CN102091060A - Drug for treating or preventing hypogonadism, sexual dysfunction and/or sterility mediated by glucocorticoid and application thereof - Google Patents
Drug for treating or preventing hypogonadism, sexual dysfunction and/or sterility mediated by glucocorticoid and application thereof Download PDFInfo
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- CN102091060A CN102091060A CN2009102535895A CN200910253589A CN102091060A CN 102091060 A CN102091060 A CN 102091060A CN 2009102535895 A CN2009102535895 A CN 2009102535895A CN 200910253589 A CN200910253589 A CN 200910253589A CN 102091060 A CN102091060 A CN 102091060A
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Abstract
The invention relates to application of the following 13 compounds such as a compound LG13 and the like in preparing a drug for preventing or treating diseases such as hypogonadism. The 13 compounds can treat or prevent the hypogonadism, sexual dysfunction and/or sterility which are mediated by glucocorticoids by dually regulating 11 beta hydroxy steroid dehydrogenases 1. Besides, the invention also relates to a medicinal composite contained in the compound LG13 and a kit.
Description
Technical field
The invention belongs to medical technical field, particularly, the present invention relates to the application of 13 compound L G02-LG13 in preparation resistance adenasthenia sexual dysfunction and/or sterile medicine.In addition, the invention still further relates to the pharmaceutical composition of the one or more chemical compounds among the inclusion compound LG02-LG13 and kit etc.
Background technology
Now, about 500,000,000 the sexual function patient of significantly going down is arranged in the world.The survey showed that for the Chinese male present situation that China sexology meeting sex medicine Professional Committee carries out, and sexual function occurs above the people who has had 9.7% among 40 years old the man and significantly go down.At present high efficiency, allegro working method and serious competition bring immense pressure on psychology and the health for many people.Done a large-scale sampling survey according to up-to-date Beijing Communist Youth League and shown that about 60% people is in stress state; These all can influence its normal sexual function.Stress pressure inducement glucocorticoid level increase (Monder C 1994 Endocrinology134:1193-1198).Stress can descend by blood serum induced testosterone levels by pressure, cause testicular function to be degenerated, make sexual disorder and reproductive performance weaken (Hardy MP et al 2005.Cell Tissue Res.322:147-53).The testosterone secretion minimizing not only causes sexual dysfunction but also causes obstacle such as psychological obstacle, amyotrophy, obesity and the hypertension of related system widely.The mankind, serious mental pressure, relative or spouse's death etc. all can cause sperm quantity reduction (Fenster L 1997, Journal of Andrology, 18:194).Stress be considered to cause one of sterile factor clinically by pressure, minimizing stress become the preparation measures they (Hjollund NH 2004 Epidemiology 15:21) that breeds child by pressure.On physiology, stress is regulated the balance of keeping interior environment by body to the compensatory of stresser.Over-drastic glucocorticoid activity be stress sign.Male's Cushing's syndrome patient glucocorticoid increases, and plasma testosterone concentration reduces.
The male, interstitialcellstimulating hormone (ICSH) is the main driving factors that interstitial cell produces testosterone, and the glucocorticoid that adrenal cortical cell produces is an inhibitive factor.Glucocorticoid also suppresses the luteotropic hormone secretion.Glucocorticoid plays a role by combining with glucocorticoid receptor (GR).Interstitial cell has glucocorticoid receptor (GR), and the glucocorticoid of prompting acth secretion can directly influence these cells.Stress improve the glucocorticoid level, suppress the synthetic of testosterone simultaneously.
(11 β-HSD) are the crucial enzymes that the catalysis glucocorticoid transforms to 11 β hydroxy steroid dehydrogenase types, the level of glucocorticoid and activity.11 β-HSD comprises two kinds of enzyme: 11 β-HSD1 and 11 β-HSD2.Their effect is opposite, and the main effect of 11 β-HSD1 is to promote the conversion of nonactive glucocorticoid to active glucocorticoid, and 11 β-HSD2 then only promotes the conversion of active glucocorticoid to nonactive glucocorticoid.Wherein, 11 β-HSD1 is an oxidoreductase, contains two kinds of enzyme forms of reductase and oxidase again, and wherein reductase promote the conversion of nonactive glucocorticoid to active glucocorticoid, and oxidasic action direction is opposite, accounts for back burner in the highest flight.On apparent, 11 β-HSD1 mainly shows as reductase activity.11 β-HSD1 exists pituicyte and interstitial cell to regulate glucocorticoid level (Ge RS et al 1997.Endocrinology138:2435-42).
External existing how tame large-scale pharmaceutical companies has begun the research of 11 beta-HSD 1 inhibitors, as BVT7702,138768 and NCB13793 etc., wherein, 11 β of Incyte company-HSD1 selective depressant NCB13793 is carrying out II phase clinical research treatment type ii diabetes.
Yet regrettably, present 11 beta-HSD 1 inhibitors of reporting all simultaneously (mixings) suppress 11 β-HSD1 oxidase and two kinds of forms of reductase, embody inhibition on apparent, thereby play the effect of the active glucocorticoid of reduction 11 β-HSD1 reductase.11 β-HSD1 oxidase has the effect identical with 11 β-HSD2, can reduce glucocorticoid concentration.Though in the mixing inhibition of 11 beta-HSD 1 inhibitors of having reported to 11 β-HSD1, the influence that the inhibited oxidation enzyme is produced will certainly be offset the part drug effect of inhibitor less than suppressing the influence that reductase produced.And, suppress the generation that 11 β-HSD1 reductase could only prevent and stop hydrocortisone, it is high to stop blood sugar concentration to be given birth to, but but can't reduce the glucocorticoid concentration that has raise.It is synthetic that the glucocorticoid level that has raise in the local organization will suppress testosterone.Still not having 11 beta-HSD 1 inhibitors in the world, to be used for the treatment of gonad function low.
For this reason, the inventor discovers and will seem even more important at therapeutic process than present selective depressant to 11 β-HSD1 dual regulation (that is, suppress 11 β-HSD1 reductase and activate 11 β-HSD1 oxidase).This have a fully optionally chemical compound of 11 β-HSD1, will form optimal medicine by " 11 β-HSD1 → glucocorticoid → testosterone " passage performance resistance gland hypofunction.
The inventor is on working foundation for many years, curcumin (code name LG01) and 12 1 have been found, 4-pentadiene-3-ketone compounds (code name LG02-LG13) is brought into play drug action by suppress more efficiently 11 β of 11 β-HSD1-HSD1 dual regulation mechanism than present selectivity, such mechanism is except having the good selectivity 11 β-HSD1 and 11 β-HSD2, reduction and oxidation catalysis function to 11 β-HSD1 all have intensive regulating action, suppress 11 β-HSD1 reductase and activate 11 β-HSD1 oxidase, play dual reduction glucocorticoid, alleviate the effect of the low symptom of gonad function, experiment in vivo and vitro confirms that all this compounds has good resistance adenasthenia sexual dysfunction and/or sterile effect.
Summary of the invention
The object of the invention is to provide a kind of new application, has wherein used and can reduce the active of 11 β-HSD1 reductase simultaneously and increase the oxidasic active chemical compound of 11 β-HSD1.In addition, the present invention also aims to the low dose pharmaceutical compositions, kit and the respective application that provide new.
Particularly, in first aspect, the invention provides found curcumin (code name LG01) and 14 as follows 1,4-pentadiene-3-ketone compounds (code name LG02-LG13) is in preparation treatment or preventative adenasthenia sexual dysfunction and/or sterile application.
Discover that through the inventor compound L G01-LG13 can reduce the active of 11 β-HSD1 reductase simultaneously and increase the oxidasic activity of 11 β-HSD1, therefore be effective in very much treatment or prevention metabolic disease.
Preferably in first aspect, described hypogonadism sexual dysfunction and/or sterile with respect to health or normal individual, organ, tissue or cell report, activity with 11 β-HSD1 reductase increases and/or the oxidasic active symptom that reduces of 11 β-HSD1, and the activity that more preferably has 11 β-HSD1 reductase increases and the oxidasic active symptom that reduces of 11 β-HSD1.More preferably, described hypogonadism sexual dysfunction and/or sterile be because the activity of 11 β-HSD1 reductase increases and/or oxidasic active reduction of 11 β-HSD1 caused.Discover through the inventor, because LG01-LG13 can reduce the active of 11 β-HSD1 reductase simultaneously and increase the oxidasic activity of 11 β-HSD1, thus in the first aspect present invention more preferably described hypogonadism sexual dysfunction and/or sterile be because the activity of 11 β-HSD1 reductase increases and the oxidasic active reduction of 11 β-HSD1 causes.
Preferably in first aspect, described hypogonadism sexual dysfunction and/or sterile be can be by reducing the active of 11 β-HSD1 reductase and/or increase that the oxidasic activity of 11 β-HSD1 is treated or the hypogonadism sexual dysfunction that prevents and/or sterile, more preferably described hypogonadism sexual dysfunction and/or sterilely be activity that can be by reducing by 11 β-HSD1 reductase and increase that the oxidasic activity of 11 β-HSD1 is treated or the hypogonadism sexual dysfunction that prevents and/or sterile.Discover through the inventor, because the LG01-LG13 chemical compound can reduce the active of 11 β-HSD1 reductase simultaneously and increase the oxidasic activity of 11 β-HSD1, thus in the first aspect present invention more preferably described hypogonadism sexual dysfunction and/or sterile by reducing by 11 β-HSD1 reductase activity and increase arbitrary approach (preferably simultaneously by these two approach) in the oxidasic activity of 11 β-HSD1 and treat or prevent.For example, described hypogonadism sexual dysfunction and/or the sterile hypogonadism sexual dysfunction that is selected from.In the specific embodiment of the present invention, described hypogonadism sexual dysfunction and/or the sterile hypogonadism sexual dysfunction that is selected from.In the preferred embodiments of the disclosure, described hypogonadism sexual dysfunction and/or sterile be the hypogonadism sexual dysfunction.
Preferably in first aspect, through preparation process, described medicine contains one or more in the LG01-LG13 chemical compound of effective dose.Effective dose can be unit dosage form (as, a slice, a pin, a ball or potion) medicine in content, also can be the patient's of required treatment/prevention unit dose (as, per weight dosage).Drug manufacturer can be at an easy rate average weight by the patient colony of required treatment/prevention with the content in the medicine of the patient's of required treatment/prevention the per weight dosage unit of being converted into dosage form, for example, the average weight of adult patient can be 60kg, therefore multiply by adult's per weight dosage by average weight, can obtain the content of the medicine of the unit dosage form that is used for being grown up.In the present invention, the patient can be a mammal, as people, rabbit, Canis familiaris L. or Mus.Dose,equivalent conversion relation according to known laboratory animal of those of ordinary skills and people (usually can be referring to the instruction of medicine administrative organs such as FDA, SFDA, also can referring to " Huang Jihan etc. in the pharmacological testing between animal and the dose,equivalent between the animals and human beings body convert. Chinese clinical pharmacology and therapeutics, 2004Sep; 9 (9): 1069-1072 ") can derive people's per weight dosage from the dosage of laboratory animal.For example, for laboratory animal mice commonly used, according to above-mentioned document, its conversion relation with the adult is about 12: 1; For experimental animal rat commonly used, according to above-mentioned document, its conversion relation with the adult is about 6: 1.In the present invention, effective dose (in content) can be preferably 0.1mg-500mg of 10ug-1g, is more preferably 1mg-100mg.
Therefore be not limited to theory, preferably in first aspect, described medicine contains in the LG01-LG13 chemical compound of effective dose, the LG13 that preferably contains the dosage of 1-10mg/kg Wistar rat, be more preferably the LG13 of the dosage that contains 1-6mg/kg Wistar rat, as contain the LG13 of the dosage of 5mg/kg Wistar rat.In the specific embodiment of the present invention, selected representational 1,4-pentadiene-3-ketone compounds is LG13.In the preferred embodiments of the disclosure, the dosage of preferred LG13 be the dosage of 1-6mg/kg Wistar rat.
Correspondingly, in second aspect, the invention provides pharmaceutical composition, it contains in these 12 chemical compounds of LG02-LG13 of effective dose one, preferably contains the LG13 of the dosage of 1-10mg/kg Wistar rat, and pharmaceutically acceptable carrier.The preferred low dose pharmaceutical compositions of the present invention is preferred for prevention or therapeutic adenasthenia sexual dysfunction and/or sterile.Pharmaceutically acceptable carrier used herein refers to nontoxic filler, stabilizing agent, diluent, adjuvant or other pharmaceutical adjuncts.For example, diluent, excipient are as water, normal saline etc.; Filler is as starch, sucrose etc.; Binding agent is as cellulose derivative, alginate, gelatin and/or polyvinylpyrrolidone; Wetting agent is as glycerol; Disintegrating agent is as agar, calcium carbonate and/or sodium bicarbonate; Absorption enhancer is as quaternary ammonium compound; Surfactant is as hexadecanol; Absorption carrier is as Kaolin and/or soap clay; Lubricant is as Pulvis Talci, calcium stearate/magnesium, Polyethylene Glycol etc.In addition, pharmaceutical composition of the present invention can also further contain other adjuvant, as flavouring agent, sweeting agent etc.Known technology according to this area, can pharmaceutical composition be made various dosage forms according to the needs of therapeutic purposes, route of administration, preferred said composition is a unit dosage form, as lyophilized preparation, tablet, capsule, powder, emulsion agent, aqueous injection or spray, more preferably this pharmaceutical composition be injection type (as, lyophilized injectable powder) or peroral dosage form (as, tablet, capsule).Wherein, pharmaceutically acceptable carrier mentioned above is meant the pharmaceutical carrier of pharmaceutical field routine.
Correspondingly, in the third aspect, the invention provides kit, it comprises the pharmaceutical composition of second aspect present invention, and the label of indication low dosage administration.In this article, as do not have opposite explanation, described low dosage refers to the dosage of 1-10mg/kg Wistar rat, and the dosage of 3-8mg/kg Wistar rat preferably is as the dosage of 5mg/kg Wistar rat.Kit all is a kind of common product for masses, can easily find in pharmacy.Usually, kit comprises the container that the pharmaceutical composition of face is put in the present invention second is housed that in other words, the pharmaceutical composition of second aspect present invention is contained in the container of kit of the present invention.Container can be the container commonly used of pharmaceutical composition that can hold LG13 and second aspect present invention such as bottle, box, syringe etc.Medicine can include only a container, also can comprise a plurality of containers.Label can be attached on the said vesse, perhaps directly prints on the said vesse, also can exist with form independently, as the kit front cover of stating container or the description that directly provides can be provided.Label indication is with the chemical compound of low dosage (among the LG01-LG13 one or more) administration, wherein, the indication of label specifically can be represented with per weight dosage, also can represent with the absolute dosage of specific crowd, as " adult's consumption " or " child's consumption ", at this moment need simply to convert according to the body weight situation.If what adorn in the container is compositionss such as medicine, preparation, then can be according to the content of chemical compound in the unit form of administration (as, a pin), and low dosage is converted into content, with the label indication, this is easily to people.As required, as conveniently transporting, depositing, kit can further be packed in the into bigger packing, and this also within the scope of the invention.
In fourth aspect, the invention provides as follows 12 1,4-pentadiene-3 ketone compounds (code name LG02-LG13) is reducing the active of 11b-HSD1 reductase and is increasing application in the oxidasic activity of 11b-HSD1
For the ease of understanding, the present invention has quoted open source literature, and these documents are in order more clearly to describe the present invention, its in full content all include this paper in and carry out reference.Below will describe in detail the present invention by specific embodiment and accompanying drawing.It needs to be noted that these descriptions only are exemplary descriptions, do not constitute limitation of the scope of the invention.According to the argumentation of this description, many variations of the present invention, change have been obviously all concerning one of ordinary skill in the art.
Description of drawings
The catalysis sketch map of Figure 111 β hydroxyl dehydrogenase.
The chemosynthesis sketch map of 2 compound L G02-LG13 of Figure 21.
The sketch map of Fig. 3 dual regulation 11 β-HSD1 mechanism
Shown in A figure, present 11 β that report-HSD1 selective depressant all only refers to the one-level selectivity between 11 β-HSD1 and the 11 β-HSD2, does not relate to as yet the selectivity between 11 β-HSD1 reductase and two catalysis directions of oxidase.Such inhibitor suppresses 11 β-HSD1 reductase and oxidase simultaneously, but because reductase in the highest flight, thereby be presented as the inhibition reductase on apparent, and reduce partial concentration of cortisol, may not influence and cause the whole body cortisol levels by pressure or Cushing's syndrome.Have not yet to see 11 β-HSD1 reductase and oxidase filler test and have the optionally report of 11 beta-HSD 1 inhibitors of secondary respectively.Though the influence that present inhibitor inhibited oxidation enzyme is produced is less than suppressing the influence that reductase produced, its defective is: (1) will certainly offset the part drug effect of inhibitor; (2) two-way inhibition 11 β-HSD1 can only stop the conversion of cortisone to hydrocortisone, but but can't reduce the whole body concentration of cortisol that has raise, and the cortisol levels that has raise in the tissue will be kept and suppress the synthetic of testosterone; Existing concentration of cortisol need make its cortisone that is converted into non-activity by stimulating 11 β-HSD1 oxidase, particularly because circulation glucocorticoid level is too high, as pressure and hypercortisolism.
B figure is depicted as ideal 11 β-HSD1 dual modulators (compound L G13 of the present invention is 11 β-HSD1 dual modulators), it can suppress 11 β-HSD1 reductase and activate 11 β-HSD1 oxidase simultaneously, reduce glucocorticoid activity by a larger margin, final performance is prevention or therapeutic adenasthenia sexual dysfunction and/or sterile effect better, forms ideal medicine by " 11 β-HSD1 → glucocorticoid → testosterone " passage performance resistance adenasthenia sexual dysfunction and/or sterile effect.
Fig. 4 curcumin (LG01) and LG13 in the rat testicle Interstitial cell to 11b-HSD1 reductase and oxidasic dual regulation effect.A figure expression curcumin is to the oxidasic effect of 11b-HSD1, and B figure expression LG13 is to the effect (n=4) of 11 β-HSD1 reductase.Oxidase active passes through 0.025 * 10
6Add hydrocortisone (25nM) in the rat testicle Interstitial cell and handle measurement after 30 minutes.11 β-HSD1 reductase passes through 0.05 * 10
6Add cortisone (25nM) in the rat testicle Interstitial cell and handle measurement after 120 minutes.
Fig. 5 curcumin (LG01) and LG13 to stress the effect of the low prophylactic treatment of inductive testosterone level.Oral totally 2 days once a day of curcumin and LG13.The SD rat is fixing stress 3 hours.The variation of taking blood and measuring serum testosterone.Mean±SEM(n＝10)。* represent significant difference, * is P＜0.05.100 and the 200mg/kg curcumin and 1 and 5mg/kgLG13 return to fully stress not level of serum testosterone.Show the minimizing of curcumin and LG13 prevention irritability testosterone.
The specific embodiment
The present invention further specifies in following embodiment.These embodiment are for illustrative purposes, rather than are used for limiting the scope of the invention.
The synthetic logical method of embodiment 1LG02-LG13
The corresponding substituted benzaldehyde of 10mmol is dissolved in the 10mL dehydrated alcohol, adds corresponding Ketocyclopentane, acetone or Ketohexamethylene behind the stirring at room 5min, continue to stir 10min, solution no change.Sodium metal is dissolved in methanol, is configured to the Feldalat NM/methanol solution of 18% (w/v).Slowly drip this sodium methoxide solution 1.5mL (containing Feldalat NM 5mmol) in reaction solution, behind the stirring reaction 2-5h, a large amount of insoluble yellows appear, with TLC detection reaction liquid, the black splotch that no longer occurs raw material 2-bromobenzaldehyde under the 320nm uviol lamp, the distinct displaing yellow of product speckle.Stopped reaction, with reacting liquid filtering, product washes with water earlier, after washing twice, 30 ℃ of vacuum drying and spend the night with ice ethanol, ice acetone subsequently yellow powder shape product, after silica gel chromatography purity all greater than 98% chemical compound.
LG02:2,5-pair-(4-fluorobenzene methylene) Ketocyclopentane, yield 88%, 239～240 ℃ of fusing points.
1H-NMR (CDCl
3) δ: 3.10 (4H, s, CH
2-CH
2), 7.14 (4H, t, J=8.4Hz, Ar-H
2,6* 2), 7.59 (4H, t, J=9Hz, Ar-H
3,5* 2), 7.61 (2H, s, Ar-CH=C * 2) .ESI-MS m/z:297.13 (M+1)
+, calcd for C
19H
14F
2O:296.31.
LG03:2,5-pair-(2-bromobenzene methylene) Ketocyclopentane, yield 87%, 163 ℃ of fusing points.
1H-NMR (CDCl
3) δ: 2.98 (4H, s, CH
2-CH
2), 7.22 (2H, q, J=3.8Hz, Ar-H
4* 2), 7.36 (2H, q, J=7.4Hz, Ar-H
6* 2), 7.53 (2H, q, J=3.8Hz, Ar-H
5* 2), 7.66 (2H, q, J=4Hz, Ar-H
3* 2), 7.86 (2H, s, Ar-CH=C * 2) .ESI-MS m/z:418.94 (M+1)
+, calcd for C
19H
14Br
2O:418.12.
LG04:2,5-pair-(3-bromobenzene methylene) Ketocyclopentane, yield 91%, 186 ℃ of fusing points.
1H-NMR (CDCl
3) δ: 3.12 (4H, s, CH
2-CH
2), 7.30 (2H, t, J=15.6Hz, Ar-H
5* 2), 7.50～7.52 (6H, m), 7.73 (2H, s, Ar-CH=C * 2) .ESI-MS m/z:418.98 (M+1)
+, calcd for C
19H
14Br
2O:418.12.
LG05:2,5-pair-(4-(N, N-dimethylamino propoxyl group) benzylidene) Ketocyclopentane, yield 72%, 154 ℃ of fusing points.
1H-NMR (CDCl
3) δ: 1.98 (4H, m, CH
2* 2), 2.26 (12H, s, N-CH
3* 4), 2.46 (4H, t, J=7.4Hz, CH
2-N * 2), 3.08 (4H, s, CH
2-CH
2), 4.07 (4H, t, J=6.2Hz, O-CH
2* 2), 6.96 (4H, d, J=8.8Hz, Ar-H
2,6* 2), 7.73 (2H, s, Ar-CH=C * 2), 7.56 (4H, d, J=8.8Hz, Ar-H
3,5* 2) .ESI-MS m/z:463.33 (M+1)
+, calcd for C
29H
38N
2O
3: 462.62.
LG06:2,6-pair-(2-trifluoromethyl benzylidene) Ketohexamethylene, yield 65%, 107～108 ℃ of fusing points.
1H-NMR (CDCl
3) δ: 1.72 (2H, m), 2.63 (4H, t, J=5.2Hz, CH
2-CH
2), 7.33 (2H, d, J=7.2Hz, Ar-H
6* 2), 7.44 (2H, t, J=7.6Hz, Ar-H
4* 2), 7.55 (2H, t, J=7.4Hz, Ar-H
5* 2), 7.71 (2H, d, J=7.6Hz, Ar-H
3* 2), 7.96 (2H, s, CH=C * 2) .ESI-MS m/z:410.77 (M+), calcd for C
22H
16F
6O:410.37.
LG07:1,5-two (4-hydroxy phenyl)-1,4-pentadiene-3-ketone, yield 92%, 246～248 ℃ of fusing points.
1H-NMR (DMSO-d
6) δ: 6.83 (4H, d, J=8.4Hz, Ar-H
2,6* 2), 7.07 (2H, d, J=16Hz, C=CH-O * 2), 7.58 (4H, d, J=8.4Hz, Ar-H
3,5* 2), 7.66 (2H, d, J=16Hz, Ar-CH=C * 2), 10.03 (2H, s, OH * 2) .ESI-MS m/z:267.09 (M+1)
+, calcd for C
17H
14O
3: 266.29.
LG08:2,6-pair-(4-fluorobenzene methylene) Ketohexamethylene, yield 69%, 156 ℃ of fusing points.
1H-NMR (CDCl
3) δ: 1.81 (2H, q, J=12Hz, CH
2), 2.90 (4H, t, J=5.4Hz, CH
2* 2), 7.12 (4H, m, Ar-H
2,6* 2), 7.45 (4H, m, Ar-H
3,5* 2), 7.76 (2H, s, Ar-CH=C * 2) .ESI-MS m/z:311.11 (M+1)
+, calcd for C
20H
16F
2O:310.34.
LG09:2,6-pair-(2-bromobenzene methylene) Ketohexamethylene, yield 83%, 120 ℃ of fusing points.
1H-NMR (CDCl
3) δ: 1.75 (2H, q, J=9.3Hz, CH
2), 2.75 (4H, m, J=6.1Hz, C-CH
2* 2), 7.18～7.35 (6H, m, Ar-H), 7.64 (2H, m, Ar-H), 7.86 (2H, s, Ar-CH=C * 2) .ESI-MS m/z:432.98 (M+1)
+, calcd for C
20H
16Br
2O:432.15.
LG10:2,6-is two-(4-phenol methylene) Ketohexamethylene, yield 59%, fusing point＞300 ℃.
1H-NMR (DMSO-d
6) δ: 1.71 (2H, m), 2.84 (4H, s, C-CH
2* 2), 6.83 (4H, d, J=6.0Hz, Ar-H
2,6* 2), 7.40 (4H, d, J=6.0Hz, Ar-H
3,5* 2), 7.53 (2H, s, Ar-CH=C * 2), 9.50 (2H, br, Ar-OH * 2) .ESI-MS m/z:305.18 (M-1)
+, calcdfor C
20H
18O
3: 306.36.
LG11:2,5-pair-(2,3-dimethoxy benzylidene) Ketocyclopentane, yield 72%, 142 ℃ of fusing points.
1H-NMR (CDCl
3) δ: 3.02 (4H, s, CH
2-CH
2), 3.99 (12H, s, O-CH
3* 4), 6.96 (2H, d, J=8Hz, Ar-H
6* 2), 7.11 (2H, t, J=7.8Hz, Ar-H
5* 2), 7.18 (2H, d, J=7.6Hz, Ar-H
4* 2), 7.93 (2H, s, CH=C * 2) .ESI-MS m/z:381.29 (M+1)
+, calcd for C
23H
24O
5: 380.4.
LG12:2,6-pair-(2,3-dimethoxy benzylidene) Ketohexamethylene, yield 88%, 138 ℃ of fusing points.
1H-NMR (CDCl
3) δ: 1.79 (2H, m), 3.12 (4H, s, CH
2-CH
2), 3.99 (12H, s, O-CH
3* 4), 6.71 (2H, d, J=8Hz, Ar-H
6* 2), 7.17 (2H, t, J=7.8Hz, Ar-H
5* 2), 7.22 (2H, d, J=7.6Hz, Ar-H
4* 2), 8.02 (2H, s, CH=C * 2) .ESI-MSm/z:394.46 (M)
+, calcd for C
23H
24O
5: 394.18.
LG13:1,5-two (2-bromophenyl)-1,4-pentadiene-3-ketone, yield 81.1%.97 ℃ of fusing points;
1H-NMR (CDCl
3) δ: 7.03 (2H, d, J=16Hz, C=CH-CO * 2), 7.22～7.63 (8H, m, Ar-H), 8.09 (2H, d, J=16Hz, Ar-CH=C * 2) .ESI-MS m/z:393.10 (M+1)
+, calcd for C
17H
12Br
2O:392.08.
Embodiment 2 external dual regulation 11b-HSD1
Hepatocyte separates with Interstitial cell: use CO
2After smother play is put to death rat, extract testis to extract and the purification Interstitial cell, method is with reference to [SalvaA, et al.J Androl.2001,22,665-671].The purity of Interstitial cell is measured (is the steroidal substrate with the 0.4mM etiocholanolone) by 3 β-hydroxyl steroid dehydrogenase activity histochemical staining method, this method ripe Interstitial cell more than 95% that can dye; Pertoft and is adopted in the separation of hepatic parenchymal cells
Described method [Cell Separation:Methods and Selected Applications.pp:1-23, Academic Press, Orlando, F, 1987], promptly in-situ perfusion does not have the calcium buffer in rat liver, and disperse obtains hepatic parenchymal cells by the density gradient centrifugation separation and purification in 0.05% collagenase solution.
Human 11b-HSD1 gene transfection and CHOP cell strain are cultivated: according to Ge et al (Ge et al 2000.J Androl.21 (2): 303-10.) human 11b-HSD1 gene transfection of transfection and cultivation CHOP cell strain.
The preparation of microsomal protein: Mus Interstitial cell, Hepar Mus cell and human liver cell microsome are by Ge RS, and et al reported method is prepared [Ge RS, et al.Endocrinology, 1997,138:435-42].
Detect at 11 β HSD oxidase and reductase activity: the utilization detection [
3H]-cortisone or [
3H]-concentration of 11-hydrocortisone characterizes 11 β-HSD1 oxidase or reductase activity respectively.Add 25nM[in the active detector tube of each 11 β-HSD1
3H]-cortisone (this concentration is within cortisone physiologically active concentration range).Former generation Interstitial cell or hepatocyte containing 25nM[
3H]-cultivate 120min in the culture fluid of cortisone (reductase activity), or [
3H]-11-hydrocortisone (oxidase active) culture fluid in cultivate 30min.The chemicals of variable concentrations is hatched jointly.Detect for 11 β in the microsome-HSD1 are active, microsome is hatched with 11 β-HSD1 substrate NADPH, stops with 2ml ice ether after being reflected at certain hour.Then, with the steroidal in the organic solvent extraction Incubating Solution, after the drying, be mobile phase in the stream of nitrogen gas with chloroform/methanol (9: 1), separate steroidal by thin layer chromatography, [
3H]-cortisone or [
3H]-radioactivity of 11-hydrocortisone by scanning radiometer detect (System AR2000, Bioscan Inc., Washington, DC, USA), the conversion ratio between cortisone and the hydrocortisone is calculated by their radioactive standard number itself to be determined.The detection method of 11 β-HSD2 is as the oxidasic detection method of 11 β-HSD1.
Compound treatment and detection: according to above-mentioned measure at 11 β-HSD1 oxidase and reductase activity detection method active, according to suppressing or the concentration conversion of onset becomes IC
50And EC
50Value.Testing result shown in following table 1 and accompanying drawing 4,
Table 112 a compound L G02-LG13 is to the active * of 11b-HSD1 reductase, 11b-HSD1 oxidase and 11b-HSD2
* A: rat Interstitial cell; B: rat testicle Interstitial cell microsome; C: people 11b-HSD1 transfection CHOP cell; D: people's liver microsomes; E: rat kidney microsome; F: people's kidney microsome.
The inventor has tested 13 compound L G02-LG13 altogether in cell or the microsome system in six active to inhibition or the activation of 11 β-HSD1 reductase, 11 β-HSD1 oxidase and 11 β-HSD2.From table 1 as seen, these 13 chemical compounds not only can be under the situation that does not influence 11 β-HSD2 optionally the prostatitis suppress 11 β-HSD1 reductase, can also obviously activate 11 β-HSD1 oxidase, play the effect of dual regulation 11 β-HSD1, may regulate the effect of intravital glucocorticoid activity and performance treatment type ii diabetes with getting twice the result with half the effort.Wherein, compound L G06, LG09, LG12 and LG13 have the very strong dual regulation effect to 11 β-HSD1, and it suppresses the IC of 11 β-HSD1 reductase
50Value all reaches the nM rank, and activates the oxidasic EC of 11 β-HSD1
50Value reaches the nM rank equally.In addition, referring to accompanying drawing 4 of the present invention, LG13 becomes good dose-effect dependence to active the reaching of the inhibition of 11 β-HSD1 reductase to the oxidasic activity that activates of 11 β-HSD1.
Embodiment 3 curcumins and LG13 to stress the effect of the low prophylactic treatment of inductive testosterone level
Rat (available from Chinese Academy of Sciences's Shanghai animal center) is fed with normal diet respectively.Respectively stress (stress group) and stress (have stress group), 10 every group.Oral totally 2 days once a day of curcumin and LG13.The SD rat is fixing stress 3 hours (Dong Q.et al 2004, J Androl 25:973-981).The variation of taking blood and measuring serum testosterone.The result shown in accompanying drawing 5 of the present invention, 100 and the 200mg/kg curcumin and 1 and 5mg/kg LG13 return to fully stress not level of serum testosterone.Show the minimizing of curcumin and LG13 prevention irritability testosterone.
The safety experiment of embodiment 4LG13
Be dissolved in 1% the Carboxymethyl cellulose sodium solution LG13 is outstanding, the Balb/C mice of getting 14-18g is (male, full diet is fed), being divided into 4 groups, is respectively the LG13 group of negative group (the normal raising do not irritated stomach), group of solvents (irritating the Carboxymethyl cellulose sodium solution of stomach same amount), 400mg/kg, the LG13 group of 800mg/kg, every group eight, gastric infusion, once a day, continuous irrigation stomach 14 days.Do not have mice in 14 days because of toxicity death, do not observe Deviant Behavior and the situation of administration mice yet.
Be dissolved in 1% the Carboxymethyl cellulose sodium solution LG13 is outstanding, get eight of the Balb/C mices (male, full diet is fed) of 14-18g, irritate stomach LG13 with the dosage of 3g/kg, once a day, continuous irrigation stomach 3 days, and then observed 3 days.Do not have mice in 6 days because of toxicity death, do not observe Deviant Behavior and the situation of administration mice yet.
The pharmacokinetics experiment of embodiment 5LG13
According to method and the Liang G that medicine inspection department is recommended, et al.Bioorg.Med.Chem., 2009, the described method of 17:2623-2631, the mice pharmacokinetics of detection LG13, the main pharmacokinetic data available that records sees Table 3.As can be seen from Table 3, the chemical compound dosage of same oral 500mg/kg, LG13 blood drug level peak value reaches 4.1 μ g/ml.Clearance rate (CL) lower (125.4) in the LG13 body correspondingly shows that body declines to a great extent to the removing ability of chemical compound.The dose that LG13 enters in the blood plasma is bigger, and AUC0-t and AUC0-∞ value reach 12.053 and 14.907mgh/L respectively.As seen, LG13 has suitable advantage aspect each parameter of pharmacokinetics.
The pharmacokinetic data * of table 3LG13
* AUC: area under curve; t
1/2: the half-life; MRT: mean residence time; CL: clearance rate; C
Max: the highest blood drug level; T
Max: peak time.
Claims (10)
1. the application of the arbitrary chemical compound that is selected from 13 chemical compounds as follows in preparation treatment or preventative adenasthenia sexual dysfunction and/or sterile medicine
2. application according to claim 1, wherein said hypogonadism sexual dysfunction and/or sterile owing to the glucocorticoid mediation causes.
3. application according to claim 1, wherein said hypogonadism sexual dysfunction and/or sterile be can be by reducing by the 11 β hydroxy steroid dehydrogenase types 1 (reductase of 11 β-HSD1) active and/or increase that the oxidasic activity of 11 β-HSD1 is treated or the hypogonadism sexual dysfunction that prevents and/or sterile.
4. according to the described application of aforementioned arbitrary claim, the hypogonadism sexual dysfunction that wherein said hypogonadism sexual dysfunction and/or the sterile glucocorticoid that is selected from pressure, disease and old and feeble mediation too much cause and/or sterile.
5. application according to claim 4, wherein said hypogonadism sexual dysfunction and/or sterile be sexual dysfunction.
6. application according to claim 5, wherein said medicine contains the LG13 of effective dose, preferably contains the LG13 of the dosage of 1-10mg/kgWistar rat.
7. pharmaceutical composition, it contains the LG13 of effective dose, preferably contains the LG13 of the dosage of 1-10mg/kg Wistar rat, and pharmaceutically acceptable carrier.
8. pharmaceutical composition according to claim 7, it is used for prevention or therapeutic adenasthenia sexual dysfunction and/or sterile.
9. kit, it comprises claim 7 or 8 described pharmaceutical compositions, and the label of indication low dosage administration.
10. the arbitrary chemical compound that is selected from 13 chemical compounds as follows is reducing the active of 11 β-HSD1 reductase and/or is increasing application in the oxidasic activity of 11 β-HSD1
Priority Applications (2)
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|---|---|---|---|
| CN2009102535895A CN102091060A (en) | 2009-12-10 | 2009-12-10 | Drug for treating or preventing hypogonadism, sexual dysfunction and/or sterility mediated by glucocorticoid and application thereof |
| PCT/CN2010/075829 WO2011029359A1 (en) | 2009-09-12 | 2010-08-10 | MEDICAMENTS CONTAINING 11β HYDROXYSTEROID DEHYDROGENASE 1 DOUBLE REGULATORS AND USES THEREOF |
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|---|---|---|---|
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| CN112245414A (en) * | 2020-10-15 | 2021-01-22 | 四川大学华西医院 | Application of curcumin or its drug-carrying system in preparation of drugs for treating penile erectile dysfunction |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1646473A (en) * | 2002-04-17 | 2005-07-27 | 北卡罗来纳查佩尔山大学 | Novel curcumin analogues and uses thereof |
| US20050187255A1 (en) * | 2002-04-17 | 2005-08-25 | Kuo-Hsiung Lee | Novel curcumin analogues and uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1646473A (en) * | 2002-04-17 | 2005-07-27 | 北卡罗来纳查佩尔山大学 | Novel curcumin analogues and uses thereof |
| US20050187255A1 (en) * | 2002-04-17 | 2005-08-25 | Kuo-Hsiung Lee | Novel curcumin analogues and uses thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112245414A (en) * | 2020-10-15 | 2021-01-22 | 四川大学华西医院 | Application of curcumin or its drug-carrying system in preparation of drugs for treating penile erectile dysfunction |
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