WO2000078760A1 - Procede de preparation de sildenafil, agent et procede d'obtention d'un comprime mixte a base de sildenafil et de chlorhydrate d'apomorphine - Google Patents

Procede de preparation de sildenafil, agent et procede d'obtention d'un comprime mixte a base de sildenafil et de chlorhydrate d'apomorphine Download PDF

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WO2000078760A1
WO2000078760A1 PCT/CN2000/000145 CN0000145W WO0078760A1 WO 2000078760 A1 WO2000078760 A1 WO 2000078760A1 CN 0000145 W CN0000145 W CN 0000145W WO 0078760 A1 WO0078760 A1 WO 0078760A1
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cyclodextrin
compound
sildenafil
apomorphine hydrochloride
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PCT/CN2000/000145
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English (en)
Chinese (zh)
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Ding Sheng Ding
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The Biochemical Pharmaceutical Factory Of Zhuhai Sez
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Priority to CNB008049912A priority Critical patent/CN1157393C/zh
Priority to AU52048/00A priority patent/AU5204800A/en
Publication of WO2000078760A1 publication Critical patent/WO2000078760A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • the present invention relates to a method for preparing sildenafil, a bulk drug for treating sexual dysfunction, and sildenafil and hydrochloric acid.
  • Apomorphine compound oral tablet preparation hereinafter referred to as apoxidi
  • a preparation method thereof and more specifically, the present invention relates to the preparation of sildenafil by reacting a compound containing a sulfonyl chloride group with piperazine ammonium salt.
  • Sildenafil citrate also known as sildenafil citrate
  • apomorphine hydrochloride are used to form a compound oral tablet preparation and a method for preparing such a compound oral tablet preparation belongs to the field of medicine. Background technique
  • Sildenafil 5- [2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) phenyl] -1-methyl-3 -N-propyl-1, 6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one, the chemical structure is shown in the structural formula (I), the compound can selectively inhibit cGMP PDE without inhibiting cM! P PDE, an early drug for the treatment of cardiovascular diseases, was previously disclosed in EP-A-0463756.
  • sildenafil citrate has a clinical effect in treating male erectile dysfunction, see WO-A- 94/28902 and CN1124926A; its mechanism of action is through the type 5 phosphodiesterase ( Highly selective inhibition of PDE 5 ), increase the level of cyclic guanylic acid (cGMP), enhance the effect of NO released by the penis, relax the smooth muscle of the cavernous body, increase blood flow to the penis and erect, and its preparation is called hiebone or Viagra .
  • CSILD sildenafil citrate
  • Apomorphine hydrochloride (AP0 for short) is an old medicine that has been used clinically for many years. It is a dopamine receptor stimulant. Because of its excitatory role in the medulla oblongata center, it has been administered by subcutaneous injection for a long time to induce vomiting and rescue poisoned patients. It was found in the 1960s that it can induce penile erections, stimulate dopamine receptors during sexual stimulation, increase the electrical nerve impulses from the brain to the erectile tissues, and transmit through the spinal cord through the genital nerves to release NO from the penis and increase blood flow to the penis.
  • the physical and chemical properties of sildenafil citrate are relatively stable.
  • the oral bioavailability is about 40%.
  • the dosage of oral tablets is 25-100mg / person (70kg) based on the amount of sildenafil, which is equivalent to that of sildenafil citrate.
  • CN1057464A and CN1168376A disclose methods for preparing sildenafil and its derivatives.
  • the sildenafil derivative (IV) is prepared by reacting a compound having the general formula (II) with an excess of (III) in CN1057464A; by using this method, a series of derivatives of the compound (IV) can be obtained in a yield 21—88%, see reaction formula 1, when compound (IV) is specifically reaction 1
  • the key step of the above reaction is the ring-closure reaction of the compound of structural formula (V).
  • the yield of the cyclization reaction can reach 95%, and the total yield can reach 51.7% or 47.8%. Under appropriate conditions, the product obtained does not require further purification treatment.
  • OBJECTS OF THE INVENTION The object of the present invention is to disclose a new method for synthesizing sildenafil. The method is simpler than the existing methods, and after the reaction, the product can be directly obtained without the need for post-treatment.
  • Another object of the present invention is to provide a buccal tablet containing didenafil citrate and apomorphine hydrochloride, which is hereinafter referred to as apsidil (APSD) by oral mucosal route, avoiding liver
  • apsidil apsidil
  • W has stronger drug efficacy and better treatment effect, and enables patients with sexual dysfunction to obtain more effective and satisfactory treatment.
  • a method for preparing a buccal tablet of a combination preparation of two dinafil citrate and apomorphine hydrochloride is provided in the T.
  • the method adopts a cyclodextrin, liposome or cellulose process, Including apomorphine hydrochloride and denafil citrate separately or in combination with apomorphine hydrochloride and denafil, the formed inclusion compound can be made into buccal tablets, which can improve the apomorphine hydrochloride.
  • Stability, anti-oxidation, anti-decomposition eliminate the mutual interference between the two main drugs, can hide the bitter taste of the drug, and reduce side effects. Joke
  • the acyl halide can be reacted with a hinge salt to obtain a sulfonamide compound. Under appropriate conditions, the reaction is easier to perform.
  • the obtained product can be purified to obtain a pure sulfonamide compound after neutralization and water washing treatment. .
  • the compound of the formula (VI) is reacted with various salts of 1-methylpiperazine, that is, the compound of the formula (VB), and the salt obtained after the reaction! I.
  • Structure with VI you only need to be neutralized and washed, and you can get Sildenafil that meets the pharmaceutical standards. The purity is 98%. In some cases, you need to recrystallize without With other post-treatments, the reaction yield is high.
  • Apomorphine hydrochloride mainly acts on the human brain and nerve center, stimulates dopamine receptors, and passes through the genital nerves to congest penile blood vessels; sildenafil citrate acts as a peripheral blood vessel to congest the cavernous body to achieve Yin erection.
  • apomorphine hydrochloride plays a role in the human brain and nerve center.
  • the drug has a fast acting tablet, a fast acting effect, and citrate.
  • Dinafil is mainly used in peripheral blood vessels and has a long-lasting effect, so it can enhance the efficacy after compounding.
  • the present invention has no great significance.
  • the researchers of the present invention mainly explored a compound preparation made of a mixture of sildenafil citrate and apomorphine hydrochloride in adults to reduce siliceous citrate In the case of phenafil, it can reduce by-products, overcome the slow onset of sildenafil citrate (the negative psychological effects of slow onset are obvious in sexual behavior), and improve the drug at the same time.
  • the process for preparing compound buccal tablets according to the present invention can overcome the unpleasant taste of apomorphine hydrochloride; the researchers of the present invention determined the amount of the human body that can be accepted and its effect through the fire test. And found that sildenafil citrate compound preparation and mixing apomorphine hydrochloride formed, its efficacy is much higher than both the superposition effect.
  • FIG. 1 is a 1H-NMR spectrum of sildenafil of the present invention.
  • Figure 5 is the DTA spectrum of ⁇ -cyclodextrin
  • Figure 6 is the DTA spectrum of apomorphine hydrochloride
  • Figure 7 is a DTA spectrum of stearic acid
  • M 9 is the DTA spectrum of apomorphine hydrochloride after cyclodextrin inclusion
  • m 11 is an optical microscope photograph of e-cyclodextrin
  • m 12 is a photomicrograph of stearic acid
  • sildenafil preparation process a compound of formula (VI) can be reacted with a 1-methylpiperazine hinge salt compound of formula (W) to form sildenafil Non-salt compound 01); and the reaction is easy to proceed at room temperature.
  • the reaction takes 1 to 8 hours to generate a salt of the two dinafin compound with the structure 1.
  • the mixture is diluted with water, and the pH value is adjusted with an alkaline solution to make the structural formula (I).
  • Sildenafil compounds exist in free form, and the purity can reach or exceed 98%, and the yield is about 79-95%. In short, the above reaction products only need to be neutralized and washed, and no longer need to be separated by chromatography.
  • reaction 3 where ⁇ and ⁇ are reverse ionization ⁇ , ⁇ can be F ⁇ , CI--, Br ⁇ , ⁇ ; ⁇ can be M 2 -to M ⁇ , that is, a single salt or a double salt.
  • the 1-methylpiperazine salt compound may be selected from the group consisting of 1-methylpiperazine hydrochloride, hydrobromide, hydrofluorate, hydroiodate, sulfate, sulfite, nitrate, phosphate
  • Other inorganic salts, C1- 8 acid organic salts, double salts or double salts, and the preferred 1-methylpiperazine salts are selected from the hydrochloride hydrochloride.
  • Suitable solvents in reaction 3 may be selected from C1-C6 alcohols, 1,2-dimethoxyacetamidine, 1,2-monoethoxyethane, dimethylsulfoxide, dimethylformamide, dimethyl Acetylacetamide, N-methylpyrrolidone, preferred solvents are ethanol, 2-propanol and dimethylformamide.
  • the alkali solution in the neutralization reaction is selected from inorganic bases such as potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, and sodium bicarbonate, or organic bases such as methylamine, ammonia, and pyridine.
  • inorganic bases such as potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, and sodium bicarbonate
  • organic bases such as methylamine, ammonia, and pyridine.
  • the preferred alkali solutions are sodium hydroxide and carbonic acid.
  • Sodium, ammonia and pyridine, most preferred are sodium hydroxide and sodium carbonate.
  • the 1-methylpiperazine salt compound is 1-methylpiperazine monohydrochloride
  • the solvent is ethanol
  • the alkaline solution is a sodium hydroxide solution.
  • sildenafil citrate prepared by the method of the present invention can be obtained by any method in the prior art.
  • the present invention uses an acid chloride to directly react with a hinge salt, and the reaction is performed in a shorter time, the reaction is easy, the product does not need to be purified, and the yield is high; and Can be obtained for direct medicinal use
  • the method of the present invention is more convenient and effective than the prior art.
  • the oral bioavailability is less than 4%.
  • the present invention firstly encapsulates apomorphine hydrochloride with cyclodextrin, liposomes, or cellulose to form an oral tablet.
  • the stability of apomorphine hydrochloride can be improved, and the apomorphine hydrochloride can be masked. Very strong bitterness, and the drug is evenly absorbed in the oral mucosa, which can reduce the side effects of nausea and blood pressure.
  • cyclodextrin is selected as the inclusion agent, because cyclodextrin has the characteristics of molecular micro-reward, and the three-dimensional structure is a ring-shaped hollow cylindrical shape with narrow upper and lower ends,
  • the exterior and entrance are hydrophilic and the interior is hydrophobic. It can accommodate molecules or groups of other hydrophobic substances of suitable shape and size to be embedded in their voids to form clathrates.
  • Apomorphine hydrochloride and sildenafil citrate are guest molecules, and the respective organic parts can enter the cyclodextrin molecule or be connected by hydrogen bonds to protect the guest molecules. Therefore, light and air can reduce apomorphine hydrochloride.
  • the effect of morphine increases its stability and can mask the bitterness of the two main drugs.
  • the main medicine is contained in a cylinder of cyclodextrin, under the action of oral saliva and enzymes, the tablets are gradually contained, which can make the main medicine absorbed through the oral mucosa in a balanced manner, which reduces apoxidi nausea and lowers blood pressure.
  • Side effects avoid first-pass effects of the liver, and improve the bioavailability of the drug.
  • cyclopaste is selected from one or more combinations of the following groups:. _Cyclodextrin (. ⁇ ), ⁇ -cyclodextrin ( ⁇ -CD), Y-cyclodextrin ( ⁇ -CD), hydroxypropyl- ⁇ _cyclodextrin (HP- ⁇ -CD), B Cyclodextrin (E- ⁇ -CD), dimethyl- ⁇ -cyclodextrin (DM- ⁇ -CD), trimethyl- ⁇ -cyclodextrin (TM- ⁇ -CD), monoglycosyl- ⁇ -cyclodextrin (Gi. P-CD), diglycosyl- ⁇ -cyclodextrin (G 2.
  • the cyclodextrin-encapsulated apoxidi oral preparation of the present invention further contains a wetting and thickening agent, an acidic medium, a lubricant, a flavoring agent, a filler, a coloring agent, and a preservative.
  • the wetting tackifier is selected from hypromellose, ethyl methyl cellulose, ethyl cellulose, poly alpha-hydroxyethyl methacrylate, povidone, polyvinyl acetate, cellulose acetate, gelatin , Dextrin, white dextrin, microcrystalline cellulose, formazan Cellulose, methyl acrylate, acrylic resins I-IV, hydroxyethyl methyl cellulose, hydroxy ethyl cellulose, carbomer, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose More than one combination.
  • the acidic medium may be selected from one or a combination of stearic acid, palmitic acid, palmitic acid, ascorbic acid, and the like.
  • the lubricant may be one or more combinations of organic and inorganic salts such as magnesium stearate and calcium stearate.
  • sucrose as a bulking agent and flavoring agent
  • two or more kinds of mannitol, IS A sugar to other synthetic sugars, menthol, and flavor are added as the flavoring agent.
  • Saturated solution method, ultra Lubo method, freeze-drying method, and grinding method can be used to encapsulate the above drugs.
  • the saturated solution method when used for encapsulation, the apomorphine hydrochloride is unstable in aqueous solution, light, and air. It is easy to be oxidized to green, and the inclusion yield is low; other methods such as ultrasonic method and freeze-drying method are relatively expensive, while the grinding method has no similar problems, and the method is simple, so the grinding method is preferred.
  • one or more of the above wetting and thickening agents are selected, and stearic acid is used as an acidic medium to ensure the stability of apomorphine hydrochloride.
  • stearic acid is used as an acidic medium to ensure the stability of apomorphine hydrochloride.
  • apomorphine hydrochloride may be included, or sildenafil citrate and apomorphine hydrochloride may be separately included, and then mixed and granulated to reduce mutual interference between the two components and ensure that each For stability, it is also possible to encapsulate both dinafil citrate and apomorphine hydrochloride simultaneously with cyclodextrin.
  • cyclodextrin ⁇ -CD
  • ⁇ -CD cyclodextrin
  • the ratio is 3: 1-7: 1, the inclusion time is 30-180 minutes, and the HPMC concentration is 3%, the inclusion effect is better.
  • the cyclodextrin apomorphine hydrochloride ratio is preferably 4: 1 -6: 1
  • the inclusion time is 40-50 minutes and the HPMC concentration is 3%; the most preferred ratio of cyclodextrin apomorphine hydrochloride is 5: 1, the inclusion time is 45 minutes and the HPMC concentration is 3%.
  • the present invention also determines the use of sweeteners and other excipients according to the requirements of the formulation science and the characteristics of the drug.
  • the best formula for obtaining apoxidi oral buccal tablets is as follows:
  • ⁇ -cyclodextrin ( ⁇ -CD) into the mortar, add the wetting binder solution, grind it evenly, then add the acidic medium and apomorphine hydrochloride and continue to grind until it is fully contained, and set aside (as raw material 1) .
  • ffl Quantify the fine powder, mix the flavor and flavoring agent and sieve it once, then mix with the whole batch of granules, and finally add magnesium stearate to mix and tablet.
  • Steps 1 to 2 ij is the same as above 1 to 2;
  • the preparation process of the present invention further includes:
  • 3 ⁇ 4-cyclodextrin ( ⁇ -CD) into the mortar and add a suitable 3 ⁇ 4 binder solution, grind evenly, then add stearic acid, apomorphine hydrochloride, and sildenafil citrate, and continue to grind until Completely inclusive, prepare Sichuan (as raw material III), and then use the above process to prepare buccal tablets.
  • apomorphine hydrochloride and sildenafil citrate are separately or simultaneously encapsulated with lecithin, and the resulting liposome ⁇ has a stable structure and can cover the bitterness of both drugs .
  • the formula for preparing liposomes is as follows: Sildenafil citrate 20-120g
  • the method of encapsulating the two main drugs is as follows: Put sildenafil in a pH 7.2 phosphate buffer solution and stir well, then add egg yolk lecithin, polyethylene glycol, and Tween-80, mix thoroughly and dry. Pass through 30 mesh sieve and set aside. Add apomorphine to a pH 6.8 phosphate buffer solution and stir well, then add egg yolk lecithin, cholesterol, and polyethylene glycol 2000. Mix well, ventilate and dry at 50 ° C.
  • two drugs are directly encapsulated with cellulose, and the formula is as follows:
  • the preparation process is as follows: first disperse HPMC ffl EtoH, dissolve polyethylene glycol W distilled water, and then combine the two, and the concentration of PEG 6000 is 1.5% for future use. Mix sildenafil citrate and mannitol evenly, add some of the above preparations to make a soft material; mix apomorphine hydrochloride with an acidic medium, add the above preparations and mix well; Maternal law
  • the “daughter-in-law” method mentioned here refers to: when the use of the main component is small, in order to make the main component evenly dispersed in all the auxiliary materials, the main material and the small auxiliary materials are mixed and dispersed ob, Then the uniformly mixed materials are uniformly mixed with the remaining auxiliary materials.
  • the number of auxiliary materials used and the number of premixing those skilled in the art will determine the properties of the auxiliary materials and then combine the two into all the auxiliary materials. Mix evenly, add Sichuan liquid to make soft material, granulate with 16 mesh, blast dry, whole grain, add spices, slippery material to tablet.
  • the M of apomorphine hydrochloride is 0.18- 0.72mg / kg, which is an effective agent based on the body surface area between humans and humans.
  • 3 ⁇ 4 is: when sildenafil citrate 30-120mg / person (70kg), apomorphine hydrochloride 2-8mg / person (70kg) has a better effect on promoting the sexual behavior of male and female rats hunting female human rats.
  • sildenafil citrate 40-50mg / person (70kg), apomorphine hydrochloride 3- 6mg / person (70kg), it is better to promote male rats to hunt for sexual behavior of female rats Effect.
  • the present invention conducted a series of animal tests.
  • Circulation and Respiratory System Using ordinary SD rats, three doses of the test drug were administered sublingually at one time, and the blood pressure, electrocardiogram, respiration and other relevant indicators of the animals were measured before and after administration. The test results showed that when the proposed clinical dose was 3 times, there was no significant change in blood pressure, ECG QRS, ST, T wave, rhythm, and respiratory rate of the animals.
  • Acute toxicity LD 50 in mice by intragastric administration: 960.96mg / kg ; LD 50 in mice by intraperitoneal injection : 150. 48mg / kg ; in accordance with the acute toxicity classification standard for chemicals formulated in 1997, this product is classified as low toxicity level.
  • CSILD in the table is sildenafil citrate
  • apoxidi can rapidly increase the penis length and diameter of male rhesus monkeys.
  • the increase in diameter is of statistical significance, and the drug effect increases with dose.
  • the enhancement compared with the positive control Viagra group, its onset time is earlier, the effect of the low-dose group is slightly stronger than Viagra, and the effect of the medium-dose group close to the Viagra group, the effect is significantly enhanced; the specific results are shown in Table 3 and Table 4, In Tables 3 and 4, The doses in the high and low dose groups were 16. 2, 5. 4, and 1.8 mg / kg, and the doses in the Viagra group were 5.6 mg / kg with sildenafil citrate.
  • the efficacy of aposilidi in each trial was better than that of sildenafil citrate in each dose group, only In the test for reducing the penile smooth muscle of the rhesus monkey, the decrease of aposilidi in the low-dose group was lower than that of sildenafil citrate, mainly due to the small EMG base number of the four animals in the apocydi group before administration.
  • the range of variation is narrow; it is particularly important to emphasize that in the above-mentioned animal experiments, the dosage of apoxidi and sildenafil citrate in the middle-dose group is slightly lower but close to that in the low-dose group.
  • the dosage is lower than that of didenafil citrate, but even low-dose apocylide is more effective than sildenafil citrate alone.
  • Table 7 The specific results are shown in Table 7.
  • the efficacy of the apocedi low-dose 3 ⁇ 4 group is better than that of the T Viagra group or equivalent.
  • the strength of the apocedi low-dose 3 ⁇ 4 group is basically similar to that of the positive control Viagra group.
  • the apocedi low-dose 3 ⁇ 4 group is equivalent to 46 mg of human agent.
  • the Viagra group is equivalent to a human agent 3 ⁇ 4 lOOmg / time / person (based on two-denafil), indicating that sildenafil citrate Combined with apomorphine hydrochloride, the two play a synergistic role, which can reduce the use of fenamic acid and dinafil and improve the efficacy.
  • the compound preparation of the present invention affects the animal's sexual function in humans and unilaterals (Viagra), which is characterized by fast onset, low dosage, and appropriate maintenance time, which is convenient for patients to master and use; and the treatment in the prior art
  • the drug for erectile dysfunction is used as a single agent in the central nervous system, and it is used as a single agent in different peripheral blood vessels.
  • the apocylide developed by the present invention will act on the nerve center pyramidal dopamine receptor agonist apochloride hydrochloride.
  • Morphine and sildenafil citrate a PD inhibitor that acts on peripheral blood vessels, combine the two characteristics of rapid drug action of the nervous system and long-lasting effect of peripheral vascular enzyme inhibitors, enabling the two to exert synergistic effects. It can reduce the dosage of sildenafil citrate even if the onset time of the drug is earlier (effective at 15min), without reducing the drug effect, and can maintain a proper time.
  • sildenafil according to the present invention.
  • the examples are only used to illustrate the present invention, but not to limit the present invention.
  • a Merck silica gel 60F254 chromatography plate was used for purity check, and a high performance liquid chromatography (HPLC O 4. 6 * 250mmC18 column, phosphate buffer pH 7.0. Methanol as mobile phase) was used. Determine the content.
  • the 1H NMR spectrum was measured with a Varian INOVA-400; elemental analysis was performed with a Heraeus Rapid-CHNO elemental analyzer.
  • This example relates to 5- [2-ethoxy-5- (4-methylpiperidinylsulfonyl) phenyl] 1-methyl-3-n-propyl-1, 6-dihydro-
  • the method for preparing 7H-pyrazolo [4. 3-d] pyrimidin-7-one (compound I) is as follows: Compound (VI) is selected from 5- (5-chlorosulfonyl-2-ethoxyphenyl) )-1-methyl-3 -n-propyl-1, 6-dihydro-7H-pyrazolo [4. 3-d] pyrimidine-7-one 7. 5g (0.
  • the elemental analysis values of dinafil citrate were obtained by reacting the two dinafil compounds with citric acid: C49. 70%, H5. 68%, N12. 40%, S5. 00%; Theoretical value: C50. 37%, H5. 85%, N12. 59%, S4. 80%. 13C—MNR spectrum is shown in Figure 2, and mass spectrum is shown in Figure 3.
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • Examples 13-19 relate to the yields obtained by using other double salts, and the method is the same as that of Example 1.
  • TLC thin-layer chromatography
  • HPLC high-performance liquid chromatography
  • the purity of the sildenafil citrate was 98.4%
  • the purity of apomorphine hydrochloride was 98.8%.
  • the solvent was physiological saline; the selected animals were sexually mature female and male SD fire rats, body M 200-280g, male and female, two days before the experiment, female rats were injected with estradiol benzoate, and the male and female were fed in separate cages.
  • Drug M sildenafil citrate 3.60mg / kg body weight, apomorphine hydrochloride 0.45 mg / kg body weight, the aforementioned drug was formulated with 5% hydroxypropyl methylcellulose 3ml in a paste .
  • test drugs, animals, and experimental methods are the same as those in Experimental Example 1.
  • Table 11 shows the average number of times that male rats capture female rats when the test drug doses and ratios in Experimental Examples 2-20 are different.
  • Table 11 Cedi citrate 33 and apomorphine hydrochloride ⁇ -1; effects of different dosage ratios on male rats' sexual behavior
  • CSILD (mg / human equivalent dose APO (mg / kg human equivalent HPMC arrest experimental example)
  • the effective agent M is: Sildenafil citrate 20-120mg / person (70kg), apomorphine hydrochloride 2-10mg / person (70kg), promote male Rats have a certain effect in hunting female rats for sexual behavior.
  • the amount of sildenafil citrate is 2.70-10. 8rag / kg
  • the use of apomorphine hydrochloride is 0.18-0.72mg / kg, which is calculated based on the body surface area between humans and rats, etc.
  • the effective dose is: 30-120mg / person (70kg) of dinafil citrate, 2-8mg / person (70kg) of apomorphine hydrochloride have good effects on promoting the sexual behavior of male rats in pursuit of female rats.
  • sildenafil citrate When the amount of sildenafil citrate is 3.6-6. 5mg / kg, the amount of apomorphine hydrochloride is 0.27-0. 54mg / kg, which is equivalent to the body surface area between humans and rats.
  • the dosage is: when sildenafil citrate 40-50mg / person (70kg) and apomorphine hydrochloride 3-6mg / person (70kg), it has a better effect on promoting male rats to pursue the sexual behavior of female rats .
  • Example Cyclodextrin AP0 HPMC Grinding time Included evaluation Name Dosage g (g)%, ml (minutes) Price
  • Optical microscope (NIKON, eyepiece CFWN 010X / 20, objective lens 4 / 0.13) photos show that ⁇ -cyclodextrin, apomorphine hydrochloride and stearic acid all have regular crystal forms under the optical microscope, ⁇ -cyclodextrin
  • the mixture of apomorphine hydrochloride and stearic acid is a mixture of three crystal forms under an optical microscope.
  • After ⁇ -cyclodextrin is incorporated into apomorphine hydrochloride the original compounds of the compounds are included under the optical microscope. The crystalline material was quenched, and a new structure with different original crystals appeared.
  • the photos are shown in Figure 10-13.
  • sildenafil citrate inclusion compound 2. Put 3 g of cyclodextrin into the mortar, add 4.2 ml of HPMC solution, grind evenly, and then add sildenafil citrate lg for 45 minutes to obtain sildenafil citrate inclusion compound.
  • the bitterness of the inclusion compound is basically fire extinguishing and the taste is good.
  • Example 44 A similar method as described in Example 44 was used to change the type of cyclodextrin and the ratio of tilinafil citrate, the concentration of HPMC with Wtt, and the milling time to prepare the inclusion compound of tilenafil citrate, as shown in the table. As shown in Figure 14, the taste of the drug is improved.
  • the soft material is sieved with 16 mesh sieve, and the thin pan is baked. Baking temperature is controlled below 6CTC, ventilated and dried, after drying, the granules are W 16 mesh whole granules.
  • Example 59 The method of Example 59 above is used to prepare apoxidi compound oral buccal tablets. Each formulation is used to prepare 1000 apo surface, see ⁇ body results.
  • Table] 6 Table 17, Table 1 ⁇ 8:
  • This embodiment is a compound preparation, and the two main drugs are grouped and combined. 1. Put 40g of sildenafil citrate in 50ml of pH 7.2 phosphate buffer solution and stir well, then add 40g of egg yolk lecithin, 8g of polyethylene glycol 2000, 4g of Tween-80 to mix thoroughly and dry, Pass 30 mesh sieve and set aside.
  • the two are gradually expanded to a certain extent with the auxiliary method using the auxiliary method, and then the two are combined into all the auxiliary materials, mixed thoroughly and mixed, and the spare liquid is added to make a soft material, granulated at 16 mesh, and blow dried under 60 ° C.
  • Whole granules, flavored, slippery, can be compressed into tablets.
  • Example 19 The method of Example 1 was used to prepare the two dinafils, and the reaction time was changed to the solvent. The results are shown in Table 19:
  • Sildenafil was prepared by the method of Example 1, except that the compound (VI) was selected from W 5- (5-mosulfonyl-2-ethoxyphenyl) -1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4. 3-d] pyrimidin_7_one yielded a 78% yield of dinafinil.
  • Example 100
  • Sildenafil was prepared by the method of Example 1, except that the compound (VI) was selected from W 5- (5-fluorosulfonyl-2-ethoxyphenyl) -1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4. 3-d] pyrimidin-7-one, yielding a sildenafil yield of 95%.
  • the following is an animal experiment of the pharmacodynamics of the compound preparation of the present invention, as follows:
  • the purpose of this experimental example is to observe the effects of apoxidi on male rats' sexual behavior.
  • This experimental example and the following experimental examples refer to apocylide as 98.4% sildenafil citrate and 98.8% apochloride
  • the animals used in this experimental example are clean Sprague-Dawlay rats, 200-280g in body size, half male and half female, a total of 100 animals.
  • the pharmacodynamic test of this experimental example consists of three groups of high, medium, and low doses.
  • the high dose 3 ⁇ 4 group is 37.8 mg / kg
  • the medium dose M group is 12. 6 mg / kg
  • the low dose 3 ⁇ 4 group is 4. 2itig. / kg.
  • the positive control group used Viagra at 9mg / kg as sildenafil, and 12.6mg / kg as sildenafil citrate; formulated with distilled water; the negative control group was 5% hydroxypropyl methylcellulose; apo Formulated with 5% hydroxypropyl methylcellulose; Table 20 Test drug doses
  • Test method Female rats were intramuscularly administered with estradiol benzoate, 0.1 mg / head two days before the test, to promote their entry into estrus; male rats were randomly divided into apocedidiol (37.8 mg / kg) ), Medium (12.6 mg / kg), low (4.2 mg / kg) three dose groups; 5% hydroxypropyl methylcellulose negative control group and positive control-Viagra group (9.0 mg / kg), a total of Five groups of 10 animals.
  • mice were given the corresponding test drugs according to body S. After the administration, the test animals were placed in observation cages (31 X 24 X 20cm) in a 1: 1 ratio of males and females. Keep the room quiet and observe the male rats' sexual behavior.
  • the indicators are:
  • Capture incubation period means the time from when the male and female animals catch the cage to the first time the male mouse catches the female rat;
  • Capture times Observe the number of times the male rats capture the female rats within 60 minutes;
  • Climbing incubation period It refers to the time from when the male and female animals are closed to the first climb of the male rat after the cage is closed;
  • the high, medium, and low doses of apocylide described in this experimental example are all effects of Viagra 9. Omg / kg.
  • the conclusion shows that low dose sildenafil (4.2 mg / kg of apoxidi Equivalent to sildenafil base 2.85mg / kg and apomorphine hydrochloride (0.2mg / kg) and apomorphine compound preparation has a stronger drug effect ffl than that of monodenafil (9.0mg / kg),
  • the above conclusion also shows that the effect of apoxidi on the sexual behavior of humans and mice described in this experimental example, the intensity of its pharmacological effect increases with the increase of the dosage.
  • test drug The test drug, agent M setting, animal model, and route of administration are equivalent to Experimental Example 21.
  • Test method Castration surgery of animals: Male rats of S-200-260g were taken and adapted in the test environment for 1-2 days, and then castration surgery was performed, that is, anesthetized animals were administered with sodium pentobarbital femoral cavity ( Anesthesia; 3 ⁇ 4 is 45mg / kg), the animals are lying on their backs, and a 1 cm incision is made in the depression in the middle of the bilateral testes, the testes are squeezed out, the wound is ligated, and the outer skin is sutured. Use iodine to eliminate 3 ⁇ 4 suture, and then intramuscularly inject limamycin (4 I. U./kg) to prevent infection.
  • Grouped administration test The animals with successful operation were ranked 10th and randomly divided into five groups, 12 in each group, namely the PI I drug group (Viagra group), three high, medium, and low doses of the test drug 3 ⁇ 4 group, Hypromellose control group; each group was given the corresponding drug once, and the control group was given the corresponding formulation solvent (5% hypromellose), and 15min, 30min, and 60rain were given before administration. Measure the penis diameter and length of the animal, and observe the latency of the penis to the penis erection (seconds).
  • Test data processing The comparison of the test results before and after the administration, the paired test and the comparison test between the groups were used for statistical processing. Based on this, the efficacy was evaluated. The results are as follows:
  • the Viagra group is 12.6rag / kg based on sildenafil citrate. Compared with before administration, ** P ⁇ 0.01, * P ⁇ 0.05; APSD each agent ⁇ : Compared with Viagra group, U P ⁇ 0.05, S # P ⁇ 0.01.
  • the high-, medium-, and low-dose groups of apoxidi had no significant effect on the change of the diameter of the penis in humans and rats, and had an effect on the length of the yin.
  • the Viagra group is 12.6nig / kg based on sildenafil citrate.
  • the effect of Apo on the diameter (mm) and length (mm) of castrated rats See Table 23:
  • Viagra group is 12.6mg / kg based on dicralnafil citrate.
  • This experimental example describes the effect of apoffidi on the length and length of male cynomolgus monkeys.
  • the drugs and preparation methods used in this experiment are the same as those in Experimental Example 21; aposidedichuan is formulated with 5% hydroxypropyl methylcellulose; Viagra Prepared with distilled water, see Table 24 for A.
  • Viagra group is 5.6mg / kg based on sildenafil citrate.
  • Animals 5-11kg male macaques (FJLA-103) provided by the Fujian Non-Human Primate Experimental Animal Center, 4 animals in each group, a total of 20; apoxidi was administered via the buccal capsule mucosa, and Viagra was orally administered medicine.
  • the test drug apoxidi was divided into two dose groups, respectively 16.2rag / kg, 5.4mg / kg, and 1.8mg / kg; [5
  • Negative drug control group 5% hydroxypropyl cellulose solution.
  • Test procedure The animals were randomly divided into five groups, namely the PII drug group (Viagra group), the test drug high, medium and low three doses of the M group, the solvent control group, 4 animals in each group, each group corresponding to a single administration
  • the control group was given the corresponding formulation solvent (5% light propyl methylcellulose), and the penis diameter and length of the animals were measured 15min, 30min, 45min, and 60min before the administration, respectively.
  • Test data processing The test results were statistically processed by paired t test before and after administration. The results are shown in Tables 25 and 26.
  • test drug dose setting, animal model, administration route, and test data processing are the same as in Experimental Example 23.
  • the test method is to randomly divide the animals into five groups, namely the positive drug group (Viagra group), Test the high, medium and low dose groups, the solvent control group. 4 animals per group. Animals in each group were anaesthetized with a dose of 10 mg / kg of ketamine. The anesthetized animals were placed on the operating table supine, lying on their backs, and their limbs were selected. One side of the male monkey's penis was selected as the cavernous body.
  • the cavernous cavity internal pressure (ICP) and smooth muscle electricity test side, the cavernous sinus smooth muscle electromyogram (EMG) reference electrode was fixed on the inside of the male monkey's thigh, and the penis and scrotal skin were routinely disinfected.
  • the concentric needle electrode is inserted into the cavernous body of the penis on one side, and the angle of the needle is 45 ", the depth is 0.5 to 0.8 cm, and the signal is amplified by the DC preamplifier and recorded by the automatic balance recorder. Keep away from the electrode 1. 1.5 cm An 8-gauge needle was inserted into the sponge, and a pressure transducer was connected.
  • the pressure signal was input to the automatic balance recorder to dynamically and simultaneously record the EMG and ICP before the administration. Then, the corresponding drugs were given in groups of dose M. The changes in EMG and II ICP values were observed at 30, 45, and 60 minutes. The results are shown in Tables 27 and 28.
  • the Viagra group is 5.6 mg / kg based on sildenafil citrate; the comparison of each group before and after administration, ** P ⁇ 0. 01, * P ⁇ 0. 05 ,; between groups Compare ft P ⁇ 0.05.
  • CONCLUSION Apocelid excites the erection of cynomolgus monkey erection, it can increase the pressure of corpus cavernosum ⁇ and the reduction of penile smooth muscle electricity, in the dose of 1. 8-16. 2mg / kg 3 ⁇ 4: the range can be obvious Increased Yin significantly: Cavernous cavity pressure, lowering yin-smooth muscle potential; Low-dose group increased macula monkey penile cavernous cavity pressure, and lowering yin: The effect of smooth muscle was similar to that of Viagra group; but at 15 minutes, Apo The effect of Xidi Dian Viagra, suggest that Apo and Onpa have a faster effect than Viagra, and the effect of increasing the internal pressure of the cavernous cavity of the penis is most obvious 15-45min after administration. The effect of lowering yin_smooth muscle potential is most obvious at 30-45rnin. The effect of apoxidi in reducing penile smooth muscle potential and increasing the pressure in the cavernous cavity of the
  • Viagra group is calculated as 12.6mg / kg based on dicralnafil; ** P ⁇ 0.01, * P ⁇ 0.05 compared with pre-dose; compared with Viagra group, each dose of APSD group, SP ⁇ 0.05, ⁇ 0.01 Table 25 Comparison of changes in yin ⁇ ⁇ (degree) of cynomolgus monkeys before and after administration
  • Solvent control group 4 60.75 ⁇ 5.12 65.00 ⁇ 10.80 60.00 ⁇ 4.08 62.50 ⁇ 5.07 60.50 ⁇ 7.94
  • APSD low dose group 4 1.8 78.25 ⁇ 5.68 87.25 ⁇ 8.62 90.00 ⁇ 4.55 * 89.75 ⁇ 5.91 * 84.75 ⁇ 7.76
  • Viagra group 4 4.0 62.75 ⁇ 4.57 68.00 ⁇ 8.83 68.25 ⁇ 4.72 68.00 ⁇ 6.73 65.75 ⁇ 8.50
  • the Viagra group in Tables 25 and 26 is 12.6 mg / k g based on sildenafil citrate ; comparison before and after administration, P ⁇ 0.01, * P ⁇ 0.05c
  • the Viagra group is calculated as 5.6mg / kg based on dicralnafil citrate.
  • the comparison of each group before and after administration is ** P ⁇ 0.01, * P ⁇ 0.05, and the comparison between the groups # P ⁇ 0.05 .

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Abstract

L'invention concerne un procédé de préparation de sildénafil ainsi qu'un agent et un procédé d'obtention d'un comprimé mixte à base de sildénafil et de chlorhydrate d'apomorphine. Le procédé de préparation du sildénafil consiste à faire réagir le composé avec du chlorure et du sel d'ammonium, puis à neutraliser et rincer à l'eau le mélange obtenu afin de le purifier. De plus, ce procédé nécessite une durée réduite de réaction, le produit obtenu n'a pas à être purifié et le rendement est élevé ce qui est un avantage en comparaison avec le procédé de production actuel. L'invention concerne aussi un comprimé mixte comprenant un chlorhydrate d'apomorphine et un citrate de sildénafil et enrobé d'une cyclodextrine, d'un liposome ou d'une cellulase. Ce comprimé est mélangé par la suite à des composés auxiliaires, recouvert de manière à augmenter la stabilité du chlorhydrate d'apomorphine et à masquer son amertume réduisant ainsi les effets secondaires, tels que les nausées et une chute de pression. On peut réduire la quantité de chlorhydrate contenue dans les comprimés mixtes faisant l'objet de cette invention tout en augmentant leur efficacité thérapeutique pour le traitement de troubles de l'érection.
PCT/CN2000/000145 1999-06-21 2000-06-08 Procede de preparation de sildenafil, agent et procede d'obtention d'un comprime mixte a base de sildenafil et de chlorhydrate d'apomorphine WO2000078760A1 (fr)

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CNB008049912A CN1157393C (zh) 1999-06-21 2000-06-08 一种阿扑西地复方口含片制剂及其制备方法
AU52048/00A AU5204800A (en) 1999-06-21 2000-06-08 Process for preparing sildenafil, and troche which comprises sildenafil and apomorphine

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102250039A (zh) * 2011-05-16 2011-11-23 浙江大学 N-甲基哌嗪盐离子液体及其制备方法

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Publication number Priority date Publication date Assignee Title
CN1057464A (zh) * 1990-06-20 1992-01-01 美国辉瑞有限公司 吡唑并嘧啶酮类抗心绞痛剂
CN1124926A (zh) * 1993-06-09 1996-06-19 辉瑞研究及发展公司 用于治疗阳痿的吡唑并嘧啶酮类
CN1168376A (zh) * 1996-06-14 1997-12-24 辉瑞研究开发公司 制备喜勃酮的方法
CA2235642A1 (fr) * 1998-05-15 1998-08-03 Torcan Chemical Ltd. Methodes pour preparer le sildenafil
WO1999028319A1 (fr) * 1997-11-28 1999-06-10 Mochida Pharmaceutical Co., Ltd. NOUVEAUX COMPOSES PRESENTANT UN EFFET INHIBITEUR DE cGMP-PDE
WO1999067231A1 (fr) * 1998-06-19 1999-12-29 Nicox S.A. Sels de nitrate de medicaments anti-hypertenseurs
EP0994115A2 (fr) * 1998-10-12 2000-04-19 Pfizer Limited Procédé pour la préparation de pyrazolo-(4,3-d)pyrimidin-7-ones et leurs intermédiaires

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1057464A (zh) * 1990-06-20 1992-01-01 美国辉瑞有限公司 吡唑并嘧啶酮类抗心绞痛剂
CN1124926A (zh) * 1993-06-09 1996-06-19 辉瑞研究及发展公司 用于治疗阳痿的吡唑并嘧啶酮类
CN1168376A (zh) * 1996-06-14 1997-12-24 辉瑞研究开发公司 制备喜勃酮的方法
WO1999028319A1 (fr) * 1997-11-28 1999-06-10 Mochida Pharmaceutical Co., Ltd. NOUVEAUX COMPOSES PRESENTANT UN EFFET INHIBITEUR DE cGMP-PDE
CA2235642A1 (fr) * 1998-05-15 1998-08-03 Torcan Chemical Ltd. Methodes pour preparer le sildenafil
WO1999067231A1 (fr) * 1998-06-19 1999-12-29 Nicox S.A. Sels de nitrate de medicaments anti-hypertenseurs
EP0994115A2 (fr) * 1998-10-12 2000-04-19 Pfizer Limited Procédé pour la préparation de pyrazolo-(4,3-d)pyrimidin-7-ones et leurs intermédiaires

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102250039A (zh) * 2011-05-16 2011-11-23 浙江大学 N-甲基哌嗪盐离子液体及其制备方法

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