CN102727477A - Application of retinoic acid and its derivatives in preparation of drugs preventing and treating diabetes - Google Patents
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Abstract
The invention discloses application of a retinoic acid and its derivatives in preparation of drugs preventing and treating diabetes. The retinoic acid and its derivatives can inhibit the occurrence of inflammation induced insulin resistance by inhibiting AP-1 activity, thus further delaying and relieving the occurrence and symptoms of type II diabetes. Therefore, retinoic acid and its derivatives are a drug candidate molecule that boasts great development prospects and is used for prevention and treatment of type II diabetes. By giving the retinoic acid and its derivative compounds as well as preparations, diabetes attacks can be inhibited and blocked. At the same time, the small molecular drugs adopted in the invention are characterized by easy acquisition, low price, stable property, as well as convenient storage and transport.
Description
Technical field
The invention belongs to the biological medicine technology field, be specifically related to tretinoin and derivative compound thereof and prevent and treat the application in the disease medicament that diabetes are main pathological characters in preparation.
Background technology
Diabetes are to have a strong impact on the healthy disease of people's life.Along with people's life style in recent years, the variation of dietary habit, the onset diabetes rate has continuous rising, and age of onset has the trend of continuous rejuvenation.Diabetes are divided into insulin-dependent (I type) and non-insulin-depending type (II type) two big classes generally, in the diabetics, are the type ii diabetes patient more than 90%.Nearest basic research proves; Follow the lipid peroxidation of physiologic factor generations such as obesity can cause for a long time, low-level chronic inflammatory disease, some inflammatory factor of long-term accumulative total can cause significant insulin resistant; Make body to insulin insensitivity, cause diabetic symptom then.Therefore to this pathogenesis, can develop treatment means and medicine targetedly.Discovering that through the inventor in the process of insulin resistance that factors such as obesity cause, AP-1 is the mediation factor of a key, is the key signal molecule that chronic inflammatory reaction is induced insulin resistant.Retionic acid and derivant thereof can be through suppressing the activity of AP-1, the generation of the inductive insulin resistant of inflammation-inhibiting, and then delay and alleviate the generation and the symptom of type ii diabetes.Therefore retionic acid and derivant thereof are a kind of molecule drug candidates that is used to prevent and treat type ii diabetes with very big development prospect.
Summary of the invention
The object of the present invention is to provide a kind of activity that can pass through to suppress transcription factor AP-1; Effectively suppress to reduce inflammation inductive insulin resistant effect, prevent and treat the application in the medicine of diabetes in preparation thereby the chemical compound of symptom that can diabetes-alleviating is tretinoin and derivant thereof.
Tretinoin and the application of derivant in preparation control diabetes medicament thereof with following structural formula (I) of the present invention,
Wherein, R1 is COOH or COH or CH2OH; R2, R4, R5, R6, R8, R9 respectively do for oneself H or C1-C6 alkyl; R3, R7 respectively do for oneself H or C1-C6 alkyl or aromatic radical or halogen or nitro or alkoxyl.Structure includes but not limited to following chemical compound shown in the structure formula I at this moment:
chemical compound 9:2-methyl-5-ethyl-9-(2; 6, the 6-trimethyl cyclohexene) nona tetraenoic acid
chemical compound 21:3-propyl group-9-(2; 6, the 6-trimethyl cyclohexene) nona tetraenoic acid
Said R1 is preferably COOH; Said aromatic radical is preferably and does not replace or the substituted phenyl of alkyl.
Said alkyl-substituted phenyl is preferably single or polysubstituted aminomethyl phenyl and comprises p-methylphenyl or 2-aminomethyl phenyl or 2,4-3,5-dimethylphenyl or 2,6-3,5-dimethylphenyl or 2,4,6-trimethylphenyl etc.
In the structure formula I, can preferably work as R1 is COOH; R2, R4, R5, R6, R8, R9 is H; R3 is H or C1-C6 alkyl, and R7 is H or C1-C6 alkyl or unsubstituted phenyl or alkyl-substituted phenyl or halogen or nitro or alkoxyl.
In the structure formula I, also can preferably work as R1-COOH; R2, R4, R5, R6, R7, R8, R9 is H; R3 is unsubstituted phenyl or alkyl-substituted phenyl or halogen or nitro or alkoxyl.
In the structure formula I, also can preferably work as R1 is COOH; R2, R4, R5, R6, R8, R9 is H; R3 is unsubstituted phenyl or alkyl-substituted phenyl or halogen or nitro or alkoxyl, and R7 is not for replacing or alkyl-substituted phenyl.
Said alkyl-substituted phenyl is preferably single or polysubstituted aminomethyl phenyl and comprises p-methylphenyl or 2-aminomethyl phenyl or 2,4-3,5-dimethylphenyl or 2, and 6-3,5-dimethylphenyl or 2,4,6-trimethylphenyl etc., most preferred alkyl-substituted phenyl is a p-methylphenyl.
The application of retinoic acid derivatives in preparation control diabetes medicament with following structural formula (II) of the present invention,
Wherein, R1 ' is COOH or COH or CH2OH; R2 ', R4 ', R5 ', R6 ', R8 ', R9 ' respectively do for oneself H or C1-C6 alkyl; R3 ', R7 ' respectively do for oneself H or C1-C6 alkyl or aromatic radical or halogen or nitro or alkoxyl, structure includes but not limited to following chemical compound shown in structural formula this moment (II):
chemical compound 4: (2E, 4E, 6E, 8E)-9-(5; 5,8,8-tetramethyl-5; 6,7,8-tetralyl-2-yl)-2; 4,6,8-tetraene aldehyde C-9
chemical compound 24: (2E, 4E, 6E; 8E)-9-(2,3,3; 6,6-pentamethyl-cyclohexene-1-yl)-3-p-methylphenyl-2,4; 6,8-tetraene n-nonanoic acid
chemical compound 42: (2E, 4E, 6E, 8E)-9-(5; 5,8,8-tetramethyl-5,6; 7,8-tetralyl-2-yl)-3,7-di-p-tolyl-2; 4,6,8-tetraene n-nonanoic acid
Said R1 ' is preferably COOH; Said aromatic radical is preferably and does not replace or the substituted phenyl of alkyl;
Said alkyl-substituted phenyl is preferably single or polysubstituted aminomethyl phenyl and comprises p-methylphenyl or 2-aminomethyl phenyl or 2,4-3,5-dimethylphenyl or 2,6-3,5-dimethylphenyl or 2,4,6-trimethylphenyl etc.
In the structural formula (II), preferred, working as R1 ' is COOH; R2 ', R4 ', R5 ', R6 ', R8 ', R9 ' is H; R3 ' is H or C1-C6 alkyl, and R7 ' is H or C1-C6 alkyl or unsubstituted phenyl or alkyl-substituted phenyl or halogen or nitro or alkoxyl.
In the structural formula (II), also can preferably work as R1 ' is COOH; R2 ', R4 ', R5 ', R6 ', R7 ', R8 ', R9 ' is H; R3 ' is unsubstituted phenyl or alkyl-substituted phenyl or halogen or nitro or alkoxyl.
In the structural formula (II), also preferably R1 ' is COOH; R2 ', R4 ', R5 ', R6 ', R8 ', R9 ' is H; R3 ' is H or C1-C6 alkyl or unsubstituted phenyl or alkyl-substituted phenyl or halogen or nitro or alkoxyl, and R7 ' is not for replacing or alkyl-substituted phenyl.
Said alkyl-substituted phenyl is preferably single or polysubstituted aminomethyl phenyl and comprises p-methylphenyl or 2-aminomethyl phenyl or 2,4-3,5-dimethylphenyl or 2, and 6-3,5-dimethylphenyl or 2,4,6-trimethylphenyl etc., most preferred alkyl-substituted phenyl is a p-methylphenyl.
Tretinoin of the present invention and derivant thereof can be processed pharmaceutically acceptable various dosage form according to the method for conventional medicine preparation, adopt different administering modes according to pharmaceutical dosage form then.
Compound structure list of references of the present invention (Nature, 372:107-110,1994.) report can be become service organization to provide by the compounds of specialty, the chemical compound that the present invention uses is from Shanghai Yaoming Kangde New Medicine Development Co., Ltd.
Tretinoin of the present invention and derivative compound thereof can oral, vein, nasal cavity, rectum or other any mode administrations that can carry the active substance of effective dose.Proper dosage is those dosage that can obtain needed final quantity.Also possibly need different dosages and prevent and treat different disease.
Research worker with routine techniques can be confirmed the most effectively dosage and 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.
Active reagent can be through a pharmaceutical carrier or diluent administration.This reagent of being provided of invention can also for example chemotherapy or immune activation medicine be perhaps prevented and treated medication combined administration with other reagent.The pharmaceutical carrier that this invention is suitable for or the instance of diluent comprise any physiological buffer that is dissolved with the water solublity organic carrier, and for example cyclodextrin phosphate buffer and pH7.0's to 7.4 contains suitable other buffer of water solublity organic carrier.Suitable water solublity organic carrier includes, but are not limited to cyclodextrin, Semen Maydis oil, DMSO, capsule etc.
The present invention is through carrying out illustration to diabetes model in the body.The animal here 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.Detect in the body of rabbit diabetes model by the active model that detects of the drug disposition of extensive recognition and acceptance, also can be other biology people for example simultaneously, but being not limited only to the people provides reference.
The invention has the beneficial effects as follows provides a kind of tretinoin and derivative compound thereof to prevent and treat the application of diabetes disease in preparation, through give tretinoin and derivative compound thereof with and preparation suppress and block the outbreak of diabetes.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.
The specific embodiment
Following Example should not regarded as the restriction to connotation of the present invention in order to explain the present invention but these those skilled in the technology concerned should be appreciated that it.
[zoopery example]
The oral liquid of tretinoin and derivative compound thereof is to the treatment of the inductive diabetes model of high glucose and high fat.
1, laboratory animal: female new zealand white rabbit, body weight 1.8kg-2.0kg.
2, experiment medicine: respectively chemical compound is dissolved with Semen Maydis oil, it is subsequent use to be made into the 2.0mg/ml liquid storage.Compound number of using in the experiment and structure such as above-mentioned shown in.
3, experimental technique:
Get 288 female new zealand white rabbits, body weight 1.8kg-2.0kg is divided into 48 groups at random with animal, and 6 every group, i.e. normal control group, diabetic model group, respectively with the treatment group of chemical compound 1--chemical compound 46 treatments.The normal control group utilizes common feedstuffs (rabbit is used the standard common feedstuff, Standard Laboratory Chow for Rabbits, Shanghai Shengwang Experimental Animal Ranch (P.R.China) company) to raise.Diabetes model treated animal and each treatment experimental group are supplied with the high lipolysaccharide feedstuff that contains the sucrose of 10% Adeps Sus domestica and 37% above-mentioned rabbit in the standard test feedstuff, and oral administration of compound is treated.In experiment beginning back (0 week back), 4 week the back, 8 week the back, 12 week the back, 16 week the back, 20 week back and after 24 weeks; Make and respectively organize rabbit and go on a hunger strike a night; Take a blood sample from arteria auricularis; Use the commercially available glucose assays test kit that utilizes enzyme process (Glucose Determination Kit (Glucose oxidase-peroxidase method), Shanghai Rongsheng Biotech Inc. (P.R.China) manufactured), measure the concentration of glucose (mg/dl) in the blood plasma.
Experimental result is as shown in table 1:
Table 1: the evaluation of pesticide effectiveness of tretinoin and derivant water soluble preparation intraperitoneal administration thereof
| Group | 0 week | 4 weeks | 8 weeks | 12 weeks | 16 weeks | 20 weeks | 24 weeks |
| Model group | 53.5±6.2 | 108.6±9.3 | 115.5±9.4 | 121.5±9.5 | 126.9±8.2 | 132.9±7.6 | 132.3±8.2 |
| Normal group | 54.1±5.3 | 60.6±6.5 | 49.7±4.4 | 71.6±10.6 | 59.7±11.3 | 66.8±9.9 | 54.7±8.5 |
| Chemical compound 1 | 55.2±7.2 | 55.4±3.2 | 63.2±6.1 | 48.3±1.1 | 48.2±4.3 | 60.9±3.4 | 67.8±3.5 |
| Chemical compound 2 | 71.4±0.6 | 53.5±7.5 | 63.5±4.5 | 69.3±0.7 | 69.8±7.8 | 42.9±2.8 | 53.7±9.2 |
| Chemical compound 3 | 61.2±3.1 | 69.5±9.8 | 48.5±2.9 | 56.5±3.6 | 43.9±1.8 | 61.4±8.7 | 60.3±8.8 |
| Chemical compound 4 | 49.9±8.7 | 65.1±6.7 | 62.4±4.6 | 65.8±1.6 | 70.5±2.4 | 57.4±7.1 | 62.5±3.2 |
| Chemical compound 5 | 62.2±4.3 | 64.2±1.6 | 70.6±6.9 | 45.4±9.3 | 48.4±1.2 | 42.2±8.7 | 64.1±8.7 |
| Chemical compound 6 | 61.6±4.4 | 56.7±7.4 | 64.5±2.4 | 51.9±4.8 | 55.8±7.1 | 61.3±7.9 | 65.9±7.7 |
| Chemical compound 7 | 65.8±6.1 | 66.4±5.7 | 65.3±7.7 | 51.5±7.2 | 54.6±9.8 | 60.3±2.5 | 65.2±4.3 |
| Chemical compound 8 | 52.3±9.8 | 71.1±9.1 | 57.4±4.3 | 48.5±7.8 | 55.3±2.9 | 43.4±0.9 | 69.3±8.8 |
| Chemical compound 9 | 57.5±6.5 | 52.2±1.7 | 55.4±4.4 | 71.1±8.8 | 48.5±4.9 | 57.1±0.3 | 58.2±0.2 |
| Chemical compound 10 | 57.8±9.5 | 59.5±4.8 | 55.7±0.7 | 49.4±4.5 | 54.8±9.9 | 47.7±6.0 | 65.2±5.1 |
| Chemical compound 11 | 49.2±0.9 | 65.3±2.4 | 55.5±2.1 | 53.1±7.2 | 57.3±7.6 | 45.1±6.3 | 69.7±1.7 |
| Chemical compound 12 | 49.2±9.7 | 60.1±6.1 | 67.3±6.1 | 71.8±3.7 | 54.1±1.5 | 53.1±4.8 | 51.2±1.3 |
| Chemical compound 13 | 65.6±4.7 | 63.5±8.1 | 51.2±3.8 | 43.3±4.8 | 42.2±1.8 | 53.6±4.7 | 63.6±9.7 |
| Chemical compound 14 | 45.3±5.6 | 70.1±9.2 | 50.9±1.4 | 61.4±7.1 | 66.2±2.9 | 59.2±5.3 | 63.8±6.5 |
| Chemical compound 15 | 58.5±2.6 | 59.2±1.2 | 47.8±6.9 | 69.4±3.8 | 54.8±2.3 | 58.7±8.3 | 54.9±0.3 |
| Chemical compound 16 | 62.3±2.4 | 42.9±0.9 | 51.5±9.4 | 58.4±4.6 | 67.2±9.7 | 46.9±9.9 | 62.1±4.8 |
| Chemical compound 17 | 53.1±0.6 | 58.6±6.2 | 50.3±8.5 | 66.1±9.1 | 67.9±6.4 | 59.5±0.6 | 51.4±7.8 |
| Chemical compound 18 | 67.5±5.7 | 63.6±0.3 | 60.8±9.1 | 60.9±3.8 | 64.9±7.1 | 42.4±6.9 | 54.5±5.3 |
| Chemical compound 19 | 51.9±8.3 | 56.9±1.1 | 55.5±8.2 | 67.6±4.7 | 44.7±5.2 | 55.2±6.2 | 59.1±0.3 |
| Chemical compound 20 | 71.3±8.8 | 56.9±4.6 | 58.1±2.4 | 56.1±8.7 | 60.6±1.7 | 68.2±9.8 | 54.7±9.3 |
| Chemical compound 21 | 65.5±4.8 | 58.2±1.1 | 44.2±3.8 | 42.4±8.1 | 68.6±5.2 | 67.7±3.7 | 56.2±7.5 |
| Chemical compound 22 | 45.3±5.9 | 65.4±2.8 | 52.1±7.9 | 50.2±7.3 | 70.2±1.6 | 67.5±3.4 | 47.9±5.4 |
| Chemical compound 23 | 54.9±3.9 | 70.7±6.2 | 55.5±3.1 | 53.1±7.4 | 54.1±3.5 | 63.4±8.2 | 55.2±2.1 |
| Chemical compound 24 | 55.7±4.6 | 53.4±4.5 | 65.8±7.7 | 55.8±1.7 | 48.7±1.8 | 55.5±3.7 | 57.1±5.5 |
| Chemical compound 25 | 54.3±3.7 | 58.6±5.9 | 52.7±0.1 | 56.6±4.8 | 44.5±7.8 | 43.1±4.3 | 47.6±0.4 |
| Chemical compound 26 | 66.5±1.1 | 55.8±7.2 | 46.9±5.8 | 71.9±1.1 | 71.8±2.6 | 49.1±5.8 | 43.8±6.3 |
| Chemical compound 27 | 52.5±7.4 | 71.8±3.9 | 42.5±1.7 | 69.3±9.5 | 67.9±7.4 | 57.8±0.5 | 48.9±6.5 |
| Chemical compound 28 | 54.8±2.8 | 50.5±6.4 | 67.9±2.4 | 66.7±7.8 | 59.2±7.3 | 49.2±7.3 | 52.7±5.5 |
| Chemical compound 29 | 55.8±6.3 | 48.5±8.7 | 63.1±8.9 | 60.1±0.3 | 61.2±3.1 | 58.8±3.5 | 49.1±7.1 |
| Chemical compound 30 | 55.3±3.2 | 63.6±1.4 | 54.7±9.5 | 61.6±7.7 | 52.9±0.8 | 59.3±2.5 | 64.4±0.7 |
| Chemical compound 31 | 59.3±7.9 | 64.5±4.7 | 46.3±1.9 | 64.8±7.7 | 46.4±8.4 | 68.4±2.8 | 59.7±0.9 |
| Chemical compound 32 | 48.5±5.7 | 44.7±6.7 | 47.1±6.1 | 47.8±5.2 | 54.7±4.1 | 65.9±8.8 | 47.6±5.5 |
| Chemical compound 33 | 52.1±5.1 | 65.8±5.2 | 55.8±6.1 | 61.2±8.3 | 70.7±5.7 | 42.6±9.3 | 53.2±9.1 |
| Chemical compound 34 | 53.6±6.7 | 46.6±1.5 | 67.3±6.2 | 45.2±5.5 | 54.1±6.8 | 57.5±8.3 | 48.8±1.3 |
| Chemical compound 35 | 66.8±2.8 | 53.4±0.1 | 66.7±4.9 | 51.3±0.4 | 67.1±5.6 | 71.3±2.2 | 58.3±8.5 |
| Chemical compound 36 | 67.5±2.1 | 59.8±1.3 | 70.8±1.9 | 45.3±5.4 | 55.1±2.6 | 64.9±3.9 | 47.9±0.5 |
| Chemical compound 37 | 47.8±3.8 | 52.7±1.9 | 66.1±2.8 | 64.5±6.7 | 63.8±5.9 | 57.1±3.8 | 49.8±0.2 |
| Chemical compound 38 | 54.1±6.3 | 47.8±1.3 | 64.6±2.7 | 57.8±3.7 | 54.4±6.2 | 70.7±0.4 | 61.8±5.5 |
| Chemical compound 39 | 61.7±0.2 | 71.1±3.8 | 66.7±4.7 | 50.3±8.8 | 63.4±1.9 | 42.3±3.9 | 62.9±2.7 |
| Chemical compound 40 | 47.2±7.4 | 54.9±4.6 | 61.6±9.8 | 49.6±3.4 | 60.6±5.9 | 66.2±7.8 | 47.4±8.3 |
| Chemical compound 41 | 50.6±9.7 | 49.2±6.1 | 55.7±2.7 | 46.1±5.8 | 46.1±8.2 | 42.7±9.5 | 54.2±8.4 |
| Chemical compound 42 | 44.6±0.9 | 56.8±7.2 | 63.7±6.6 | 64.3±7.4 | 45.8±3.9 | 64.2±6.1 | 65.5±1.8 |
| Chemical compound 43 | 64.7±5.1 | 51.3±9.2 | 70.8±3.7 | 69.9±2.2 | 52.2±3.6 | 71.3±9.7 | 46.7±2.2 |
| Chemical compound 44 | 55.2±7.2 | 55.4±3.2 | 63.2±6.4 | 48.3±1.1 | 48.2±4.3 | 60.9±3.4 | 67.8±3.5 |
| Chemical compound 45 | 60.4±0.2 | 70.1±3.3 | 65.7±4.4 | 50.6±8.2 | 63.2±1.5 | 42.7±3.3 | 62.5±2.6 |
| Chemical compound 46 | 57.7±0.4 | 65.6±3.2 | 66.6±4.3 | 49.3±8.6 | 62.4±1.9 | 42.5±3.7 | 62.3±2.5 |
Data show with the form of mean+SD that all significant difference is confirmed through the ANOVA check.
When P≤0.05, be regarded as having significant difference.
Therapeutic outcome shows that the diabetes animal model blood sugar level behind tretinoin and derivatives for treatment thereof obviously reduces (P≤0.05), explains and uses tretinoin and derivant thereof can treat diabetes preferably.
Claims (10)
1. the tretinoin and the application of derivant in preparation control diabetes medicament thereof that have following structural formula (I),
Wherein, R1 is COOH or COH or CH2OH; R2, R4, R5, R6, R8, R9 respectively do for oneself H or C1-C6 alkyl; R3, R7 respectively do for oneself H or C1-C6 alkyl or aromatic radical or halogen or nitro or alkoxyl.
2. application as claimed in claim 1 is characterized in that: R1 is COOH; R2, R4, R5, R6, R8, R9 is H; R3 is H or C1-C6 alkyl, and R7 is H or C1-C6 alkyl or unsubstituted phenyl or alkyl-substituted phenyl or halogen or nitro or alkoxyl.
3. application as claimed in claim 1 is characterized in that: R1 is COOH; R2, R4, R5, R6, R7, R8, R9 is H; R3 is unsubstituted phenyl or alkyl-substituted phenyl or halogen or nitro or alkoxyl.
4. application as claimed in claim 1 is characterized in that: R1 is COOH; R2, R4, R5, R6, R8, R9 is H; R3 is unsubstituted phenyl or alkyl-substituted phenyl or halogen or nitro or alkoxyl, and R7 is not for replacing or alkyl-substituted phenyl.
5. application as claimed in claim 4 is characterized in that: R7 is a p-methylphenyl.
6. the application of retinoic acid derivatives in preparation control diabetes medicament that has following structural formula (II),
Wherein, R1 ' is COOH or COH or CH2OH; R2 ', R4 ', R5 ', R6 ', R8 ', R9 ' respectively do for oneself H or C1-C6 alkyl; R3 ', R7 ' respectively do for oneself H or C1-C6 alkyl or aromatic radical or halogen or nitro or alkoxyl.
7. application as claimed in claim 6 is characterized in that: R1 ' is COOH; R2 ', R4 ', R5 ', R6 ', R8 ', R9 ' is H; R3 ' is H or C1-C6 alkyl, and R7 ' is H or C1-C6 alkyl or unsubstituted phenyl or alkyl-substituted phenyl or halogen or nitro or alkoxyl.
8. application as claimed in claim 6 is characterized in that: R1 ' is COOH; R2 ', R4 ', R5 ', R6 ', R7 ', R8 ', R9 ' is H; R3 ' is unsubstituted phenyl or alkyl-substituted phenyl or halogen or nitro or alkoxyl.
9. application as claimed in claim 6 is characterized in that: R1 ' is COOH; R2 ', R4 ', R5 ', R6 ', R8 ', R9 ' is H; R3 ' is H or C1-C6 alkyl or unsubstituted phenyl or alkyl-substituted phenyl or halogen or nitro or alkoxyl, and R7 ' is not for replacing or alkyl-substituted phenyl.
10. like each described application among the claim 1-9, it is characterized in that: said tretinoin and derivant thereof are processed pharmaceutically acceptable dosage form according to the method for conventional medicine preparation.
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