- Preparation method of posaconazole intermediate 1-(4-aminophenyl)-4-(4-hydroxylphenyl)piperazine
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The invention discloses a preparation method of a posaconazole intermediate, namely 1-(4-aminophenyl)-4-(4-hydroxylphenyl)piperazine, belonging to the field of medicinal chemistry. The preparation method comprises the following steps: S1, with chlorobromobenzene and anhydrous piperazine as raw materials, generating 1,4-bis(4-chlorophenyl)piperazine under certain conditions; S2, performing single-side methylation on the product generated in the step S1 to obtain 1-(4-methoxyphenyl)-4-(4-chlorophenyl)piperazine; S3, performing ammoniation on the product in the step S2 to obtain 1-(4-methoxyphenyl)-4-(4-aminophenyl)piperazine; and S4, demethylating the product obtained in the step S3, and carrying out crystallizing and purifying to obtain the 1-(4-aminophenyl)-4-(4-hydroxylphenyl)piperazine.The raw materials used in the preparation method are very cheap; reaction conditions are relatively simple; the method is easy to implement; yield is high; and the cost of a final product can be obviously reduced.
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Paragraph 0036-0037
(2020/07/15)
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- Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic
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Itraconazole (ITZ) is an FDA-approved member of the triazole class of antifungal agents. Two recent drug repurposing screens identified ITZ as a promising anticancer chemotherapeutic that inhibits both the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized and evaluated first- and second-generation ITZ analogues for their anti-Hh and antiangiogenic activities to probe more fully the structural requirements for these anticancer properties. Our overall results suggest that the triazole functionality is required for ITZ-mediated inhibition of angiogenesis but that it is not essential for inhibition of Hh signaling. The synthesis and evaluation of stereochemically defined des-triazole ITZ analogues also provides key information as to the optimal configuration around the dioxolane ring of the ITZ scaffold. Finally, the results from our studies suggest that two distinct cellular mechanisms of action govern the anticancer properties of the ITZ scaffold.
- Pace, Jennifer R.,Deberardinis, Albert M.,Sail, Vibhavari,Tacheva-Grigorova, Silvia K.,Chan, Kelly A.,Tran, Raymond,Raccuia, Daniel S.,Wechsler-Reya, Robert J.,Hadden, M. Kyle
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supporting information
p. 3635 - 3649
(2016/05/24)
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- Design and synthesis of some new 1-phenyl-3/4-[4-(aryl/heteroaryl/alkyl-piperazine1-yl)-phenyl-ureas as potent anticonvulsant and antidepressant agents
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A series of 1-phenyl-3/4-[4-(aryl/heteroaryl/alkyl-piperazine1-yl)-phenyl-urea derivatives (29–42) were designed, synthesized and evaluated for their anticonvulsant activity by using maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) seizure tests. The acute neurotoxicity was checked by rotarod assay. Most of the test compounds were found effective in both seizure tests. Compound 30 (1-{4-[4-(4-chloro-phenyl)-piperazin-1-yl]-phenyl}-3-phenyl-urea) exhibited marked anticonvulsant activity in MES as well as scPTZ tests. The phase II anticonvulsant quantification study of compound 30 indicates the ED50value of 28.5?mg/kg against MES induced seizures. In addition, this compound also showed considerable protection against pilocarpine induced status epilepticus in rats. Seizures induced by 3-mercaptopropionic acid model and thiosemicarbazide were significantly attenuated by compound 30, which suggested its broad spectrum of anticonvulsant activity. Interestingly, compound 30 displayed better antidepressant activity than standard drug fluoxetine. Moreover, compound 30 appeared as a non-toxic chemical entity in sub-acute toxicity studies.
- Mishra, Chandra Bhushan,Kumari, Shikha,Tiwari, Manisha
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p. 603 - 617
(2016/07/06)
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- ITRACONAZOLE ANALOGUES AND METHODS OF USE THEREOF
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Disclosed herein are analogues of itraconazole that are both angiogenesis and hedgehog signaling pathway inhibitors. The compounds are expected to be useful in the treatment of cancer, particularly cancers that are dependent upon the hedgehog signaling pathway such as basal cell carcinoma and medulloblastoma.
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Paragraph 0072
(2015/09/22)
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- Design, synthesis and pharmacological evaluation of N-[4-(4-(alkyl/aryl/heteroaryl)-piperazin-1-yl)-phenyl]-carbamic acid ethyl ester derivatives as novel anticonvulsant agents
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A series of alkyl/aryl/heteroaryl piperazine derivatives (37-54) were designed and synthesized as potential anticonvulsant agents. The target compounds are endowed with satisfactory physicochemical as well as pharmacokinetic properties. The synthesized compounds were screened for their in vivo anticonvulsant activity in maximal electroshock (MES) and subcutaneous pentylenetetrazole (sc-PTZ) seizure tests. Further, neurotoxicity evaluation was carried out using rotarod method. Structure activity relationship studies showed that compounds possessing aromatic group at the piperazine ring displayed potent anticonvulsant activity. Majority of the compounds showed anti-MES activity whereas compounds 39, 41, 42, 43, 44, 50, 52, and 53 exhibited anticonvulsant activity in both seizure tests. All the compounds except 42, 46, 47, and 50 did not show neurotoxicity. The most active derivative, 45 demonstrated potent anticonvulsant activity in MES test at the dose of 30 mg/kg (0.5 h) and 100 mg/kg (4 h) and also delivered excellent protection in sc-PTZ test (100 mg/kg) at both time intervals. Therefore, compound 45 was further assessed in PTZ-kindling model of epilepsy which is widely used model for studying epileptogenesis. This compound was effective in delaying onset of PTZ-evoked seizures at the dose of 5 mg/kg in kindled animals and significantly reduced oxidative stress better than standard drug phenobarbital (PB). In result, compound 45 emerged as a most potent and safer anticonvulsant lead molecule.
- Kumari, Shikha,Mishra, Chandra Bhushan,Tiwari, Manisha
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supporting information
p. 1092 - 1099
(2015/02/19)
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- Impact of absolute stereochemistry on the antiangiogenic and antifungal activities of itraconazole
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Itraconazole is used clinically as an antifungal agent and has recently been shown to possess antiangiogenic acitivity. Itraconazole has three chiral centers that give rise to eight stereoisomers. The complete role of stereochemistry in the two activities of itraconazole, however, has not been addressed adequately. For the first time, all eight stereoisomers of itraconazole (1a?h) have been synthesized and evaluated for activity against human endothelial cell proliferation and for antifungal activity against five fungal strains. Distinct antiangiogenic and antifungal activity profiles of the trans stereoisomers, especially 1e and 1f, suggest different molecular mechanisms underlying the antiangiogenic and antifungal activities of itraconazole.
- Shi, Wei,Nacev, Benjamin A.,Bhat, Shridhar,Liu, Jun O.
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scheme or table
p. 155 - 159
(2010/10/19)
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- CHIRALLY PURE ISOMERS OF ITRACONAZOLE AND INHIBITORS OF LANOSTEROL 14A- DEMETHYLASE FOR USE AS ANGIOGENESIS INHIBITORS
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Described herein are methods of inhibiting angiogenesis, and treating or preventing a disease or disorder (or symptoms thereof) associated with angiogenesis, wherein an anti-angiogenesis compound is administered to a subject.
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Page/Page column 46-47
(2008/12/04)
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- Sequential mono-N-arylation of piperazine nitrogens. Part 1: A simplified method and its application to the preparation of a key N,N'-biaryl piperazine antifungal intermediate
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A simple sequential N-arylation of piperazine without the use of a protecting group, catalyst, specialized equipment or a large excess of piperazine, and its application towards the preparation of the key differentially N,N'-biarylated piperazine antifungal intermediate N-(4-hydroxyphenyl)-N'-(4-aminophenyl)piperazine, 6, is described.
- Hepperle, Michael,Eckert, Jeffrey,Gala, Dinesh
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p. 5655 - 5659
(2007/10/03)
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- Antimycotic azoles. 7. Synthesis and antifungal properties of a series of novel triazol-3-ones
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A series of novel triazol-3-ones has been synthesized, and their in vitro and in vivo antifungal properties are reported. Traconazole. which displays a pronounced oral activity against vaginal candidosis in rats and against microsporosis in guinea pigs, has been selected for clinical evaluation.
- Heeres,Backx,Van Cutsem
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p. 894 - 900
(2007/10/02)
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- Heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl)methyl-1H-imidazoles and 1H-1,2,4-triazoles
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Novel heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl)methyl-1H-imidazoles and 1H-1,2,4-triazoles, useful as antifungal and antibacterial agents.
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