- METHODS FOR THE TREATMENT OF OBESITY USING APREMILAST
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Methods of treating, managing or preventing obesity and overweight are disclosed. Specific methods encompass the administration of apremilast, alone or in combination with additional active agents or treatment regimens.
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Paragraph 0081
(2019/05/22)
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- APREMILAST FOR THE TREATMENT OF A LIVER DISEASE OR A LIVER FUNCTION ABNORMALITY
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Methods of treating, managing or preventing liver disease are disclosed. Specific methods encompass the administration of apremilast, alone or in combination with additional active agents or treatment regimens.
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Paragraph 0100
(2019/09/15)
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- NOVEL PROCESS FOR THE PREPARATION OF 1-(3-ETHOXY-4-METHOXY-PHENYL)-2-METHYLSULFONYL-ETHANAMINE
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The present invention relates to a process for the preparation of 1-(3-ethoxy-4-methoxy-phenyl)-2-methylsulfonyl-ethanamine, an intermediate for the preparation of apremilast via a compound of Formula (V) wherein R is (C1-C4)alkyl, (C1-C4)haloalkyl, -O(C1-C4)alkyl, or –O-benzyl, and L is a leaving group.
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- NOVEL PROCESS FOR PREPARATION OF APREMILAST
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The present invention related to a novel compound of Formula II, its enantiomers or acid addition salts thereof and process for its preparation. The compound of Formula II can be used for preparation of N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide also known as apremilast.
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- Synthesis process of apremilast intermediate
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The invention discloses a synthesis process of an apremilast intermediate. The synthesis process comprises the following steps: (a) carrying out reaction on 3-ethoxyl-4-methoxystyrene and methanesulfonyl chloride under the action of a ruthenium catalyst to generate 4-[(1-chloro-2-methylsulfonyl)-ethyl]-2-ethoxyl-1-methoxybenzene; and (b) carrying out reaction on 4-[(1-chloro-2-methylsulfonyl)-ethyl]-2-ethoxyl-1-methoxybenzene and an alcohol liquid of ammonia, so as to obtain 1-(3-ethoxyl-4-methoxyl)phenyl-2-methylsulfonylethylamine. The synthesis process is simple and convenient to operate, and special reaction conditions are not needed, so that the synthesis process is more suitable for industrial production.
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- PROCESS FOR PREPARATION OF APREMILAST
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The present invention relates to a process for preparation of apremilast. The present invention relates to p-xylene solvate of apremilast and process for its preparation.
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Paragraph 00115
(2017/03/14)
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- A synthetic apps is special method for the preparation of intermediates
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The invention relates to a preparation method for synthesizing an apremilast intermediate. The preparation method comprises the following steps of: carrying out condensation reaction on 3-ethoxyl-4-methoxyl-benzoate and dimethyl sulfone under an alkaline condition to generate 2-(3-ethoxy-4-methoxyphenyl)-1-methylsulfonyl acetone; reacting the compound II and chiral amine in the presence of an acidic catalyst to obtain 1-N-substituted amino-1-(3-ethoxyl-4-methoxyl) phenyl-2-methylsulfonyl ethylene (III), and directly hydrogenating the obtained compound III in the presence of a hydrogenation catalyst without separating the compound III to obtain a product (S)-1-(3-ethoxyl-4-methoxyl) phenyl-2-methanesulfonyl ethylamine (I), namely the apremilast intermediate, wherein the apremilast intermediate can be further prepared into N-acetyl L-leucinate. The invention also provides a preparation method of apremilast. The preparation method disclosed by the invention has the advantages of simple process flow, safety, environmental friendliness and low cost and is favorable to clean industrialized production.
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- The purity of effecting apps is special a process for the preparation of (by machine translation)
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The invention discloses a apps is special of effecting the purity of the preparation method, 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-b-2-amine and N-acetyl-L-leucine salt forming reaction to obtain (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-b-2-ylamine-N-acetyl-L-leucine salt, the purified (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-b-2-ylamine-? N-acetyl-L-leucine salt with 3-acetyl amino phthalic anhydride in the presence of toluene and acetic acid react to generate the receive? (S)-2-[ 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetyl amino indoline -1, 3-diketone, through the acetone and ethanol mixed solvent recrystallization to obtain stereomeride relatively pure apps is special. The advantage of this invention lies in: the invention by replacing the solvent, adding catalyst, reaction time is greatly shortened, the chiral purity as high as 99.8% apps is special of. (by machine translation)
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Paragraph 0012; 0019; 0020
(2016/10/08)
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- Preparation method of Apremilast and intermediate
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The invention provides a preparation method of Apremilast and its intermediate. The invention provides an Apremilast intermediate as shown in the formula III. According to the preparation method, the compound as shown in the formula III reacts with methanesulfinate to obtain a compound as shown in the formula IV; the compound as shown in the formula IV undergoes reductive amination to obtain a compound as shown in the formula V; the compound as shown in the formula V and asymmetry acid undergo salifying to obtain a compound as shown in the formula VI; and the compound as shown in the formula VI reacts with 3-acetamido-phthalic anhydride to obtain Apremilast. By the method for synthesizing Apremilast, usage of an n-butyllithium hexane solution can be avoided. Production cost is reduced, and operation process is convenient. In addition, safety in the industrial production is raised to a great extent, and the preparation method is more suitable for industrial continuous production. According to the preparation method of 3-acetamido-phthalic anhydride, yield is raised to 81%. As the yield is high, the method provided by the invention is extremely suitable for industrial production of Apremilast.
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- Preparation of (S)-1-(4-methoxy-3-ethoxy)phenyl-2-methylsulfonyl ethylamine and preparation method of apremilast
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The invention relates to preparation of (S)-1-(4-methoxy-3-ethoxy)phenyl-2-methylsulfonyl ethylamine and a preparation method of apremilast. 4-methoxy-3-ethoxy phenylmagnesium bromide is prepared from 4-methoxy-3-ethoxy bromobenzene through Grignard reaction; 4-methoxy-3-ethoxy phenylmagnesium bromide is in addition reaction with methylsulfonyl acetonitrile, and then hydrolysis and reduction are carried out, so that (R,S)-1-(4-methoxy-3-ethoxy)phenyl-2-methylsulfonyl ethylamine (III) is obtained; separation and filtering are carried out, so that (S)-1-(4-methoxy-3-ethoxy)phenyl-2-methylsulfonyl ethylamine N-acetyl-L-leucine salt (IV) is obtained; through neutralization, (S)-1-(4-methoxy-3-ethoxy)phenyl-2-methylsulfonyl ethylamine (II) is obtained; the compound (II) is subjected to imidization, so that apremilast (1) is obtained. The mother liquor obtained after separation is recycled and converted into a compound IV, so that discharge of waste liquid is reduced, environment friendliness is realized and the cost is reduced.
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- AN IMPROVED PROCESS FOR PREPARATION OF APREMILAST AND NOVEL POLYMORPHS THEREOF
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The present invention provides an improved process for preparation of an intermediate of apremilast. The present invention also provides an improved process for preparation of apremilast. This invention also provides novel polymorphs of apremilast. The present invention also provides pharmaceutical compositions of novel polymorphs of apremilast. This invention also provides a process for preparation of novel polymorphs of apremilast, which are cost-effective, robust, and viable at plant scale.
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- Methods for treating diseases using isoindoline compounds
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Methods of treating a disease selected from dermatomyositis, prurigo nodularis, pyoderma gangrenosum, alopecia areata, hidradenitis suppurtiva, rosacea, lichen planus, giant cell arteritis, Sjogren's syndrome, gout, chronic prostatitis, posterior uveitis, vulvodynia and interstitial cystitis in a human are disclosed. Specific methods encompass the administration of (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, cyclopropyl {2-[(15)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl}carboxamide or a combination thereof, or a pharmaceutically acceptable prodrug, metabolite, polymorph, salt, solvate or clathrate thereof.
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Page/Page column 27
(2016/08/17)
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- Methods and compositions using PDE4 inhibitors for the treatment and management of autoimmune and inflammatory diseases
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Methods of treating, preventing, or managing autoimmune inflammatory diseases and disorders including but not limited to spondylitis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, osteoarthritis, ankylosing spondylitis, and rheumatoid arthritis by the administration of phosphodiesterase 4 (PDE4) inhibitors in combination with other therapeutics are disclosed. Pharmaceutical compositions, dosage forms, and kits suitable for use in methods of the invention are also disclosed.
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Page/Page column 23
(2016/05/02)
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- CONTROLLED RELEASE ORAL DOSAGE FORMS OF POORLY SOLUBLE DRUGS AND USES THEREOF
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Provided herein are controlled release oral dosage forms of poorly soluble drugs, methods of making the dosage forms, and methods of their use for the treatment of various diseases and/or disorders.
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Paragraph 0216
(2016/06/06)
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- IMPROVED PROCESS FOR THE PREPARATION OF APREMILAST
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The present invention relates to novel processes for the preparation of apremilast of formula I, or a pharmaceutically acceptable salt thereof.
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Page/Page column 17; 18
(2016/10/04)
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- COMPOSITIONS AND METHODS FOR THE TREATMENT OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASES WITH PDE4 MODULATORS
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Provided herein are methods of treating, preventing or managing atherosclerosis by administering a PDE4 modulator. Pharmaceutical compositions, dosage forms, and kits suitable for use in methods are also provided.
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Paragraph 0188
(2016/04/26)
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- USE OF PDE4 INHIBITORS AND COMBINATIONS THEREOF FOR THE TREATMENT OF CYSTIC FIBROSIS
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Methods of treating cystic fibrosis by administering a PDE4 inhibitor in combination with one or more cystic fibrosis transmembrane conductance regulator (CFTR) potentiators, including ivacaftor, and/or one or more CFTR correctors, including lumacaftor. Pharmaceutical compositions, dosage forms, and kits suitable for use in methods of the invention are also disclosed.
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Paragraph 0113
(2016/02/16)
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- METHODS FOR THE TREATMENT OF BONE LOSS
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Provided herein are methods of treating, preventing and/or managing bone loss using (+)-2- [ 1 -(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-4-acetylaminoisoindolin- 1,3-dione, alone or in combination with other therapeutics.
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Page/Page column 21
(2014/05/24)
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- ASYMMETRIC SYNTHETIC PROCESSES FOR THE PREPARATION OF AMINOSULFONE COMPOUNDS
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Processes for synthesizing aminosulfone compounds are provided. Aminosulfone compounds obtained using methods provided herein are useful in production or synthesis of sulfone group containing isoindoline based compounds.
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- METHODS AND COMPOSITIONS USING PDE4 INHIBITORS FOR THE TREATMENT AND MANAGEMENT OF AUTOIMMUNE AND INFLAMMATORY DISEASES
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Methods of treating, preventing, or managing autoimmune inflammatory diseases and disorders including but not limited to spondylitis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, osteoarthritis, ankylosing spondylitis, and rheumatoid arthritis by the administration of phosphodiesterase 4 (PDE4) inhibitors in combination with other therapeutics are disclosed. Pharmaceutical compositions, dosage forms, and kits suitable for use in methods of the invention are also disclosed.
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- Methods for treating cutaneous lupus using aminoisoindoline compounds
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Methods of treating cutaneous lupus in a human are disclosed. Specific methods encompass the administration of (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (ACTIMID?), 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (REVLIMID?), or cyclopropyl 2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl}carboxamide, alone or alternatively, in combination with a second active agent.
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Page/Page column 14
(2010/11/27)
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- (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione: methods of using and compositions thereof
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Stereomerically pure (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, substantially free of its (?) isomer, and prodrugs, metabolites, polymorphs, salts, solvates, hydrates, and clathrates thereof are discussed. Also discussed are methods of using and pharmaceutical compositions comprising the (+) enantiomer of 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione are disclosed. The methods include methods of treating and/or preventing disorders ameliorated by the reduction of levels of TNF-α or the inhibition of PDE4.
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