HK1231873A - 5-type phosphodiesterase inhibitor and application thereof - Google Patents

Description

Novel phosphodiesterase type 5 inhibitors and uses thereof

Technical Field

The present application relates to the field of medicine, in particular to selective phosphodiesterase type 5 (PDE5) inhibitors and their use in the treatment and/or prevention of a disease or condition, wherein such inhibition is considered beneficial.

Background

Erectile Dysfunction (ED) has a major impact on male psychology and physiology. PDE5 inhibitors have been found to be effective in treating ED. For example, loving (Cialis) of Lily, the chemical structure of which is shown below:

PDE5 inhibitors have been found to improve ED for a variety of reasons, and have been shown to have little difference between compounds with respect to onset of action, but greater differences in half-life. For example, the half-life of Cilii in human body is as long as 24-36 hours, while the half-life of both drugs, Vancide produced by Pesper pharmaceutical company and Ailida produced by Bayer pharmaceutical company, is only about 4-5 hours.

Due to the different half-lives of the drugs, people of different ages and different constitutions will choose products with different half-lives to meet different needs. However, there is a great difference between the half-lives of these three drugs. Thus, there remains a need for new phosphodiesterase type 5 inhibitors.

Summary of The Invention

In one aspect, the present application relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

in another aspect, the present application relates to a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient or diluent,

in another aspect, the application relates to the use of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment and/or prevention of a disease or condition associated with phosphodiesterase type 5 in a mammal, wherein inhibition of phosphodiesterase type 5 is considered beneficial,

in another aspect, the present application relates to the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment and/or prevention of erectile dysfunction in a human,

the compound represented by formula (I) or a pharmaceutically acceptable salt thereof of the present application has a good inhibitory effect on PDE5 and good pharmacokinetic properties, has an appropriate half-life and biological metabolism in vivo, and thus, is easily developed as a clinical drug.

Detailed description of the invention

In the following description, certain specific details are included to provide a thorough understanding of various disclosed embodiments. One skilled in the relevant art will recognize, however, that the embodiments may be practiced without one or more of the specific details, or with other methods, components, materials, and so forth.

Throughout this specification and the claims which follow, unless the context requires otherwise, the words "comprise" and "comprise" are to be construed in an open, inclusive sense, i.e., "including but not limited to".

Reference throughout this specification to "one embodiment" or "an embodiment" or "in another embodiment" or "in certain embodiments" means that a particular reference element, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

It should be understood that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It will also be understood that the term "or" is generally employed in its sense including "and/or" unless the context clearly dictates otherwise.

Definition of

The term "carrier" is defined as a compound that facilitates the introduction of the compound into a cell or tissue. For example, dimethyl sulfoxide is commonly used as a carrier because it facilitates the introduction of certain compounds into cells or tissues of an organism.

The term "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, etc. that has been recognized by the national drug and food administration as being useful for humans or animals in a variety of forms that have no adverse effects on the pharmaceutical composition.

The term "pharmaceutically acceptable salts" means those salts that retain the biological effects and properties of the PDE5 inhibitors of the present application and are not biologically or otherwise unacceptable. For example, pharmaceutically acceptable salts do not interfere with the beneficial effects of the agents of the present application in inhibiting PDE5, and include "pharmaceutically acceptable acid addition salts".

The term "pharmaceutically acceptable acid addition salts" refers to those salts that retain the biological effectiveness and properties of the free base, which are biologically or otherwise suitable and are formed using inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or organic acids such as, but not limited to, acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzenecarboxylic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclohexylsulfamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, mucic acid, gentisic acid, Glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1, 5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

The term "mammal" includes humans and domestic animals, such as laboratory animals and domestic pets, such as cats, dogs, pigs, cows, sheep, goats, horses and rabbits, as well as non-domestic animals, such as wild animals and the like.

The term "pharmaceutical composition" refers to a formulation of a compound of the present application with a vehicle generally accepted in the art for delivery of biologically active compounds to mammals such as humans. Such media include all pharmaceutically acceptable carriers, diluents or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. There are a variety of methods in the art for administering compounds or pharmaceutical compositions, including, but not limited to, oral administration, injection administration, inhalation administration, parenteral administration, and topical administration.

The term "pharmaceutically acceptable" is defined as a carrier, excipient, or diluent that does not abrogate the biological activity and properties of the compound.

The term "therapeutically effective amount" refers to an amount of a compound of the present application which, when administered to a mammal, preferably a human, is sufficient to effectively treat a disease or condition associated with PDE5 in a mammal, preferably a human. The amount of the compound of the present application that constitutes a "therapeutically effective amount" will vary according to the compound, the disease state and its severity, and the age of the mammal to be treated, but can be determined routinely by those skilled in the art, given their own knowledge and this disclosure.

As used herein, "treating" or "treatment" encompasses treating a related disease or condition in a mammal, preferably a human, suffering from the related disease or condition and includes:

(I) preventing the occurrence of a disease or condition in a mammal, particularly when the mammal is susceptible to said disease condition but has not been diagnosed as having such a disease condition;

(II) inhibiting the disease or disease state, i.e. preventing its occurrence; or

(III) alleviating the disease or condition, i.e., causing regression of the disease or condition.

Detailed description of the preferred embodiments

In one aspect, the present application relates to a compound represented by formula (I):

the compounds represented by formula (I) are potent and selective PDE5 inhibitors, have good pharmacokinetic properties, and have a suitable half-life and biological metabolism in vivo to meet the needs of patients.

Pharmaceutical composition

In another aspect, the present application relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient or diluent and a therapeutically effective amount of a compound represented by formula (I):

in certain embodiments, the pharmaceutical composition is formulated into a pharmaceutical dosage form suitable for oral, buccal, intravenous, intraperitoneal, subcutaneous, intramuscular, inhalation, or epidermal administration, and the like, preferably oral or buccal administration.

In certain embodiments, the pharmaceutical composition is formulated into a suitable dosage form, including, but not limited to, tablets, capsules, lozenges, pills, granules, powders, solutions, emulsions, suspensions, dispersions, syrups, gels, or aerosols.

In certain embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable surfactant, film-forming substance, coating aid, stabilizer, dye, flavoring agent, fragrance, flavor, excipient, lubricant, disintegrant, glidant, solubilizer, filler, solvent, diluent, suspending agent, tonicity modifier, buffer, preservative, antioxidant, sweetener, colorant, and/or binder. Pharmaceutically acceptable carriers, excipients or diluents for therapeutic use are well known in the medical field and are described, for example, in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing co., Easton, PA (1990), the entire contents of which are incorporated herein by reference.

The pharmaceutical compositions of the present application may be manufactured in accordance with known procedures, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting operations.

Thus, according to the present application, the pharmaceutical composition used may be formulated into a pharmaceutically acceptable formulation using one or more pharmaceutically acceptable excipients, carriers, diluents and/or adjuvants in a conventional manner. Suitable formulations depend on the chosen route of administration. Any suitable formulation techniques, carriers and excipients known in the art may be used.

Therapeutic uses

In a further aspect, the present application relates to the use of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of a disease or condition associated with PDE5 in a mammal, wherein inhibition of PDE5 is considered beneficial,

in certain embodiments, the mammal is a human.

In certain embodiments, the disease or condition associated with PDE5 is erectile dysfunction.

Formulation, route of administration and effective dose

Another aspect of the present application relates to formulations, routes of administration, and effective dosages comprising a compound represented by formula (I), or a pharmaceutically acceptable salt thereof. Such formulations are useful in the treatment of diseases or disease states associated with PDE5, as described above.

The compound represented by formula (I) or a pharmaceutically acceptable salt thereof of the present application may be administered in the form of pharmaceutical preparations including those suitable for oral administration (including buccal administration and sublingual administration), topical administration or parenteral administration (including intramuscular administration, intradermal administration, intraperitoneal administration, subcutaneous administration and intravenous administration), or the compound may be administered in a form suitable for administration by aerosolization, inhalation or insufflation. General information on Drug delivery systems can be found in Ansel et al, Pharmaceutical delivery Forms and Drug delivery systems (Lippencott Williams & Wilkins, Baltimore Md. (1999)).

In various aspects, a pharmaceutical formulation comprises: carriers and excipients (including, but not limited to, buffers, carbohydrates, antioxidants, bacteriostats, chelating agents, suspending agents, thickening agents, and/or preservatives); water; an oil; a physiological saline solution; a flavoring agent; a colorant; an anti-sticking agent; and other acceptable additives, adjuvants or binders; other pharmaceutically acceptable auxiliary substances required to approximate physiological conditions, such as pH buffers, tonicity adjusting agents, emulsifiers, wetting agents, preservatives and the like. It will be appreciated that although any suitable carrier known to those skilled in the art may be used to administer the compositions of the present application, the type of carrier will vary depending on the route of administration.

As is well known in the art, the concentration of the drug can be adjusted, the pH of the solution buffered, and isotonicity adjusted to be compatible with intravenous injection.

The compounds represented by formula (I) or pharmaceutically acceptable salts thereof of the present application may be formulated as sterile solutions or suspensions in suitable vehicles as are well known in the art. The pharmaceutical composition may be sterilized by a commonly known sterilization technique, or may be sterile-filtered. The resulting aqueous solution may be packaged for use as is, or lyophilized, the lyophilized formulation being combined with a sterile solution prior to administration.

For oral administration, the compounds represented by formula (I) or pharmaceutically acceptable salts thereof of the present application can be readily formulated by combining them with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the present application to be formulated as tablets, pills, dragees, capsules, lozenges, liquids, gels, syrups, powders, suspensions, elixirs, and the like, for oral ingestion by a patient to be treated.

Pharmaceutical compositions suitable for use herein include compositions in which the active ingredient is present in an effective amount (i.e., an amount effective to achieve a therapeutic and/or prophylactic benefit in an individual). The actual amount effective for a particular application will depend on the condition or conditions being treated, the condition of the individual, the formulation and route of administration, and other factors known to those skilled in the art. Determination of an effective amount of a PDE5 inhibitor is within the ability of those skilled in the art, in light of the disclosure herein, and can be determined using routine optimization techniques.

An effective amount for use in humans can be determined from animal models. For example, a dose for use in humans may be formulated to achieve circulating, hepatic, topical and/or gastrointestinal concentrations found to be effective in animals. One skilled in the art can determine an effective amount for human use, particularly in light of the animal model experimental data described herein. Based on animal data and other types of similar data, one skilled in the art can determine an effective amount of a composition of the present application suitable for use in humans.

An effective amount, as it relates to the PDE5 inhibitors of the present application, generally means a dosage range, route of administration, formulation, etc., recommended or approved by any of the various regulatory or counseling agencies (e.g., FDA, SDA) in medical or pharmaceutical technology, or by the manufacturer or supplier.

In addition, appropriate dosages of PDE5 inhibitors may be determined based on in vitro experimental results. For example, the in vitro potency of an agent to inhibit PDE5 provides information that can be used to develop effective in vivo dosages that achieve similar biological effects.

Having now generally described various aspects, these aspects will be more readily understood by reference to the following examples, which are provided by way of illustration and are not intended to be limiting unless otherwise specified.

Examples

Example 1 preparation of a Compound represented by the formula (I) (No.: DDCI01)

Step 1:

TABLE A

To a 500mL reaction flask equipped with a reflux condenser were added the reaction reagents and solvents shown in table a. In N₂The reaction was carried out under reflux at 120 ℃ for 6h under an atmosphere. Completion of the reaction was monitored by Thin Layer Chromatography (TLC). The reaction mixture was cooled to room temperature, and then filtered to remove Cs₂CO₃Solid, with CH₂Cl₂The filter cake is washed. The filtrate was concentrated to dryness under reduced pressure, and the residue obtained was taken up with CH₂Cl₂Dissolution was followed by washing with water and saturated NaCl solution once each. The organic phase was over anhydrous MgSO₄Drying, filtering, and concentrating under reduced pressure to dryness to obtain crude product. The crude product obtained was purified by silica gel column chromatography to give 24.4g of pure product in 80% yield.

Step 2:

TABLE B

To a 500mL reaction flask equipped with a reflux condenser were added the reaction reagents and solvents shown in table B. After stirring the reaction at 100 ℃ under reflux for 6h, the completion of the reaction was monitored by TLC. The reaction was cooled to room temperature, then cooled to 0 ℃ and left at 0 ℃ overnight. Precipitating out solid, filtering, and using small amount of CH to filter cake₃NO₂Washing and then using CH₂Cl₂Washed to white. After drying, 60g (white powder) of the product are obtained, with a yield of 96%.

And step 3:

watch C

To a 1L reaction flask was added the product from step 2, Et₃N、CH₂Cl₂Then stirring at room temperature to obtain a clear solution, cooling to 0 ℃ in an ice bath, and slowly dropwise adding CH of chloroacetyl chloride₂Cl₂Solution while maintaining the reaction temperature at 0-5 ℃. After the addition, the reaction was continued in an ice bath (0 ℃ to 5 ℃) and monitored by TLC until the reaction was complete. The reaction solution is filtered, and a small amount of CH is used for filter cakes₂Cl₂Washed and dried to give 32.4g (containing Et) of a white solid₃Hcl, but could be used directly in the next reaction). The filtrate was taken with 10% K₂CO₃Washing with a saturated NaCl solution, layering, and removing the solventThe organic phase was over anhydrous MgSO₄Drying, filtering and concentrating to dryness. The residue is reused with CH₃OH∶H₂Recrystallization from 4: 1O gave 31g of a tan solid.

And 4, step 4:

table D

The product from step 3, Et was added to a 1L reaction flask at room temperature₃After N and DMF, stir well, then slowly add hydrazine hydrate solution in DMF dropwise and stir the reaction at room temperature overnight. After completion of the reaction was monitored by TLC, purified water of about 3 times the volume of the reaction mixture was slowly added to the reaction mixture in an ice water bath, and after vigorously stirring for 2 hours, the mixture was allowed to stand and filtered. Washing the filter cake with water, washing with isopropanol and drying to obtain the crude product. Finally, the crude product was used in small amounts of CHCl₃Reflux for 20min, filter, and dry to give 35.5g of pure product.

The overall yield for both step 3 and step 4 was 82%.

¹HNMR(d-DMSO，400M)：11.01(s，1H)，7.55(d，J＝7.6Hz，1H)，7.29(d，J＝8.0Hz，1H)，7.07(t，J＝7.2Hz，1H)，7.02(t，J＝7.2Hz，1H)，6.87(d，J＝1.2Hz，1H)，6.80(dd，J＝8.4，1.6Hz，1H)，6.77(d，J＝8.0Hz，1H)，6.09(s，1H)，5.12(s，2H)，4.44(dd，J＝11.6，3.6Hz，1H)，4.26(dd，J＝16.8，1.6Hz，1H)，3.96(d，J＝17.2Hz，1H)，3.56(dd，J＝16.0，4.4Hz，1H)，2.98(dd，J＝15.6，12.0Hz，1H).¹³CNMR(d-DMSO，100M)：166.76，165.09，147.53，146.54，137.56，136.7，134.50，126.23，121.73，119.77，119.35，118.59，111.79，108.43，107.40，105.27，56.05，55.89，53.81，23.94.

Example 2: inhibition of PED5

The method comprises the following steps: the half inhibitory concentration IC of the sample was determined by the dose-effect relationship of the sample to the inhibitory ability of PDE5A (E904, SIGMA-ALDRICH) using Sildenafil (S1431, select) as a positive control and using a homogeneous Time resonance energy transfer (HTF) method (Cat.No.62GM2PEB, Cisbio)₅₀。

Sample (I)	IC50Value of
		Cialis	111.6nM

DDCI01	33.6nM
		DDCI02Note that	566.2nM

Note: the structure of compound DDCI02 is shown below:

example 3: pharmacokinetic Studies

The experimental method comprises the following steps:

preparing a stock solution: 1.13 mg Cialis, 1.15 mg DDCI02 and 1.23 mg DDCI01 were weighed and dissolved in 1.13, 1.15, 1.23 ml dimethylsulfoxide, respectively, to make 1.00 mg/ml stock solutions.

The sample preparation method comprises the following steps: one-step protein precipitation method

A precipitant: acetonitrile (verapamil with 5.00 ng/ml)

Preparation of standard curve and quality control sample: transfer 5.00 microliters of standard curve or quality control working fluid and 45.0 microliters of blank plasma to a 1.5 milliliter centrifuge tube. The final concentrations of the standard curve samples were 1.00, 2.50, 5.00, 10.0, 50.0, 100, 500, and 1000 ng/ml, respectively. The concentrations of the quality control samples were 2.50, 5.00, 50.0 and 800 ng/ml, respectively. The diluted quality control sample concentration was 5000 ng/ml.

Plasma sample preparation: transfer 100 microliter of precipitant to 10.0 microliter of sample to be tested, standard curve sample and quality control sample, respectively. After 3.00 min vortex shaking and 5.00 min centrifugation (12000 rpm), 10 μ l of supernatant was aspirated for LC-MS/MS analysis.

Number of rats: each group had 3 rats per rat group,

the administration mode comprises the following steps: the medicine is taken orally and the medicine is taken orally,

blood sampling time points: 0 minute, 15 minutes, 30 minutes, 1h, 2h, 4h, 6h, 8h, 24h

The experimental results are as follows:

DDCI01：

DDCI02

Cialis

pharmacokinetic results indicate that DDCI01 is at C_maxAnd AUC are obviously superior to Cialis and DDCI02, and the in vivo half-life (t) of SD rats_1/2) Studies have shown that DDCI01 is slightly shorter than cialis and longer than DDCI 02.

Example 4: pharmacodynamics study of erection function of normal rat

Detecting the pressure change of the rat blood pressure and the internal pressure change of the cavernous body:

after the rats were anesthetized with 2% pentobarbital (3 mg/kg), the right carotid artery was isolated and connected to a pressure transducer of a Powerlab recorder via a PE-50 silica gel catheter to record the continuous change in arterial blood pressure (the blood pressure of the rats began to drop rapidly at the beginning of electrical stimulation and the blood pressure quickly returned to normal after the end of stimulation). And then taking down the abdominal median incision, extending to the scrotum mediastinum, exposing penis feet at two sides, inserting a No. 23 sleeve needle into the left penis foot, connecting the left penis foot with a pressure sensor of a Powerlab recorder through a PE-50 silica gel catheter, wherein the catheter contains heparin normal saline (250 units/ml), stimulating cavernous nerve emitting sections of the left pelvic ganglion of the experimental group by using the bilateral electrodes, adjusting a Powerlab system to enable the parameters of the electrical stimulation pelvic ganglion to be wave width of 2.56ms, frequency of 7.98HZ, current of 3mA, duration of 40s, and recording the internal pressure change of the cavernous body.

And (3) detecting the erectile function: the rat is orally taken once, the erection function of the animal is detected by stimulating the pelvic nerve with the electrode 2, 6 and 24 hours after the administration, the arterial blood pressure change value before and after stimulation, the intracavernosal pressure change value/blood pressure change value before and after stimulation, the intracavernosal pressure change value before and after stimulation and the penis fading time of the rat after stimulation are recorded. The main evaluation indexes of the erectile function are the internal pressure change value of the cavernous body and the withdrawal time of the cavernous body of the penis.

Table 1: data on 2-hour blood pressure changes (mean. + -. standard deviation) after administration to rats of each experimental group

Note: p < 0.05, P < 0.01 compared to control.

The blood pressure before animal stimulation is measured two hours after drug administration

Table 2: sponge internal pressure variation data 2 hours after administration of drug to rats of each experimental group (mean. + -. standard deviation)

Note: p < 0.05, P < 0.01 compared to control.

Table 3: data of penis withdrawal time 2 hours after administration to rats of each experimental group (mean. + -. standard deviation)

Group of	Differential blood pressure/differential pressure in cavernous body before and after stimulation	Regression time (S)
			Negative control group	38.14±13.17	9.75±4.92
Tadalafil group	89.75±33.30	40.50±21.14*
			DDCI-01 Low dose group	105.52±41.17*	38.00±10.42*
DDCI-01 Medium dose group	128.64±35.20*	40.75±4.79*
			DDCI-01 high dose group	136.85±41.98**	101.00±21.56**

Note: p < 0.05, P < 0.01 compared to control.

Table 4: data on blood pressure changes 6 hours after administration to rats in each experimental group (mean. + -. standard deviation)

Note: compared with a control group, the composition has no significant difference

Table 5: data of intracavernosal pressure changes (mean. + -. standard deviation) 6 hours after administration to rats of each experimental group

Note: p < 0.05, P < 0.01 compared to control.

Table 6: data of penis withdrawal time (mean. + -. standard deviation) 6 hours after administration to rats of each experimental group

Group of	Differential blood pressure/differential pressure in cavernous body before and after stimulation	Regression time (S)
			Negative control group	39.30±15.86	9.50±2.52
Tadalafil group	117.16±42.07*	44.25±13.35**
			DDCI-01 Low dose group	94.70±33.16*	47.75±11.79*
DDCI-01 Medium dose group	106.19±16.03*	48.00±23.85*
			DDCI-01 high dose group	159.65±33.86**	64.00±19.37**

Note: p < 0.05, P < 0.01 compared to control.

Table 7: data on the 24-hour blood pressure changes (mean. + -. standard deviation) after administration to rats of each experimental group

Note: compared with a control group, the composition has no significant difference

Table 8: data of intracavernosal pressure changes 24 hours after administration to rats (mean. + -. standard deviation) for each experimental group

Note: p < 0.01 compared to control group.

Table 9: data of penis withdrawal time 24 hours after administration to rats of each experimental group (mean. + -. standard deviation)

Group of	Differential blood pressure/differential pressure in cavernous body before and after stimulation	Regression time (S)
			Negative control group	49.67±5.59	8.75±1.71
Tadalafil group	107.99±32.42	41.25±10.34*
			DDCI-01 Low dose group	92.05±31.72	23.75±12.84
DDCI-01 Medium dose group	106.03±44.12	41.25±14.50*
			DDCI-01 high dose group	113.00±38.23	60.75±24.14**

Note: p < 0.05, P < 0.01 compared to control.

The results shown in the table show that after the compound DDCI-01 is administered to normal rats, the low, medium and high doses can obviously increase the pressure difference in the cavernous body and prolong the penis regression time, namely, the compound can obviously enhance the erectile function of the normal rats. In the experiment, the administration dosage of the tadalafil group is close to the normal administration dosage of a human body, and is similar to the evaluation results of the DDCI-01 low and medium dosage groups.

EXAMPLE 5 DDCI-01 Bioavailability Studies

Preparation and addition of compounds: compounds were diluted with DMSO gradient; starting from 10mM stock solution, compounds Cialis and DDCI-01 were diluted three-fold with DMSO. Mu.l of reaction buffer was added to each well of a compound dilution plate (V96MicroWell Plates), and 1. mu.l of compound DMSO dilution was added thereto, followed by mixing well. 5. mu.l of the diluted compound was added to each well of a reaction plate (96-well microplate); the final concentrations of the compounds were: 10000, 3333, 1111, 370.4, 123.5, 41.2, 13.7, 4.6, 1.5, 0.51, 0.17[ nM ];

the inhibition of various Phosphodiesterase (PDE) activities by compounds was evaluated using a relevant kit. The specific screening results are shown in table 1.

Inhibition of various phosphodiesterase activities by the compounds of table 10.

The results of DDCI-01 measurements on 7 other PDE subtypes showed that DDCI-01 had weak inhibitory effects on PDE6C (IC50 > 10 μ M) and PDE11A (IC50 ═ 2.6 μ M), and no significant inhibitory effects on PDElA, 2A, 3A, 4A1A and 7A (0% inhibition of enzyme activity at 10 μ M).

Claims (7)

1. A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof,

2. a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient or diluent,

3. use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or a pharmaceutical composition according to claim 2 in the manufacture of a medicament for the treatment and/or prevention of a disease or condition associated with phosphodiesterase type 5 in a mammal, wherein inhibition of phosphodiesterase type 5 is considered beneficial,

4. the use of claim 3, wherein the mammal is a human.

5. The use of claim 3, wherein the disease or condition associated with phosphodiesterase type 5 is erectile dysfunction.

6. The use according to any one of claims 3-5, wherein the medicament is for oral, topical, intramuscular, intradermal, intraperitoneal, subcutaneous, intravenous or inhalation administration, preferably oral administration.

7. The use according to any one of claims 3 to 6, wherein the medicament is selected from tablets, capsules, lozenges, dragees, pills, granules, powders, solutions, emulsions, suspensions, dispersions, syrups, gels, or aerosols.