GAOH derivative and medical application thereof

Abstract

The invention provides a GAOH derivative of a new structure. The compounds have great curative effects on inflammatory bowel diseases, hepatitis viruses, foot swelling, ear swelling, arthritis, pneumonia, nephritis, rhinitis, cerebral apoplexy, myocardial ischemia, atherosclerosis, arrhythmia, autoimmune disease, senile dementia, depression, schizophrenia, malignancy and tumor adjuvant therapy, virus infectious diseases, peptic ulcer, analgesia, antianaphylaxis, antiendotoxin, antishock and diabetes or diabetic complication.

Description

technical field

[0001] The invention belongs to the field of medicine, and in particular relates to a GAOH derivative and its application in preparing medicines for treating inflammatory diseases and cardiovascular and cerebrovascular diseases. Background technique

[0002] Inflammation is a very common and important basic pathological process. Trauma infection on the body surface and most common and frequently-occurring diseases of various organs (such as inflammatory bowel disease, pneumonia, hepatitis, nephritis, etc.) are all inflammatory diseases, which are troublesome diseases. A common disease in people's normal life. It is generally believed that acute inflammation mainly manifests as infiltration and activation of lymphocytes, which have immune and defense functions, and can prevent and control the invasion and damage of pathogens. However, if the inflammatory factors continue to act, they can cause chronic inflammation, cell and tissue damage, and various diseases...

Examples

Embodiment 1

[0036] (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10,13-dihydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-1,2,3 , Preparation of 4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b-octahydroperylene-2-acid (GAOH for short)

[0037]

[0038] The preparation of formula n compound

[0039]Dissolve 4.7g of the compound of formula m in 100mL of a mixture of acetone and water with a volume ratio of 1:1.2, stir for 15min, control the temperature at 5°C, add 10mL of Jones reagent dropwise, after the dropwise addition, turn to room temperature and continue stirring , TLC detects that the reaction is complete, filters, collects the filtrate, reclaims acetone, the residue is neutralized to neutral with saturated anhydrous sodium bicarbonate, filters, extracts three times with 300mL dichloromethane, combines the dichloromethane layers, concentrates, and dries to prepare Obtain formula n compound;

[0040] The preparation of formula p compound

[0041] Get 0.468g formula n compound, 0.22g SeO 2 In a 50mL...

Embodiment 2

[0046] (2S,4aS,6aR,6bS,8aS,10S,12aS,12bS,14bR)-12b-fluoro-10,13-dihydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-1 , Preparation of 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b-octahydroperylene-2-acid (GAOHF for short):

[0047]

[0048] Under nitrogen protection, 4.86g formula a compound and 4.09gCeCl 3 ·7H 2 Dissolve O in 150mL methanol, cool down to -20°C, and quickly add 0.41g NaBH 4 , TLC detected that the reaction was complete; the solvent was removed by rotary evaporation, dissolved in 150 mL of ethyl acetate, washed successively with 10% hydrochloric acid aqueous solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and ethyl acetate was removed by rotary evaporation to obtain GAOHF.

Embodiment 3

[0050] (2S,4aS,6aR,6bS,8aS,10S,12aS,12bS,14bR)-12b-fluoro-10,13-dihydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-1 ,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosan-2-acid (referred to as GAOHF -1) Preparation

[0051]

[0052] The preparation of formula c compound

[0053] Under nitrogen protection, dissolve 4.7g of the compound of formula b in 150mL of methanol, cool down to -20°C, and quickly add 0.41g of NaBH 4 , TLC detected that the reaction was complete; the solvent was removed by rotary evaporation, dissolved in 150 mL of ethyl acetate, washed successively with 10% aqueous hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, filtered, and ethyl acetate was removed by rotary evaporation to obtain the compound of formula c .

[0054] The preparation of formula d compound

[0055] Add 4.72g of the compound of formula c into a 250mL round bottom flask, add 100mL of DMF and 2.4mL of Py, stir, and slowly drop into 3mL of CH at 0°C 3 SO 2 Af...

technical field

[0001] The invention belongs to the field of medicine, and in particular relates to a GAOH derivative and its application in preparing medicines for treating inflammatory diseases and cardiovascular and cerebrovascular diseases. Background technique

[0002] Inflammation is a very common and important basic pathological process. Trauma infection on the body surface and most common and frequently-occurring diseases of various organs (such as inflammatory bowel disease, pneumonia, hepatitis, nephritis, etc.) are all inflammatory diseases, which are troublesome diseases. A common disease in people's normal life. It is generally believed that acute inflammation mainly manifests as infiltration and activation of lymphocytes, which have immune and defense functions, and can prevent and control the invasion and damage of pathogens. However, if the inflammatory factors continue to act, they can cause chronic inflammation, cell and tissue damage, and various diseases...

Examples

Embodiment 1

[0036] (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10,13-dihydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-1,2,3 , Preparation of 4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b-octahydroperylene-2-acid (GAOH for short)

[0037]

[0038] The preparation of formula n compound

[0039]Dissolve 4.7g of the compound of formula m in 100mL of a mixture of acetone and water with a volume ratio of 1:1.2, stir for 15min, control the temperature at 5°C, add 10mL of Jones reagent dropwise, after the dropwise addition, turn to room temperature and continue stirring , TLC detects that the reaction is complete, filters, collects the filtrate, reclaims acetone, the residue is neutralized to neutral with saturated anhydrous sodium bicarbonate, filters, extracts three times with 300mL dichloromethane, combines the dichloromethane layers, concentrates, and dries to prepare Obtain formula n compound;

[0040] The preparation of formula p compound

[0041] Get 0.468g formula n compound, 0.22g SeO 2 In a 50mL...

Embodiment 2

[0046] (2S,4aS,6aR,6bS,8aS,10S,12aS,12bS,14bR)-12b-fluoro-10,13-dihydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-1 , Preparation of 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b-octahydroperylene-2-acid (GAOHF for short):

[0047]

[0048] Under nitrogen protection, 4.86g formula a compound and 4.09gCeCl 3 ·7H 2 Dissolve O in 150mL methanol, cool down to -20°C, and quickly add 0.41g NaBH 4 , TLC detected that the reaction was complete; the solvent was removed by rotary evaporation, dissolved in 150 mL of ethyl acetate, washed successively with 10% hydrochloric acid aqueous solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and ethyl acetate was removed by rotary evaporation to obtain GAOHF.

Embodiment 3

[0050] (2S,4aS,6aR,6bS,8aS,10S,12aS,12bS,14bR)-12b-fluoro-10,13-dihydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-1 ,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosan-2-acid (referred to as GAOHF -1) Preparation

[0051]

[0052] The preparation of formula c compound

[0053] Under nitrogen protection, dissolve 4.7g of the compound of formula b in 150mL of methanol, cool down to -20°C, and quickly add 0.41g of NaBH 4 , TLC detected that the reaction was complete; the solvent was removed by rotary evaporation, dissolved in 150 mL of ethyl acetate, washed successively with 10% aqueous hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, filtered, and ethyl acetate was removed by rotary evaporation to obtain the compound of formula c .

[0054] The preparation of formula d compound

[0055] Add 4.72g of the compound of formula c into a 250mL round bottom flask, add 100mL of DMF and 2.4mL of Py, stir, and slowly drop into 3mL of CH at 0°C 3 SO 2 Af...

Images