CN102429901B - Application of indole-3-carbinol, diindolylmethane and derivatives thereof in preparation of medicaments for preventing and treating renal fibrosis - Google Patents
Application of indole-3-carbinol, diindolylmethane and derivatives thereof in preparation of medicaments for preventing and treating renal fibrosis Download PDFInfo
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- CN102429901B CN102429901B CN 201110341886 CN201110341886A CN102429901B CN 102429901 B CN102429901 B CN 102429901B CN 201110341886 CN201110341886 CN 201110341886 CN 201110341886 A CN201110341886 A CN 201110341886A CN 102429901 B CN102429901 B CN 102429901B
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- indole
- carbinol
- dim
- methyl hydride
- renal fibrosis
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- VFTRKSBEFQDZKX-UHFFFAOYSA-N 3,3'-diindolylmethane Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4NC=3)=CNC2=C1 VFTRKSBEFQDZKX-UHFFFAOYSA-N 0.000 title abstract description 8
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
The invention provides new application of indole-3-carbinol, diindolylmethane and derivatives thereof in preparation of medicaments for preventing and treating renal fibrosis. The indole-3-carbinol (I3C), diindolylmethane (DIM) and derivatives thereof can be used for preventing and treating the renal fibrosis by inhibiting the activation of renal fibroblasts. The DIM, the I3C and the derivatives thereof can effectively reduce the pathogenetic symptoms of a renal fibrosis animal model, and can become candidate medicament molecules for preventing and treating the renal fibrosis. Meanwhile, the small molecular medicaments are easily obtained, have low price and stable properties, are convenient to preserve and transport, and have broad application prospects.
Description
Technical field
The invention belongs to the biological medicine technology field, be specifically related to the application in the medicine of preparation control renal fibrosis of Indole-3-carbinol, di-indole methyl hydride and derivant thereof.
Background technology
Renal fibrosis is that renal fibrosis is a kind of pathophysiological change, be the function of kidney by health to damage, then to damaging, until the progressive process of afunction.Kidney is owing to being subject to wound, infection, inflammation, blood circulatory disorder, and the multiple paathogenic factor such as immunoreation stimulates, and its intrinsic cell is impaired, develop into the later stage a large amount of collagen depositions of appearance and gather, cause excess of the kidney matter to harden gradually, form cicatrix, until kidney completely loses organ function.The process of the interior intrinsic cell fibrosis of kidney, sclerosis is the process of renal fibrosis namely.Renal fibrosis is take the abnormal deposition of extracellular matrix (ECM) as feature.It is fibroblastic overactivity that the basic pathology of renal fibrosis is learned reason, is suppressed to fibrocellular overactivity, can effectively suppress the development of renal fibrosis.
3,3'-Diindolylmethane (DIM) and precursor molecule Indole-3-carbinol (I3C) thereof are to be found in the cloud tongue to belong to, and the micromolecular compound of clear and definite physiologically active is arranged in one in Cruciferae class plant.The applicant finds in early-stage Study, and DIM can produce the expression of initiatively removing the gene of free radical in a large number by inducing cell, improves the ability that cell antioxidation and free radical resisting injure.Free radical is a key factor that promotes fibroblast activation great expression fibrosis material in the renal fibrosis process, therefore, DIM can pass through the fibroblastic activation degree of this substrate inhibition, slow down and suppress generation and the development of renal fibrosis, can develop as a class specific medicament of control renal fibrosis.
Summary of the invention
The object of the present invention is to provide a kind of disease symptom that can effectively suppress the renal fibrosis animal model, the molecule drug candidate that can be used as treatment constitutional renal fibrosis is the application in the medicine of preparation control renal fibrosis of Indole-3-carbinol, di-indole methyl hydride and derivant thereof.
Indole-3-carbinol and the application of derivant in preparation control renal fibrosis medicine thereof with structure formula I of the present invention, in the structure formula I, R1, R2, R4, R5, R6, R7 respectively do for oneself H or halogenic substituent or nitro or C1-C10 alkyl or C1-C10 alkoxyl.
（Ⅰ）
Preferably, in described structure formula I, as R1, R2, R4, R5, R6, when R7 is hydrogen, the compound shown in this structural formula is Indole-3-carbinol;
When R5 is halogenic substituent or nitro or C1-C10 alkyl or C1-C10 alkoxyl, R1, R2, R4, R6, R7 are hydrogen, at this moment, the compound shown in this structure formula I comprises: 5-chloro-Indole-3-carbinol, 5-bromo-Indole-3-carbinol, 5-fluoro-Indole-3-carbinol; 5-nitro-Indole-3-carbinol; 5-methyl-Indole-3-carbinol, 5-ethyl-Indole-3-carbinol, 5-propyl group-Indole-3-carbinol, 5-butyl-Indole-3-carbinol, 5-amyl group-Indole-3-carbinol, 5-methoxyl group-Indole-3-carbinol, 5-ethyoxyl-Indole-3-carbinol, 5-propoxyl group-Indole-3-carbinol, 5-butoxy-Indole-3-carbinol, 5-amoxy-Indole-3-carbinol etc.;
When R1 is C1-C10 alkyl or C1-C10 alkoxyl, R2, R4, R5, R6, R7 are hydrogen, at this moment, the compound shown in this structure formula I comprises: N-methyl-Indole-3-carbinol, N-ethyl-Indole-3-carbinol, N-propyl group-Indole-3-carbinol, N-butyl-Indole-3-carbinol, N-amyl group-Indole-3-carbinol, N-methoxyl group-Indole-3-carbinol, N-ethyoxyl-Indole-3-carbinol, N-propoxyl group-Indole-3-carbinol, N-butoxy-Indole-3-carbinol, N-amoxy-Indole-3-carbinol etc.;
When R2 is C1-C10 alkyl or C1-C10 alkoxyl, R1, R4, R5, R6, R7 are hydrogen, at this moment, the compound shown in this structure formula I comprises: 2-methyl-Indole-3-carbinol, 2-ethyl-Indole-3-carbinol, 2-propyl group-Indole-3-carbinol, 2-butyl-Indole-3-carbinol, 2-amyl group-Indole-3-carbinol, 2-methoxyl group-Indole-3-carbinol, 2-ethyoxyl-Indole-3-carbinol, 2-propoxyl group-Indole-3-carbinol, 2-butoxy-Indole-3-carbinol, 2-amoxy-Indole-3-carbinol etc.;
Di-indole methyl hydride and the application of derivant in preparation control renal fibrosis medicine thereof with structure formula II of the present invention,
（Ⅱ）
Wherein, respectively do for oneself hydrogen or halogen substituent group or nitro or C1-C10 alkyl or C1-C10 alkoxyl of R1, R2, R4, R5, R6, R7, R1 ', R2 ', R4 ', R5 ', R6 ', R7 '.
Preferably, in described structure formula II, as R1, R2, R4, R5, R6, R7, R1 ', R2 ', R4 ', R5 ', R6 ', when R7 ' is hydrogen, the compound shown in this moment this structural formula is di-indole methyl hydride;
When R5 and R5 ' are halogenic substituent or nitro or C1-C10 alkyl or C1-C10 alkoxyl simultaneously, R1, R2, R4, R6, R7, R1 ', R2 ', R4 ', R6 ', R7 ' are hydrogen, at this moment, shown in the structure formula II, compound comprises: 5,5 '-two chloro-di-indole methyl hydrides, 5,5 '-two bromo-di-indole methyl hydrides or 5,5 '-two fluoro-di-indole methyl hydrides; 5,5 '-dinitro-di-indole methyl hydride; 5,5 '-dimethyl-di-indole methyl hydride, 5,5 '-diethyl-di-indole methyl hydride, 5,5 '-dipropyl-di-indole methyl hydride, 5,5 '-dibutyl-di-indole methyl hydride, 5,5 '-diamyl-di-indole methyl hydride, 5,5 '-dimethoxy-di-indole methyl hydride, 5,5 '-diethoxy-di-indole methyl hydride, 5,5 '-dipropoxy-di-indole methyl hydride, 5,5 '-dibutoxy-di-indole methyl hydride or 5,5 '-two amoxys-di-indole methyl hydride etc.
When R1 and R1 ' are C1-C10 alkyl or C1-C10 alkoxyl simultaneously, R2, R4, R5, R6, R7, R2 ', R4 ', R5 ', R6 ', R7 ' are hydrogen, at this moment, shown in the structure formula II, compound comprises: N, N '-dimethyl-di-indole methyl hydride, N, N '-diethyl-di-indole methyl hydride, N, N '-dipropyl-di-indole methyl hydride, N, N '-dibutyl-di-indole methyl hydride, N, N '-diamyl-di-indole methyl hydride.N, N '-dimethoxy-di-indole methyl hydride, N, N '-diethoxy-di-indole methyl hydride, N, N '-dipropoxy-di-indole methyl hydride, N, N '-dibutoxy-di-indole methyl hydride or N, N '-two amoxys-di-indole methyl hydride etc.
when R2 and R2 ' are C1-C10 alkyl or C1-C10 alkoxyl simultaneously, R1, R4, R5, R6, R7, R1 ', R4 ', R5 ', R6 ', R7 ' is hydrogen, at this moment, shown in the structure formula II, compound comprises: 2, 2 '-dimethyl-di-indole methyl hydride, 2, 2 '-diethyl-di-indole methyl hydride, 2, 2 '-dipropyl-di-indole methyl hydride, 2, 2 '-dibutyl-di-indole methyl hydride, 2, 2 '-diamyl-di-indole methyl hydride, 2, 2 '-dimethoxy-di-indole methyl hydride, 2, 2 '-diethoxy-di-indole methyl hydride, 2, 2 '-dipropoxy-di-indole methyl hydride, 2, 2 '-dibutoxy-di-indole methyl hydride or 2, 2 '-two amoxys-di-indole methyl hydride etc.
The application in preparation control renal fibrosis medicine of Indole-3-carbinol of the present invention, di-indole methyl hydride and derivant thereof, single compound Indole-3-carbinol or a kind of use of di-indole methyl hydride or derivatives thereof can prevent and treat renal fibrosis, so obvious, various forms of being mixed of above-claimed cpd also can reach certain therapeutic effect.
The substitutive derivative that synthesizes I3C with commercial available indole substituent may be to obtain these compounds method the most easily.The derivant of DIM equally can be by the method preparation of formaldehyde condensation indole substituent.Yet the latter's inferior position is that the formation of by-product makes the needed DIM derivant of separation and purification more complicated.
Compound provided by the present invention is by the indole that synthesizes the preparation replacement with dimethyl formamide condensation indole substituent-3-acetaldehyde, thereby substituted indole-3-acetaldehyde product is by using methanol and sodium borohydride to process the substitutive derivative that its aldehyde radical of reduction obtains I3C.Indole-3-carbinol (I3C) is very unstable in gastric acid environment in vivo, condensation reaction can occur form the oligomer 3,3'-Diindolylmethane.The substitutive derivative of di-indole methyl hydride of the present invention (DIM) is that the substitution product by condensation Indole-3-carbinol (I3C) is synthesized, and this can be by taking to realize (the derivant preparation of I3C and DIM is with reference to US Patent No. 5948808) such as the methods such as phosphate buffer processing of pH value 5.5 left and right.
Adopt Indole-3-carbinol of the present invention (I3C), di-indole methyl hydride (DIM) and derivant thereof, combine with multiple pharmaceutically acceptable carrier, by as oral cavity, vein, nasal cavity, rectum or other any administering modes that can carry the active substance of effective dose, can be prepared into various liquid preparations such as injection, oral liquid formulations etc., also can be prepared into various effectively and be easy to solid preparation such as capsule, the suppository etc. of administration.Wherein, be used for injection or liquid preparation for oral use, its required carrier can be the medically acceptable carriers such as sterilized water, Sterile Saline or water solublity organic carrier such as cyclodextrin, Semen Maydis oil, olive oil, ethyl oleate, glycols; The solid drug-delivery preparation can add solid preparation adjuvant commonly used such as excipient glucose, lactose, cellulose etc. in preparation, also can add lubricant Polyethylene Glycol, magnesium stearate etc., and the required adjunct ingredients of solid preparation such as binding agents, correctives, then by operation molding such as mixing, granulations.The effective dose of the active substance in above-mentioned these preparations is the amount that the renal fibrosis symptom is obviously reduced, research worker with routine techniques can be determined the most effective dosage and the time consideration administering mode of the reagent that this invention provides, drug metabolism, and some other pharmacokinetic parameter drug distribution for example, clearance rate etc.
The present invention carries out illustration by the renal fibrosis model.Animal herein includes, but are not limited to: mice, rat, performing animal includes, but are not limited to cat, Canis familiaris L., and some other animal for example but be not limited to cattle, sheep, pig, horse, primate for example but be not limited to monkey and people.
The present invention proposes the new application in Indole-3-carbinol, di-indole methyl hydride and derivative compound preparation control renal fibrosis medicine thereof.
Find in animal experiment, DIM and I3C and derivative compound thereof can effectively reduce the disease symptom of renal fibrosis animal model, can become the molecule drug candidate of control renal fibrosis.Simultaneously, small-molecule drug used in the present invention is easy to obtain, and is cheap, and stable in properties is convenient to storage and transport, has broad application prospects.
The specific embodiment
Following experimental example in order to explain the present invention, is not still the restriction to flesh and blood of the present invention.
[compound preparation]
Embodiment 1
(5-chloro-indole-3-methanol and 5, the preparation of 5 '-dichloro di-indole methyl hydride)
The 0.86ml phosphoryl chloride phosphorus oxychloride is slowly joined in the dimethyl formamide that 2.9ml is cooled to 0 ℃ in advance.8.6mmol 5-chloro-indole (being purchased from Nanjing sharp horse Fine Chemical Co., Ltd) is dissolved in the dimethyl formamide of 1.0ml, then slowly add in the phosphoryl chloride phosphorus oxychloride solution of aforementioned pre-cooling, formed suspension was 37 ℃ of heating 60 minutes, until the yellow solution of clarification becomes flaxen pasty mass.Then add the frozen water of 1ml in this pasty mass, more slowly add 10ml to contain the aqueous solution of 3.75 gram KOH.This mixture heated is rear cooling to boiling, filter, washing, air drying can obtain 5-chloro-indole-3-acetaldehyde.
1.0 gram 5-chloro-indole-3-acetaldehyde are dissolved in 5.0ml methanol, continue to add solid sodium borohydride, until excessive.Then add 50ml water in reactant, be cooled to 0 ℃, filter, the lucifuge vacuum drying obtains 5-chloro-indole-3-methanol, yield approximately 90%.
It is in 5.5 phosphate buffer that 1.0 gram 5-chloro-indole-3-methanol are joined pH, stirring at room 6 hours, and course of reaction is monitored by thin layer chromatography (TLC).Product is filtered, and the lucifuge vacuum drying namely obtains 5,5 '-dichloro di-indole methyl hydride, yield approximately 85%.
Embodiment 2
(5-nitroindoline-3-methanol and 5, the preparation of 5 '-dinitro di-indole methyl hydride)
The 5-nitroindoline can be bought acquisition (Nanjing sharp horse Fine Chemical Co., Ltd) by business.The 0.92ml phosphoryl chloride phosphorus oxychloride is slowly joined in the dimethyl formamide that 2.9ml is cooled to 0 ℃ in advance.8.2mmol 5-nitroindoline is dissolved in the dimethyl formamide of 1.0ml, then slowly adds in the phosphoryl chloride phosphorus oxychloride solution of aforementioned pre-cooling, formed suspension was 42 ℃ of heating 90 minutes, until the yellow solution of clarification becomes flaxen pasty mass.Then add the frozen water of 1ml in this pasty mass, more slowly add 10ml to contain the aqueous solution of 3.75 gram KOH.This mixture heated is rear cooling to boiling, filter, washing, air drying can obtain 5-nitroindoline-3-acetaldehyde.
1.0 gram 5-nitroindoline-3-acetaldehyde are dissolved in 5.0ml methanol, continue to add solid sodium borohydride, until excessive.Then add 50ml water in reactant, be cooled to 0 ℃, filter, the lucifuge vacuum drying obtains 5-nitroindoline-3-methanol, yield approximately 87%.
It is in 5.5 phosphate buffer that 1.0 gram 5-nitroindoline-3-methanol are joined pH, stirring at room 6 hours, and course of reaction is monitored by thin layer chromatography (TLC).Product is filtered, and the lucifuge vacuum drying namely obtains 5,5 '-dinitro bis (indolyl) methane, yield approximately 80%.
Embodiment 3
(5-amyl group Indole-3-carbinol and 5, the preparation of 5 '-diamyl-di-indole methyl hydride)
5-amyl group indole can be bought acquisition (Nanjing sharp horse Fine Chemical Co., Ltd) by business.The 0.82ml phosphoryl chloride phosphorus oxychloride is slowly joined in the dimethyl formamide that 2.9ml is cooled to 0 ℃ in advance.9.2mmol 5-amyl group indole is dissolved in the dimethyl formamide of 1.0ml, then slowly adds in the phosphoryl chloride phosphorus oxychloride solution of aforementioned pre-cooling, formed suspension was 37 ℃ of heating 40-60 minute, until the yellow solution of clarification becomes flaxen pasty mass.Then add the frozen water of 1ml in this pasty mass, more slowly add 10ml to contain the aqueous solution of 3.75 gram KOH.This mixture heated is rear cooling to boiling, filter, washing, air drying can obtain 5-amyl group indole-3-acetaldehyde.
1.0 gram 5-amyl group indole-3-acetaldehyde are dissolved in 5.0ml methanol, continue to add solid sodium borohydride, until excessive.Then add 50ml water in reactant, be cooled to 0 ℃, filter, the lucifuge vacuum drying obtains 5-amyl group Indole-3-carbinol, yield approximately 85%.
It is in 5.5 phosphate buffer that 1.0 gram 5-amyl group Indole-3-carbinols are joined pH, stirring at room 10 hours, and course of reaction is monitored by thin layer chromatography (TLC).Product is filtered, and the lucifuge vacuum drying namely obtains 5,5 '-diamyl bis (indolyl) methane, yield approximately 70%.
Embodiment 4
(N-methoxy-Indole-3-methanol and N, the preparation of N '-dimethoxy-di-indole methyl hydride)
The N-methoxy-Indole can be bought acquisition (Nanjing sharp horse Fine Chemical Co., Ltd) by business.The 0.86ml phosphoryl chloride phosphorus oxychloride is slowly joined in the dimethyl formamide that 2.9ml is cooled to 0 ℃ in advance.8.9mmol N-methoxy-Indole is dissolved in the dimethyl formamide of 1.0ml, then slowly adds in the phosphoryl chloride phosphorus oxychloride solution of aforementioned pre-cooling, formed suspension was 40 ℃ of heating 60-90 minute, until the yellow solution of clarification becomes flaxen pasty mass.Then add the frozen water of 1ml in this pasty mass, more slowly add 10ml to contain the aqueous solution of 3.75 gram KOH.This mixture heated is rear cooling to boiling, filter, washing, air drying can obtain N-methoxy-Indole-3-acetaldehyde.
1.0 gram N-methoxy-Indole-3-acetaldehyde are dissolved in 5.0ml methanol, continue to add solid sodium borohydride, until excessive.Then add 50ml water in reactant, be cooled to 0 ℃, filter, the lucifuge vacuum drying obtains N-methoxy-Indole-3-methanol, yield approximately 80%.
It is in 5.5 phosphate buffer that 1.0 gram N-methoxy-Indole-3-methanol are joined pH, stirring at room 12 hours, and course of reaction is monitored by thin layer chromatography (TLC).Product is filtered, and the lucifuge vacuum drying namely obtains N, N '-dimethoxy bis (indolyl) methane, yield approximately 70%.
Embodiment 5
(1-butyl-2 methyl indole-3-methanol and 1,1 '-dibutyl-2, the preparation of 2 '-dimethyl di-indole methyl hydride)
1-butyl-2 methyl indole can be bought acquisition (Nanjing sharp horse Fine Chemical Co., Ltd) by business.The 0.82ml phosphoryl chloride phosphorus oxychloride is slowly joined in the dimethyl formamide that 2.9ml is cooled to 0 ℃ in advance.8.2mmol 1-butyl-2 methyl indole is dissolved in the dimethyl formamide of 1.0ml, then slowly add in the phosphoryl chloride phosphorus oxychloride solution of aforementioned pre-cooling, formed suspension was 42 ℃ of heating 90 minutes, until the yellow solution of clarification becomes flaxen pasty mass.Then add the frozen water of 1ml in this pasty mass, more slowly add 10ml to contain the aqueous solution of 3.8 gram KOH.This mixture heated is rear cooling to boiling, filter, washing, air drying can obtain 1-butyl-2 methyl indole-3-acetaldehyde.
1.0 gram 1-butyl-2 methyl indole-3-acetaldehyde are dissolved in 5.0ml methanol, continue to add solid sodium borohydride, until excessive.Then add 50ml water in reactant, be cooled to 0 ℃, filter, the lucifuge vacuum drying obtains 1-butyl-2 methyl indole-3-methanol, yield approximately 85%.
It is in 5.5 phosphate buffer that 1.0 gram 1-butyl-2 methyl indole-3-methanol are joined pH, stirring at room 6 hours, and course of reaction is monitored by thin layer chromatography (TLC).Product is filtered, and the lucifuge vacuum drying namely obtains 1,1 '-dibutyl-2,2 '-dimethyl bis (indolyl) methane, yield approximately 80%.
Embodiment 6
(4-bromo indole-3-methanol and 4, the preparation of 4 '-dibromo di-indole methyl hydride)
The 0.86ml phosphoryl chloride phosphorus oxychloride is slowly joined in the dimethyl formamide that 2.9ml is cooled to 0 ℃ in advance.8.6mmol 4-bromo indole (being purchased from Nanjing sharp horse Fine Chemical Co., Ltd) is dissolved in the dimethyl formamide of 1.0ml, then slowly add in the phosphoryl chloride phosphorus oxychloride solution of aforementioned pre-cooling, formed suspension was 37 ℃ of heating 60 minutes, until the yellow solution of clarification becomes flaxen pasty mass.Then add the frozen water of 1ml in this pasty mass, more slowly add 10ml to contain the aqueous solution of 3.75 gram KOH.This mixture heated is rear cooling to boiling, filter, washing, air drying can obtain 4-bromo indole-3-acetaldehyde.
1.0 gram 4-bromo indole-3-acetaldehyde are dissolved in 5.0ml methanol, continue to add solid sodium borohydride, until excessive.Then add 50ml water in reactant, be cooled to 0 ℃, filter, the lucifuge vacuum drying obtains 4-bromo indole-3-methanol, yield approximately 90%.
It is in 5.5 phosphate buffer that 1.0 gram 4-bromo indole-3-methanol are joined pH, stirring at room 6 hours, and course of reaction is monitored by thin layer chromatography (TLC).Product is filtered, and the lucifuge vacuum drying namely obtains 4,4 '-dibromo di-indole methyl hydride, yield approximately 85%.
[zoopery example]
1, Indole-3-carbinol, di-indole methyl hydride and derivant thereof the impact on the Rats Undergoing Unilateral Urethral Ligation kidney region fibrosis
1.1 material
respectively with I3C, DIM, 5-chloro-Indole-3-carbinol (5-Cl-I3C), 5,5 '-two chloro-di-indole methyl hydrides (5,5 '-Cl-DIM), 5-amyl group-Indole-3-carbinol (5-C5-I3C), 5,5 '-diamyl-di-indole methyl hydride (5,5 '-C5-DIM), 5-methoxyl group-Indole-3-carbinol (5-MOE-I3C), 5,5 '-dimethoxy-di-indole methyl hydride (5,5 '-MOE-DIM), 5-nitro-Indole-3-carbinol (5-NO-I3C), 5,5 '-dinitro-di-indole methyl hydride (5,5 '-NO-DIM), N-methyl-Indole-3-carbinol (N-Me-I3C), N, and N '-dimethyl-di-indole methyl hydride (N, N '-Me-DIM), N-methoxyl group-Indole-3-carbinol (N-MOE-I3C), N, and N '-dimethoxy-di-indole methyl hydride (N, N '-MOE-DIM), 2-amyl group-Indole-3-carbinol (2-C5-I3C), 2,2 '-diamyl-di-indole methyl hydride (2,2 '-C5-DIM), 2-methoxyl group-Indole-3-carbinol (2-MOE-I3C), 2,2 '-dimethoxy-di-indole methyl hydride (2,2 '-MOE-DIM), 1-butyl-2-methyl-Indole-3-carbinol (1Bu-2Me-I3C), 1,1 '-dibutyl-2,2 '-dimethyl-di-indole methyl hydride (1,1 ' Bu-2,2 ' Me-DIM), (4,4 '-Br-DIM) to be made into the oral liquid storage of 2.0mg/ml with Semen Maydis oil dissolving standby for 4-bromo-Indole-3-carbinol (4-Br-I3C) and 4,4 '-two bromo-di-indole methyl hydrides.
Hydroxyproline (HYP) test kit; Fibronectin (FN) test kit.
Laboratory animal regular grade Wistar rat, male, body weight 150-200g, SD rat.
1.2 test method and result
with rat, be divided at random the sham operated rats group, model control group and use respectively I3C, DIM, 5-chloro-Indole-3-carbinol (5-Cl-I3C), 5,5 '-two chloro-di-indole methyl hydrides (5,5 '-Cl-DIM), 5-amyl group-Indole-3-carbinol (5-C5-I3C), 5,5 '-diamyl-di-indole methyl hydride (5,5 '-C5-DIM), 5-methoxyl group-Indole-3-carbinol (5-MOE-I3C), 5,5 '-dimethoxy-di-indole methyl hydride (5,5 '-MOE-DIM), 5-nitro-Indole-3-carbinol (5-NO-I3C), 5,5 '-dinitro-di-indole methyl hydride (5,5 '-NO-DIM), N-methyl-Indole-3-carbinol (N-Me-I3C), N, and N '-dimethyl-di-indole methyl hydride (N, N '-Me-DIM), N-methoxyl group-Indole-3-carbinol (N-MOE-I3C), N, and N '-dimethoxy-di-indole methyl hydride (N, N '-MOE-DIM), 2-amyl group-Indole-3-carbinol (2-C5-I3C), 2,2 '-diamyl-di-indole methyl hydride (2,2 '-C5-DIM), 2-methoxyl group-Indole-3-carbinol (2-MOE-I3C), 2,2 '-dimethoxy-di-indole methyl hydride (2,2 '-MOE-DIM), 1-butyl-2-methyl-Indole-3-carbinol (1Bu-2Me-I3C), 1,1 '-dibutyl-2,2 '-dimethyl-di-indole methyl hydride (1,1 ' Bu-2,2 ' Me-DIM), 4-bromo-Indole-3-carbinol (4-Br-I3C) and 4,4 '-two bromo-di-indole methyl hydrides (treatment group of 4,4 '-Br-DIM) treatment, 10 every group.1 week of animal feeding, each rat with 10% chloral hydrate 3.0ml/kg intraperitoneal injection of anesthesia after, the Rat Right lateral position is fixed on operating-table, use iodine tincture after cropping, 75% alcohol disinfecting field of operation, row left side abdomen otch, successively cut skin, muscle and each layer of stomach wall, expose and separate the left side ureter, sham operated rats is only cut abdominal cavity and free left side ureter, but not ligation and cutting off, other respectively organize rat 4-0 silk thread ligation twice, upper one ligation point is positioned at right inferior pole of kidney level, then cut off ureter between twice ligation point, layer-by-layer suture, postoperative was put to death each treated animal after 10% chloral hydrate anesthesia in 10 days, get blood, press Fibronectin and measure explanation mensuration Fibronectin.Normal saline is retained left kidney after lavation repeatedly, and nephridial tissue is fixed through 4% paraformaldehyde buffer.Cut appropriate nephridial tissue, press the explanation of hydroxyproline kit measurement and measure hydroxyproline.
Routine pathology is learned and is checked:
FN, HYP carry out the T check to each group.The results are shown in Table 1.Medication therapy groups obviously reduces FN, HYP level (comparing P＜0.01 with model control group).
Table 1: Indole-3-carbinol, di-indole methyl hydride and derivant thereof the impact on the Rats Undergoing Unilateral Urethral Ligation kidney region fibrosis
| Group | Number of cases (only) | Hydroxyproline (μ g/g) | Fibronectin (mg/L) |
| Sham operated rats | 10 | 320±55 | 5.3±1.4 |
| Model control group | 10 | 748±152 | 25.4±5.3 |
| I3C | 10 | 544±94 | 16.2±4.8 |
| DIM | 10 | 562±89 | 14.8±5.4 |
| 5-Cl-I3C | 10 | 550±91 | 14.9±5.2 |
| 5,5’-Cl-DIM | 10 | 501±98 | 14.1±4.8 |
| 5-C5-I3C | 10 | 547±116 | 16.1±4.8 |
| 5,5’-C5-DIM | 10 | 560±85 | 14.4±5.7 |
| 5-MOE-I3C | 10 | 508±102 | 15.5±5.4 |
| 5,5’-MOE-DIM | 10 | 503±85 | 14.6±5.7 |
| 5-NO-I3C | 10 | 543±104 | 15.6±4.3 |
| 5,5’-NO-DIM | 10 | 525±81 | 15.7±5.1 |
| N-Me-I3C | 10 | 549±77 | 16.3±5.2 |
| N,N’-Me-DIM | 10 | 537±96 | 15.1±3.5 |
| N-MOE-I3C | 10 | 524±91 | 16.3±4.5 |
| N,N’-MOE-DIM | 10 | 551±74 | 14.4±4.1 |
| 2-C5-I3C | 10 | 565±105 | 15.9±4.7 |
| 2,2’-C5-DIM | 10 | 530±98 | 15.1±3.9 |
| 2-MOE-I3C | 10 | 525±84 | 15.8±3.6 |
| 2,2’-MOE-DIM | 10 | 561±99 | 14.3±5.5 |
| 1Bu-2Me-I3C | 10 | 540±87 | 16.2±5.9 |
| 1,1’Bu-2,2’Me-DIM | 10 | 514±78 | 14.2±4.1 |
| 4-Br-I3C | 10 | 542±72 | 16.4±4.9 |
| 4,4’-Br-DIM | 10 | 544±94 | 16.2±4.8 |
Claims (8)
1. the Indole-3-carbinol and the application of derivant in preparation control renal fibrosis medicine thereof that have following structural formula (I),
Wherein, R1 is hydrogen or C1-C10 alkyl or C1-C10 alkoxyl; R2 is hydrogen or C1-C10 alkyl or C1-C10 alkoxyl; R5 is hydrogen or halogen substituent group or nitro; R4, R6, R7 are hydrogen.
2. application according to claim 1 is characterized in that: in described structure formula I, R5 is halogenic substituent or nitro, and R1, R2, R4, R6, R7 are hydrogen.
3. application according to claim 1 is characterized in that: in described structure formula I, R1 is C1-C10 alkyl or C1-C10 alkoxyl, and R2, R4, R5, R6, R7 are hydrogen.
4. application according to claim 1 is characterized in that: in described structure formula I, R2 is C1-C10 alkyl or C1-C10 alkoxyl, and R1, R4, R5, R6, R7 are hydrogen.
5. the di-indole methyl hydride and the application of derivant in preparation control renal fibrosis medicine thereof that have following structural formula (II),
Wherein, R1 and R1 ' are hydrogen or C1-C10 alkyl or C1-C10 alkoxyl; R2 and R2 ' are hydrogen or C1-C10 alkyl or C1-C10 alkoxyl; R5 and R5 ' are hydrogen or halogen substituent group or nitro; R4, R6, R7, R4 ', R6 ', R7 ' are hydrogen.
6. application according to claim 5 is characterized in that: in described structure formula II, R5 and R5 ' are halogenic substituent or nitro simultaneously, and R1, R2, R4, R6, R7, R1 ', R2 ', R4 ', R6 ', R7 ' are hydrogen.
7. application according to claim 5 is characterized in that: in described structure formula II, R1 and R1 ' are C1-C10 alkyl or C1-C10 alkoxyl simultaneously, and R2, R4, R5, R6, R7, R2 ', R4 ', R5 ', R6 ', R7 ' are hydrogen.
8. application according to claim 5 is characterized in that: in described structure formula II, R2 and R2 ' are C1-C10 alkyl or C1-C10 alkoxyl simultaneously, and R1, R4, R5, R6, R7, R1 ', R4 ', R5 ', R6 ', R7 ' are hydrogen.
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| CN103463005B (en) * | 2013-10-11 | 2015-06-17 | 嵊州市诺米克进出口有限公司 | Application of racemosins A in preparation of medicine treating or preventing renal fibrosis |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004052854A2 (en) * | 2002-12-10 | 2004-06-24 | Wyeth | Aryl, aryloxy, and alkyloxy substituted 1h-indol-3-yl glyoxylic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1) |
| WO2007022321A2 (en) * | 2005-08-17 | 2007-02-22 | Wyeth | Substituted indoles and use thereof |
| WO2007053452A1 (en) * | 2005-11-01 | 2007-05-10 | Targegen, Inc. | Bi-aryl meta-pyrimidine inhibitors of kinases |
| WO2008138232A1 (en) * | 2007-05-14 | 2008-11-20 | Shanghai Hengrui Pharmaceutical Co., Ltd. | Pyrrolo-nitrogenous heterocyclic derivatives, the preparation and the pharmaceutical use thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004052854A2 (en) * | 2002-12-10 | 2004-06-24 | Wyeth | Aryl, aryloxy, and alkyloxy substituted 1h-indol-3-yl glyoxylic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1) |
| WO2007022321A2 (en) * | 2005-08-17 | 2007-02-22 | Wyeth | Substituted indoles and use thereof |
| WO2007053452A1 (en) * | 2005-11-01 | 2007-05-10 | Targegen, Inc. | Bi-aryl meta-pyrimidine inhibitors of kinases |
| WO2008138232A1 (en) * | 2007-05-14 | 2008-11-20 | Shanghai Hengrui Pharmaceutical Co., Ltd. | Pyrrolo-nitrogenous heterocyclic derivatives, the preparation and the pharmaceutical use thereof |
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Effective date of registration: 20170522 Address after: 230088, Hefei province high tech Zone Innovation Avenue 2800, innovation industry park two, E District 1, B, building 2, Anhui Patentee after: Hefei Jian Jian Pharmaceutical Technology Co., Ltd. Address before: 230088 No. 26, phreatic East Road, hi tech Zone, Anhui, Hefei Patentee before: Hefei Botai Pharmaceutical Biotechnology Development Co., Ltd. |