in the presence of different inhibitor concentrations and a small amount of substrate.
  • the present invention employs IC 5 .
  • the ratio of PDE6/IC 5 () PDE5 is used to judge the selectivity of the compounds of this patent for PDE6 and PDE5.
  • the calculation results show that most of the compounds of the examples have stronger selectivity than sildenafil. Therefore, relative to sildenafil The compounds of the invention are less likely to cause visual impairment.

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Abstract

The invention relates to the pharmaceutical technology field, especially relates to pyrazolopyrimidinone-containing phenyl guanidine derivatives represented by formula I, pharmaceutically acceptable salts or solvates thereof. The invention also relates to pharmaceutical compositions containing such compounds and the preparation of such compounds. The compounds have stronger inhibitory effect against phosphodiesterase V than sildenafil, and have higher selectivity than to phosphodiesterase VI which distributes in retina, thus can be used in the treatment for vascular disorders such as erectile dysfunction of male.

Description

含有吡唑并嘧啶酮的苯基胍衍生物、 其药物组合物及其制备方法和用途 技术领域  Phenylhydrazine derivative containing pyrazolopyrimidinone, pharmaceutical composition thereof, and preparation method and use thereof
本发明涉及一类含有吡唑并嘧啶酮的苯基胍衍生物、 其药学上可接受的盐 或其溶剂化物， 本发明还涉及含有该类化合物的药物组合物以及该类化合物的 制备方法， 本发明化合物可有效地抑制 V型磷酸二酯酶（PDE5 ) ， 从而可应用 于男性勃起功能障碍等多种血管障碍性疾病的治疗。 背景技术  The present invention relates to a phenylhydrazine derivative containing a pyrazolopyrimidinone, a pharmaceutically acceptable salt thereof or a solvate thereof, and to a pharmaceutical composition containing the compound and a process for preparing the same, The compound of the present invention can effectively inhibit the V-type phosphodiesterase (PDE5), and can be applied to the treatment of various vascular disorders such as male erectile dysfunction. Background technique
辉瑞公司推出的西地那非（WO94/28902 )是第一种用于治疗男性勃起障碍 的口服 PDE5抑制剂。 它通过抑制平滑肌细胞内的 V型磷酸二酯酶， 使得该酶 的底物 cGMP水平升高， 引起平滑肌的松弛与血管舒张， 从而增加该处的血液 流量而导致勃起。  Sildenafil (WO94/28902) from Pfizer is the first oral PDE5 inhibitor for the treatment of male erectile dysfunction. By inhibiting the V-type phosphodiesterase in smooth muscle cells, it increases the cGMP level of the substrate of the enzyme, causing relaxation and vasodilation of smooth muscle, thereby increasing blood flow and causing erection.
其后各大制药公司和研究小组开发了大量其他结构的 PDE5 抑制剂。 W098/49166, W099/54333 , WO 01/87888 公开了另一系列吡唑并 [4,3-d]嘧啶 -7- 酮衍生物； WO2004/096810公开了一系列 5,7-二胺吡唑并 [4,3-d]嘧啶化合物； WO2004/ 108726 公开了一系歹' j二氢吡咯并 [2,3-d]嘧啶 -4-酮化合物； WO2004/101567 公开了一系列咪唑并 [l,5-a]-l,3,5-三嗪 4(3H)-酮化合物； WO2006/ 126081 , WO2006/126083 , WO2007/020521 , CA02339677中公开了一 系列吡啶并吡嗪酮化合物； WO2005089752 公开了一系列四环咔啉化合物； WO2005/012303 和 WO2007/002125 公开了一系列黄嘌呤类化合物； WO03/0207242公开了一系列多环胍黄嘌呤化合物， 它们也都显示出较强的抑制 V型磷酸二酯酶（PDE5 )活性。  Since then, major pharmaceutical companies and research groups have developed a number of other structural PDE5 inhibitors. W098/49166, W099/54333, WO 01/87888 discloses another series of pyrazolo[4,3-d]pyrimidin-7-one derivatives; WO2004/096810 discloses a series of 5,7-diamine pyrazoles And [4,3-d]pyrimidine compounds; WO2004/108726 discloses a series of 二' j dihydropyrrolo[2,3-d]pyrimidin-4-one compounds; WO2004/101567 discloses a series of imidazo[1] , 5-a]-l,3,5-triazine 4(3H)-one compound; WO2006/126081, WO2006/126083, WO2007/020521, CA02339677, discloses a series of pyridopyrazinone compounds; WO2005089752 discloses A series of tetracyclic porphyrin compounds; WO2005/012303 and WO2007/002125 disclose a series of xanthine compounds; WO03/0207242 discloses a series of polycyclic xanthine compounds, which also all exhibit strong inhibition of V-type phosphate Diesterase (PDE5) activity.
研发中的 PDE5抑制剂还用于糖尿病消化道症状、 胰岛素耐受和高血脂。 尽管西地那非取得了较显著的临床疗效， 但由于其对 PDE5 以外的其他碑 酸二酯酶（PDE ) 同工酶也有不同程度的抑制作用， 临床表现出头痛、 潮红、 消 化不良、 鼻塞、 视物模糊、 光敏、 视物色淡等毒副作用。 一方面， 这些副作用 与剂量相关， 因此发现作用更强的 PDE5抑制剂， 才有可能减低剂量、 降低毒副 作用； 另一方面， 视觉紊乱症状是西地那非对存在于视网膜的 VI型磷酸二酯酶 ( PDE6 )也有抑制作用的结果， 所以提高选择性， 尤其相对于 PDE6的选择性， 是寻找新的 PDE5抑制剂的又一目标。 发明内容 PDE5 inhibitors in development are also used for diabetic gastrointestinal symptoms, insulin resistance and hyperlipidemia. Although sildenafil has achieved significant clinical efficacy, it also has different degrees of inhibition on other PDE isozymes other than PDE5, clinically showing headache, flushing, indigestion, and nasal congestion. , blurred vision, photosensitivity, light color and other toxic side effects. On the one hand, these side effects are dose-related, so it is possible to reduce the dose and reduce the side effects by finding a stronger PDE5 inhibitor. On the other hand, the symptom of visual disorder is sildenafil for type VI phosphate present in the retina. Esterase (PDE6) also has the effect of inhibition, so increasing selectivity, especially relative to PDE6, is another goal in the search for new PDE5 inhibitors. Summary of the invention
因此， 本发明的目的在于提供一类如下通式 I所示的含有吡唑并嘧啶酮的 苯基胍衍生物、 其药学上可接受的盐或其溶剂化物；  Accordingly, it is an object of the present invention to provide a phenylhydrazine derivative containing a pyrazolopyrimidinone represented by the following formula I, a pharmaceutically acceptable salt thereof or a solvate thereof;
本发明的另一目的是提供含有上述含有吡唑并嘧啶酮的苯基胍衍生物、 其 药学上可接受的盐或其溶剂化物的药物组合物；  Another object of the present invention is to provide a pharmaceutical composition comprising the above-mentioned pyrazolopyrimidinone-containing phenylhydrazine derivative, a pharmaceutically acceptable salt thereof or a solvate thereof;
本发明的还一目的在于提供上述含有吡唑并嘧啶酮的苯基胍衍生物的制备 方法；  Still another object of the present invention is to provide a process for producing the above phenyl hydrazine derivative containing a pyrazolopyrimidinone;
本发明的再一目的是提供上述含有吡唑并嘧啶酮的苯基胍衍生物、 其药学 上可接受的盐或其溶剂化物作为 V型磷酸二酯酶抑制剂在制备治疗男性勃起功 能障碍等多种血管障碍性疾病的药物中的用途。  Still another object of the present invention is to provide a pyridazopyrimidinone-containing phenylhydrazine derivative, a pharmaceutically acceptable salt thereof or a solvate thereof as a V-type phosphodiesterase inhibitor for the preparation of a male erectile dysfunction Use in medicines for a variety of vascular disorders.
本发明人设计和合成了一系列新的如下面通式 I所示的含有吡唑并嘧啶酮 的苯基胍衍生物、 其药学上可接受的盐或其溶剂化物：  The present inventors have designed and synthesized a series of novel phenyl hydrazine derivatives containing a pyrazolopyrimidinone as shown in the following formula I, pharmaceutically acceptable salts thereof or solvates thereof:
Figure imgf000004_0001
Figure imgf000004_0001
R1代表 H、 d-C6烷基、 C3-C6链烯基、 C3-C6环烷基、 d-C3卤代烷基或被 C3-C6环烷基取代的 d-C3烷基； R 1 represents H, dC 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl, dC 3 haloalkyl or C 3 -C 6 cycloalkyl substituted dC 3 alkyl;
R2代表 C2-C6烷基、 C3-C6链烯基、 C3-C6环烷基、 d-C3卤代烷基或被 C3-C6 环烷基取代的 d-C3烷基； R 2 represents C 2 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl, dC 3 haloalkyl or C 3 -C 6 cycloalkyl substituted dC 3 alkyl;
R3代表 Q-C6烷基、 C3-C6环烷基、 C3-C6链烯基、 d-C3卤代烷基、 ¾ Q-C3 烷氧基取代的 CrC3烷基或被 C3-C6环烷基取代的 CrC3烷基； R 3 represents QC 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 alkenyl, dC 3 haloalkyl, 3⁄4 QC 3 alkoxy substituted C r C 3 alkyl or by C 3 - C 6 cycloalkyl substituted C r C 3 alkyl;
R4和 R5各自独立地代表 H、 芳基、 C¾Rn或取代或未取代的 CrC3烷基， 其中所述的取代基选自 OH、 d-C4烷氧基和卤素； R 4 and R 5 each independently represent H, aryl, C¾R n, or a substituted or unsubstituted C r C 3 alkyl group, Wherein the substituent is selected from the group consisting of OH, dC 4 alkoxy and halogen;
R6和 R7各自独立地代表： H、 CrC6烷基、 C3-C6链烯基、 C3-C6环烷基、 OH、 OR10, CN、 N02、 NR8R9、 CONR8R9、 COR10,芳基、 Het或被取代基取代的 Q-C3 烷基， 所述的取代基选自 OH、 d-C4烷氧基、 C3-C6环烷基、 卤素、 NR8R9、 芳 基和 Het; 未取代或选择性地被一个或者多个取代基取代的脒基， 所述的取代基 选自 d-C6烷基、 C3-C6环烷基、 芳基和 Het; 或者 R6和 R7可以与它们相连的氮 原子共同构成 4 ~ 8元杂环基， 该杂环基为吗啉基、 硫吗啉基、 哌啶基、 吡咯烷 基或哌嗪基， 上述杂环基并且可以选择性地被选自 OH、 CrC6烷基、 d-C4烷氧 基、 C3-C6环烷基、 芳基和 Het中的一个或者多个取代基取代； R 6 and R 7 each independently represent: H, C r C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl, OH, OR 10 , CN, N0 2 , NR 8 R 9 , CONR 8 R 9 , COR 10 , aryl, Het or a substituted QC 3 alkyl group, the substituent being selected from the group consisting of OH, dC 4 alkoxy, C 3 -C 6 cycloalkyl, halogen And NR 8 R 9 , aryl and Het; an indenyl group which is unsubstituted or optionally substituted by one or more substituents selected from dC 6 alkyl, C 3 -C 6 cycloalkyl, The aryl group and Het; or R 6 and R 7 may form a 4-8 membered heterocyclic group together with the nitrogen atom to which they are attached, and the heterocyclic group is morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl or Piperazinyl, the above heterocyclic group and optionally one or more selected from the group consisting of OH, C r C 6 alkyl, dC 4 alkoxy, C 3 -C 6 cycloalkyl, aryl and Het Substituent substitution;
或者 R4和 R6或者 R5和 R6与其相连的两个氮原子能够形成 5 - 7元环； R8和 R9各自独立地代表 H、 Ci-C6烷基、芳基、 Het或被取代基取代的 Q-C3 烷基， 所述的取代基选自 d-C4烷氧基、 C3-C6环烷基、 芳基和 Het， 或者 R8和 R9可以与它们所连接的氮原子共同构成氮杂环丁烷基、 吡咯烷基、 哌啶基或吗 啉基； Or R 4 and R 6 or R 5 and R 6 together with two nitrogen atoms capable of forming a 5-7-membered ring; R 8 and R 9 each independently represent H, Ci-C 6 alkyl, aryl, Het or a QC 3 alkyl group substituted with a substituent selected from dC 4 alkoxy, C 3 -C 6 cycloalkyl, aryl and Het, or a nitrogen to which R 8 and R 9 may be attached Atoms together form azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl;
R10代表 d-C6烷基、 C3-C4链烯基、 C3-C6环烷基、 芳基、 Het或被取代基取 代的 d-C3烷基， 所述的取代基选自 OH、 Q-C4烷氧基、 C3-C6环烷基、 芳基和 Het; R 10 represents dC 6 alkyl, C 3 -C 4 alkenyl, C 3 -C 6 cycloalkyl, aryl, Het or dC 3 alkyl substituted with a substituent selected from OH, QC 4 alkoxy, C 3 -C 6 cycloalkyl, aryl and Het;
R11代表 CrC6烷基、 C3-C6链烯基、 C3-C6环烷基或芳基； R 11 represents C r C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl or aryl;
卤素代表F、 Cl、 Br或 I；  Halogen represents F, Cl, Br or I;
芳基代表取代或未取代的苯基， 所述的取代为选自卤素、 d-C3烷基、 Q-C3 烷氧基、 CF3、 CN和 N02中的一个或多个取代基所取代； An aryl group represents a substituted or unsubstituted phenyl group, and the substitution is substituted with one or more substituents selected from the group consisting of halogen, dC 3 alkyl, QC 3 alkoxy, CF 3 , CN and NO 2 ;
Het代表含有 1 ~ 4个杂原子的芳香 5 ~ 6元杂环基， 所述的杂原子选自 N、 S和 0， 且该杂环基可以选择性地被选自卤素、 d-C3烷基、 d-C3烷氧基、 CF3、 CN和 N02中的一个或多个取代基取代。 在本发明优选的实施方案中： Het represents an aromatic 5- to 6-membered heterocyclic group having 1 to 4 hetero atoms, the hetero atom is selected from N, S and 0, and the heterocyclic group may be optionally selected from halogen, dC 3 alkyl. Substituting one or more substituents of dC 3 alkoxy, CF 3 , CN and NO 2 . In a preferred embodiment of the invention:
R1代表 Ci-C4烷基或 C3-C6环烷基； R 1 represents a Ci-C 4 alkyl group or a C 3 -C 6 cycloalkyl group;
R2代表 C2-C4烷基或 C3-C6环烷基； R 2 represents a C 2 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group;
R3代表 CrC3烷基或被 CrC3烷氧基取代的 CrC3烷基; R 3 represents C r C 3 alkyl or C r C 3 alkyl substituted by C r C 3 alkoxy;
R4和 R5各自独立地代表11、 芳基或 C¾Rn; R6和 R7各自独立地代表： H、 d-C6烷基、 C3-C6环烷基、 芳基或被取代基 取代的 d-C3烷基， 所述的取代基选自 OH、 d-C4烷氧基、 C3-C6环烷基、 NR8R9 和芳基； 取代或未被取代的脒基， 所述的取代基选自 d-C4烷基、 C3-C6环烷基、 NR8R9和芳基； 或者 R6和 R7可以与它们相连的氮原子共同构成 4 ~ 8元杂环基， 该杂环基为吗啉基、 硫吗啉基、 哌啶基、 吡咯基或哌嗪基； R 4 and R 5 each independently represent 11, aryl or C 3⁄4R n ; R 6 and R 7 each independently represent: H, dC 6 alkyl, C 3 -C 6 cycloalkyl, aryl or dC 3 alkyl substituted by a substituent selected from OH, dC 4 Alkoxy, C 3 -C 6 cycloalkyl, NR 8 R 9 and aryl; substituted or unsubstituted fluorenyl, said substituent being selected from dC 4 alkyl, C 3 -C 6 cycloalkyl , NR 8 R 9 and aryl; or R 6 and R 7 may form a 4-8 membered heterocyclic group together with the nitrogen atom to which they are attached, the heterocyclic group being morpholinyl, thiomorpholinyl, piperidinyl, Pyrrolyl or piperazinyl;
或者 R5、 R6与其相连的两个氮原子共同形成二氢咪唾基； Or R 5 and R 6 together with two nitrogen atoms connected thereto to form a dihydroamido group;
R8和 R9各自独立地代表 H、 Ci-C6烷基、芳基、 Het或被取代基取代的 Q-C3 烷基， 所述的取代基选自 d-C4烷氧基、 C3-C6环烷基、 芳基和 Het， 或者 R8和 R9可以与它们所连接的氮原子共同构成氮杂环丁烷基、 吡咯烷基、 哌啶基或吗 啉基； R 8 and R 9 each independently represent H, Ci-C 6 alkyl, aryl, Het or a substituted QC 3 alkyl group, the substituent being selected from dC 4 alkoxy, C 3 -C 6 cycloalkyl, aryl and Het, or R 8 and R 9 may together with the nitrogen atom to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl;
R11代表 d-C6烷基或苯基； R 11 represents dC 6 alkyl or phenyl;
Het代表吡啶基。 在本发明进一步优选的实施方案：  Het represents a pyridyl group. In a further preferred embodiment of the invention:
R1代表甲基； R 1 represents a methyl group;
R2代表乙基或正丙基； R 2 represents an ethyl or n-propyl group;
R3代表甲基、 乙基或正丙基； R 3 represents a methyl group, an ethyl group or a n-propyl group;
1 4为11、 乙基或苄基； 1 4 is 11, ethyl or benzyl;
1 5为11、 乙基或苯基； 1 5 is 11, ethyl or phenyl;
R6和 R7各自独立地代表： H、 甲基、 乙基、 苯基、 苄基、 3-吡啶甲基或者 被取代基取代的 C2-C3烷基， 所述的取代基选自羟基和 Ν,Ν-二甲胺基； 未取代 的或被苯基取代的脒基； 或者当 R6和 R7同时不为 Η时， R6和 R7可以与它们相 连的氮原子共同构成吗啉基、 哌啶基、 Ν-甲基哌嗪基或吡咯烷基； R 6 and R 7 each independently represent: H, methyl, ethyl, phenyl, benzyl, 3-pyridylmethyl or C 2 -C 3 alkyl substituted with a substituent selected from the group consisting of Hydroxyl and anthracene, fluorenyl-dimethylamino; unsubstituted or substituted phenyl group; or when R 6 and R 7 are not simultaneously argon, R 6 and R 7 may be combined with the nitrogen atom to which they are attached Morpholinyl, piperidinyl, hydrazine-methylpiperazinyl or pyrrolidinyl;
或者 R5、 R6与其相连的两个氮原子共同形成二氢咪唾基。 在本发明最优选的实施方案中， 所述的含有吡唑并嘧啶酮的苯基胍衍生物 选自如下化合物： Alternatively, R 5 and R 6 together with the two nitrogen atoms to which they are attached form a dihydroamido group. In a most preferred embodiment of the invention, the pyrazolopyrimidinone-containing phenylhydrazine derivative is selected from the group consisting of:
1) N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧基 苯基] -Ν'-甲基胍； 1) N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxybenzene Base] - Ν '-methyl hydrazine;
2) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -Ν'-甲基胍；2) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxy Benzene Base] - Ν '-methyl hydrazine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-乙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -Ν'-甲基胍；Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-ethylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxybenzene Base] - Ν '-methyl hydrazine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基] -Ν'-乙基 -Ν"-甲基胍；)-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl] -Ν'-ethyl-Ν"-methyl oxime;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基] -Ν'-苯基 -Ν"-甲基胍；)-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl] -Ν'-phenyl-indole"-methylhydrazine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧苯 基] -Ν'-苯基 -Ν"-甲基胍；)-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl] -Ν'-phenyl-indole"-methylhydrazine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基] -Ν, Ν'-二乙基 -Ν"-甲基胍；)-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl] -Ν, Ν'-diethyl-hydrazine"-methyl hydrazine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -Ν'-乙基胍；Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxybenzene Base] -Ν'-ethyl hydrazine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -Ν'-乙基胍；)-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxybenzene Base] -Ν'-ethyl hydrazine;
0) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -Ν', Ν"-二乙基胍；0) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxy Phenyl]-Ν', Ν"-diethyl hydrazine;
1) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -Ν'-苯基 -N"-乙基胍；1) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxy Phenyl]-Ν'-phenyl-N"-ethyl hydrazine;
2) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -Ν'-苯基 -N"-乙基胍；2) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxy Phenyl]-Ν'-phenyl-N"-ethyl hydrazine;
3) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -N, Ν', Ν"-三乙基胍；3) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxy Phenyl] -N, Ν', Ν"-triethyl hydrazine;
4) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -N, Ν', Ν"-三乙基胍；4) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxy Phenyl] -N, Ν', Ν"-triethyl hydrazine;
5) Ν-苄基 -Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4- 乙氧苯基] -Ν',Ν"-二乙基胍；5) Ν-benzyl-Ν-[3-(6,7-dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl) -4-ethoxyphenyl]-Ν', Ν"-diethyl hydrazine;
6) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基] -Ν', Ν'-二乙基胍；6) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl ] -Ν', Ν'-diethyl hydrazine;
7) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧苯 基] -Ν', Ν'-二乙基胍；7) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxybenzene Base] -Ν', Ν'-diethyl hydrazine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-乙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -Ν', Ν'-二乙基胍；Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-ethylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxybenzene Base] -Ν', Ν'-diethyl hydrazine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代- 丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -Ν', Ν', Ν"-三乙基胍；)-[3-(6,7-Dihydro-1-methyl-7-oxo-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxyphenyl] -Ν', Ν', Ν"-triethyl hydrazine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代- 丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -Ν'-苯基 -Ν", Ν"-二乙基胍；)-[3-(6,7-Dihydro-1-methyl-7-oxo-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl] -Ν'-phenyl-Ν", Ν"-diethyl hydrazine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代- 丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -Ν'-苯基 -Ν", Ν"-二乙基胍；)-[3-(6,7-Dihydro-1-methyl-7-oxo-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxyphenyl] -Ν'-phenyl-Ν", Ν"-diethyl hydrazine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代- 丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -Ν, Ν', Ν", Ν"-四乙基胍；)-[3-(6,7-Dihydro-1-methyl-7-oxo-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxyphenyl] -Ν, Ν', Ν", Ν"-tetraethyl hydrazine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代- 丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -吡咯烷基 -1-甲脒；)-[3-(6,7-Dihydro-1-methyl-7-oxo-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl] -pyrrolidino-1-carboxamidine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代- 丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -吡咯烷基 -1-甲脒；)-[3-(6,7-Dihydro-1-methyl-7-oxo-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxyphenyl] -pyrrolidino-1-carboxamidine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代- 乙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -吡咯烷基 -1-甲脒；Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-ethylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxyphenyl] -pyrrolidino-1-carboxamidine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代- 丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -Ν'-乙基-吡咯烷基 -1-甲脒；)-[3-(6,7-Dihydro-1-methyl-7-oxo-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl] -Ν'-ethyl-pyrrolidino-1-carboxamidine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代- 丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -Ν'-乙基-吡咯烷基 -1-甲脒；)-[3-(6,7-Dihydro-1-methyl-7-oxo-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxyphenyl] -Ν'-ethyl-pyrrolidino-1-carboxamidine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代- 丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基] -Ν'-苯基-吡咯烷基 -1-甲脒；)-[3-(6,7-Dihydro-1-methyl-7-oxo-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl]-indole '-Phenyl-pyrrolidinyl-1-carboxamidine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代- 丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -Ν'-苯基 -吡咯烷基- 1 -甲脒；)-[3-(6,7-Dihydro-1-methyl-7-oxo-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxyphenyl] -Ν'-phenyl-pyrrolidinyl-1 - formazan;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代- 丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -哌啶基 -1-甲脒；)-[3-(6,7-Dihydro-1-methyl-7-oxo-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl] -piperidinyl-1-carboxamidine;
) Ν-[3-(6,7-二氢 -1 -甲基 -7-氧代- 丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧苯 基]-哌 -1-甲脒；Ν-[3-(6,7-Dihydro-1 -methyl-7-oxo-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl]-piperidin -1-甲脒;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代- I-乙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -哌啶基 -1-甲脒；Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-I-ethylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxybenzene -piperidinyl-1-carboxamidine;
) N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基- 吡唑并 [4,3-d]嘧啶- -基) -4-乙氧苯 基] -Ν'-乙基-哌啶基 -1-甲脒；N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propyl-pyrazolo[4,3-d]pyrimidin-yl)-4-ethoxybenzene -]'-ethyl-piperidinyl-1-carboxamidine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基- 吡唑并 [4,3-d]嘧啶- -基) -4-丙氧苯 基] -Ν'-乙基-哌啶基 -1-甲脒；Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propyl-pyrazolo[4,3-d]pyrimidin-yl)-4-propoxybenzene -]'-ethyl-piperidinyl-1-carboxamidine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基- 吡唑并 [4,3-d]嘧啶- -基) -4-乙氧苯 基] -Ν'-苯基-哌啶基- 1 -甲脒；Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propyl-pyrazolo[4,3-d]pyrimidin-yl)-4-ethoxybenzene -]'-phenyl-piperidinyl- 1 -formamidine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基- 吡唑并 [4,3-d]嘧啶- -基) -4-丙氧苯 基] -Ν'-苯基-哌啶基 -1-甲脒；Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propyl-pyrazolo[4,3-d]pyrimidin-yl)-4-propoxybenzene -]'-phenyl-piperidinyl-1-carboxamidine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基- 吡唑并 [4,3-d]嘧啶- -基) -4-乙氧苯 基]—4—甲基哌嗪基 -1—甲脒；Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propyl-pyrazolo[4,3-d]pyrimidin-yl)-4-ethoxybenzene 4- 4-methylpiperazinyl-1 - formazan;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基- 吡唑并 [4,3- 嘧啶- -基) -4-丙氧苯 基]—4—甲基哌嗪基 -1—甲脒；)-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propyl-pyrazolo[4,3-pyrimidin-yl)-4-propoxyphenyl] 4-methylpiperazinyl-1 - formazan;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基- 吡唑并 [4,3-d]嘧啶- -基) -4-乙氧苯 基] -Ν'-乙基 -4-甲基哌嗪基- 1 -甲脒；Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propyl-pyrazolo[4,3-d]pyrimidin-yl)-4-ethoxybenzene -]'-ethyl-4-methylpiperazinyl- 1 -formamidine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基- 吡唑并 [4,3-d]嘧啶- -基) -4-乙氧苯 基] -Ν'-苯基 -4-甲基哌嗪基- 1 -甲脒；Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propyl-pyrazolo[4,3-d]pyrimidin-yl)-4-ethoxybenzene -]'-Phenyl-4-methylpiperazinyl- 1 -formamidine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基- 吡唑并 [4,3-d]嘧啶- -基) -4-丙氧苯 基] -Ν'-苯基 -4-甲基哌嗪基- 1 -甲脒；Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propyl-pyrazolo[4,3-d]pyrimidin-yl)-4-propoxybenzene -]'-Phenyl-4-methylpiperazinyl- 1 -formamidine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基- 吡唑并 [4,3- 嘧啶- -基) -4-乙氧苯 基]-吗啉基 -1-甲脒；)-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propyl-pyrazolo[4,3-pyrimidin-yl)-4-ethoxyphenyl] -morpholinyl-1-carboxamidine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基- 吡唑并 [4,3-d]嘧啶- -基) -4-丙氧苯 基]-吗啉基 -1-甲脒；Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propyl-pyrazolo[4,3-d]pyrimidin-yl)-4-propoxybenzene Methyl]-morpholinyl-1-carboxamidine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-乙基- 吡唑并 [4,3-d]嘧啶- -基) -4-丙氧苯 基] -吗啉基 -1—甲脒；Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-ethyl-pyrazolo[4,3-d]pyrimidin-yl)-4-propoxybenzene -morpholino-1 - formazan;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基- 吡唑并 [4,3-d]嘧啶- -基) -4-乙氧苯 基] -Ν'-苯基-吗啉基 - 1 -甲脒；Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propyl-pyrazolo[4,3-d]pyrimidin-yl)-4-ethoxybenzene -]'-phenyl-morpholinyl-1-methylhydrazine;
) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基- 吡唑并 [4,3-d]嘧啶- -基) -4-丙氧苯 基] -Ν'-苯基-吗啉基 -1-甲脒；Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propyl-pyrazolo[4,3-d]pyrimidin-yl)-4-propoxybenzene -]'-phenyl-morpholinyl-1-carboxamidine;
) ^[3-(6,7-二氢-1-甲基-7-氧代-3-丙基- 吡唑并 [4,3-d]嘧啶- -基) -4-乙氧苯 基] |-Ν'-苄基胍； ^[3-(6,7-Dihydro-1-methyl-7-oxo-3-propyl-pyrazolo[4,3-d]pyrimidin-yl)-4-ethoxybenzene Base] |-Ν'-benzyl hydrazine;
48)N-| [3-(6,7-二氢 -1-甲基 -7-氧代 -3- -丙基 吡唑并 [4,3- 嘧啶- -5-基〕 1-4-丙氧苯 基] |-Ν'-苄基胍；  48) N-| [3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl] 1-4- Propoxyphenyl] |-Ν'-benzyl hydrazine;
49)N-| [3-(6,7-二氢 -1-甲基 -7-氧代 -3- -丙基 吡唑并 [4,3-d]嘧啶- -5-基〕 1-4-乙氧苯 基] |-Ν'-乙基 -Ν"-苄基胍；  49) N-| [3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl] 1- 4-ethoxyphenyl] |-Ν'-ethyl-oxime"-benzyl hydrazine;
50)N-| [3-(6,7-二氢 -1-甲基 -7-氧代 -3- -丙基 吡唑并 [4,3-d]嘧啶- -5-基〕 1-4-乙氧苯 基] |-Ν'-苯基 -Ν"-苄基胍；  50) N-| [3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl] 1- 4-ethoxyphenyl] |-Ν'-phenyl-indole "-benzyl hydrazine;
51)N-| [3-(6,7-二氢 -1-甲基 -7-氧代 -3- -丙基 吡唑并 [4,3-d]嘧啶- -5-基〕 1-4-丙氧苯 基] |-Ν'-苯基 -Ν"-苄基胍；  51) N-| [3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl] 1- 4-propoxyphenyl] |-Ν'-phenyl-indole"-benzyl hydrazine;
52)N-| [3-(6,7-二氢 -1-甲基 -7-氧代 -3- -丙基 吡唑并 [4,3-d]嘧啶- -5-基〕 1-4-乙氧苯 基] Ι-Ν, Ν'-二乙基 -Ν"-苄基胍；  52) N-| [3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl] 1- 4-ethoxyphenyl] Ι-Ν, Ν'-diethyl-fluorene"-benzyl hydrazine;
53)N-| [3-(6,7-二氢 -1-甲基 -7-氧代 -3- -丙基 吡唑并 [4,3- 嘧啶- -5-基〕 1-4-丙氧苯 基] |-Ν'-乙基- Ν'-(2-羟乙基) -胍；  53) N-| [3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl] 1-4- Propoxyphenyl] |-Ν'-ethyl-Ν'-(2-hydroxyethyl)-indole;
54)N-| [3-(6,7-二氢 -1-甲基 -7-氧代 -3- -丙基 吡唑并 [4,3- 嘧啶- -5-基〕 1-4-乙氧苯 基] |- Ν'-甲基- Ν'-(Ν,Ν-二甲基 -2-胺乙基) -胍；  54) N-| [3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl] 1-4- Ethoxyphenyl] |- Ν'-methyl-Ν'-(Ν,Ν-dimethyl-2-aminoethyl)-oxime;
55)N-| [3-(6,7-二氢 -1-甲基 -7-氧代 -3- -丙基 吡唑并 [4,3- 嘧啶- -5-基〕 1-4-乙氧苯 基] |-Ν'-甲基 -Ν'-(2-羟乙基) -胍；  55) N-| [3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl] 1-4- Ethoxyphenyl] |-Ν'-methyl-Ν'-(2-hydroxyethyl)-indole;
56)N-| [3-(6,7-二氢 -1-甲基 -7-氧代 -3- -丙基 吡唑并 [4,3- 嘧啶- -5-基〕 1-4-丙氧苯 基] |-Ν'-甲基 -Ν'-(2-羟乙基) -胍；  56) N-| [3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl] 1-4- Propoxyphenyl] |-Ν'-methyl-Ν'-(2-hydroxyethyl)-indole;
57)N-| [3-(6,7-二氢 -1-甲基 -7-氧代 -3- -乙基 吡唑并 [4,3- 嘧啶- -5-基〕 1-4-丙氧苯 基] |-Ν'-甲基 -Ν'-(2-羟乙基) -胍；  57) N-| [3-(6,7-Dihydro-1-methyl-7-oxo-3-ethylpyrazolo[4,3-pyrimidin-5-yl] 1-4- Propoxyphenyl] |-Ν'-methyl-Ν'-(2-hydroxyethyl)-indole;
58)N-| [3-(6,7-二氢 -1-甲基 -7-氧代 -3- -丙基 吡唑并 [4,3- 嘧啶- -5-基〕 1-4-丙氧苯 基] |-Ν'-(3-吡啶甲基) -胍；  58) N-| [3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl] 1-4- Propoxyphenyl] |-Ν'-(3-pyridylmethyl)-indole;
59)N-| [3-(6,7-二氢 -1-甲基 -7-氧代 -3- -丙基 吡唑并 [4,3- 嘧啶- -5-基〕 1-4-乙氧苯 基] |-Ν'-(3-吡啶甲基) -胍；  59) N-| [3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl] 1-4- Ethoxyphenyl] |-Ν'-(3-pyridylmethyl)-indole;
60) l-[ 3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 - 1 吡唑并 [4,3 - 嘧啶- .5-基)-4-乙氧苯 基] |-双胍；  60) l-[ 3-(6,7-Dihydro-1-methyl-7-oxo-3-propyl- 1 pyrazolo[4,3-pyrimidine-.5-yl)-4-B Oxyphenyl]]-biguanide;
61) l-[ 3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 - 1 吡唑并 [4,3 - 嘧啶- .5-基) '-4-丙氧苯 基] |-双胍；  61) l-[ 3-(6,7-Dihydro-1-methyl-7-oxo-3-propyl- 1 pyrazolo[4,3-pyrimidine-.5-yl) '-4- Propoxyphenyl] |-biguanide;
62) 1-乙基 -1-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙 氧苯基]—双胍； 62) 1-Ethyl-1-[3-(6,7-dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4 - B Oxyphenyl]-biguanide;
63) 1-乙基 -1-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙 氧苯基]—双胍；  63) 1-Ethyl-1-[3-(6,7-dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4 -propoxyphenyl]-biguanide;
64) N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基] -N'-(3-羟丙基) -胍；  64) N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl ] -N'-(3-hydroxypropyl)-indole;
65) 1-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧苯 基] -N'-(3-羟丙基) -胍；  65) 1-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl ] -N'-(3-hydroxypropyl)-indole;
66) N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基] -Ν'-苯基 -N"-(3-羟丙基) -胍；  66) N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl ] -Ν'-phenyl-N"-(3-hydroxypropyl)-indole;
67) N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基] -Ν'-苯基胍； 67) N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl ] -Ν'-phenyl hydrazine;
68) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧苯 基] -Ν'-苯基胍；  68) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl ] -Ν'-phenyl hydrazine;
69) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基] -Ν', Ν'-二 (2-羟基乙基) -胍；  69) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl ] -Ν', Ν'-bis(2-hydroxyethyl)-oxime;
70) 2-{2-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧 苯基]胺基 -4,5-二氢 -咪唑 -1-基}-乙醇；  70) 2-{2-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-B Oxyphenyl]amino-4,5-dihydro-imidazol-1-yl}-ethanol;
71) 2-{2-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧 苯基]胺基 -4,5-二氢 -咪唑 -1-基}-乙醇；  71) 2-{2-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propane Oxyphenyl]amino-4,5-dihydro-imidazol-1-yl}-ethanol;
72) 2-{2-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-乙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧 苯基]胺基 -4,5-二氢 -咪唑 -1-基}-乙醇； 72) 2-{2-[3-(6,7-Dihydro-1-methyl-7-oxo-3-ethylpyrazolo[4,3-pyrimidin-5-yl)-4-propane Oxyphenyl]amino-4,5-dihydro-imidazol-1-yl}-ethanol;
73) 1-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基 ]—5-苯基双胍； 73) 1-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl ] 5-phenylbiguanide;
在上述定义中， 除非特别说明， 含三个或多个碳原子的烷基或烷氧基可以 是直链或支链的。 In the above definition, an alkyl group or alkoxy group having three or more carbon atoms may be straight-chain or branched unless otherwise specified.
通式 I的化合物可含有一个或多个手性中心， 因此可存在立体异构体， 即 对映异构体、 非对映异构体或其混合物。 若通式 I化合物中含有链烯基或亚烯 基， 则还可以存在顺式 (Ε)和反式 (Ζ)异构现象。 因此， 本发明化合物可以为单个 异构体或各异构体的混合物。 顺 /反异构体可以通过本领域技术人员公知的常规技术（例如， 色谱法和 分步结晶）来分离。 The compounds of formula I may contain one or more chiral centers and thus stereoisomers, ie, enantiomers, diastereomers or mixtures thereof, may be present. If the compound of formula I contains an alkenyl or alkenylene group, cis (Ε) and trans (Ζ) isomerism may also be present. Thus, the compounds of the invention may be individual isomers or mixtures of individual isomers. The cis/trans isomers can be separated by conventional techniques well known to those skilled in the art (e.g., chromatography and fractional crystallization).
用于制备 /分离单独的对映异构体的常规技术包括从合适的光学纯前体进 行手性合成， 或者釆用诸如手性高效液相色谱（HPLC )对外消旋化合物（或盐 或衍生物的外消旋化合物）进行拆分。  Conventional techniques for preparing/separating individual enantiomers include chiral synthesis from a suitable optically pure precursor, or racemic compound (or salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). The racemic compound of the compound is resolved.
另外可选地， 可以使外消旋体（或外消旋的前体） 与合适的光学活性化合 物（如醇）反应， 或者在结构式 I的化合物含有酸部分或碱部分的情况下， 与碱 或酸（如 1-苯基乙胺或酒石酸）反应。 得到的非对映异构混合物可以通过色谱 和 /或分步结晶分离， 通过本领域技术人员公知的方式将非对映异构体中的一 种或两种转化成相应的纯的对映异构体。  Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound such as an alcohol, or in the case where the compound of formula I contains an acid moiety or a base moiety, Or an acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture can be separated by chromatography and/or fractional crystallization, converting one or both of the diastereomers to the corresponding pure enantiomers by means well known to those skilled in the art. Structure.
通式 I的化合物可存在互变异构体的形式， 而本发明包括了其混合物和单 一的互变异构体。  The compounds of formula I may exist in the form of tautomers, and the invention includes mixtures thereof and single tautomers.
本发明包括通式 I的化合物的放射标记衍生物， 这些衍生物适用于生物学 研究。  The invention includes radiolabeled derivatives of the compounds of formula I which are suitable for use in biological research.
本发明提供的通式 I所示的含有吡唑并嘧啶酮的苯基胍衍生物含有碱性中 心， 因此通式 I所示的 AT生物可以与酸形成酸加成盐， 例如， 该 AT生物与无机 酸如盐酸、 氢溴酸、 石充酸或碑酸， 或与有机羧酸或有机磺酸形成的无毒酸加成 盐。 通式 I的衍生物还可与碱反应形成药用金属盐， 特别是无毒碱金属盐 （例 如钠盐和钾盐；)。 优选的药学上可接受的盐是甲磺酸盐和盐酸盐。  The pyridylpyrimidinone-containing phenylhydrazine derivative represented by the formula I provided by the present invention contains a basic center, and thus the AT organism represented by the formula I can form an acid addition salt with an acid, for example, the AT organism. A non-toxic acid addition salt with a mineral acid such as hydrochloric acid, hydrobromic acid, sulphuric acid or lithic acid, or with an organic carboxylic acid or an organic sulfonic acid. Derivatives of formula I can also be reacted with a base to form pharmaceutically acceptable metal salts, especially non-toxic alkali metal salts (e.g., sodium and potassium salts;). Preferred pharmaceutically acceptable salts are the methanesulfonate and the hydrochloride.
本发明包括通式 I的化合物的任何前药形式。  The invention includes any prodrug form of the compound of formula I.
本发明还包括通式 I的化合物的可药用溶剂化物 （例如水合物）。  The invention also includes pharmaceutically acceptable solvates (e.g., hydrates) of the compounds of formula I.
本发明还包括通式 I的化合物和各种盐的多种晶型。  The invention also includes a plurality of crystalline forms of the compound of formula I and various salts.
本发明提供了制备通式 I所示化合物的方法。  The present invention provides a process for the preparation of compounds of formula I.
本发明还包括制备过程中的新的中间体及其制备方法， 例如下述的通式 II、 The invention also includes novel intermediates in the preparation process and preparation methods thereof, such as the following formula II,
IV、 VI、 VII的化合物及其制备方法。 Compounds of IV, VI, VII and methods for their preparation.
根据 R6、 R7取代基的不同， 通式 I化合物可以分为三类不同的制备方法： ( i ) 通式 I化合物 （R6、 R7都不为 H， 也不为取代或未取代脒基）可从通 式 II所示吡唑并嘧啶酮的苯基^脲衍生物（其中 R R2、 R3、 R4、 R5如前述定 义和优选）和通式 III化合物（其中 R6、 R7如前述定义）发生亲核取代反应制 备。
Figure imgf000013_0001
Depending on the substituents of R 6 and R 7 , the compounds of formula I can be divided into three different preparation methods: (i) compounds of formula I (R 6 and R 7 are not H, nor substituted or unsubstituted a phenylurea derivative of the pyrazolopyrimidinone of the formula II (wherein RR 2 , R 3 , R 4 , R 5 are as defined and preferred above) and a compound of the formula III (wherein R 6 , R 7 as defined above) is prepared by nucleophilic substitution reaction.
Figure imgf000013_0001
通式 II化合物， 通常在 50-150。C下， 在适当的溶剂中 (优选甲醇、 乙醇、 乙腈、 乙二醇单甲醚、 Ν,Ν-二甲基甲酰胺、 Ν-甲基吡咯烷 -2-酮等极性溶剂）， 或 不使用溶剂， 加入或不加有机碱（优选三乙胺）， 反应时间为 0.1小时 -1天， 与 1-10倍量的通式 III化合物发生亲核取代反应得到通式 I化合物  The compound of formula II, usually at 50-150. In C, in a suitable solvent (preferably methanol, ethanol, acetonitrile, ethylene glycol monomethyl ether, hydrazine, hydrazine-dimethylformamide, fluorene-methylpyrrolidin-2-one, etc.), or Without the use of a solvent, with or without an organic base (preferably triethylamine), the reaction time is from 0.1 hour to 1 day, and a nucleophilic substitution reaction with a compound of the formula III is carried out in an amount of from 1 to 10 times to obtain a compound of the formula I.
( ii ) 通式 I化合物 （1 6为11， R7为未取代脒基）可从通式 IV所示吡啶并 嘧啶酮衍生物（其中 R R2、 R3、 R4如前述定义和优选）和通式 V化合物通过 亲核加成反应制备。 (ii) a compound of the formula I ( 16 is 11 and R 7 is an unsubstituted fluorenyl group) which may be derived from a pyridopyrimidinone derivative of the formula IV (wherein RR 2 , R 3 , R 4 are as defined and preferred above) The compound of the formula V is prepared by a nucleophilic addition reaction.
Figure imgf000013_0002
Figure imgf000013_0002
通式 IV化合物， 通常在 0-50。C下， 在适当的溶剂中 (优选乙醇、 丁醇、 乙 腈、 乙二醇单甲醚、 Ν,Ν-二甲基甲酰胺、 Ν-甲基吡咯烷 -2-酮、 二氧六环、 二甲 亚砜或水)，加入等摩尔量无机或有机酸（优选盐酸）成盐后，再在 50-200。C下， 反应时间为 1小时 -2天， 与等摩尔量的通式 V化合物通过亲核加成反应得到通 式 I化合物。  A compound of formula IV, usually at 0-50. In C, in a suitable solvent (preferably ethanol, butanol, acetonitrile, ethylene glycol monomethyl ether, hydrazine, hydrazine-dimethylformamide, hydrazine-methylpyrrolidin-2-one, dioxane, Dimethyl sulfoxide or water), after adding an equimolar amount of an inorganic or organic acid (preferably hydrochloric acid) to form a salt, is further in the range of 50-200. The reaction time is from 1 hour to 2 days at C, and a compound of the formula I is obtained by a nucleophilic addition reaction with an equimolar amount of the compound of the formula V.
(iii) 通式 I化合物 （1 6为11， R7为取代脒基）可从通式 IV化合物 （其中 R R2、 R3、 R4如前述定义和优选）与 NaN(CN)2得到通式 VI， 再与通式 III通 过亲核加成反应制备。
Figure imgf000014_0001
第一步， 通式 IV化合物， 通常在 0-50。C下， 在适当的溶剂中 (优选乙醇、 丁醇、 乙腈、 乙二醇单甲醚、 Ν,Ν-二甲基甲酰胺、 Ν-甲基吡咯烷 -2-酮、 二氧六 环、 二甲亚砜或水）， 加入等摩尔量无机或有机酸（优选盐酸） 成盐后， 再在 50-200。C下， 反应时间为 1小时 -2天， 与等摩尔量的二氰胺钠亲核加成得到通 式 VI化合物； (iii) a compound of the formula I ( 16 is 11 and R 7 is a substituted fluorenyl group) which is obtainable from a compound of the formula IV wherein RR 2 , R 3 , R 4 are as defined and preferred above, and NaN(CN) 2 Formula VI is further prepared by a nucleophilic addition reaction with Formula III.
Figure imgf000014_0001
The first step is a compound of formula IV, usually at 0-50. In C, in a suitable solvent (preferably ethanol, butanol, acetonitrile, ethylene glycol monomethyl ether, hydrazine, hydrazine-dimethylformamide, hydrazine-methylpyrrolidin-2-one, dioxane, Dimethyl sulfoxide or water), after adding an equimolar amount of an inorganic or organic acid (preferably hydrochloric acid) to form a salt, and then at 50-200. C, the reaction time is 1 hour - 2 days, nucleophilic addition with an equimolar amount of sodium dicyanamide to obtain a compound of the formula VI;
第二步， 通式 VI化合物， 通常在 50-200。C下， 在适当的溶剂中 (优选乙醇、 丁醇、 乙腈、 乙二醇单甲醚、 Ν,Ν-二甲基甲酰胺、 Ν-甲基吡咯烷 -2-酮、 二氧六 环、 二甲亚砜或水)， 反应时间为 1小时 -2天， 与等摩尔量通式 III化合物的无 机或有机酸（优选盐酸）盐， 亲核加成得到通式 I化合物。  The second step, a compound of formula VI, is usually in the range of 50-200. In C, in a suitable solvent (preferably ethanol, butanol, acetonitrile, ethylene glycol monomethyl ether, hydrazine, hydrazine-dimethylformamide, hydrazine-methylpyrrolidin-2-one, dioxane, The reaction time is from 1 hour to 2 days, and is nucleophilicly added to an equimolar amount of an inorganic or organic acid (preferably hydrochloric acid) salt of the compound of the formula III to give a compound of the formula I.
运用成熟的有机化学合成方法， 通式 II化合物可从通式 VII化合物 （其中 Using a well-established organic chemical synthesis method, a compound of formula II can be obtained from a compound of formula VII
R R2、 R3、 R4、 US如前述定义）制备： Preparation of RR 2 , R 3 , R 4 , US as defined above):
Figure imgf000014_0002
Figure imgf000014_0002
νπ π  Νπ π
通式 VII化合物，通常在 0-80。C下，在适当的溶剂中 (优选二氯甲烷、氯仿、 甲醇、 乙醇、 乙腈、 乙二醇单甲醚、 Ν,Ν-二甲基甲酰胺、 二氧六环）， 反应 0.1-12 小时， 与碘甲烷亲核加成得到通式 II化合物。  The compound of formula VII, usually at 0-80. C, in a suitable solvent (preferably dichloromethane, chloroform, methanol, ethanol, acetonitrile, ethylene glycol monomethyl ether, hydrazine, hydrazine-dimethylformamide, dioxane), reaction 0.1-12 hours , nucleophilic addition with methyl iodide to give a compound of formula II.
运用成熟的有机化学合成方法， 通式 VII化合物可从通式 IV化合物 （其中 R R2、 R3 、 R4如前述定义）制备。
Figure imgf000015_0001
Using a well-established organic chemical synthesis, a compound of formula VII can be prepared from a compound of formula IV wherein RR 2 , R 3 , R 4 are as defined above.
Figure imgf000015_0001
通式 IV化合物，通常在 0-120。C下，在适当的溶剂中 (优选水、 甲醇、 乙醇、 乙腈、 二氯甲烷、 氯仿、 乙二醇单甲醚、 Ν,Ν-二甲基甲酰胺、 二氧六环、 二甲 亚砜)， 当 R5为 Η时在酸性条件下（优选醋酸和^酸）， 与通式 VIII化合物反应 0.1-12小时， 亲核加成得到通式 VII化合物； A compound of formula IV, usually at 0-120. C, in a suitable solvent (preferably water, methanol, ethanol, acetonitrile, dichloromethane, chloroform, ethylene glycol monomethyl ether, hydrazine, hydrazine-dimethylformamide, dioxane, dimethyl sulfoxide) , when R 5 is hydrazine, under acidic conditions (preferably acetic acid and acid), react with a compound of the formula VIII for 0.1 to 12 hours, and nucleophilic addition to obtain a compound of the formula VII;
运用成熟的有机化学合成方法， 通式 IV化合物可从通式 IX化合物 （其中 R R2、 R3 、 R4如前述定义）制备。 Using a well-established organic chemical synthesis, a compound of formula IV can be prepared from a compound of formula IX wherein RR 2 , R 3 , R 4 are as defined above.
Figure imgf000015_0002
Figure imgf000015_0002
通式 III、 V、 VIII、 X、 XI化合物从国药试剂公司购买得到， IX根据文献 制备 (方法参见 Bioorg. Med. Chem.; 9; 7; 2001; 1895-1900.)。  Compounds of the general formula III, V, VIII, X, and XI are commercially available from the National Pharmaceutical Co., Ltd., and IX is prepared according to the literature (for details, see Bioorg. Med. Chem.; 9; 7; 2001; 1895-1900.).
同时， 本发明也提供了含有所述通式 I化合物的可药用的组合物。  At the same time, the invention also provides pharmaceutically acceptable compositions containing the compounds of formula I.
该组合物由一种或多种通式 I化合物（或其药学上可接受的盐，或它们的可 药用溶剂化物） 与至少一种可药用辅料组成。 药用辅料的选择因给药途径和作 用特点而异， 通常是填充剂、 稀释剂、 粘合剂、 润湿剂、 崩解剂、 润滑剂、 乳 化剂、 助悬剂等。  The composition consists of one or more compounds of formula I (or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof) and at least one pharmaceutically acceptable adjuvant. The choice of pharmaceutical excipients will vary depending on the route of administration and the nature of the action, and are usually fillers, diluents, binders, wetting agents, disintegrating agents, lubricants, emulsifiers, suspending agents and the like.
本发明的组合物可以口服、 注射（静脉、 肌肉、 皮下和冠状动脉内）、 舌下、 经颊、 经直肠、 经尿道、 经阴道、 经鼻、 吸入或局部途径给药。 优选的途径是 口服。  The compositions of the invention may be administered orally, by injection (intravenous, intramuscular, subcutaneous and intracoronary), sublingual, buccal, rectal, transurethral, vaginal, nasal, inhalation or topical routes. The preferred route is oral.
通式 I化合物在上述组合物中的所占的比例为总重量的 0.1%〜99.9%， 优选 1%〜99%。  The proportion of the compound of the formula I in the above composition is from 0.1% to 99.9%, preferably from 1% to 99%, based on the total mass.
本发明还提供了通式 I化合物的可药用的组合物的制备方法。 通常将通式 I 化合物与可药用辅料相混合， 经常规的制备方法制成适于一定途径给药的形式 (剂型）。 剂型包括片剂、 胶嚢剂、 颗粒剂、 丸剂、 溶液剂、 混悬剂、 乳剂、 软 膏、 膜剂、 霜剂、 气雾剂、 注射剂、 栓剂等。 优选片剂和胶嚢剂。 The invention also provides a process for the preparation of a pharmaceutically acceptable composition of a compound of formula I. The compound of the formula I is usually mixed with a pharmaceutically acceptable adjuvant and prepared in a form suitable for administration by a conventional preparation method. (Formulation). Dosage forms include tablets, capsules, granules, pills, solutions, suspensions, emulsions, ointments, films, creams, aerosols, injections, suppositories, and the like. Preferred are tablets and capsules.
片剂和胶嚢剂的组方可含有一种或多种通式 I化合物，以及一种或多种常用 辅料， 例如淀粉、 蔗糖、 乳糖、 葡萄糖、 微晶纤维素、 甘露糖等填充剂； 羧甲 基纤维素、 明胶、 海藻酸盐和聚乙烯吡咯烷酮等粘合剂； 甘油等润湿剂； 琼脂、 乙基纤维素、 羧甲基淀粉钠、 碳酸钙等崩解剂； 硬脂酸镁、 滑石粉、 聚乙二醇 等润滑剂。  The composition of the tablet and the capsule may contain one or more compounds of the formula I, and one or more common excipients, such as starch, sucrose, lactose, glucose, microcrystalline cellulose, mannose and the like; Binders such as carboxymethyl cellulose, gelatin, alginate and polyvinylpyrrolidone; wetting agents such as glycerin; disintegrants such as agar, ethyl cellulose, sodium carboxymethyl starch, calcium carbonate; magnesium stearate , talc, polyethylene glycol and other lubricants.
本发明化合物的使用剂量一般为每天 l〜500mg， 优选 10〜100mg， 分单次或 多次使用。 但在必要时， 可适当偏离上述剂量。 专业人员可根据具体情况和专 业知识， 确定最佳剂量。 这些情况包括疾病的严重程度、 患者的个体差异、 制 剂的特性和给药途径等。  The compound of the present invention is usually administered in a dose of from 1 to 500 mg, preferably from 10 to 100 mg per day, in single or multiple doses. However, if necessary, the above doses may be appropriately deviated. Professionals can determine the optimal dose based on the specific situation and expertise. These conditions include the severity of the disease, individual differences in the patient, characteristics of the formulation, and route of administration.
此外，本发明还提供了通式 I化合物或其药学上可接受的盐，或它们的可药 用溶剂化物， 或其可药用的组合物作为人用药物的用途。  Furthermore, the present invention provides the use of a compound of the formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable composition thereof, as a human medicament.
本发明还提供了通式 I化合物或其药学上可接受的盐，或它们的可药用溶剂 化物， 在制备治疗或预防需要使用 CGMP PDE5抑制剂的疾病的药物中的用途。  The invention further provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment or prevention of a condition in which a CGMP PDE5 inhibitor is required.
本发明也提供了通式 I化合物或其药学上可接受的盐，或它们的可药用溶剂 化物， 或其可药用的组合物， 在制备用来治疗或预防男性勃起功能障碍、 良性 前列腺增生、 女性性功能障碍、 早产、 痛经、 膀胱出口梗阻、 失禁、 不稳定的 和变异的 Prinzmetal心绞痛、 高血压、 肺动脉高压、 充血性心衰、 肾衰竭、 动脉 粥样硬化、 中风、 周围血管疾病、 雷诺氏症、 炎症性疾病、 支气管炎、 慢性哮 喘、 过敏性哮喘、 过敏性鼻炎、 青光眼、 以及特征为肠蠕动障碍的疾病 （例如 应激性肠综合症） 的人用药物中的用途。  The invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable composition thereof, for use in the treatment or prevention of male erectile dysfunction, benign prostate Hyperplasia, female sexual dysfunction, premature labor, dysmenorrhea, bladder outlet obstruction, incontinence, unstable and variant Prinzmetal angina, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, stroke, peripheral vascular disease Uses in human medicines for Raynaud's disease, inflammatory diseases, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, and diseases characterized by intestinal motility disorders such as stress bowel syndrome.
通式 I所示化合物具有比西地那非更强的 PDE5抑制活性，且相对于分布在 视网膜的 PDE6有更高的选择性。因此本发明提供的化合物可望在临床上表现出 更佳的安全性和有效性， 临床应用前景广阔。 具体实施方式  The compound of formula I has a stronger PDE5 inhibitory activity than sildenafil and is more selective than PDE6 distributed in the retina. Therefore, the compounds provided by the present invention are expected to exhibit better safety and efficacy in clinical practice, and have broad clinical application prospects. Detailed ways
制备例和实施例 Preparation examples and examples
下列实施例进一步解释了本发明的化合物及其中间体的合成方法， 但并不 限制本发明的范围。 ^ NMR在 Mercury-400或 Mercury-300核磁共振波语仪 ( Varian公司）上完成。 常规缩写如下： s， 单峰； d， 双峰； t, 三重峰； q， 四 重峰； m， 多重峰； br， 宽峰。 室温指 20-25。C 制备例 1 The following examples further illustrate the synthesis of the compounds of the invention and their intermediates, but do not limit the scope of the invention. ^ NMR on Mercury-400 or Mercury-300 NMR Wave Instrument Completed on (Varian). The general abbreviations are as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. Room temperature refers to 20-25. C Preparation Example 1
5-(5-乙胺基 -2-乙氧基苯基) -1-甲基 -3-丙基 吡唑并 [4,3- 嘧啶 -7(6/ )-酮  5-(5-ethylamino-2-ethoxyphenyl)-1-methyl-3-propylpyrazolo[4,3-pyrimidin-7(6/)-one
Figure imgf000017_0001
Figure imgf000017_0001
将 5-(5-氨基 -2-乙氧基苯基) -1-甲基 -3-丙基 吡唑并 [4,3- 嘧啶 -7(6/ )-酮（制备 方法参见 Bioorg. Med. Chem.; 9; 7; 2001 ; 1895-1900. ) ( 2.4g, 7.3mmol )溶于 50ml 80 %的乙腈水溶液，加入 0.14g 5 % Pd/C和 5g甲酸铵，氮气保护，室温搅拌 20h。 滤去钯炭，蒸干溶剂，用 50mlC¾Cl2溶解，分别用水（50ml )和饱和盐水（50ml ) 洗涤，无水 Na2S04干燥， 浓缩至干，得到白色固体粗品。 以硅胶柱层析纯化（洗 脱剂： 10%石油醚 -乙酸乙酯），得标题化合物 2.4g，产率 92.1%。 !H NMR (CDC13) δ: 8.31 (IH, d), 7.35 (IH, dd), 7.13 (IH, d), 4.27 (3H, s), 4.21 (2H, q), 4.01 (2H, q), 2.92 (2H, t), 1.85 (2H, m), 1.36 (3H, t), 1.18 (3H, t), 1.02 (3H, t)。 制备例 2 5-(5-Amino-2-ethoxyphenyl)-1-methyl-3-propylpyrazolo[4,3-pyrimidin-7(6/)-one (see Bioorg. Med for preparation) Chem.; 9; 7; 2001; 1895-1900. ) (2.4g, 7.3mmol) dissolved in 50ml of 80% aqueous acetonitrile, added with 0.14g of 5% Pd/C and 5g of ammonium formate, protected with nitrogen, stirred at room temperature for 20h . Palladium-carbon was filtered off, the solvent was evaporated to dryness, dissolved with 50mlC¾Cl 2, washed with water (50ml) and saturated brine (50ml), dried over anhydrous Na 2 S0 4, and concentrated to dryness to give a crude product as a white solid. Purification by silica gel column chromatography (EtOAc:EtOAc:EtOAc ! H NMR (CDC1 3) δ : 8.31 (IH, d), 7.35 (IH, dd), 7.13 (IH, d), 4.27 (3H, s), 4.21 (2H, q), 4.01 (2H, q) , 2.92 (2H, t), 1.85 (2H, m), 1.36 (3H, t), 1.18 (3H, t), 1.02 (3H, t). Preparation Example 2
5-(5-乙胺基 -2-丙氧基苯基) -1-甲基 -3-丙基 吡唑并 [4,3- 嘧啶 -7(6/ )-酮  5-(5-ethylamino-2-propoxyphenyl)-1-methyl-3-propylpyrazolo[4,3-pyrimidin-7(6/)-one
Figure imgf000017_0002
Figure imgf000017_0002
按照制备例 1相同的方法， 以 5-(5-氨基 -2-丙氧基苯基) -1-甲基 -3-丙基 吡唑并 [4,3- 嘧啶 -7(6/ )-酮 （制备方法参见 Bioorg. Med. Chem.; 9; 7; 2001 ; 1895-1900. )为原料。产物粗品经硅胶柱层析纯化，产率 90.3 %。 ^ NMR (CDC13) δ: 8.31 (IH, d), 7.35 (IH, dd), 7.13 (IH, d), 4.27 (3H, s), 4.21 (2H, t), 4.01 (2H, q), 2.92 (2H, t), 2.03 (2H, m), 1.85 (2H, m), 1.36 (3H, t), 1.18 (3H, t), 1.02 (3H, t)。 制备例 3 In the same manner as in Preparation Example 1, 5-(5-amino-2-propoxyphenyl)-1-methyl-3-propylpyrazolo[4,3-pyrimidin-7(6/)- Ketones (see Bioorg. Med. Chem.; 9; 7; 2001; 1895-1900.) for the preparation. The crude product was purified by silica gel column chromatography (yield: ^ NMR (CDC1 3 ) δ: 8.31 (IH, d), 7.35 (IH, dd), 7.13 (IH, d), 4.27 (3H, s), 4.21 (2H, t), 4.01 (2H, q), 2.92 (2H, t), 2.03 (2H, m), 1.85 (2H, m), 1.36 (3H, t), 1.18 (3H, t), 1.02 (3H, t). Preparation Example 3
5-(5-苄胺基 -2-丙氧基苯基) -1-甲基 -3-丙基 吡唑并 [4,3- 嘧啶 -7(6/ )-酮  5-(5-benzylamino-2-propoxyphenyl)-1-methyl-3-propylpyrazolo[4,3-pyrimidin-7(6/)-one
Figure imgf000018_0001
Figure imgf000018_0001
将 5-(5-氨基 -2-乙氧基苯基) -1-甲基 -3-丙基 吡唑并 [4,3- 嘧啶 -7(6Η)-酮 ( l.Og, 3.0匪 ol )溶于 100ml甲醇， 緩慢滴加苯甲醛 ( 0.33g, 3.1mmol )， TLC显 示反应结束后， 用冰浴冷却， 分批加入 NaBH4 ( O. l lg, 3.1 mmol )。 反应结束后， 蒸干乙醇， 二氯甲烷（30ml )溶解， 用水和饱和食盐水洗涤， 无水 Na2S04干燥， 浓缩， 用甲醇 /二氯甲烷重结晶， 得到标题化合物 1.05g， 产率： 82.3%。 ifi NMR (CDC13) δ: 7.55 (IH, d), 7.45-7.36 (6H, m), 7.20 (IH, d), 4.99 (2H, s), 4.16 (3H, s), 4.11 (2H, q), 2.75 (2H, t), 1.72 (2H, m), 1.31 (3H, t), 0.93 (3H, t)。 制备例 4 5-(5-Amino-2-ethoxyphenyl)-1-methyl-3-propylpyrazolo[4,3-pyrimidin-7(6Η)-one (1.Og, 3.0匪ol Dissolved in 100 ml of methanol, and slowly added benzaldehyde (0.33 g, 3.1 mmol). After TLC showed that the reaction was completed, it was cooled with ice bath, and NaBH 4 (O.l lg, 3.1 mmol) was added in portions. After completion of the reaction, ethanol was evaporated to dryness, dichloromethane (30ml) was dissolved, washed with water and saturated brine, dried over anhydrous Na 2 S0 4, concentrated, methanol / dichloromethane and recrystallized to give 1.05 g of the title compound, yield : 82.3%. Ifi NMR (CDC1 3 ) δ: 7.55 (IH, d), 7.45-7.36 (6H, m), 7.20 (IH, d), 4.99 (2H, s), 4.16 (3H, s), 4.11 (2H, q ), 2.75 (2H, t), 1.72 (2H, m), 1.31 (3H, t), 0.93 (3H, t). Preparation Example 4
N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧基苯 基] -硫脲  N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl] -thiourea
Figure imgf000018_0002
Figure imgf000018_0002
5-(5-氨基 -2-乙氧基苯基) -1-甲基 -3-丙基 吡唑并 [4,3- 嘧啶 -7(6/ )-酮 ( 40g, 0.12mol )和 NH4SCN ( 80g, 1.05mol )溶解在 500ml醋酸和 500ml水的混 合液中， 加热回流 5h， 将反应液倒入 1 升冰水中， 滤出固体， 用冰水洗涤， DMF/H20重结晶得到纯品 31.4g，产率 66.5%。 NMR (DMSO-i/6) δ: 7.55 (IH, d), 7.35 (IH, dd), 7.24 (IH, d), 4.17 (3H, s), 4.10 (2H, q), 2.78 (2H, t), 1.73 (2H, m), 1.17 (3H, t), 1.02 (3H, t)。 制备例 5 N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-ί ]嘧啶 -5-基) -4-丙氧基苯 基] -硫脲 5-(5-Amino-2-ethoxyphenyl)-1-methyl-3-propylpyrazolo[4,3-pyrimidin-7(6/)-one (40g, 0.12mol) and NH 4 SCN (80g, 1.05mol) was dissolved in a mixture of 500ml of acetic acid and 500ml of water, heated to reflux for 5h, the reaction solution was poured into 1 liter of ice water, the solid was filtered off, washed with ice water, DMF/H 2 0 recrystallized Pure product 31.4 g was obtained with a yield of 66.5%. NMR (DMSO-i/ 6 ) δ: 7.55 (IH, d), 7.35 (IH, dd), 7.24 (IH, d), 4.17 (3H, s), 4.10 (2H, q), 2.78 (2H, t ), 1.73 (2H, m), 1.17 (3H, t), 1.02 (3H, t). Preparation Example 5 N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-ί]pyrimidin-5-yl)-4-propoxybenzene Thiourea
Figure imgf000019_0001
Figure imgf000019_0001
按照制备例 4相同的方法， 以 5-(5-氨基 -2-丙氧基苯基) -1-甲基 -3-丙基 吡唑并 [4,3- 嘧啶 -7(6 )-酮和 NH4SCN反应， 重结晶溶剂为 DMF/¾0。 产率 61.8%。 ifi NMR (DMSO-i/e) δ: 7.53 (IH, d), 7.33 (IH, dd), 7.23 (IH, d), 4.17 (3H, s) 4.09 (2H, t), 2.78 (2H, t), 1.73 (4H, m), 1.17 (3H, t), 1.02 (3H, t)。 制备例 6 In the same manner as in Preparation Example 4, 5-(5-amino-2-propoxyphenyl)-1-methyl-3-propylpyrazolo[4,3-pyrimidin-7(6)-one Reacts with NH 4 SCN and the recrystallization solvent is DMF/3⁄40. The yield was 61.8%. Ifi NMR (DMSO-i/e) δ: 7.53 (IH, d), 7.33 (IH, dd), 7.23 (IH, d), 4.17 (3H, s) 4.09 (2H, t), 2.78 (2H, t ), 1.73 (4H, m), 1.17 (3H, t), 1.02 (3H, t). Preparation Example 6
N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-乙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧基苯 基] -硫脲  N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-ethylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl] -thiourea
Figure imgf000019_0002
Figure imgf000019_0002
按照制备例 4相同的方法， 以 5-(5-氨基 -2-丙氧基苯基) -1-甲基 -3-乙基 吡唑并 [4,3- 嘧啶 -7(6/ )-酮 （制备方法参见 Bioorg. Med. Chem.; 9; 7; 2001 ; 1895-1900. )和 NH4SCN反应， 重结晶溶剂为 DMF/¾0。产率 67.7%。 NMR (DMSO-i/e) δ: 7.53 (IH, d), 7.33 (IH, dd), 7.23 (IH, d), 4.17 (3H, s), 4.06 (2H, t), 2.78 (2H, q), 1.74 (4H, m), 1.17 (3H, t), 1.00 (3H, t)。 制备例 7 In the same manner as in Preparation Example 4, 5-(5-amino-2-propoxyphenyl)-1-methyl-3-ethylpyrazolo[4,3-pyrimidin-7(6/)- Ketone (for preparation, see Bioorg. Med. Chem.; 9; 7; 2001; 1895-1900.) and NH 4 SCN, the recrystallization solvent is DMF/3⁄40. The yield was 67.7%. NMR (DMSO-i/e) δ: 7.53 (IH, d), 7.33 (IH, dd), 7.23 (IH, d), 4.17 (3H, s), 4.06 (2H, t), 2.78 (2H, q ), 1.74 (4H, m), 1.17 (3H, t), 1.00 (3H, t). Preparation Example 7
N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧基苯 基] -Ν'-乙基硫脲
Figure imgf000020_0001
N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl] -Ν'-ethylthiourea
Figure imgf000020_0001
5-(5-氨基 -2-乙氧基苯基) -1-甲基 -3-丙基 吡唑并 [4,3-ί ]嘧啶 -7(6/ )-酮（ 6g, 18.3mmol )和异石克氰酸乙酯（ 2.5g, 28.7mmol )在无水乙醇中回流 3h， 滤出生产 的白色固体，甲醇洗涤固体，干燥得到纯品 6.8g，产率
Figure imgf000020_0002
NMR (DMSO-i/6) δ: 7.53 (1Η, d), 7.33 (1H, dd), 7.15 (1H, d), 4.17 (3H, s), 4.10 (2H, q), 3.19 (2H, q), 2.77 (2H, t), 1.74 (2H, m), 1.34 (3H, t), 1.11 (3H, t), 0.93 (3H, t)。 制备例 8 5-(5-Amino-2-ethoxyphenyl)-1-methyl-3-propylpyrazolo[4,3-ί]pyrimidine-7(6/)-one (6g, 18.3mmol) Ethyl isocyanoic acid ethyl ester (2.5 g, 28.7 mmol) was refluxed in absolute ethanol for 3 h, and the white solid produced was filtered out, and the solid was washed with methanol and dried to give 6.8 g of pure product.
Figure imgf000020_0002
NMR (DMSO-i/ 6 ) δ: 7.53 (1Η, d), 7.33 (1H, dd), 7.15 (1H, d), 4.17 (3H, s), 4.10 (2H, q), 3.19 (2H, q ), 2.77 (2H, t), 1.74 (2H, m), 1.34 (3H, t), 1.11 (3H, t), 0.93 (3H, t). Preparation Example 8
N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧基苯 基] -Ν'-乙基硫脲  N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl] -Ν'-ethylthiourea
Figure imgf000020_0003
Figure imgf000020_0003
按照制备例 7相同的方法， 以 5-(5-氨基 -2-丙氧基苯基) -1-甲基 -3-丙基 吡唑并 [4,3- 嘧啶 -7(6 )-酮和异硫氰酸乙酯反应， 产率 89.6%。 NMR (DMSO-i/e) δ: 7.53 (1Η, d), 7.33 (1H, dd), 7.15 (1H, d), 4.17 (3H, s), 4.10 (2H, t), 3.19 (2H, q), 2.77 (2H, t), 1.75 (4H, m), 1.34 (3H, t), 1.12 (3H, t), 0.93 (3H, t)。 制备例 9  In the same manner as in Preparation Example 7, 5-(5-amino-2-propoxyphenyl)-1-methyl-3-propylpyrazolo[4,3-pyrimidin-7(6)-one The reaction with ethyl isothiocyanate gave a yield of 89.6%. NMR (DMSO-i/e) δ: 7.53 (1Η, d), 7.33 (1H, dd), 7.15 (1H, d), 4.17 (3H, s), 4.10 (2H, t), 3.19 (2H, q ), 2.77 (2H, t), 1.75 (4H, m), 1.34 (3H, t), 1.12 (3H, t), 0.93 (3H, t). Preparation Example 9
N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧基苯 基] -Ν'-苯基硫脲
Figure imgf000021_0001
N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl] -Ν'-phenylthiourea
Figure imgf000021_0001
按照制备例 7相同的方法， 以 5-(5-氨基 -2-乙氧基苯基) -1-甲基 -3-丙基 吡唑并 [4,3- 嘧啶 -7(6 )-酮和异硫氰酸苯酯反应， 产率 86.4%。 NMR (DMSO-i/e) δ: 7.63 (IH, d), 7.43 (3H, m), 7.36-7.19 (4H, m), 4.16 (3H, s), 4.10 (2H, q), 2.78 (2H, t), 1.74 (2H, m), 1.35 (3H, t), 0.93 (3H, t)。 制备例 10  In the same manner as in Preparation Example 7, 5-(5-amino-2-ethoxyphenyl)-1-methyl-3-propylpyrazolo[4,3-pyrimidin-7(6)-one The reaction with phenyl isothiocyanate gave a yield of 86.4%. NMR (DMSO-i/e) δ: 7.63 (IH, d), 7.43 (3H, m), 7.36-7.19 (4H, m), 4.16 (3H, s), 4.10 (2H, q), 2.78 (2H , t), 1.74 (2H, m), 1.35 (3H, t), 0.93 (3H, t). Preparation Example 10
N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧基苯 基]界苯基硫脲  N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl] Phenylthiourea
Figure imgf000021_0002
Figure imgf000021_0002
按照制备例 7相同的方法， 以 5-(5-氨基 -2-丙氧基苯基) -1-甲基 -3-丙基 吡唑并 [4,3- 嘧啶 -7(6 )-酮和异硫氰酸苯酯反应， 产率 88.3%。 NMR (DMSO-i/e) δ: 7.63 (IH, d), 7.43 (3H, m), 7.36-7.19 (4H, m), 4.16 (3H, s), 4.10 (2H, t), 2.78 (2H, t), 1.74 (4H, m), 1.35 (3H, t), 0.93 (3H, t)。 制备例 11  In the same manner as in Preparation Example 7, 5-(5-amino-2-propoxyphenyl)-1-methyl-3-propylpyrazolo[4,3-pyrimidin-7(6)-one The reaction with phenyl isothiocyanate gave a yield of 88.3%. NMR (DMSO-i/e) δ: 7.63 (IH, d), 7.43 (3H, m), 7.36-7.19 (4H, m), 4.16 (3H, s), 4.10 (2H, t), 2.78 (2H , t), 1.74 (4H, m), 1.35 (3H, t), 0.93 (3H, t). Preparation 11
Ν,Ν' -二乙基 -N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5- 基)—4-乙氧基苯基] -硫脲  Ν,Ν'-Diethyl-N-[3-(6,7-dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl) —4-ethoxyphenyl]-thiourea
Figure imgf000021_0003
按照制备例 7相同的方法，以制备例 1化合物为原料。产率 92.0%。 ^ NMR (DMSO- δ: 7.75 (IH, d), 7.61 (IH, dd), 7.25 (IH, d), 4.17 (3H, s), 4.15 (2H, q), 4.01 (2H, q), 3.19 (2H, t), 2.79 (2H, t), 1.76 (2H, m), 1.32 (3H, t), 1.19 (3H, t), 1.11 (3H, t), 0.95 (3H, t)。 制备例 12
Figure imgf000021_0003
The compound of Preparation Example 1 was used as a starting material in the same manner as in Preparation 7. The yield was 92.0%. ^ NMR (DMSO- δ: 7.75 (IH, d), 7.61 (IH, dd), 7.25 (IH, d), 4.17 (3H, s), 4.15 (2H, q), 4.01 (2H, q), 3.19 (2H, t), 2.79 (2H, t), 1.76 (2H, m), 1.32 (3H, t), 1.19 (3H, t), 1.11 (3H, t), 0.95 (3H, t). 12
Ν,Ν'-二乙基 -N- [3-(6,7-二氢 - 1 -甲基 -7-氧代 -3 -丙基 - 吡唑并 [4,3- 嘧啶 -5- 基) -4-丙氧基苯基] -硫脲  Ν,Ν'-Diethyl-N-[3-(6,7-dihydro-1 1-methyl-7-oxo-3-propyl-pyrazolo[4,3-pyrimidin-5-yl) -4-propoxyphenyl]-thiourea
Figure imgf000022_0001
Figure imgf000022_0001
按照制备例 7相同的方法，以制备例 2化合物为原料。产率 91.5%。 ifi NMR (DMSO- δ: 7.75 (IH, d), 7.61 (IH, dd), 7.25 (IH, d), 4.17 (3H, s), 4.15 (2H, t), 4.01 (2H, q), 3.19 (2H, t), 2.79 (2H, t), 1.76 (4H, m), 1.32 (3H, t), 1.19 (3H, t), 1.11 (3H, t), 0.95 (3H, t)。 制备例 13  The compound of Preparation Example 2 was used as a starting material in the same manner as in Preparation 7. The yield was 91.5%. Ifi NMR (DMSO- δ: 7.75 (IH, d), 7.61 (IH, dd), 7.25 (IH, d), 4.17 (3H, s), 4.15 (2H, t), 4.01 (2H, q), 3.19 (2H, t), 2.79 (2H, t), 1.76 (4H, m), 1.32 (3H, t), 1.19 (3H, t), 1.11 (3H, t), 0.95 (3H, t). 13
N-苄基 -N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧 基苯基] -Ν'-乙基硫脲  N-benzyl-N-[3-(6,7-dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propane Oxyphenyl]-Ν'-ethylthiourea
Figure imgf000022_0002
Figure imgf000022_0002
按照制备例 7相同的方法， 以制备例 3化合物为原料。 产率 93%。 ifi NMR (DMSO-i/e) δ: 7.71 (IH, d), 7.51 (IH, dd), 7.44-7.20 (5H, m), 7.13 (IH, d), 5.32 (2H, s), 4.15 (3H, s), 4.08 (2H, q), 3.19 (2H, q), 2.76 (2H, t), 1.74 (2H, m), 1.35 (3H, t), 1.10 (3H, t), 0.93 (3H, t)。 制备例 14 N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-ί ]嘧啶 -5-基) -4-乙氧基苯 基] -S-甲基异硫脲氢碘酸盐 The compound of Preparation Example 3 was used as a starting material in the same manner as in Preparation 7. The yield was 93%. Ifi NMR (DMSO-i/e) δ: 7.71 (IH, d), 7.51 (IH, dd), 7.44-7.20 (5H, m), 7.13 (IH, d), 5.32 (2H, s), 4.15 ( (3H, s) , t). Preparation Example 14 N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-ί]pyrimidin-5-yl)-4-ethoxybenzene -S-methylisothiourea hydroiodide
Figure imgf000023_0001
Figure imgf000023_0001
将制备例 4化合物 10g悬浮于 500ml甲醇中， 加入 5.5g碘甲烷， 回流至溶 液澄清， 继续反应 lh。 停止加热， 蒸干甲醇， 得到淡黄色油状物， 冷却固化， 用乙酸乙酯-乙醇重结晶， 得到淡黄色固体 14.3g， 产率 92.3%。 NMR (DMSO-i/e) δ: 7.61 (1Η, d), 7.47 (1H, dd), 7.28 (1H, d), 4.17 (3H, s), 4.14 (2H, q), 2.78 (2H, t), 2.49 (3H, s), 1.74 (2H, m), 1.35 (3H, t), 0.93 (3H, t)。 制备例 15  10 g of the compound of Preparation Example 4 was suspended in 500 ml of methanol, 5.5 g of methyl iodide was added, and the mixture was refluxed until the solution was clarified, and the reaction was continued for 1 h. The heating was stopped, and the title compound was evaporated. m. NMR (DMSO-i/e) δ: 7.61 (1Η, d), 7.47 (1H, dd), 7.28 (1H, d), 4.17 (3H, s), 4.14 (2H, q), 2.78 (2H, t ), 2.49 (3H, s), 1.74 (2H, m), 1.35 (3H, t), 0.93 (3H, t). Preparation 15
N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧基苯 基] -S-甲基异硫脲氢碘酸盐  N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl] -S-methylisothiourea hydroiodide
Figure imgf000023_0002
Figure imgf000023_0002
按照制备例 14相同的方法， 以制备例 5化合物为原料。 重结晶溶剂是乙酸 乙酯-乙醇。 产率 93%。。 !H NMR (DMSO-d) δ: 7.59 (1Η, d), 7.46 (1H, dd), 7.28 (1H, d), 4.16 (3H, s), 4.10 (2H, t), 2.78 (2H, t), 2.48 (3H, s), 1.74 (4H, m), 1.34 (3H, t), 0.96 (3H, t)。 制备例 16 The compound of Preparation Example 5 was used as a starting material in the same manner as in Preparation 14. The recrystallization solvent was ethyl acetate-ethanol. The yield was 93%. . ! H NMR (DMSO-d) δ: 7.59 (1Η, d), 7.46 (1H, dd), 7.28 (1H, d), 4.16 (3H, s), 4.10 (2H, t), 2.78 (2H, t ), 2.48 (3H, s), 1.74 (4H, m), 1.34 (3H, t), 0.96 (3H, t). Preparation Example 16
N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-乙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧基苯 基] -S-甲基异硫脲氢碘酸盐
Figure imgf000024_0001
N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-ethylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl] -S-methylisothiourea hydroiodide
Figure imgf000024_0001
按照制备例 14相同的方法， 以制备例 6化合物为原料。 重结晶溶剂是乙 酸乙酯 -乙醇。 产率 92.5%。 !H NMR (DMSO-i/6) δ: 7.59 (1Η, d), 7.47 (1H, dd), 7.28 (1H, d), 4.17 (3H, s), 4.14 (2H, t), 2.78 (2H, t), 2.45 (3H, s), 1.74 (4H, m), 1.35 (3H, t), 0.93 (3H, t)。 制备例 17 The compound of Preparation Example 6 was used as a starting material in the same manner as in Preparation 14. The recrystallization solvent was ethyl acetate-ethanol. The yield was 92.5%. ! H NMR (DMSO-i / 6) δ: 7.59 (1Η, d), 7.47 (1H, dd), 7.28 (1H, d), 4.17 (3H, s), 4.14 (2H, t), 2.78 (2H , t), 2.45 (3H, s), 1.74 (4H, m), 1.35 (3H, t), 0.93 (3H, t). Preparation Example 17
N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧基苯 基] - Ν'-乙基 -S-甲基异硫脲氢碘酸盐  N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl] - Ν'-ethyl-S-methylisothiourea hydroiodide
Figure imgf000024_0002
Figure imgf000024_0002
按照制备例 14相同的方法， 以制备例 7化合物为原料。 重结晶溶剂是乙酸 乙酯-乙醇。产率 94%。 ifi NMR (DMSO-i/e) δ: 7.59 (1Η, d), 7.47 (1H, dd), 7.28 (1H, d), 4.17 (3H, s), 4.10 (2H, q), 3.19 (2H, q), 2.78 (2H, t), 2.43 (3H, s), 1.74 (2H, m), 1.35 (3H, t), 1.12 (3H, t), 0.93 (3H, t)。 制备例 18  The compound of Preparation Example 7 was used as a starting material in the same manner as in Preparation 14. The recrystallization solvent was ethyl acetate-ethanol. The yield was 94%. Ifi NMR (DMSO-i/e) δ: 7.59 (1Η, d), 7.47 (1H, dd), 7.28 (1H, d), 4.17 (3H, s), 4.10 (2H, q), 3.19 (2H, q), 2.78 (2H, t), 2.43 (3H, s), 1.74 (2H, m), 1.35 (3H, t), 1.12 (3H, t), 0.93 (3H, t). Preparation 18
N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧基苯 基] - Ν'-乙基 -S-甲基异硫脲氢碘酸盐  N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl] - Ν'-ethyl-S-methylisothiourea hydroiodide
Figure imgf000024_0003
按照制备例 14相同的方法， 以制备例 8化合物为原料。 重结晶溶剂是乙酸 乙酯-乙醇。 产率 93.6%。 ^ NMR (DMSO- ） δ: 7.62 (1Η, d), 7.49 (1H, dd), 7.26 (1H, d), 4.15 (3H, s), 4.07 (2H, t), 3.53 (2H, q), 2.76 (2H, t), 2.56 (3H, s), 1.74 (4H, m), 1.27 (3H, t), 0.95 (3H, t), 0.92 (3H, t)。 制备例 19
Figure imgf000024_0003
The compound of Preparation Example 8 was used as a starting material in the same manner as in Preparation 14. The recrystallization solvent was ethyl acetate-ethanol. The yield was 93.6%. ^ NMR (DMSO- ) δ: 7.62 (1Η, d), 7.49 (1H, dd), 7.26 (1H, d), 4.15 (3H, s), 4.07 (2H, t), 3.53 (2H, q), 2.76 (2H, t), 2.56 (3H, s), 1.74 (4H, m), 1.27 (3H, t), 0.95 (3H, t), 0.92 (3H, t). Preparation Example 19
N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧基苯 基]— Ν'-苯基 -S-甲基异硫脲氢碘酸盐  N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl] — Ν'-phenyl-S-methylisothiourea hydroiodide
Figure imgf000025_0001
Figure imgf000025_0001
按照制备例 14相同的方法， 以制备例 9化合物为原料。 重结晶溶剂是乙酸 乙酯-乙醇。 产率 93.6%。 !H NMR (DMSO-i/6) δ: 7.72 (1Η, d), 7.52 (1H, dd), 7.44-7.20 (5H, m), 7.14 (1H, d), 4.15 (3H, s), 4.10 (2H, q), 2.78 (2H, t), 2.45 (3H, s), 1.75 (2H, m), 1.30 (3H, t), 0.95 (3H, t)。 制备例 20 The compound of Preparation Example 9 was used as a starting material in the same manner as in Preparation 14. The recrystallization solvent was ethyl acetate-ethanol. The yield was 93.6%. ! H NMR (DMSO-i / 6) δ: 7.72 (1Η, d), 7.52 (1H, dd), 7.44-7.20 (5H, m), 7.14 (1H, d), 4.15 (3H, s), 4.10 (2H, q), 2.78 (2H, t), 2.45 (3H, s), 1.75 (2H, m), 1.30 (3H, t), 0.95 (3H, t). Preparation Example 20
N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧基苯 基]— Ν'-苯基 -S-甲基异硫脲氢碘酸盐  N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl] — Ν'-phenyl-S-methylisothiourea hydroiodide
Figure imgf000025_0002
Figure imgf000025_0002
按照制备例 14相同的方法， 以制备例 10化合物为原料。 重结晶溶剂是乙 酸乙酯 -乙醇。 产率 92.5%。 !H NMR (DMSO-i/6) δ: 7.72 (1Η, d), 7.52 (1H, dd), 7.44-7.20 (5H, m), 7.14 (1H, d), 4.15 (3H, s), 4.10 (2H, t), 2.78 (2H, t), 2.43 (3H, s), 1.75 (4H, m), 1.30 (3H, t), 0.95 (3H, t)。 制备例 21 The compound of Preparation Example 10 was used as a starting material in the same manner as in Preparation 14. The recrystallization solvent was ethyl acetate-ethanol. The yield was 92.5%. ! H NMR (DMSO-i / 6) δ: 7.72 (1Η, d), 7.52 (1H, dd), 7.44-7.20 (5H, m), 7.14 (1H, d), 4.15 (3H, s), 4.10 (2H, t), 2.78 (2H, t), 2.43 (3H, s), 1.75 (4H, m), 1.30 (3H, t), 0.95 (3H, t). Preparation Example 21
Ν,Ν'-二乙基 -Ν- [3-(6,7-二氢 - 1 -甲基 -7-氧代 -3 -丙基 - 吡唑并 [4,3- 嘧啶 -5- 基)—4—乙氧基苯基] -S-甲基异硫脲氢碘酸盐  Ν,Ν'-Diethyl-indole-[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-pyrazolo[4,3-pyrimidin-5-yl) )—4-ethoxyphenyl]-S-methylisothiourea hydroiodide
Figure imgf000026_0001
Figure imgf000026_0001
按照制备例 14相同的方法， 以制备例 11化合物为原料。 重结晶溶剂是乙 酸乙酯 -乙醇。 产率 94.1%。 ^ NMR (DMSO- δ: 7.68 (IH, d), 7.58 (IH, dd), 7.28 (IH, d), 4.17 (2H, q), 4.15 (3H, s), 3.99 (2H, q), 3.48 (2H, q), 2.76 (2H, t), 2.41 (3H, s), 1.73 (2H, m), 1.32 (3H, t), 1.21 (3H, t), 1.15 (3H, t), 0.92 (3H, t)。 制备例 22  The compound of Preparation Example 11 was used as a starting material in the same manner as in Preparation 14. The recrystallization solvent was ethyl acetate-ethanol. The yield was 94.1%. ^ NMR (DMSO- δ: 7.68 (IH, d), 7.58 (IH, dd), 7.28 (IH, d), 4.17 (2H, q), 4.15 (3H, s), 3.99 (2H, q), 3.48 (2H, q), 2.76 (2H, t), 2.41 (3H, s), 1.73 (2H, m), 1.32 (3H, t), 1.21 (3H, t), 1.15 (3H, t), 0.92 ( 3H, t). Preparation Example 22
Ν,Ν'-二乙基 -N- [3-(6,7-二氢 - 1 -甲基 -7-氧代 -3 -丙基 - 吡唑并 [4,3- 嘧啶 -5- 基)—4—丙氧基苯基] -S-甲基异硫脲氢碘酸盐  Ν,Ν'-Diethyl-N-[3-(6,7-dihydro-1 1-methyl-7-oxo-3-propyl-pyrazolo[4,3-pyrimidin-5-yl) )-4-propoxyphenyl]-S-methylisothiourea hydroiodide
Figure imgf000026_0002
Figure imgf000026_0002
按照制备例 14相同的方法， 以制备例 12化合物为原料。 重结晶溶剂是乙 酸乙酯 -乙醇。产率 94%。 ^ NMR (DMS0- ) δ: 7.69 (IH, d), 7.58 (IH, dd), 7.28 (IH, d), 4.17 (3H, s), 4.06 (2H, t), 4.00 (2H, q), 3.48 (2H, q), 2.75 (2H, t), 2.42 (3H, s), 1.73 (4H, m), 1.21 (3H, t), 1.15 (3H, t), 0.94 (3H, t), 0.92 (3H, t)。 制备例 23  The compound of Preparation Example 12 was used as a starting material in the same manner as in Preparation 14. The recrystallization solvent was ethyl acetate-ethanol. The yield was 94%. ^ NMR (DMS0-) δ: 7.69 (IH, d), 7.58 (IH, dd), 7.28 (IH, d), 4.17 (3H, s), 4.06 (2H, t), 4.00 (2H, q), 3.48 (2H, q), 2.75 (2H, t), 2.42 (3H, s), 1.73 (4H, m), 1.21 (3H, t), 1.15 (3H, t), 0.94 (3H, t), 0.92 (3H, t). Preparation Example 23
N-苄基 -N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧 基苯基]— Ν'-乙基 -S-甲基异硫脲氢碘酸盐
Figure imgf000027_0001
N-benzyl-N-[3-(6,7-dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propane Oxyphenyl]-Ν'-ethyl-S-methylisothiourea hydroiodide
Figure imgf000027_0001
按照制备例 14相同的方法， 以制备例 13化合物为原料。 重结晶溶剂是乙 酸乙酯 -乙醇。产率 SH
Figure imgf000027_0002
δ: 7.51 (1Η, d), 7.47-7.28 (6H, m), 7.24 (1H, d), 4.51 (2H, s), 4.17 (3H, s), 4.10 (2H, q), 3.30 (2H, q), 2.78 (2H, t), 2.45 (3H, s), 1.75 (2H, m), 1.36 (3H, t), 1.13 (3H, t), 0.93 (3H, t)。 制备例 24 The compound of Preparation Example 13 was used as a starting material in the same manner as in Preparation 14. The recrystallization solvent was ethyl acetate-ethanol. Yield SH
Figure imgf000027_0002
δ: 7.51 (1Η, d), 7.47-7.28 (6H, m), 7.24 (1H, d), 4.51 (2H, s), 4.17 (3H, s), 4.10 (2H, q), 3.30 (2H, q), 2.78 (2H, t), 2.45 (3H, s), 1.75 (2H, m), 1.36 (3H, t), 1.13 (3H, t), 0.93 (3H, t). Preparation 24
N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧基苯 基] -Ν'-氰基胍  N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl] -Ν'-cyanoquinone
Figure imgf000027_0003
Figure imgf000027_0003
5-(5-胺基 -2-乙氧基苯基) -1-甲基 -3-丙基 吡唑并 [4,3- 嘧啶 -7(6Η)-酮（ lg, 3mmol )溶于乙二醇单甲醚，加入浓盐酸 0.25ml，常温搅拌 20分钟，加入 NaN(CN)2 ( 0.27g, 3mmol )在回流温度下， 搅拌 8小时。 蒸干溶剂， 用水（ 20ml )和乙醇 ( 20ml ) 分别洗涤固体。 烘干得到标题化合物 0.84g。 产率 69.7%。 NMR (DMSO- δ: 7.78 (1Η, d), 7.30 (1H, dd), 7.15 (1H, d), 4.25 (2H, q), 4.23 (3H, s), 2.84 (2H, t), 1.80 (2H, m), 1.22 (3H, t), 0.99 (3H, t)。 实施例 1 5-(5-Amino-2-ethoxyphenyl)-1-methyl-3-propylpyrazolo[4,3-pyrimidin-7(6Η)-one ( lg, 3 mmol ) dissolved in B The diol monomethyl ether was added with 0.25 ml of concentrated hydrochloric acid, stirred at room temperature for 20 minutes, and NaN(CN) 2 (0.27 g, 3 mmol) was added and stirred at reflux temperature for 8 hours. The solvent was evaporated to dryness, and the solid was washed with water (20 ml) and ethanol (20 ml). Drying gave 0.84 g of the title compound. The yield was 69.7%. NMR (DMSO- δ: 7.78 (1Η, d), 7.30 (1H, dd), 7.15 (1H, d), 4.25 (2H, q), 4.23 (3H, s), 2.84 (2H, t), 1.80 ( 2H, m), 1.22 (3H, t), 0.99 (3H, t). Example 1
N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧基苯 基] -Ν'-甲基胍
Figure imgf000028_0001
N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl] - Ν '-Methyl hydrazine
Figure imgf000028_0001
将制备例 14化合物（ 500mg， 0.95mmol )加入到 20ml曱胺醇溶液中， 在回 流温度下搅拌 10小时， 减压浓缩冷却后的反应液。 得到的膏状固体用 4ml乙酸 乙酯洗涤后， 溶于 CH2C12 ( 100ml )， 用 10 %NaOH ( 20ml ), 饱和食盐水（40ml ) 洗涤，无水 Na2S04干燥，浓缩。用乙酸乙酯-甲醇重结晶，得到白色固体（ 3 OOmg )， 产率 83%。 ^ NMR^DMSO-^) δ: 7.78 (1H， d), 7.51 (1H, dd), 7.13 (1H， d)， 4.16 (3K s)， 4.10 (2H， q)， 2.89 (3H, s), 2.78 (2H, t), 1.74 (2H, m)， 1.34 (3H, t), 0.93 (3H, t)。 实施例 2-7 The compound of Preparation Example 14 (500 mg, 0.95 mmol) was added to a solution of 20 ml of a solution of a solution of the amine. The mixture was stirred at reflux temperature for 10 hours, and the cooled reaction mixture was concentrated under reduced pressure. After the resulting cream solid was washed with 4ml of ethyl acetate, dissolved in CH 2 C1 2 (100ml), with 10% NaOH (20ml), dried with saturated brine (40ml) dried over anhydrous Na 2 S0 4, and concentrated. Recrystallization from ethyl acetate-methanol gave a white solid (3. ^ NMR^DMSO-^) δ: 7.78 (1H, d), 7.51 (1H, dd), 7.13 (1H, d), 4.16 (3K s), 4.10 (2H, q), 2.89 (3H, s), 2.78 (2H, t), 1.74 (2H, m), 1.34 (3H, t), 0.93 (3H, t). Example 2-7
按照实施例 1的相同方法， 从制备例化合物 15、 16、 17、 19、 20、 21与甲 胺醇溶液反应， 分别制备实施例 2~7的化合物。  The compounds of Examples 2 to 7 were separately prepared by reacting the preparation compounds 15, 16, 17, 19, 20, 21 with a solution of the methylamine in the same manner as in Example 1.
Figure imgf000028_0002
Figure imgf000029_0001
实施例 8
Figure imgf000028_0002
Figure imgf000029_0001
Example 8
N-[3-(6，7-二氢 -1-曱基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -Ν'-乙基胍 HN丫 NH N-[3-(6,7-Dihydro-1-indenyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl ] -Ν'-ethyl hydrazine HN丫NH
NHC2H5 NHC 2 H 5
将制备例 14化合物（ 150mg，0.28mmol )加入到 15ml乙胺醇溶液中， 在回 流温度下搅拌 10小时， 减压浓缩冷却后的反应液。 得到的膏状固体用 4ml乙酸 乙酯洗涤后， 溶于 C¾C12 ( 100ml )， 用 10 % NaOH ( 20ml ), 饱和食盐水（40ml ) 洗涤，无水 Na2S04干燥，浓缩。用 c H 乙酸乙酯-曱醇重结晶，得到白色固体（97mg )， 产率 86%。 ^ NMRCDMSO-^) δ: 7.53 (1H， d)， 7.35 (1H， dd), 7.22 (1H， d), 4.17 (3H, s)， 4.14 (2H， q), 3.20 (2H, q), 2.77 (2H, t)， 1.74 (2H, m)， 1.34 (3H, t)， 1.14 (3H, t), 0.93 (3H, t)。 实施例 9-15 The compound of Preparation Example 14 (150 mg, 0.28 mmol) was added to 15 ml of ethylamine alcohol solution, and the mixture was stirred at reflux temperature for 10 hours, and the cooled reaction mixture was concentrated under reduced pressure. After the resulting cream solid was washed with 4ml of ethyl acetate, dissolved C¾C1 2 (100ml), with 10% NaOH (20ml), dried with saturated brine (40ml) dried over anhydrous Na 2 S0 4, and concentrated. The crystals were recrystallized from EtOAc EtOAc (EtOAc) ^ NMRCDMSO-^) δ: 7.53 (1H, d), 7.35 (1H, dd), 7.22 (1H, d), 4.17 (3H, s), 4.14 (2H, q), 3.20 (2H, q), 2.77 (2H, t), 1.74 (2H, m), 1.34 (3H, t), 1.14 (3H, t), 0.93 (3H, t). Example 9-15
按照实施例 8 的相同方法， 从制备例化合物 15、 17、 19、 20、 21、 22、 23 与乙胺醇溶液反应， 分别制备实施例 9~15的化合物。  The compounds of Examples 9 to 15 were separately prepared by reacting the Preparation Compounds 15, 17, 19, 20, 21, 22, 23 with an ethanolamine solution in the same manner as in Example 8.
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000030_0001
Figure imgf000031_0001
实施例 16  Example 16
N-[3-(6,7-二氢 -1-曱基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基〗 -Ν'， Ν'-二乙基胍  N-[3-(6,7-Dihydro-1-indenyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl] Ν', Ν'-diethyl hydrazine
Figure imgf000031_0002
将制备例 14化合物（ 500mg， 0.95mmol )加入到 20ml乙醇溶液中， 加入二 乙胺（0.2g，2.7mmol), 在回流温度下搅拌 10小时， 减压浓缩冷却后的反应液。 得到的膏状固体用 4ml乙酸乙酯洗涤后， 溶于 C¾C12 (100ml), 用 10%NaOH (20ml), 饱和食盐水（40ml) 洗涤， 无水 Na2S04干燥， 浓缩。 用乙酸乙酯-甲 醇重结晶，得到白色固体（290mg)， 产率 72%。 ^NMR (DMSO- ) δ: 7.15 (1H, d), 7.05 (1H， dd), 6.90 (1H, d)， 4.15 (3H, s), 4.08 (2H， q), 3.34 (4H, q), 2.78 (2H， t), 1.74 (2H, m), 1.32 (3H, t), 1.10 (6H, t)， 0.93 (3H, t)。 实施例 17-22
Figure imgf000031_0002
The compound of Preparation Example 14 (500 mg, 0.95 mmol) was added to 20 ml of ethanol, and diethylamine (0.2 g, 2.7 mmol) was added thereto, and the mixture was stirred at reflux temperature for 10 hours, and the cooled reaction mixture was concentrated under reduced pressure. After the resulting cream solid was washed with 4ml of ethyl acetate, dissolved C¾C1 2 (100ml), with 10% NaOH (20ml), dried with saturated brine (40ml) dried over anhydrous Na 2 S0 4, and concentrated. Recrystallization from ethyl acetate-methanol gave a white solid (290 mg). ^NMR (DMSO- ) δ: 7.15 (1H, d), 7.05 (1H, dd), 6.90 (1H, d), 4.15 (3H, s), 4.08 (2H, q), 3.34 (4H, q), 2.78 (2H, t), 1.74 (2H, m), 1.32 (3H, t), 1.10 (6H, t), 0.93 (3H, t). Example 17-22
按照实施例 16的相同方法， 从制备例化合物 15、 16、 18、 19、 20、 22与乙 二胺反应， 分别制备实施例 17〜22的化合物。  The compounds of Examples 17 to 22 were separately prepared by reacting the Preparation Compounds 15, 16, 18, 19, 20, 22 with ethylenediamine in the same manner as in Example 16.
Figure imgf000032_0001
Figure imgf000033_0001
实施例 23
Figure imgf000032_0001
Figure imgf000033_0001
Example 23
N-[3-(6，7-二氢 -1-曱基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯基] - 吡咯烷基 -1-甲脒  N-[3-(6,7-Dihydro-1-indenyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl ] - Pyrrolidin-1-carboxamidine
Figure imgf000033_0002
Figure imgf000033_0002
将制备例 14化合物（ 400mg， 0.76mmol )加入到 20ml乙醇溶液中， 加入吡 咯烷（ 0.2g, 2.8mmol ), 在回流温度下搅拌 10小时， 减压浓缩冷却后的反应液。 得到的膏状固体用 4ml乙酸乙酯洗涤后， 溶于 CH2C12 ( 100ml ), 用 10 %NaOH ( 20ml ), 饱和食盐水（40ml ) 洗涤， 无水 Na2S04干燥， 浓缩。 用乙酸乙酯-曱 醇重结晶，得到白色固体（212mg ), 产率 66%。 ^ NMR (DMS0-4) δ: 7.50 (1H: d), 7.29 (1H， dd), 7.21 (1H, d)， 4.16 (3H, s)， 4.14 (2H, q)， 3.45 (4H， br), 2.78 (2H, t); 1.95 (4H, br), 1.74 (2H， m)， 1.35 (3H, t)， 0.93 (3H, t)。 实施例 24-29 The compound of Preparation Example 14 (400 mg, 0.76 mmol) was added to 20 ml of ethanol solution, and pyrrolidine (0.2 g, 2.8 mmol) was added thereto, and the mixture was stirred at reflux temperature for 10 hours, and the cooled reaction mixture was concentrated under reduced pressure. After the resulting cream solid was washed with 4ml of ethyl acetate, dissolved in CH 2 C1 2 (100ml), with 10% NaOH (20ml), dried with saturated brine (40ml) dried over anhydrous Na 2 S0 4, and concentrated. Ethyl acetate-曱 The alcohol was recrystallized to give a white solid (212 mg). ^ NMR (DMS0-4) δ: 7.50 (1H : d), 7.29 (1H, dd), 7.21 (1H, d), 4.16 (3H, s), 4.14 (2H, q), 3.45 (4H, br) , 2.78 (2H, t) ; 1.95 (4H, br), 1.74 (2H, m), 1.35 (3H, t), 0.93 (3H, t). Example 24-29
按照实施例 23的相同方法， 从制备例化合物 15、 16、 17、 18、 19、 20与吡 咯烷反应， 分别制备实施例 24~29的化合物。  The compounds of Examples 24 to 29 were separately prepared by reacting the Preparation Compounds 15, 16, 17, 18, 19, 20 with pyrrolidine in the same manner as in Example 23.
Figure imgf000034_0001
Figure imgf000035_0001
实施例 30
Figure imgf000034_0001
Figure imgf000035_0001
Example 30
N-[3-(6,7-二氢 -1-曱基 -7-氧代 -3-丙基 吡唑并 [4，3-d]嘧啶 -5-基) -4-乙氧苯基] - 哌啶基 -1-曱脒  N-[3-(6,7-Dihydro-1-indenyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl ] - piperidinyl-1-anthracene
Figure imgf000035_0002
Figure imgf000035_0002
将制备例 14化合物（ 350mg, 0.66mmol )加入到 20ml乙醇溶液中， 加入哌 啶（0.25g， 2.9mmol )， 在回流温度下搅拌 10小时， 减压浓缩冷却后的反应液。 得到的膏状固体用 4ml乙酸乙酯洗涤后， 溶于 CH2C12 ( 100ml ), 分别用 1M盐 酸、 10 %NaOH ( 20ml )和饱和食盐水（40ml )洗涤， 有机相用无水 Na2S04干 燥， 减压浓缩。 用乙酸乙酯-甲醇重结晶， 得到白色固体（187mg ), 产率 75%。 The compound of Preparation Example 14 (350 mg, 0.66 mmol) was added to 20 ml of ethanol, and piperidine (0.25 g, 2.9 mmol) was added thereto, and the mixture was stirred at reflux temperature for 10 hours, and the cooled reaction mixture was concentrated under reduced pressure. After the resulting cream solid was washed with 4ml of ethyl acetate, washed with dissolved (100ml), 1M hydrochloric acid, respectively, 10% NaOH (20ml) and saturated brine (40ml) CH 2 C1 2, the organic phase was dried over anhydrous Na 2 S0 4 was dried and concentrated under reduced pressure. Recrystallization from ethyl acetate-methanol gave a white solid (187 mg).
Ή NMR (DMS0-4) δ: 7.53 (1H, d), 7.33 (1H, dd), 7.22 (1H, d)， 4.17 (3H, s)， 4.12 (2H, q)， 3.48 (4H, br), 2.78 (2H, t)， 1.74 (2H, m)， 1.63 (6H, br), 1.36 (3H, t), 0.94 (3H: t)。 实施例 31-36 NMR NMR (DMS0-4) δ: 7.53 (1H, d), 7.33 (1H, dd), 7.22 (1H, d), 4.17 (3H, s), 4.12 (2H, q), 3.48 (4H, br) , 2.78 (2H, t), 1.74 (2H, m), 1.63 (6H, br), 1.36 (3H, t), 0.94 (3H : t). Example 31-36
按照实施例 30的相同方法， 从制备例化合物 15、 16、 17、 18、 19、 20与 哌啶反应， 分别制备实施例 31〜36的化合物。
Figure imgf000036_0001
N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基 ]_4-甲基哌嗪基 -1-甲脒 The compounds of Examples 31 to 36 were separately prepared by reacting the Preparation Compounds 15, 16, 17, 18, 19, 20 with piperidine in the same manner as in Example 30.
Figure imgf000036_0001
N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl ]_4-methylpiperazinyl-1-carboxamidine
Figure imgf000037_0001
Figure imgf000037_0001
将制备例 14化合物（200mg， 0.38mmol )加入到 10ml正丁醇中， 加入 N- 曱基哌，秦 ( 0.15g, 1.5mmol )在回流温度下搅拌 6小时。 减压浓缩冷却后的反应 液， 得到的油状物溶于 C¾C12 ( 100ml )， 分别用 1M盐酸、 10 %NaOH ( 20ml ) 和饱和食盐水（40ml )洗涤， 有机相用无水 Na2S04干燥， 减压浓缩。 用乙酸乙 酯-甲醇重结晶， 得到白色固体（74mg )， 产率 43%。 ^ NMR MSO-^ S .M (1H， d), 7.04 (IH, dd), 6.87 (IH, d)， 4.16 (3H， s), 4.10 (2H, q)， 3.47 (4H, t)， 2.78 (2H， t), 2.34 (4H, t)， 2.20 (3H, s)， 1.74 (2H, m)， 1.33 (3H, t)， 0.94 (3H, t)。 实施例 38-41 The compound of Preparation Example 14 (200 mg, 0.38 mmol) was added to 10 ml of n-butanol, and N- decylperidine, hexane (0.15 g, 1.5 mmol) was stirred at reflux temperature for 6 hours. After cooling the reaction solution under reduced pressure and the concentrated oil was dissolved C¾C1 2 (100ml), 1M hydrochloric acid, respectively, 10% NaOH (20ml) and saturated brine (40ml) washed organic phase was dried over anhydrous Na 2 S0 4 Dry and concentrate under reduced pressure. Recrystallization from ethyl acetate-methanol gave a white solid (yield: 74 mg). ^ NMR MSO-^ S .M (1H, d), 7.04 (IH, dd), 6.87 (IH, d), 4.16 (3H, s), 4.10 (2H, q), 3.47 (4H, t), 2.78 (2H, t), 2.34 (4H, t), 2.20 (3H, s), 1.74 (2H, m), 1.33 (3H, t), 0.94 (3H, t). Example 38-41
按照实施例 37的相同方法， 从制备例化合物 15、 17、 19、 20与 N-曱基哌 嗪反应， 分别制备实施例 38〜41的化合物。  The compounds of Examples 38 to 41 were separately prepared by the same procedures as in Example 37 from the preparation of Compounds 15, 17, 19, 20 and N-mercaptopiperazine.
Figure imgf000037_0002
Figure imgf000038_0001
实施例 42
Figure imgf000037_0002
Figure imgf000038_0001
Example 42
N-[3-(6，7-二氢 -1-曱基 -7-氧代 -3-丙基 吡唑并 [4，3- 嘧啶 -5-基) -4-乙氧苯基] - 吗啉基 -1-甲脒  N-[3-(6,7-Dihydro-1-indenyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl]- Morpholinyl-1-carboxamidine
Figure imgf000038_0002
Figure imgf000038_0002
将制备例 14化合物（ 200mg, 0.38mmol )加入到 10ml正丁醇中， 加入吗啡 啉（0.15g, 1.7mmol )在回流温度下搅拌 8小时。 减压浓缩冷却后的反应液， 得 到的油状物溶于 C¾C12 ( 100ml ), 分别用 1M盐酸、 10 %NaOH ( 20ml )和饱和 食盐水（40ml )洗涤， 有机相用无水 Na2S04干燥， 减压浓缩。 用乙酸乙酯 -甲醇 重结晶， 得到白色固体（67mg ), 产率 40%。 iH NMR
Figure imgf000038_0003
d), 7.15 (2H, dd), 4.15 (3H, s), 4.12 (2H, q), 3.81 (4H, t)， 3.59 (4H， t)， 2.89 (2H， t), 1.87 (2H, m)， 1.35 (3H, t)， 1.00 (3H, t)。 实施例 43-46 The compound of Preparation 14 (200 mg, 0.38 mmol) was added to 10 ml of n-butanol, and morpholine (0.15 g, 1.7 mmol) was added and stirred at reflux temperature for 8 hours. After cooling the reaction solution under reduced pressure and the concentrated oil was dissolved C¾C1 2 (100ml), 1M hydrochloric acid, respectively, 10% NaOH (20ml) and saturated brine (40ml) washed organic phase was dried over anhydrous Na 2 S0 4 Dry and concentrate under reduced pressure. Recrystallization from ethyl acetate-methanol gave a white solid (yield: 67). iH NMR
Figure imgf000038_0003
d), 7.15 (2H, dd), 4.15 (3H, s), 4.12 (2H, q), 3.81 (4H, t), 3.59 (4H, t), 2.89 (2H, t), 1.87 (2H, m ), 1.35 (3H, t), 1.00 (3H, t). Examples 43-46
按照实施例 42的相同方法， 从制备例化合物 15、 16、 19、 20与吗啡啉反 应， 分别制备实施例 43~46的化合物。 In the same manner as in Example 42, from the preparation of the compounds of Examples 15, 16, 19, 20 and morphine The compounds of Examples 43 to 46 were prepared separately.
Figure imgf000039_0002
实施例 47
Figure imgf000039_0002
Example 47
N-[3-(6，7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -Ν'-苄基胍  N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl ] -Ν'-benzyl hydrazine
Figure imgf000039_0001
将制备例 14化合物（ 150mg， 0.28mmol )加入到 20ml乙醇溶液中， 加入苄 胺（0.15g, 1.4mmol )， 在回流温度下搅拌 10小时。 减压浓缩冷却后的反应液， 得到的油状物溶于 C¾C12 ( 100ml )， 分别用 1M盐酸、 10 %NaOH ( 20ml )和饱 和食盐水（40ml )洗涤， 有机相用无水 Na2S04干燥， 减压浓缩。 用乙酸乙酯- 甲醇重结晶，得到白色固体（77mg ),产率 59%。 ^ NMR CDMSO-^ S: 7.40-7.15 (6H, m)， 7.02 (1H, dd), 6.90 (1H， d), 4.37 (2H， s)， 4.15 (3H, s)， 4.08 (2H, q), 2.78 (2H, t), 1.74 (2H, m)， 1.32 (3H, t)， 0.93 (3H， t)。 实施例 48-52
Figure imgf000039_0001
The compound of Preparation Example 14 (150 mg, 0.28 mmol) was added to 20 ml of ethanol, and benzylamine (0.15 g, 1.4 mmol) was added, and the mixture was stirred at reflux temperature for 10 hours. After cooling the reaction solution under reduced pressure and the concentrated oil was dissolved C¾C1 2 (100ml), 1M hydrochloric acid, respectively, 10% NaOH (20ml) and saturated brine (40ml) washed organic phase was dried over anhydrous Na 2 S0 4 Dry and concentrate under reduced pressure. Recrystallization from ethyl acetate-methanol gave a white solid (yield: ^ NMR CDMSO-^ S: 7.40-7.15 (6H, m), 7.02 (1H, dd), 6.90 (1H, d), 4.37 (2H, s), 4.15 (3H, s), 4.08 (2H, q) , 2.78 (2H, t), 1.74 (2H, m), 1.32 (3H, t), 0.93 (3H, t). Examples 48-52
按照实施例 47的相同方法， 从制备例化合物 15、 17、 19、 20、 21与苄胺 反应， 分别制备实施例 48〜52的化合物。  The compounds of Examples 48 to 52 were separately prepared by the same procedures as in Example 47, from the preparation of Compounds 15, 17, 19, 20, 21 and benzylamine.
Figure imgf000040_0001
Figure imgf000041_0001
实施例 53
Figure imgf000040_0001
Figure imgf000041_0001
Example 53
N-[3-(6，7-二氢 -1-曱基 -7-氧代 -3-丙基 吡唑并 [4，3- 嘧啶 -5-基) -4-丙氧苯 基] -Ν'-乙基- Ν'-(2-羟乙基) -胍  N-[3-(6,7-Dihydro-1-indenyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl] - Ν'-Ethyl-Ν'-(2-hydroxyethyl)-胍
Figure imgf000041_0002
Figure imgf000041_0002
将制备例 15化合物（ 250mg, 0.57mmol )加入到 20ml乙醇中， 加入 2- (乙胺 基) -乙醇（0.25g，2.3mmol )在回流温度下， 搅拌 15小时， 将反应液浓缩至干， 得到的固体溶于 CH2C12 ( 100ml )， 用 10 %NaOH ( 20ml )， 水 ( 30mlx2 )饱和食 盐水（40ml )洗涤， 无水 Na2S04干燥， 浓缩。 用乙酸乙酯和乙醇重结晶， 得到 白色固体（112mg )， 产率 51.5%。 ^ NMR (CDC13) δ: 8.16 (1H， d)， 7.15 (1H， dd)， 7.03 (1H， d), 4.37 (2H, t), 4.27 (3H, s), 4.22 (2H, t), 3.59 (2H, t)， 3.16 (2H, q)， 2.91 (2H, t)， 1.78 (4H, m)， 1.56 (3H, t), 1.18 (3H, t), 1.03 (3H, t)。 实施例 54 The compound of Preparation 15 (250 mg, 0.57 mmol) was added to 20 ml of ethanol, and 2-(ethylamino)-ethanol (0.25 g, 2.3 mmol) was added at reflux temperature for 15 hours, and the reaction mixture was concentrated to dryness. the resulting solid was dissolved in CH 2 C1 2 (100ml), and washed, dried 10% NaOH (20ml) water (30mlx2) saturated brine (40ml) dried over anhydrous Na 2 S0 4, and concentrated. Recrystallization from ethyl acetate and ethanol gave a white solid (112 mg). ^ NMR (CDC1 3 ) δ: 8.16 (1H, d), 7.15 (1H, dd), 7.03 (1H, d), 4.37 (2H, t), 4.27 (3H, s), 4.22 (2H, t), 3.59 (2H, t), 3.16 (2H, q), 2.91 (2H, t), 1.78 (4H, m), 1.56 (3H, t), 1.18 (3H, t), 1.03 (3H, t). Example 54
N-[3-(6，7-二氢 -1-曱基 -7-氧代 -3-丙基 -17/-吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯基] - Ν'-曱基- Ν'-(Ν，Ν-二甲基 -2-胺乙基) -胍
Figure imgf000042_0001
N-[3-(6,7-Dihydro-1-indenyl-7-oxo-3-propyl-17/-pyrazolo[4,3-pyrimidin-5-yl)-4-ethoxylate Phenyl] - Ν'-fluorenyl- Ν'-(Ν,Ν-dimethyl-2-aminoethyl)-胍
Figure imgf000042_0001
将制备例 14化合物（ 250mg, 0.57mmol )加入到 20ml乙醇中，加入 Ν， Ν， Ν'- 三曱基乙二胺（0.20g，2.0mmol )在回流温度下， 搅拌 15小时， 将反应液浓缩至 干， 得到的固体溶于 CH2C12 ( 100ml ), 用 10 % NaOH ( 20ml )， 水（ 30mlx2 )饱 和食盐水（40ml )洗涤， 无水 Na2S04干燥， 浓缩。 用乙酸乙酯和乙醇重结晶， 得到白色固体（ 112mg )，产率 51.5%。 NMR (D20) δ: 7.56 (1H， d)， 7.42 (IH, dd), 7.20 (IH, d)， 4.15 (2H, q), 4.09 (3H, s)， 3.87 (2H, t)， 3.47 (2H, t), 3.16 (3H, s), 2.91 (6H， s)， 2.77 (2H, t), 1.67 (2H， m)， 1.32 (3H, t), 0.84 (3H, t)。 实施例 55 The compound of Preparation Example 14 (250 mg, 0.57 mmol) was added to 20 ml of ethanol, and hydrazine, hydrazine, Ν'-trimethylethylenediamine (0.20 g, 2.0 mmol) was added at reflux temperature for 15 hours. concentrated to dryness, the resulting solid was dissolved in CH 2 C1 2 (100ml), with 10% NaOH (20ml), water (30mlx2) and saturated brine, dried water (40ml) dried over anhydrous Na 2 S0 4, and concentrated. Recrystallization from ethyl acetate and ethanol gave a white solid (112 mg). NMR (D 2 0) δ: 7.56 (1H, d), 7.42 (IH, dd), 7.20 (IH, d), 4.15 (2H, q), 4.09 (3H, s), 3.87 (2H, t), 3.47 (2H, t), 3.16 (3H, s), 2.91 (6H, s), 2.77 (2H, t), 1.67 (2H, m), 1.32 (3H, t), 0.84 (3H, t). Example 55
N-[3-(6，7-二氢 -1-曱基 -7-氧代 -3-丙基 吡唑并 [4，3-ί ]嘧啶 -5-基) -4-乙氧苯 基] -Ν'-曱基 -Ν'-(2-羟乙基) -胍  N-[3-(6,7-Dihydro-1-indenyl-7-oxo-3-propylpyrazolo[4,3-ί]pyrimidin-5-yl)-4-ethoxyphenyl ] -Ν'-曱-Ν'-(2-hydroxyethyl)-胍
Figure imgf000042_0002
Figure imgf000042_0002
将制备例 14化合物（ 250mg, 0.57mmol )加入到 20ml乙醇中， 加入 2- (甲胺 基) -乙醇（0.25g，2.3mmol )在回流温度下， 搅拌 15小时， 将反应液浓缩至干， 得到的固体溶于 CH2C12 ( 100ml )， 用 10 % NaOH ( 20ml )， 水 ( 30mlx2 )饱和食 盐水（40ml )洗涤， 无水 Na2S04干燥， 浓缩。 用乙酸乙酯和乙醇重结晶， 得到 白色固体（112mg ), 产率 51.5%。 ^ NMR^CDCls) δ: 8.19 (IH, d), 7.18 (IH, dd), 6.93 (IH, d)， 4.39 (2H, t)， 4.27 (3H, s), 4.22 (2H， t)， 3.59 (2H, t)， 3.06 (3H, s)， 2.91 (2H, t), 1.87 (2H, m)， 1.56 (3H, t)， 1.03 (3H, t)。 实施例 56-57 The compound of Preparation 14 (250 mg, 0.57 mmol) was added to 20 ml of ethanol, and 2-(methylamino)-ethanol (0.25 g, 2.3 mmol) was added at reflux temperature for 15 hours, and the reaction mixture was concentrated to dryness. the resulting solid was dissolved in CH 2 C1 2 (100ml), and washed, dried 10% NaOH (20ml) water (30mlx2) saturated brine (40ml) dried over anhydrous Na 2 S0 4, and concentrated. Recrystallization from ethyl acetate and ethanol gave a white solid (112 mg). ^ NMR^CDCls) δ: 8.19 (IH, d), 7.18 (IH, dd), 6.93 (IH, d), 4.39 (2H, t), 4.27 (3H, s), 4.22 (2H, t), 3.59 (2H, t), 3.06 (3H, s), 2.91 (2H, t), 1.87 (2H, m), 1.56 (3H, t), 1.03 (3H, t). Examples 56-57
按照实施例 55的相同方法， 从制备例化合物 15、 16与 2-甲胺基乙醇反应， 分别制备实施例 56~57的化合物。
Figure imgf000043_0001
实施例 58 The compounds of Examples 56-57 were prepared by the same procedure as in Example 55 from the preparation of Compounds 15 and 16 and 2-methylaminoethanol.
Figure imgf000043_0001
Example 58
N-[3-(6，7-二氢 -1-曱基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧苯 基] _N'-(3-吡啶甲基) -胍  N-[3-(6,7-Dihydro-1-indenyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl]_N '-(3-Pyridylmethyl)-胍
Figure imgf000043_0002
Figure imgf000043_0002
将制备例 15化合物（ 250mg, 0.57mmol )加入到 20ml乙醇中， 加入 3-胺曱 基吡啶（0.22g, 2.0mmol )在回流温度下， 搅拌 15小时， 将反应液浓缩至干， 得 到的固体溶于 C¾C12 ( 100ml )， 用 10 %NaOH ( 20ml )， 水（ 30mlx2 )饱和食盐 水（40ml )洗涤， 无水 Na2S04干燥， 浓缩。 用乙酸乙酯和乙醇重结晶， 得到白 色固体（ 112mg )，产率 51.5%。 ^ NMR^CDsOD) δ: 8.60-8.39 (2Η, m)， 7.88 (1H, m), 7.43 (2H, m), 7.11 (2H, m), 4.54 (2H, s)， 4.21 (3H, s), 4.04 (2H, t)， 2.84 (2H, t)， 1.77 (4H, m), 0.98 (3H, t), 0.95 (3H, t)。 实施例 59 N-[3-(6，7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4，3- 嘧啶 -5-基) -4-乙氧苯 基] -N'-(3-吡啶甲基) -胍 The compound of Preparation Example 15 (250 mg, 0.57 mmol) was added to 20 ml of ethanol, and 3-aminomercaptopyridine (0.22 g, 2.0 mmol) was added at reflux temperature for 15 hours, and the reaction mixture was concentrated to dryness. dissolved C¾C1 2 (100ml), with 10% NaOH (20ml), water (30mlx2) saturated brine (40ml), dried over anhydrous Na 2 S0 4, and concentrated. Recrystallization from ethyl acetate and ethanol gave a white solid (112 mg). ^ NMR^CDsOD) δ: 8.60-8.39 (2Η, m), 7.88 (1H, m), 7.43 (2H, m), 7.11 (2H, m), 4.54 (2H, s), 4.21 (3H, s) , 4.04 (2H, t), 2.84 (2H, t), 1.77 (4H, m), 0.98 (3H, t), 0.95 (3H, t). Example 59 N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl]- N'-(3-pyridylmethyl)-oxime
Figure imgf000044_0001
Figure imgf000044_0001
按照实施例 58的相同方法， 从制备例化合物 14与 3-氨曱基吡啶反应， 制 备实施例 59的化合物。 !H NMR (DMSO- 6) δ: 8.63 (1Η， d), 8.55 (1Η, dd), 7.80 (3H m), 7.42-7.30 (2H, m), 7.17 (1H, d), 4.58 (2H, s), 4.26 (3H, s), 4.24 (2H, q), 2.86 (2H: t), 1.81 (2H, m)， 1.51 (3H, t)， 1.00 (3H, t)。 实施例 60 The compound of Example 59 was prepared by the same procedure as in Example 58 from the preparation of compound 14 and 3-aminopyridylpyridine. ! H NMR (DMSO- 6) δ : 8.63 (1Η, d), 8.55 (1Η, dd), 7.80 (3H m), 7.42-7.30 (2H, m), 7.17 (1H, d), 4.58 (2H, s), 4.26 (3H, s), 4.24 (2H, q), 2.86 (2H : t), 1.81 (2H, m), 1.51 (3H, t), 1.00 (3H, t). Example 60
l-[3-(6，7-二氢 -1-曱基 -7-氧代 -3-丙基 吡唑并 [4，3- 嘧啶 -5-基) -4-乙氧苯基] -双 胍 L-[3-(6,7-Dihydro-1-indenyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl]- Double
Figure imgf000044_0002
Figure imgf000044_0002
5-(5-氨基 -2-乙氧基苯基) -1-曱基 -3-丙基 吡唑并 [4，3- 嘧啶 -7(6^)-酮 ( lOOmg, 0.3mmol )溶于 10ml甲醇， 加入浓盐酸 25 L， 冰浴冷却下搅拌 0.5 小时， 蒸干甲醇得到的白色固体溶于正丁醇， 加入二氰二胺（25mg， 0.3mmol ) 在回流温度下，搅拌 6小时，将反应液浓缩至干。得到的膏状固体用乙醇（ 10ml ) 洗涤后， 加入到 10ml含有 NaOCH3 ( 14mg )的甲醇溶液中， 室温下搅拌 0.5小 时。蒸干甲醇，用蒸馏水（ 30mlx2 )洗涤固体。40°C下干燥，得到白色固体（ 50mg ), 产率 36.5%。 NMR (DMSO-d6) δ: 7.69 (IH, d)， 7.46 (1H， dd), 7.14 (1H, d)， 4.16 (3H， s)， 4.12 (2H, q)， 2.79 (2H, t)， 1.75 (2H, m)， 1.34 (3H, t)， 0.94 (3H, t)。 实施例 61-63 5-(5-Amino-2-ethoxyphenyl)-1-indolyl-3-propylpyrazolo[4,3-pyrimidin-7(6^)-one (100 mg, 0.3 mmol) is soluble 10 ml of methanol, 25 L of concentrated hydrochloric acid was added, and the mixture was stirred for 0.5 hour under ice-cooling, and the white solid obtained by evaporation of methanol was dissolved in n-butanol, and dicyandiamine (25 mg, 0.3 mmol) was added, and the mixture was stirred at reflux temperature for 6 hours. The reaction was concentrated to dryness. The obtained paste solid was washed with ethanol (10 ml), and then added to 10 ml of a methanol solution containing NaOCH 3 (14 mg), and stirred at room temperature for 0.5 hour. The methanol was evaporated to dryness, and the solid was washed with distilled water (30mlx2). Drying at 40 ° C gave a white solid (50 mg). NMR (DMSO-d 6 ) δ: 7.69 (IH, d), 7.46 (1H, dd), 7.14 (1H, d), 4.16 (3H, s), 4.12 (2H, q), 2.79 (2H, t) , 1.75 (2H, m), 1.34 (3H, t), 0.94 (3H, t). Examples 61-63
按照实施例 60的相同方法， 从 5-(5-氨基 -2-丙氧基苯基) -1-甲基 -3-丙基 吡唑并 [4，3-ί ]嘧啶 -7(6//)-酮、制备例化合物 1和 2与二氰二胺反应，分别制备实 施例 61 - 63的化合物。
Figure imgf000045_0001
实施例 64 In the same manner as in Example 60, from 5-(5-amino-2-propoxyphenyl)-1-methyl-3-propylpyrazolo[4,3-ί]pyrimidine-7 (6/ /)-ketone, Preparation Examples Compounds 1 and 2 were reacted with dicyandiamide to prepare the compounds of Examples 61 to 63, respectively.
Figure imgf000045_0001
Example 64
N-[3-(6,7-二氢 -1-曱基 -7-氧代 -3-丙基 吡唑并 [4，3- 嘧啶 -5-基) -4-乙氧苯 基] _N'-(3-羟丙基) -胍  N-[3-(6,7-Dihydro-1-indenyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl]_N '-(3-hydroxypropyl)-胍
Figure imgf000045_0002
Figure imgf000045_0002
将制备例 14化合物（ 200mg， 0.38mmol )加入到 20ml乙醇中， 加入正丙醇 胺（ 180mg， 2.4mmol )在回流温度下， 搅拌 15小时， 将反应液浓缩至干， 得到 的油状物溶于 CH2C12 ( 100ml ), 用水（30mlx3 )、 10 %NaOH ( 20ml )、 饱和食 盐水（40ml )洗涤， 有机相用无水 Na2S04干燥， 减压浓缩。 用乙酸乙酯-甲醇重 结晶，得到白色固体（ 48mg )，产率 28%。 NMR (DMSO- ） δ: 7.56 (IH, d), 7.37 (IH, dd), 7.25 (1H， d), 4.17 (3H， s)， 4.08 (2H, q)， 3.52 (2H, t)， 3.31 (2H, t)， 2.80 (2H, t)， 1.73 (4H， m)， 1.37 (3H, t), 0.95 (3H， t)。 实施例 65-66 The compound of Preparation 14 (200 mg, 0.38 mmol) was added to 20 ml of ethanol, and n-propanolamine (180 mg, 2.4 mmol) was added at reflux temperature for 15 hours, and the reaction mixture was concentrated to dryness. CH 2 C1 2 (100ml), washed with water (30mlx3), 10% NaOH ( 20ml), saturated brine (40ml) washed organic phase was dried over anhydrous Na 2 S0 4, and concentrated under reduced pressure. Recrystallization from ethyl acetate-methanol gave a white solid (yield: 48 mg). NMR (DMSO- ) δ: 7.56 (IH, d), 7.37 (IH, dd), 7.25 (1H, d), 4.17 (3H, s), 4.08 (2H, q), 3.52 (2H, t), 3.31 (2H, t), 2.80 (2H, t), 1.73 (4H, m), 1.37 (3H, t), 0.95 (3H, t). Examples 65-66
按照实施例 64的相同方法， 从制备例化合物 15、 19与正丙醇胺反应， 制 备实施例 65 - 66的化合物。  The compounds of Examples 65 to 66 were prepared by the same procedure as in Example 64 from the preparation of Compounds 15 and 19 and n-propanolamine.
Figure imgf000046_0002
实施例 67
Figure imgf000046_0002
Example 67
N-[3-(6，7-二氢 -1-曱基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基] -Ν'-苯基胍  N-[3-(6,7-Dihydro-1-indenyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl]- Ν'-phenyl hydrazine
Figure imgf000046_0001
Figure imgf000046_0001
将制备例 14化合物（ 200mg, 0.38mmol )加入到 3ml苯胺中， 在 130°C下搅 拌 15小时。 将冷却后的反应液溶于 CH2C12 ( 100ml )， 分别用 1M盐酸（ 15ml )、The compound of Preparation Example 14 (200 mg, 0.38 mmol) was added to 3 ml of aniline and stirred at 130 ° C for 15 hours. The cooled reaction solution was dissolved in CH 2 C1 2 (100 ml), respectively, using 1M hydrochloric acid (15 ml),
10 %NaOH ( 20ml )和饱和食盐水（40ml )洗涤， 有机相用无水 Na2S04干燥， 减压浓缩。用乙酸乙酯-曱醇重结晶，得到白色固体（48mg )，产率 28%。 ^ NMR (CDCls) δ: 8.01 (IH, d), 7.37-7.05 (6H, m)， 6.91 (IH, d), 4.26 (3H, s)， 4.19 (2H， q), 2.89 (2H, t)， 1.83 (2H, m)， 1.54 (3H, t)， 1.00 (3H, t)。 实施例 68 N-[3-(6，7-二氢 -1-曱基 -7-氧代 -3-丙基 吡唑并 [4,3- ^嘧啶 -5-基) -4-丙氧苯 基] -Ν'-苯基胍 10% NaOH (20ml) and saturated brine (40ml) washed organic phase was dried over anhydrous Na 2 S0 4, and concentrated under reduced pressure. Recrystallization from ethyl acetate-methanol afforded a white solid (yield: 48%). ^ NMR (CDCls) δ: 8.01 (IH, d), 7.37-7.05 (6H, m), 6.91 (IH, d), 4.26 (3H, s), 4.19 (2H, q), 2.89 (2H, t) , 1.83 (2H, m), 1.54 (3H, t), 1.00 (3H, t). Example 68 N-[3-(6,7-Dihydro-1-indenyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl] -Ν'-phenyl hydrazine
Figure imgf000047_0001
Figure imgf000047_0001
按照实施例 67的相同方法， 制备例 15化合物与苯胺反应， 得到实施例 68 的化合物， 产率 31%。 NMR (CDC13) δ: 7.64 (1H， d), 7.50-7.27 (6H, m), 7.23 (IH, d)， 4.16 (3H, s), 4.05 (2H， t), 2.75 (2H, t)， 1.71 (4H, m), 0.93 (6H, t)„ 实施例 69 The compound of Preparation 15 was reacted with aniline in the same manner as in Example 67 to give the compound of Example 68, yield 31%. NMR (CDC1 3 ) δ: 7.64 (1H, d), 7.50-7.27 (6H, m), 7.23 (IH, d), 4.16 (3H, s), 4.05 (2H, t), 2.75 (2H, t) , 1.71 (4H, m), 0.93 (6H, t) „ Example 69
N-[3-(6,7-二氢 -1-曱基 -7-氧代 -3-丙基 吡唑并 [4,3-^1嘧啶 -5-基) -4-乙氧苯 基] -Ν'， Ν'-二 (2-羟基乙基) -胍  N-[3-(6,7-Dihydro-1-indenyl-7-oxo-3-propylpyrazolo[4,3-^1 pyrimidin-5-yl)-4-ethoxyphenyl ] -Ν', Ν'-bis(2-hydroxyethyl)-胍
Figure imgf000047_0002
Figure imgf000047_0002
将制备例 14化合物（ 150mg， 0.28mmol )加入到 20ml乙醇中， 加入二乙醇 胺（84mg, 0.8mmol )在 70°C下搅拌 15小时。 减压浓缩冷却后的反应液。 得到 的膏状固体用 4ml乙酸乙酯洗涤后，溶于 C¾C12 ( 100ml )，分别用水（ 30mlx2 )、 10 %NaOH ( 20ml )和饱和食盐水（40ml )洗涤。 有机相用无水 Na2S04干燥， 减压浓缩。用乙酸乙酯-曱醇重结晶，得到白色固体（75mg ),产率 56%。 'H NMR (DMSO- 6) δ: 7.65 (IH, d), 7.49 (1H， dd), 7.06 (IH, d), 4.16 (3H, s)， 4.09 (2H, q), 3.58 (4H， t)， 3.43 (4H, t), 2.78 (2H, t), 1.74 (2H, m)， 1.30 (3H, t)， 0.94 (3H, t)。 实施例 70 The compound of Preparation 14 (150 mg, 0.28 mmol) was added to 20 ml of ethanol, and diethanolamine (84 mg, 0.8 mmol) was added and stirred at 70 ° C for 15 hours. The cooled reaction solution was concentrated under reduced pressure. The obtained paste solid was washed with 4 ml of ethyl acetate, and then dissolved in C3⁄4 C1 2 (100 ml), and washed with water (30 mlx2), 10% NaOH (20 ml) and saturated brine (40 ml). The organic phase was dried over anhydrous Na 2 S0 4, and concentrated under reduced pressure. Recrystallization from ethyl acetate-methanol gave a white solid (75 mg). 'H NMR (DMSO- 6 ) δ: 7.65 (IH, d), 7.49 (1H, dd), 7.06 (IH, d), 4.16 (3H, s), 4.09 (2H, q), 3.58 (4H, t ), 3.43 (4H, t), 2.78 (2H, t), 1.74 (2H, m), 1.30 (3H, t), 0.94 (3H, t). Example 70
2-{2-[3-(6，7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4，3- 嘧1 基) -4-乙氧苯基] 胺基 -4，5-二氢-咪唑- 1 -基} -乙醇
Figure imgf000048_0001
2- {2- [3- (6,7-dihydro-1-methyl-7-oxo-3-propyl-pyrazolo [4,3-pyrimidin-1-yl) -4-ethoxyphenyl] Amino-4,5-dihydro-imidazolium-1-yl}-ethanol
Figure imgf000048_0001
将制备例 14化合物（ 200mg， 0.38mmol )加入到二乙醇胺（ 3ml )中，在 100 °C下搅拌 8小时， 将反应液溶于 CH2C12 ( 100ml ), 分别用水（ 30mlx3 )、 10 % NaOH ( 20ml )和饱和食盐水（40ml )洗涤。 有机相用无水 Na2S04干燥， 减压 浓缩。用乙酸乙酯-甲醇重结晶，得到白色固体（ 57mg )，产率 33%。 !H NMR (CDC13) δ: 8.18 (IH, d), 7.15 (IH, dd), 6.92 (IH, d)， 4.45 (2H, t), 4.26 (3H, s)， 4.22 (2H, q)， 3.92 (2H, t), 3.69 (2H, t), 3.55 (2H, t), 2.93 (2H, t), 1.87 (2H, m), 1.55 (3H, t)， 1.03 (3H, t)。 实施例 71-72 The compound of Preparation 14 (200 mg, 0.38 mmol) was added to diethanolamine (3 ml), and the mixture was stirred at 100 ° C for 8 hours, and the reaction solution was dissolved in CH 2 C1 2 (100 ml), respectively, with water (30 ml x 3 ), 10 % Wash with NaOH (20 ml) and saturated brine (40 ml). The organic phase was dried over anhydrous Na 2 S0 4, and concentrated under reduced pressure. Recrystallization from ethyl acetate-methanol gave a white solid (yield: 57 mg). ! H NMR (CDC1 3) δ : 8.18 (IH, d), 7.15 (IH, dd), 6.92 (IH, d), 4.45 (2H, t), 4.26 (3H, s), 4.22 (2H, q) , 3.92 (2H, t), 3.69 (2H, t), 3.55 (2H, t), 2.93 (2H, t), 1.87 (2H, m), 1.55 (3H, t), 1.03 (3H, t). Examples 71-72
按照实施例 70相同的方法， 从制备例化合物 15、 16与二乙醇胺反应， 制 备实施例 71-72化合物。  The compounds of Examples 71-72 were prepared by the same procedure as in Example 70 from the preparation of Compounds 15 and 16 and diethanolamine.
Figure imgf000048_0002
实施例 73 l-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯基] -5- 苯基双胍
Figure imgf000048_0002
Example 73 L-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl]- 5-phenylbiguanide
Figure imgf000049_0001
Figure imgf000049_0001
将制备例 24化合物（ 200mg, 0.57mmol )加入到 10ml正丁醇中， 加入苯胺 盐酸盐（0.25g， 2.3mmol )在回流温度下， 搅拌 6小时。 反应液浓缩至干， 用乙 酸乙酯和乙醇分别洗涤得到的固体。 将固体加入到 10ml含有 NaOCH3 ( 30mg ) 的甲醇溶液中， 室温下搅拌 0.5小时。蒸干曱醇， 用蒸馏水（30mlx2 )洗涤固体。 40°C下干燥， 得到白色固体（112mg )， 产率 51.5%。 ^ NMR (DMSO- ） δ: 7.86 (IH, d), 7.42 (IH, dd), 7.30 (5H, m), 7.15 (IH, d), 4.24 (3H, s)， 4.20 (2H， q), 2.85 (2H, t)， 1.79 (2H, m)， 1.45 (3H, t), 0.97 (3H, t)。 实施例 74胶嚢剂 处方 含有吡唑并嘧啶酮的苯基胍衍生物 20. Og 淀粉 80. Og 乳糖 60. Og 微晶纤维素 35g The compound of Preparation Example 24 (200 mg, 0.57 mmol) was added to 10 ml of n-butanol, and aniline hydrochloride (0.25 g, 2.3 mmol) was added and stirred at reflux temperature for 6 hours. The reaction solution was concentrated to dryness, and the obtained solid was washed with ethyl acetate and ethyl alcohol. The solid was added to 10 ml of a methanol solution containing NaOCH 3 (30 mg), and stirred at room temperature for 0.5 hour. The decyl alcohol was evaporated to dryness, and the solid was washed with distilled water (30 ml x 2 ). Drying at 40 ° C gave a white solid (112 mg). ^ NMR (DMSO- ) δ: 7.86 (IH, d), 7.42 (IH, dd), 7.30 (5H, m), 7.15 (IH, d), 4.24 (3H, s), 4.20 (2H, q), 2.85 (2H, t), 1.79 (2H, m), 1.45 (3H, t), 0.97 (3H, t). Og 糖。 60. Og Microcrystalline cellulose 35g Og Lactose 80. Og Lactose 60g
10%聚乙烯吡咯烷酮乙醇溶液 适量 硬脂酸镁 0. 5g 共制 1000粒 将含含有吡唑并嘧啶酮的苯基胍衍生物及各种辅料过 80目筛，按处方量称取， 以 10%聚乙烯吡咯烷酮乙醇溶液为粘合剂， 用 16 目筛制成适宜的颗粒， 65°C干 燥， 14目筛整粒， 加入硬脂酸镁混合均匀， 测颗粒含量， 计算装量， 装入胶嚢， 即得。 实施例 75 片剂（湿制粒法) 10% polyvinylpyrrolidone ethanol solution appropriate amount of magnesium stearate 0. 5g Manufacture of 1000 tablets phenyl hydrazine derivative containing pyrazolopyrimidinone and various excipients through a 80 mesh sieve, weighed according to the prescription, to 10 % polyvinylpyrrolidone ethanol solution as binder, using 16 mesh sieve to make suitable granules, drying at 65 ° C, 14 mesh sieve granules, adding magnesium stearate to mix evenly, measuring particle content, calculating the loading, loading Glue, that is. Example 75 Tablets (wet granulation method)
处方  Prescription
含有吡唑并嘧啶酮的苯基胍衍生物 20. Og  Phenylhydrazine derivative containing pyrazolopyrimidinone 20. Og
乳糖 120. Og  Lactose 120. Og
微晶纤维素 40. Og  Microcrystalline cellulose 40. Og
8%淀粉浆 适量  8% starch slurry
羧曱基淀粉钠 10. Og  Carboxymethyl starch sodium 10. Og
硬脂酸镁 i. o g  Magnesium stearate i. o g
共制 1000片 将含有吡唑并嘧啶酮的苯基胍衍生物、 微晶纤维素、 乳糖、 羧曱基淀粉钠 过 80 目筛， 混匀， 用 8%淀粉浆制软材， 16 目制粒， 干燥、 整粒后， 加入硬脂 酸镁混合均匀， 测定颗粒含量， 计算片重， 压片， 即得。 实施例 76 片剂（粉末压片法）  Co-made 1000 pieces of phenyl hydrazine derivative containing pyrazolopyrimidinone, microcrystalline cellulose, lactose, sodium carboxymethyl starch, sieved through 80 mesh, mixed, made of soft material with 8% starch slurry, 16 mesh system After the granules are dried and granulated, the magnesium stearate is added and mixed uniformly, the content of the granules is measured, the tablet weight is calculated, and the tablet is obtained. Example 76 Tablets (Powder Tableting Method)
处方  Prescription
含有吡唑并嘧啶酮的苯基胍 生物 20. 0g  Phenylhydrazine containing pyrazolopyrimidinone 20. 20.g
微晶纤维素 30. 0g  Microcrystalline cellulose 30. 0g
无水乳糖 45. 0g  Anhydrous lactose 45. 0g
聚乙烯吡咯烷酮 3. 0g  Polyvinylpyrrolidone 3. 0g
微粉硅胶 0. 2g  Micronized silica gel 0. 2g
硬脂酸镁  Magnesium stearate
共制 1000片 将含含有吡唑并嘧啶酮的苯基胍衍生物与微晶纤维素、 无水乳糖、 .聚乙烯吡 咯烷酮、 微粉硅胶于混合机中混匀， 然后加入硬脂酸镁混匀， 压片即得。 化合物活性测定 Co-made 1000 pieces Mixing the phenylhydrazine derivative containing pyrazolopyrimidinone with microcrystalline cellulose, anhydrous lactose, polyvinylpyrrolidone, and microsilica gel in a mixer, then adding magnesium stearate to mix, and compressing Got it. Compound activity assay
螓抑制活性试验  Antimony inhibitory activity test
酶抑制活性测试所用的酶是采用类似于文献报道的方法 (Thrombosis Res. 1991,62,31和 J.Biol.Chem. 1997,272,2714), ^巴不同组织经适当处理， 用 FPLC分离 出试验所需的酶。 确切的说， 从人的血小板中获得 PDE5,从牛的视网膜中分离 出 PDE6。 酶一经分离立即进行酶的抑制活性试验， 酶的抑制试验是采用 TRKQ7100和 TRKQ7090试剂盒， 直接检测 AMP/GMP的闪烁接近测定， 大致是 这样进行的， 在不同抑制剂浓度和少量底物存在下， 加入 ΙΟμΙ的緩沖液 (50mM Tris/HCl PH 7.5, 8.3mM MgCl2, 1.7mM EGTA),水至最终体积为 ΙΟΟμΙ,用固定量 的酶引发反应， 30°C保温 30分钟， 然后用 50μ1含有硫酸锌的硅酸 4乙珠终止反应， 摇动 20分钟后， 暗处沉降 30分钟， 在 BECKMAN LS6500 MULTI-PURPOSE SCINTILLATION COUNTER上计数， 然后根据计数值算出本发明化合物对酶的 半数抑制率（IC50 ) 。 The enzyme used in the enzyme inhibition activity test was similar to that reported in the literature (Thrombosis Res. 1991, 62, 31 and J. Biol. Chem. 1997, 272, 2714), and different tissues were appropriately treated and separated by FPLC. The enzyme required for the test. Specifically, PDE5 is obtained from human platelets and PDE6 is isolated from the retina of cattle. Once the enzyme is isolated, the enzyme inhibition activity test is carried out. The enzyme inhibition test is a direct detection of the AMP/GMP scintillation proximity assay using the TRKQ7100 and TRKQ7090 kits. This is roughly the case, in the presence of different inhibitor concentrations and a small amount of substrate. Add ΙΟμΙ buffer (50 mM Tris/HCl pH 7.5, 8.3 mM MgCl 2 , 1.7 mM EGTA), water to a final volume of ΙΟΟμΙ, initiate the reaction with a fixed amount of enzyme, incubate at 30 ° C for 30 minutes, then use 50 μl The reaction was terminated by zinc silicate 4B, and after shaking for 20 minutes, it was allowed to settle in the dark for 30 minutes, counted on a BECKMAN LS6500 MULTI-PURPOSE SCINTILLATION COUNTER, and then the half inhibition rate of the compound of the present invention to the enzyme was calculated based on the count value (IC 50 ).
PDE5抑制活性实验 PDE5 inhibitory activity experiment
按照上述方法，测定了本发明的通式 1部分化合物对人血小板 PDE5的抑制 活性， 测定结果如下表所示：  The inhibitory activity of the compound of the formula 1 of the present invention against human platelet PDE5 was measured according to the above method, and the results are shown in the following table:
Figure imgf000051_0001
由上表化合物对 PDE5的抑制活性 (IC5o)可知， 本发明中的大多数化合物具 有比西地那非更强 PDE5抑制活性， 因此， 口服给药所需剂量比西地那非更少， 引起副反应的几率也相对较小。
Figure imgf000051_0001
From the inhibitory activity of the above compounds against PDE5 (IC 5 o), it is known that most of the compounds of the present invention have stronger PDE5 inhibitory activity than sildenafil, and therefore, the dose required for oral administration is less than that of sildenafil. The probability of causing side reactions is also relatively small.
PDE6抑制活性实验 PDE6 inhibitory activity experiment
考虑到本发明化合物可能对分布于视网膜的 PDE6抑制作用，进而引起视觉 障碍作用，我们按上述方法，测定了本发明的通式 1部分化合物对牛视网膜 PDE6 的抑制活性， 测定结果如下表所示：  In view of the fact that the compound of the present invention may inhibit PDE6 distributed in the retina and thereby cause visual dysfunction, we determined the inhibitory activity of the compound of the formula 1 of the present invention on bovine retina PDE6 as described above, and the results are shown in the following table. :
Figure imgf000052_0001
Figure imgf000052_0001
本发明采用 IC5。PDE6/ IC5() PDE5的比值来判断本专利化合物对于 PDE6和 PDE5的选择性，计算结果表明大部分实施例化合物具有比西地那非更强的选择 性， 因此， 相对西地那非本发明化合物引起视觉障碍的可能性更小。 The present invention employs IC 5 . The ratio of PDE6/IC 5 () PDE5 is used to judge the selectivity of the compounds of this patent for PDE6 and PDE5. The calculation results show that most of the compounds of the examples have stronger selectivity than sildenafil. Therefore, relative to sildenafil The compounds of the invention are less likely to cause visual impairment.

Claims

权利 要 求 Rights request
1、 一种由下述通式 I所示的含有吡唑并嘧啶酮的苯基胍衍生物、 其药学上可接 受的盐或其溶剂化物： A phenylhydrazine derivative containing a pyrazolopyrimidinone represented by the following formula I, a pharmaceutically acceptable salt thereof or a solvate thereof:
Figure imgf000053_0001
Figure imgf000053_0001
R1代表 H、 d-C6烷基、 C3-C6链烯基、 C3-C6环烷基、 d-C3卤代烷基或被 C3-C6环烷基取代的 d-C3烷基； R 1 represents H, dC 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl, dC 3 haloalkyl or C 3 -C 6 cycloalkyl substituted dC 3 alkyl;
R2代表 C2-C6烷基、 C3-C6链烯基、 C3-C6环烷基、 d-C3 [¾代烷基或被 C3-C6 环烷基取代的 CrC3烷基； R 2 represents C 2 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl, dC 3 [ 3⁄4 alkyl or C r substituted by C 3 -C 6 cycloalkyl C 3 alkyl;
R3代表 d-C6烷基、 C3-C6环烷基、 C3-C6链烯基、 d-C3卤代烷基、 ¾ d-C3 烷氧基取代的 CrC3烷基或被 C3-C6环烷基取代的 CrC3烷基； R 3 represents dC 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 alkenyl, dC 3 haloalkyl, 3⁄4 dC 3 alkoxy substituted C r C 3 alkyl or C 3 - C 6 cycloalkyl substituted C r C 3 alkyl;
R4和 R5各自独立地代表11、 芳基、 C¾Rn或取代或未取代的 CrC3烷基， 其中所述的取代基选自 OH、 CrC4烷氧基和卤素； R 4 and R 5 each independently represent an 11, an aryl group, C¾R n, or a substituted or unsubstituted C r C 3 alkyl, wherein said substituents are selected from OH, C r C 4 alkoxy and halogen;
R6和 R7各自独立地代表： H、 d-C6烷基、 C3-C6链烯基、 C3-C6环烷基、 OH、 OR10, CN、 N02、 NR8R9、 CONR8R9、 COR10,芳基、 Het或被取代基取代的 d-C3 烷基， 所述的取代基选自 OH、 d-C4烷氧基、 C3-C6环烷基、 卤素、 NR8R9、 芳 基和 Het; 未取代或选择性地被一个或者多个取代基取代的脒基， 所述的取代基 选自 CrC6烷基、 C3-C6环烷基、 芳基和 Het; 或者 R6和 R7可以与它们相连的氮 原子共同构成 4 ~ 8元杂环基， 该杂环基为吗啉基、 硫吗啉基、 哌啶基、 吡咯烷 基或哌嗪基， 上述杂环基并且可以选择性地被选自 OH、 CrC6烷基、 CrC4烷氧 基、 C3-C6环烷基、 芳基和 Het中的一个或者多个取代基取代； R 6 and R 7 each independently represent: H, dC 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl, OH, OR 10 , CN, N0 2 , NR 8 R 9 , CONR 8 R 9 , COR 10 , aryl, Het or dC 3 alkyl substituted by a substituent selected from OH, dC 4 alkoxy, C 3 -C 6 cycloalkyl, halogen, NR 8 R 9 , aryl and Het; an indenyl group which is unsubstituted or optionally substituted by one or more substituents selected from C r C 6 alkyl, C 3 -C 6 cycloalkyl, The aryl group and Het; or R 6 and R 7 may form a 4-8 membered heterocyclic group together with the nitrogen atom to which they are attached, and the heterocyclic group is morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl or Piperazinyl, the above heterocyclic group and optionally one selected from the group consisting of OH, C r C 6 alkyl, C r C 4 alkoxy, C 3 -C 6 cycloalkyl, aryl and Het Substituted by multiple substituents;
或者 R4和 R6或者 R5和 R6与其相连的两个氮原子能够形成 5 - 7元环；Or R 4 and R 6 or R 5 and R 6 together with two nitrogen atoms capable of forming a 5- to 7-membered ring;
R8和 R9各自独立地代表 H、 Ci-C6烷基、芳基、 Het或被取代基取代的 d-C3 烷基， 所述的取代基选自 d-C4烷氧基、 C3-C6环烷基、 芳基和 Het, 或者 R8和 R9可以与它们所连接的氮原子共同构成氮杂环丁烷基、 吡咯烷基、 哌啶基或吗 啉基； R 8 and R 9 each independently represent H, Ci-C 6 alkyl, aryl, Het or a substituted dC 3 alkyl group, the substituent being selected from dC 4 alkoxy, C 3 -C 6 cycloalkyl, aryl and Het, or R 8 and R 9 may together with the nitrogen atom to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl or Olinyl group;
R10代表 d-C6烷基、 C3-C4链烯基、 C3-C6环烷基、 芳基、 Het或被取代基取 代的 d-C3烷基， 所述的取代基选自 OH、 d-C4烷氧基、 C3-C6环烷基、 芳基和 Het; R 10 represents dC 6 alkyl, C 3 -C 4 alkenyl, C 3 -C 6 cycloalkyl, aryl, Het or dC 3 alkyl substituted with a substituent selected from OH, dC 4 alkoxy, C 3 -C 6 cycloalkyl, aryl and Het;
R11代表 CrC6烷基、 C3-C6链烯基、 C3-C6环烷基或芳基； R 11 represents C r C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl or aryl;
卤素代表F、 Cl、 Br或 I；  Halogen represents F, Cl, Br or I;
芳基代表取代或未取代的苯基， 所述的取代为选自卤素、 d-C3烷基、 d-C3 烷氧基、 CF3、 CN和 N02中的一个或多个取代基所取代； An aryl group represents a substituted or unsubstituted phenyl group, and the substitution is substituted with one or more substituents selected from the group consisting of halogen, dC 3 alkyl, dC 3 alkoxy, CF 3 , CN and NO 2 ;
Het代表含有 1 ~ 4个杂原子的芳香 5 ~ 6元杂环基， 所述的杂原子选自 N、 S和 0, 且该杂环基可以选择性地被选自卤素、 d-C3烷基、 d-C3烷氧基、 CF3、 CN和 N02中的一个或多个取代基取代； Het represents an aromatic 5- to 6-membered heterocyclic group having 1 to 4 hetero atoms, the hetero atom is selected from N, S and 0, and the heterocyclic group may be optionally selected from halogen, dC 3 alkyl. Substituting one or more substituents of dC 3 alkoxy, CF 3 , CN and NO 2 ;
在通式 I所示的含有吡唑并嘧啶酮的苯基胍衍生物含有一个或多个手性中 心的情况下， 所述^ ·生物可以为对映异构体、 非对映异构体或其混合物；  In the case where the pyrazolopyrimidinone-containing phenylhydrazine derivative of the formula I contains one or more chiral centers, the organism may be an enantiomer or a diastereomer. Or a mixture thereof;
在通式 I所示的含有吡唑并嘧啶酮的苯基胍衍生物中含有链烯基或亚烯基 混合物；  The phenyl hydrazine derivative containing pyrazolopyrimidinone represented by Formula I contains an alkenyl or alkenylene mixture;
在通式 I所示的含有吡唑并嘧啶酮的苯基胍衍生物存在互变异构体的形式 的情况下， 所述衍生物可以为单一的互变异构体或其混合物。  In the case where the pyrazolopyrimidinone-containing phenylhydrazine derivative represented by the formula I exists in the form of a tautomer, the derivative may be a single tautomer or a mixture thereof.
2、 根据权利要求 1所述的含有吡唑并嘧啶酮的苯基胍衍生物、 其药学上可 接受的盐或其溶剂化物， 其特征在于：  The phenyl hydrazine derivative containing a pyrazolopyrimidinone according to claim 1, a pharmaceutically acceptable salt thereof or a solvate thereof, which is characterized in that:
R1代表 d-C4烷基或 C3-C6环烷基； R 1 represents dC 4 alkyl or C 3 -C 6 cycloalkyl;
R2代表 C2-C4烷基或 C3-C6环烷基； R 2 represents a C 2 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group;
R3代表 Ci-C3烷基或被 Ci-C3烷氧基取代的 CrC3烷基； R 3 represents a Ci-C 3 alkyl or Ci-C 3 alkoxy-substituted C r C 3 alkyl;
R4和 R5各自独立地代表11、 芳基或 C¾R"; R 4 and R 5 each independently represent 11, aryl or C 3⁄4R";
R6和 R7各自独立地代表： H、 CrC6烷基、 C3-C6环烷基、 芳基或被取代基 取代的 d-C3烷基， 所述的取代基选自 OH、 d-C4烷氧基、 C3-C6环烷基、 NR8R9 和芳基； 取代或未被取代的脒基， 所述的取代基选自 CrC4烷基、 C3-C6环烷基、 NR8R9和芳基； 或者 R6和 R7可以与它们相连的氮原子共同构成 4 ~ 8元杂环基， 该杂环基为吗啉基、 硫吗啉基、 哌啶基、 吡咯基或哌嗪基； R 6 and R 7 each independently represent: H, C r C 6 alkyl, C 3 -C 6 cycloalkyl, aryl or dC 3 alkyl substituted with a substituent selected from OH, dC 4 alkoxy, C 3 -C 6 cycloalkyl, NR 8 R 9 and aryl; substituted or unsubstituted fluorenyl, said substituent being selected from C r C 4 alkyl, C 3 -C 6 cycloalkyl, NR 8 R 9 and aryl; or R 6 and R 7 may form a 4-8 membered heterocyclic group together with the nitrogen atom to which they are attached, the heterocyclic group being morpholinyl, thiomorpholinyl, Piperidinyl, pyrrolyl or piperazinyl;
或者 R5、 R6与其相连的两个氮原子共同形成二氢咪唑基； R8和 R9各自独立地代表 H、 Ci-C6烷基、芳基、 Het或被取代基取代的 d-C3 烷基， 所述的取代基选自 d-C4烷氧基、 C3-C6环烷基、 芳基和 Het, 或者 R8和 R9可以与它们所连接的氮原子共同构成氮杂环丁烷基、 吡咯烷基、 哌啶基或吗 啉基； Or R 5 and R 6 together with two nitrogen atoms connected thereto form a dihydroimidazolyl group; R 8 and R 9 each independently represent H, Ci-C 6 alkyl, aryl, Het or a substituted dC 3 alkyl group, the substituent being selected from dC 4 alkoxy, C 3 -C 6 cycloalkyl, aryl and Het, or R 8 and R 9 may together with the nitrogen atom to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl;
R11代表 d-C6烷基或苯基； R 11 represents dC 6 alkyl or phenyl;
Het代表吡啶基。  Het represents a pyridyl group.
3、 根据权利要求 2所述的含有吡唑并嘧啶酮的苯基胍衍生物、 其药学上可 接受的盐或其溶剂化物， 其特征在于：  The pyrazolopyrimidinone-containing phenylhydrazine derivative according to claim 2, a pharmaceutically acceptable salt thereof or a solvate thereof, which is characterized in that:
R1代表甲基； R 1 represents a methyl group;
R2代表乙基或正丙基； R 2 represents an ethyl or n-propyl group;
R3代表甲基、 乙基或正丙基； R 3 represents a methyl group, an ethyl group or a n-propyl group;
1 4为11、 乙基或苄基； 1 4 is 11, ethyl or benzyl;
1 5为11、 乙基或苯基； 1 5 is 11, ethyl or phenyl;
R6和 R7各自独立地代表： H、 甲基、 乙基、 苯基、 苄基、 3-吡啶甲基或者 被取代基取代的 C2-C3烷基， 所述的取代基选自羟基和 Ν,Ν-二甲胺基； 未取代 的或被苯基取代的脒基； 或者当 R6和 R7同时不为 Η时， R6和 R7可以与它们相 连的氮原子共同构成吗啉基、 哌啶基、 Ν-甲基哌嗪基或吡咯烷基； R 6 and R 7 each independently represent: H, methyl, ethyl, phenyl, benzyl, 3-pyridylmethyl or C 2 -C 3 alkyl substituted with a substituent selected from the group consisting of Hydroxyl and anthracene, fluorenyl-dimethylamino; unsubstituted or substituted phenyl group; or when R 6 and R 7 are not simultaneously argon, R 6 and R 7 may be combined with the nitrogen atom to which they are attached Morpholinyl, piperidinyl, hydrazine-methylpiperazinyl or pyrrolidinyl;
或者 R5、 R6与其相连的两个氮原子共同形成二氢咪唑基。 Alternatively, R 5 and R 6 together with the two nitrogen atoms to which they are attached form a dihydroimidazolyl group.
4、 根据权利要求 3所述的含有吡唑并嘧啶酮的苯基胍衍生物、 其药学上可 接受的盐或其溶剂化物， 其特征在于， 所述衍生物选自如下化合物之一： The pyrazolopyrimidinone-containing phenylhydrazine derivative according to claim 3, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein the derivative is one selected from the group consisting of:
1) N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧基 苯基] -Ν'-甲基胍； 1) N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxybenzene Base] - Ν '-methyl hydrazine;
2) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -Ν'-甲基胍； 2) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxy Phenyl] - Ν '-methyl hydrazine;
3) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-乙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧苯 基] -Ν'-甲基胍； 3) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-ethylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl ] - Ν '-methyl hydrazine;
4) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基] -Ν'-乙基 -Ν"-甲基胍；  4) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl ] -Ν'-ethyl-Ν"-methyl oxime;
5) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基] -Ν'-苯基 -Ν"-甲基胍； 6) N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧苯 基] -Ν'-苯基 -N"-甲基胍； 5) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl ] -Ν'-phenyl-Ν"-methyl hydrazine; 6) N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl ] -Ν'-phenyl-N"-methylindole;
7) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基] -Ν, Ν'-二乙基 -Ν"-甲基胍；  7) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl ] -Ν, Ν'-diethyl-hydrazine"-methyl hydrazine;
8) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -Ν'-乙基胍； 8) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxy Phenyl]-Ν'-ethyl hydrazine;
9) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -Ν'-乙基胍；  9) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxy Phenyl]-Ν'-ethyl hydrazine;
10) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -Ν', Ν"-二乙基胍；  10) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxy Phenyl]-Ν', Ν"-diethyl hydrazine;
11) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -Ν'-苯基 -N"-乙基胍；  11) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxy Phenyl]-Ν'-phenyl-N"-ethyl hydrazine;
12) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -Ν'-苯基 -N"-乙基胍；  12) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxy Phenyl]-Ν'-phenyl-N"-ethyl hydrazine;
13)Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -N, Ν', Ν"-三乙基胍； 13) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxy Phenyl] -N, Ν', Ν"-triethyl hydrazine;
14) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -N, Ν', Ν"-三乙基胍；  14) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxy Phenyl] -N, Ν', Ν"-triethyl hydrazine;
15) Ν-苄基 -Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4- 乙氧苯基] -Ν',Ν"-二乙基胍；  15) Ν-Benzyl-indole-[3-(6,7-dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl) -4-ethoxyphenyl]-Ν', Ν"-diethyl hydrazine;
16) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基] -Ν', Ν'-二乙基胍；  16) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl ] -Ν', Ν'-diethyl hydrazine;
17) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧苯 基] -Ν', Ν'-二乙基胍；  17) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl ] -Ν', Ν'-diethyl hydrazine;
18)Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-乙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -Ν', Ν'-二乙基胍； 18) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-ethylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxy Phenyl]-Ν', Ν'-diethyl hydrazine;
19) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -Ν', Ν', Ν"-三乙基胍；  19) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxy Phenyl]-Ν', Ν', Ν"-triethyl hydrazine;
20) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -Ν'-苯基 -N", Ν"-二乙基胍； 21) N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -Ν'-苯基 -N", Ν"-二乙基胍； 20) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxy Phenyl]-Ν'-phenyl-N", Ν"-diethyl hydrazine; 21) N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxy Phenyl]-Ν'-phenyl-N", Ν"-diethyl hydrazine;
22) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -N, Ν', Ν", Ν"-四乙基胍；  22) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxy Phenyl] -N, Ν', Ν", Ν"-tetraethyl hydrazine;
23) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -吡咯烷基 -1-甲脒； 23) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxy Phenyl]-pyrrolidin-1-carboxylate;
24) N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -吡咯烷基 -1-甲脒；  24) N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxy Phenyl]-pyrrolidin-1-carboxylate;
25) N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-乙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -吡咯烷基 -1-甲脒；  25) N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-ethylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxy Phenyl]-pyrrolidin-1-carboxylate;
26) N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -Ν'-乙基-吡咯烷基 -1-甲脒；  26) N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxy Phenyl]-Ν'-ethyl-pyrrolidinyl-1-carboxamidine;
27) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -Ν'-乙基-吡咯烷基 -1-甲脒；  27) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxy Phenyl]-Ν'-ethyl-pyrrolidinyl-1-carboxamidine;
28) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基] -Ν'-苯基 -吡咯烷基- 1 -甲脒； 28) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl ] -Ν'-phenyl-pyrrolidinyl-1 - formazan;
29) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -Ν'-苯基-吡咯烷基 -1-甲脒；  29) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxy Phenyl]-Ν'-phenyl-pyrrolidinyl-1-carboxamidine;
30) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -哌啶基 -1-甲脒；  30) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxy Phenyl]-piperidinyl-1-carboxamidine;
31) N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧苯 基] -哌啶基 -1-甲脒；  31) N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl - piperidinyl-1-carboxamidine;
32) N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-乙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -哌啶基 -1-甲脒；  32) N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-ethylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxy Phenyl]-piperidinyl-1-carboxamidine;
33)N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -Ν'-乙基-哌啶基 -1-甲脒； 33) N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxy Phenyl]-Ν'-ethyl-piperidinyl-1-carboxamidine;
34) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -Ν'-乙基-哌啶基 -1-甲脒；  34) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxy Phenyl]-Ν'-ethyl-piperidinyl-1-carboxamidine;
35) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -Ν'-苯基-哌啶基 -1-甲脒； 36) N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3 丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -Ν'-苯基-哌啶基 -1-甲脒； 35) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxy Phenyl]-Ν'-phenyl-piperidinyl-1-carboxamidine; 36) N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxybenzene -]'-phenyl-piperidinyl-1-carboxamidine;
37) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3 丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基]—4—甲基哌嗪基 -1—甲脒；  37) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxybenzene 4- 4-methylpiperazinyl-1 - formazan;
38) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3 丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧苯 基]—4—甲基哌嗪基 -1—甲脒；  38) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl] 4-methylpiperazinyl-1 - formazan;
39) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3 丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -Ν'-乙基 -4-甲基哌嗪基- 1 -甲脒；  39) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxybenzene -]'-ethyl-4-methylpiperazinyl- 1 -formamidine;
40) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3 丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -Ν'-苯基 -4-甲基哌嗪基- 1 -甲脒；  40) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxybenzene -]'-Phenyl-4-methylpiperazinyl- 1 -formamidine;
41) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3 丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -Ν'-苯基 -4-甲基哌嗪基- 1 -甲脒；  41) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxybenzene -]'-Phenyl-4-methylpiperazinyl- 1 -formamidine;
42) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3 丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基]-吗啉基 -1-甲脒；  42) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl] -morpholinyl-1-carboxamidine;
43) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3 丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基]-吗啉基 -1-甲脒；  43) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxybenzene Methyl]-morpholinyl-1-carboxamidine;
44) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3 乙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基]-吗啉基 -1-甲脒；  44) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3ethylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxybenzene Methyl]-morpholinyl-1-carboxamidine;
45) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3 丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -Ν'-苯基-吗啉基 -1-甲脒；  45) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxybenzene -]'-phenyl-morpholinyl-1-carboxamidine;
46) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3 丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -Ν'-苯基-吗啉基 -1-甲脒；  46) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxybenzene -]'-phenyl-morpholinyl-1-carboxamidine;
47) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3 丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -Ν'-苄基胍； 47) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxybenzene Base] - Ν '-benzyl hydrazine;
48) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3 丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧苯 基] -Ν'-苄基胍； 48) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl] - Ν ' -Benzyl hydrazine ;
49) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3 丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -Ν'-乙基 -Ν"-苄基胍；  49) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxybenzene ]]-Ν'-ethyl-Ν"-benzyl hydrazine;
50) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3 丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -Ν'-苯基 -Ν"-苄基胍； 51) N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-丙氧苯 基] -Ν'-苯基 -N"-苄基胍； 50) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxybenzene ]]-Ν'-phenyl-indole"-benzyl hydrazine; 51) N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxy Phenyl]-Ν'-phenyl-N"-benzyl hydrazine;
52) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3-d]嘧啶 -5-基) -4-乙氧苯 基] -N, Ν'-二乙基 -Ν"-苄基胍；  52) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxy Phenyl]-N, Ν'-diethyl-fluorene"-benzyl hydrazine;
53)Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧苯 基] -Ν'-乙基- Ν'-(2-羟乙基) -胍； 53) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl ] -Ν'-ethyl-Ν'-(2-hydroxyethyl)-oxime;
54) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基]- Ν'-甲基- Ν'-(Ν,Ν-二甲基 -2-胺乙基) -胍；  54) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl ]- Ν'-Methyl-Ν'-(Ν,Ν-dimethyl-2-aminoethyl)-胍;
55) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基] -Ν'-甲基 -Ν'-(2-羟乙基) -胍；  55) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl ] -Ν'-methyl-Ν'-(2-hydroxyethyl)-oxime;
56) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧苯 基] -Ν'-甲基 -Ν'-(2-羟乙基) -胍；  56) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl ] -Ν'-methyl-Ν'-(2-hydroxyethyl)-oxime;
57) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-乙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧苯 基] -Ν'-甲基 -Ν'-(2-羟乙基) -胍；  57) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-ethylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl ] -Ν'-methyl-Ν'-(2-hydroxyethyl)-oxime;
58)Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧苯 基] -Ν'-(3-吡啶甲基) -胍； 58) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl ] -Ν'-(3-pyridylmethyl)-oxime;
59) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基] -Ν'-(3-吡啶甲基) -胍；  59) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl ] -Ν'-(3-pyridylmethyl)-oxime;
60) 1-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基]-双胍；  60) 1-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl ]-胍胍;
61) 1-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧苯 基]-双胍；  61) 1-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl ]-胍胍;
62) 1-乙基 -1-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙 氧苯基] -双胍；  62) 1-Ethyl-1-[3-(6,7-dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4 -ethoxyphenyl]-biguanide;
63)1-乙基 -1-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙 氧苯基] -双胍； 63) 1-Ethyl-1-[3-(6,7-dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4 -propoxyphenyl]-biguanide;
64) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基] -Ν'-(3-羟丙基) -胍；  64) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl ] -Ν'-(3-hydroxypropyl)-oxime;
65) 1-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧苯 基] -Ν'-(3-羟丙基) -胍； 66) N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基] -Ν'-苯基 -N"-(3-羟丙基) -胍； 65) 1-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl ] -Ν'-(3-hydroxypropyl)-oxime; 66) N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl ] -Ν'-phenyl-N"-(3-hydroxypropyl)-indole;
67) N-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基] -Ν'-苯基胍；  67) N-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl ] -Ν'-phenyl hydrazine;
68) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧苯 基]界苯基胍；  68) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propoxyphenyl界 phenyl hydrazine;
69) Ν-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基] -Ν', Ν'-二 (2-羟基乙基) -胍；  69) Ν-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl ] -Ν', Ν'-bis(2-hydroxyethyl)-oxime;
70) 2-{2-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基]胺基 -4,5-二氢-咪唑- 1 -基} -乙醇；  70) 2-{2-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-B Oxyphenyl]amino-4,5-dihydro-imidazolium-1-yl}-ethanol;
71) 2-{2-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧苯 基]胺基 -4,5-二氢-咪唑- 1 -基} -乙醇；  71) 2-{2-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-propane Oxyphenyl]amino-4,5-dihydro-imidazolium-1-yl}-ethanol;
72) 2-{2-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-乙基 吡唑并 [4,3- 嘧啶 -5-基) -4-丙氧苯 基]胺基 -4,5-二氢-咪唑- 1 -基} -乙醇；  72) 2-{2-[3-(6,7-Dihydro-1-methyl-7-oxo-3-ethylpyrazolo[4,3-pyrimidin-5-yl)-4-propane Oxyphenyl]amino-4,5-dihydro-imidazolium-1-yl}-ethanol;
73) 1-[3-(6,7-二氢 -1-甲基 -7-氧代 -3-丙基 吡唑并 [4,3- 嘧啶 -5-基) -4-乙氧苯 基 ]-5-苯基双胍。 73) 1-[3-(6,7-Dihydro-1-methyl-7-oxo-3-propylpyrazolo[4,3-pyrimidin-5-yl)-4-ethoxyphenyl ]- 5 -Phenylbiguanide.
5、 根据权利要求 1所述的含有吡唑并嘧啶酮的苯基胍衍生物、 其药学上可 接受的盐或其溶剂化物， 其特征在于， 所述药学上可接受的盐为所述含有吡唑 并嘧啶酮的苯基胍衍生物与盐酸、 氢溴酸、 硫酸、 磷酸、 有机羧酸或有机横酸 形成的酸加成盐， 或者与碱形成的钠盐或钾盐。  The pyrazolopyrimidinone-containing phenylhydrazine derivative, a pharmaceutically acceptable salt thereof or a solvate thereof, according to claim 1, wherein the pharmaceutically acceptable salt is the content An acid addition salt of a phenylhydrazine derivative of a pyrazolopyrimidinone with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, an organic carboxylic acid or an organic acid, or a sodium or potassium salt formed with a base.
6、 根据权利要求 1所述的含有吡唑并嘧啶酮的苯基胍衍生物、 其药学上可 接受的盐或其溶剂化物， 其特征在于， 所述溶剂化物为所述含有吡唑并嘧啶酮 的苯基胍衍生物的水合物。  The pyrazolopyrimidinone-containing phenylhydrazine derivative, a pharmaceutically acceptable salt thereof or a solvate thereof, according to claim 1, wherein the solvate is the pyrazolopyrimidine a hydrate of a phenyl hydrazine derivative of a ketone.
7、 由通式 IV所示的吡啶并嘧啶酮衍生物：  7. A pyridopyrimidinone derivative represented by the formula IV:
Figure imgf000060_0001
Figure imgf000060_0001
其中， R1代表 H、 d-C6烷基、 C3-C6链烯基、 C3-C6环烷基、 d-C3卤代烷 基或被 C3-C6环烷基取代的 d-C3烷基； Wherein, R 1 stands H, dC 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl, dC 3 haloalkoxy a dC 3 alkyl group substituted with a C 3 -C 6 cycloalkyl group;
R2代表 C2-C6烷基、 C3-C6链烯基、 C3-C6环烷基、 d-C3 [¾代烷基或被 C3-C6 环烷基取代的 crc3烷基； R 2 represents C 2 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl, dC 3 [ 3⁄4 alkyl or c r substituted by C 3 -C 6 cycloalkyl c 3 alkyl;
R3代表 d-C6烷基、 C3-C6环烷基、 C3-C6链烯基、 d-C3卤代烷基、 ¾ d-C3 烷氧基取代的 crc3烷基或被 c3-c6环烷基取代的 crc3烷基； R 3 represents dC 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 alkenyl, dC 3 haloalkyl, 3⁄4 dC 3 alkoxy substituted c r c 3 alkyl or c 3 - a c 6 cycloalkyl substituted c r c 3 alkyl group;
R4代表 H、 芳基、 C¾Rn或取代或未取代的 CrC3烷基， 其中所述的取代 基选自 OH、 d-C4烷氧基和卤素， R 4 represents H, aryl, C¾R n, or a substituted or unsubstituted C r C 3 alkyl, wherein said substituents are selected from OH, dC 4 alkoxy and halogen,
卤素代表F、 Cl、 Br或 I；  Halogen represents F, Cl, Br or I;
芳基代表取代或未取代的苯基， 所述的取代为选自卤素、 d-C3烷基、 d-C3 烷氧基、 CF3、 CN和 N02中的一个或多个取代基所取代。 The aryl group represents a substituted or unsubstituted phenyl group which is substituted with one or more substituents selected from the group consisting of halogen, dC 3 alkyl, dC 3 alkoxy, CF 3 , CN and NO 2 .
8、 根据权利要求 7所述的吡啶并嘧啶酮衍生物， 其特征在于：  8. The pyridopyrimidinone derivative according to claim 7, wherein:
R1代表 d-C4烷基或 C3-C6环烷基； R 1 represents dC 4 alkyl or C 3 -C 6 cycloalkyl;
R2代表 C2-C4烷基或 C3-C6环烷基； R 2 represents a C 2 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group;
R3代表 Ci-C3烷基或被 Ci-C3烷氧基取代的 CrC3烷基； R 3 represents a Ci-C 3 alkyl or Ci-C 3 alkoxy-substituted C r C 3 alkyl;
R4代表 H、 芳基或 C¾Rn。 R 4 represents H, aryl or C3⁄4R n .
9、 根据权利要求 8所述的吡啶并嘧啶酮衍生物， 其特征在于：  9. The pyridopyrimidinone derivative according to claim 8, wherein:
R1代表甲基； R 1 represents a methyl group;
R2代表乙基或正丙基； R 2 represents an ethyl or n-propyl group;
R3代表甲基、 乙基或正丙基； R 3 represents a methyl group, an ethyl group or a n-propyl group;
1 4为11、 乙基或苄基。 1 4 is 11, ethyl or benzyl.
10、 由通式 II所示的吡唑并嘧啶酮的苯基疏脲衍生物：  10. A phenyl sulfa urea derivative of pyrazolopyrimidinone represented by the general formula II:
Figure imgf000061_0001
Figure imgf000061_0001
其中， R1代表 H、 d-C6烷基、 C3-C6链烯基、 C3-C6环烷基、 d-C3卤代烷 基或被 C3-C6环烷基取代的 d-C3烷基； Wherein, R 1 stands H, dC 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl group, a substituted dC 3 haloalkyl or C 3 -C 6 cycloalkyl group dC 3 ;
R2代表 C2-C6烷基、 C3-C6链烯基、 C3-C6环烷基、 d-C3 [¾代烷基或被 C3-C6 环烷基取代的 CrC3烷基； R 2 represents C 2 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl, dC 3 [ 3⁄4 alkyl or by C 3 -C 6 a cycloalkyl-substituted C r C 3 alkyl group;
R3代表 d-C6烷基、 C3-C6环烷基、 C3-C6链烯基、 d-C3卤代烷基、 ¾ d-C3 烷氧基取代的 crc3烷基或被 c3-c6环烷基取代的 crc3烷基； R 3 represents dC 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 alkenyl, dC 3 haloalkyl, 3⁄4 dC 3 alkoxy substituted c r c 3 alkyl or c 3 - a c 6 cycloalkyl substituted c r c 3 alkyl group;
R4和 R5各代表 H、 芳基、 C¾Rn或取代或未取代的 CrC3烷基， 其中所述 的取代基选自 OH、 CrC4烷氧基和卤素， R 4 and R 5 each represent H, aryl, C¾R n, or a substituted or unsubstituted C r C 3 alkyl, wherein said substituents are selected from OH, C r C 4 alkoxy and halogen,
卤素代表F、 Cl、 Br或 I；  Halogen represents F, Cl, Br or I;
芳基代表取代或未取代的苯基， 所述的取代为选自卤素、 d-C3烷基、 d-C3 烷氧基、 CF3、 CN和 N02中的一个或多个取代基所取代。 The aryl group represents a substituted or unsubstituted phenyl group which is substituted with one or more substituents selected from the group consisting of halogen, dC 3 alkyl, dC 3 alkoxy, CF 3 , CN and NO 2 .
11、根据权利要求 10所述的吡唑并嘧啶酮的苯基硫脲衍生物，其特征在于： R1代表 d-C4烷基或 C3-C6环烷基； The phenylthiourea derivative of pyrazolopyrimidinone according to claim 10, wherein R 1 represents a dC 4 alkyl group or a C 3 - C 6 cycloalkyl group;
R2代表 C2-C4烷基或 C3-C6环烷基； R 2 represents a C 2 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group;
R3代表 Ci-C3烷基或被 Ci-C3烷氧基取代的 CrC3烷基； R 3 represents a Ci-C 3 alkyl or Ci-C 3 alkoxy-substituted C r C 3 alkyl;
R4和 R5代表 H、 芳基或 C¾Rn。 R 4 and R 5 represent H, aryl or C3⁄4R n .
12、根据权利要求 11所述的吡唑并嘧啶酮的苯基硫脲衍生物，其特征在于： R1代表甲基； The phenylthiourea derivative of pyrazolopyrimidinone according to claim 11, wherein R 1 represents a methyl group;
R2代表乙基或正丙基； R 2 represents an ethyl or n-propyl group;
R3代表甲基、 乙基或正丙基； R 3 represents a methyl group, an ethyl group or a n-propyl group;
1 4为11、 乙基或苄基； 1 4 is 11, ethyl or benzyl;
1 5为11、 乙基或苯基。 1 5 is 11, ethyl or phenyl.
13、 一种权利要求 1所述的通式 I所示的含有吡唑并嘧啶酮的苯基胍衍 生物的制备方法， 其特征在于：  A method for producing a pyrazolopyrimidinone-containing phenyl fluorene derivative of the formula I according to claim 1, which is characterized in that:
(i)当 R R2、 R3、 R4、 R5、 R6、 R7如权利要求 1定义， 且 R6、 R7都不为 H、 取代或未取代脒基时， 所述制备方法包括如下步骤： (i) when RR 2 , R 3 , R 4 , R 5 , R 6 , R 7 are as defined in claim 1, and R 6 and R 7 are not H, substituted or unsubstituted fluorenyl groups, the preparation method Including the following steps:
Figure imgf000062_0001
由通式 I I所示化合物与通式 I I I所示化合物通过亲核取代反应制得通式 I 所示化合物；
Figure imgf000062_0001
The compound of the formula I is obtained by a nucleophilic substitution reaction between a compound of the formula II and a compound of the formula III;
(ii)当 I 1、 R2、 R3、 R4、 R5如权利要求 1定义， R6为 H, R7为未取代的脒基 时， 所述制备方法包括如下步骤： (ii) When I 1 , R 2 , R 3 , R 4 , R 5 are as defined in claim 1, R 6 is H, and R 7 is an unsubstituted fluorenyl group, the preparation method comprises the following steps:
Figure imgf000063_0001
Figure imgf000063_0001
!ί口成反应制得通式 I所 示 ^汙生物；  ί口成反应 produced by the general formula I;
当 I 1、 R2、 R3、 R4、 R5如权利要求 1定义， R6为 H, R7为取代的脒基时， 制备方法包括如下步骤： When I 1 , R 2 , R 3 , R 4 , R 5 are as defined in claim 1, R 6 is H, and R 7 is a substituted fluorenyl group, the preparation method comprises the following steps:
Figure imgf000063_0002
Figure imgf000063_0002
IV IV
VI VI
由通式 IV所示化合物与 NaN(CN)2通过亲核加成反应制得通式 VI所示化合 物， 通式 VI所示化合物再与通式 III所示化合物通过亲核加成反应制得通式 I 所示 ^生物。 A compound of the formula VI is obtained by a nucleophilic addition reaction with a compound of the formula IV and NaN(CN) 2 , and a compound of the formula VI is further reacted with a compound of the formula III by a nucleophilic addition reaction. The formula II shows the organism.
14、 一种抑制 V型磷酸二酯酶的药物组合物， 其特征在于， 所述的组合物包 含治疗有效量的一种或多种权利要求 1〜6所述的吡唑并嘧啶酮的苯基胍衍生物、 其药学上可接受的盐或其溶剂化物， 并包含至少一种可药用辅料。  A pharmaceutical composition for inhibiting a V-type phosphodiesterase, characterized in that the composition comprises a therapeutically effective amount of one or more benzenes of the pyrazolopyrimidinone according to claims 1 to 6. A base derivative, a pharmaceutically acceptable salt thereof, or a solvate thereof, and comprising at least one pharmaceutically acceptable adjuvant.
15、 权利要求 1至 6中任意一项所述的含有吡唑并嘧啶酮的苯基胍衍生物、 其药学上可接受的盐或其溶剂化物在制备治疗或预防需要使用 cGMP PDE5抑 制剂的疾病的药物中的用途。  The pyrazolopyrimidinone-containing phenylhydrazine derivative according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof or a solvate thereof, for use in the preparation of a treatment or prevention requiring the use of a cGMP PDE5 inhibitor Use in medicines for diseases.
16、 根据权利要求 15所述的用途， 所述的含有吡唑并嘧啶酮的苯基胍衍生 物、 其药学上可接受的盐或其溶剂化物在制备治疗或预防男性勃起功能障碍、 良性前列腺增生、 女性性功能障碍、 早产、 痛经、 膀胱出口梗阻、 失禁、 不稳 定的和变异的 Prinzmetal心绞痛、 高血压、 肺动脉高压、 充血性心衰、 肾衰竭、 动脉粥样硬化、 中风、 周围血管疾病、 雷诺氏症、 炎症性疾病、 支气管炎、 慢 性哮喘、 过敏性哮喘、 过敏性鼻炎、 青光眼、 以及特征为肠蠕动障碍的疾病的 药物中的用途。 16. The use according to claim 15, wherein the pyrazolopyrimidinone-containing phenylhydrazine derivative is derived , pharmaceutically acceptable salts thereof or solvates thereof for the preparation or treatment of erectile dysfunction, benign prostatic hyperplasia, female sexual dysfunction, premature labor, dysmenorrhea, bladder outlet obstruction, incontinence, instability and variation of Prinzmetal angina in males , hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, stroke, peripheral vascular disease, Raynaud's disease, inflammatory disease, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, And use in a medicament characterized by a disease of intestinal peristalsis.
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CN101456862B (en) * 2007-12-12 2012-10-24 上海特化医药科技有限公司 Phenylguanidine derivates containing pyrazolo pyrimidinone, medicament composition thereof as well as preparation method and application thereof
CN103755709A (en) * 2014-01-15 2014-04-30 广东药学院 Microwave-assisted preparation method of sildenafil derivatives
CN115097026A (en) * 2022-06-08 2022-09-23 河北常山生化药业股份有限公司 Method for detecting pyrazolopyrimidine benzene sulfonate compound from medicine

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