The Synthesis Of A Novel Antidepressant Prx-00023

Depressive disorder is a kind of psychiatric disorders, characterized by low mood, abnormalities in sleep patterns, emotional and physical withdrawal and is often associated with severe morbidity, increased risk of suicide and in some cases psychotic symptoms. There are several factors that appear to precipitate the diesae including biological, psychological and socio-cultural factors, et al. But the exact cause of depressive disorder remains poorly understood. Several neurotransmitters, for example, serotonin, noradrenaline, dopamine, glutamate andγ-amino-butyric acid have all been implicated in the aetiology of depression.Serotonin (5-HT) is an important neurotransmitter. It is not only involved in a variety of physiological functions such as vasoconstriction, thermoregulation, sexual behavior, pain, appetite and sleep, but also implicated in neuropsychiatric disturbances such as depression, anxiety, and psychosis. Especially, the deficiency of 5-HT plays an important role in the depressive disorder. So there are many effective 5-HT receptor agonists and partial agonists which can increase the 5-HT levels to improve or treat the depressive disorder in the maket which contain elective serotonin reuptake inhibitors (SSRIs)-fluoxetine and serotonin noradrenaline reuptake inhibitors (SNRIs)- Venlafaxine, et al. But most of the drugs used for depression suffer from troublesome side effects. For example, SSRIs, which makes up 60% of the worldwide antidepressant market, is frequently associated with sexual dysfunction, appetite disturbances, and sleep disorders. They can increase 5-HT levels in the brain, but they can indirectly sitmulate all serotonergic receptors because of their low selectivities, which is believed to lead to adverse side effects associated with these drugs.Prx-00023(N-[3-[4-(4-cyclohexylmethanesulfonylamino-but-yl)-piperazin-1-yl]-phenyl]-acetamide Hydrochloride) is a novel and effective 5-HT1A receptor agonist for the treatment of depression discovered by EPIX company using G-Protein Coupled Receptors (GPCR) modeling, screening and lead optimization technology. The data of clinical trials demonstrate that it is a ligand for the 5-HT1A receptor of its good toleration, high affinity and high selectivity, and behaves as a full agonist. The result from Phase III clinical trial of Prx-00023 demonstrates that it has excellent curative effect and poor side effects in the treatment of depression. Some data demonstrate that the impact on sexual function and sleep, in patients receiving Prx-00023, were similar to placebo. So, Prx-00023 is to be a potential popular drug in the future antidepressant market.Objective: The aim is to synthesize a novel and effective antidepressant Prx-00023 (selective 5-HT1A agonist ) in a new method through refering to the pertinent literatures and designing the synthesis line, which can offer the evidences for discovering some new high activity molecules in its further derivatives'preparation.Methods: There are several intermediates to be synthesized in the new designed synthesis line . The specific steps refer to:(1)In the course of preparing the compound A(1-(3-nitro-phenyl)-piperazine), you can get more products through adding some catalysts into the system and changing the way of adding the raw materials into the solution.(2)The intermediate C(N-[4-[4-(3-nitro-phenyl)-piperazin- 1-yl]-butyl]phthalimide) can be obtained through nucleophilic substitution reaction from phthalimide potassium salt, 1,4-dibromobutane and intermediate A, and then you can get the comound D(4-[4-(3-nitro-phenyl)-piperazin-1-yl]butylamine) following its hydrazinolysis.(3)Cyclohexyl-ethanesulfonic acid sodium salt can be obtained through halogeno-reaction and sulfonation from cyclohexylmethanol, then it is acidified by concentrated hydrochloric acid and reacts with SOCl2, so intermediate G(cyclohexyl-methanesulfonly chloride) is prepared.(4)The compound H(C-cyclohexyl-N-[4-[4-(3-nitro-phenyl) piperazin-1-yl]-butyl]-methanesulfonamide) is prepared through nucleophilic substitution reaction from intermediates D and G firstly, and then you can obtain the target compound prx-00023 following its reduction reaction, acetylation and salification.Results:①The yield of intermediate A has reached to 64.8% through changing the experimental conditions, and itis higher 19.8% than the yield 45% in the the pertinent li-terature. The melting point of intermediate A is determinedin the range of 224.0~226.0℃.②The intermediate C is synthesized and the product is yellow solid. The yield is 91.3% and the melting point of it is determined in the range of 149.4~149.7℃. The propo-sed structure is initially characterized by 1H-NMR spectros-copy.③Intermediate D is prepared in a new method, and theproduct is yellow solid. The yield is 87.2%, and the melti-ng point of it is determined in the range of 45.0~46.0℃.④Compound G is synthesized, but it is used into the next reaction directly without purification because of its in-stability.⑤The intermediate H is synthesized and the product is white solid. The yield is 92.0%, and the melting point of it is determined in the range of 82.0~83.0℃. The proposedstructure is characterized by 1H-NMR spectroscopy and HPLC-MS.⑥The target compound Prx-00023 is prepared in a new method. It is white solid and the yield is 86.0%, and the melting point of it is determined in the range of 201.9~ 202.0℃, Rf=0.56(CH3OH : CH2Cl2=1 : 10). The proposed structure is characterized by 1H-NMR spectroscopy and HPLC-MS. Conclusions: After several experiments and summaries, the yield of intermediate A is increased through changing experimental conditions, and intermediates D and G are prepared in new synthesis lines, then the synthesis of the target compound Prx-00023 is finished firstly in our country, which is a novel 5-HT1A agonist used for treatment of depression and can offer the evidences for discovering some new high activity molecules in its further derivatives'preparation.