HK1184786B - Derivatives of 6, 7-dihydro-3h-oxazolo [3, 4-a] pyrazine-5, 8- dione - Google Patents

Abstract

The present invention describes a series of derivatives of 6, 7-dihydro-3H-oxazolo [3, 4-a] pyrazine-5, 8-dione, mixtures thereof, their pharmaceutically acceptable salts, which are inhibitors of PDE-5, possessing vasodilatator properties and relaxing effects. In particular, the derivative (J¾)-3-(l,3- benzodioxol-5-yl ) -1- ( lH-indol-3-yl ) -7-methyl-6, 7- dihydro [1, 3] oxazolo [3, 4-a] pyrazine-5, 8-dione, its enantiomer (S) -3- (1, 3-benzodioxol-5-yl) -1- ( lH-indol-3-yl ) -7-methyl-6, 7- dihydro [1,3] oxazolo [3, 4-a] pyrazine-5, 8-dione. The present invention describes, additionally, processes for the preparation of said compounds, pharmaceutical compositions containing them, as well as uses as inhibitors of the enzyme phosphodiesterase type 5 (PDE-5) in the treatment of the erectile dysfunction and PDE-5 inhibitor treatable disorders.

Description

Derivatives of 6, 7-dihydro-3H-oxazolo [3,4-a ] pyrazine-5, 8-dione

Technical Field

The present invention discloses a series of derivatives of 6, 7-dihydro-3H-oxazolo [3,4-a ] pyrazine-5, 8-dione, mixtures thereof, pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, processes for their preparation, methods of inhibiting phosphodiesterase, their use as phosphodiesterase inhibitors, and their use as phosphodiesterase type 5 (PDE-5) inhibitors. In particular, the derivative (R) -3- (1, 3-benzodioxo-5-yl) -1- (1H-indol-3-yl) -7-methyl-6, 7-dihydro [1,3] oxazolo [3,4-a ] pyrazine-5, 8-dione, its enantiomer (S) -3- (1, 3-benzodioxo-5-yl) -1- (1H-indol-3-yl) -7-methyl-6, 7-dihydro [1,3] oxazolo [3,4-a ] pyrazine-5, 8-dione, and/or mixtures thereof (in any proportions).

Also disclosed are the use of derivatives of 6, 7-dihydro-3H-oxazolo [3,4-a ] pyrazine-5, 8-dione, mixtures thereof (in any ratio) and/or pharmaceutically acceptable salts thereof for the treatment of erectile dysfunction, tissue relaxation treatable diseases, and/or health conditions and PDE-5 inhibitor treatable diseases. In particular, the derivative (R) -3- (1, 3-benzodioxo-5-yl) -1- (1H-indol-3-yl) -7-methyl-6, 7-dihydro [1,3] oxazolo [3,4-a ] pyrazine-5, 8-dione, its enantiomer (S) -3- (1, 3-benzodioxo-5-yl) -1- (1H-indol-3-yl) -7-methyl-6, 7-dihydro [1,3] oxazolo [3,4-a ] pyrazine-5, 8-dione, and/or mixtures thereof (in any proportions).

Background

Because of the suspicion of adverse reactions that oral administration can cause to humans, male impotence was treated by intracavernosal injection and other methods before the first oral treatment appeared. Papaverine and pentoxifylline, for example, are used for the treatment of erectile dysfunction by intracavernosal injection. Other methods of treatment have low efficacy, such as psychotherapy and surgical transplantation.

Oral therapy is the most acceptable, as found in clinical studies using inhibitors of cGMP-PDE, particularly PDE-5. The precursor of these compounds is 5- [ 2-ethoxy-5- (4-methylpiperazinosulfonyl) phenyl]-1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-one, or sildenafil, has vasodilatory properties and nitric oxide potentiating effects. Sildenafil as medicineThe active ingredient of (1).

Later, other PDE-5 inhibitor compounds were developed and cited in a number of published technical documents and patent publications, such as sildenafil-drugAnd tadalafil-drugThe active ingredient of (1).

The compounds of the invention, derivatives of 6, 7-dihydro-3H-oxazolo [3,4-a ] pyrazine-5, 8-dione, are also inhibitors of phosphodiesterase type 5 (PDE-5).

Disclosure of Invention

The object of the present invention is to provide novel derivatives of 6, 7-dihydro-3H-oxazolo [3,4-a ] pyrazine-5, 8-dione, which are tissue relaxants, and/or phosphodiesterase inhibitors, having vasodilator properties and vasodilating effect, in particular PDE-5 inhibitors, and mixtures thereof (in any ratio), pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, which are effective in the treatment of erectile dysfunction. In particular (R) -3- (1, 3-benzodioxo-5-yl) -1- (1H-indol-3-yl) -7-methyl-6, 7-dihydro [1,3] oxazolo [3,4-a ] pyrazine-5, 8-dione, the enantiomer thereof (S) -3- (1, 3-benzodioxo-5-yl) -1- (1H-indol-3-yl) -7-methyl-6, 7-dihydro [1,3] oxazolo [3,4-a ] pyrazine-5, 8-dione, and/or mixtures thereof (in any ratio).

It is another object of the present invention to provide a method for preparing derivatives of 6, 7-dihydro-3H-oxazolo [3,4-a ] pyrazine-5, 8-dione, and mixtures thereof. In particular, (R) -3- (1, 3-benzodioxo-5-yl) -1- (1H-indol-3-yl) -7-methyl-6, 7-dihydro [1,3] oxazolo [3,4-a ] pyrazine-5, 8-dione, its enantiomer (S) -3- (1, 3-benzodioxo-5-yl) -1- (1H-indol-3-yl) -7-methyl-6, 7-dihydro [1,3] oxazolo [3,4-a ] pyrazine-5, 8-dione, and/or mixtures thereof (in any ratio).

Furthermore, the invention aims to provide a pharmaceutical composition containing an effective amount of a derivative of 6, 7-dihydro-3H-oxazolo [3,4-a ] pyrazine-5, 8-dione or a mixture thereof (in any proportion) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant. In particular to a pharmaceutical composition containing the derivative (R) -3- (1, 3-benzodioxo-5-yl) -1- (1H-indol-3-yl) -7-methyl-6, 7-dihydro [1,3] oxazolo [3,4-a ] pyrazine-5, 8-dione, its enantiomer (S) -3- (1, 3-benzodioxo-5-yl) -1- (1H-indol-3-yl) -7-methyl-6, 7-dihydro [1,3] oxazolo [3,4-a ] pyrazine-5, 8-dione, and/or mixtures thereof (in any proportions).

Another object of the present invention is to provide a medicament containing a therapeutically effective amount of a derivative of 6, 7-dihydro-3H-oxazolo [3,4-a ] pyrazine-5, 8-dione, or a mixture thereof (in any ratio), or a pharmaceutically acceptable salt thereof. In particular a medicament containing the derivative (R) -3- (1, 3-benzodioxo-5-yl) -1- (1H-indol-3-yl) -7-methyl-6, 7-dihydro [1,3] oxazolo [3,4-a ] pyrazine-5, 8-dione, its enantiomer (S) -3- (1, 3-benzodioxo-5-yl) -1- (1H-indol-3-yl) -7-methyl-6, 7-dihydro [1,3] oxazolo [3,4-a ] pyrazine-5, 8-dione, and/or mixtures thereof (in any proportions).

It is another object of the present invention to provide one or a mixture (in any ratio) of derivatives of 6, 7-dihydro-3H-oxazolo [3,4-a ] pyrazine-5, 8-dione, or a pharmaceutically acceptable salt thereof, for use in the treatment and prevention of erectile dysfunction, tissue relaxation treatable diseases and/or health conditions, and PDE-5 inhibitor treatable diseases in animals. In particular the derivative (R) -3- (1, 3-benzodioxo-5-yl) -1- (1H-indol-3-yl) -7-methyl-6, 7-dihydro [1,3] oxazolo [3,4-a ] pyrazine-5, 8-dione, its enantiomer (S) -3- (1, 3-benzodioxo-5-yl) -1- (1H-indol-3-yl) -7-methyl-6, 7-dihydro [1,3] oxazolo [3,4-a ] pyrazine-5, 8-dione, and/or mixtures thereof (in any proportions).

Drawings

Figure 1 shows the relaxing effect of compound 2 (BL 106) on human isolated ureter tissue. Fig. 1 is a graph of the concentration response of BL106 in human isolated ureter tissue. Data are mean ± SEM, n =3 experiments.

Figure 2 shows the relaxing effect of compound 2 (BL 106) on rabbit isolated pulmonary artery tissue. Fig. 2 is a graph of the concentration response of BL106 in rabbit isolated pulmonary artery tissue.

Figure 3 demonstrates the relaxation effect of compound 2 (BL 106) on human ex vivo cavernous tissue (figure 3A) and rabbit ex vivo cavernous tissue (figure 3B). Fig. 3 is a graph of the concentration response of BL106 in human ex vivo cavernous tissue (a) and rabbit ex vivo cavernous tissue (B). Data are mean ± SEM, n =3 experiments.

Detailed Description

The present invention discloses derivatives of 6, 7-dihydro-3H-oxazolo [3,4-a ] pyrazine-5, 8-dione containing structure shown in formula (I) and salts and solvates (e.g., hydrates) thereof, wherein:

R¹being aromatic, condensed or non-condensed groups, optionally with R at one or more positions^BSubstituted), heteroaromatic group containing one or more heteroatoms or indolyl group (optionally with R at one or more positions)^BSubstitute), C_1-6Alkenylcarbonyl (optionally with R at one or more positions)^BSubstituted), bicyclic aromatic group (optionally with R at one or more positions)^BSubstituted), or bicyclic heteroaryl containing one or more heteroatoms (optionally with R at one or more positions)^BInstead).

R^BIs halogen, hydroxy, nitrogen, cyano, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-3Alkyl, aryl C_1-3Alkyl, or heteroaromatic radical C_1-3An alkyl group;

R²is an aromatic radical containing one or more hetero atoms, orA bicyclic or heterocyclic aromatic group containing one or more heteroatoms, or a methylene-3, 4-dioxyphenyl group;

R³is hydrogen, halogen, C_1-6Haloalkyl, C_1-3Heteroalkyl, or C_1-3An alkyl group;

R⁴is hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-3Alkyl, aryl C_1-3Alkyl, or heteroaromatic radical C_1-3An alkyl group.

In a certain aspect, R¹"C" of_2-6An alkenylcarbonyl group "is one or more alkenyl groups containing 2 to 6 carbon atoms, conjugated or not to a carbonyl group.

In a certain aspect, R^BAnd R⁴Such as an aromatic radical C_1-3The "aryl" of the alkyl group being phenyl or substituted by halogen, C_{1- 6}Alkyl radical, C_1-6Alkoxy or methylenedioxy substituted once or many times (e.g. 1,2 or 3 times). In another aspect, R^BAnd R⁴Such as a heteroaromatic group C_1-3The "heteroaryl" of an alkyl group is a furyl or pyridyl group, optionally substituted by halogen, C_1-6Alkyl or C_1-6Alkoxy is substituted one or more times. In another aspect, R^BAnd R⁴Such as C_3-8Cycloalkyl radical C_1-3"C" of alkyl_3-8Cycloalkyl ", is a monocyclic group containing from 3 to 8 carbon atoms. Containing C₃-₆Examples of cycloalkyl groups are: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "alkyl" may represent an alkyl chain or a branched alkyl chain. E.g. C_1-4The alkyl group may be methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. The term "alkenyl" includes both straight-chain and branched alkenyl groups, such as vinyl and allyl. The term "alkynyl" embracesStraight and branched alkynyl groups are included, for example ethynyl. The term "halogen" may be a fluorine, chlorine, bromine or iodine atom. The term "halo C_1-6Alkyl (haloC)_{1- 6}alkyl) "may be an alkyl group containing 1 to 6 carbon atoms, substituted with one or more (e.g., 1,2 or 3) halogen atoms.

The compounds of formula (I) may contain one or more asymmetric centers and thus exist as enantiomers and/or diastereomers. For example, the chiral centers are identified by asterisks in structural formula (I). Thus, the present invention includes one or more enantiomers, and mixtures thereof (in any proportion).

The compounds of formula (I) may exist in different tautomeric forms and the invention encompasses one or more tautomeric forms, and mixtures thereof (in any proportion).

A pharmaceutically acceptable salt of a compound of formula (I) having a basic center, formed by the addition of a pharmaceutically acceptable acid. Some examples of salts include hydrochloride, hydrobromide, sulphate or hydrogen sulphate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulphonate, benzenesulphonate and p-toluenesulphonate salts. The compounds of formula (I) may be used in the form of pharmaceutically acceptable metal salts, especially basic metal salts with bases, for example, sodium and potassium salts.

In one embodiment, the compounds of the present invention have the structure shown in formula (I). Wherein R is¹Is indolyl, R²Is 3, 4-methylenedioxyphenyl, R³Is hydrogen, R⁴Is methyl. In a preferred embodiment, the compound of the invention is (R) -3- (benzo [ d ]][1,3]Dioxol-5-yl) -1- (1H-indol-3-yl) -7-methyl-6, 7-dihydro-3H-oxazolo [3,4-a]Pyrazine-5, 8-dione, and/or enantiomer thereof (S) -3- (benzo [ d ]][1,3]Dioxol-5-yl) -1- (1H-indoleIndol-3-yl) -7-methyl-6, 7-dihydro-3H-oxazolo [3,4-a]Pyrazine-5, 8-diones.

According to the invention, the compound (R, S) -3- (benzodioxol-5-yl) -1- (1H-indol-3-yl) -7-methyl-6, 7-dihydro [1,3]]Oxazolo [3,4-a]Pyrazine-5, 8-diones (C)2) Can be prepared from1Prepared according to scheme 1, in the presence of methylamine, using ethanol as solvent:

optional preparation compound2By the compounds3With an acid in ethanol, according to scheme 2:

compounds may be prepared according to scheme 31：

Compound (I)4Treating with acid in isopropanol, neutralizing with sodium bicarbonate, and adding3,4- (methylenedioxy) benzaldehyde. The last step of the process is the addition of chloroacetyl chloride.

Alternatively, the compounds may be prepared according to scheme 41：

In the method, the compound5Treated with acid in ethanol. After neutralization with sodium bicarbonate, chloroacetyl chloride was added.

Compounds may also be prepared according to scheme 51：

In the method, the compound6Treated with acid in dioxane. Neutralized with sodium bicarbonate and then neutralized with pyridinium chlorochromate (PCC)

Oxidation reaction takes place to form an intermediate4And treated with an acid in isopropanol. Neutralizing with sodium bicarbonate, adding3,4- (methylenedianiline) Oxy) benzaldehyde. The last step of the process is the addition of chloroacetyl chloride.

Another preparation compound1As shown in scheme 6:

in the process, in the presence of aluminium oxide (Al)₂O₃) In the presence of a compound in dichloromethane7And8reacting to form an intermediate9In the presence of calcium oxide (CaO), intermediates9And compounds10And (4) reacting.

Compound 3 can be prepared according to scheme 7:

in this process, liquid ammonia is used as solvent, intermediate9And compounds11And (4) carrying out a reaction.

Alternatively, compounds may be prepared according to scheme 83：

In this process, an intermediate is formed in the presence of calcium oxide (CaO)9And compounds12And (4) reacting.

Compounds may be prepared according to scheme 94：

In this process, the compound is reacted with (2,3) -dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ)13The treatment was carried out using tetrahydrofuran: water was used as a solvent for the reaction.

Another preparation compound4As shown in scheme 10:

in this process, the compound is reacted with pyridinium chlorochromate (PCC)14The treatment was carried out using dichloromethane as solvent for the reaction.

Compounds may be prepared according to scheme 115：

In this process, an intermediate is formed in the presence of calcium oxide (CaO)9And compounds15And (4) reacting.

Alternatively, compounds may be prepared according to scheme 125：

In this process, liquid ammonia is used as solvent, intermediate9And compounds16And (4) reacting.

Compounds may be prepared according to scheme 136：

In this process, lithium hexamethyldisilazide (LiHDMS) is used for the compound13And (6) processing. The last step of the process is the addition of iodine (I)₂）。

Compounds may be prepared according to scheme 1414：

In the method, the compound6Treated with acid in dioxane.

All compounds containing carboxymethyl groups, especially1、3、5And7can be prepared from cyano-containing (their) derivatives, for example, according to scheme 15.

For example, compounds17Treated with acid in methanol. The process may also be carried out separately from the compound18、19And20used together to prepare intermediates accordingly3、5And7。

the invention also provides a pharmaceutical composition, e.g., a suitable dosage form, wherein the composition comprises an effective amount of one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In a particular embodiment, the pharmaceutical composition further comprises other PDE-5 inhibitors, such as sildenafil, vardenafil and tadalafil; or a pharmaceutically acceptable salt thereof. In another embodiment, the pharmaceutical composition further comprises one or more compounds for the treatment of erectile dysfunction or a PDE-5 inhibitor treatable disease.

In a certain embodiment, the pharmaceutical composition is administered with a second pharmaceutical composition containing other PDE-5 inhibitors, such as sildenafil, vardenafil and tadalafil; or a pharmaceutically acceptable salt thereof. In another embodiment, the second pharmaceutical composition comprises one or more compounds for the treatment of erectile dysfunction or a PDE-5 inhibitor treatable disease. The mode of administration may be simultaneous or sequential.

The pharmaceutical compositions may be prepared by methods well known according to the state of the art. Suitably, according to the present invention, Remington's pharmaceutical sciences or similar information sources may be used to formulate a suitable formulation.

Pharmaceutical compositions for oral administration may be presented as discrete units, such as capsules, tablets, effervescent tablets, chewable tablets, pills, powders, granules and gels, or similar pharmaceutical dosage forms. Other oral dosage forms include suspensions or emulsions in aqueous or non-aqueous vehicles.

In solid dosage forms, the compounds of formula (I) may be mixed with a pharmaceutically acceptable carrier containing at least one component selected from diluents, binders, disintegrants, lubricants, coloring agents and flavoring agents. Typical inert diluents are calcium carbonate, calcium hydrogen phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrates, dextrin, cyclodextrin, dextrose excipient, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar and powdered sugar. The binder may be one or more substances, for example, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethylcellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol and alginate. The disintegrant may be selected from the group consisting of low substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium, starch, crystalline cellulose, hydroxypropyl starch, and partially pregelatinized starch, and croscarmellose sodium. Typical lubricants are stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, and sucrose.

In the case of capsules, tablets, effervescent tablets and pills, the dosage forms may also contain buffering agents. The soft capsule can be prepared into a mixture containing the compound shown in the structural formula (I) and vegetable oil. The hard gelatin capsules may contain small particles of a compound of formula (I) in combination with a solid powdered carrier such as a cellulose derivative of lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, gelatin. Additionally, tablets and pills can be prepared with enteric coatings.

In a specific embodiment, the dosage form is a controlled/sustained/modified release dosage form comprising, but not limited to, a biocompatible polymer, a pharmaceutically acceptable polymer matrix, a liposome, a PEG-liposome, or a cyclodextrin derivative matrix, depending on the carrier or matrix.

The pharmaceutical compositions may be administered by a variety of routes of administration, including, but not limited to, oral, intracavernosal injection, topical and transdermal delivery through the skin to various sites or parenteral routes. The particular mode of choice will depend on the compound in the composition, the erectile dysfunction being treated, the tissue relaxation treatable disease and/or health condition, or the severity of the disease treatable by the PDE-5 inhibitor, and the dosage required to produce therapeutic efficacy. Preferably, the compositions of the present invention are in a form for oral administration for the convenience of the patient and the regimen.

Tissue relaxants are used to promote various tissue relaxants for treatment or as therapeutic adjuvants in the treatment and surgery associated with calculus (Korkes, F et al, JBrasNefrol. (2009)31(1): 55), prostate enlargement (e.g., benigrostatic hypertiasia) (WO 9911279), and ureteral stenosis (vanderf et al, bjuinternationary (2002)90: 588). Other tissue relaxation treatable diseases and/or health conditions are known and disclosed in the art.

PDE-5 inhibitors are used to block cGMP degradation, prolong the efficacy of Nitric Oxide (NO) in various tissues, for example, to maintain NO-induced relaxation of airways and vessels (Barnes, p.j. et al, (1995)), and to maintain NO-induced protection of tissues (Duff 1n, r. et al, BrJPharmacol. (2008)153(4): 623). Such behavior in tissues has been shown to be beneficial in the treatment of several diseases, here those treatable by PDE-5 inhibitors, including pulmonary hypertension (commercially treated with sildenafil citrate); bronchitis, chronic asthma, hypertension (EP 758653, US 7569572); raynaud's phenomenon (ghoflanih.a. et al, natrev drug discov.2006,5: 689); right heart failure (Ghofrani et al (2003) AJRCCM167(8): 1139); nerve regeneration and functional recovery following Stroke (Zhang et al, (2002) Stroke33: 2675-; coronary artery dilation (Haicox et al, (2002) JAmColl Cardiol40: 1232); female sexual arousal disorder (Nehra et al (2001) WorldJurol.19(1): 115); angina and heart failure (Reffelmann et al, Circ. (2003)108(2): 239). Other PDE-5 inhibitor treatable diseases are known and disclosed in the art.

A therapeutically effective amount for treating erectile dysfunction is an amount sufficient to ameliorate erectile dysfunction or to reduce symptoms of erectile dysfunction or even to restore erectile function. A therapeutically effective amount for treating a PDE-5 inhibitor-treatable disease is an amount sufficient to ameliorate said disease or reduce a symptom of said disease. The effective amount will depend on the particular condition being treated and its severity; characteristics of the individual patient including age, condition, size and weight; synchronous treatment; and the mode of administration. These factors are well known to those skilled in the art and can be determined without undue experimentation. In general, the dosage of the compound of formula (I) ranges from 0.01mg/kg body weight per day to 100mg/kg body weight per day, preferably from 0.1mg/kg body weight per day to 10mg/kg body weight per day. Multiple doses per day may be considered to achieve suitable systemic levels of active ingredients in the compositions of the invention.

The following examples describe the invention in more detail. It should be noted that the present invention is not limited to the following.

Example 1

Preparation of compound 2(R, S) -3- (1, 3-benzodioxo-5-yl) -1- (1H-indol-3-yl) -7-methyl-6, 7-dihydro [1,3] oxazolo [3,4-a ] pyrazine-5, 8-dione.

Preparation of intermediate Compound 4

To DDQ (22.8 g; 1.0 mol) in l000ml of THF: H₂0(9:1) in a mixed solvent, 2- [ (t-butyloxycarbonyl) amino group was added]Methyl (1H-indol-3-yl) propionate (80.0 g; 0.251 mol). The reaction mixture was mixed for 3 hours. Additional aliquots of DDQ were added until all starting material was consumed (TLC). The reaction mixture was then washed with saturated NaHCO₃The solution was washed and the product was extracted with dichloromethane. The organic phases were combined and MgSO₄And (5) drying. Part of the solvent was removed and 3g of activated carbon was added to the mixture. The mixture was mixed for 30 minutes, then allowed to equilibrate to ambient temperature and filtered. The solvent was removed by rotary evaporation to dryness. The resulting oil was dissolved in acetone (70.0 mL) with heating. The resulting solution was cooled in an ice bath to form 2- [ (tert-butoxycarbonyl) amino group]Precipitation of methyl (E) -3- (1H-indol-3-yl) oxopropanoate, filtration of the precipitate and drying at 60 ℃ in a heater.

Preparation of intermediate Compound 1

To 2- [ (tert-butoxycarbonyl) amino group]To a suspension of methyl (4) -3- (1H-indol-3-yl) oxopropanoate (6.23 g; 19.0 mmol) in 200mL isopropanol was added 2.0mL36% HCl. The reaction mixture was mixed for 3 hours. An additional aliquot of 36% HCl was added until all had goneAll the raw materials are consumed. After completion of the reaction, the reaction mixture was cooled to ambient temperature. Add an aliquot of NaHCO₃The solution is neutralized. 3,4- (methylenedioxy) benzaldehyde (2.86 g; 19 mmol) was added to the solution and mixed for 24 hours with magnetic stirring to form 2- [ (E) - (1, 3-benzodioxol-5-ylmethylene) amino]Precipitation of methyl (E) -3- (1H-indol-3-yl) oxopropanoate, filtration of the precipitate and drying at 60 ℃ in a heater.

Reacting 2- [ (E) - (1, 3-benzodioxol-5-ylmethylene) amino group]Methyl-3- (1H-indol-3-yl) oxopropanoate (5.46 g; 15.0 mmol) was added to a solution of pyridine (10 mL) in 50mL dry dichloromethane. Using CaCO₃The suspension was mixed for 30 minutes in a drying tube under magnetic stirring. Chloroacetyl chloride (2.3 mL, 30.0 mmol) was dissolved in 2.5mL of dry dichloromethane. The resulting solution was added dropwise to the reaction mixture over 30 minutes. After a further 3 hours, 100ml of CuSO was added₄Is added to the reaction mixture. The organic phase was extracted in a separatory funnel and separated. The aqueous phase was washed with 50mL of dichloromethane and the organic phase was separated. The organic phases were combined. The washing process was repeated more than twice. The organic phase was washed with a saturated aqueous solution of NaCl. Separating the organic phase with MgSO₄And (5) drying. The solvent was removed by rotary evaporation to give isolated methyl 3- (chloroacetyl) -5- (1H-indol-3-yl) -2-phenyl-2, 3-dihydro-1, 3-oxazole-4-carboxylate1。

Preparation of Compound 2

To a mixture of 3- (chloroacetyl) -5- (1H-indol-3-yl) -2-phenyl-2, 3-dihydro-1, 3-oxazole-4-carboxylic acid methyl ester (5.46 g, 12.4 mmol)1To 100mL of ethanol solution, 10mL of 40% aqueous methylamine solution was added. The reaction mixture was mixed for 24 hours with magnetic stirring to form (R, S) -3- (1, 3-benzodioxol-5-yl) -1- (1H-indol-3-yl) -7-methyl-6, 7-dihydro [1,3] -l]Oxazolo [3,4-a]Pyrazine-5, 8-diones2Precipitation of (4). The product obtained had the following characteristics: m.p.279-281 ℃. HRMS (E1): m/zcal [ C₂₂H₁₈N₃O₅]404,1246;found:404,1239.1V(KBr):3322,1647,1613,1467cm^-1。NMR¹R(300MHz,DMSO-d6):=11.87(s,1H);9.00(s,1H);7.87(d,1H,J=9.0Hz);7.48(d,1H,J=9.0Hz);7.14(m,5H);7.00(d,1H,J=9.0Hz);6.06(s,2H);4.20(s,2H);2.94(s,3H).NMR¹³C(125MHz,DMSO-d6):=158.3;156.7;148.2;147.5;147.3;135.7;130.9;130.7;125.1;122.0;121.2;120.4;120.2;112.0;108.1;106.4;104.7;102.2;101.3;90.1;52.7;32.2。

Example 2

Compound (I)2Effects on human cavernosa and ureters, and rabbit cavernosa and pulmonary arteries.

Tissue of

Human sponges and ureters were derived from post-operative waste tissue, which was placed in ice-cold Krebs (Krebs) solution for rapid transport to the laboratory.

Male New Zealand white rabbits (2-2.5 kg) were used to obtain penile and pulmonary artery tissue, which was excised and transferred to ice-cold Kreb's solution to obtain two strips and four rings from each of the cavernous body (CC) and pulmonary artery, respectively.

Isometric tension record

The sponge strips, pulmonary artery and ureter were placed in 10ml organ bath containing Krebs solution at 37 deg.C, pH7.4, with 95% O₂And 5% CO₂The mixed gas of (2) continues to bubble. The tissue was strained to a constant force of 5mN, allowing equilibration for 60 min. Isometric tension changes were recorded using a PowerLab4/30 data acquisition system (Chartsoftware, version7.0; ADinstruments, Coloradosprings, CO). To obtain the compound2(named BL106 in FIGS. 1,2 and 3) (0.001-10 μ M) cumulative concentration response curves in the cavernous bars, pulmonary artery rings and ureters contracted by norepinephrine (NOR 10 μ M) (Sigma, StLouis, Mo). For each sample, compounds were plotted2(named BL106 in FIGS. 1,2 and 3). For pulmonary artery, memory is also mapped1H- [1,2,4 ] in the absence or presence of a soluble guanylate cyclase inhibitor]Oxadiazoles [4,3-a ]]Quinoxalin-1-one (ODQ 10 μm) (Sigma, St. Louis, Mo.) conditions2Concentration response curve of (c). Control loops (treated with 40 mdmso) were run simultaneously with the experimental bars and loops.

Relaxation of the human ureter

Norepinephrine causes sustained contraction of human ureteral tissue. Compound (I)2(BL 106) (0.0001-1 μ Μ) produced concentration-dependent relaxation of ureter tissue (pEC 50:6.29 and Emax49%, n = 3) (fig. 1).

Relaxation of pulmonary artery in rabbits

Norepinephrine (3 or10 μm) caused a sustained contraction of the rabbit pulmonary arteries (17.4 mN). Compound (I)2(BL 106) (0.001-10 μm) produced a concentration-dependent relaxation of the pulmonary artery ring (pEC 50:6.23[588 nM)]And Emax62%, n = 3) (fig. 2).

Relaxation of human cavernous body

Norepinephrine causes the human corpus cavernosum to contract continuously. Compound (I)2(BL 106) (0.001-10 μ Μ) produced a concentration dependent relaxation of the corpus cavernosum (pEC 50:7.65 and Emax71%, n = 3) (fig. 3A).

Relaxation of rabbit cavernous body

Norepinephrine (3 or10 μm) caused the rabbit corpus cavernosum to contract continuously (13.8 mN). Compound 2 (BL 106) produced a concentration-dependent relaxation of the corpus cavernosum (pEC 50:5.92[1.2 μ Μ ] and Emax:91%, n = 3) (fig. 3B).

Claims (14)

1. A compound, wherein the compound is of formula (II):

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein the compound is an (R) -isomer, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein the compound is an (S) -isomer, or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

5. A process for the preparation of a compound according to claim 1, which comprises reacting a compound of formula (I) with methylamine and ethanol1Preparation of the Compounds2

6. The method of claim 5, wherein the method further comprises administering a compound of formula (I)4Preparation of the Compounds1Hydrochloric acid, sodium bicarbonate, 3,4- (methylenedioxy) benzaldehyde and chloroacetyl chloride in isopropanol

7. The method of claim 5, wherein the method further comprises administering a compound of formula (I)5Preparation of the Compounds1Hydrochloric acid, sodium bicarbonate and chloroacetyl chloride in ethanol

8. The method of claim 5, wherein the method further comprises administering a compound of formula (I)17Preparation methodCompound (I)1Using methanol and hydronium ions

9. The method of claim 6, further comprising administering a compound of formula (I)13Preparation of the Compounds4Using a mixed solvent of (2,3) -dichloro-5, 6-dicyano-1, 4-benzoquinone, tetrahydrofuran and water

10. The method of claim 6, further comprising administering a compound of formula (I)14Preparation of the Compounds4Using pyridinium chlorochromate and methylene chloride

11. The method of claim 6, further comprising administering a compound of formula (I)6Preparation of the Compounds4Using hydrochloric acid, sodium bicarbonate, pyridinium chlorochromate and methylene chloride in dioxane

12. The method of claim 7, wherein the method further comprises administering a compound of formula (I)19Preparation of the Compounds5Using methanol and a hydrated ion

13. A process for preparing a compound of claim 1, wherein the process comprises reacting a compound of formula (I) with a compound of formula (II)3Preparation of the Compounds2Hydrochloric acid and sodium bicarbonate in ethanol

14. The method of claim 13, further comprising administering a compound of formula (I)18Preparation of the Compounds3Using methanol and a hydrated ion