CN1143677C - Use of nitrophenyl salicyl amine as spermicide - Google Patents
Use of nitrophenyl salicyl amine as spermicide Download PDFInfo
- Publication number
- CN1143677C CN1143677C CNB011069694A CN01106969A CN1143677C CN 1143677 C CN1143677 C CN 1143677C CN B011069694 A CNB011069694 A CN B011069694A CN 01106969 A CN01106969 A CN 01106969A CN 1143677 C CN1143677 C CN 1143677C
- Authority
- CN
- China
- Prior art keywords
- niphesamide
- spermicide
- present
- test
- contraceptive
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention discloses use of nitrophenyl salicyl amine as a spermicide, particularly use for preparing external application contraceptive medicines. The present invention has a strong killing function for sperms of a human body in a short time at a very low concentration of 2.5 mg/L, and the killing ratio is 100%. The effect is 10 to 21 times of the spermicide-nonoxynol used at present, and the present invention has no stimulation function to mucosa, and has no three cause functions (teratogenicity, carcinogenicity and mutagenicity). The present invention is the external application spermicide which has the advantages of high efficiency, safety (LD50 is 1420.21 mg/kg), convenient operation, kill and suppression of fungus, gonococcus and trichomonad. The present invention can be used for replacing the external application contraceptive medicine made of nonoxynol.
Description
(chemical name is: new purposes N-(4-nitrobenzophenone)-5-chlorosamide) relates in particular to the new purposes in pharmaceutical field to the present invention relates to Niphesamide.
Present (lady's) contraception medicament mainly is divided into two kinds of vagina spermicide and oral contraceptives.Because oral contraceptive exist to disturb shortcomings such as human endocrine and toxic and side effects are bigger,, more and more be subject to people's attention so the vagina spermicide is applied widely with it, kill that essence is effective, toxic and side effects is little, do not disturb advantage such as endocrine.At present both at home and abroad the spermicide that uses has 6 kinds of nonoxynolums (NP-9) etc., and wherein nonoxynolum is the most frequently used.It is reported that it is minimum, and to kill smart concentration be 150mg/L (Americana report minimum kill smart concentration be 50mg/L), its major side effects is vaginal mucosa irritation symptom and burn feeling.After the also possible transvaginal mucosa of nonoxynolum is absorbed by the body, cause that transaminase SGOT obviously increases, and might cause liver injury.
For overcoming above-mentioned defective, a kind of new external applied contraceptive active component is provided, we study Niphesamide.Niphesamide is the salicylamide derivant, is a kind of noval chemical compound, its synthetic method, structural formula and as the existing report of the purposes of other medicines.The Yi Jianmin of this seminar etc. are at " Zhongnan Polytechnic Univ's journal "-99, reported the synthetic of Niphesamide on 30 (5)-519-521, Shi Tianyi etc. are in " fine chemistry industry "-98,15 (5)-14-16 have reported that " treating different things alike " method synthesizes Niphesamide, and CN1075137A discloses Snailicide (Niphesamide Niphensamide) and synthesis technique (number of patent application is 93110462.9) thereof; US4708953 discloses the salicylamide analog derivative and as the application of root nodule pathogenic bacteria agent for killing.
Show (novelty assessment report is attached) according to the project novelty assessment report of province Scientific and Technical Information Institute March 5 calendar year 2001, except that looking into the relevant paper that the member of seminar of new projects delivers, other does not see the bibliographical information identical with the technology of the present invention characteristics.
Its structural formula of Niphesamide of the present invention is:
Wherein, R
1=R
3=H, R
2=Cl works as R
2=R
3=H, R
1=Cl; R
1=R
2=Cl, R
3=H; R
1=H, R
2=R
3=Cl; R
1=R
2=R
3Then the derivant of Niphesamide during=Cl.The Niphesamide molecular formula is C
13H
9O
4N
2Cl, molecular weight 292,251～252 ℃ of fusing points, pale yellow powder, be insoluble to acid, atomic water-soluble, be slightly soluble in organic solvents such as ethanol, acetone, ether, benzene, chloroform, can be dissolved in pyridine, dimethyl sulfoxine, rare NaOH, KOH aqueous solution and the ammonia solution, in Reducing agent, be reduced and lose activity.Niphesamide produces the concentration of biological effect at 0.5～2mg.L, Zhang Yifu, Xu You, Shi Tianyi have reported " measuring the content of Niphesamide in the water with ultraviolet spectrophotometry " on " spectroscopy and spectrum analysis " 2000 the 20th the 2nd phases of volume, the detection effect of this detection method is more satisfactory.
The chemical compound Niphesamide can be synthesized by 5-chloro-salicylic acid, thionyl chloride, paranitroanilinum reaction, and synthetic method mainly contains " method for the treatment of different things alike " and " stepwise synthesis " two kinds.Knownly can and kill schistosomicide intermediate host---the molluscicide of oncomelania as plant root nodule pathogenic bacteria agent for killing.
The object of the present invention is to provide the new purposes of Niphesamide, promptly, also provide a kind of new active component simultaneously for external applied contraceptive as the new application of preparation spermicide.
For achieving the above object, we study as spermicide and the application in the preparation external applied contraceptive Niphesamide.The external animal toxicity test that kills smart test and send relevant department to carry out in smart test and the animal body that kills that carries out according to us, and killing and suppress experiment to mycete, gonococcus, infusorian, general pharmacological research and three tests of genetic toxicity show, Niphesamide can be used as a kind of new efficient, safe, inexpensive, easy to use and have the multi-pharmaceutics external use sperm killing agent of killing mould fungus inhibition, gonococcus, infusorian effect concurrently.
In order to understand essence of the present invention better, as the relevant test and the result of spermicide its new purposes in pharmaceutical field is described with Niphesamide below.Similarly, with niclosamide same pharmacological effect is arranged also, difference is the difference on use amount only.
Adopt the synthetic Niphesamide of the method for fractional steps, its basic step is:
(1) under the sodium hydroxide effect, generates t-butyl hypochlorate by the tert-butyl alcohol and chlorine earlier;
(2) again salicylic acid and first step product are reacted 5-chloro-salicylic acid (also can directly on market, buy the 5-chloro-salicylic acid);
(3) 5-chloro-salicylic acid and thionyl chloride effect are generated amide, back and paranitroanilinum react thick product;
(4) purify the thick product of gained to such an extent that pale yellow crystalline powder is standby.
1, the external test of killing smart effect of Niphesamide
(1) Niphesamide is made into 50mg/L solution with 5% aseptic glucose injection, and then with 5% Glucose Liquid be diluted to 20,10,5,2.5, the solution for standby of 1mg/L concentration;
(2) Freshman seminal fluid is provided by the man of health normal fertility, treat seminal fluid liquefaction after, press blood cell counting and count, sperm concentration is 7.2 * 10
7Individual/ml vigor＞83%.Former seminal fluid is with 10 times of 5% aseptic D/W dilutions, and is standby.
(3) seminal fluid that has diluted and medicinal liquid be constant temperature in 37 ℃ of water temperature casees all, get 1ml and diluted seminal fluid, add in the small test tube that the 1ml medicinal liquid is housed, after test tube places and gently mixes in the thermostatic water tank, get mixed liquor 0.5ml, place on the slide immediately, microscopically is observed (* 100), writes down the sperm count of living in 20 seconds, 3 minutes respectively, repeats 3～5 times.Observed result, during Niphesamide liquor strength 2.5 〉=mg/L, the smart number of living in 20 seconds, 3 minutes is 0, and killing rate is 100%, and when liquor strength was 1mg/L, the smart number of living in 20 seconds, 3 minutes was 2～30, and killing rate is 98.33%～99.8%.The result shows that work is skillful in extremely strong killing in vitro effect to Niphesamide to human body.
2, the acute toxicity test of Niphesamide
(1) the oral acute toxicity test of mice
Intragastrically is measured Niphesamide to white mice LD by two step trial test methods
50Be 1420mg/kg, judge that according to the fractionated standard of China's poisonous substance per os acute toxicity Niphesamide belongs to low toxicity to mammalian toxicity, high dose causes that the cardinal symptom that chmice acute is poisoned is central nervous system's toxic reaction.
(2) rabbit skin irritant test and eye conjunctiva irritant test
With three of test rabbits, select a 4 * 4cm every rabbit abdominal part both sides
2The zone evenly cuts off hair, tests in second day.It is Niphesamide ointment 1.25 grams that every rabbit is coated with dose, evenly be applied to a side cropping district, opposite side is the isotonic saline solution check plot, behind the coating 4h, with warm suds detergency test district skin, no any reaction behind the coating 24h, then every day coating 1 time, reaction appears in skin behind the coating three times, and examines and write down skin irritation reaction and recovery situation.With three of experimental rabbits, 20% Niphesamide suspension 0.1ml is splashed in the rabbit one branch hole conjunctival sac, make and close one's eyes and oppress nasolacrimal duct, with isotonic saline solution that medicine in the eye conjunctival sac is fully clean after 1 minute, opposite side compares with isotonic saline solution.Observe and write down 1,12,24,48,72 and the 96h medicine to the irritant reaction and the recovery situation thereof of eye conjunctiva.The result shows that Niphesamide has the minimal irritation reaction to rabbit skin, to eye conjunctiva vacuum response.
(3) three tests of genetic toxicity
Send Niphesamide sample to " Beijing Scientific and Technical Cooperation Centre branch of Nat'l Pharmaceutical ﹠ Biological Products Control Institute " to do three tests of genetic toxicity: the result is negative for (1) histidine auxotroph Salmonella typhimurium mutagenesis testing (Salmonella reversion test); (2) NIH mouse marrow cell micro nuclear test, microscopy bone marrow polychromatic erythrocyte micronucleus brings out rate, and the result shows relatively there was no significant difference of Niphesamide and negative control group (Oleum Sesami group); (3) CHL cells in vitro chromosomal aberration test, test shows under activation and disactivation condition, Niphesamide acts at 24 hours and 48 hours the CHL cell and does not all bring out obvious distortion, and promptly Niphesamide is negative to CHL cells in vitro chromosomal aberration test result.Therefore, the survey report of three tests of genetic toxicity shows that Niphesamide does not have mutagenicity, no teratogenecity, non-carcinogenesis.
The above results shows: Niphesamide toxicity is little, and mucosa is had no stimulation, and does not have three and causes effect (teratogenesis, carcinogenic, mutagenesis), and (2.5mg/l) still has great killing action to the human body sperm during extremely low concentration, kills rapidly, and killing rate is 100%.Its effect is 20 times of the present spermicide Nonoxynol-9 that uses.(the Nonoxynol-9 minimal effective concentration of killing sperm is 50mg/l, and each component spermicide least concentration of alkane benzene polyalcohol ether is 150～250mg/l).Therefore Niphesamide is 2.5～5mg/L as the suitable concentration that spermicide uses, it is the new active component of external applied contraceptive, alternative nonoxynolum is prepared into contraceptive membrane or other exterior-applied formulation such as water preparation, tablet, suppository etc., and it is 0.02～0.08 gram that everyone each dosage of insurance contraception consumption is converted former powder.
From above result, can draw and the invention has the advantages that:
1, product is easy to synthesize (synthetic route weak point, process drum list, yield height; 2, production cost low (about 5～100,000 yuan of Niphesamide per ton); 3, kill smart effective (external kill smart least concentration be 2.5mg/L); 4, toxicity is low, and is safe; 5, having concurrently extremely, gonococcus, infusorian, mycete etc. prevent and treat the effect of part gynaecopathia.
From the performance of Niphesamide and spermicide nonoxynolum commonly used more as can be seen: Niphesamide is a kind of safer, efficient, inexpensive contraceptive active component, can be used as the renewal product of nonoxynolum, replace nonoxynolum and be prepared into multi-pharmaceutics external applied contraceptives such as contraceptive membrane.
The relevant performance with spermicide nonoxynolum commonly used of table 1 Niphesamide relatively
| Compare content | Nonoxynolum | Niphesamide |
| 1, external minimum spermaticide substrate concentration (mg/L) 2, white mice LD 50(mg/kg) 3, the external osteocyte micronucleus test 4 of NIH white mice, Ame ' s test 5, CHL cells in vitro chromosomal aberration test 6, to mucocutaneous stimulation 7, whether medicine absorbs 8 on mucosa, influence to liver | 150～250 (domestic) 50 (U.S.'s product), 124.2 ± 9.8 (Americanas) cloudy cloudy light (doe vagina mucosa) absorb the human liver are had infringement (domestic technical magazine has report) | 2.5 the cloudy cloudy nothing (lagophthalmos mucous membrane) of～5.0 1420.21 (food additives amounts) does not absorb nothing (small white mouse, rabbit) |
Embodiment 1: adopt the synthetic former medicine of Niphesamide of the method for fractional steps, (pale yellow crystalline powder), be made into the solution for standby of 2.5mg/L concentration with 5% aseptic glucose injection, get the Freshman seminal fluid and dilute 10 times with 5% aseptic D/W, diluted in the seminal fluid at 1mL, add 1mL Niphesamide medicinal liquid, watching the smart number of living at microscopically is 0, and killing rate is 100%.
Embodiment 2: get the former medicine 100g of Niphesamide, replace nonoxynolum by the method that well known to a person skilled in the art with Niphesamide and prepare the Niphesamide contraceptive membrane, every of this contraceptive membrane contains former powder 0.02 gram.Using method is identical with the nonoxynolum contraceptive membrane.
Embodiment 3: get the former medicine 100g of Niphesamide, prepare the Niphesamide contraceptive membrane with the method among the embodiment 2, every of wherein said contraceptive membrane contains former powder 0.08 gram, and using method is with embodiment 2.
Claims (2)
1, Niphesamide is as the application of spermicide.
2, application according to claim 1 is characterized in that: Niphesamide is in the application of preparation in the external applied contraceptive, and the application of double as antifungal, gonococcus, infusorian agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011069694A CN1143677C (en) | 2001-03-24 | 2001-03-24 | Use of nitrophenyl salicyl amine as spermicide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011069694A CN1143677C (en) | 2001-03-24 | 2001-03-24 | Use of nitrophenyl salicyl amine as spermicide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1314152A CN1314152A (en) | 2001-09-26 |
| CN1143677C true CN1143677C (en) | 2004-03-31 |
Family
ID=4655924
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB011069694A Expired - Fee Related CN1143677C (en) | 2001-03-24 | 2001-03-24 | Use of nitrophenyl salicyl amine as spermicide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1143677C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3927334A4 (en) * | 2019-02-22 | 2022-04-20 | The Regents of The University of California | Nonhormonal unisex contraceptives |
-
2001
- 2001-03-24 CN CNB011069694A patent/CN1143677C/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3927334A4 (en) * | 2019-02-22 | 2022-04-20 | The Regents of The University of California | Nonhormonal unisex contraceptives |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1314152A (en) | 2001-09-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6248343B1 (en) | Therapeutic antimicrobial compositions | |
| CN112868662A (en) | Low-temperature efficient compound disinfectant and preparation method thereof | |
| US4297341A (en) | Spermicidal composition | |
| CN1143677C (en) | Use of nitrophenyl salicyl amine as spermicide | |
| Qian et al. | Spermicidal effect in vitro by the active principle of garlic | |
| Narayanan et al. | Anti-oxidant and anti-inflammatory activity of synthesized 3 (Substituted) chromen-2-One | |
| CN104396957B (en) | For preventing and treating the microemulsion of tea tree tea geometrid | |
| EP1591125A1 (en) | Pharmaceutical composition comprising extracts of lichens and hypericum | |
| CN106109293B (en) | Composition with acne removing effect and preparation method thereof | |
| CN101584715B (en) | Spray for preventing and treating skin damnification and resisting infection | |
| BE1001251A4 (en) | Pharmaceutical composition containing organic complex zinc and method for preparing the active product. | |
| CN102327273B (en) | Compound clobetasol propionate nano-medicament and preparation method thereof | |
| Sahu et al. | Antioxidative characteristics of ethanol and aqueous extracts of Curcuma amada rhizomes | |
| DE69432880T2 (en) | Composition containing aluminum complexes for the treatment of chemical or thermal injuries | |
| WO2019210664A1 (en) | Application of spermidine salt in control of pine wilt disease | |
| CN110170064A (en) | A kind of garbage disposal antibacterial deodorant and its preparation process | |
| US2648621A (en) | Chlorinated nu-ethyl acetanilide insecticide spray composition | |
| DD220025A5 (en) | METHOD FOR PRODUCING BENZAMIDINE DERIVATIVES | |
| CN111887249A (en) | Environment-friendly nontoxic rodenticide | |
| CN111067814A (en) | Antibacterial skin cleaning product | |
| Diamante et al. | Final safety assessment of thiodipropionic acid and its dialkyl esters as used in cosmetics | |
| CN109258716A (en) | A kind of composition pesticide and preparation method thereof | |
| CN109197882A (en) | A kind of emamectin benzoate B2a/B2b benzoate emulsion and preparation method thereof | |
| CN109673669A (en) | A kind of preparation method and applications of nanometer of micro emulsion iodine | |
| WO2005049483A2 (en) | Reactive chlorine compounds, the derivatives, anions, and salts thereof, method for the production thereof, and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C06 | Publication | ||
| PB01 | Publication | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |