CN103965112A - Compound with antiandrogen activity as well as preparation method and application of compound - Google Patents
Compound with antiandrogen activity as well as preparation method and application of compound Download PDFInfo
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- CN103965112A CN103965112A CN201410200232.1A CN201410200232A CN103965112A CN 103965112 A CN103965112 A CN 103965112A CN 201410200232 A CN201410200232 A CN 201410200232A CN 103965112 A CN103965112 A CN 103965112A
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- compound
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- androgen antagonist
- antagonist activity
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
Abstract
The invention belongs to the technical field of biological medicines and particularly relates to a compound with antiandrogen activity as well as a preparation method and application of the compound. The compound provided by the invention has the chemical name as follows: 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5, 5-dimethyl-2, 4-dioxo-1-imidazolyl)butyl acetate. The preparation method comprises the step of enabling an intermediate compound IV and 4-bromobutyl acetate to react at the temperature of 10-60 DEG C under the catalysis of a catalyst to prepare the compound. The compound can be used for preparing antiandrogen drugs. The preparation method is simple; in addition, the obtained compound is high in bioavailability and antiandrogen activity.
Description
Technical field
The invention belongs to biological medicine technology field, be specifically related to a kind of active substance with androgen antagonist.
Background technology
Androgenetic alopecia (AGA) is very common a kind of alopecia form, and such alopecia symptom all may occur masculinity and femininity.The reason that women also has AGA is in women's body, also to have male sex hormone.And nonowner can have AGA symptom, show not have people's Probability of familial inheritance background can be smaller.This is a kind of heredity trichomadesis disease of androgen-dependent, is a kind of PD, if let go unchecked, it is serious that alopecia symptom can be tending towards.AGA is one of modal alopecia symptom, and each age group all can be fallen ill, and men and women's both sexes all can be got involved, although patient is without significant discomfort, because affecting an urgent demand treatment attractive in appearance.
In human body cell matter, contain 5α-reductase, meeting and testosterone react and become Standone (DHT).DHT enters nucleus, and for metabolic system generation effect, therefore the manufacture meeting especially with the ATP material of cellular energy effect is obstructed.When the ATP as calorie source cannot generate, the albumen that therefore cannot carry out hair is synthetic, and hair matricyte loses vigor, and starts keratinization, becomes hair resting stage.And the hair that enters resting stage, will alopecia in about 3 months.Generally speaking, DHT is the real arch-criminal of AGA, can produce toxic action to hair follicle, makes hair follicle atrophy gradually, causes the growth cycle of hair to shorten, thus the process of triggering male type alopecia.
Treating one of method of this kind of symptom is by suppressing 5α-reductase activity, is converted into 5α-dihydrotestosterone thereby reduce testosterone; Can be by reaching this object such as oestrogenic hormon or 5α-reductase inhibitor.Oestrogenic hormon all proves that AGA is had to certain curative effect as finasteride as minoxidil and 5α-reductase inhibitor.
French Patent 2693461 and US Patent No. 5411981 have proposed a kind of new compound (4 (3-(4-hydroxyl butyl)-4,4-dimethyl-2,5-dioxy-1-imidazolyl)-2-(trifluoromethyl) cyanobenzene) (structural formula I) treats AGA, but the object being not yet generally used for the treatment of at present.United States Patent (USP) 2003/229129 is thought the reason that said structure is not also commonly used, may be not ideal enough in bioavailability, therefore this structure is improved, a kind of new compound 4-(3-(4-cyano group-3-(trifluoromethyl) phenyl)-5 has been proposed, 5-dimethyl-2,4-dioxy-1-imidazolyl) butyl myristinate (structural formula II).This structure has improved bioavailability because ester dissolubility greatly increases.But in the research of carrying out at us, find, the solubleness of structural formula II in ethanol only has 0.01%, and this has seriously limited its generally application, and therefore we have done further improvement to this structure.
Summary of the invention
In order to overcome the deficiencies in the prior art, the object of the present invention is to provide a kind of compound with high bioavailability, high resistance androgenic activity.Its preparation method is simple.
A kind of compound with androgen antagonist activity provided by the invention, its chemical name is 4-(3-(4-cyano group-3-(trifluoromethyl) phenyl)-5,5-dimethyl-2,4-dioxy-1-imidazolyl) butylacetic acid ester, shown in the following formula III of structural formula:
The present invention also provides the preparation method of the above-mentioned compound with androgen antagonist activity, and its concrete steps comprise: under catalyst, by midbody compound and 4-brombutyl acetic ester, obtain having the compound of androgen antagonist activity 10-60 DEG C of reaction; Wherein said catalyzer is selected from sodium Metal 99.5, sodium hydrogen, sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide any; Described midbody compound is as shown in structural formula IV:
Preparation method's of the present invention reaction equation is as follows:
The effect experiment of the compound obtaining in the present invention shows that the compounds of this invention has good androgen antagonist activity, therefore can be further used for preparing androgen antagonist medicine.
Beneficial effect of the present invention is: the solubleness of this compound in ethanol reaches 2.5g/100g.Good bioavailability and curative effect in preliminary drug test, are also demonstrated.This compound probably becomes a kind of new 5α-reductase inhibitor that can generally use.
Brief description of the drawings
Fig. 1 is the 1HNMR spectrogram of the compound that obtains of the present invention.
Embodiment
Below in conjunction with drawings and Examples, the present invention is further elaborated.
In the present invention according to documents and materials (Cogan, Peter S.; Koch, Tad H.; Journal of Medicinal Chemistry; Vol.46; Nb.24; (2003); P.5258-5270) described method obtains midbody compound IV.
Embodiment 1
10g compounds Ⅳ (33.6mmol) and 10g compound V (51mmol) join among the DMF of the 50ml in stirring between 20 DEG C to 25 DEG C, be stirred to molten clear after, in reaction solution, add 2.5g sodium Metal 99.5 (0.1mol).Reaction solution stirring at room temperature reaction 24 hours then adds 2.5ml saturated ammonium chloride solution cancellation sodium Metal 99.5 in reaction solution.Gained reaction solution pours in 250ml frozen water, stir separate out precipitation, suction filtration, after filter cake vacuum-drying in 200ml ethanol recrystallization, obtain product compound III 3.73g, yield 27%.
Embodiment 2
Between 0 DEG C to 5 DEG C, 2.5g sodium hydrogen (0.1mol) joins in the DMF of the 20ml in stirring in batches, the solution that the DMF of 10g compounds Ⅳ (33.6mmol) and 30ml is formed is added drop-wise in the suspension of sodium hydrogen and DMF formation, after dropwising, 10g compound V (51mmol) is joined again.Reaction solution stirring at room temperature reaction 24 hours then adds 2.5ml saturated ammonium chloride solution cancellation sodium hydrogen in reaction solution.Gained reaction solution pours in 250ml frozen water, stir separate out precipitation, suction filtration, after filter cake vacuum-drying in 200ml ethanol recrystallization, obtain product compound III 4.05g, yield 29.3%.
Embodiment 3
10g compounds Ⅳ (33.6mmol) and 10g compound V (51mmol) join among the DMF of the 50ml in stirring between 20 DEG C to 25 DEG C, be stirred to molten clear after, in reaction solution, add 10g salt of wormwood (72.4mmol).Reaction solution stirring at room temperature reaction 72 hours.Gained reaction solution pours in 250ml frozen water, stir separate out precipitation, suction filtration, after filter cake vacuum-drying in 500ml ethanol recrystallization, obtain product compound III 11.29g, yield 81.6%.Fusing point: 99 DEG C～101 DEG C.Nuclear-magnetism confirms structure.H NMR(CDCl3，400MHz)δ1.54(s，6H，CH3)，1.77(m，4H，CH2)，2.06(s，3H，CH3)，3.39(m，2H，CH2)，4.12(m，4H，CH2)，7.91(d，1H，CH)，8.01(dd，1H，CH)，8.16(d，1H，CH)。The solubleness of compound III in ethanol reaches 2.5g/100g.
Embodiment 4 androgen antagonist activity experiments (Hershberger test)
One, animal model is made and grouping medication
SPF level SD male rat in 6 week age (purchased from Beijing Vital River Experimental Animals Technology Co., Ltd.), adaptability was raised after 4 days, confirm to carry out castration operation (extracing bilateral testes and epididymis) after foreskin separation of animal, postoperative to give penicillin anti-infective, continues to raise 7 days.
Reject and infect and unhealthy rat, choose 30 mouse, be divided at random 5 groups by body weight, be respectively the basic, normal, high dosage group of negative control group, positive controls and medicine to be tested.Medicine to be tested is 4-(3-(4-cyano group-3-(trifluoromethyl) phenyl)-5,5-dimethyl-2,4-dioxy-1-imidazolyl) the butylacetic acid ester that the present invention obtains.
Androlin that every rat is given [100 μ g/ (kg.d)] is dissolved in 0.5ml peanut oil, through left abdomen subcutaneous injection, respectively organizes the equal administration of rat, injects continuously 7 days.
Negative control group rat gives 0.5ml peanut oil, continuous 7 days of subcutaneous injection.
Positive control is flutamide, is dissolved in ethanol, and being diluted to ethanol final concentration with peanut oil is 2.5wt%, and dosage is that every rat gives 0.5ml, continuous 7 days of subcutaneous injection.
Every rat of medicine group to be measured is dissolved in the tested material of the corresponding dosage of 0.5ml peanut oil, continuous 7 days of subcutaneous injection.
Two, the mensuration of hormone in sexual gland and liver kidney weight and serum
Rat after administration 24 hours the last time, with cutting off thoracic cavity after etherization, heart blood sampling, puts in vitro, centrifugal, gets supernatant, preserves at-70 DEG C to be measured.Get the sexual gland affiliated group (comprise ventral prostate, dorsal part prostate gland, seminal vesicle and solidify gland, levator ani) of rat, separate liver and kidney.Liver, kidney and levator ani before fixing in title, and before veutro, show slightly, dorsal part prostate gland, seminal vesicle and solidify gland after 10wt% formalin fixedly spends the night, careful arrangement and remove its hetero-organization and fat around, weighs, record.Application I-serum testosterone (T) radioimmunoassay kit, human serum follotropin (FSH) radioassay kit and short corpus luteum (LH) radioimmunoassay medicine box, adopt radioimmunoassay method, measure T, FSH and LH level in rat blood serum.
Three, the impact of medicine to be measured (target compound of the present invention) on rat property accessory organ weight
Table 1 is the comparison of medicine to be measured to rat property accessory organ weight.
By finding out in table 1, the compounds of this invention all reduces the weight of rat property ventral prostate, dorsal part prostate gland, seminal vesicle and levator ani.That is to say, in the body of the compounds of this invention, inject the growth of the property subsidiary organ that can effectively suppress to be caused by male sex hormone.
Four, the impact of medicine to be measured (target compound of the present invention) on rat blood serum hormone
Table 2 is the impact of medicine to be measured (target compound of the present invention) on rat blood serum hormone.The LH level of the compounds of this invention is the same with positive control as can be seen from Table 2, obviously increases.Therefore also progressive explanation, compound of the present invention has estrogen antagonist activity.
Table 2
| Group | Dosage (mg/kg) | T(ng/ml) | FSH(mIU/ml) | LH(IU/L) |
| Negative control | 0 | 0.95 | 0.93 | 0.71 |
| Medicine low dose group to be tested | 45 | 0.91 | 0.77 | 1.24 |
| Dosage group in medicine to be tested | 90 | 0.94 | 0.75 | 1.29 |
| Medicine high dose group to be tested | 180 | 0.92 | 0.91 | 1.49 |
| Positive control | 20 | 0.97 | 0.80 | 1.69 |
Claims (3)
1. a compound with androgen antagonist activity, is characterized in that, its molecular structure is as follows:
2. a preparation method with the compound of androgen antagonist activity, is characterized in that, concrete steps are included under catalyst, by midbody compound and 4-brombutyl acetic ester, 10-60 DEG C of reaction, obtains having the compound of androgen antagonist activity; Wherein: described catalyzer is selected from sodium Metal 99.5, sodium hydrogen, sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide any; The molecular structural formula of described midbody compound is as follows:
3. the application of the compound with androgen antagonist activity as claimed in claim 1 in preparing androgen antagonist medicine.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410200232.1A CN103965112A (en) | 2014-05-13 | 2014-05-13 | Compound with antiandrogen activity as well as preparation method and application of compound |
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| CN201410200232.1A CN103965112A (en) | 2014-05-13 | 2014-05-13 | Compound with antiandrogen activity as well as preparation method and application of compound |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022199289A1 (en) * | 2021-03-22 | 2022-09-29 | 中国药科大学 | Novel androgen receptor degrader, preparation method, and medical use |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0494819A1 (en) * | 1991-01-09 | 1992-07-15 | Roussel Uclaf | Phenylimidazolidines, their process for fabrication, their application as medicaments and the pharmaceutical compositions containing them |
| CN1112416A (en) * | 1994-02-16 | 1995-11-29 | 鲁索-艾克勒夫公司 | Cosmetic or pharmaceutical compositions consisting of liposomes |
| CN1044234C (en) * | 1992-07-08 | 1999-07-21 | 鲁索-艾克勒夫公司 | New substituted phenylimidazolidines, their preparation process, their use as medicaments and the pharmaceutical compositions containing them |
| US6242611B1 (en) * | 1995-12-22 | 2001-06-05 | Hoechst Marion Roussel | Phenylimidazolidines containing nitrooxy or carbonyloxy groups |
| WO2003093243A1 (en) * | 2002-04-27 | 2003-11-13 | Aventis Pharma Deutschland Gmbh | Preparations for the topical application of anti-androgenically active substances |
| US20030229129A1 (en) * | 2002-04-27 | 2003-12-11 | Kraemer Karl Theodor | Preparations for topical administration of substances having antiandrogenic activity |
-
2014
- 2014-05-13 CN CN201410200232.1A patent/CN103965112A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0494819A1 (en) * | 1991-01-09 | 1992-07-15 | Roussel Uclaf | Phenylimidazolidines, their process for fabrication, their application as medicaments and the pharmaceutical compositions containing them |
| CN1044234C (en) * | 1992-07-08 | 1999-07-21 | 鲁索-艾克勒夫公司 | New substituted phenylimidazolidines, their preparation process, their use as medicaments and the pharmaceutical compositions containing them |
| CN1112416A (en) * | 1994-02-16 | 1995-11-29 | 鲁索-艾克勒夫公司 | Cosmetic or pharmaceutical compositions consisting of liposomes |
| US6242611B1 (en) * | 1995-12-22 | 2001-06-05 | Hoechst Marion Roussel | Phenylimidazolidines containing nitrooxy or carbonyloxy groups |
| WO2003093243A1 (en) * | 2002-04-27 | 2003-11-13 | Aventis Pharma Deutschland Gmbh | Preparations for the topical application of anti-androgenically active substances |
| US20030229129A1 (en) * | 2002-04-27 | 2003-12-11 | Kraemer Karl Theodor | Preparations for topical administration of substances having antiandrogenic activity |
| TW200407312A (en) * | 2002-04-27 | 2004-05-16 | Aventis Pharma Gmbh | Preparations for topical administration of substances having antiandrogenic activity |
Non-Patent Citations (1)
| Title |
|---|
| 郭宗儒: "《药物化学总论》", 30 November 1994, article "疏水键", pages: 66-67 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022199289A1 (en) * | 2021-03-22 | 2022-09-29 | 中国药科大学 | Novel androgen receptor degrader, preparation method, and medical use |
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Application publication date: 20140806 |