CN101264071A - Reproductive system promoting medicine - Google Patents
Reproductive system promoting medicine Download PDFInfo
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- CN101264071A CN101264071A CNA2007100644403A CN200710064440A CN101264071A CN 101264071 A CN101264071 A CN 101264071A CN A2007100644403 A CNA2007100644403 A CN A2007100644403A CN 200710064440 A CN200710064440 A CN 200710064440A CN 101264071 A CN101264071 A CN 101264071A
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- modafinil
- sulfinyl
- acetamide
- benzhydryl
- drug
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Abstract
The invention relates to a drug reacting on the reproductive system of the mammalian, in particular to a drug which can be used for improving reproductive ability and sexuality of the male mammalian. The drug is characterized in that: more specifically, the drug is one of optical isomers in the 2-[(diphenylmethyl) sulfinyl] acetamide, namely (+)-2-[(diphenylmethyl) sulfinyl] acetamide and derivatives. The drug has the advantages that: the drug can be used for promoting increase of the quantity and improvement of the quality (such as survival rate, active degree and morphology of the sperm) of the sperm of the male mammalian, increasing the volume and the weight of the testis and improving sexuality; thus the drug can be used for improving reproductive ability and sexuality of the male mammalian and promoting reproductive health.
Description
(1) technical field
The present invention relates to a kind of medicine that acts on mammalian reproductive system, especially a kind ofly can be used to improve the fertility of boar and the medicine of sexuality.More specifically say and the invention relates to the 2-[(benzhydryl) sulfinyl] (+)-2-[(benzhydryl of one of optical isomer in the acetamide) sulfinyl] acetamide and derivant thereof; they can be used to promote the increase of boar sperm quantity and the raising of quality (as sperm survival rate, mobility, form etc.); increase testicular volume and weight; improve sexuality; thereby improve the fertility of boar; promote healthy reproduction, can be used to prophylactic treatment lowly educate, sterile or promote prenatal and postnatal care or prophylactic treatment sexuality low.Sperm quality is pressed WHO regulation, mainly comprises the mobility, abnormal rate, survival rate of sperm etc.The people also is one of mammal, so this patent indication mammal includes the people.
(2) background technology
The 2-[(benzhydryl) sulfinyl] acetamide, general modafinil by name (Modafinil), English chemistry 2-[(diphenylmethyl by name) sulfinyl] acetamide, chemical constitution is as follows:
The modafinil chemical structural formula
Molecular formula is C
15H
15NO
2S, molecular weight is 273.36, is the short agent of waking up that U.S. Cephalon company develops and at first went on the market with trade name Modiodal in France in 1994.Simultaneously, this medicine obtained the drugs approved by FDA listing in 1998, be used for narcolepsy (Narcolepsy).One chirality sulphur atom is arranged in this molecular structure, so molecule has chirality, modafinil is by i.e. (-)-2-[(benzhydryl of two optical isomers of equivalent) sulfinyl] acetamide and (+)-2-[(benzhydryl) sulfinyl] acetamide forms.The preparation and the mentation thereof of raceme modafinil have been described in the U.S. Pat 4177290.European patent EP 023106 discloses (-)-2-[(benzhydryl) sulfinyl] acetamide and (+)-2-[(benzhydryl) sulfinyl] acetamide and preparation thereof, and (-)-2-[(benzhydryl has been described) sulfinyl] acetamide is in the effect of nerve aspect spiritual.Document about modafinil and radical derivative also has a lot, discloses the parkinsonian purposes of modafinil to treat as U.S. Pat 5180745; And for example European patent EP 0283362 discloses modafinil oxide modafinil sulfone and preparation thereof; WO95/01171 and WO95/01333 disclose the effect that modafinil and derivant thereof are improved the feed behavior.U.S. Pat 19990929 discloses modafinil and has had the effect that increases mankind spermatozoon quantity, improves the sperm motility degree, improves sex life ability and improve female fertility, thereby can be used for treating sterile and sexual disorder.The description of this patent shows, raceme modafinil dosage 200mg/kg/day uses to make the sperm quantity of normal SD rats reach 168% of blank group after 30 days, and the 400mg/kg/day group reaches 360% of blank group.Embodiment shows that the raceme modafinil has the effect that increases the male rat sperm quantity and improve sperm quality.Though this patent has comprised the effect of modafinil and optics allosome thereof in its claim, the concrete short spermatogenesis effect of not mentioned at all modafinil respective optical allosome in the description, the difference of also not mentioned modafinil optical isomer effect.
We are surprised to find under study for action, modafinil optical isomer d-modafinil and left-handed modafinil (all recording with 2% methanol solution) have diverse effect, the effect of reproductive system such as the short boar spermatogenesis of modafinil is to be produced by wherein d-modafinil, and left-handed modafinil does not have this effect.The short spermatogenesis and the sexual function improvement effect that are modafinil are to be produced by d-modafinil fully, and left-handed modafinil does not wherein not only play a driving role to spermatogenesis and sexual function, is the main cause that causes the nervus centralis side effect on the contrary.
D-modafinil and derivant thereof can greatly improve quantity and the vigor that boar comprises people's sperm, promote the raising of sperm quantity and quality, promote the increase of testicular volume weight and the improvement of quality, sexual function improvement.Therefore, d-modafinil comprises prevention and treatment boar that the people is few smart, aspect the azoospermia and in the therapeutic dysfunction, have important function, the effect that simultaneously but seldom has the neural spiritual aspect of DL modafinil, thereby make it in prevention with treat sterile and can not influence sleep during sexual disorder, substantially do not have the side effect of neural spiritual aspect, an ideal prophylactic treatment boar (especially male) sterilely low educates, the medicine of sexual disorder thereby become.
(3) summary of the invention
The present invention improves medicine in order to obtain a short safely and effectively boar spermatogenesis and sexual function, also be for overcome modafinil prevention and treatment boar few essence, azoospermia, teratospermia, the necrospermia azoospermia is sterile and raising mammal sexuality in the central excitation side effect.The present invention has scrutinized the difference of modafinil optical isomer effect in short boar spermatogenesis and sexual function raising, be surprised to find and have only d-modafinil and derivant thereof that the facilitation of this reproductive system function is arranged, and left-handed modafinil does not have this effect.And d-modafinil has easily by metabolism, its short characteristics partly decline, thereby make it can be when promoting that boar spermatogenesis and sexual function improve, the short effect of waking up of no modafinil, also eliminate the maincenter side effect of modafinil, thereby become the ideal medicament of reproductive system disease prophylactic treatment.
Specifically, the present invention is for chemical compound, the acceptable salt of its pharmacopedics, precursor compound shown in (I) or comprise wherein that the compositions of arbitrary chemical entities improves boar in preparation
Comprise the application in people's sperm quantity and quality and the sexual function medicine, wherein:
A is a phenyl; Fluorine, chlorine, bromine, trifluoromethyl, nitro, amino, C
1-4Alkyl, hydroxyl, C
1 -4Alkoxyl, methylene dioxy base (O-CH
2-O-) list replaces or polysubstituted phenyl.
R
1Be phenyl; Fluorine, chlorine, bromine, trifluoromethyl, nitro, amino, C
1-4Alkyl, C
1-4Alkoxyl, methylene dioxy base (O-CH
2-O-) list replaces or polysubstituted phenyl; Pyridine radicals.
R
2, R
3Can be identical or different, be hydrogen; Methyl.
Z is hydroxyl, C
1-6Alkoxyl or alkylamino-NR
4R
5, R
4, R
5Can be identical or different, be hydrogen; Picolyl; C
1-8Alkyl; Hydroxyl; C
1-4Alkoxyl.
Preferred chemical compound is (+)-2-[(benzhydryl) sulfinyl]-acetamide ((+)-d-modafinil)); (+)-2-[(4-chlorphenyl benzyl) sulfinyl]-acetamide, structure is as follows:
D-modafinil is used for mammal, and dosage is pressed body surface area and calculated, and adopts international formula 1gS=0.8762+0.698*1gW to calculate body surface area, then can be 1～1000mg/m
2/ day, preferred 5～600mg/m
2/ day, most preferably 10～400mg/m
2/ day.When using on the person, dosage can be 1～2000mg/day, preferred 10～1000mg/day, most preferably 15～600mg/day.D-modafinil can be made various dosage forms, and administration by all means is as oral quick release sheet (capsule), slow-release tablet (capsule), the mixed rotary liquid of routine or make transdermal absorption formulation topical etc.General fast-release tablet can adopt on d-modafinil and the pharmacopedics acceptable auxiliary mixed pressuring plate promptly, as d-modafinil and lactose, starch, magnesium silicate, croscarmellose, polyvidone, magnesium stearate, Pulvis Talci can be mixed together granulation, tabletting gets final product.This is that general technical staff is easy to and can expects.
Therefore sulfoxide compound described in the present invention can learn easily that the chemical compound that such sulfydryl replaces also has similar activity by sulfhydryl compound oxidation and getting in vivo.
D-modafinil described in the present invention refers to that all the modafinil optical isomer is made into the optically-active that 2% methanol solution records, as described in European patent EP 0233106.
This compounds can prepare by method described in the European patent EP 0233106.Preparation as d-modafinil; the benzhydrylsulfinyl guanidine-acetic acid that can be earlier splits DL with dextrorotation Alpha-Methyl benzene methanamine becomes dextrorotation benzhydrylsulfinyl guanidine-acetic acid; methylate with dimethyl sulfate then, logical at last ammonia promptly gets dextrorotation benzhydrylsulfinyl yl acetamide.
D-modafinil of the present invention and derivant thereof have the effect that promotes the boar spermatogenesis, can improve the quality and quantity of sperm in the boar seminal fluid, and the quality that improves sperm comprises mobility, survival rate and sperm morphology etc.D-modafinil of the present invention and derivant thereof also have the boar of promotion testicular volume weight to be increased, and improves the testis quality, the effect of prestige and sexual function that raises libido, thus improve the sexuality of boar comprehensively.Therefore, d-modafinil of the present invention and derivant thereof both can be used for treating relevant diseases such as oligoasthenospermia and sexual dysfunction, also can be used for preventing often showing as the sexual disorder that oligoasthenospermia and hyposexuality, erection problem etc. are showed, or take at ordinary times and be used to promote especially people's healthy reproduction of boar.
(4) specific embodiment
The invention will be further described below by embodiment.It should be understood that the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, under design prerequisite of the present invention, simple modifications of the present invention is all belonged to the scope of protection of present invention.
Embodiment 1:(+)-and the 2-[(benzhydryl) sulfinyl] preparation of acetamide
A) sulfinyl (+)-2-[(benzhydryl)] preparation of acetic acid (+)-Alpha-Methyl benzene methanamine salt
Get 27.4g DL benzhydrylsulfinyl guanidine-acetic acid and add in the there-necked flask of a 1000ml, add 500ml water, add 13g (+)-Alpha-Methyl benzene methanamine, heating for dissolving is taken advantage of heat filtering, and the filtrate natural cooling is separated out crystal, filters, and gets product.This product is recrystallization twice in 300ml water again, gets 17g (+)-2-[(benzhydryl) sulfinyl] acetic acid (+)-Alpha-Methyl benzene methanamine salt, m.p.:148-150 ℃, α
D 20=+93 ° (95% alcoholic solution).
B) sulfinyl (+)-2-[(benzhydryl)] preparation of acetic acid
It is in 30-40 ℃ the water that products therefrom 17g of last step is dissolved in the 800ml temperature, adds the 7ml concentrated hydrochloric acid then and stirs cooling, filter, white crystal (+)-2-[(benzhydryl) sulfinyl] acetic acid, m.p.:185-188 ℃, α
D 20=+40 ° (1% methanol solution).
C) sulfinyl (+)-2-[(benzhydryl)] preparation of methyl acetate
With 16.45g (+)-2-[(benzhydryl) sulfinyl] acetic acid is suspended from the 300ml deionized water; add 16.8g sodium bicarbonate and 18.8ml dimethyl sulfate in 20 ℃; stirring reaction is 18 hours under this temperature; filter washing, drying; get (+)-2-[(benzhydryl) sulfinyl] methyl acetate; yield is 60%, m.p.:109-110 ℃, and α
D 20=+22.5 ° (4% methanol solution).
D) sulfinyl (+)-2-[(benzhydryl)] preparation of acetamide
With 8.6g (+)-2-[(benzhydryl) sulfinyl] acetamide is dissolved in the 100ml absolute methanol; feed exsiccant ammonia then; after reaction is finished; reclaim under reduced pressure methanol gets solid, uses ethyl alcohol recrystallization; get product (+)-2-[(benzhydryl) sulfinyl] acetamide; yield is 50%, m.p.:153-154 ℃, and α
D 20=+20 ° (2% methanol solution).
Embodiment 2:(-)-and the 2-[(benzhydryl) sulfinyl] preparation of acetamide
According to European patent EP 0233106 method, operation is fully with embodiment 1, only use (-)-the Alpha-Methyl benzene methanamine replaces (+)-Alpha-Methyl benzene methanamine to get final product.
Embodiment 3:(+)-and the 2-[(benzhydryl) sulfinyl] acetamide, (-)-2-[(benzhydryl) sulfinyl] the short boar Spermatogenic action 1 of acetamide and modafinil
A) animal: normal adult male SD rat; totally 80; be divided into 1 group of medicine (give (+)-2-[(benzhydryl) sulfinyl] acetamide), 2 groups of (giving (-)-2-[(benzhydryl) sulfinyls of medicine] acetamide), 4 groups of medicine 3 groups (giving modafinil) and solvent control groups, 20 every group.
B) administering mode: stomach is irritated method, and the solvent control group gavages 3% gelatinized corn starch liquid 2ml//day at every turn; Each administration group is now with the current every day, respectively medicine is ground to form fine powder, is mixed with medicinal liquid (2ml//day) with 3% gelatinized corn starch then.Per two weeks are adjusted dosage.
C) dosage: medicine is 50mg/kg/day.
D) observation index: administration was put to death after 30 days, and every animal is got sperm, testis, tail of epididymis and prostata tissue in the tail of epididymis tube chamber, observes following index: sperm quantity and mobility, testicular weight; Respectively testis, tail of epididymis and prostata tissue are fixed, dehydration, paraffin embedding, section, dyeing, use microscopic examination then.
E) result:
Respectively organize the variation of SD rat testicle weight and seminal fluid sperm count after table 1. medication
1 group and 3 groups average sperm count ± s of every gram seminal fluid of administration are respectively (1688.9 ± 540.6) * 10
4/ g, (819.8 ± 259.6) * 10
4/ g than matched group remarkable increase is arranged all, and matched group only is (487.5 ± 310.5) * 10
4/ g, 2 groups of administrations are similar to matched group, and not having significantly increases, and is (479.3 ± 322.7) * 10
4/ g.1,3 groups of sperm quantities of medicine are respectively 346% and 168% of matched group, are significantly higher than matched group.1 group of rat testicle weight of administration is than 4 groups of increases of blank, and 2,3 groups of rat testicle weight of administration are not seen increase for 4 groups than blank.Histological observation shows: administration 1 treated animal convoluted tubule of testis spermatogenesis is obvious by stages, compares very rule of spermatogenesis with matched group, and the generating process cell does not have degradation phenomena; Meiosis synchronously is very obviously clear mutually; Be full of a large amount of mature sperms in the administration treated animal tail of epididymis tube chamber, between pipe between matter part obviously lack than matched group, epithelium light cell function is active, the prostate function also is in active stage, visible a large amount of amyloid secretions in the tube chamber; 3 groups make moderate progress, but not as 1 group effective; And 2 groups of administrations are identical with matched group, and do not see 1 group of above-mentioned administration, 3 groups phenomenon.In the administration process, 1 group of administration, matched group are not seen the excited sample effect of SD rat, and 2 groups, 3 groups SD rats of administration are comparatively excited.
F) discuss: The above results clearlys show; short boar Spermatogenic action that modafinil has and the effect that promotes rat testicle weight to increase are d-isomer ((+)-2-[(benzhydryl) sulfinyls by wherein] acetamide)) produce its levo form ((-)-2-[(benzhydryl) sulfinyl] acetamide)) then there is not this reproductive system effect.Show all that to male rat semen analysis behind the d-modafinil (promoting sperm quantity to increase and the quality raising) and histological observation d-modafinil has short Spermatogenic action; And rat testicle weight and histological observation show that d-modafinil can improve the sexual function of rat, improve sexuality, thereby improve the healthy reproduction level.On the contrary, left-handed modafinil group is then similar to matched group, does not have the effect that promotes that male rat spermatogenesis and sexuality improve.
Embodiment 4: d-modafinil is to the short Spermatogenic action of oligoasthenospermia model SD rat
G) animal: oligoasthenospermia model adult male SD rats; totally 80; be divided into 1 group of medicine (give (+)-2-[(benzhydryl) sulfinyl] acetamide), 2 groups of (giving (-)-2-[(benzhydryl) sulfinyls of medicine] acetamide), 4 groups of medicine 3 groups (giving modafinil) and solvent control groups, 20 every group.
H) administering mode: stomach is irritated method, and the solvent control group gavages 3% gelatinized corn starch liquid 2ml//day at every turn; Each administration group is now with the current every day, respectively medicine is ground to form fine powder, is mixed with medicinal liquid (2ml//day) with 3% gelatinized corn starch then.Per two weeks are adjusted dosage.
I) dosage: medicine is 50mg/kg/day.
J) observation index: administration was put to death after 30 days, and every animal is got sperm, testis, tail of epididymis and prostata tissue in the tail of epididymis tube chamber, observes following index: sperm quantity and mobility, testicular weight; Respectively testis, tail of epididymis and prostata tissue are fixed, dehydration, paraffin embedding, section, dyeing, use microscopic examination then.
K) result:
1 group and 3 groups average sperm counts of every gram seminal fluid of administration reach the normal rat level, than matched group remarkable increase are arranged all, and 2 groups of administrations are similar to matched group, than normal rat much less.1 group of rat testicle weight of administration is heavy than 4 groups of blanks; And slightly increase of contrast of administration 2; 3 groups of rat testicle weight are not seen increase for 4 groups than blank.Histological observation shows: administration 1 treated animal convoluted tubule of testis spermatogenesis is obvious by stages, and the spermatogenesis rule is full of a large amount of mature sperms in the tail of epididymis tube chamber; 3 groups make moderate progress, but not as 1 group effective; And 2 groups of administrations are identical with matched group, and spermatogenic cell is impaired serious.
1) discuss: The above results clearlys show; short boar Spermatogenic action that modafinil has and the effect that promotes rat testicle weight to increase are d-isomer ((+)-2-[(benzhydryl) sulfinyls by wherein] acetamide)) produce its levo form ((-)-2-[(benzhydryl) sulfinyl] acetamide)) then there is not this reproductive system effect.Show all that to male rat semen analysis behind the d-modafinil (promoting sperm quantity to increase and the quality raising) and histological observation d-modafinil has short Spermatogenic action; And rat testicle weight and histological observation show that d-modafinil can improve the sexual function of rat, improve sexuality, thereby improve the healthy reproduction level.On the contrary, left-handed modafinil group is then similar to matched group, does not have the effect that promotes that male rat spermatogenesis and sexuality improve, and is the main matter that produces the mental excitation effect on the contrary.
Claims (5)
1. chemical compound shown in the formula (I), the acceptable salt of its pharmacopedics promote the male food in one's mouth in preparation
The breast animal comprises that people's spermatogenesis or sexuality improve the application in the medicine, and wherein: a is a phenyl; Fluorine, chlorine, bromine, trifluoromethyl, nitro, amino, C
1-4Alkyl, hydroxyl, C
1-4Alkoxyl, methylene dioxy base (O-CH
2-O-) list replaces or polysubstituted phenyl.R
1Be phenyl; Fluorine, chlorine, bromine, trifluoromethyl, nitro, amino, C
1-4Alkyl, C
1-4Alkoxyl, methylene dioxy base (O-CH
2-O-) list replaces or polysubstituted phenyl; Pyridine radicals.
R
2, R
3Can be identical or different, be hydrogen; Methyl.
Z is hydroxyl, C
1-6Alkoxyl or amido-NR
4R
5, R
4, R
5Can be identical or different, be hydrogen; Picolyl; C
1-8Alkyl; Hydroxyl; C
1-4Alkoxyl.
2. according to claim 1, described formula (I) chemical compound is
(+)-2-[(benzhydryl) sulfinyl]-acetamide.
3. according to claim 1, described formula (I) chemical compound is
(+)-2-[(4-chlorphenyl benzyl) sulfinyl]-acetamide.
4. according to claim 2, dosage is 10～400mg/m
2/ day.
5. according to claim 4, administration time is the empty stomach in early morning, and number of times is administration once a day.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100644403A CN101264071A (en) | 2007-03-15 | 2007-03-15 | Reproductive system promoting medicine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100644403A CN101264071A (en) | 2007-03-15 | 2007-03-15 | Reproductive system promoting medicine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101264071A true CN101264071A (en) | 2008-09-17 |
Family
ID=39986921
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007100644403A Pending CN101264071A (en) | 2007-03-15 | 2007-03-15 | Reproductive system promoting medicine |
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|---|---|
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9132682B2 (en) | 2009-03-31 | 2015-09-15 | Brother Kogyo Kabushiki Kaisha | Tape unit and tape cassette |
| CN110760577A (en) * | 2019-11-21 | 2020-02-07 | 深圳市龙华区人民医院 | Application of KRT6A gene methylation in asthenospermia diagnostic agent and kit |
-
2007
- 2007-03-15 CN CNA2007100644403A patent/CN101264071A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9132682B2 (en) | 2009-03-31 | 2015-09-15 | Brother Kogyo Kabushiki Kaisha | Tape unit and tape cassette |
| CN110760577A (en) * | 2019-11-21 | 2020-02-07 | 深圳市龙华区人民医院 | Application of KRT6A gene methylation in asthenospermia diagnostic agent and kit |
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Open date: 20080917 |