- Process for Making Biologically Active Compounds and Intermediates Thereof
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A process of manufacturing biologically active compounds, their analogs, pharmaceutically acceptable salts, solvates, polymorphs, isotopic variants, and intermediates thereof. Notably, the compounds of the formula IA, 1B, 1C. 1D. 1E, 1F and IG for which novel processes have been disclosed, selectively act on the cannabinoid receptors, and with high affinity. The processes for the preparation of the compounds enable the syntheses of cannabinoid modulators on a large-scale that are eco-friendly and economically viable. Additionally, the processes disclosed enable the synthesis of cannabinoid modulators with high purity and in high yield for their use in making drug substance and drug products.
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- Discovery of rimonabant and its potential analogues as anti-TB drug candidates
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Rimonabant and its analogues have been synthesized in moderate to good yields using a simple synthetic route. All the newly synthesized compounds were subjected to in vitro screening against M. tuberculosis and M. smegmatis. The most potent analogue JMG-14 exhibits MIC value of 3.13 compared to 3.25 and 50 μ/ml for ethambutol and pyrazinamide, respectively. The molecular docking reveals that pyrazole ring, number and position of halogen atoms play a crucial role in deciding interactions with MTCYP-121. These findings open up a new avenue in the search of potent anti-TB drugs with rimonabant and its novel analogue JMG-14 as lead molecules.
- Gajbhiye,More,Patil, Manoj D.,Ummanni,Kotapalli,Yogeeswari,Sriram,Masand
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p. 2960 - 2971
(2015/03/14)
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- PYRAZOLE CARBOXYLIC ACID ANALOGUES AS ANTI-MYCOBACTERIAL DRUG CANDIDATES
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The present invention relates to the pyrazole carboxylic acid analogues of Formula (1) or stereoisomers, or esters or pharmaceutically acceptable salts thereof, as potent anti- mycobacterial agents. Formula Further it discloses the pharmaceutical composition comprising compounds of Formula-I for the treatment of mycobacterial infections.
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Page/Page column 14; 15
(2014/11/13)
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- Synthesis, hypoglycemic activity and molecular modeling studies of pyrazole-3-carbohydrazides designed by a CoMFA model
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Diabetes and obesity are two universal health problems that constitute a research objective of several groups due to the lack of efficient and safe drug treatment. In this sense, cannabinoid receptor 1 (CB1) has attracted interest because of its role in food intake and metabolic balance, two targets in the control of metabolic syndrome. In this work, novel 1,5-diaryl pyrazole derivatives were synthesized in accordance with the pKi prediction of a previously reported CoMFA model by our group. To further investigate the biological activity of these compounds in metabolic disorders, their hypoglycemic activity in an in vivo model was tested. Interestingly, a high degree of correlation was observed between the predicted pKi and hypoglycemic effect 7 h after administration. Compounds 4, 9 and 13 showed the most significant plasma glucose reduction with decreases of 60%, 64% and 60% respectively. This result not only surpasses the activity of the lead rimonabant, but also that of the reference drug glibenclamide. Moreover, PASS prediction and molecular docking in an excellent validated homology model of CB1 suggest that these compounds would probably act as CB1 antagonists/inverse agonists and therefore, anti-obesity agents. The ligand-receptor complexes demonstrate that 1,5-diaryl pyrazole derivatives bind to the proposed binding site where a hydrophobic moiety interacts with the phenyl rings in the pyrazole nucleus and Lys192 forms a hydrogen bond with the oxygen of the carbonyl group. Dynamics simulations were also carried out to study the stability of the ligand-receptor complexes where the most active compounds showed smaller ΔG values and more hydrogen bonds throughout the simulation. These compounds are considered useful leads for further optimization in the treatment of such metabolic illnesses.
- Hernández-Vázquez, Eduardo,Aguayo-Ortiz, Rodrigo,Ramírez-Espinosa, Juan José,Estrada-Soto, Samuel,Hernández-Luis, Francisco
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- PROCESS FOR PREPARING FORM I OF RIMONABANT
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The present invention describes new process for the preparation of Form I of Rimonabant through the intermediate formation of the corresponding acid addition salt.
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Page/Page column 6
(2010/01/12)
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- PROCESS FOR THE PREPARATION OF RIMONABANT
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The present invention relates to a new process for the preparation of Rimonabant through the formation of an intermediate compound of formula (VII). The invention further relates to a process for the preparation of the compound of formula (VII).
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Page/Page column 8-9
(2009/10/22)
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- A facile and regioselective synthesis of rimonabant through an enamine-directed 1,3-dipolar cycloaddition
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Rimonabant is a high-potency cannabinoid type-1 (CB1) receptor inverse agonist that has recently been approved in the European Union as a treatment for obesity. Current methods of synthesis require several steps that have long reaction times and/or lack regioselectivity. Here we present a novel, regioselective synthesis of rimonabant though an enamine-directed 1,3-dipolar cycloaddition. In addition, we present a new and more reactive hydrazonoyl halide for the generation of the requisite nitrile imine dipole.
- Donohue, Sean R.,Halldin, Christer,Pike, Victor W.
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p. 2789 - 2791
(2008/09/19)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF RIMONABANT
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The present invention relates to an industrially advantageous, eco-friendly process for the re aration of rimonabant of formula-(I), staring from l-(4-chlorophenyl)-propan-l-one in high yields and high purity by using mild reaction conditions and avoiding use of toxic and expensive reagents, as well as stringent reaction conditions. The present invention relates to an isolated impurity of rimonabant, referred to as "Bis impurity" and removal thereof.1 The present invention also relates to novel crystalline form-Ill of rimonabant and processes for its preparation and conversion to form-I of rimonabant.
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Page/Page column 15-17
(2008/12/05)
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- POLYMORPHIC FORM OF RIMONABANT HYDROCHLORIDE AND PROCESSES FOR PREPARATION THEREOF
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Provided is a crystalline form of Rimonabant hydrochloride, processes for its preparation and pharmaceutical compositions containing such crystalline form of Rimonabant hydrochloride.
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Page/Page column 12-13
(2008/12/08)
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- PROCESS FOR PREPARATION OF PYRAZOLE DERIVATIVES
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A process for preparation of Pyrazole derivatives adapted for one pot reaction involving the use of a pyclizing agent and involving the step of amidation in the presence of a catalyst. The steps for isolation and purification of found Pyrazole derivatives are also disclosed.
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- Synthesis of rimonabant regioisomer
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A novel synthesis route for a rimonabant regioisomer was developed.
- Kumar, Kotagiri Vijay,Reddy, Jambula Mukunda,Suthrapu, Sashi Kanth,Rao, Chitneni Prasad,Reddy, P. Pratap,Bhattacharya, Apurba,Bandichhor, Rakeshwar
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experimental part
p. 1091 - 1093
(2009/10/24)
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- NOVEL PROCESS FOR THE PREPARATION OF 5-(4-CHLOROPHENYL)-1-(2,4-DICHLOROPHENYL)-4-METHYL-N-(PIPERIDIN-1-YL)PYRAZOLE-3-CARBOXAMIDE
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The present invention relates to a novel process for the preparation of certain pyrazole derivatives, in particular for the preparation of Rimonabant. The process employs carbon-nitrogen-coupling of a pyrazole-derivative in the presence of a transition metal catalyst.
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Page/Page column 8
(2008/12/08)
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- RIMONABANT FORMS AND METHODS OF MAKING THE SAME
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Various solid state forms of rimonabant have been found, including a particulate amorphous form as well as several hydrates and solvates.
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Page/Page column 18
(2008/12/07)
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- Novel polymorphic forms of N-piperidino-5-(4-chlorophenyl)-1-(2, 4-dichlorphenyl)-4-methyl-3-pyrazolecarboxamide
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The present invention relates to novel polymorphic forms of N-piperidino-5-(4-chlorophenyl)-1-(2, 4-dichlorphenyl)-4-methyl-3-pyrazolecarboxamide and to novel methods for their preparation. More particularly the invention relates to the preparation of a monohydrate of N-piperidino-5-(4-chlorophenyl)-1-(2, 4-dichlorphenyl)-4-methyl-3-pyrazolecarboxaniide rimonabant and to a novel anhydrous form of N-piperidino-5-(4-chlorophenyl)-1-(2, 4-dichlorphenyl)-4-methyl-3-pyrazolecarboxamide, and to pharmaceutical compositions thereof.
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Page/Page column 8
(2008/12/07)
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- CRYSTALLINE AND AMORPHOUS FORMS OF RIMONABANT AND PROCESSES FOR OBTAINING THEM
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Novel crystalline polymorphic Form III of rimonabant and an amorphous form of rimonabant. Crystalline form III of rimonabant is prepared by dissolving rimonabant in an aprotic polar solvent such as acetonitrile or tetrahydrofuran, pouring the solution into water and stirring the resulting mixture. Amorphous form of rimonabant is prepared by dissolving in and alcohol of formula ROH, wherein R is an alkyl, such as methanol or isopropyl alcohol, and stirring the mixture. Rimonabant of formula (I) is obtained in such a way that an ester of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxylic acid of formula (III), wherein R is a Cl-C5 alkyl group, phenyl group or a substituted phenyl group, preferably methyl or ethyl, is reacted, in a solvent, preferably in a solvent from the group of diethyl ether, tetrahydrofuran, dioxan, dichloromethane, acetonitrile, toluene or their mixtures, or in an excess of N-aminopiperidine, with N-aminopiperidine with catalysis by at least one Lewis acid at a temperature from 0° C to the boiling point of the solvent or mixture of solvents used. Pharmaceutical compositions containing the above forms and use of the above forms for the manufacture of a medicament the treatment of obesity, for curing of the habit of smoking or for the treatment of Alzheimer or Parkinson diseases are also described.
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Page/Page column 14-15
(2008/12/06)
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- Trimethylaluminium mediated amide bond formation in a continuous flow microreactor as key to the synthesis of rimonabant and efaproxiral
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A safe, functional-group-tolerant and high-throughput version of the trimethylaluminium mediated amide bond formation reaction has been developed in a microreactor system; rimonabant and efaproxiral were prepared to illustrate the utility of the method. The Royal Society of Chemistry.
- Gustafsson, Tomas,Ponten, Fritiof,Seeberger, Peter H.
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p. 1100 - 1102
(2008/09/21)
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- Solid and crystalline rimonabant and processes for preparation, and pharmaceutical composition thereof
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The present invention relates to the solid state chemistry of N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazolecarboxamide which international nonproprietary name is rimonabant, its preparation and pharmaceutical compositions containing said novel polymorph. Thus, the subject of the present invention is a novel polymorphic form of rimonabant, called form III, it also relates to methods for preparing rimonabant in its polymorphic form III, and an amorphous form
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Page/Page column 5-6
(2008/12/06)
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- POLYMORPHS OF RIMONABANT
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Crystalline form C of rimonabant and amorphous rimonabant, processes for their preparation and pharmaceutical compositions thereof.
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Page/Page column 5
(2008/06/13)
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- IMPROVED PROCESS FOR RIMONABANT
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The present invention provides an improved and commercially viable process for the preparation of rimonabant substantially free of amide impurity, namely 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl-4-methyl-pyrazole-3-carboxamide and its pharmaceutically acceptable acid addition salts thereof. Thus, for example, 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl-4-methyl-pyrazole-3-carboxylic acid chloride is reacted with 1-minopiperidine in the presence of a base and optionally using a phase transfer catalyst such as tetra-butylammonium bromide in a biphasic reaction medium containing water and a water-immiscible solvent to obtain pure rimonabant.
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Page/Page column 7-8
(2008/06/13)
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- POLYMORPHS OF RIMONABANT
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Crystalline form C of rimonabant and amorphous rimonabant, processes for their preparation and pharmaceutical compositions thereof.
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Page/Page column 13
(2008/06/13)
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- POLYMORPHIC FORMS OF RIMONABANT BASE AND PROCESSES FOR PREPARATION THEREOF
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The present invention provides process for crystalline forms of Rimonabant base, including processes that prepare crystalline forms of Rimonabant base. Also provided is a crystalline Rimonabant base form I having a substantially reduced residual solvent content, including processes that prepare such crystalline Rimonabant form I. These crystalline forms of Rimonabant base may be in a pharmaceutical compositions further comprising at least one pharmaceutically acceptable excipient.
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Page/Page column 29
(2008/12/07)
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- Synthesis and cannabinoid activity of a variety of 2,3-substituted 1-benzo[b]thiophen derivatives and 2,3-substituted benzofuran: Novel agonists for the CB1 receptor
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An exploratory chemical effort has been undertaken to develop a novel series of compounds as selective CB1 agonists. It is hoped that compounds of this type will have clinical utility in pain control and cerebral ischaemia following stroke or traumatic head injury. We report here medicinal chemistry studies directed towards the investigation of several classes of 1-benzo[b]thiophen and benzofuran derivatives as novel CB1 agonists. We have discovered a novel series of compounds, which contain a 1-benzo[b]thiophen or a benzofuran group as the central aromatic group. Our investigation of this series of compounds has enhanced our understanding of the importance of binding sites within the CB1 receptor for favourable CB1 potency. Our understanding of these factors allowed us to modify the structure of a 1-benzothiophen derivative and improve its potency at the CB1 receptor. CSIRO 2008.
- Moloney, Gerard P.,Angus, James A.,Robertson, Alan D.,Stoermer, Martin J.,Robinson, Michael,Lay, Lucy,Wright, Christine E.,McRae, Ken,Christopoulos, Arthur
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p. 484 - 499
(2008/12/20)
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- PREPARATION AND UTILITY OF SUBSTITUTED PYRAZOLE COMPOUNDS WITH CANNABINOID RECEPTOR ACTIVITY
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The present disclosure is directed to modulators of CB-1 type receptors and pharmaceutically acceptable salts and prodrugs thereof, the chemical synthesis thereof, and the medical use of such compounds for the treatment and/or management of the severity and duration of obesity, metabolic syndrome, dyslipidemia, glucose imbalance, the inability to maintain weight loss, insulin resistance, a cardiovascular disorder, memory loss, drug dependence, a depressive disorder, a panic disorder, an obsessive-compulsive disorder, anxiety, post-traumatic stress syndrome, and any other condition in which it is beneficial to inhibit, inversely agonize or modulate a cannabinoid receptor are described.
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Page/Page column 28-29
(2010/11/29)
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- Novel crystalline forms of an antagonist of CB1 cannabinoid receptor and preparation method thereof
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The present invention relates to several crystalline forms and an amorphous form of an antagonist of CB1 cannabinoid receptor and methods for their preparation. The present invention is also directed towards pharmaceutical compositions comprising these polymorphs ofrimonabant. The invention provides method of treating obesity, smoking cessation, overweight and related diseases by administering to a patient in need thereof a therapeutically effective amount of the different polymorphic forms and the amorphous form of the current invention.
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Page/Page column 7
(2008/06/13)
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- PROCESS FOR PREPARING RIMONABANT
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Processes for preparing rimonabant.
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Page/Page column 19-20
(2010/11/28)
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- POLYMORPHIC FORMS OF RIMONABANT
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Polymorphic crystalline Forms III, IV, V, and VI of rimonabant, amorphous rimonabant, and amorphous rimonabant in an intimate dispersion with a pharmaceutically acceptable carrier.
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Page/Page column 20-21
(2008/06/13)
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- An improved synthesis of rimonabant: Anti-obesity drug
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A novel, cost-effective, and efficient process was developed for the large-scale synthesis of Rimonabant 1, an anti-obesity drug. The process involves the conversion of 4-chloro propiophenone 2 to cyclized acid 6 as a key intermediate that afforded Rimonabant 1 in good yield.
- Kotagiri, Vijay Kumar,Suthrapu, Sashikanth,Reddy, Jambula Mukunda,Rao, Chitneni Prasad,Bollugoddu, Vijaybhaskar,Bhattacharya, Apurba,Bandichhor, Rakeshwar
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p. 910 - 912
(2012/12/30)
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- Polymorphic form of rimonabant method for preparing it and pharmaceutical compositions containing it
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The present invention relates to a novel crystalline polymorph of rimonabant, its method of preparation and the pharmaceutical compositions containing this novel polymorph.
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Page/Page column 6
(2010/02/10)
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- Tritiation of SR141716 by metallation-iodination-reduction: Tritium-proton nOe study
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The central cannabinoid receptor antagonist SR141716, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1 H-pyrazole-3-carboxamide, was synthesized from commercially available starting materials. Condensation of an aryl hydrazine with a diketone followed by base promoted isomerization/cyclization of the intermediate anti-imine gave the pyrazole acid which was converted to the title hydrazide via its acid chloride. Facile iodination via metallation followed by in situ trapping with an iodine source gave a modest yield of the iodinated SR 141716. The iodine was selectively reduced with tritium gas and catalyst while retaining the three aryl chlorine atoms in the structure. The tritiated SR 141716 exhibited a tritium-proton nOe both definitively identifying the position of the tritium as well as the sought isomer of the diarylpyrazole. This work provides a direct method for the preparation of preferred iodinated aryl substrates that offer advantages where selectivity and high incorporation in catalytic reduction is sought. Copyright
- Seltzman, Herbert H.,Carroll, F. Ivy,Burgess, Jason P.,Wyrick, Christopher D.,Burch, David F.
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- The Synthesis and Pharmacological Evaluation of the Cannabinoid Antagonist SR 141716A
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The synthesis of the cannabinoid antagonist SR141716A is described from 4`-chloropropiophenone (1) in a four step sequence in an overall yield of 12 percent. The pharmacological results clearly demonstrate that SR141716A is able to antagonize the in vivo effects of the prototypical cannabinoid agonist Δ9-THC.
- Dutta, Aloke K.,Sard, Howard,Ryan, William,Razdan, Raj K.,Compton, David R.,Martin, Billy R.
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- Synthesis, Spectral Studies and Tritiation of the Cannabinoid Antagonist SR141716A
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An efficient synthesis of the cannabinoid antagonist SR141716A is presented and the structure is established by nOe experiments; tritiated SR141716A is synthesized by a novel sequence of metallation-iodination-tritiation and the labelled site is shown by tritium NMR and tritium-hydrogen nOe experiments.
- Seltzman, Herbert H.,Carroll, F. Ivy,Burgess, Jason P.,Wyrick, Christopher D.,Burch, David F.
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p. 1549 - 1550
(2007/10/02)
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