CN101259119B - Application of serine protease inhibitor and its derivative in fertility regulation - Google Patents
Application of serine protease inhibitor and its derivative in fertility regulation Download PDFInfo
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- CN101259119B CN101259119B CN 200710037928 CN200710037928A CN101259119B CN 101259119 B CN101259119 B CN 101259119B CN 200710037928 CN200710037928 CN 200710037928 CN 200710037928 A CN200710037928 A CN 200710037928A CN 101259119 B CN101259119 B CN 101259119B
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Abstract
The invention provides a reversible embryo implantation inhibitor, i.e. 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF) and live derivatives or pharmaceutically acceptable salts thereof. The invention also discloses the application of live derivatives or pharmaceutically acceptable salts of AEBSF in preparing compositions used for inhibiting the implantation of embryos.
Description
Technical field
The invention belongs to biotechnology and fertility adjusting field, specifically, the present invention relates to a kind of embryo nidation inhibitor and the application in fertility is regulated thereof, described inhibitor is 4-(2-aminoethyl) benzene sulfonyl fluorine (AEBSF) and reactive derivative or its pharmaceutically acceptable salt.
Background technology
Embryo nidation (claiming the embryo to implant again) is meant that the embryo who is in the state of activation interacts with being in the uterus of accepting attitude, causes embryo's trophoderm and endometrium to set up the process that is closely connected at last.It is a mammal and a human distinctive reproductive physiology step.Just calculating after finishing real conceivedly because of implantation process, so give birth to regulation and control at the embryo nidation process, do not have ethical issues, is an ideal fertility regulation and control medical instrument effect link.In addition,, transplant back embryo implantation smoothly, become the key that influences artificial Assisted Reproductive Technology ART (ART/IVF) success rate at present along with technology such as the In vitro culture of oocyte and maturation, external fertilization, in-vitro oosperm culture and growth improve constantly.
The embryo is one and half allosome tissues with respect to parent, is subject to parent and repels, and can only (i.e. " implantation window ") could be admitted by the parent endometrial tissue in a certain period of time.The embryo nidation process finish synchronous growth, parent endometrium endometrial receptivity and the formation of " implantation window " and the formation of parent uterine cancer cell local immunity toleration that depends on parent uterus and embryo, relate to the adjusting of the propagation of cell and differentiation, local immunity function.Female, the effect of progestogen in implantation is very clear and definite, their effects in reproductive process grow up existing flute body class contraceptive with regard to being based on.But owing to female, progestogen are endocrine hormones, its effect is a general, also is not optimal fertility regulatory factor therefore.
In the process of embryo nidation, embryo's syneytiotrophoblast is secreted a series of protease, and (extracellular matrix ECM), promotes endometrial reconstruct by the endometrial extracellular matrix of degrading.Extracellular matrix is some macromolecular substances that cell produces, and comprises collagen protein, non-collagen sugar albumen and proteoglycan three major types.Most of compositions of people's endometrium ECM change along with the variation of the different phase of menstrual cycle, and relevant with implantation is secretion mid-term and deciduaization.Early the pregnancy period blastocyst sticks to the endometrium of deciduaization.During implantation, zona pellucida dissolves disappearance fully, and the trophoderm of inner cell mass side at first contacts with endometrium, extracellular proteinase, and at breach of inner membrance stripping, blastocyst is absorbed in breach then, gradually by embedding wherein.For the embryo behind the implantation can be survived, syneytiotrophoblast will destroy the blood capillary and the vein blood vessel of decidua and penetrate spiral artery, induces spiral artery to become the blood vessel of the high blood flow of lower resistance, to satisfy the nutritional need of body early embryo.
For various reasons, people's pair factor relevant with embryo nidation also known little about it, present known inhibition embryo nidation also seldom, so this area presses for new can be used for of exploitation and suppresses the material of embryo nidation.
Summary of the invention
The purpose of this invention is to provide inhibitor and the purposes in fertility is regulated thereof that a kind of new can be used for suppresses embryo nidation.
In a first aspect of the present invention, a kind of purposes of chemical compound is provided, described chemical compound is 4-(2-aminoethyl) benzene sulfonyl fluorine or its reactive derivative or its pharmaceutically acceptable salt, and wherein, described chemical compound is used to prepare compositions or the utensil of regulating fertility.
In another preference, described chemical compound is 4-(2-aminoethyl) benzene sulfonyl fluorine.
In another preference, described chemical compound is the 4-shown in the following formula (2-aminoethyl) benzene sulfonyl fluorine hydrochlorate.
In another preference, described reactive derivative is to have the derivant that serine protease suppresses active 4-(2-aminoethyl) benzene sulfonyl fluorine.
In another preference, described compositions is a pharmaceutical composition.
In another preference, described pharmaceutical composition is for suppressing the compositions of embryo nidation.
In another preference, described pharmaceutical composition is a contraceptive.
In another preference, described utensil is that contraceptive device comprises (but being not limited to): pessary or intrauterine device etc.
In a second aspect of the present invention, a kind of utensil of regulating fertility is provided, described utensil is the contraceptive device that is used for the women, and wherein said contraceptive device also comprises the releasing parts that is used at vagina or intrauterine release 4-(2-aminoethyl) benzene sulfonyl fluorine or its reactive derivative or its pharmaceutically acceptable salt.
In another preference, described releasing parts is arranged at or is fixed in the body of contraceptive device.
In another preference, described releasing parts is a slow release layer.
In another preference, described utensil is that contraceptive device comprises (but being not limited to): pessary or intrauterine device etc.
In a third aspect of the present invention, a kind of contraceptive device of non-therapeutic purposes is provided, this method comprises: use 4-(2-aminoethyl) benzene sulfonyl fluorine or its reactive derivative or its pharmaceutically acceptable salt for the female mammal of needs contraception.
In another preference, described using is local application, more preferably is intravaginal or intrauterine local application.
In a fourth aspect of the present invention, a kind of purposes of chemical compound is provided, described chemical compound is the purposes of 4-(2-aminoethyl) benzene sulfonyl fluorine or its reactive derivative and pharmaceutically acceptable salt thereof, and wherein said chemical compound is used as the inhibitor that suppresses embryo nidation.
In another preference, described chemical compound is 4-(2-aminoethyl) benzene sulfonyl fluorine.
In another preference, described chemical compound is 4-(2-aminoethyl) benzene sulfonyl fluorine hydrochlorate.
Others of the present invention are conspicuous because the technology of this paper is open to those skilled in the art.
The specific embodiment
The inventor finds by further investigation, be surprised to find that first 4-(2-aminoethyl) benzene sulfonyl fluorine or its reactive derivative (comprising pharmaceutically acceptable salt) can suppress embryo nidation, and this inhibitory action is reversible, therefore is particularly suitable for this compounds is used for regulating fertility.
Particularly, the inventor studies show that, 4-(2-aminoethyl) benzene sulfonyl fluorine can very effectively and safely suppress embryo's implantation.
The protease that works in embryo nidation can be divided into three major types according to their catalytic activity: matrix metalloproteinase, cysteine proteinase and serine protease.In biology, at most to serine protease research.Their common feature is in its active center serine residue to be arranged, and is the strongest at the neutral pH environment activity.They distribute very wide, and its kind is also maximum, has more than 20 family.And serine protease such as the tPA relevant with implantation that find at present, uPA, kallidinogenase, implantation serine protease-1 (ISP1), implantation serine protease-2 (ISP2) all belong to the S1 family of Chymotrypsin.The u-PA that discoveries such as Monzon, people's trophocyte produce has a tangible protein dissolution activity external, can the outer fiber adhesion albumen of degradation of cell, in embryo nidation, play a significant role.Recently, two kinds of serine proteases that O ' Sullivan etc. find, ISP1 and ISP2 also may play a significant role in embryo nidation.The inventor finds after deliberation, will resist ISP2 antibody to inject uterine cavity, can suppress embryo nidation, and be dosage effect.4-(2-aminoethyl) benzene sulfonyl fluorine or its reactive derivative or its pharmaceutically acceptable salt have similarity to the inhibitory action of embryo nidation and the inhibitory action of anti-ISP2 antibody.
The inventor's research prompting, the mechanism that 4-(2-aminoethyl) benzene sulfonyl fluorine or its reactive derivative or its pharmaceutically acceptable salt suppress embryo nidation may be to disturb embryo's implantation by the activity that suppresses serine protease (wherein may comprise tPA, the various serine proteases of Chymotrypsin S1 families such as uPA, kallidinogenase, ISP1, ISP2).Certainly, should understand the influence that protection scope of the present invention is not subjected to this mechanism.
As used herein, " active component " refers to 4-(2-aminoethyl) benzene sulfonyl fluorine or its reactive derivative or its pharmaceutically acceptable salt.
As used herein, term " 4-(2-aminoethyl) benzene sulfonyl fluorine " refers to following formula: compound:
The English name of 4-(2-aminoethyl) benzene sulfonyl fluorine: 4-(2-Aminoethyl) benzenesulfonylfluoride (abbreviation: AEBSF); Molecular formula: C
8H
10NSO
2F.AEBSF is a kind of serpin, can suppress trypsin, Chymotrypsin, fibrinolysin, thrombin and kallikrein.
As used herein, term " The compounds of this invention " refers to AEBSF and reactive derivative thereof, and this term also comprises the pharmaceutically acceptable salt of AEBSF and reactive derivative thereof.
The present invention also comprises the reactive derivative of AEBSF.As used herein, term " reactive derivative " is meant that the serine protease that has kept AEBSF basically suppresses active derivant.
As used herein, term " pharmaceutically acceptable salt " is meant the inorganic acid addition salt or the organic acid addition salt of nontoxic relatively The compounds of this invention.These salt can be in last separation of chemical compound and purification process in situ preparation, or the chemical compound of purification is reacted with its free alkali form and suitable organic or inorganic acid, again the salt that forms is separated and makes.Exemplary salt comprises hydrobromate, hydrochlorate, sulfate, sulphite, acetate, oxalates, valerate, oleate, palmitate, stearate, laruate, borate, benzoate, lactate, phosphate, toluate, citrate, maleate, fumarate, succinate, tartrate, benzoate, mesylate, gluconate, Lactobionate and lauryl sulfonate etc.They can comprise the cation based on alkali metal and alkaline-earth metal, as sodium, lithium, potassium, calcium, magnesium etc., and do not have toxic amine, quaternary amine and amine cation, include but not limited to: amine, tetramethyl amine, tetraethyl amine, methylamine, dimethylamine, trimethylamine, triethylamine, ethamine etc.
A kind of preferred salt is inorganic acid addition salt, particularly preferably is the hydrochlorate of AEBSF, and its structural formula is as follows:
The molecular formula of 4-(2-aminoethyl) benzene sulfonyl fluorine hydrochlorate: C
8H
10NSO
2FHCl; Molecular weight is 239.7.This chemical compound water soluble, more stable in the aqueous solution of pH＜7, can store 6 months in 4 ℃; In the aqueous solution of pH＞7, then unstable, should prepare in use.
As used herein, term " mammal " comprises animals such as (but being not limited to) people, monkey, cattle, sheep, pig, rabbit, Mus, cat, Canis familiaris L..Preferred mammal comprises Primate, rodent, Canis animals and felid and various domestic animal and house pet etc.
Compositions is regulated in fertility
The present invention also provides a kind of fertility to regulate compositions, and it contains AEBSF of the present invention and the pharmaceutically acceptable carrier or the excipient of safe and effective amount.This class carrier comprises (but being not limited to): saline, buffer, glucose, water, glycerol, ethanol and combination thereof.Pharmaceutical preparation should be complementary with administering mode.Pharmaceutical composition of the present invention can be made into the injection form, for example is prepared by conventional method with normal saline or the aqueous solution that contains glucose and other adjuvant.Pharmaceutical composition such as tablet and capsule can be prepared by conventional method.Pharmaceutical composition such as injection, solution, tablet and capsule should be made under aseptic condition.The dosage of active component is the contraception effective dose, for example every day about 1 microgram/kg body weight-Yue 10 mg/kg body weight.In addition, polypeptide of the present invention also can use with other contraceptives.
4-(2-aminoethyl) benzene sulfonyl fluorine or its reactive derivative or its pharmaceutically acceptable salt can be oral, parenteral (intravenous, intramuscular or subcutaneous), topical (intravaginal or intrauterine administration are for example as powder, ointment or drop).A kind of particularly preferred method of application is local application, more preferably is intravaginal or intrauterine local application.
The solid dosage forms that is used for oral administration comprises capsule, tablet, pill, powder and granule.In these solid dosage formss, reactive compound mixes with at least a conventional inert excipient (or carrier), as sodium citrate or dicalcium phosphate, or mixes with following compositions: (a) filler or bulking agent, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binding agent, for example, hydroxy methocel, alginate, gelatin, polyvinyl pyrrolidone, sucrose and arabic gum; (c) wetting agent, for example, glycerol; (d) disintegrating agent, for example, agar, calcium carbonate, potato starch or tapioca, alginic acid, some composition silicate and sodium carbonate; (e) retarding solvent, for example paraffin; (f) absorb accelerator, for example, quaternary ammonium compound; (g) wetting agent, for example spermol and glyceryl monostearate; (h) adsorbent, for example, Kaolin; (i) lubricant, for example, Talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture.In capsule, tablet and the pill, dosage form also can comprise buffer agent.
Solid dosage forms such as tablet, sugar pill, capsule, pill and granule can adopt coating and the preparation of shell material, as casing and other material well known in the art.They can comprise opacifying agent, and, discharge in the mode that the release of reactive compound or chemical compound can postpone in this compositions certain part in digestive tract.The example of adoptable embedding component is polymeric material and Wax.In case of necessity, reactive compound also can with above-mentioned excipient in one or more form microencapsulation form.
The liquid dosage form that is used for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.Except the active ingredient beyond the region of objective existence, liquid dosage form can comprise the conventional inert diluent that adopts in this area, as water or other solvent, solubilizing agent and emulsifying agent, example is known, the mixture of ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethyl formamide and oil, particularly Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, maize embryo oil, olive oil, Oleum Ricini and Oleum sesami or these materials etc.
Except these inert diluents, compositions also can comprise auxiliary agent, as wetting agent, emulsifying agent and suspending agent, sweeting agent, the agent of tender flavor and spice.
Except the active ingredient beyond the region of objective existence, suspension can comprise suspending agent, for example, and the mixture of ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, microcrystalline Cellulose, aluminium methoxide and agar or these materials etc.
The compositions that is used for parenteral injection can comprise physiologically acceptable aseptic moisture or anhydrous solution, dispersion liquid, suspension or emulsion and be used for being dissolved into again the aseptic Injectable solution or the sterilized powder of dispersion liquid.Suitable moisture and nonaqueous carrier, diluent, solvent or excipient comprise water, ethanol, polyhydric alcohol and suitable mixture thereof.
The dosage form that is used for the The compounds of this invention of topical comprises powder, ointment, powder or propellant.Active component under aseptic condition with physiologically acceptable carrier and any antiseptic, buffer agent, or the propellant that may need in case of necessity is mixed together.
When making pharmaceutical composition, be that the AEBSF albumen of safe and effective amount or its antagonist, agonist are applied to mammal, wherein this safe and effective amount is usually at least about 1 microgram/kg body weight, and in most of the cases be no more than about 10 mg/kg body weight, preferably this dosage is about 10 micrograms/kg body weight-Yue 1 mg/kg body weight.Certainly, concrete dosage also should be considered route of administration, use the factors such as health status of object, and these all are within the skilled practitioners skill.
Contraceptive device
The present invention also provides a kind of utensil of regulating fertility, and described utensil is for containing the contraceptive device of 4-(2-aminoethyl) benzene sulfonyl fluorine or its reactive derivative or its pharmaceutically acceptable salt.
In contraceptive device of the present invention, comprise the releasing parts that is used at vagina or intrauterine release 4-(2-aminoethyl) benzene sulfonyl fluorine or its reactive derivative or its pharmaceutically acceptable salt.In another preference, described contraceptive device is pessary or intrauterine device.
Should be understood that described releasing parts can be independent, also can make up.For example, releasing parts can be an independent releasing member or the combination type releasing member combined with miscellaneous part, or is bonded in or is integrated in the releasing layer of miscellaneous part.
A kind of optimal way is to add a releasing layer (for example slow release layer) on the pessary of routine or intrauterine device, this releasing layer can be in intravaginal or in utero discharge 4-(2-aminoethyl) benzene sulfonyl fluorine or its reactive derivative or its pharmaceutically acceptable salt in a period of time, thereby suppressed embryo nidation.
Usually, the releasing member in contraceptive device should contain the 5-5000 milligram, more preferably 10-2500 milligram, the 4-of 20-1000 milligram (2-aminoethyl) benzene sulfonyl fluorine or its reactive derivative or its pharmaceutically acceptable salt best.
Major advantage of the present invention is,
(a) 4-(2-aminoethyl) benzene sulfonyl fluorine or its reactive derivative or its pharmaceutically acceptable salt have the obvious suppression effect to embryo nidation;
(b) by intravaginal or intrauterine topical 4-(2-aminoethyl) benzene sulfonyl fluorine or its reactive derivative or its pharmaceutically acceptable salt, it is good to have a very high safety.
(c) inhibitory action to embryo nidation is reversible.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.
Embodiment 1
AEBSF is to the inhibitory action of embryo nidation
(1) raising of laboratory animal and copulation:
The bull ICR mice (body weight 35～40 grams) and the female ICR mice (body weight 25～30 grams) in 8～10 ages in week are mated raising in 2: 1 ratios, morning next day is by checking that female mouse vagina bolt is to judge whether copulation, seeing bolt same day as pregnant D1 days, and will with a collection of detect pregnant D1 days mices divide into groups at random.
(2) preparation of injection solution:
The chemical compound that uses is the hydrochlorate of AEBSF, and its structural formula is as follows:
1, AEBSF high dose group: 200 μ g/ μ L (preparing) with normal saline,
2, dosage group among the AEBSF: 20 μ g/ μ L (preparing) with normal saline,
3, AEBSF low dose group: 2 μ g/ μ L (preparing) with normal saline.
(3) inject time and method:
In 8:00～10:00 in the pregnant D3 days mornings,, will prepare in advance and inject in the cavity of uterus near the position of ovary from mice both sides cornua uteri upper end with microsyringe at the injection solution of 35 ℃ of following preheatings, each cornua uteri injects 15 μ L solution.With injecting identical solution in two cornua uteris of a mice, separate groups of mice is by setting the different injection solution of injection.Put to death mice in pregnant D8 days (the visible embryo of naked eyes) 9:00 in the morning, complete uterine cancer cell and ovary are peeled off, the embryo number and the corpus luteum number of every Side cornua uteri and ovary counted.
(4) result:
Compare with matched group, suppression ratio is 32%, and the suppression ratio of basic, normal, high dosage group is respectively 16%, 53%, 87%; Tangible dosage effect is arranged.
Table 1AEBSF is to the inhibitory action of embryo nidation
| Group | Injection solution | Cornua uteri number (n) | Corpus luteum number/cornua uteri (X ± SD) | Embryo number/cornua uteri (X ± SD) | Suppression ratio |
| Matched group | Normal saline | 10 | 6.1±1.7 | 5.5±1.6 | - |
| Low dose group | 2μg/μL AEBSF | 10 | 5.8±2.3 | 4.4±2.0 | 16％ |
| Middle dosage group | 20μg/μL AEBSF | 12 | 5.7±2.1 | 2.4±2.2 | 53％ |
| Group | Injection solution | Cornua uteri number (n) | Corpus luteum number/cornua uteri (X ± SD) | Embryo number/cornua uteri (X ± SD) | Suppression ratio |
| High dose group | 200μg/μL AEBSF | 20 | 5.8±2.6 | 0.7±0.9 | 87％ |
Embodiment 2
The reversibility of AEBSF antifertility action
The antifertility action of considering contraceptive must be reversible, by zoopery the reversibility of the anti-implantation effect of AEBSF has been carried out observation analysis in the present embodiment.Method is as follows:
Same batch of female adult mice is divided into two groups, and the AEBSF with normal saline and 200 μ g/ μ L concentration handled respectively in gravidic pregnant the 3rd day for the first time, observed its pregnancy outcome; Place after one month, copulation does not once more give any processing, observes its pregnancy outcome.
The result is as shown in table 2.The result shows that the AEBSF of 200 μ g/ μ L concentration has tangible antifertility action, and should effect reversible (table 2)
The reversibility result of study of table 2.AEBSF antifertility action
Embodiment 3
The pharmaceutical composition that contains 4-(2-aminoethyl) benzene sulfonyl fluorine hydrochlorate
In the present embodiment, the gel for preparing a vagina administration.Method is as follows:
With 10 kilograms of polyoxyethylene polyoxypropylene polymer Carbopol 941s (Poloxamer941) and 2 kilograms of nonionic surfactant (poloxamer Poloxamer188 (being F68), available from last Hydron is medical auxiliary materials technology company limited) place agitator, the acetate buffer solution that adds 60L 0.6M, stir evenly at 23～25 ℃, mixing speed 100～300rpm, it is dissolved fully, about 3～4 hours of process, add 100 gram 4-(2-aminoethyl) benzene sulfonyl fluorine hydrochlorates, stirring and dissolving, adding 0.5L polydimethylchlorosilane (available from the good economic trade development company limited in last Haiyang), stirred standing over night, centrifugal 15min 1～2 hour, remove bubble, thereby make the gel that contains 4-(2-aminoethyl) benzene sulfonyl fluorine hydrochlorate.
This gel can be used for vagina administration.
Embodiment 4
The contraceptive device that contains 4-(2-aminoethyl) benzene sulfonyl fluorine hydrochlorate
Apply the gel that one deck embodiment 3 prepares in the pessary inboard of routine or outside in pessary, after the drying, this gel forms one and contains the releasing layer of 4-(2-aminoethyl) benzene sulfonyl fluorine hydrochlorate, thereby makes the contraceptive device that contains 4-(2-aminoethyl) benzene sulfonyl fluorine hydrochlorate.
At embryo nidation in earlier stage,, discharge the AEBSF of doses in uterus, can suppress embryo's implantation, thereby reach the purpose that avoids conception and control birth by uterus local medicine-applying systems such as pessary, intrauterine device.
List of references:
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2.Salamonsen LA，Nie GY.Proteinase at the endometrial-trophoblastinterface：their role in implantation.Rev Endocr MetabDisord，2002，3(2)：133-143
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8.Monzon-Bordonaba F，Wang CL，Feinberg RF.Fibronectinase activityin cultured human trophoblasts is mediated by urokinase-type plasminogenactivator.Am J Obstet Gynecol 1997，176(1)：5865
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10.O’Sullivan CM，Liu SY，Rancourt SL，Rancourt DE.Regulation ofthe strypsin-related proteinase ISP2 by progesterone in endometrialgland epithelium during implantation in mice.Reproduction.2001，122(2)：235-44.
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All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (8)
1. the purposes of a chemical compound, described chemical compound is 4-(2-aminoethyl) benzene sulfonyl fluorine or its pharmaceutically acceptable salt, it is characterized in that described chemical compound is used to prepare compositions or the utensil of regulating fertility, wherein said adjusting fertility is contraception or suppresses embryo nidation.
2. purposes as claimed in claim 1 is characterized in that, described chemical compound is 4-(2-aminoethyl) benzene sulfonyl fluorine.
3. purposes as claimed in claim 1 is characterized in that, described chemical compound is the 4-shown in the following formula (2-aminoethyl) benzene sulfonyl fluorine hydrochlorate
4. as arbitrary described purposes among the claim 1-3, it is characterized in that described compositions is a pharmaceutical composition.
5. purposes as claimed in claim 4 is characterized in that, described pharmaceutical composition is for suppressing the compositions of embryo nidation.
6. purposes as claimed in claim 4 is characterized in that described pharmaceutical composition is a contraceptive.
7. as arbitrary described purposes among the claim 1-3, it is characterized in that described utensil is a contraceptive device, comprise pessary or intrauterine device.
8. utensil of regulating fertility, described utensil is the contraceptive device that is used for the women, it is characterized in that, described contraceptive device also comprises the releasing parts that is used for discharging at vagina or intrauterine 4-(2-aminoethyl) benzene sulfonyl fluorine or its pharmaceutically acceptable salt.
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| WO2002081665A2 (en) * | 2001-04-06 | 2002-10-17 | Rancourt Derrick E | Implantation serine proteinases |
| US6844180B2 (en) * | 2000-10-12 | 2005-01-18 | Ferring Bv | Serine protease genes related to DPPIV |
| US20060183175A1 (en) * | 2004-12-21 | 2006-08-17 | Yale University | Diagnosis of preeclampsia |
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| US6844180B2 (en) * | 2000-10-12 | 2005-01-18 | Ferring Bv | Serine protease genes related to DPPIV |
| WO2002081665A2 (en) * | 2001-04-06 | 2002-10-17 | Rancourt Derrick E | Implantation serine proteinases |
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| 黄萍等.重组着床丝氨酸蛋白酶-2(ISP2)在昆虫细胞中的表达.生殖与避孕25 8.2005,25(8),451-455. * |
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