68 results about "Pimavanserin" patented technology

Combinations of 5-HT2A inverse agonists or antagonists such as pimavanserin with antipsychotics such as risperidone are shown to induce a rapid onset of antipsychotic action and increase the number of responders when compared to therapy with the antipsychotic alone. These effects can be achieved at a low dose of the antipsychotic, thereby reducing the incidence of side effects. The combinations are also effective at decreases the incidence of weight gain and increased glucose or prolactin levels caused by the antipsychotic.

The present invention relates to an intermediate of pimavanserin and a similar compound thereof, and a preparation method thereof, and a method for preparing pimavanserin and a similar compound thereof. According to the present invention, the raw materials required by the intermediate have characteristics of low price, easy obtaining, easy separation purification and no requirement of post-treatment, the next step reaction can be directly performed through the one-pot method to prepare the pimavanserin and the similar compound thereof, the operation is simple, and the economical, efficient, safe and environmentally friendly synthesis process is provided for the preparation of the pimavanserin and the similar compound thereof; and with the application of the intermediate to prepare the pimavanserin, the high toxicity and the use of the difficultly-operated phosgene can be avoided, and the total yield of the reaction can achieves the level in the prior art even the higher level.

The invention discloses a preparation method of pimavanserin. The method comprises the following two steps: firstly, 4-isobutoxy benzene methylamine and carbonyl diimidazole are subjected to acylation reaction to obtain N-(4-isobutoxy phenyl)-1H-imidazole-1-formamide, and the N-(4-isobutoxy phenyl)-1H-imidazole-1-formamide and N-(4-fluorophenyl)-1-methylpiperidine-4-amine are subjected to urea reaction, so as to obtain the pimavanserin. The prepared pimavanserin is good in quality and high in yield, the reagent toxicity is relatively low, the operation is simple and easy to control, and the pimavanserin is suitable for industrial production.

As disclosed herein, co-administration of pimavanserin with an agent that ameliorates one or more cholinergic abnormalities can have a synergistic effect on the efficacy of the agent. Disclosed herein are compositions which include pimavanserin in combination with an agent that ameliorates one or more cholinergic abnormalities. Also disclosed herein are methods for ameliorating or treating a disease condition characterized by one or more cholinergic abnormalities that can include administering pimavanserin in combination with an agent that ameliorates one or more cholinergic abnormalities.

As disclosed herein, co-administration of pimavanserin with an agent that ameliorates one or more cholinergic abnormalities can have a synergistic effect on the efficacy of the agent. Disclosed herein are compositions which include pimavanserin in combination with an agent that ameliorates one or more cholinergic abnormalities. Also disclosed herein are methods for ameliorating or treating a disease condition characterized by one or more cholinergic abnormalities that can include administering pimavanserin in combination with an agent that ameliorates one or more cholinergic abnormalities.

The invention provides a novel synthesis method for pimavanserin. The method comprises the steps that a compound formula (1a) is adopted as a raw material for preparing an active urea compound formula (1) and then subjected to a reaction with a compound formula (2) under an alkaline system to obtain a pimavanserin free alkali formula (3), and then pimavanserin free alkali forms a salt with tartaric acid to obtain a pimavanserin half tartrate formula (4). The method is simple in technological path, low in cost and suitable for industrial production. The formula is shown in the description, wherein HmA is the general formula of m-basic acid, HnA is the general formula of n-basic acid, m and n are 1 or 2 or 3, and the m-basic acid and the n-basic acid are selected from sulfuric acid, hydrochloric acid, phosphoric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, methanoic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid or tartaric acid.

The invention discloses a method for safely preparing pimavanserin and tartrate thereof by utilizing triphosgene. The synthetic route is as shown in the specification. The raw materials used by the method disclosed by the invention are safe, the cost is low, and the production cost is effectively reduced. The method disclosed by the invention is mild in reaction conditions, usage of phosgene thatis high in toxicity and difficult to operate can be avoided, and industrial production is easily realized.

Disclosed herein are methods for obtaining N-(4-fluorobenzyl)-N-(l-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide (pimavanserin) comprising the step of contacting an intermediate according to Formula (A) or a salt thereof, with an intermediate Formula B, or a salt thereof, to produce pimavanserin or a salt thereof wherein Y is -ORi or -NR2aR2b; R3 is hydrogen or substitutedor unsubstituted heteroalicyclyl, R4 is substituted or unsubstituted aralkyl; X is -OR22 or -NR23R24; (wherein R22 is hydrogen or substituted or unsubstituted C1-6alkyl and one of R23 and R24 is hydrogen and the other is hydrogen or N- methylpiperidin-4-yl); and R21 is -OCH2CH(CH3)2 or F; Also disclosed herein is the tartrate salt of N-(4-fluorobenzyl)-N-(l-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide and methods for obtaining the salt.

The invention relates to a preparation method of a pimavanserin intermediate which is 1-isobutoxy-4-isocyanatomethylbenzene. The preparation method comprises that 4-isobutoxyphenylmethanamine as an initial raw material and a bis(trichloromethyl)carbonate solution undergo a reaction under appropriate conditions to produce a desired product. The preparation method is free of highly toxic chemicals, has stable processes and a high yield and is suitable for industrial production.

The present invention relates to a pimavanserin preparation method, wherein 4-isobutoxybenzaldehyde is adopted as a starting raw material, the reaction condition is mild, the gas reaction material is avoided, the product yield is high, the process operation is simple, the special equipment request does not exist, and the method is especially suitable for industrial production.

The invention discloses a pimavanserin intermediate and a preparation method of pimavanserin. A structural general formula of the pimavanserin intermediate is shown in the description; the pimavanserin intermediate is prepared by carrying out reductive amination on 4-isobutoxybenzaldehyde and carbamate; a synthesis route is shown in the description; the pimavanserin is obtained through ammonolysisreaction. According to the preparation method of the pimavanserin intermediate, the target intermediate is obtained in one step through reductive amination reaction and reaction steps of the pimavanserin are extremely simplified; used raw materials are safe and the cost is low; reaction conditions are moderate and phosgene which has great toxicity and is uneasy to operate is not used, so that thepreparation method is easy to realize in industry; the intermediate and a product are easy to separate and purify, and the next-step reaction can be directly carried out to prepare the pimavanserin,without the need of separating the pimavanserin; the preparation method is simple to operate and the yield is higher than that of the prior art; the synthesis cost of the pimavanserin is reduced.

The invention discloses a preparation method of pimavanserin. The preparation method comprises the following steps of mixing 1-(4-fluorobenzyl)-1-(4-methylpiperidyl)urea, 4-isobutoxybenzaldehyde and tetraisopropyl titanate in a solvent, reducing through hydroborate, and then obtaining the pimavanserin through purification. A synthesis method provided by the invention is succinct and high-efficiency, mild in reaction condition, easy to control and high in yield.

The invention discloses a preparation method of a pimavanserin key intermediate. A synthesis route comprises a process shown in the description. According to the method disclosed by the invention, used raw materials are safe and the cost is low, so that the production cost is effectively reduced. The method disclosed by the invention has moderate reaction conditions and the utilization of phosgenewhich has great toxicity and is not easy to operate can be avoided, so that the method is easy to realize in industry.

The invention discloses a preparation method of Pimavanserin. The preparation method comprises the following steps: (1) adopting 4-isobutoxy benzaldehyde to react with hydroxylamine hydrochloride in an alkaline liquor to prepare 4-isobutoxy benzaldoxime; (2) adopting a reducing agent to reduce the 4-isobutoxy benzaldoxime so as to generate 4-isobutoxy benzylamine; (3) adopting a carbonyl compound to react with the 4-isobutoxy benzylamine to prepare N-(4-isobutoxy benzyl) phenyl carbamate; and (4) adopting the N-(4-isobutoxy benzyl) phenyl carbamate to react with N-(4-fluorobenzyl)-1-methyl piperidine-4-amine, and thus obtaining the Pimavanserin. Heating is not needed when the 4-isobutoxy benzaldoxime is prepared in the method, so that the energy consumption is reduced; zinc powder is used for replacing hydrogen and palladium carbon so as to generate the 4-isobutoxy benzylamine, and low-cost easily-obtained diphenyl carbonate is used for replacing hypertoxic carbonyl chloride and expensive DPPA, so that the safety is improved, and the environmental protection is facilitated.

The invention discloses a method for preparing a crystal form B of pimavanserin semi-tartrate. The method comprises the following steps of adding the pimavanserin semi-tartrate into absolute methanol, stirring, heating, and dissolving; cooling, crystallizing, filtering, and drying, so as to obtain the crystal form B of the pimavanserin semi-tartrate, wherein the weight and volume ratio of the pimavanserin semi-tartrate to the absolute methanol is 1:(4 to 5)g / ml. The method has the advantages that by using the absolute methanol as the solvent, the crystal form B of the pimavanserin semi-tartrate is successfully prepared; the method is simple and convenient, the production efficiency is high, the economic benefit is good, and the method is suitable for industrialized production.

The invention provides an improved method for preparing pimavanserin and tartrate thereof. The method comprises the following steps: taking a compound 4-(4-fluorobenzylamino)-1-methylpiperidine as a starting material and carrying out acylation reaction on the starting material and triphosgene in the presence of triethylamine to prepare a compound (4-fluorobenzyl)-(1-methylpiperidine-4-yl)carbamyl chloride; then taking the (4-fluorobenzyl)-(1-methylpiperidine-4-yl)carbamyl chloride and 4-isobutoxybenzylamine to react in the presence of triethylamine, so as to prepare the pimavanserin and the tartrate thereof. The method provided by the invention is simple, efficient and economical and the quality of an intermediate is controllable, so that the method is suitable for industrial preparation.

The invention belongs to the field of pharmaceutic preparation, and particularly relates to a pimavanserin tablet and a preparation method thereof. The pimavanserin tablet is composed of active components of pimavanserin, colloidal silicon dioxide, polyethylene glycol, a filling agent selected from dextrin, corn starch, pregelatinized starch, cellulose microciystalline, mannitol and lactose, a disintegrating agent selected from carboxymethyl starch sodium, croscarmellose sodium, low-substituted hydroxypropyl cellulose and crospovidone, and a lubricating agent selected from magnesium stearate,talcum powder, and sodium stearyl fumarate. The pimavanserin tablet has good stability, and can significantly improve drug dissolution and bioavailability.

The invention belongs to the field of medicine preparations and relates to a tartaric acid pimavanserin oral instant film and a preparation method thereof. The tartaric acid pimavanserin oral instant film is good in taste, can be quickly dissolved in the oral cavity when taken without water, and is particularly suitable for the aged and patients suffering from dysphagia. A preparation process of the tartaric acid pimavanserin oral instant film is simple and easy to implement, auxiliary materials are common and moderate in price, and industrial prospects are good. Each tartaric acid pimavanserin oral instant film contains 20 mg of tartaric acid pimavanserin. The invention further provides the preparation process of the tartaric acid pimavanserin oral instant film.

The invention discloses tartaric acid pimavanserin impurities, namely N-(4-isobutoxy benzyl) diphenyl aminodiphthalate (impurity A), 4-isobutoxy benzyl carbonic acid phenyl ester (impurity B), 4-fluorobenzyl (1-methylpiperidine-4-yl) carbonic acid-4-isobutoxy benzyl ester (impurity C) and N-( isobutoxy benzyl)-N'-(4-fluorobenzyl) urea (impurity E). In addition, the invention further discloses a preparation method of tartaric acid pimavanserin impurities A, B, C and E and an N,N'-bis(4-isobutoxy benzyl) urea (impurity D). Through application of the tartaric acid pimavanserin impurities as reference substances in research on the quality of the tartaric acid pimavanserin intermediate, a crude drug and a compound preparation thereof, a solid foundation is laid for research on the quality of tartaric acid pimavanserin.

The invention relates to application of pimavanserin in preparation of antitumor drugs, belongs to the technical field of medicines, and particularly relates to novel application of pimavanserin in preparation of antitumor drugs. The structural formula of the pimavanserin is shown in the formula I. The biological activity test of the compound shows that the compound has antitumor activity and is a novel antitumor drug.

The present invention includes composition and methods for treating cancers comprising administering to a subject a pharmaceutical composition comprising Pimavanserin or derivatives thereof in an amount sufficient to treat the reproductive cancer in the subject and a pharmaceutically acceptable carrier.

The invention discloses a preparation method of a pimavanserin hemitartrate crystal form C. The method includes the steps of: (1) under the protection of an inert gas, adding pimavanserin free alkali into butanone, and conducting dissolving, then adding tartaric acid to carry out reaction to obtain a reaction solution; (2) carrying out crystallization, filtering and drying on the reaction solution obtained in step (1), thus obtaining the pimavanserin hemitartrate crystal form C. The method adopts pimavanserin free alkali as the raw material, and successfully prepares the pimavanserin hemitartrate crystal form C. Compared with the prior art, the method provided by the invention is simple, safe and environment-friendly, shortens the stirring crystallization time from 3 days to 2-3 hours, greatly improves the production efficiency, has good economic benefits, and is very suitable for industrial production.

The invention provides a method for preparing a pimavanserin crystal form C. The method comprises the step of: conducting reflux on a tartrate crystal A of N-(4-fluorobenzyl)-N-(1-methylpiperidine-4-yl)-N'-(4-(2-methyl propoxy)-phenyl methyl) urea in acetone for 3-6 h to obtain the pimavanserin crystal form C. The invention creatively realizes the crystal form transformation of pimavanserin by simple heating and refluxing, does not need deoxidation treatment of solvent, or the protection of inert gas, or addition of seeds; and the operation steps are simple without harsh conditions, and are more conducive to industrialization.

The invention discloses a method for preparing a pimavanserin hemitartrate crystal form B. The method comprises the following steps: adding pimavanserin hemitartrate into water; and after the pimavanserin hemitartrate is dissolved, concentrating and drying to obtain the pimavanserin hemitartrate crystal form B, wherein the weight-to-volume ratio of the pimavanserin hemitartrate to the water is 1:(4-6) g / ml. By using the nontoxic harmless water as the solvent, the pimavanserin hemitartrate crystal form B is successfully prepared. Besides, the method is simple and convenient, has the advantages of high safety, environment friendliness, high production efficiency and favorable economic benefits, and is very suitable for industrialized production.

The present disclosure relates to novel, safe and efficient processes for the synthesis of Pimavanserin and salts thereof, as well as novel intermediates that can be used in these processes.

The invention relates to a one-pot preparation method for pimavanserin. The method prepares pimavanserin (a compound IV) from 4-isobutoxybenzylamine as shown in a formula (II) or a salt thereof, a carbonylation reagent as shown in a formula (III) and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine as shown in a formula (I) by using a one-pot process. The method is highly efficient, high in yield, low in cost, safe, environment friendly and suitable for industrial production, and has great application value.

The invention belongs to the field of pharmaceutical preparations and particularly relates to a pimavanserin nanocrystalline capsule and a preparation method thereof. The preparation method comprisesthe following steps: 1) adding pimavanserin and poloxamer 188 to water, and carrying out mixing to obtain a mixed solution; 2) homogenizing the mixed solution for 3 times to obtain a suspension; 3) performing spray drying on the suspension in a spray dryer; and 4) after mixing with other auxiliary materials, performing capsule filling. The prepared pimavanserin capsule can significantly increase the dissolution rate so as to improve the bioavailability of the medicine in vivo.

Combinations of 5-HT2A inverse agonists or antagonists such as pimavanserin with antipsychotics such as risperidone are shown to induce a rapid onset of antipsychotic action and increase the number of responders when compared to therapy with the antipsychotic alone. These effects can be achieved at a low dose of the antipsychotic, thereby reducing the incidence of side effects. The combinations are also effective at decreases the incidence of weight gain and increased glucose or prolactin levels caused by the antipsychotic.

The invention relates to a pharmaceutical composition containing pimavanserin and a preparation method for the pharmaceutical composition. According to the composition suitable for preparing the orally disintegrating tablet, active ingredients are contained, a disintegrating agent and a diluent are also contained, in addition, a proper amount of a flavoring agent, a lubricant and a flow aid can also be contained. The composition has the advantages of being simple in prescription and mature in process, and only common tablet production equipment is adopted. The pharmaceutical composition can berapidly disintegrated within 30 s in an oral cavity and is not required to be taken with water, the medication compliance of Parkinson's disease is improved, and the economic loss caused by drug discarding by a patient can be avoided.