49 results about "Cariprazine" patented technology

The invention discloses a preparation method of cariprazine (Cariprazine, RGH 188). The method includes the preparation steps of preparing 4-[2-[4-(2,3-dichlorophenyl)piperazine]-1-based]ethyl]cyclohexanone by making 4-(2-hydroxyethyl)cyclohexanone and 1-(2,3-dichlorophenyl)piperazine subjected to a condensation reaction, preparing trans-4-[[2-]4-(2,3-dichlorophenyl)piperazine]-1-based]ethyl]cyclohexylamine by making the obtained intermediate subjected to a reduction ammonolysis reaction, and preparing cariprazine by making the intermediate and N,N-dimethylcarbamyl chloride subjected to an acylation reaction. According to the preparation method, raw materials can be easily obtained, the process is simple, and the method is economical, environmentally friendly and suitable for industrialized production.

The invention discloses a 3-cyclohexyl-1,1-dimethylurea compound as well as a preparation method and application thereof. The 3-cyclohexyl-1,1-dimethylurea compound is used for preparing an antischizophrenic drug cariprazine. Compared with the prior art and report literatures, the preparation method of the 3-cyclohexyl-1,1-dimethylurea compound has the remarkable advantages of being free of removal of protecting groups such as Boc group, high in atom economy, low in cost and easy in getting of raw materials, mild in reaction condition, stable in yield, simple and convenient to operate, controllable in product quality, high in product purity, less in three waste pollution and easy to produce industrially. The structure formula of the 3-cyclohexyl-1,1-dimethylurea compound is as shown in (I) in the specification.

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.

The invention provides a preparation method for a trans 4-amino-cyclohexyl acetate derivative. The preparation method comprises the following steps that a formula (please see the description for the formula) is provided, wherein R is methyl or ethyl; a compound III is prepared from the raw materials of 4-amino cyclohexanone II and is subjected to hydrogenation reduction, a compound I crude product is obtained, acid is added, and salt is formed; and a compound I is prepared by adding alkali. According to the preparation method, 4-amino cyclohexanone not protected by amino is adopted as raw materials, witting reaction is conducted, and then through catalytic hydrogenation, the trans crude product of the preparation method is obtained. The crude product can be subjected to salifying crystallization so as to obtain the purer trans product, and the trans:syn ratio is 95-99.9:5-0.1. The product compound is high in purity and can be used for preparing cariprazine. Operation is simple, the raw materials are easy to obtain, industrial production is suitable, and large application value is achieved.

The invention belongs to the technical field of organic synthesis, and provides a novel method for synthesizing cariprazine. The novel method comprises the following steps: firstly, carrying out condensation reaction on trans-2-(4-(3,3-dimethyl ureido) cyclohexyl) acetic acid and 1-(2,3-dichlorophenyl) piperazine to obtain 3-(trans-4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-2-oxo-ethyl}-cyclohexyl)-1,1-dimethylurea; and secondly, reducing 3-(trans-4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-2-oxo-ethyl}-cyclohexyl)-1,1-dimethylurea by using borane to obtain the cariprazine. The method hasthe advantages that process steps are greatly shortened, the purity of a final product is ensured and the total yield is obviously increased.

The invention relates oral phamiaceuticai compositions for the modified release delivery of cariprazine (trans-N-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-l-yl]-ethyl]-cyclohexyl}-N',N'- dimethylurea) or pharmaceutically acceptable salts thereof for less than daily dosing. The invention also relates to the use of said compositions in the treatment and / or prevention of pathological conditions which require the modulation of dopamine receptors. The invention also relates to the process for the preparation of said modified release pharmaceutical compositions.

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.

The invention belongs to the technical field of medicines and particularly relates to a cariprazine trihydrate compound. The obtained cariprazine trihydrate compound contains three crystallization waters and has the advantages as follows: the purity is high, the stability is good and moisture-absorption weight gain is not remarkable under the high-humidity condition.

In the process of the present invention, cariprazine is prepared by converting (trans-4-amino-cyclohexyl)-acetic acid ethyl ester hydrochloride to trans-4-aminocyclohexyl) acetic acid or its hydrochloride by hydrolysis, from the obtained product with addition of dimethylcarbamoyl derivative as a suitable reagent (trans-4-{[(dimethylamino)carbonyl]amino}cyclohexyl) acetic acid is formed, then the obtained compound is linked to 1-{2,3-dichlorophenyl)˜piperazine in the presence of carboxylic acid activating coupling reagent, and so 1,1-dimethyl-3-[trans-4-(2-oxo-2-(4-(2,3-dichlorophenyl)piperazin-1-yl-ethyl)cyclohexyl] urea is formed, which is converted to cariprazine borane adduct of formula (2) in the presence of reducing agent, and finally the product itself is eliminated directly or is obtained from its salt by a known method. The invention also relates to a group of intermediate compounds that are formed and / or used in the process according to the present invention.

The invention relates oral pharmaceutical compositions for the modified release delivery of cariprazine (trans-N-{4[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-N′,N′-dimethylurea) or pharmaceutically acceptable salts thereof for less than daily dosing. The invention also relates to the use of said compositions in the treatment and / or prevention of pathological conditions which require the modulation of dopamine receptors. The invention also relates to the process for the preparation of said modified release pharmaceutical compositions.

The present invention relates to trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N′,N′-dimethylurea (cariprazine), its salts, close analogs, derivatives, pharmaceutical compositions, metabolites and combinations for use in the treatment of symptoms of autism spectrum disorder in general, and preferably the object of the present invention is to treat one or more symptoms of autism.Furthermore, it was also found that cariprazine, its salts, close analogs, derivatives, pharmaceutical compositions, metabolites and combinations are suitable for treatment of conditions such as Asperger's syndrome, atypical autism (otherwise known as pervasive developmental disorder not otherwise specified; PDD-NOS), Rett syndrome, childhood disintegrative disorder, attention deficit hyperactivity disorder (ADHD) and sensory integration dysfunction.

The invention discloses an orally disintegrating tablet of cariprazine and a preparation method thereof. The orally disintegrating tablet of cariprazine comprises, by mass, 0.8 to 3.6% of cariprazinehydrochloride, 0 to 2.0% of a binder, 16 to 48% of a disintegrating agent, a diluent and a lubricant. The orally disintegrating tablet of cariprazine can be rapidly disintegrated and dissolved out inthe oral cavity, has good hardness and wear resistance, and can improve the compliance of patients, mitigate the burden of nursing people, effectively prevent psychopaths from hiding and spitting cariprazine and improve treatment effect. The preparation method for the orally disintegrating tablet of cariprazine is simple, can carry out production in conventional workshops for oral solid preparations, has low production cost and is capable of realizing large-scale industrial production.

The present invention relates to stabilized pharmaceutical formulations comprising therapeutically effective amount of Cariprazine premix / solid dispersion, or its pharmaceutically acceptable salts, esters, hydrates and solvates thereof, at least one diluent which is not having low water activity and optionally one or more excipients selected from lubricant, disintegrant and buffering agent or combinations thereof. The present invention further relates to process for preparation and method of using such stable formulations comprising Cariprazine.

The present application relates to a synthesis method for cariprazine, comprising performing an acylation reaction between a compound represented by formula (I) and dimethylcarbamoyl chloride in a reaction solvent in the presence of an aqueous solution of an inorganic base, so as to obtain the cariprazine compound represented by formula (II). The synthesis method overcomes defects in the prior art such as a long reaction time, large size impurities and the difficulty of purification, and provides a new method suitable for commercial production wherein the reaction is fast, impurity sizes are small, the product is easily purified, the purity of the product can reach 99.0% or more, and the yield is high.

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.

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 organic solvent, an acid-binding agent and an additive to obtain the cariprazine. The preparation method of cariprazine provided by the invention hasthe advantages of short reaction time, high reaction yield, few byproducts, simple post-treatment and suitability for industrial production, and overcomes the problems of difficult solvent recovery,environmental pollution, complex operation and the like in the prior art.

The invention provides a cariprazine hydrochloride injection preparation and its preparation method and application. When the injection preparation is used, it is a suspension aqueous solution, wherein the concentration of cariprazine hydrochloride is relatively high, and the stability is good, and a higher dosage can be obtained in a limited injection volume, and it can also be used according to the long-acting administration time. The dose can be flexibly adjusted, and by controlling the particle size distribution and the injection dose, a long-acting effect can be achieved. After injection, the preparation can release cariprazine continuously for at least 1 week, and can be administered once a week or more. Long dosing intervals to increase patient compliance. The invention also provides a preparation method of the cariprazine hydrochloride injection preparation, the injection preparation prepared by the method has good stability and high safety, the method is simple and easy, and is suitable for industrial production.

The invention discloses a preparation method of a cariprazine-hydrophilic material blend solid preparation. The solid preparation comprises a cariprazine-hydrophilic material blend and other pharmaceutically acceptable ingredients, wherein the cariprazine-hydrophilic material blend effectively improves the dissolution speed of cariprazine in the solid preparation, is favorable for improving the bioavailability of a drug, and is used to treat a patient with schizophrenia and diphasic I type related psychlampsia or mixed episode, and the process is simple and convenient and is suitable for industrial production.

The patent discloses long-term injectable formulations and delivery systems of cariprazine and related salts and derivatives in the prevention and treatment of various psychotic diseases, such as schizophrenia, mania, and bipolar disorder. The dosage forms are either microsphere, microparticle, nanoparticle drug delivery systems in a pharmaceutically acceptable carrier, or devices that contain long-term injectable formulation of such cariprazine and related salts and derivatives.

The invention relates to a method for preparing cariprazine and an intermediate thereof, and the method comprises the following steps: taking trans-4-aminocyclohexane acetate hydrochloride as a starting material, and carrying out Boc protection, reduction, halogenation, nucleophilic substitution, Boc protection removal and amidation reaction to prepare the cariprazine. The alcoholic hydroxyl group of the trans-2-{1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl} ethanol is activated and converted into a group easy to leave, the alcoholic hydroxyl group is creatively converted into the halogen atom, the reaction condition is mild, the yield is high, the raw material medicine which is high in purity and low in impurity content and meets the medicinal requirement can be obtained, and the method is suitable for industrial production.

The invention provides a preparation method of cariprazine and an intermediate compound. The preparation method disclosed by the invention is simple in process, high-temperature and high-pressure conditions are not needed, a precious catalyst is not used, the cost is saved, and the prepared cariprazine is high in yield and purity.

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.

The present invention relates to trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea (cariprazine), its salts, close analogs, derivatives, pharmaceutical compositions, metabolites and combinations for use in the treatment of symptoms of autism spectrum disorder in general, and preferably the object of the present invention is to treat one or more symptoms of autism. Furthermore, it was also found that cariprazine, its salts, close analogs, derivatives, pharmaceutical compositions, metabolites and combinations are suitable for treatment of conditions such as Asperger's syndrome, atypical autism (otherwise known as pervasive developmental disorder not otherwise specified; PDD-NOS), Rett syndrome, childhood disintegrative disorder, attention deficit hyperactivity disorder (ADHD) and sensory integration dysfunction.

The invention provides a kind of preparation method of cariprazine, it comprises the steps: trans-2-(trans-4-(3,3-dimethylureido) cyclohexyl) derivative reacts in acid-binding agent Reaction with 1‑(2,3‑dichlorophenyl)piperazine or its salts under conditions, followed by reaction with reducing agent to generate cariprazine. The synthesis route of cariprazine of the present invention has few steps, simple process and meets production requirements.

The invention relates to a preparation method of cariprazine. The invention provides a novel intermediate of cariprazine and a method for preparing cariprazine from the intermediate. According to the method, use of a genotoxic impurity dimethyl carbamoyl chloride is avoided, so that the safety is good, the product yield and purity are ideal, and the method is suitable for industrial production.

The invention belongs to the technical field of organic synthesis, and provides a novel method for synthesizing cariprazine. The novel method comprises the following steps: firstly, carrying out condensation reaction on trans-2-(4-(3,3-dimethyl ureido) cyclohexyl) acetic acid and 1-(2,3-dichlorophenyl) piperazine to obtain 3-(trans-4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-2-oxo-ethyl}-cyclohexyl)-1,1-dimethylurea; and secondly, reducing 3-(trans-4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-2-oxo-ethyl}-cyclohexyl)-1,1-dimethylurea by using borane to obtain the cariprazine. The method hasthe advantages that process steps are greatly shortened, the purity of a final product is ensured and the total yield is obviously increased.

The invention provides a preparation method of cariprazine and an intermediate thereof. The invention discloses a preparation method of a cariprazine intermediate 5, which comprises the following steps: a) carrying out condensation reaction on 2-[1-(4-amino]-cyclohexyl)-ethyl acetate hydrochloride 1 and an amino protection reagent in a solvent in the presence of alkali to obtain a cariprazine intermediate 2; b) in a solvent, hydrolyzing the cariprazine intermediate 2 under an alkaline condition, and then acidifying to obtain a cariprazine intermediate 3; and c) carrying out condensation reaction on the cariprazine intermediate 3 and 1-(2, 3-dichlorophenyl)-piperazine 4 in an organic solvent in the presence of a catalyst and alkali to obtain the cariprazine intermediate 5. The preparation method has the advantages of easily available raw materials, simple operation and high reaction yield, and is suitable for industrial production.