CN102210675B - Application of 2,3-didetonindoline in preparation of medicine for improving spermatogenesis dysfunction - Google Patents
Application of 2,3-didetonindoline in preparation of medicine for improving spermatogenesis dysfunction Download PDFInfo
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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Abstract
The invention relates to application of 2,3-didetonindoline in preparation of a medicine for improving spermatogenesis dysfunction. The 2,3-didetonindoline is a natural product or an artificially synthesized product, is low in toxicity and less in side effect, and has excellent functions in improving spermatogenesis dysfunction and promoting procreation.
Description
Technical field
The present invention relates to indole-2, (indole-2 3-dione) improves the application in the dyszoospermia medicine in preparation to the 3-diketone.
Background technology
Environment in recent years pollution, drug influence and various electromagnetism involve radiating influence, and mankind spermatozoon quality and quantity descend has become the Andriatrics Dept. common disease.According to statistics, having 40% among the sterility and infertility male, to belong to sperm quality unusual, and human sperm's quantity on average descends with 2% speed.It is poor that the testicular spermatogenic function obstacle mainly shows as oligospermia, azoospermia and motility of sperm.Male infertility treatment due to the dyszoospermia is mainly contained Drug therapy, operative treatment and artificial auxiliary procreation technology.Wherein operative treatment is primarily aimed at the patient that reproductive tract are blocked, though doctor trained in Western medicine is sufficient in theory for the treatment of dyszoospermia, implements especially difficult; And artificial auxiliary procreation technology expensive, risk is high, and most of patient has spent a lot of money, does not only have effect, and control on the contrary and go wrong, be not that all patients can both accept therefore.Main application hormone of Drug therapy and GTH; These medicine Spermatogenic actions mainly are the functions through the adjusting hypothalamic pituitary gonadal axis, the spermatogenesis process of adjustment and stimulation human body, and its curative effect is also imprecise; And very big to people's infringement, cause the exogenous hormones dependence syndrome easily.Therefore, need badly at present exploitation a kind of with strong points, toxicity is little improves the dyszoospermia medicine.
Indole-2,3-diketone are to come from Lobster and keep its necessary a kind of natural marine active substance of surviving, and are the single orange red organic natural materials of composition, and monomer can synthesize, and chemical constitution is clear and definite, its molecular formula C
8H
5NO
2Molecular weight 147.13, structural formula is:
Indole-2, the 3-diketone
Indole-2,3-diketone have been proved to be a kind of human body endogenous material, are present in (Glover V in normal person's urine; Halket J M; Watking Pjet al.J Neurochem 5 J 1988,656), very long biological evolution process from the Lobster to the mankind; Indole-2,3-diketone exist in body and obviously have potential biological value.We carry out more than ten years and concentrate on studies, and find that it has antiviral, anti-cardiovascular disease, antiinflammatory and antifungic action, and obtain 4 patents of invention (indole-2, the application ZL200510105691.2 of 3-diketone in preparation antiviral or immunostimulant agent medicine; Indole-2, the application ZL200510045475.3 of 3-diketone in the preparation cardiovascular and cerebrovascular diseases medicament; Indole-2, the application ZL200810055735.9 of 3-diketone in the preparation anti-inflammatory drug; Indole-2, the application ZL 200810055736.6 of 3-diketone in the anti-human body fungi-medicine of preparation).
Other there are some researches show indole-2, and the 3-diketone mainly distributes in the brain of rat and tissue, and concentration is higher than its hetero-organization (VivetteGlover nearly a hundred times in epididymis; S K Bhattacharya; M Sandler Indian Journal of Experimental Biology 1991, Vol.29,1-5); According to the genetic evolution teleology; We infer indole-2, and the 3-diketone has protective effect to sperm, and the described antiinflammatory of patents in early stage, antiviral and antibacterial action also help the effect of its protection sperm.Crack indole-2, the 3-diketone will produce far reaching significance to the male genetic protection to the effect of sperm.The inventor concentrates on studies for a long time and a large amount of experiments show, indole-2,3-diketone have the good dyszoospermia effect that improves; Its toxicity is low; Side effect is little, and improving in preparation has good prospects for application aspect the dyszoospermia medicine, has huge new drug development and is worth.
Summary of the invention
The purpose of this invention is to provide indole-2, the 3-diketone improves the application in the dyszoospermia medicine in preparation.
Indole of the present invention-2,3-diketone are natural product or synthetic product.Its purification process comprises: press 1 with ultra-pure water and dehydrated alcohol: the 1-8 mixed adds synthetic or natural indole-2, the 3-diketone; In magnetic stirrer, slowly be heated to dissolving; Cooling is the Chinese red crystallization gradually then, and heating-up temperature is 50-80 ℃, the elimination supernatant; Repeat purification 1-3 time as stated above, its crystallization purity reaches 99%; With purified indole-2,3-diketone grind into powder is crossed 80 mesh sieves, with medical starch by 1: 1-10 part by weight mixing processes 50 or the capsule of 100mg specification.Or with purified indole-2,3-diketone grind into powder is crossed 80 mesh sieves, processes 50 or the tablet of 100mg specification by wet granulation technology.
Instructions of taking: be used to improve dyszoospermia, available capsule or tablet, everyone 200mg every day can divide one after each meal 2 times.
Indole-2, it is following that the 3-diketone improves the beneficial effect of using in the dyszoospermia medicine in preparation:
Proved indole-2, the 3-diketone has the effect of the dyszoospermia of improvement.Accomplished clinical preceding pharmacodynamic study in mice gossypol acetate antifertility model.Adopted the mice dyszoospermia model due to the classical gossypol acetate, observed the indole-2 of various dose, the 3-diketone is within a certain period of time to the improvement effect of mice spermatogenesis and fertility damage.Research shows:
The sperm motility of the antifertility model mice due to 1, the indole-2,3-diketone Dichlorodiphenyl Acetate gossypol and sperm number average increase.
The pregnancy rate of the antifertility model mice due to 2, the indole-2,3-diketone Dichlorodiphenyl Acetate gossypol and average tire number average increase.
3, indole-2,3-diketone chmice acute toxicity LD
50=1091 ± 359mgkg
-1, prove indole-2 at 6 months long term toxicity tests of Wistar rat; The 3-diketone does not have influence to feed situation and behavioral activity etc., and index no abnormality seens such as blood biochemical are observed also no abnormality seen in the histopathology of 22 kinds of internal organs and tissue; Indole-2 is described, 3-diketone toxicity is low.
Description of drawings
Fig. 1 is each experimental mice testis tissue section.
The specific embodiment
Further set forth indole of the present invention-2 through embodiment and Test Example below, the 3-diketone improves the beneficial effect of using in the dyszoospermia medicine in preparation.
Embodiment 1: the preparation of tablet
With ultra-pure water and dehydrated alcohol mixed by 1: 5, add indole-2, the 3-diketone, under the magnetic stirrer effect, 60 ℃ of following heating for dissolving, recrystallization gets the crystallization of aciculiform Chinese red under the room temperature, presses the aforesaid operations recrystallization 3 times.80 mesh sieves were pulverized in crystallization, took by weighing indole-2, and 3-diketone 100mg, lactose 100mg, starch 295mg mix homogeneously are used wet granulation, and drying is mixed with the 5mg magnesium stearate behind the granulate, and tabletting is processed the tablet that every weight is 500mg.
Embodiment 2: capsular preparation
With ultra-pure water and dehydrated alcohol mixed by 1: 5, add indole-2, the 3-diketone, under the magnetic stirrer effect, 60 ℃ of following heating for dissolving, recrystallization gets the crystallization of aciculiform Chinese red under the room temperature, presses the aforesaid operations recrystallization 3 times.80 mesh sieves were pulverized in crystallization, took by weighing indole-2,3-diketone 100mg, lactose 100mg, starch 295mg mix homogeneously, and filled capsules is processed each pure heavy capsule of 500mg that is.
Test Example 1: indole-2, the 3-diketone improves the dyszoospermia pharmacodynamic study
Experiment material
1, indole-2,3-diketone: provide by Qingdao Medical College's pharmacology group.Gossypol acetate, Beijing middle cotton purple light biotechnology Co., Ltd. lot number 061116;
2, Kunming (KM) plants mice: in half and half, 6 week of male and female, 18-22g is provided by Qingdao of Shandong province medicine inspecting institute Experimental Animal Center.
Experimental technique
1, indole-2, the 3-diketone is tested antifertility model male mice sperm and testicualr development influence: animal divides into groups to raise 48 of healthy male mices, and body weight is 18～25g, is divided into 1. blank control group at random, i.e. the normal saline group; 2. model group is the gossypol acetate group; 3. gossypol acetate and indole-2, and the basic, normal, high dosage of 3-diketone is irritated the stomach group.Tried fasting 16h overnight before the thing, can't help water.Gossypol acetate (20mgkg except that blank control group
-1) irritate stomach, handle 30d continuously.Indole-2,3-diketone corresponding dosage were irritated stomach continuous 38 days, and mice cervical vertebra dislocation method is put to death, and won the bilateral epididymis and placed and fill the 1ml phosphate buffered saline and shred, and added the 1ml dilution again, after the piping and druming, drew sperm suspension behind static 3～5min gently.Microscopically is observed sperm motility.In small beaker, add 0.5mL formaldehyde mixing again, draw 10 μ L spermatozoa diluents with micro suction dispenser and drip on people's blood count plate, count the sperm count in 5 medium squares, multiply by 10 again
9, be sperm count in every liter of seminal fluid (individual/L).
Get mouse testis; Peel off its epididymis and surface fat; Put into the wide mouthed bottle that Bouin liquid is housed respectively rapidly and fix 24 hours; Section, dehydration, waxdip, embedding, dyeing, with the spermatogonium of microscopic examination mouse testis, primary spermatocyte, the number of spermatid and through experimental group and matched group to judgment experiment result recently.
2, indole-2,3-diketone are to the fertility influence of antifertility model male mice: in irritating stomach the 31st day, in the night quiet environment; By female: hero=1: 1 same cage, continuous 8 days, i.e. 2 sexual cycles; All put to death, and write down conceived Mus number and the average tire of pregnant Mus in 15～21 days after jenny is with cage.
Experimental result
1, indole-2, the 3-diketone influences antifertility model male mice sperm
Compare with blank control group, model group sperm sperm concentration and activity ratio all reduce, and show sperm quantity and the activity ratio influential (P＜0.05) of gossypol acetate to male mice; Compare with model group; Indole-2, basic, normal, high dose groups sperm concentration of 3-diketone and activity ratio increase (P＜0.05), show indole-2; The 3-diketone can alleviate the situation that male mice sperm quantity that gossypol acetate causes and activity ratio descend, and dose-effect relationship is arranged.
Table 1 indole-2,3-diketone antifertility model mice sperm influence (
n=8)
Annotate: compare with blank control group,
aP＜0.01; Compare with model group,
bP＜0.01
2, indole-2, the 3-diketone influences antifertility model male mice testicualr development
Compare with blank control group, model group spermatogonium, primary spermatocyte and spermatid number obviously reduce, and show that gossypol acetate is to male mice testicualr development influential (P＜0.01); Compare with model group; Indole-2; The basic, normal, high dose groups spermatogonium of 3-diketone, primary spermatocyte and spermatid number all increase; Show indole-2, the 3-diketone can alleviate the situation that male mice spermatogonium, primary spermatocyte and spermatid number that gossypol acetate causes descend.
Table 2 indole-2, the 3-diketone is to male lead poisoning mouse testis development impact (
n=8)
Annotate: compare with blank control group,
aP＜0.01; Compare with model group,
bP＜0.01,
cP＜0.05
3, indole-2, the 3-diketone is to antifertility model male mice fertility influence
Compare with blank control group, the female Mus number and the average tire of pregnant Mus of model group significantly reduce, and show that gossypol acetate has antifertility action.With model group relatively, indole-2, the 3-diketone is low, in and the conceived Mus number of high dose group and the average tire number of pregnant Mus all raise, show indole-2, the 3-diketone can alleviate the gossypol acetate antifertility action, and dose-effect relationship is arranged.
Table 3 indole-2, the 3-diketone is to the influence of antifertility model male mice fertility
Annotate: compare with blank control group,
aP＜0.01; Compare with model group,
bP＜0.01
Test Example 2: indole-2, the acute chronic toxicity test of 3-diketone
Experiment material
1, animal
Mice is planted in Kunming (KM): in half and half, 6 week of male and female, 18-22g is provided by Qingdao of Shandong province medicine inspecting institute Experimental Animal Center.
2, medicine and reagent
Indole-2,3-diketone, tragcanth
Experimental technique
1, animal divides into groups
50 of Kunming mouses, 160 of rats, male and female have concurrently, and body weight 18-20g, 180-220g are divided into 5 groups at random, 10 every group; Fasting 12h before the experiment freely drinks water; The control room temperature is at 20 ± 2 ℃.
2, the outfit of medicine
Tragcanth is mixed with 1.25% solution with normal saline, and indole-2,3-diketone are made into the suspension of desired concn with tragcanth.
3, medication
Disposable ig, dosage is respectively 3,2,1.5,1,0.7gkg
-1,, than being 0.7, ig volume 0.6ml/ is only between group.Tested the morning and carry out.
4, median lethal dose(LD 50) (LD
50) measure
The death and the survival of each treated animal of 24h are calculated mortality rate after the observation administration, adopt the Sun Shi improved method to calculate LD
50
Experimental result
1, indole-2, the general performance of the acute chronic toxicity test animal of 3-diketone
That the poisoning animal shows as less is moving, dispirited, walking shakiness etc.Surviving animals is observed 7d, well-grown, and weight increase, postmortem, conscience kidney brain etc. is organized the no abnormal variation of perusal.
2, median lethal dose(LD 50) (LD
50) measure
Be the mortality rate of 24h after the medication, adopt the Sun Shi improved method to calculate LD
50=1091 ± 359mgkg
-1(95% credibility interval is 751～1374mgkg
-1).
For guaranteeing the long-term prescription safety, according to State Food and Drug Administration, national I kind new medicine chronic toxicity test standard, to indole-2, the 3-diketone carries out safety overall merit.Indole-2; The 3-diketone does not make significant difference for rat continuous irrigation stomach 3 months, 6 months and 7th month convalescent period by 1.17,58.5,117 times various dose of clinical consumption to body weight gain, feed situation and the behavioral activity etc. of rat, hematology, the blood biochemical of rat are learned and each item index such as electrocardiogram does not also have tangible adverse effect.The histopathology of 22 kinds of internal organs and tissue is observed and the relatively equal no abnormality seen of blank group.
The result shows, indole-2, and the long-term heavy dose of oral medication of 3-diketone does not have obvious damage to animal, finds to be a kind of safe and reliable medicine because of accumulating the toxic reaction to the body generation.
Claims (7)
1. indole-2, the 3-diketone improves the application in the dyszoospermia medicine in preparation.
2. application according to claim 1 is characterized in that described indole-2, and the 3-diketone is natural product or synthetic product.
3. application according to claim 1; It is characterized in that described indole-2; The 3-diketone is through following method purification: with ultra-pure water and dehydrated alcohol by 1: the 1-8 mixed adds indole-2, the 3-diketone; In magnetic stirring apparatus, slowly be heated to dissolving, cooling is the crystallization of aciculiform Chinese red gradually then.
4. application according to claim 3 is characterized in that said heating-up temperature is 50-80 ℃.
5. application according to claim 3 is characterized in that the crystallization of resulting aciculiform Chinese red again by repeating purification 1-3 time with quadrat method, to reduce heavy metal ion.
6. application according to claim 1 is characterized in that with described indole-2 3-diketone grind into powder is crossed 80 mesh sieves, with medical starch by 1: 1-10 part by weight mixing processes 50 or the capsule of 100mg specification.
7. application according to claim 1 is characterized in that with described indole-2 3-diketone grind into powder is crossed 80 mesh sieves, processes 50 or the tablet of 100mg specification by wet granulation technology.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101325613A CN102210675B (en) | 2011-05-16 | 2011-05-16 | Application of 2,3-didetonindoline in preparation of medicine for improving spermatogenesis dysfunction |
| PCT/CN2012/075512 WO2012155827A1 (en) | 2011-05-16 | 2012-05-15 | Use of indole-2,3-dione in preparing medicine for improving dyszoospermia |
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|---|---|---|---|
| CN2011101325613A CN102210675B (en) | 2011-05-16 | 2011-05-16 | Application of 2,3-didetonindoline in preparation of medicine for improving spermatogenesis dysfunction |
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