WO2019000504A1 - 5型磷酸二酯酶抑制剂及其制备方法和用途 - Google Patents

5型磷酸二酯酶抑制剂及其制备方法和用途 Download PDF

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WO2019000504A1
WO2019000504A1 PCT/CN2017/093149 CN2017093149W WO2019000504A1 WO 2019000504 A1 WO2019000504 A1 WO 2019000504A1 CN 2017093149 W CN2017093149 W CN 2017093149W WO 2019000504 A1 WO2019000504 A1 WO 2019000504A1
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tetrahydro
pyrimidin
pyrrolo
pyrido
ethylthiophen
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PCT/CN2017/093149
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French (fr)
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娄红祥
郑泓波
孙斌
李琳
高云
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山东大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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  • the invention belongs to the field of medicine and pharmacy, and particularly relates to a preparation method of a compound of ⁇ -tetrahydroporphyrin and a kind of pyrrolo[3,4-b]quinolinone and as a type 5 phosphodiesterase inhibitor. Treatment related medical conditions.
  • Type 5 phosphodiesterase specifically hydrolyzes cGMP, which regulates the level of intracellular cGMP and is involved in many key biophysiological processes in the body.
  • the main function of the action of PDE5 inhibitors is to accumulate intracellular cGMP by inhibiting the hydrolysis of cGMP by cDE5. Therefore, PDE5 is an ideal drug target for the treatment of diseases such as male erectile dysfunction (MED) and pulmonary hypertension (PAH) related to cGMP levels.
  • MED male erectile dysfunction
  • PAH pulmonary hypertension
  • Tribulus terrestris L. is a traditional Chinese medicine.
  • the total saponins of scorpion saponins play an important role in the cardiovascular system, which can significantly increase the blood supply to the ischemic area, improve the cerebral circulation and protect the ischemic brain tissue.
  • sputum is also considered to have the effect of improving sexual function. Therefore, the structural modification and modification of the active natural products isolated from sputum is of great significance for the design of new PDE5 inhibitors.
  • the present invention relates to the following technical solutions:
  • X represents a sulfur atom or an oxygen atom
  • Y represents a carbon atom or a nitrogen atom
  • R 1 represents a hydrogen atom, a chlorine atom, a methyl group or a methoxy group
  • R 2 represents a hydrogen atom, a bromine atom, a pyridine, a fluorine-substituted pyridine or a methoxy-substituted benzene ring;
  • R 3 represents a hydrogen atom, a C1-C10 alkyl group, a C1-C10 alkoxy group or a C1-C4 alkyl alcohol, and the position of the R 3 substituent is at the C-3, C-4 or C-5 position.
  • the compound of the formula (I) is:
  • the pharmaceutically acceptable salt of the above compound is preferably a salt of the above compound with an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid or hydrobromic acid; or a salt of an organic acid such as methanesulfonic acid, toluenesulfonic acid or trifluoroacetic acid.
  • an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid or hydrobromic acid
  • an organic acid such as methanesulfonic acid, toluenesulfonic acid or trifluoroacetic acid.
  • the present invention also provides a process for the preparation of the above compound or a pharmaceutically acceptable salt thereof, and the synthesis route of the compound is as follows:
  • X represents a sulfur atom or an oxygen atom
  • Y represents a carbon atom or a nitrogen atom
  • R 1 represents a hydrogen atom, a chlorine atom, a methyl group or a methoxy group
  • R 2 represents a hydrogen atom, a bromine atom, a pyridine, a fluorine-substituted pyridine or a methoxy-substituted benzene ring;
  • R 3 represents a hydrogen atom, a C1-C10 alkyl group, a C1-C10 alkoxy group or a C1-C4 alkyl alcohol, and the R 3 substituent is at a C-3, C-4 or C-5 position;
  • the formula (VIII) is an organoboron reagent, preferably a 2-borate, a boronic acid ester or a boric acid of a heterocyclic compound, further preferably a heterocyclic 2-fluoroboric acid potassium compound, the heterocyclic 2-fluoroboric acid potassium salt
  • the structural formula of the compound is as follows:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt thereof, which may be used either as a monomer or as a mixture of isomers.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers, excipients and/or diluents.
  • the pharmaceutical composition comprises one or more pharmaceutically or food acceptable excipients.
  • the excipients used may be solid or liquid.
  • Solid form preparations include powders, tablets, dispersion granules, capsules, pills, and suppositories. Powders and tablets may contain from about 0.1% to about 99.9% active ingredient.
  • Suitable solid adjuvants can be magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, pills and capsules are solid dosage forms suitable for oral administration.
  • the liquid form preparations include solutions, suspensions and emulsions, and examples thereof are aqueous solutions for parenteral injection or water-propylene glycol solutions, or oral solutions in which sweeteners and contrast agents are added. In addition, it can also be used as a small water needle for injection, a freeze-dried powder for injection, a large infusion or a small infusion.
  • the pharmaceutical composition is a solid oral preparation, a liquid oral preparation or an injection.
  • the pharmaceutical composition is a tablet, a dispersible tablet, an enteric coated tablet, a chewable tablet, an orally disintegrating tablet, a capsule, a sugar coating agent, a granule, a dry powder, an oral solution, a small water injection needle for injection, and an injection. Freeze dry powder, large infusion or small infusion.
  • the present invention also discloses the above compounds, and pharmaceutically acceptable salts thereof, or pharmaceutically acceptable pharmaceutical compositions containing any of the entities for the preparation of a medicament for treating, alleviating or preventing a disease or disease state associated with PDE5 in a mammal.
  • Use in medicine for example, the use of a PDE5 inhibitor.
  • Such diseases include, but are not limited to, male erectile dysfunction (MED), female sexual dysfunction (FSD), premature labor, dysmenorrhea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable, and variant ( Principe Tortoll) angina, hypertension, lung Arterial hypertension (PAH), congestive heart failure, arteriosclerosis, stroke, peripheral vascular disease, disease with reduced vascular disease, chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma or characterized by intestinal motility disorder The disease.
  • the disease is male erectile dysfunction (MED) or pulmonary hypertension (PAH).
  • MED male erectile dysfunction
  • PAH pulmonary hypertension
  • the pharmaceutically acceptable pharmaceutical composition of the compound of the formula (I) or the formula (II) prepared according to the present invention and a pharmaceutically acceptable salt thereof or any one of the entities thereof can be used for the preparation of prophylaxis and/or Or treatment of male erectile dysfunction (MED), female sexual dysfunction (FSD), premature labor, dysmenorrhea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (Prinz Moto Angina, hypertension, pulmonary hypertension (PAH), congestive heart failure, arteriosclerosis, stroke, peripheral vascular disease, disease with reduced vascular disease, chronic asthma, bronchitis, allergic asthma, allergic rhinitis, Glaucoma or an agent characterized by a disease of intestinal motility disorder.
  • another subject of the present invention is a treatment for male erectile dysfunction (MED), female sexual dysfunction (FSD), premature labor, dysmenorrhea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, and stability.
  • MED male erectile dysfunction
  • FSD female sexual dysfunction
  • BPH benign prostatic hyperplasia
  • terapéuticaally effective amount refers to the amount of therapeutic agent required to treat, ameliorate, a targeted disease or condition or to exhibit a detectable therapeutic effect.
  • the compounds of the invention are effective over a relatively wide dosage range.
  • the dosage of a pharmaceutically acceptable pharmaceutical composition comprising a compound of the formula (I) or formula (II) of the present invention and a pharmaceutically acceptable salt thereof containing any one of the entities may be determined by a doctor according to the relevant circumstances. . These conditions include: the subject's physical condition, route of administration, age, weight, individual response to the drug, severity of symptoms, and the like.
  • the compound of the above formula (I) or formula (II), a pharmaceutically acceptable salt thereof or the pharmaceutical composition may also be used in combination with at least one other for the treatment, alleviation or prevention of mammals and PDE5 during treatment.
  • a drug combination for a related disease or disease state can be used to treat, including but not limited to, male erectile dysfunction (MED), female sexual dysfunction (FSD), premature labor, dysmenorrhea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable, and variability.
  • PAH pulmonary hypertension
  • the compound prepared by the invention has the advantages of clear target, high safety and outstanding active effect, and has good application in preparing medicine for treating PDE5-related diseases, especially male erectile dysfunction (MED) or pulmonary hypertension (PAH). prospect;
  • MED male erectile dysfunction
  • PAH pulmonary hypertension
  • the preparation method of the compound of the invention is simple, the reaction condition is mild, the raw material is cheap and easy to obtain, and only a structural modification and modification of 2 to 3 steps can rapidly and massively prepare and obtain a plurality of compounds having a completely new structure, and have good at the same time.
  • the economy is extremely large in industrial production value.
  • Figure 1 (a) shows the relaxation of compound IIA and its optically pure enantiomer against arterial contraction caused by norepinephrine
  • Figure 1 (b) shows compound IIB and its optically pure enantiomer Relaxation of arterial contraction caused by norepinephrine
  • Figure 2 (a) is an HPLC chromatogram of the compound II-A optical isomer (R)-IIA;
  • Figure 2 (b) is an HPLC chromatogram of the compound II-A optical isomer (S)-IIA;
  • Figure 3 (a) is an HPLC chromatogram of the compound II-B optical isomer (R)-IIB;
  • Figure 3 (b) is an HPLC chromatogram of the compound II-B optical isomer (S)-IIB;
  • Figure 4 (a) shows the inhibition rate of PDE5 by different concentrations of compound II-A
  • Figure 4 (b) shows the inhibition rate of PDE5 by different concentrations of sildenafil.
  • X represents a sulfur atom or an oxygen atom
  • Y represents a carbon atom or a nitrogen atom
  • R 1 represents a hydrogen atom, a chlorine atom, a methyl group or a methoxy group
  • R 2 represents a hydrogen atom, a bromine atom, a pyridine, a fluorine-substituted pyridine or a methoxy-substituted benzene ring;
  • R 3 represents a hydrogen atom, a C1-C10 alkyl group, a C1-C10 alkoxy group or a C1-C4 alkyl alcohol, and the R 3 substituent is at a C-3, C-4 or C-5 position;
  • the present invention also includes pharmaceutically acceptable salts, prodrug compounds and active metabolites of these compounds;
  • the compounds of the formula (I) and the formula (II) respectively contain an asymmetric hand-type carbon atom, respectively, in the form of two enantiomers, there is a significant difference in the inhibitory activity of the enantiomers.
  • the invention therefore includes the individual enantiomers of formula (I) and formula (II), racemates or mixtures thereof in any ratio. Separation of the enantiomers can be accomplished by conventional techniques.
  • the compounds of the formula (II) II-A and II-B can be subjected to fractional crystallization by resolution on a hand-type HPLC column or a suitable salt or derivative thereof; the compound of the formula (II) can also be optically pure (I)
  • the compound is prepared by a corresponding chemical reaction, and the single enantiomer of the compound of formula (I) can be resolved by HPLC chromatography or by diastereomeric reaction of the racemate with an appropriately optically active acid or base.
  • the isomer salts are fractionally crystallized; optically pure compounds of formula (I) can also be prepared by chemical reaction under suitable catalytic conditions.
  • stereoisomers of the compounds of formula (I) or formula (II) will be embraced within the scope of the invention.
  • a method for preparing the above compound is disclosed, and the synthetic route provided by the present invention is as follows.
  • the preparation method can rapidly synthesize the compound of the formula (I) and the formula (II) or an analogue thereof, in particular It is suitable for the synthesis of ⁇ -tetrahydroporphyrin substituted at the C-1 position and related derivatives thereof, such as pyrrolo[3,4-b]quinolinone compounds.
  • the compound of the formula (III) can generally be purchased directly from a commercial product. If it is not commercially available, it can be prepared according to the literature using a corresponding starting material such as indole-3-carbaldehyde.
  • R 1 may be a hydrogen atom, a chlorine atom, a methyl group or a methoxy group;
  • the compound of the formula (IV) can be referred to the literature to obtain the corresponding ⁇ -tetrahydroporphyrin by the Pictet-Spengler reaction with the tryptamine hydrochloride of the compound of the formula (III), and the reaction yield is generally more than 90%.
  • the compound (V) can be produced via the compound (IV) and the corresponding halogenated aromatic ring starting material, wherein Y and R 2 represent the meanings as described above. Specifically, Y represents a carbon atom or a nitrogen atom, and R 2 represents hydrogen. An atom, a bromine atom, a pyridine ring or a benzene ring, wherein R 2 is introduced into the pyridine ring or the benzene ring is mainly carried out by palladium-catalyzed Suzuki coupling, Stille coupling.
  • the synthetic compound (V) is mainly used in the following three ways:
  • halogenated Aromatic Hydrocarbons Most of the halogenated aromatic hydrocarbons are commercially available or prepared as described below for the Suzuki coupling reaction.
  • the conversion rate is generally greater than 90%, and the corresponding compound can be obtained by recrystallization; when the boric acid is pyridine-4-boronic acid or pyridine-3-boronic acid, column chromatography separation is required. The corresponding pure products were obtained in a yield of 42% and 46%, respectively; wherein the palladium catalyst may also be a catalyst such as Pd 2 (dba) 3 , palladium acetate or palladium dichloride.
  • N-arylation process when the aromatic ring is a pyrimidine ring, it is mainly prepared by aromatic nucleophilic substitution reaction of compound IV with a halogenated compound; when the aromatic ring is a pyridine ring, that is, Y represents a carbon atom, similar
  • the aromatic nucleophilic substitution reaction has a yield of less than 5% and is therefore generally prepared by Buchwald-Hartwig reaction conditions.
  • the phosphorus ligand may be BINAP or a similar derivative thereof.
  • Compound V is cross-dehydrogenically coupled with the corresponding organoboron reagent VIII under oxidative conditions to form the corresponding C-1 substituted porphyrin derivative I.
  • X represents a sulfur atom or an oxygen atom
  • R 3 represents a C1-C10 alkyl group, a C1-C10 alkoxy group or a C1-C4 alkyl alcohol, and the position of the substituent is C-3, C- 4 or C-5.
  • the oxidizing agent is selected from the group consisting of dichlorodicyanobenzoquinone, tetramethylpiperidine oxynitride, trityl salt, tert-butylperoxide or hydroxyphthalimide; organoboron reagent VIII
  • the 2-borate, borate or boric acid of the heterocyclic compound can be used; the preparation method of the oxidizing agent TEMPO tetrafluoroborate is described in J. Med. Chem. 2016, 59, 5063-5076.
  • the specific process for preparing the potassium fluoroborate test compound and the chemical reaction process for cross-dehydrogenation coupling are as follows:
  • the preparation of the fluoroborate compound can be prepared by referring to the corresponding literature, and the complex five-membered heterocyclic derivative of the substituent can also be prepared according to the literature.
  • Compound V is obtained by reacting a heterocyclic 2-fluoroboric acid potassium compound VIII in the presence of TEMPO.
  • the compound of the formula (II) is mainly obtained by oxidation of a compound of the formula (I) via Winterfeldt.
  • the chemical process can be carried out in the presence of potassium t-butoxide/oxygen or in the presence of 18-crown-6 or potassium superoxide.
  • the base can be replaced with sodium hydride. It should be particularly noted that when the molecule represented by R 3 contains a silylated alkyl alcohol, the basic reaction conditions of potassium t-butoxide can simultaneously remove the silicon protecting group.
  • the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable pharmaceutical composition containing any one of the entities is disclosed.
  • MED male erectile dysfunction
  • FSD female sexual dysfunction
  • BPH benign prostatic hyperplasia
  • bladder outlet obstruction incontinence, and stability.
  • Preferred therapeutic conditions are male erectile dysfunction (MED) and pulmonary hypertension (PAH).
  • the present invention measures the in vitro inhibitory activity of the compound against PDE5 by the method of J. Biomol. Screen., 2002, 7, 215-222, and indicates that the above compound or a pharmaceutically acceptable salt thereof is prepared for the treatment and/or prevention of lactation.
  • the structures of the compounds of the formulae (I) and (II) and the symbols of X, Y, R 1 , R 2 and R 3 have the same meanings as described above.
  • the IC 50 value of the particularly preferred monomeric compound AI represented by the general formula (II) for PDE5 inhibition and the selective multiple of some of the PDE isoforms are as follows.
  • b SN Sidenafil, sildenafil, PDE 5-6 for experimental data, PDE 1-4 selective data reference J. Med. Chem. 2002, 45, 4094-4096; PDE11 selective data reference Int. J. Clin. Pract. 2006, 60, 967-975.
  • the invention also relates to the effect of preferred compounds IIA, IIB on vasodilation.
  • Preparation of isolated isolated arterial rings in rabbits, determination of preferred aortic ring tension for norepinephrine (NE) pre-contraction The effect and calculation of the relaxation rate of the vascular ring after the action of IIA, IIB and its optically pure enantiomers.
  • NE norepinephrine
  • the present invention also provides pharmacokinetic parameters of preferred compounds (R)-IIA, (R)-IIB.
  • a 45 ⁇ L enzymatic reaction system was prepared at the following concentrations: 40 mM MOPS, pH 7.5, 0.5 mM EDTA, 15 mM MgCl 2 , 0.15 mg/ml BSA, 1 mM DTT, 0.05% Proclin 200, 15 ng/ml PDE 5, 100 nM FAM- Cyclic-3', 5'-AMP and 100 nM Compound II-A (or equal concentrations of DMSO). After the reaction system was kept at 25 ° C for 1 h, 100 ⁇ L of the diluted IMAP solution was added and shaken at a low speed for 1 h at 25 ° C.
  • the inhibition rate of PDE5 was determined by compound II-A at 8 concentrations of 0.03nM-1 ⁇ M.
  • the dose and inhibition rate were transformed by nonlinear regression equation and calculated by Prism GraphPad software to obtain the corresponding IC 50 values.
  • the results for Compound II-A and the positive control sildenafil were as follows.
  • the IC 50 value of Compound II-A was calculated to be 0.60 ⁇ 0.01 nM, and the IC 50 value of sildenafil was 3.1 ⁇ 0.57 nM.

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Abstract

提供了一种5型磷酸二酯酶抑制剂、其制备方法及在用于制备治疗、缓解或预防哺乳动物与PDE5相关的疾病或疾病状态的药物中的用途。该化合物的结构式为 I 或 II 。该化合物制备方法简单，反应条件温和，原料廉价易得，制备得到抑制剂靶点明确，安全性高，活性效果突出，在制备治疗与PDE5相关的疾病特别是男性勃起功能障碍(MED)或肺动脉高压(PAH)的药物中具有很好的应用前景。

Description

5型磷酸二酯酶抑制剂及其制备方法和用途 技术领域
本发明属于医药制药领域，具体涉及一类β-四氢咔啉和一类吡咯并[3,4-b]喹啉酮的化合物的制备方法及其作为5型磷酸二酯酶抑制剂用于治疗相关的医学病症。
背景技术
5型磷酸二酯酶特异性水解cGMP，负责调节细胞内cGMP的水平，参与很多体内关键性的生物生理学过程。PDE5抑制剂的作用的主要功能是通过抑制PDE5对cGMP的水解，使细胞内cGMP的蓄积。因此PDE5是治疗与cGMP水平相关的如男性勃起功能障碍(Male Erectile dysfunction,MED)、肺动脉高压(Pulmonary Hypertension,PAH)等疾病的理想药物靶点。
目前用作PDE5抑制剂商品化的药物产品有吡唑并嘧啶酮类化合物西地那非(Sildenafil)、伐地那非(Vardenafil)，β-咔啉类化合物他拉达非(Tadalafl)，以及0。在研的小分子化合物也常见报道。其中，美国强生公司的Sui等人曾在J.Med.Chem.,2002,45,4094-4096；J.Med.Chem.,2003,46,441-44；J.Med.Chem.,2005,48,2126-33报道了一系列的吡咯并[3,4-b]喹啉酮类化合物、合成方法及其对PDE5的体内及体外的抑制活性，指出了该类化合物具有较好的PDE5的抑制作用，并对各磷酸二酯酶亚型具有较好的选择性。因此，吡咯并[3,4-b]喹啉酮类化合物对于发现新型PDE5抑制剂类药物具有极大的发展潜力。
天然产物因其具有种类多样、结构复杂、手性明确、构象固定等特点，是研发新药的重要来源。因此以廉价易得的天然产物作为起始原料或药物前体，对其进行结构改造和修饰，可以迅速构建并大规模制备药物，同时还可有效降低生产成本。蒺藜(Tribulus terrestris L.)是一种传统中药，其中蒺藜总皂苷对心血管系统具有重要的作用，能够显著增加缺血部位的血供，起到改善脑循环、保护缺血脑组织。此外，蒺藜也被认为具有提高性功能的作用。因此，对从蒺藜中分离出的活性天然产物进行结构改造和修饰对设计新型PDE5抑制剂类药物具有重要意义。
发明内容
发明人研究发现，蒺藜已分离提取的一种天然产物Tribulusterine(C16H12N2O2，
Figure PCTCN2017093149-appb-000001
)，对PDE5具有较弱的抑制活性，其IC50＝4.92uM，因此在其结构的基础上进行了活性优化，从而得到了一系列强效的PDE5抑制剂。
具体的，本发明涉及以下技术方案：
一种如式(I)或式(II)所示的化合物或其药学上可接受的盐，
Figure PCTCN2017093149-appb-000002
其中，
X代表硫原子或氧原子；
Y代表碳原子或氮原子；
R1代表氢原子，氯原子，甲基或甲氧基；
R2代表氢原子，溴原子，吡啶，氟取代的吡啶或甲氧基取代的苯环；
R3代表氢原子，C1-C10的烷基，C1-C10的烷氧基或C1-C4的烷基醇，R3取代基的位置为C-3、C-4或C-5位。
上述化合物的实例如下：
通式(I)所示化合物为：
1-(5-乙基噻吩-2-基)-2-(5-(吡啶-2-基)嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
1-(5-乙基呋喃-2-基)-2-(5-(吡啶-2-基)嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
1-(5-乙基噻吩-2-基)-2-(5-(吡啶-3-基)嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
1-(5-乙基噻吩-2-基)-2-(5-(吡啶-4-基)嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
1-(5-乙基噻吩-2-基)-2-(5-(2-氟吡啶-3-基)嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
2-([2,3'-联吡啶]-6'-基)-1-(5-乙基噻吩-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
2-(5-(3,4-二甲氧基苯基)嘧啶-2-基)-1-(5-乙基噻吩-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
1-(5-乙基噻吩-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
1-(5-乙基噻吩-2-基)-2-(吡啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
1-(5-乙基噻吩-2-基)-2-(5-(甲氧基苯基)嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
2-(5-溴嘧啶-2-基)-1-(5-乙基噻吩-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
1-(5-乙基噻吩-2-基)-6-甲基-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
1-(5-乙基噻吩-2-基)-6-甲氧基-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
6-氯-1-(5-乙基噻吩-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
1-(4,5-二甲基噻吩-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
1-(3-甲基噻吩-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
1-(4-甲基噻吩-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
1-(5-甲基噻吩-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
1-(5-丙基噻吩-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
1-(5-丁基噻吩-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
2-(嘧啶-2-基)-1-(噻吩-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
1-(5-(2-丙氧基乙基)噻吩-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
1-(5-(2-丁氧基甲基)噻吩-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
1-(5-(2-(异戊氧基)乙基)噻吩-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
3-(3-(羟甲基)呋喃-2-基)--2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
1-(5-甲基呋喃-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
1-(5-乙基呋喃-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
1-(5-戊基呋喃-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
1-(呋喃-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚，
及通式(II)所示的化合物：
3-(5-乙基噻吩-2-基)-2-(5-(吡啶-2-基)嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
(R)-3-(5-乙基噻吩-2-基)-2-(5-(吡啶-2-基)嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b] 喹啉-9-酮；
(S)-3-(5-乙基噻吩-2-基)-2-(5-(吡啶-2-基)嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(5-乙基呋喃-2-基)-2-(5-(吡啶-2-基)嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
(R)-3-(5-乙基呋喃-2-基)-2-(5-(吡啶-2-基)嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
(S)-3-(5-乙基呋喃-2-基)-2-(5-(吡啶-2-基)嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(5-乙基噻吩-2-基)-2-(5-(吡啶-4-基)嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(5-乙基噻吩-2-基)-2-(5-(吡啶-3-基)嘧啶-2-基)--1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(5-乙基噻吩-2-基)-2-(5-(2-氟吡啶-3-基)嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；2-([2,3'-联吡啶]-6'-基)-3-(5-乙基噻吩-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
2-(5-(3,4-二甲氧基苯基)嘧啶-2-基)-3-(5-乙基噻吩-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(5-乙基噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(5-乙基噻吩-2-基)-2-(吡啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(5-乙基噻吩-2-基)-2-(5-(4-甲氧基苯基)嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
2-(5-溴嘧啶-2-基)-3-(5-乙基噻吩-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(5-乙基噻吩-2-基)-7-甲基-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(5-乙基噻吩-2-基)-7-甲氧基-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
7-氯-3-(5-乙基噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(5-(羟甲基)噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(5-(2-羟乙基)噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(5-(2-丙氧基乙基)噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(5-(2-丁氧基甲基)噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(5-(2-(异戊氧基)乙基)噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(4,5-二甲基噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(3-甲基噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(4-甲基噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(5-甲基噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(5-丙基噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(5-丁基噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
2-(嘧啶-2-基)-3-(噻吩-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(3-(羟甲基)呋喃-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(4-(羟甲基)呋喃-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(5-甲基呋喃-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(5-乙基呋喃-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(5-戊基呋喃-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
3-(呋喃-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮。
上述化合物药学上可接受的盐优选为上述化合物与无机酸，如盐酸、硫酸、硝酸或氢溴酸形成的盐；或有机酸，如甲磺酸、甲苯磺酸或三氟乙酸形成的盐。
本发明还提供上述化合物或其药学上可接受的盐的制备方法，所述化合物的制备合成路线如下：
Figure PCTCN2017093149-appb-000003
其中，
X代表硫原子或氧原子；
Y代表碳原子或氮原子；
R1代表氢原子，氯原子，甲基或甲氧基；
R2代表氢原子，溴原子，吡啶，氟取代的吡啶或甲氧基取代的苯环；
R3代表氢原子，C1-C10的烷基，C1-C10的烷氧基或C1-C4的烷基醇，R3取代基的位置为C-3、C-4或C-5位；
式(VIII)为有机硼试剂，优选为杂环化合物的2-硼酸盐、硼酸酯或硼酸，进一步优选为杂环-2-氟硼酸钾化合物，所述杂环-2-氟硼酸钾化合物结构式如下：
Figure PCTCN2017093149-appb-000004
本发明还提供一种药物组合物，该药物组合物包含上述的化合物或其药学上可接受的盐，既可以作为单体使用，也可以作为异构体的混合物使用。
优选的，所述药物组合物还包含一种或多种药学上可接受的载体、赋形剂和/或稀释剂。
优选的，所述药物组合物包含一种或多种药学上或食品学上可接受的辅料。所用辅料可为固态或液态。固态形式的制剂包括粉剂、片剂、分散颗粒、胶囊、药丸及栓剂。粉剂及片剂可包含约0.1％至约99.9％的活性成分。适当的固体辅料可以是碳酸镁、硬脂酸镁、滑石粉、糖或者乳糖。片剂、粉剂、药丸及胶囊为适于口服用的固态剂型。液态形式的制剂包括溶液、悬浮液及乳液，其实施例为非经肠注射用水溶液或水-丙二醇溶液，或添加甜味剂及造影剂的口服溶液。此外，还可制成注射用小水针、注射用冻干粉针、大输液或小输液。
优选的，所述药物组合物为固体口服制剂、液体口服制剂或注射剂。
进一步优选的，所述药物组合物为片剂、分散片、肠溶片、咀嚼片、口崩片、胶囊、糖衣剂、颗粒剂、干粉剂、口服溶液剂、注射用小水针、注射用冻干粉针、大输液或小输液。
本发明还公开了上述化合物及其药学上可接受的盐或者含有其任何一种实体的药学上可接受的药物组合物用于制备治疗、缓解或预防哺乳动物与PDE5相关的疾病或疾病状态的药物中的用途。例如制备PDE5抑制剂的用途。所述疾病包括但不限于男性勃起功能障碍(MED)、女性性功能障碍(FSD)、早产、痛经、良性前列腺增生(BPH)、膀胱出口阻塞、失禁、稳定型、不稳定型和变异型(普林兹默托尔氏)心绞痛、高血压、肺 动脉高压(PAH)、充血性心力衰竭、动脉硬化、中风、外周血管疾病、减少血管全开的疾病、慢性哮喘、支气管炎、变应性哮喘、过敏性鼻炎、青光眼或其特征为肠动力紊乱的疾病。
优选的，所述疾病为男性勃起功能障碍(MED)或肺动脉高压(PAH)。
根据本发明制备得到的式(I)或式(II)所示化合物和其药学上可接受的盐或者含有其任何一种实体的药学上可接受的药物组合物是可以用于制备预防和/或治疗男性勃起功能障碍(MED)、女性性功能障碍(FSD)、早产、痛经、良性前列腺增生(BPH)、膀胱出口阻塞、失禁、稳定型、不稳定型和变异型(普林兹默托尔氏)心绞痛、高血压、肺动脉高压(PAH)、充血性心力衰竭、动脉硬化、中风、外周血管疾病、减少血管全开的疾病、慢性哮喘、支气管炎、变应性哮喘、过敏性鼻炎、青光眼或其特征为肠动力紊乱的疾病的药剂。
有鉴于此，本发明的另一主题是，一种治疗遭受男性勃起功能障碍(MED)、女性性功能障碍(FSD)、早产、痛经、良性前列腺增生(BPH)、膀胱出口阻塞、失禁、稳定型、不稳定型和变异型(普林兹默托尔氏)心绞痛、高血压、肺动脉高压(PAH)、充血性心力衰竭、动脉硬化、中风、外周血管疾病、减少血管全开的疾病、慢性哮喘、支气管炎、变应性哮喘、过敏性鼻炎、青光眼或其特征为肠动力紊乱的疾病的方法，所述方法包括施用治疗有效量的如式(I)或式(II)所示化合物或其药学上可接受的盐或者含有其任何一种实体的药学上可接受的药物组合物。
本文使用的术语“治疗有效量”表示治疗、改善靶向的疾病或病症或者表现出可检测的治疗效果所需的治疗剂的量。
本发明的化合物在相当宽的剂量范围内是有效的。实际服用本发明式(I)或式(II)所示化合物，其药学上可接受的盐者含有其任何一种实体的药学上可接受的药物组合物的剂量可由医生根据有关的情况来决定。这些情况包括：被治疗者的身体状态、给药途径、年龄、体重、对药物的个体反应，症状的严重程度等。
在治疗过程中，上述式(I)或式(II)所示化合物、其药学上可接受的盐或者所述药物组合物还可以与至少一种其它用于治疗、缓解或预防哺乳动物与PDE5相关的疾病或疾病状态的药物合用。这些药物可用于治疗包括但不限于男性勃起功能障碍(MED)、女性性功能障碍(FSD)、早产、痛经、良性前列腺增生(BPH)、膀胱出口阻塞、失禁、稳定型、不稳定型和变异型(普林兹默托尔氏)心绞痛、高血压、肺动脉高压(PAH)、充血性心力衰竭、动脉硬化、中风、外周血管疾病、减少血管全开的疾病、慢性哮喘、 支气管炎、变应性哮喘、过敏性鼻炎、青光眼或其特征为肠动力紊乱的疾病。
本发明的有益效果：
本发明制备得到的化合物具有靶点明确、安全性高，活性效果突出，在制备治疗与PDE5相关的疾病特别是男性勃起功能障碍(MED)或肺动脉高压(PAH)的药物中具有很好的应用前景；
同时，本发明化合物制备方法简单，反应条件温和，原料廉价易得，仅通过2至3步的结构修饰和改造，即可快速、大规模制备并获得多种具有全新结构的化合物，同时具有良好的经济性，极具大规模工业化生产价值。
附图说明
图1(a)为化合物IIA及其光学纯的对映异构体对由去甲肾上腺素引起的动脉收缩的舒张作用；图1(b)为化合物IIB及其光学纯的对映异构体由去甲肾上腺素引起的动脉收缩的舒张作用；
图2(a)为化合物II-A光学异构体(R)-IIA的HPLC色谱图；图2(b)为化合物II-A光学异构体(S)-IIA的HPLC色谱图；
图3(a)为化合物II-B光学异构体(R)-IIB的HPLC色谱图；图3(b)为化合物II-B光学异构体(S)-IIB的HPLC色谱图；
图4(a)为不同浓度化合物II-A对PDE5的抑制率；图4(b)为不同浓度西地那非对PDE5的抑制率。
具体实施方式
应该指出，以下详细说明都是例示性的，旨在对本申请提供进一步的说明。除非另有指明，本文使用的所有技术和科学术语具有与本申请所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是，这里所使用的术语仅是为了描述具体实施方式，而非意图限制根据本申请的示例性实施方式。如在这里所使用的，除非上下文另外明确指出，否则单数形式也意图包括复数形式，此外，还应当理解的是，当在本说明书中使用术语“包含”和/或“包括”时，其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
本发明的一种具体实施方式中，提供一种如式(I)或式(II)所示的化合物：
Figure PCTCN2017093149-appb-000005
其中，
X代表硫原子或氧原子；
Y代表碳原子或氮原子；
R1代表氢原子，氯原子，甲基或甲氧基；
R2代表氢原子，溴原子，吡啶，氟取代的吡啶或甲氧基取代的苯环；
R3代表氢原子，C1-C10的烷基，C1-C10的烷氧基或C1-C4的烷基醇，R3取代基的位置为C-3、C-4或C-5位；
除通式(I)和通式(II)表示的化合物外，本发明还包括这些化合物的药学上可接受的盐、前药化合物和活性代谢产物；
同时，由于式(I)及式(II)化合物物分别含有一个不对称手型碳原子，分别以两种对映异构体的形式存在，对映体的抑制活性存在显著差别。因此本发明包括式(I)及式(II)的单独的对映异构体，外消旋体或其任意比例的混合物。对映异构体的分离可以通过常规技术来完成。例如，式(II)化合物II-A及II-B可以通过手型HPLC色谱柱进行拆分或其适当的盐或衍生物进行分级结晶；式(II)化合物也可以通过光学纯的式(I)化合物进行相应的化学反应制备得到，而式(I)化合物的单一对映体则可以通过HPLC色谱柱进行拆分或将外消旋体与适当光学活性的酸或碱反应生成的非对映异构体盐分级结晶；光学纯的式(I)化合物也可以在适当的催化条件下通过化学反应制备得到。因此，式(I)或式(II)所示化合物的立体异构形式将包括在本发明保护范围内。
本发明的又一具体实施方式中，公开了上述化合物的制备方法，本发明提供的合成路线如下，使用该制备方法可以快速的合成式(I)及式(II)化合物或其类似物，特别适合合成C-1位取代的β-四氢咔啉及其相关的衍生物，如吡咯并[3,4-b]喹啉酮类化合物。
Figure PCTCN2017093149-appb-000006
1)式(III)化合物一般可以直接购买商品化的产品，如无法购得，可使用相应的原料，如吲哚-3-甲醛按照文献进行制备。如前所述，R1可以是氢原子，氯原子，甲基或甲氧基；
Figure PCTCN2017093149-appb-000007
2)式(IV)的化合物可参照文献，以式(III)化合物色胺盐酸盐经Pictet-Spengler反应得到相应β-四氢咔啉，反应收率一般大于90％。
Figure PCTCN2017093149-appb-000008
3)化合物(V)可经由化合物(IV)与相应的卤代芳环原料制备得到，其中Y和R2表示含义如前所述，具体的，Y表示碳原子或氮原子，R2表示氢原子，溴原子，吡啶环或苯环，其中R2引入吡啶环或苯环主要通过钯催化的Suzuki偶联、Stille偶联进行。合成化合物(V)主要通过以下3种方式：
i)卤代芳烃的准备：大部分卤代芳烃可商购或照如下的Suzuki偶联反应制备。当硼酸为苯基硼酸或取代的苯基硼酸时，转化率一般大于90％，可以通过重结晶得到相应化合物；当硼酸为吡啶-4-硼酸或吡啶3-硼酸时，需要进行柱层析分离得到相应纯品，产率分别为42％和46％；其中钯催化剂也可以使用Pd2(dba)3、醋酸钯、二氯化钯等催化剂。
Figure PCTCN2017093149-appb-000009
ii)N-芳基化的过程：当芳环为嘧啶环时，主要通过化合物IV与卤代化合物进行芳香亲核取代反应制备得到；当芳环为吡啶环，即Y表示碳原子时，类似的芳香亲核取代反应只有小于5％的产率，因此一般通过Buchwald-Hartwig反应条件制备得到。在钯催化的偶联反应中，磷配体可以为BINAP或其类似的衍生物。
Figure PCTCN2017093149-appb-000010
iii)制备R2基团为2-吡啶基的化合物，则需要通过R2为Br的中间体与2-三丁基锡吡啶通过Stille反应得到。其中钯催化剂也可以使用Pd(dppf)2Cl2、二氯化钯等催化剂。
Figure PCTCN2017093149-appb-000011
4)化合物V与相应的有机硼试剂VIII在氧化条件进交叉脱氢偶联，生成相应的C-1位取代的咔啉衍生物I。如前所述，X代表硫原子或氧原子；R3代表C1-C10的烷基，C1-C10的烷氧基或C1-C4的烷基醇，取代基的位置为C-3、C-4或C-5位。
在该化学过程中，氧化剂选用二氯二氰基苯醌，四甲基哌啶氮氧化物，三苯甲基盐，过氧化叔丁醇或羟基邻苯二甲酰亚胺；有机硼试剂VIII可以选用杂环化合物的2-硼酸盐、硼酸酯或硼酸；氧化剂TEMPO四氟硼酸盐的制备方法参照文献J.Med.Chem.2016,59,5063-5076。具体的制备氟硼酸钾盐试化合物的过程和交叉脱氢偶联的化学反应过程如下所述：
i)氟硼酸盐化合物的制备可参照相应的文献制备得到，取代基复杂的五元杂环衍生物也可以按照文献制备。
Figure PCTCN2017093149-appb-000012
ii)化合物V与杂环-2-氟硼酸钾化合物VIII在TEMPO存在的条件下反应得到。
Figure PCTCN2017093149-appb-000013
5)式(II)化合物主要以式(I)化合物为原料经由Winterfeldt氧化得到。该化学过程可以在叔丁醇钾/氧气存在的条件下反应或在18-冠醚-6/超氧化钾的存在的条件下进行。其中碱可以更换为氢化钠。需要特别指出，当R3表示的分子内含有硅醚化的烷基醇时，叔丁醇钾的碱性反应条件可以同时将硅保护基脱除。
Figure PCTCN2017093149-appb-000014
本发明的又一具体实施方式中，公开了所述式(I)或式(II)化合物，或者它们的药学可接受的盐或者含有其任何一种实体的药学上可接受的药物组合物用于制备哺乳动物与PDE5相关的疾病或疾病状态的药物用途。通过相应的给药方式，改用途用于治疗或预防性治疗男性勃起功能障碍(MED)、女性性功能障碍(FSD)、早产、痛经、良性前列腺增生(BPH)、膀胱出口阻塞、失禁、稳定型、不稳定型和变异型(普林兹默托尔氏)心绞痛、高血压、肺动脉高压(PAH)、充血性心力衰竭、动脉硬化、中风、外周血管疾病、减少血管全开的疾病、慢性哮喘、支气管炎、变应性哮喘、过敏性鼻炎、青光眼或其特征为肠动力紊乱的疾病。优选的治疗疾病是男性勃起功能障碍(MED)和肺动脉高压(PAH)。
本发明参照文献J.Biomol.Screen.,2002,7,215-222的方法，测定了化合物对PDE5的体外抑制活性，并指出上述化合物或其药物可接受的盐在制备用于治疗和/或预防哺乳动物的与PDE5相关的疾病或疾病状态的药物中的用途，其中抑制PDE5的过程被认为是有益的。
特别优选的单体化合物I-F，IIA-IIQ对PDE5的抑制率如下表。其中，式(I)和式(II)化合物结构和X、Y、R1、R2、R3各符号的含义如前所述。
Figure PCTCN2017093149-appb-000015
Figure PCTCN2017093149-appb-000016
特别优选的通式(II)所示的单体化合物A-I对PDE5抑制作用的IC50值及部分化合物对其他PDE亚型的选择性倍数值如下。
Figure PCTCN2017093149-appb-000017
Figure PCTCN2017093149-appb-000018
a未测定bSN＝Sidenafil，西地那非，PDE5-6为实验数据，PDE1-4的选择性数据参考文献J.Med.Chem.2002,45,4094-4096；PDE11的选择性数据参考文献Int.J.Clin.Pract.2006,60,967-975.
本发明同样涉及优选化合物IIA，IIB对血管扩张的作用。参考文献Am.J.Respir.Crit.Care.Med.2004,169,227-234.制作家兔离体离体动脉血管环，测定优选的化合物对去甲肾上腺素(NE)预收缩的主动脉环张力的影响，并计算IIA，IIB及其光学纯的对映异构体作用后血管环的舒张率。结果如图1所示，在10-6M的浓度下，化合物IIA,(R)-IIA,IIB,(R)-IIB可以使离体动脉环完全舒张，而其对映体的药效活性则较差。
此外，本发明同样提供了优选化合物(R)-IIA，(R)-IIB的药物动力学参数。参考文献J.Chromatogr.B 2016,1011,62-68，对(R)-IIA，(R)-IIB在Wistar大鼠体内的药物代谢动力学过程进行了研究，结果如下表所示。
Figure PCTCN2017093149-appb-000019
Figure PCTCN2017093149-appb-000020
以下实施例进一步解释了本发明的化合物及中间体的合成、制备方法，化合物体内、体外的活性测定及药代动力学的研究方法，但并不限制本发明的范围。
实施例1
5-乙基呋喃-2-三氟硼酸钾的制备。向圆底烧瓶中先后加入以下试剂和溶剂2-乙基呋喃(1.9g,20mmol,1eq)；四氢呋喃15mL。氮气保护的条件下，0℃滴加10mL的正丁基锂溶液(2.5M,己烷溶液，继续搅拌3h。将反应液在-78℃的条件下滴加至硼酸三甲酯(2.28g,22mmol,1.1eq)的四氢呋喃(5mL)中。滴加完成后，恢复至室温搅拌0.5h后重新冷却至0℃，滴加1M的盐酸20mL至pH为5-6。用乙酸乙酯萃取后蒸干，重结晶得5-乙基呋喃-2-硼酸纯品1.25g。0℃下向圆底烧瓶中加入5-乙基呋喃-2-硼酸(610mg,4.35mmol,1eq)，KHF2(1.1g,13.05mmol,3eq)；甲醇1.5mL，水3.8mL。反应搅拌10min后蒸干，高真空过夜抽干。固体加入丙酮回流0.5h，过滤，蒸干滤液，用乙醚重结晶的标题化合物，460mg，2步产率为23％。1HNMR(400MHz,DMSO)δ5.89(d,J＝2.8Hz,1H),5.74(d,J＝2.3Hz,1H),2.60–2.51(m,2H),1.14(t,J＝7.5Hz,3H).13C NMR(101MHz,DMSO)δ155.6,111.1,103.4,21.4,13.1.19F NMR(376MHz,DMSO)δ-138.2。
实施例2
5-乙基噻吩-2-三氟硼酸钾的制备。向圆底烧瓶中先后加入以下试剂和溶剂2-乙基噻吩(5g,44.6mmol,1eq)；四氢呋喃60mL，氮气保护的条件下，-78℃滴加21mL的正丁基锂溶液(2.5M,己烷溶液)，搅拌0.5h后缓慢升温至-20℃后搅拌1h。反应液重新冷却至-78℃后，滴加硼酸三甲酯(5g,50mmol,1.1eq)的四氢呋喃(25mL)溶液中。滴加完成后，反应恢复至室温并继续搅拌1h。向烧瓶中滴加KHF2(20.8g,267.6mmol,6eq)的水溶液并搅拌1h后蒸干，高真空过夜抽干。固体加入丙酮回流0.5h，过滤，蒸干滤液，用乙醚重结晶的标题化合物3.5g，产率为36％。1H NMR(400MHz,DMSO)δ6.63(d,J＝12.9Hz,1H),2.75(q,J＝7.5Hz,1H),1.23(t,J＝7.5Hz,2H)，13C NMR(101MHz,DMSO)δ145.2,127.0,123.5,23.2,16.9。
实施例3
2-氯-5-(4-甲氧基苯基)嘧啶的制备。向微波反应管中加入以下试剂和溶剂5-溴-2-氯 嘧啶(400mg,2.06mmol,1eq)，对甲氧基硼酸(343mg,2.3mmol,1.1eq)，四三苯基膦钯(120mg,0.1mmol,0.05eq)和碳酸钾(855mg,6mmol,3eq)；甲苯12mL，甲醇3mL。向其中通氮气约15min，置于微波反应器中，110℃条件下反应30min。将反应冷却后，过滤除去碳酸钾固体，减压条件下将滤液蒸干，剩余物用乙酸乙酯溶解，随后分别用水和饱和NaCl溶液各洗涤一次，有机相用无水MgSO4干燥，过滤，减压浓缩至干，得到粗产品，用乙酸乙酯重结晶后得到330mg纯品。1H NMR(400MHz,CDCl3)δ8.80(s,2H),7.52(d,J＝8.8Hz,2H),7.07(d,J＝8.7Hz,2H),3.89(s,3H)。
实施例4
2-氯-5-(吡啶-3-基)嘧啶的制备。按照实施例3相同的方法，以吡啶-3-硼酸与5-溴-2-氯嘧啶反应，柱层析得到纯品化合物。1H NMR(400MHz,CDCl3)δ8.83-8.73(m,3H),8.67(dd,J＝4.7,1.3Hz,1H),7.82(dt,J＝7.9,1.9Hz,1H),7.41(dd,J＝7.8,5.0Hz,1H)。
实施例5
化合物2-([2,3'-联吡啶]-6'-基)-1-(5-乙基噻吩-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚的制备。
1,2,3,4-四氢-β-咔啉。向圆底烧瓶中先后加入如下的预先配制的溶液，色胺盐酸盐(4.9g,24.9mmol,1eq)溶于78mL水，乙醛酸一水合物(2.6g,27.4mmol,1.1eq)溶于6mL水，KOH(1.38g,24.9mmol,1eq)溶于6mL水。反应室温下搅拌1小时后，生成白色固体，将反应液过滤并用6.5mL水洗固体。将固体烘干后转移至烧瓶中，加入48.75mL水和6.63mL浓盐酸，回流0.5h后补加6.63mL浓盐酸，再继续继续回流0.5h后冷至室温并析出大量晶体。反应液过滤并用6.5mL水洗固体，固体溶于78mL水并转移至圆底烧瓶中，加热至55℃后加入20％KOH溶液至pH值大于12，恢复至室温，过滤并用6.5mL水洗固体。白色固体高真空抽干得目标化合物3.1g,产率72.6％。1H NMR(400MHz,DMSO)δ10.67(s,1H),7.35(d,J＝7.7Hz,1H),7.27(d,J＝7.9Hz,1H),7.05–6.96(m,1H),6.96–6.86(m,1H),3.87(s,2H),2.99(t,J＝5.6Hz,2H),2.60(t,J＝5.6Hz,2H).13C NMR(101MHz,DMSO)δ135.9,134.5,127.7,120.6,118.6,117.6,111.2,107.3,43.8,43.1,22.6.ESI-MS m/z 173[M+H]+。
2-(5-溴吡啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚。向圆底烧瓶中加入以下试剂和溶剂，1,2,3,4-四氢-β-咔啉(172mg,1mmol,1eq),2,5-二溴吡啶(260mg,1.1mmol,1.1eq),叔丁醇钠(135mg,1.4mmol,1.4eq)，DPPP(33mg,0.08mmol,0.08eq),Pd2(dba)3(37mg,0.04mmol,0.04eq)，二甲基甲酰胺6mL。N2条件下，80℃反应18h。蒸干反应液，过 滤除去固体杂质，滤液蒸干后行柱层析分离得到产品，85mg，产率为26％。1HNMR(400MHz,CDCl3)δ8.14(d,J＝2.2Hz,1H),7.93(s,1H),7.51(dd,J＝9.1,2.5Hz,1H),7.42(d,J＝7.7Hz,1H),7.26(d,J＝7.9Hz,1H),7.09(td,J＝8.1,7.6,1.3Hz,3H),7.06–6.99(m,2H),6.65(d,J＝9.1Hz,1H),4.74(s,2H),3.86(t,J＝5.7Hz,2H),2.90–2.78(m,2H).ESI-MS m/z 328[M+H]+。
2-([2,3'-联吡啶]-6'-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚。向圆底烧瓶中加入以下试剂和溶剂，2-(5-溴嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚(0.987g,3mmol,1eq)，2-三丁基锡吡啶(1.27g,5.7mmol,1.9eq)，三苯基膦钯(346mg,0.3mmol,0.1eq)；二氧六环9mL。N2条件下，加热至105℃反应20h，TLC检测反应完全。反应冷却后，减压条件下条件下将反应液蒸干，柱层析分离得到580mg纯品，产率为59％。1HNMR(400MHz,DMSO)δ10.92(s,1H),8.88(d,J＝2.3Hz,1H),8.60(ddd,J＝4.8,1.7,0.9Hz,1H),8.27(dd,J＝9.0,2.5Hz,1H),7.88(d,J＝8.0Hz,1H),7.81(td,J＝7.7,1.8Hz,1H),7.41(d,J＝7.7Hz,1H),7.33(d,J＝8.0Hz,1H),7.26(ddd,J＝7.3,4.8,1.1Hz,1H),7.13–6.90(m,3H),4.88(s,2H),4.03(t,J＝5.6Hz,2H),2.82(t,J＝5.4Hz,2H).13C NMR(101MHz,DMSO)δ159.4,154.9,149.9,146.7,137.5,136.4,136.1,132.7,127.1,123.8,122.0,121.1,119.3,118.9,117.9,111.5,107.5,107.3,43.5,43.4,20.8.ESI-MS m/z 327[M+H]+。
2-([2,3'-联吡啶]-6'-基)-1-(5-乙基噻吩-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚。圆底烧瓶中加入以下试剂和溶剂，2-([2,3'-联吡啶]-6'-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚(326mg,1mmol,1eq)，5-乙基噻吩-2-三氟硼酸钾(327mg,1.5mmol,1.5eq)，TEMPO(243mg,1mmol,1eq)；二氯甲烷20mL。反应室温下搅拌30min后，加入饱和的Na2CO3溶液终止，分出有机相，用饱和NaCl洗涤一次，分液。有机相用无水MgSO4干燥，过滤，浓缩至干。柱层析分离得到纯品320mg，产率为74％。1H NMR(400MHz,DMSO)δ11.07(s,1H),8.91(d,J＝1.4Hz,1H),8.60(d,J＝4.3Hz,1H),8.27(d,J＝8.9Hz,1H),7.90(d,J＝7.9Hz,1H),7.82(t,J＝7.6Hz,1H),7.46(d,J＝7.7Hz,1H),7.32(d,J＝8.0Hz,1H),7.30–7.20(m,2H),7.14(d,J＝9.0Hz,1H),7.08(t,J＝7.5Hz,1H),6.99(t,J＝7.4Hz,1H),6.74(d,J＝2.8Hz,1H),6.68(s,1H),4.49(d,J＝10.7Hz,1H),3.53–3.40(m,1H),2.97–2.76(m,2H),2.72(q,J＝7.4Hz,2H),1.17(t,J＝7.5Hz,3H).13C NMR(101MHz,DMSO)δ157.9,154.8,149.8,146.9,146.7,141.6,137.6,136.6,136.4,133.6,126.7,126.6,123.8,123.2,122.1,121.7,119.3,119.0,118.4,111.7,108.5,107.1,50.3,38.9,23.3,20.9,16.3.ESI-MS m/z 437[M+H]+。
实施例6
化合物3-(5-乙基噻吩-2-基)-2-(5-(吡啶-2-基)嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮的制备
2-(5-溴嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚。向圆底烧瓶中加入以下试剂和溶剂，1,2,3,4-四氢-β-咔啉(10g,58mmol,1eq),5-溴-2氯嘧啶(12.35g,64mmol,1.1eq)，DIEA(15g,116mmol,2eq)；二甲基甲酰胺100mL。反应在N2条件下，加热至120℃并反应6h。冷却至室温后加入水并用乙酸乙酯萃取多次，有机相用无水MgSO4干燥，过滤，减压条件下蒸干得粗产品，用乙酸乙酯打浆后过滤，得16g目标化合物纯品，产率为84％。1HNMR(400MHz,DMSO)δ10.93(s,1H),8.52(s,2H),7.40(d,J＝7.7Hz,3H),7.32(d,J＝8.0Hz,3H),7.17–7.01(m,3H),7.01–6.81(m,3H),4.91(s,2H),4.12(t,J＝5.7Hz,2H),2.77(t,J＝5.5Hz,2H).13C NMR(101MHz,DMSO)δ160.3,158.6,136.4,132.0,127.0,121.2,118.9,118.0,111.5,107.4,106.0,42.8,42.4,20.8.ESI-MS m/z 329[M+H]+。
1-(5-乙基噻吩-2-基)-2-(5-(吡啶-2-基)嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚。按照实施例5中步骤3和步骤4相同的方法，以2-(5-溴嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚为反应原料，经过两步反应后，柱层析分离得到纯品化合物360mg。两步反应的收率分别为71％和84％。1H NMR(400MHz,DMSO)δ12.19(s,1H),9.12(s,2H),8.62(d,J＝4.1Hz,1H),8.17(d,J＝8.0Hz,1H),7.94(d,J＝7.9Hz,1H),7.85(t,J＝6.9Hz,1H),7.64(dt,J＝14.5,7.9Hz,2H),7.41–7.30(m,2H),7.12(d,J＝3.2Hz,1H),6.71(s,2H),4.88(d,J＝14.1Hz,1H),4.73(dd,J＝13.8,2.2Hz,1H),2.69(q,J＝7.4Hz,2H),1.13(t,J＝7.5Hz,3H).13C NMR(101MHz,DMSO)δ173.6,159.5,156.9,153.3,153.0,150.1,150.0,147.3,141.0,140.4,137.7,132.2,127.1,125.6,125.3,123.7,122.7,122.3,119.5,119.1,118.9,114.0,61.8,50.2,23.2,16.0.ESI-MS m/z 438[M+H]+。
3-(5-乙基噻吩-2-基)-2-(5-(吡啶-2-基)嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮法A，圆底烧瓶中加入以下试剂和溶剂，1-(5-乙基噻吩-2-基)-2-(5-(吡啶-2-基)嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚(178mg,0.4mmol,1eq),t-BuOK(136mg,0.3mmol,3eq)；二甲基甲酰胺8mL。向烧瓶内不断通入氧气，反应搅拌12h后加水终止反应。反应液加入乙酸乙酯萃取3次，蒸干，柱层析分离得到标题化合物38mg，产率为21％。1H NMR(400MHz,DMSO)δ12.19(s,1H),9.12(s,2H),8.62(d,J＝4.1Hz,1H),8.17(d,J＝8.0Hz,1H),7.94(d,J＝7.9Hz,1H),7.85(t,J＝6.9Hz,1H),7.64(dt,J＝14.5, 7.9Hz,2H),7.41–7.30(m,2H),7.12(d,J＝3.2Hz,1H),6.71(s,2H),4.88(d,J＝14.1Hz,1H),4.73(dd,J＝13.8,2.2Hz,1H),2.69(q,J＝7.4Hz,2H),1.13(t,J＝7.5Hz,3H).13C NMR(101MHz,DMSO)δ173.6,159.5,156.9,153.3,153.0,150.1,150.0,147.3,141.0,140.4,137.7,132.2,127.1,125.6,125.3,123.7,122.7,122.3,119.5,119.1,118.9,114.0,61.8,50.2,23.2,16.0.ESI-MS m/z 452[M+H]+。
法B，向圆底烧瓶中小心的加入以下试剂和溶剂，1-(5-乙基噻吩-2-基)-2-(5-(吡啶-2-基)嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚(180mg,0.4mmol,1eq),18-冠醚-6(105mg,0.4mmol,1eq)，K2O2(170mg,2.4mmol,6eq)；二甲基甲酰胺8mL。反应搅拌8h后小心的加水终止反应，反应液加入乙酸乙酯萃取3次，蒸干，柱层析分离得到产品15mg，产率为8％。
实施例7
3-(5-乙基呋喃-2-基)-2-(5-(吡啶-2-基)嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮的制备。按照实施例6中相同的方法，以2-(5-(吡啶-2-基)嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚，5-乙基呋喃-2-三氟硼酸钾为反应原料，柱层析分离得到标题化合物。1H NMR(400MHz,DMSO)δ12.17(s,1H),9.11(s,2H),8.63(d,J＝4.3Hz,1H),8.17(d,J＝8.0Hz,1H),7.94(d,J＝7.9Hz,1H),7.85(t,J＝7.5Hz,1H),7.75–7.56(m,2H),7.34(dt,J＝12.3,6.7Hz,2H),6.53(s,1H),6.48(d,J＝1.8Hz,1H),6.06(s,1H),4.87(d,J＝13.9Hz,1H),4.76(dd,J＝13.9,2.2Hz,1H),1.06(t,J＝7.5Hz,3H).13C NMR(101MHz,DMSO)δ173.5,159.7,157.6,156.9,153.0,150.1,149.7,148.4,141.0,137.7,132.1,125.7,125.2,123.7,122.7,122.2,119.4,119.1,114.6,110.3,105.6,60.2,50.4,21.2,12.1.ESI-MS m/z 436[M+H]+。
实施例8
3-(5-乙基噻吩-2-基)-2-(5-(吡啶-3-基)嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮的制备。按照实施例6中相同的方法，以1,2,3,4-四氢-β-咔啉，2-氯-5-(吡啶-3-基)嘧啶，5-乙基噻吩-2-三氟硼酸钾为反应原料，柱层析分离得到标题化合物。1H NMR(400MHz,DMSO)δ12.14(s,1H),8.91(d,J＝2.0Hz,1H),8.86(s,2H),8.54(dd,J＝4.7,1.4Hz,1H),8.18(dd,J＝7.8,0.8Hz,1H),8.09(dt,J＝8.0,1.9Hz,1H),7.71–7.56(m,2H),7.46(dd,J＝7.9,4.8Hz,1H),7.35(dd,J＝14.5,1.5Hz,1H),7.13(d,J＝3.5Hz,1H),6.72(d,J＝3.5Hz,1H),6.67(d,J＝2.7Hz,1H),4.86(d,J＝14.1Hz,1H),4.74(dd,J＝14.1,2.8Hz,1H),2.69(q,J＝7.5Hz,2H),1.13(t,J＝7.5Hz,3H).13C NMR(101MHz,DMSO)δ173.6, 159.1,156.7,150.1,148.7,147.2,147.1,141.0,140.7,133.4,132.1,131.1,127.0,125.6,125.2,124.3,123.7,120.6,119.0,113.9,61.8,50.1,23.2,16.0.ESI-MS m/z 452[M+H]+。
实施例9
3-(5-乙基噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮的制备。按照实施例6中相同的方法，以1,2,3,4-四氢-β-咔啉，2-氯嘧啶，5-乙基噻吩-2-三氟硼酸钾为反应原料，柱层析分离得到标题化合物。1H NMR(400MHz,DMSO)δ12.16(s,1H),8.45(d,J＝3.9Hz,2H),8.17(d,J＝8.0Hz,1H),7.80–7.55(m,2H),7.35(t,J＝7.1Hz,1H),7.09(d,J＝3.3Hz,1H),6.75(t,J＝4.7Hz,1H),6.70(d,J＝3.2Hz,1H),6.62(d,J＝2.5Hz,1H),4.80(d,J＝14.1Hz,1H),4.66(dd,J＝14.1,2.7Hz,1H),2.68(q,J＝7.5Hz,2H),1.13(t,J＝7.5Hz,3H).13C NMR(101MHz,DMSO)δ173.6,159.6,158.5,150.2,147.1,140.8,132.1,126.8,125.6,125.2,123.7,119.1,114.1,111.5,61.6,49.9,23.2,16.0.ESI-MS m/z 361[M+H]+。
实施例10
3-(5-羟甲基)噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮的制备。按照实施例1和实施例6中相同的方法，以1,2,3,4-四氢-β-咔啉，2-氯嘧啶，5-羟甲基噻吩为反应原料，柱层析分离得到标题化合物。1H NMR(400MHz,DMSO)δ12.17(s,1H),8.44(d,J＝4.1Hz,2H),8.22–8.11(m,1H),7.71–7.58(m,2H),7.35(t,J＝7.2Hz,1H),7.14(d,J＝3.5Hz,1H),6.81(d,J＝3.5Hz,1H),6.75(t,J＝4.8Hz,1H),6.63(d,J＝2.8Hz,1H),5.36(t,J＝5.7Hz,1H),4.81(d,J＝14.1Hz,1H),4.68(dd,J＝14.1,3.1Hz,1H),4.50(d,J＝5.3Hz,2H).13C NMR(101MHz,DMSO)δ173.6,159.5,158.5,150.2,146.6,142.7,141.0,132.1,126.4,125.6,125.2,124.0,123.7,119.0,114.0,111.5,61.6,58.8,50.0.ESI-MS m/z 363[M+H]+。
实施例11
化合物II-A和II-B的手性拆分。采用HPLC法，使用大赛璐的制备设备和大赛璐手性柱对手性异构体分离，收集其相应组分。旋转蒸发除去溶剂，得到光学异构体的纯品，化合物II-A和II-B光学异构体色谱图如图2、图3所示。相应的色谱条件如下表所示：
Figure PCTCN2017093149-appb-000021
Figure PCTCN2017093149-appb-000022
实施例12
化合物II-A对PED-5的抑制活性的测定。配制45μL的酶促反应体系，各组分浓度如下：40mM MOPS，pH 7.5,0.5mM EDTA，15mM MgCl2，0.15mg/ml BSA，1mM DTT，0.05％Proclin 200，15ng/ml PDE5，100nM FAM-Cyclic-3’,5’-AMP和100nM化合物II-A(或等浓度的DMSO)。反应体系在25℃条件下保持1h后，加入100μL稀释的IMAP溶液并在25℃条件下低速振动1h。读取样品的在360nm和480nm激发光下的荧光数值，重复实验3次。计算PDE5的酶活和化合物II-A对PDE5的抑制率。化合物II-A在100nM浓度下对PED-5的抑制作用实验结果如下，西地那非为阳性对照。
Figure PCTCN2017093149-appb-000023
测定化合物II-A在0.03nM-1μM共计8个浓度下对PDE5的抑制率，将剂量和抑制率经一定变换后用非线性回归方程拟合，用Prism GraphPad软件计算，得到相应IC50数值。化合物II-A和阳性对照西地那非的结果如下，计算化合物II-A的IC50值为0.60±0.01nM，西地那非的IC50值为3.1±0.57nM。
实施例13
化合物II-B对其他PDE亚型的抑制活性的测定。按照实施例12中相同的方法，PDE酶亚型分别改为PDE1，PDE2，PDE3，PDE4，PDE6和PDE11与相应的底物FAM-Cyclic-3’,5’-AMP或FAM-Cyclic-3’,5’-GMP反应，计算化合物II-A在相应的浓度倍数下对各PDE亚型的抑制作用，结果如下表所示：
Figure PCTCN2017093149-appb-000024
Figure PCTCN2017093149-appb-000025
aPDE1-4相应浓度下的抑制率％(浓度)bPDE6，PDE11的IC50值
实施例14
化合物(R)-IIA在Wistar大鼠中的药物代谢动力学研究。配制0.5mg/mL的生理盐水注射液和2.5mg/mL的水溶口服液，分别按照静脉注射或口服给药的方式处理每组6只大鼠。在给药后0.1，0.25，0.5，0.75，1，2，4，6，12，24h采血后制备得到血浆样品。取血浆样品50μL与5μL内标样品混匀后，经3min的涡旋震荡和10min的离心(14000转/分钟)后，吸取10μL上清液用于LC-MS/MS分析。计算药物含量后使用Drug and Statistics Software version 2.0软件进行分析得相应的药物动力学参数。结果如下表。
化合物IIA：
Figure PCTCN2017093149-appb-000026
Figure PCTCN2017093149-appb-000027
化合物IIB：
Figure PCTCN2017093149-appb-000028
Figure PCTCN2017093149-appb-000029
Figure PCTCN2017093149-appb-000030
以上所述仅为本申请的优选实施例而已，并不用于限制本申请，对于本领域的技术人员来说，本申请可以有各种更改和变化。凡在本申请的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本申请的保护范围之内。

Claims (10)

  1. 一种如式(I)或式(II)所示的化合物，或其药学上可接受的盐，
    Figure PCTCN2017093149-appb-100001
    其中，
    X代表硫原子或氧原子；
    Y代表碳原子或氮原子；
    R1代表氢原子，氯原子，甲基或甲氧基；
    R2代表氢原子，溴原子，吡啶，氟取代的吡啶或甲氧基取代的苯环；
    R3代表氢原子，C1-C10的烷基，C1-C10的烷氧基或C1-C4的烷基醇，R3取代基的位置为C-3、C-4或C-5位。
  2. 如权利要求1所述化合物，或其药学上可接受的盐，其特征在于，其是选自下列化合物，
    其中，通式(I)所示化合物为：
    1-(5-乙基噻吩-2-基)-2-(5-(吡啶-2-基)嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    1-(5-乙基呋喃-2-基)-2-(5-(吡啶-2-基)嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    1-(5-乙基噻吩-2-基)-2-(5-(吡啶-3-基)嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    1-(5-乙基噻吩-2-基)-2-(5-(吡啶-4-基)嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    1-(5-乙基噻吩-2-基)-2-(5-(2-氟吡啶-3-基)嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    2-([2,3'-联吡啶]-6'-基)-1-(5-乙基噻吩-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    2-(5-(3,4-二甲氧基苯基)嘧啶-2-基)-1-(5-乙基噻吩-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    1-(5-乙基噻吩-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    1-(5-乙基噻吩-2-基)-2-(吡啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    1-(5-乙基噻吩-2-基)-2-(5-(甲氧基苯基)嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    2-(5-溴嘧啶-2-基)-1-(5-乙基噻吩-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    1-(5-乙基噻吩-2-基)-6-甲基-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    1-(5-乙基噻吩-2-基)-6-甲氧基-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    6-氯-1-(5-乙基噻吩-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    1-(4,5-二甲基噻吩-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    1-(3-甲基噻吩-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    1-(4-甲基噻吩-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    1-(5-甲基噻吩-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    1-(5-丙基噻吩-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    1-(5-丁基噻吩-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    2-(嘧啶-2-基)-1-(噻吩-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    1-(5-(2-丙氧基乙基)噻吩-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    1-(5-(2-丁氧基甲基)噻吩-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    1-(5-(2-(异戊氧基)乙基)噻吩-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    3-(3-(羟甲基)呋喃-2-基)--2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    1-(5-甲基呋喃-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    1-(5-乙基呋喃-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    1-(5-戊基呋喃-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚；
    1-(呋喃-2-基)-2-(嘧啶-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚，
    及通式(II)所示的化合物：
    3-(5-乙基噻吩-2-基)-2-(5-(吡啶-2-基)嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    (R)-3-(5-乙基噻吩-2-基)-2-(5-(吡啶-2-基)嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    (S)-3-(5-乙基噻吩-2-基)-2-(5-(吡啶-2-基)嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(5-乙基呋喃-2-基)-2-(5-(吡啶-2-基)嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    (R)-3-(5-乙基呋喃-2-基)-2-(5-(吡啶-2-基)嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    (S)-3-(5-乙基呋喃-2-基)-2-(5-(吡啶-2-基)嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(5-乙基噻吩-2-基)-2-(5-(吡啶-4-基)嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(5-乙基噻吩-2-基)-2-(5-(吡啶-3-基)嘧啶-2-基)--1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(5-乙基噻吩-2-基)-2-(5-(2-氟吡啶-3-基)嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；2-([2,3'-联吡啶]-6'-基)-3-(5-乙基噻吩-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    2-(5-(3,4-二甲氧基苯基)嘧啶-2-基)-3-(5-乙基噻吩-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(5-乙基噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(5-乙基噻吩-2-基)-2-(吡啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(5-乙基噻吩-2-基)-2-(5-(4-甲氧基苯基)嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    2-(5-溴嘧啶-2-基)-3-(5-乙基噻吩-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(5-乙基噻吩-2-基)-7-甲基-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(5-乙基噻吩-2-基)-7-甲氧基-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    7-氯-3-(5-乙基噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(5-(羟甲基)噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(5-(2-羟乙基)噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(5-(2-丙氧基乙基)噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(5-(2-丁氧基甲基)噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(5-(2-(异戊氧基)乙基)噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(4,5-二甲基噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(3-甲基噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(4-甲基噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(5-甲基噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(5-丙基噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(5-丁基噻吩-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    2-(嘧啶-2-基)-3-(噻吩-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(3-(羟甲基)呋喃-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(4-(羟甲基)呋喃-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(5-甲基呋喃-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(5-乙基呋喃-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(5-戊基呋喃-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮；
    3-(呋喃-2-基)-2-(嘧啶-2-基)-1,2,3,4-四氢-9H-吡咯并[3,4-b]喹啉-9-酮。
  3. 如权利要求1或2所述化合物或其药学上可接受的盐，其特征在于，所述化合物药学上可接受的盐为所述化合物与无机酸形成的盐，或者与有机酸形成的盐；优选的，所述无机酸为盐酸、硫酸、硝酸或氢溴酸；所述有机酸为甲磺酸、甲苯磺酸或三氟乙酸。
  4. 如权利要求1-3任一项所述化合物或其药学上可接受的盐的制备方法，其特征在于，所述化合物的制备合成路线如下：
    Figure PCTCN2017093149-appb-100002
    其中，式(VIII)为有机硼试剂，优选为杂环化合物的2-硼酸盐、硼酸酯或硼酸，进一步优选为杂环-2-氟硼酸钾化合物，所述杂环-2-氟硼酸钾化合物结构式如下：
    Figure PCTCN2017093149-appb-100003
  5. 一种药物组合物，其特征在于，所述药物组合物包含权利要求1-3任一项所述化合物或其药学上可接受的盐，其作为单体使用或者作为异构体混合物使用。
  6. 如权利要求5所述的药物组合物，其特征在于，所述药物组合物还包含一种或多种药学上可接受的载体、赋形剂和/或稀释剂。
  7. 如权利要求5或6所述的药物组合物，其特征在于，所述药物组合物为固体口服制剂、液体口服制剂或注射剂。
  8. 如权利要求5-7任一项所述药物组合物，其特征在于，所述药物组合物为片剂、分散片、肠溶片、咀嚼片、口崩片、胶囊、糖衣剂、颗粒剂、干粉剂、口服溶液剂、注射用小水针、注射用冻干粉针、大输液或小输液。
  9. 权利要求1-3任一项所述化合物或其药学上可接受的盐或者权利要求5-8任一项所述的药物组合物在制备治疗、缓解或预防哺乳动物与PDE5相关的疾病或疾病状态的药物中的用途；
    所述疾病包括男性勃起功能障碍、女性性功能障碍、早产、痛经、良性前列腺增生、膀胱出口阻塞、失禁、稳定型、不稳定型和变异型(普林兹默托尔氏)心绞痛、高血压、肺动脉高压、充血性心力衰竭、动脉硬化、中风、外周血管疾病、减少血管全开的疾病、慢性哮喘、支气管炎、变应性哮喘、过敏性鼻炎、青光眼或其特征为肠动力紊乱的疾病；
    优选的，所述疾病为男性勃起功能障碍或肺动脉高压。
  10. 如权利要求9所述用途，其特征在于，所述用途为权利要求1-3任一项所述化合物或其药学上可接受的盐或者权利要求5-8任一项所述的药物组合物与其他至少一种用于治疗、缓解或预防哺乳动物与PDE5相关的疾病或疾病状态的药物的联合应用。
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