CN1091096C - Sertraline and its salt, and its usage for treating mammal premature ejaculation - Google Patents
Sertraline and its salt, and its usage for treating mammal premature ejaculation Download PDFInfo
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- CN1091096C CN1091096C CN00124758A CN00124758A CN1091096C CN 1091096 C CN1091096 C CN 1091096C CN 00124758 A CN00124758 A CN 00124758A CN 00124758 A CN00124758 A CN 00124758A CN 1091096 C CN1091096 C CN 1091096C
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Abstract
The present invention relates to a compound with a chemical name of (1S-4S)-4-(3, 4-dichlorophenyl)-1, 2, 3, 4-tetrahydro-N-methyl-1-naphthylamine citrate, a medicinal composition containing the compound, and the application of the medicinal composition in the treatment of mammal prospermia. The present invention also provides the application of the compound with the formula I in the treatment of mammal prospermia.
Description
The present invention relates to a kind of medical compounds and uses thereof, particularly, the present invention relates to Sertraline and salt thereof and be used for the treatment of the purposes of mammal premature ejaculation with them.
" Sertraline " is " medicine name vocabulary " middle title of using that Pharmacopoeia Commission of the Ministry of Public Health compiles and edit, and the English name of Sertraline " Sertraline " is INN title (being international title).
The known function of Sertraline is thymoleptic and anorexigenic, and it has following structural formula:
Disclose the sertraline hydrochloride compound in the U.S. Pat 4536518 that on April 20th, 1985 authorized and pointed out that this compound shows antidepressant and reduces the appetite activity in mammalian body.
The inventor is by discovering, the citric acid Sertraline has better solubility property and dissolution rate than sertraline hydrochloride, should have higher bioavailability, is more suitable in absorption of human body, is good medicinal compound; In addition, the inventor also is surprised to find, and Sertraline and salt compounds thereof have anti-premature ejaculation activity, can be used for the treatment of Mammals (comprising the mankind) premature ejaculation.
Therefore, the purpose of this invention is to provide a kind of citric acid Sertraline (SertralineCitrate) compound, its chemistry (1S-4S)-4-(3 by name, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-N-methyl isophthalic acid-naphthylamines Citrate trianion has following formula Ia structure:
HX wherein HX is a citric acid.
Another object of the present invention has provided a kind of method for the treatment of mammal premature ejaculation, and this method is that following formula I compound and pharmacologically acceptable salt thereof are used for the patient:
The pharmacologically acceptable salt of formula I compound can be the salt that the conventional acid of using forms in the free alkali of formula I compound and the field of pharmacology, optimization citric acid salt, mandelate, hydrochloride and vitriol, most preferably Citrate trianion.
The present invention provides formula I compound and pharmacologically acceptable salt thereof to treat the purposes of the medicine of mammal premature ejaculation in preparation on the other hand.
The inventor is by discovering, when formula I compound and pharmacologically acceptable salt thereof were used for the treatment of patient's premature ejaculation, with the free alkali form metering, general premature ejaculation patient with sympotoms taking dose every day was 25-50mg, and the needs of patients that the premature ejaculation degree is overweight increases to 50-100mg every day.Take the back and reached the Plasma Concentration peak in 4-8 hour.Therefore, suggestion 4-5 hour disposable this medicine of taking before sexual intercourse earlier begins to take from 25mg, and undesirable or DeGrain person can increase dosage gradually to 50mg as effect, and the insensitive person of minority medicine need increase dosage to 100mg.4 hours took effect after single was taken, and curative effect can continue to next day, about 30 hours of time length; After taking continuously 3 days, curative effect can continue 3 days again, promptly can continue about 72 hours again.
The citric acid Sertraline is a new compound, does not specifically prepare this compound in the prior art, and also the concrete activity of this compound is not reported.The inventor finds, the citric acid Sertraline has better solubility property and dissolution rate than sertraline hydrochloride, should have higher bioavailability, be more suitable in absorption of human body, be good medicinal compound, and the inventor also find, this compound has anti-premature ejaculation activity, can be used for the treatment of mammal premature ejaculation.The citric acid Sertraline can use with the form of itself, preferably uses with the pharmaceutical compositions that contains this compound and pharmaceutically useful carrier.Need to prove, because citric acid is a strong organic acid, and be triprotic acid, when it and Sertraline free alkali salify, different according to feed ratio with feeding mode, can obtain containing the citric acid sertraline salts of different free alkali ratios, and according to different post processing modes, the Citrate trianion that can obtain containing crystal water or not contain crystal water.These Citrate trianions all have activity of the present invention and purposes, all belong to the category of the claimed Citrate trianion compound of the present invention, all within protection scope of the present invention.
Therefore, the present invention also provides a kind of containing (1S-4S)-4-(3, the 4-dichlorophenyl)-1,2,3, the pharmaceutical composition of 4-tetrahydrochysene-N-methyl isophthalic acid-naphthylamines Citrate trianion and pharmaceutically acceptable carrier on the other hand.
Pharmaceutical composition of the present invention is usually with oral form administration, and the preferred oral administration composition forms is with the tablet of unit dosage form and capsule.Other alternative administration composition form is: injection, tincture, suppository, pill, syrup, emulsion, aerosol, film, granule, oral solution, suspensoid, soft capsule, hard capsule and enteric coated capsule.
The pharmaceutically acceptable carrier that uses among the present invention is the conventional pharmacy carrier that uses in the pharmaceutical chemistry field, and carrier generally includes thinner, weighting agent, disintegrating agent, wetting agent, lubricant, tinting material, seasonings or other conventional additives.
Typical carrier comprises for example Microcrystalline Cellulose, hydroxypropylcellulose, sodium starch glycolate, Magnesium Stearate, sodium hydrogen phosphate, sodium laurylsulfonate or starch etc.
The Sertraline compound can be according to the preparation of the method described in the U.S. Pat 4536518.
The present invention is in the toluene solution that the preparation Sertraline obtains, and adds amygdalic acid and promptly separates out the amygdalic acid Sertraline, obtains amygdalic acid Sertraline white crystalline powder through centrifugal drying.
Amygdalic acid Sertraline fusing point: 184～188 ℃
Solubleness: slightly soluble in chloroform (1g is dissolved in the 100ml chloroform)
Soluble,very slightly in water, ethanol, ethyl acetate (0.1g is dissolved in the above-mentioned solvent of 100ml)
Infrared spectra: see accompanying drawing 1
Further specify the present invention with embodiment below, it should be understood that these embodiment are only used for illustrating the present invention, rather than be used to limit the present invention.Except as otherwise noted, the percentage ratio among the present invention is weight percentage.Embodiment 1: the preparation of citric acid Sertraline
Add 300ml ethyl acetate, 300ml deionized water and 45g amygdalic acid Sertraline successively in the 1000ml triangular flask, stir, temperature control is regulated between the pH to 9-10 with 50% NaOH below 40 ℃, and reaction solution was left standstill 20 minutes, divides water-yielding stratum.Use 80ml ethyl acetate extraction water layer three times at every turn, after the stirring, each standing demix 20 minutes, the ethyl acetate solution that extraction is obtained joins in the above-mentioned remaining acetic acid ethyl reaction liquid, extracts acetic acid ethyl reaction liquid three times with the 80ml deionized water more at every turn, left standstill after the stirring 20 minutes at every turn, the water layer of telling discards, and ethyl acetate layer is filtered, and filtrate is poured in the clean triangular flask, stir and add 8ml Citric Acid saturated solution down at a slow speed, separate out crystallization, crystallization is 1 hour under the normal temperature, suction filtration, wash with the 50ml ethyl acetate, 40 ℃ of vacuum-drying 8 hours, citric acid Sertraline 35g, be white crystalline powder, odorless is slightly bitter.
Solubleness: easily molten in chloroform, methyl alcohol (1g is dissolved in the 4.5ml chloroform, and 1g is dissolved in the 2.3ml methyl alcohol)
Dissolving (1g is dissolved in the 13ml ethanol) in dehydrated alcohol
Soluble,very slightly in water, acetone, 0.1mol/L hydrochloric acid soln
Infrared spectra: see accompanying drawing 2 embodiment 2: the preparation of sulfuric acid Sertraline
In the ethyl acetate solution of amygdalic acid Sertraline, add among the 50%NaOH and amygdalic acid, and then from solution, separate out, promptly get sulfuric acid Sertraline white crystalline powder, be white crystalline powder through centrifugal drying with sulfuric acid and Sertraline salify.Molten point: 158～161 ℃ of solubleness: dissolving (3g is dissolved in the 99ml acetone) in acetone
Slightly soluble in methyl alcohol (0.1g is dissolved in the 100ml methyl alcohol)
Soluble,very slightly in water, ethanol, ethyl acetate, chloroform (0.1g is dissolved in the above-mentioned solvent of 100ml) embodiment 3: the preparation of sertraline hydrochloride
The preparation method of sertraline hydrochloride is identical with the preparation method of citric acid Sertraline, just changes the citric acid among the embodiment 1 into 35% hydrochloric acid and gets final product.The sertraline hydrochloride that obtains is a white crystalline powder.
Fusing point: 245～248 ℃
Solubleness: dissolving (1g is dissolved in the 9ml chloroform) in chloroform
Ethanol part omitted molten (1g is dissolved in the 70ml ethanol)
Soluble,very slightly in water
Infrared spectra: see accompanying drawing 3 embodiment 4: Sertraline is to experiment one, experiment material () medicine of the influence of rat ejaculation latency
Citric acid Sertraline: self-control;
Progynon B: Jilin pharmaceutical factory produces, lot number: 981021;
Progesterone: bio-pharmaceuticals factory in Wuhu produces, lot number: 981109; (2) animal: the Wistar rat, body weight 90～120g, Jiamusi University's Experimental Animal Center provides.Two, experimental technique and result are to the influence of normal rat ejaculation latency
Get 30 of male rats, be divided into 3 groups at random, 10 every group.Wherein one group is the normal control group, and two groups of rats are respectively Sertraline high and low dose group (irritate stomach respectively and give Sertraline 10mg/kg, 5mg/kg, be 1 time/day), 2 weeks of successive administration in addition.After the last administration 2 hours, male mouse and the female mouse of synchronization of estrus (1: 1) are mated.The female mouse of synchronization of estrus is to mate preceding 3 days, and subcutaneous injection progynon B 2 μ g/ only 1 time/day, only inject Progesterone 0.4mg/ after 72 hours.Last was injected back 4 hours, mated with male mouse.Observe and write down male mouse and pounce on and catch female mouse, the time that begins mating first the results are shown in Table 1 to the time (ejaculation latency) that mating finishes.The t check shows that Sertraline high and low dose group and normal control group compare between group, P＜0.01, and difference has the highly significant meaning, shows that Sertraline can obviously prolong the ejaculation latency of normal rat.
Table 1: Sertraline to the influence of normal rat ejaculation latency (x ± s, n=10)
* compare P＜0.01 three, experiment conclusion with the normal control group
| Group | Dosage (mg/kg) | Ejaculation latency (second) |
| Normal control | 0 | 84.6±23.1 |
| Sertraline (height) | 10 | 176.2±39.5 |
| Sertraline (low) | 5 | 161.8±36.4 |
With the normal rat is animal model, irritates stomach and gives Sertraline 5mg/kg, 10mg/kg, 1 time/day, continuous 14 days, observes its influence to the rat ejaculation latency.Experimental data is learned processing by statistics, shows that Sertraline is had obvious prolongation effect to trying the rat ejaculation latency, points out this medicine to can be used for the treatment of premature ejaculation.Embodiment 5: the solubility test of citric acid Sertraline and sertraline hydrochloride
According to " regulation that 95 editions two notes on the use seven of Chinese pharmacopoeia are (2) determines citric acid Sertraline and the sertraline hydrochloride dissolving properties in water, dehydrated alcohol and chloroform, the results are shown in following table 2: table 2
| The citric acid Sertraline | Sertraline hydrochloride | |
| Water | Soluble,very slightly | Soluble,very slightly |
| Dehydrated alcohol | Dissolving 1g is dissolved in solubleness in the 13ml ethanol: 77mg/ml | Slightly molten 1g is dissolved in solubleness in the 71ml ethanol: 14mg/ml |
| Chloroform | Easy molten 1g is dissolved in solubleness in the 4.5ml ethanol: 222mg/ml | Easy molten 1g is dissolved in solubleness in the 9ml ethanol: 110mg/ml |
Illustrate: dissolved definition is according to " the regulation execution in (2) of two note on the use seven of Chinese pharmacopoeia (95 editions).
The experimental result explanation, the solubility property of citric acid Sertraline obviously is better than sertraline hydrochloride.Embodiment 6: citric acid Sertraline and the test of sertraline hydrochloride dissolution rate
Get citric acid Sertraline and sertraline hydrochloride tablet samples respectively, according to " two (appendix VC dissolution methods of Chinese pharmacopoeia (95 editions), with the 0.1mol/l hydrochloric acid soln is solvent, and operation in accordance with the law is respectively at took a sample, filter, measure content in 5,15,30,45,60 minutes in accordance with the law.Obtain result such as following table: table 3: citric acid Sertraline dissolution rate test card
Table 4: sertraline hydrochloride dissolution rate test card
Accompanying drawing 4 is citric acid Sertraline and sertraline hydrochloride dissolution rate, wherein X-coordinate be the time (minute), ordinate zou is dissolution rate (%), the square dot curve is a citric acid Sertraline dissolution rate curve, black matrix Diamond spot curve is a sertraline hydrochloride dissolution rate curve.Conclusion (of pressure testing):
| Stripping quantity (%) | 5 minutes | 15 | 30 minutes | 45 | 60 minutes |
| The 1st | 82.2 | 95.3 | 98.3 | 101.1 | 99.7 |
| The 2nd | 84.3 | 94.2 | 97.8 | 99.5 | 99.9 |
| The 3rd | 83.6 | 96.4 | 99.3 | 100.3 | 100.1 |
| The 4th | 89.4 | 97.8 | 98.6 | 100.1 | 99.4 |
| The 5th | 88.7 | 97.2 | 97.4 | 99.8 | 101.0 |
| The 6th | 85.1 | 94.9 | 99.7 | 99.9 | 99.8 |
| Mean value | 85.5 | 95.9 | 98.5 | 100.1 | 99.9 |
| Standard deviation | 2.93 | 1.40 | 0.88 | 0.55 | 0.55 |
| The coefficient of variation | 0.03 | 0.02 | 0.01 | 0.01 | 0.01 |
| Stripping quantity (%) | 5 minutes | 15 | 30 minutes | 45 | 60 minutes |
| The 1st | 85.2 | 94.3 | 983 | 99.6 | 99.4 |
| The 2nd | 84.1 | 93.2 | 97.2 | 98.2 | 99.1 |
| The 3rd | 83.3 | 92.4 | 97.3 | 100.7 | 100.1 |
| The 4th | 82.9 | 91.3 | 94.6 | 97.5 | 98.5 |
| The 5th | 82.2 | 91.5 | 96.0 | 98.8 | 99.3 |
| The 6th | 83.8 | 93.6 | 97.4 | 98.8 | 98.8 |
| Mean value | 83.6 | 92.7 | 96.8 | 98.9 | 99.2 |
| Standard deviation | 1.04 | 1.19 | 1.31 | 1.11 | 0.55 |
| The coefficient of variation | 0.01 | 0.01 | 0.01 | 0.11 | 0.01 |
From dissolution rate tabulation and curve as can be seen, because of the solubleness of citric acid Sertraline in solvent is better than sertraline hydrochloride,, illustrate that the citric acid Sertraline is easier to dissolve and absorption in human body so the dissolution rate of citric acid Sertraline also is better than sertraline hydrochloride.
Embodiment 7: preparation one. citric acid Sertraline tablet formulation:
Citric acid Sertraline 54.24%
Microcrystalline Cellulose 25%
Hydroxypropylcellulose 3%
Sodium starch glycolate 4% (add in 2%, 2% adds)
Low-substituted hydroxypropyl cellulose 2.76%
Magnesium Stearate 1% 2. Citric Acid Sertraline sheet production technique:
1. granulate to join in the wet granulator after (1) checks citric acid Sertraline, secondary calcium phosphate, sodium starch glycolate, hydroxypropylcellulose, low substituted hydroxy Mierocrystalline cellulose, the Microcrystalline Cellulose of recipe quantity and mixed 10 minutes.(2) appropriate amount of deionized water is added in the wet granulator, makes suitable softwood.(3) 60-70 ℃ of drying.(4) will mix in Magnesium Stearate, sodium starch glycolate, the dried particle of adding, with the whole grain of 18 order nylon screens machinery.
2. compressing tablet
Make every tablet of tablet that contains Sertraline 25mg and 50mg according to this prescription.
Make every capsule preparations that contains Sertraline 25mg and 50mg according to identical prescription.Tablet: proterties is white tablets or off-white color sheet, also or may need give particular color with certain technology in tablet surface because of selling.Capsule: content is white particle and powder.
Claims (3)
1. compound, it is (1S-4S)-4-(3, the 4-dichlorophenyl)-1,2,3,4-tetrahydrochysene-N-methyl isophthalic acid-naphthylamines Citrate trianion has following formula Ia structure:
Wherein HX is a citric acid.
2. pharmaceutical composition, this pharmaceutical composition contains compound and pharmaceutically acceptable carrier of the claim 1 for the treatment of significant quantity.
3. the compound of claim 1 is used to prepare the purposes of the medicine for the treatment of mammal premature ejaculation.
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| CN00124758A CN1091096C (en) | 2000-09-15 | 2000-09-15 | Sertraline and its salt, and its usage for treating mammal premature ejaculation |
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| CN00124758A CN1091096C (en) | 2000-09-15 | 2000-09-15 | Sertraline and its salt, and its usage for treating mammal premature ejaculation |
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| CN1091096C true CN1091096C (en) | 2002-09-18 |
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| WO2005000786A1 (en) * | 2003-05-23 | 2005-01-06 | Transform Pharmaceuticals, Inc. | Sertraline compositions |
| WO2005012224A1 (en) * | 2003-07-15 | 2005-02-10 | Recordati Industria Chimica E Farmaceutica S.P.A. | Sertraline hydrochloride form ii and methods for the preparation thereof |
| WO2017000270A1 (en) * | 2015-07-01 | 2017-01-05 | 徐静 | Two crystal forms of sertraline citrate and preparation methods therefor |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4940731A (en) * | 1989-08-30 | 1990-07-10 | Pfizer Inc. | Method of treating premature ejaculation using sertraline |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4940731A (en) * | 1989-08-30 | 1990-07-10 | Pfizer Inc. | Method of treating premature ejaculation using sertraline |
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