- NEW ANALOGS AS ANDROGEN RECEPTOR AND GLUCOCORTICOID RECEPTOR MODULATORS
-
The present invention relates to novel dihydropyridine derivatives of formula (I): as modulators of nuclear receptors selected from androgen receptor and glucocorticoid receptor, to processes for their preparation, to pharmaceutical compositions comprising said compounds and to the use of said for manufacturing a medicament for the treatment of pathological conditions or diseases that can improve by modulation of androgen receptor and/or glucocorticoid receptor, selected from cancer, metastasizing cancers, benign prostate hyperplasia, polycystic ovary syndrome (PCOS), hair loss, hirsutism, acne, hypogonadism, muscle wasting diseases, cachexia, Cushing's syndrome, anti-psychotic drug induced weight gain, obesity, post-traumatic stress disorder and alcoholism.
- -
-
Paragraph 0194; 0195; 0216
(2019/05/16)
-
- Enzymatic Synergism in the Synthesis of β-Keto Esters
-
Reaction of alcohols with ethyl and tert-butyl acetoacetate catalyzed by a combination of commercially available enzymes is shown to be a convenient method for the preparation of a range of acetoacetic acid derivatives. Systematic studies proved that the combination of two or more enzymes enhances the yield of the reaction. Application of the selected enzyme mixture for enzymatic transesterification of various β-keto esters provided the respective products in excellent yields up to 96% and quantitative within 24 and 48 hours, respectively. The presented methodology is simple and mild, and can be used to prepare acetoacetates from primary and secondary alcohols. Application of a selected enzyme mixture for enzyme-catalyzed esterification of various carboxylic acids provided the respective β-hydroxy esters in excellent yields up to 96% and quantitative within 24 and 48 hours, respectively.
- Wisniewska, Catalina,Koszelewski, Dominik,Zysk, Malgorzata,Klossowski, Szymon,Zdlo, Anna,Brodzka, Anna,Ostaszewski, Ryszard
-
p. 5432 - 5437
(2015/08/24)
-
- An efficient synthesis of β-ketoesters via transesterification and its application in Biginelli reaction under solvent-free, catalyst-free conditions
-
A simple and efficient transesterification process for the synthesis of β-ketoester derivatives has been achieved by the reaction of methyl β-ketoester with higher alcohols at 110 C under solvent-free, catalyst-free conditions and its application in synthesis of 3,4-dihydropyrimidin-2(1H)-ones C-5 ester derivatives via Biginelli reaction has been described.
- Dharma Rao,Acharya,Kaushik
-
supporting information
p. 6644 - 6647
(2013/11/19)
-
- Efficient trans-acetoacylation mediated by ytterbium(III) triflate as a catalyst under solvent-free condition
-
A simple and efficient trans-acetoacylation method for the synthesis of β-keto ester derivatives has been described using ytterbium(III) triflate as a new catalyst under solvent-free condition. This method was found to be efficient and convenient for the synthesis of a wide variety of β-keto ester derivatives.
- Dharma Rao,Kaushik
-
experimental part
p. 5104 - 5106
(2011/10/08)
-
- Design and synthesis of new 1,4-dihydropyridines containing 4(5)-chloro-5(4)-imidazolyl substituent as a novel calcium channel blocker
-
New analogues of nifedipine, in which the ortho-nitro phenyl group at position 4 has been replaced by 4(5)-chloro-5(4)-imidazolyl substituent and which are able to interact with the receptor by hydrogen binding were designed, synthesized, and evaluated as calcium channel antagonists. The designed dihydropyridines were synthesized using the Hantzsch condensation and evaluated as calcium channel antagonists using the high K+ contraction of guineapig ileal longitudinal smooth muscle. A docking study was performed using the AutoDock4 program, and QSAR equations were obtained using multilinear regression. Our computational studies indicated that the oxygen of the ester (O10) and the N3′ of the imidazole ring form a hydrogen bonding interaction with the NH of HIS 363 and NH of LYS354, respectively, and that the sum of the BEHp5 and RDF075p are the most significant descriptors. The results of calcium channel antagonist evaluation demonstrated that increasing the chain length in C3 and C5 ester substituents increased activity. The most potent compound was the bis-phenylpropyl ester (5l) derivative, in that it was more active than the reference drug nifedipine and that the bis-phenylethyl ester (5k) derivative had comparable activity with nifedipine. The present research revealed that the 4(5)-chloro-5(4)-imidazolyl moiety is a bioisoster of o-nitrophenyl in nifedipine and provided novel dihydropyridines with more activity as calcium channel antagonists.
- Iman, Maryam,Davood, Asghar,Nematollahi, Ali Reza,Dehpoor, Ahmad Rerza,Shafiee, Abbas
-
experimental part
p. 1417 - 1426
(2012/05/04)
-
- BF3OEt2: An efficient catalyst for transesterification of β-ketoesters
-
A facile and selective transesterification of β-ketoesters using BF3OEt2 as catalyst is described. The emphasis has been placed on the reaction of methyl acetoacetate with a series of alcohols of different structures, leading in all cases to good to excellent yields.
- Yang, Jinhui,Ji, Congbin,Zhao, Yanmin,Li, Yunfeng,Jiang, Shizhi,Zhang, Zhiwei,Ji, Yongqiang,Liu, Wanyi
-
experimental part
p. 957 - 963
(2010/06/12)
-
- Synthesis and biological evaluation of some new 1,4-dihydropyridines containing different ester substitute and diethyl carbamoyl group as anti-tubercular agents
-
Tuberculosis is a leading infectious cause of death worldwide. Because of the concern of the resistance to most of the commonly used drugs displayed by the considered mycobacteria, most efforts have been done to introduce new anti-tubercular agents. Recent studies showed that 1,4-dihydropyridine-3,5-dicarbamoyl derivatives with lipophilic groups have significant anti-tubercular activity. In this study, we synthesized new derivatives of 1,4-dihydropyridines in which different alkyl and aryl esters and diethyl carbamoyl are substituted in C-3 and C-5 of the DHP ring. In addition nitroimidazole ring is substitutes at C-4 position. These asymmetric analogues were synthesized by a modified Hantzsh reaction using procedure reported by Meyer. The in vitro anti-tubercular activity of compounds against Mycobacterium tuberculosis was evaluated. The results indicate that the compounds containing aromatic esters are more potent than alkyl ones. The most potent aromatic compound (R = 3-phenylpropyl) exhibits comparable anti-tubercular activity (MIC = 1 μmol/ml) with reference compound isoniazide (INH) (MIC = 1 μmol/ml). Conformational analysis, SAR studies of these compounds showed that increasing in lipophilicity and rotable bonds of these compounds resulted in increasing anti-tubercular activity.
- Khoshneviszadeh, Mehdi,Edraki, Najmeh,Javidnia, Katayoun,Alborzi, Abdolvahab,Pourabbas, Bahman,Mardaneh, Jalal,Miri, Ramin
-
experimental part
p. 1579 - 1586
(2009/07/11)
-
- A nucleophilic Fe catalyst for transesterifications under neutral conditions
-
Carboxylic esters belong to the most important functional groups in organic chemistry. Strong efforts have been made in developing mild catalytic procedures for their preparation. Among the various methods developed to date, transesterifications have occupied an important space. In the present paper, a new catalytic method for this process based on the use of nucleophilic Fe(-II) complexes is presented. Evidence for the formation of an intermediate acyl Fe complex will be presented as well as investigations on scope and limitations.
- Magens, Silja,Ertelt, Melanie,Jatsch, Anja,Plietker, Bernd
-
-
- Lipophilic 4-imidazoly-1,4-dihydropyridines: Synthesis, calcium channel antagonist activity and protection against pentylenetetrazole-induced seizure
-
A group of alkyl, cycloalkyl and aryl ester analogs of nifedipine, in which the o-nitrophenyl group at position 4 is replaced by a 2-phenyl-4(5)-imidazolyl substituent, were synthesized and evaluated as calcium channel antagonist using the high K+ contraction of guinea-pig ileal longitudinal smooth muscle, and the activity of 5a-d, 8b and 8f against pentylenetetrazole (PTZ)-induced seizure was assessed. The results for symmetrical esters showed that lengthening of the methylene chain in C3 and C5 ester substituents increased activity. When increasing of the length is accompanied by increasing the hindrance, the activity decreased. In contrast to symmetrical derivatives, comparison of the activities of asymmetrical esters showed that increasing the length of the methylene chain was accompanied by a decrease in their activity. The results demonstrate that 8a was more active, and 5c and 8f were similar in effect to that of the reference drug nifedipine. The time-course of anticonvulsant effect on PTZ-induced seizure threshold of said compounds was assessed and showed that increasing the lipophilicity decreases the time needed for maximum effect. Mice treated with intraperitoneal injection of 25 mg/kg of these derivatives all exhibited increase seizure threshold as compared with control.
- Navidpour, Latifeh,Shafaroodi, Hamed,Miri, Ramin,Dehpour, Ahmad Reza,Shafiee, Abbas
-
p. 261 - 269
(2007/10/03)
-
- Sustainable transesterification of β-ketoesters catalyzed by amine grafted on silica gel
-
Transesterification of β-ketoesters with various alcohols has been effected by N,N-diethylaminopropylated silica gel (NDEAP) as a catalyst in refluxing xylene. Generality of the reaction was demonstrated by successful transesterification of olefinic alcohols, tertiary alcohols and alcohols having acid- or base-sensitive substituents. The catalyst has been efficiently recycled more than five times without any re-activation.
- Hagiwara, Hisahiro,Koseki, Aiko,Isobe, Kohei,Shimizu, Ken-Ichi,Hoshi, Takashi,Suzuki, Toshio
-
p. 2188 - 2190
(2007/10/03)
-
- Transesterification of ketoesters using Amberlyst-15
-
A facile one-to-one transesterification of ketoesters by Amberlyst-15 is described.
- Chavan,Tripura Subbarao,Dantale,Sivappa
-
p. 289 - 294
(2007/10/03)
-
- Selective Catalytic Transesterification, Transthiolesterification, and Protection of Carbonyl Compounds over Natural Kaolinitic Clay
-
Transesterification and transthiolesterification of β-keto esters with variety of alcohols and thiols and selective protection of carbonyl functions with various protecting groups catalyzed by natural kaolinitic clay are described. The clay has been found to be an efficient catalyst in transesterifying long chain alcohols, unsaturated alcohols, and phenols to give their corresponding β-keto esters in high yields. For the first time, transthiolesterification of β-keto esters with a variety of thiols has been achieved under catalytic conditions. Clay also catalyzes selective transesterification of β-keto esters by primary alcohols in the presence of secondary and tertiary alcohols giving corresponding β-keto esters. A systematic study involving the reactivity of different nucleophiles (alcohols, amines, and thiols) toward β-keto esters is also described. Sterically hindered carbonyl groups as well as α,β-unsaturated carbonyl groups underwent protection without the deconjugation of the double bond. Chemoselective protection of aldehydes in the presence of ketones has also been achieved over natural kaolinitic clay.
- Ponde, Datta E.,Deshpande, Vishnu H.,Bulbule, Vivek J.,Sudalai, Ammugam,Gajare, Anil S.
-
p. 1058 - 1063
(2007/10/03)
-
- Synthesis, rotamer orientation, and calcium channel modulation activities of alkyl and 2-phenethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates
-
A group of racemic alkyl and 2-phenethyl 1,4-dihydro-2,6-dimethyl-3- nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates (13a-q) was prepared using a modified Hantzsch reaction that involved the condensation of a 3- or 6-substituted-2-pyridinecarboxaldehyde (7a-j) with an alkyl or 2- phenethyl 3-aminocrotonate (11a-d) and nitroacetone (12). Nuclear Overhauser (NOE) studies indicated there is a significant rotamer fraction in solution where the pyridyl nitrogen is oriented above the 1,4-dihydropyridine ring, irrespective of whether a substituent is located at the 3- or 6-position. A potential H-bonding interaction between the pyridyl nitrogen free electron pair and the suitably positioned 1,4-dihydropyridine NH moiety may stablize this rotamer orientation. In vitro calcium channel antagonist and agonist activities were determined using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays, respectively. Compounds having an i-Pr ester substituent acted as dual cardioselective calcium channel agonists (GPLA)/smooth muscle-selective calcium channel antagonists (GPILSM), except for the C-4 3-nitro-2-pyridyl compound which exhibited an antagonist effect on both GPLA and GPILSM. In contrast, the compounds with a phenethyl ester group, which exhibited antagonist activity (IC50 = 10-5- 10-7 M range) on GPILSM, were devoid of cardiac agonist activity on GPLA. Structure-activity relationships showing the effect of a substituent (Me, CF3, C1, NO2, Ph) at the 3- or 6-position of a C-4 2-pyridyl moiety and a variety of ester substituents (Me, Et, i-Pr, PhCH2CH2-) upon calcium channel modulation are described. Compounds possessing a 3- or 6-substituted- 2-pyridyl moiety, in conjuction with an i-Pr ester substituent, are novel 1,4-dihydropyridine calcium channel modulators that offer a new drug design approach directed to the treatment of congestive heart failure and may also be useful as probes to study the structure-function relationships of calcium channels.
- Iqbal, Nadeem,Akula, Murthy R.,Vo, Dean,Matowe, Wandikayi C.,McEwen, Carol-Anne,Wolowyk, Michael W.,Knaus, Edward E.
-
p. 1827 - 1837
(2007/10/03)
-
- Synthesis and calcium-channel antagonist activity of 4-imidazolyl-1,4-dihydropyridines
-
The o-nitrophenyl group at position 4 of dihydropyridine of nifedipine analogues was replaced by 1-methylimidazole. These compounds were evaluated as calcium-channel antagonists using the high K+ contraction of guinea-pig ileal longitudinal smooth muscle. The results for the symmetrical esters showed that increasing the length of methylene chain of ester more than 3 units decreases activity. For cyclic esters, cyclopropylmethyl ester was more active than cyclohexylmethyl ester. Our results revealed two compounds with activities similar to the reference drug nifedipine; the symmetrical cyclopropylmethyl ester, and the asymmetrical phenethyl ethyl derivatives were the most potent antagonists tested.
- Pourmorad,Hadizadeh,Shafiee
-
p. 165 - 168
(2007/10/03)
-
- Synthesis and calcium-channel antagonist activity of nifedipine analogues containing nitroimidazolyl substituent in guinea-pig ileal smooth muscle
-
Alkyl, cycloalkyl or aryl ester analogues of nifedipine, in which the ortho-nitrophenyl group at position 4 is replaced by 1-methyl-5-nitro-2-imidazolyl substituent, were synthesized and evaluated as calcium-channel antagonists using the high K+ contraction of guinea-pig ileal longitudinal smooth muscle. The results for the symmetrical esters showed that increasing the length of methylene chain (n > 2) decreases activity. The relative activity profile for asymmetrical esters was cyclopentyl > cyclohexyl > cyclopropyl. Comparison of esters having the same methylene space showed that the cyclohexyl compounds were more active than the corresponding phenyl derivatives. In addition, asymmetrical esters possessing one R2 substituent (methyl > ethyl) indicated that increasing the length of methylene chain in the R1-substituent decreased activity. Our results demonstrate that several compounds were more active than the reference drug nifedipine. The symmetrical cyclohexyl ester (n = 0) and the asymmetrical (R1 = cyclohexyl, R2 = Me, n = 0) derivatives were the most potent antagonists tested.
- Shafiee,Miri,Dehpour,Soleymani
-
p. 541 - 543
(2007/10/03)
-
- Electronic and steric control in carbon-hydrogen insertion reactions of diazoacetoacetates catalyzed by dirhodium(II) carboxylates and carboxamides
-
Carboxylate and carboxamide ligands on dirhodium(II) catalysts can provide enormous regiocontrol in carbon-hydrogen insertion reactions of diazoacetate esters. Whereas 2,3,4-trimethyl-3-pentyl diazoacetoacetate (1) forms γ-lactone products from insertion into primary and tertiary C-H bonds in a statistical distribution (61:39) with dirhodium(II) tetrakis(perfluorobutyrate), only tertiary C-H insertion is observed with dirhodium(II) tetraacetamide. Similar results are obtained with 2-methyl-2-octyl diazoacetoacetate (3), where competition for insertion exists between secondary and primary C-H bonds and electronic factors govern regioselection. However, with 2-methyl-3-isopropyl-3-heptyl diazoacetoacetate (2) and 2-methyl-l-phenyl-2-propyl diazoacetoacetate (4), product distributions from C-H insertion are invariant with the dirhodium(II) ligands; insertion into a secondary C-H bond is favored over tertiary C-H insertion with 2 (95:5), and insertion into a primary C-H bond is preferred to benzylic secondary C-H insertion with 4 (70:30). In such cases, which are amenable to analyses by MM2 calculations, regioselectivity is determined by conformational preferences for which C-H insertion selectivity can be as random as that found with 2 and 4. When only one C-H bond site is available for insertion to form a five-membered ring product, only one γ-lactone is observed from reactions catalyzed by dirhodium(II) tetraacetate, and that product is not necessarily the one predicted by presumed electronic preferences.
- Doyle, Michael P.,Westrum, Larry J.,Wolthuis, Wendelmoed N. E.,See, Marjorie M.,Boone, William P.,Bagheri, Vahid,Pearson, Matthew M.
-
p. 958 - 964
(2007/10/02)
-