- Discovery of cariprazine (RGH-188): A novel antipsychotic acting on dopamine D3/D2 receptors
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Medicinal chemistry optimization of an impurity isolated during the scale-up synthesis of a pyridylsulfonamide type dopamine D3/D 2 compound (1) led to a series of new piperazine derivatives having affinity to both dopamine D3/
- ágai-Csongor, éva,Domány, Gy?rgy,Nógrádi, Katalin,Galambos, János,Vágó, István,Keser, Gy?rgy Miklós,Greiner, István,Laszlovszky, István,Gere, Anikó,Schmidt, éva,Kiss, Béla,Vastag, Mónika,Tihanyi, Károly,Sághy, Katalin,Laszy, Judit,Gyertyán, István,Zájer-Balázs, Mária,Gémesi, Larisza,Kapás, Margit,Szombathelyi, Zsolt
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Read Online
- C-N bond formation by consecutive continuous-flow reductions towards a medicinally relevant piperazine derivative
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A new, continuous-flow consecutive reduction method was developed for the C-N bond formation in the synthesis of the key intermediate of the antipsychotic drug cariprazine. The two-step procedure consists of a DIBAL-H mediated selective ester reduction conducted in a novel, miniature alternating diameter reactor, followed by reductive amination using catalytic hydrogenation on 5% Pt/C. The connection of the optimized modules was accomplished using an at-line extraction to prevent precipitation of the aluminum salt byproducts.
- éles, János,Bana, Péter,Fül?p, Zsolt,Greiner, István
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supporting information
(2021/05/28)
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- Nitrogen-containing ring derivative regulator as well as preparation method and application thereof
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The invention relates to a nitrogen-containing ring derivative regulator as well as a preparation method and an application thereof. In particular, the present invention relates to a compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and an application of the compound as a G-protein coupled receptor modulator in the treatment or prevention of central nervous system diseases and/or mental diseases.
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Paragraph 0227; 0228-0234
(2021/05/12)
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- Preparation method of cariprazine
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The invention provides a preparation method of cariprazine, which comprises the following steps: reacting trans-N-tert-butyloxycarbonyl-4-(2-(4-(2,3-dichlorophenyl)-piperazine-1-yl)-ethyl)-cyclohexylamine with dimethylamine under the conditions of an orga
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Paragraph 0062-0067
(2020/07/02)
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- Novel preparation method of cariprazine
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The invention belongs to the field of medicinal chemistry, and mainly relates to a preparation method of novel N'-(trans-4-{2-[4-(2,3-dichlorophenyl)-1-piperazinyl]ethyl}cyclohexyl)-N,N-dimethylurea,which is as shown in the specification.
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- New preparation method of capsazine (by machine translation)
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The present invention relates to a novel N' - (trans -4 - {2 - [4 - (2,3 -dichlorophenyl) -1 - piperazinyl] ethyl} cyclohexyl) - N, N -piperazine 2 - yl]-ethyl}-cyclohexylamine dihydrochloride monohydrate: c) trans N - {1 - {2,3 - 4 -} [1 - (-1 - 2-dichlorophenyl)-piperaz 3-yl]-ethyl}-cyclohexylamine dihydrochloride (c)-cyclohexyl}-cyclohexylamine dihydrochloride (hereinafter referred to as [-1 -4 - (2 -dichlorophenyl)-piperazinyl-4 -yl] 40 - 100 °C 2 -ethyl}-cyclohexylamine -4 - dihydrochloride 2 - (4 - b 2,3 -): c)-cyclohexyl}-cyclohexyl}-(b) 2 -4 - ethyl}-cyclohexylamine dihydrochloride 4 - (b 4 -) 2,3 - c)-1 - cyclohexyl}-cyclohexylamine dihydrochloride (b)-cyclohexylamine dihydrochloride (c) 4 - 2,3 -1 . Contrary to triphosgene, the PH was adjusted to 8 - 9, and concentrated to isolate N' - (trans -4 - {2 - [4 - (2,3 -dichlorophenyl) -1 - piperazinyl] ethyl} cyclohexyl) - N, N - dimethylurea. (by machine translation)
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Paragraph 0006-0009
(2020/06/17)
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- Preparation method of cariprazine key intermediate
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The invention relates to a preparation method of a novel cariprazine key intermediate, namely, trans-4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-cyclohexylamine dihydrochloride. The method comprises the following steps of: a) subjecting trans-2-{1-[4-(N-tert-butyloxycarbonyl)-amino] cyclohexyl}-ethanol and 1-(2,3-dichlorophenyl)piperazine to a condensation reaction to prepare trans-N-tert-butyloxycarbonyl-4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-cyclohexylamine; and b) heating the obtained trans-N-tert-butyloxycarbonyl-4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-cyclohexylamine to a temperature of 40-100 DEG C in a mixture containing aqueous hydrochloric acid/methanol to obtain the trans-N-4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-cyclohexylamine dihydrochloride.
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Paragraph 0005-0006
(2020/07/12)
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- D2 Dopamine Receptor G Protein-Biased Partial Agonists Based on Cariprazine
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Functionally selective G protein-coupled receptor ligands are valuable tools for deciphering the roles of downstream signaling pathways that potentially contribute to therapeutic effects versus side effects. Recently, we discovered both Gi/o-bi
- Shen, Yudao,McCorvy, John D.,Martini, Michael L.,Rodriguiz, Ramona M.,Pogorelov, Vladimir M.,Ward, Karen M.,Wetsel, William C.,Liu, Jing,Roth, Bryan L.,Jin, Jian
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p. 4755 - 4771
(2019/05/08)
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- Preparation method of cariprazine
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The invention provides a preparation method of cariprazine. The preparation method of the cariprazine includes that a trans-2-(trans-4-(3, 3-dimethylureido) cyclohexyl) derivative is enabled to reactwith 1-(2, 3-dichlorophenyl) piperazine or salt thereof in an acid-binding agent reaction condition, and then the cariprazine is generated in a reducing agent reaction condition. The preparation method of the cariprazine is few in a synthetic route, simple in technology and conformable to production requirements.
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Paragraph 0084-0085
(2019/10/22)
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- Cyclohexane amine D3/D2 receptor partial agonist
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The invention belongs to the technical field of biomedicine, and particularly relates to a cyclohexane amine D3/D2 receptor partial agonist, and a pharmaceutically acceptable salt, a synthesis methodand use of the cyclohexane amine D3/D2 receptor partial
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Paragraph 0059; 0060; 0064; 0065
(2019/11/12)
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- Method for preparing medicinal carliflazine composition
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The invention provides a medicinal high-purity carliflazine composition and a method for preparing the medicinal high-purity carliflazine composition. The preparation process of the medicinal carliprazine composition can obviously reduce the content of mo
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Paragraph 0046-0047
(2019/10/01)
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- Compound for preparation of cariprazine and preparation method thereof
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The invention relates to a compound for preparation of cariprazine and a preparation method thereof. The method can overcome the defects in the prior art, the used raw materials and reagents are low toxic, cheap and easily available, the reaction conditions are mild, fewer three wastes are generated, at the same time, the operation is simple and safe, and the yield is good, therefore the method is suitable for industrialized production.
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- Structure-Activity Study of N -((trans)-4-(2-(7-Cyano-3,4-dihydroisoquinolin-2(1 H)-yl)ethyl)cyclohexyl)-1 H -indole-2-carboxamide (SB269652), a Bitopic Ligand That Acts as a Negative Allosteric Modulator of the Dopamine D2 Receptor
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We recently demonstrated that SB269652 (1) engages one protomer of a dopamine D2 receptor (D2R) dimer in a bitopic mode to allosterically inhibit the binding of dopamine at the other protomer. Herein, we investigate structural determinants for allostery, focusing on modifications to three moieties within 1. We find that orthosteric "head" groups with small 7-substituents were important to maintain the limited negative cooperativity of analogues of 1, and replacement of the tetrahydroisoquinoline head group with other D2R "privileged structures" generated orthosteric antagonists. Additionally, replacement of the cyclohexylene linker with polymethylene chains conferred linker length dependency in allosteric pharmacology. We validated the importance of the indolic NH as a hydrogen bond donor moiety for maintaining allostery. Replacement of the indole ring with azaindole conferred a 30-fold increase in affinity while maintaining negative cooperativity. Combined, these results provide novel SAR insight for bitopic ligands that act as negative allosteric modulators of the D2R.
- Shonberg, Jeremy,Draper-Joyce, Christopher,Mistry, Shailesh N.,Christopoulos, Arthur,Scammells, Peter J.,Lane, J. Robert,Capuano, Ben
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p. 5287 - 5307
(2015/08/03)
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- 1,4-CYCLOHEXYLAMINE DERIVATIVES AND PROCESSES FOR THE PREPARATION THEREOF
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The invention relates to a process for the synthesis of Cariprazine, an antipsychotic compound useful in the treatment of positive and negative symptoms associated to schizophrenia, with the following structural formula: (A) The invention further relates to the synthesis of intermediates useful in the preparation of Cariprazine.
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Page/Page column 13
(2015/05/05)
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- A structure-activity analysis of biased agonism at the dopamine D2 receptor
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Biased agonism offers an opportunity for the medicinal chemist to discover pathway-selective ligands for GPCRs. A number of studies have suggested that biased agonism at the dopamine D2 receptor (D2R) may be advantageous for the treatment of neuropsychiatric disorders, including schizophrenia. As such, it is of great importance to gain insight into the SAR of biased agonism at this receptor. We have generated SAR based on a novel D2R partial agonist, tert-butyl (trans-4-(2-(3,4-dihydroisoquinolin- 2(1H)-yl)ethyl)cyclohexyl)carbamate (4). This ligand shares structural similarity to cariprazine (2), a drug awaiting FDA approval for the treatment of schizophrenia, yet displays a distinct bias toward two different signaling end points. We synthesized a number of derivatives of 4 with subtle structural modifications, including incorporation of cariprazine fragments. By combining pharmacological profiling with analytical methodology to identify and to quantify bias, we have demonstrated that efficacy and biased agonism can be finely tuned by minor structural modifications to the head group containing the tertiary amine, a tail group that extends away from this moiety, and the orientation and length of a spacer region between these two moieties.
- Shonberg, Jeremy,Herenbrink, Carmen Klein,López, Laura,Christopoulos, Arthur,Scammells, Peter J.,Capuano, Ben,Lane, J. Robert
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p. 9199 - 9221
(2014/01/06)
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- PIPERAZINE SALT AND A PROCESS FOR THE PREPARATION THEREOF
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The invention relates to novel trans N-{4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-il]-ethyl}- cyclohexylamine dihydrochloride monohydrate and a process for the preparation of the trans N- {4- {2-[4-(2,3-dichlorophenyl)-piperazine-l -il]-ethyl}-cyclohexyla
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Page/Page column 6
(2010/08/05)
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