Study On The Synthesis Methods Of Anti-Cancer Cachexia Drug Enobsoarm And Its Analogue Andarine

The etymology of the word“cachexia”derives from the Greek kakos and hexia which show a bad condition.Cachexia often follows with many severe diseases which may be malignancy,human acquired immunodeficiency syndrome and severe sepsis and so on.Nowadays,cancer-induced cachexia is one of the most common diseases,which is called“cancer cachexia”in modern medicine.Cancer cachexia is a complex multifactorial metabolic disorder,which is characterized by persistent and irreversible loss of skeletal muscle and accompanied by anorexia,metabolic imbalance and loss of adipose tissue and so on.Patients with cancer cachexia may have some bad syndromes,such as anorexia,attenuating in appetite,severe weight loss,weakness and anemia.Cancer cachexia has a severe impact on the life quality of patients,the body’s physiological function and treatment.It can also increase the risk of death in patients.In a meta-analysis of studies pertaining to patients with advanced cancer symptoms including weight loss and anorexia correlated with poor prognosis.For a long time,people recognized cancer cachexia with the mistaken idea that the disease is one of the side effects of cancer,and lacked of its exact definition,diagnosis and grading standard.Currently,the international organization has reached a consensus on the diagnosis of cachexia.Diagnostic criteria include weight loss greater than2%in individuals with body mass index(BMI)less than 20 kg/m~2,or evidence of sarcopenia with any degree of weight loss greater than 2%.The international consensus also divides this disease into three phases:pre-cachexia,cachexia and refractory cachexia.With the enactment of the clear clinical diagnostic criteria,it will be possible that cancer cachexia can be fully identified and diagnosed.The mechanism of cancer cachexia is extremely complex.Although scientists have made a series of remarkable results in its pathology research,the exact molecular mechanisms have not yet been fully understood.Now that cancer cachexia is induced by malignant,metabolic disorder and immune system abnormality,the therapeutic strategies of cancer cachexia have been focuses on stimulating the appetite,inhibiting the release of the associated inflammatory cytokines,promoting the body’s anabolic metabolism and inhibiting catabolism and so on.With the thorough researches on the pathogenesis,and further understanding of its physiological and pathological conditions going on,discovering its fundamental factors of disease progression and designing and synthesizing targeted drug are the developing trend on the treatment of cancer cachexia.Patients with cancer cachexia often have a severe condition in losing the skeletal muscle proteins,which results in the loss of the body function,reducing the quality of life.Therefore,the targets increasing patients’skeletal muscle and improving their physical function have become the current research focuses on the treatment of cancer cachexia.Selective androgen receptor modulators can promote nitrogen accumulation and increase the quality of muscle fiber and have a good anabolic function.Currently,many new drugs based on the target of the androgen receptor are under development.Enobosarm,(2S)-3-(4-cyanophenoxy)-N-[(4-cyano-3-trifluoromethyl)-phenyl]-2-hydroxy-2-methylpropanamide,is a chiral drug.And it is a nonsteroidal selective androgen receptor modulator developed by GTx,Inc for the treatment of conditions such as osteoporosis and muscle wasting.GTx has finished eight Phase I and II trials demonstrating that Enobosarm is safe and efficient in improving lean body mass and muscle function in cancer patients.Two randomized,double-blind,placebo-controlled Phase III trails were initiated in July 2011 to investigate whether the Enobosarm treatment improved lean body mass and muscle function in patients with non-small-cell lung carcinoma.Now the investigation has completed,but the result is still unknown.If Enobosarm treatment can reach the primary goal,it may be the first new drug in the prevention and treatment of weight loss and myophagism.Andarine,(2S)-3-(4-acetylaminophenoxy)-N-[(4-nitro-3-trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide,is also a selective androgen receptor modulator developed by GTx,Inc for the treatment of conditions such as osteoporosis,muscle wasting and benign prostatic hypertrophy.The structure of Andarine is similar to Enobosarm.The study on the synthesis methods of Andarine can provide technical supports for the development of new drugs with a similar structure.Objective:The aim is to establish the synthesis methods of Enobosarm and its analogue Andarine,to optimize the synthetic technologies and to establish the analytic methods.Methods:Using D-proline(5)as the chiral auxiliary,(2R)-1-methacry-loylpyrrolidin-2-carboxylic acid(7)was synthesized by the nucleophilic substitution reaction of D-proline(5)with methacyloychloride(6).The bromination reaction of intermediate 7 with N-bromobutanimide gave(3R,8a R)-3-bromomethyl-3-methyl-tetrahydro-pyrrolo[2,1-c][1,4]oxazine-1,4-dione(8).Intermediate 8 drew off the chiral auxiliary by 24%hydrobromic acid to obtain the important intermediate(2R)-3-bromo-2-hydroxy-2-methlyp-ropanoic acid(9).Compound 9 reacted with 5-amino-2-cyanobenzotrifluoride(18)mediated by thionyl chloride to give(2R)-3-bromo-N-[(4-cyano-3-trifluo-romethyl)phen-yl]-2-hydroxy-2-methypropanamide(10).The target product Enobosarm was synthesized by the nucleophilic substitution reaction of intermediate 10 and 4-cyanophenol(19)under the catalysis of anhydrous potassium carbonate.Compound 9 reacted with 4-nitro-3-trifluoromethyl-anil-ine(20)mediated by thionyl chloride to give(2R)-3-bromo-N-[(4-nitro-3-trifl-uoromethyl)phenyl]-2-hydroxy-2-methypropanamide(16).The analogue Andarine was synthesized by the nucleophilic substitution reaction of intermediate 16 and 4-acetamidophenol(21)under the catalysis of benzyltributyammonium.The structure of intermediates and target products were confirmed by melting point,infrared,mass spectrum and nuclear magnetic.High performance liquid chromatography(HPLC)method was used for the chemical and optical purity determination of the target.Results:Enobosarm and its analogue Andarine were synthesized successfully,and were confirmed by MS-ESI(m/z)and ~1H-NMR.The chemical and optical purity of Enobosarm was preliminarily determinated by HPLC method.Moreover,some of the synthetic technologies were optimized.Enobosarm:white solid,mp.90～91℃.Andarine:yellow,mp.70～91℃.Conclusion:In this research,using D-proline(5)and methacyloychloride(6)as the starting material,the target product Enobosarm and its analogue Andarine were obtained by 5 steps.Some of the synthetic technologies were optimized.The operations of the process were simple,and the generation cycle was short,and the reaction conditions were mild.