Methods of making lubiprostone and intermediates thereof

There is provided processes for preparing Lubiprostone and intermediates thereof. Also provided are compounds, including intermediates for preparing Lubiprostone as well compositions comprising Lubiprostone and other compounds, including intermediates for preparing Lubiprostone and other compounds. (I)

Anti-constipation composition

An object of the present invention is to provide an anti-constipation composition containing a halogenated-bi-cyclic compound as an active ingredient in ratio of bi-cyclic/mono-cyclic structure of at least 1:1. The halogenated-bi-cyclic compound is represented by Formula (I): where X 1 and X 2 are preferably both fluorine atoms. The composition can be used to treat constipation with out substantive side-effects, such as stomachache.

PROSTAGLANDIN SYNTHESIS AND INTERMEDIATES FOR USE THEREIN

Fused cyclopentane—4-substituted 3,5-dioxalane lactone compounds useful as an intermediate in the synthesis of prostaglandin analogs are provided. The compounds have the formula A: 2. Compound A according to wherein R represents a substituted phenyl group.3. Compound A according to wherein R represents p-methoxyphenyl5. Compound B according to wherein R′ represents p-methoxybenzyl. This invention relates to prostaglandin analogs and their synthesis. More particularly, it relates to a novel, simplified synthesis of prostaglandin analogs, and novel chemical compounds useful as intermediates in such synthesis.Prostaglandins (PGs) are organic carboxylic acids, namely cyclopentanes carrying two side chain substituents, typically linear C6-C8 side chains, bonded to adjacent positions on the cyclopentane nucleus. One of the side chains, the α-side chain, carries a terminal carboxylic acid group. Many are natural products found in mammalian organs and tissues (primary PGs), and exhibit a variety of physiological activities. Primary PGs generally have a prostanoic acid skeleton, which forms the basis of the nomenclature:A significant number of synthetic PG analogs have been made and found to have useful pharmacological properties. These may have modified skeletons, and substituted and unsaturated side chains. PGs are characterized by a hydroxyl (or ketone) substituent on the cyclopentane nucleus, position 9.Prostaglandin analogs are difficult to synthesize. Complications arise because of the requirements of the end products to have several functional groups and two side chains of significant size and complexity. Stereospecificity is commonly required, for substituent groups and for bonds in the core. Since the products are intended for pharmaceutical use, the range of industrially acceptable reagents, solvents, catalysts, etc. which can be used in their synthesis is limited to those having pharmaceutical industry acceptability.A common starting material for PG analog ...

USE OF MEXIPROSTIL IN THE TREATMENT OF INFLAMMATORY BOWEL DISEASE AND/OR OF IRRITABLE BOWEL SYNDROME

The invention relates to the use of mexiprostil in the treatment and/or prevention of inflammatory bowel disease and of irritable bowel syndrome, to the combinations of mexiprostil with other drugs, and also to a novel method for the synthesis of mexiprostil. 1. A method of treatment and/or prevention of inflammatory bowel disease (IBD) and/or of irritable bowel syndrome (IBS) comprising administering an effective amount of mexiprostil to patient in need thereof.2. The method according to claim 1 , for the treatment and/or prevention of ulcerative colitis.3. The method according to claim 1 , for the treatment and/or prevention of Crohn's disease.4. A method of treatment and/or prevention of the constipation (IBS-C) claim 1 , diarrhoeal (IBS-D) or alternating (IBS-A) variants of irritable bowel syndrome (IBS) comprising administering an effective amount of mexiprostil to patient in need thereof.5. The method according to claim 1 , wherein mexiprostil is administered at a rate of from 0.25 to 2.5 mg per day.6. The method according to claim 1 , wherein mexiprostil is administered in dosage units comprising from 0.5 to 1.5 mg of mexiprostil claim 1 , one or more times per day.7. The method according to claim 1 , wherein mexiprostil is formulated in gastroresistant and controlled-release compositions.8. The method according to claim 1 , wherein mexiprostil is formulated in compositions which comprise:a) a matrix which is composed of lipophilic compounds having a melting point of less than 90° C. and optionally of amphiphilic compounds in which the active ingredient is at least partially incorporated;b) optionally an amphiphilic matrix;c) an outer hydrophilic matrix in which the lipophilic matrix and the optional amphiphilic matrix are dispersed;d) optionally other excipients.9. The method according to claim 8 , characterized in that the composition comprises a gastroresistant coating.10. The method according to claim 1 , wherein mexiprostil is administered in combination ...

Process for the preparation of lubiprostone

Processes for preparing and purifying lubiprostone are disclosed. Intermediates and preparation thereof are also disclosed.

Compounds and methods for delivery of prostacyclin analogs

This invention pertains generally to prostacyclin analogs and methods for their use in promoting vasodilation, inhibiting platelet aggregation and thrombus formation, stimulating thrombolysis, inhibiting cell proliferation (including vascular remodeling), providing cytoprotection, preventing atherogenesis and inducing angiogenesis. Generally, the compounds and methods of the present invention increase the oral bioavailability and circulating concentrations of treprostinil when administered orally. Compounds of the present invention have the following formula:

Process to prepare treprostinil, the active ingredient in remodulin®

This present invention relates to an improved process to prepare prostacyclin derivatives. One embodiment provides for an improved process to convert benzindene triol to treprostinil via salts of treprostinil and to purify treprostinil.

Ester Derivatives of Bimatoprost Compositions and Methods

Provided herein, inter alia, are prodrugs of bimatoprost, methods of using the same and compositions including the same. 2. The compound of claim 1 , wherein R claim 1 , Rand Rare independently substituted or unsubstituted C-Calkyl.3. The compound of claim 2 , wherein R claim 2 , Rand Rare independently substituted or unsubstituted C-Calkyl.4. The compound of claim 3 , wherein R claim 3 , Rand Rare independently substituted or unsubstituted Calkyl.5. The compound of claim 4 , wherein R claim 4 , Rand Rare independently methyl.6. The compound of claim 1 , wherein R claim 1 , Rand Rare independently substituted or unsubstituted C-Ccycloalkyl.7. The compound of claim 6 , wherein R claim 6 , Rand Rare independently unsubstituted C-Ccycloalkyl.8. The compound of claim 1 , wherein R claim 1 , Rand Rare independently substituted or unsubstituted aryl.9. The compound of claim 8 , wherein R claim 8 , Rand Rare independently aryl.10. The compound of claim 1 , wherein R claim 1 , Rand Rare independently phenyl.11. The compound of claim 1 , wherein Ris substituted or unsubstituted C-Calkyl claim 1 , or substituted or unsubstituted C-Ccycloalkyl.12. The compound of claim 11 , wherein Ris substituted or unsubstituted C-Calkyl.13. The compound of claim 12 , wherein Ris substituted or unsubstituted C-Calkyl.14. The compound of claim 13 , wherein Ris substituted or unsubstituted Calkyl.15. The compound of claim 14 , wherein Ris ethyl.16. The compound of claim 11 , wherein Ris substituted or unsubstituted C-Ccycloalkyl.17. The compound of claim 1 , wherein Ris hydrogen.22. The method of claim 21 , wherein said subject suffers from alopecia.23. The method of claim 21 , wherein said subject is in need of hair growth of the cilia claim 21 , the supercilia claim 21 , scalp pili claim 21 , or body pili.24. The method of claim 21 , wherein said administering is topical administering.25. The method of claim 24 , wherein said administering is topical epidermal administering. This application ...

Prostaglandin synthesis and intermediates for use therein

Fused cyclopentane—4-substituted 3,5-dioxalane lactone compounds useful as an intermediate in the synthesis of prostaglandin analogs are provided. The compounds have the formula A: wherein R represents an aryl group such as p-methoxyphenyl. This compound can be reacted with a lower alkyl aluminum compound to open the dioxalane ring and reduce the lactone to lactol, without over-reducing to diol. The resulting compound can be functionalized to insert chemical side groups of target prostaglandins, adding the required α-side chain and then the required ω-side chain sequentially and independently of each other. The compounds and process are particularly suitable for preparing lubiprostone.

METHOD FOR TREATING SCHIZOPHRENIA

The present invention provides a novel fatty acid derivative. The present invention also provides a method for treating schizophrenia in a mammalian subject, which comprises administering to the subject in need thereof an effective amount of a fatty acid derivative. 2. The method as described in claim 1 , wherein Z is C═O.3. The method as described in claim 1 , wherein B is —CH—CH—.4. The method as described in claim 1 , wherein B is —CH—CH— and Z is C═O.5. The method as described in claim 1 , wherein L is hydroxy or oxo claim 1 , M is hydrogen or hydroxy claim 1 , N is hydrogen claim 1 , B is —CH—CH— and Z is C═O.6. A compound of 7-[2-(4 claim 1 ,4-difluoro-3-oxooctyl)-5-oxocyclopentyl]hept-2-enoic acid or functional derivative thereof.7. A compound of 7-[2-(4 claim 1 ,4-difluoro-3-oxooctyl)-5-oxocyclopentyl]hept-2-enoic acid. This is a continuation of application Ser. No. 13/566,353 filed Aug. 3, 2012, which claims benefit of Provisional Application No. 61/515,418 filed Aug. 5, 2011; the above noted prior applications are all hereby incorporated by reference.The present invention relates to a method for treating schizophrenia.Schizophrenia is a chronic, severe, and disabling brain disorder that has affected people throughout history. About 1 percent of Americans have this illness.People with the disorder may hear voices other people don't hear. They may believe other people are reading their minds, controlling their thoughts, or plotting to harm them. This can terrify people with the illness and make them withdrawn or extremely agitated.People with schizophrenia may not make sense when they talk. They may sit for hours without moving or talking. Sometimes people with schizophrenia seem perfectly fine until they talk about what they are really thinking.Families and society are affected by schizophrenia too. Many people with schizophrenia have difficulty holding a job or caring for themselves, so they rely on others for help. Treatment helps relieve many symptoms of ...

PREPARATION OF LATANOPROSTENE BUNOD OF DESIRED, PRE-DEFINED QUALITY BY GRAVITY CHROMATOGRAPHY

The subject of the invention is a process for the preparation of Latanoprostene bunod of formula (I) with a purity higher than 95% where chromatography is used applying normal phase gravity silica gel column chromatography where the used silica gel is irregular silica gel or spherical silica gel an as eluent and eluent mixture consisting of an apolar and a polar solvent is used and if desired, contamination of the purified compound of formula I arising from the solvents are removed by silica gel filtration chromatography. 2. Process a.) or b.) as defined in claim 1 , characterized in that claim 1 , the eluent mixture contains as apolar solvent straight- or branched-chain aliphatic claim 1 , cyclic or aromatic hydrocarbons claim 1 , halogenated aliphatic hydrocarbons or ether-type solvents.3. Process as defined in claim 2 , characterized in that claim 2 , as apolar solvent pentane claim 2 , hexane claim 2 , heptane claim 2 , cyclohexane claim 2 , dichloromethane or diisopropyl ether claim 2 , preferably hexane is applied.4. Process a.) or b.) as defined in claim 1 , characterized in that claim 1 , as polar solvent an alcohol- claim 1 , ester- or ketone-type solvent containing straight- or branched-chain alkyl group is applied.5. Process as defined in claim 4 , characterized in that claim 4 , as polar solvent a C1-5 alcohol claim 4 , preferably ethyl alcohol or isopropyl alcohol is applied.6. Process as defined in claim 3 , characterized in that claim 3 , the eluent mixture is a gradient mixture containing hexane and ethyl alcohol in 6:1-8:1 volume ratios.7. Process as defined in claim 4 , characterized in that claim 4 , as polar solvent a ketone-type solvent claim 4 , preferably acetone is applied.8. Process as defined in claim 3 , characterized in that claim 3 , the eluent mixture contains hexane and acetone in 2:1 volume ratio.9. Filtration chromatography process as defined in claim 1 , characterized in that claim 1 , the eluent mixture contains an apolar and a ...

Ester derivatives of bimatoprost compositions and methods

Provided herein, inter alia, are prodrugs of bimatoprost, methods of using the same and compositions including the same.

Process for the preparation of latanoprostene bunod and intermediate thereof and compositions comprising the same

Processes for preparing latanoprostene bunod and an intermediate prepared from the process. Also latanoprostene bunod compositions having high-purity latanoprostene bunod.

Amine salts of prostaglandin analogs

The present application relates to amine salts of prostaglandin analogs and their uses for the preparation of substantially pure prostaglandin analogs. Specific embodiments relate to amine salts of tafluprost and their uses for the preparation of substantially pure tafluprost.

Salts of Prostaglandin Analog Intermediates

The present invention relates to crystalline 1-adamantanamine salts, and polymorphic forms thereof, of prostaglandin analog intermediates of formula 3a, 4a and 6a, useful in the preparation of Tafluprost and Lubiprostone and processes for their preparation. The process includes combining 1-adamantanamine, water, an organic solvent, and a compound of Formula 3 or 6, thereby obtaining a suspension. The process also includes isolating the solid salt of Formula 3a or 6a from the suspension. 2. The crystalline salt of having the Formula 3a.3. The crystalline salt of claim 2 , wherein the salt is characterized by a Powder X-Ray Diffraction (PXRD) diffractogram comprising a peak claim 2 , expressed in degrees two-theta claim 2 , at 11.0+/−0.2 claim 2 , and at least four peaks claim 2 , expressed in degrees two-theta claim 2 , selected from the group consisting of: 3.7+/−0.2 claim 2 , 7.5+/−0.2 claim 2 , 8.1+/−0.2 claim 2 , 9.5+/−0.2 claim 2 , 12.9+/−0.2 claim 2 , 13.6+/−0.2 claim 2 , 15.1+/−0.2 claim 2 , 15.7+/−0.2 claim 2 , 17.0+/−0.2 claim 2 , and 20.5+/−0.2.4. The crystalline salt of claim 3 , wherein the PXRD diffractogram comprises peaks claim 3 , expressed in degrees two-theta claim 3 , at: 3.7+/−0.2 claim 3 , 7.5+/−0.2 claim 3 , 8.1+/−0.2 claim 3 , 9.5+/−0.2 claim 3 , 11.0+/−0.2 claim 3 , 12.9+/−0.2 claim 3 , 13.6+/−0.2 claim 3 , 15.1+/−0.2 claim 3 , 15.7+/−0.2 claim 3 , 17.0+/−0.2 and 20.5+/−0.2.5. The crystalline salt of claim 3 , wherein the salt is characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endothermic peak having a peak onset at approximately 78° C.6. The crystalline salt of having the Formula 4a.702. The crystalline salt of claim 6 , wherein the salt is Form APO-I characterized by a Powder X-Ray Diffraction (PXRD) diffractogram comprising a peak claim 6 , expressed in degrees two-theta claim 6 , at approximately 5.6+/−. claim 6 , and at least four peaks claim 6 , expressed in degrees two-theta claim 6 , selected from ...

Process for preparing synthetic prostacyclins

The presently disclosed subject matter provides methods of preparing synthetic prostacyclin analogues, including Beraprost, either as racemic mixtures or as single stereoisomers. Also provided are novel synthetic intermediates for use in these methods.

PROCESS FOR PREPARATION OF PROSTAGLANDIN F2 ALPHA ANALOGUES

A convergent synthesis of the prostaglandin F analogues, travoprost and bimatoprost, was developed employing Julia-Lythgoe olefination of the structurally advanced phenylsulfone with an enantiomerically pure aldehyde ω-chain synthon. The novel convergent strategy allows the synthesis of a whole series of prostaglandin analogues of high purity from a common and structurally advanced prostaglandin intermediate. 2. The process of claim 1 , wherein the α-sulfonyl carbanion of the formula (II) is generated by an alkali metal amide claim 1 , selected from the group comprising lithium N claim 1 ,N-bis(trimethylsilyl)amide claim 1 , sodium N claim 1 ,N-bis(trimethylsilyl)amide claim 1 , lithium diisopropylamide and sodium diisopropylamide.3. The process of claim 2 , wherein the α-sulfonyl carbanion of the formula (II) is generated by lithium diisopropylamide.4. The process of claim 1 , wherein the desulfonation of the β-hydroxysulfones of the formula (V) is performed by using sodium amalgam in the presence of NaHPObuffer.5. The process of claim 1 , wherein the R-Rgroups are removed by reacting the compound of the formula (VI) with hydrogen fluoride or tetra-n-butylammonium fluoride.6. The process of claim 1 , wherein the Rgroup of the compound of the formula (VII) is hydrolyzed in the presence of an aqueous solution of citric acid.7. The process of claim 1 , wherein the Rgroup of the compound of the formula (VIII) is hydrolyzed with an alkali metal hydroxide claim 1 , preferably with lithium hydroxide.8. The process of claim 1 , wherein the compound of formula (VIII) is alkylated with a C-alkyl halogen in the presence of a base claim 1 , preferably 1 claim 1 ,8-diazabicyclo[5.4.0]undec-7-en (DBU).9. The process of claim 1 , wherein the prostamid of the formula (IC) claim 1 , which is isopropyl ester of 16-[3-(trifluoromethoxy)phenoxy]-17 claim 1 ,18 claim 1 ,19 claim 1 ,20-tetranor-prostaglandin F (travoprost) claim 1 , is obtained in a diastereoisomeric excess greater than ...

PROCESS TO PREPARE TREPROSTINIL, THE ACTIVE INGREDIENT IN REMODULIN®

This present invention relates to an improved process to prepare prostacyclin derivatives. One embodiment provides for an improved process to convert benzindene triol to treprostinil via salts of treprostinil and to purify treprostinil. 1. A pharmaceutical batch of a salt of treprostinil that can be stored as a stable compound at ambient temperature and that is prepared by a method comprising (a) alkylating a benzindene triol , (b) hydrolyzing the product of step (a) to form a solution comprising treprostinil , and (c) contacting the solution comprising treprostinil from step (b) with a base to form a salt of treprostinil , wherein forming the salt of step (c) reduces the amount of one or more impurities resulting from steps (a) and/or (b) in the pharmaceutical batch , said pharmaceutical batch being at least 2.9 grams.2. The pharmaceutical batch of claim 1 , wherein the method further comprises converting the salt of treprostinil to treprostinil by acidification.3. The pharmaceutical batch of claim 1 , wherein the pharmaceutical batch has been dried under vacuum.4. The pharmaceutical batch of claim 1 , wherein the base is diethanolamine.5. A pharmaceutical product comprising a carrier and a therapeutically effective amount of a salt of treprostinil claim 1 , wherein the salt of treprostinil is from a pharmaceutical batch as claimed in .6. A pharmaceutical product comprising a carrier and a therapeutically effective amount of treprostinil claim 2 , wherein the treprostinil is from a pharmaceutical batch as claimed in .7. The pharmaceutical product of claim 5 , wherein the salt is the diethanolamine salt of treprostinil.8. A method of preparing a pharmaceutical product from a pharmaceutical batch as claimed in claim 5 , comprising storing a pharmaceutical batch of a salt of treprostinil as claimed in at ambient temperature and preparing a pharmaceutical product from the pharmaceutical batch after storage.9. A method as claimed in claim 8 , wherein the salt of ...

NEW PROCESS FOR THE PREPARATION OF HIGH PURITY PROSTAGLANDINS

The subject of the invention is a process for the preparation of high purity prostaglandin acid of the general formula II wherein the bonds marked with dotted lines represent single or double bonds wherein the double bonds may be cis- or trans oriented, Y represents 0 or CH, and Rstands for a phenyl group which is optionally substituted with CF, wherein the crude prostaglandin acid of the general formula II is purified by normal phase silicagel chromatography. 2. The process as defined in claim 1 , wherein chromatography is carried out by normal phase gravitational claim 1 , medium- or high pressure silica gel chromatography.3. The process as defined in claim 1 , wherein the applied silica gel is a spherical silica gel having average particle size in a range of 10-150 micrometer.4. The process as defined in claim 1 , wherein a multicomponent eluent mixture is applied as eluent.5. The process as defined in claim 4 , wherein the eluent mixture contains one or more apolar solvents claim 4 , one or more polar solvents and solvent of acidic character claim 4 , in a ratio of (91-73%):(24-8.7%):(0.1-4.3%).6. The process as defined in claim 5 , wherein the apolar component of the eluent mixture is straight or branched open-chain or cyclic or aromatic hydrocarbon claim 5 , optionally containing one or more substituents.7. The process as defined in claim 6 , wherein the substituent is halogen atom.8. The process as defined in claim 6 , wherein as apolar solvent aliphatic hydrocarbon is applied.9. The process as defined in claim 5 , wherein as polar solvent an alcohol- claim 5 , ether- claim 5 , ester- or ketone-type solvent is applied which contains straight or branched open-chain alkyl claim 5 , alkenyl or cyclic or cycloalkyl group.10. The process as defined in claim 9 , wherein as polar solvent Calcohol is applied.11. The process as defined in claim 10 , wherein as polar solvent isopropyl alcohol is applied.12. The process as defined in claim 5 , wherein the solvent of ...

PROCESSES AND INTERMEDIATES FOR THE PREPARATIONS OF ISOMER FREE PROSTAGLANDINS

Novel processes for the preparation of a compound of Formula I-2 substantially free of the 5,6-trans isomer: 2. A compound according to wherein Ris methyl claim 1 , phenyl claim 1 , or p-phenylphenyl. This application is a Divisional of U.S. patent application Ser. No. 14/802,026 filed Jul. 17, 2015, which is a divisional of U.S. patent application Ser. No. 13/967,473 filed Aug. 15, 2013 (now U.S. Pat. No. 9,115,109 issued Aug. 25, 2015), the contents of which are incorporated herein by reference.The present invention relates to novel processes and intermediates for the preparations of isomer free Prostaglandins and the derivatives thereof.Prostaglandin ester analogues of the following Formula I-2whereinis a single or double bond; Ris a single bond or a C-alkylene or —CHO—; and Ris a C-alkyl or an aryl or an aralkyl, each of which is unsubstituted or substituted by a C-alkyl, a halogen or a trihalomethyl; and Ris C-alkyl, such as, Latanoprost, Isoproyl unoprostone, Isoproyl cloprostenol, Travoprost and Tafluprost have been used in the management of open-angle glaucoma. The Prostaglandin ester analogues of Formula I-2 have been shown to have significantly greater hypotensive potency than the parent compound, presumably as a result of their more effective penetration through the cornea. They reduce intra-ocular pressure by enhancing uveoscleral outflow, and may also have some effect on trabecular meshwork as well.As shown in the following Scheme A:most of the Prostaglandin ester analogues of Formula I-2 disclosed in the prior art, such as in WO02096898, EP1886992, EP2143712, JP2012246301, U.S. Pat. No. 6,720,438, US2008033176, WO2010097672, and U.S. Pat. No. 7,582,779 were obtained by first synthesizing a Lactone VIII, whereinor is a protective group of carbonyl group; Pand Pare protective groups for the hydroxyl groups; is a single or double bond; Ris a single bond or a C-alkylene or —CHO—; and Ris a C-alkyl or an aryl or an aralkyl, each of which is unsubstituted or ...

NOVEL PROCESSES FOR THE PREPARATION OF PROSTAGLANDIN AMIDES

The subject of the invention is process for the preparation of the prostaglandin amides of the general formula I, where in the formula the bonds marked with dotted lines may be single or double bonds, in the case of double bounds at positions 5,6 and 13,14 they may be in cis or in trans orientation, Q stands for a hydroxyl-group and Z stands for a hydroxyl- or oxo-group, Rand Rindependently represent hydrogen atom or a straight or branched Calkyl- or aralkyl- group, optionally substituted with —ONOgroup, or an aralkyl- or aryl- group, which contains heteroatom, Rrepresents a straight or branched, saturated or unsaturated Chydrocarbon group, or a Calkylcycloalkyl- or cycloalkyl- group, or an optionally with alkyl group or halogen atom substituted phenyl-, Calkylaryl- or hetaryl- group, Y represents (CH), group or 0 atom or S atom, and where n=0-3. 4. Process according to method i.) of claim 1 , characterized in that the compound suitable to introduce the group R claim 1 , is 1 claim 1 ,1′-carbonyldiimidazole or 1 claim 1 ,1′-thiocarbonyldiimidazole.5. Process according to method ii.) of claim 1 , characterized in that for the introduction of group R claim 1 , N-hydroxysuccinimide claim 1 , N-hydroxyphthalimide claim 1 , N-hydroxy-5-norben-endo-2 claim 1 ,3-dicarboxamide claim 1 , 1-hydroxybenzotriazole claim 1 , (benzotriazol-1-yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate claim 1 , N claim 1 ,N′-disuccinimidyl carbonate or N claim 1 ,N′-disuccinimidyl oxalate are used claim 1 , in a given case in the presence of an activating agent.6. Process according to claim 5 , characterized in that the applied activating agent is N claim 5 ,N′-diisopropylcarbodiimide claim 5 , N claim 5 ,N′-dicyclohexylcarbodiimide or 2-chloro-1 claim 5 ,3-dimethylimidazolinium chloride.7. Process according to claim 1 , characterized in that the reaction is carried out in an ether-type claim 1 , or aromatic claim 1 , or polar-aprotic solvent claim 1 , or in the mixture of them.8. ...

Process for the preparation of optically active beraprost

The invention provides a new process for the preparation of optically active Beraprost of formula (I) starting from racemic Beraprost alkyl ester through hydrolysis, enantiomer esterification, preparation of diacyl-Beraprost ester diastereomers and their separation and hydrolysis.

COMPOUND FOR TREATING CARTILAGE DISORDERS

The present invention provides a compound of which active |form| is represented by a formula (A). and which can be injected into a joint cavity which is an affected part of disorders and can be accumulated in the joint cavity to exert the pharmacological effect thereof in a sustained manner, for the purpose of ameliorating cartilage disorders without developing any side effect. A compound according to the present invention, which is represented by a formula (I): 3. The compound according to claim 1 , which is selected from a group consisting of 3-{[(5Z)-7-{(1R claim 1 ,2R claim 1 ,3R claim 1 ,5R)-5-chloro-2-[(1E claim 1 ,4S)-4-(1-ethylcyclobutyl)-4-hydroxy-1-buten-1-yl]-3-hydroxycyclopentyl}-5-heptenoyl]oxy}propyl 3-(pentadecyloxy)benzoate claim 1 , 2-{[(5Z)-7-{(1R claim 1 ,2R claim 1 ,3R claim 1 ,5R)-5-chloro-2-[(1E claim 1 ,4S)-4-(1-ethylcyclobutyl)-4-hydroxy-1-buten-1-yl]-3-hydroxycyclopentyl}-5-heptenoyl]oxy}ethyl 3-(pentadecyloxy)benzoate claim 1 , 4-{[(5Z)-7-{(1R claim 1 ,2R claim 1 ,3R claim 1 ,5R)-5-chloro-2-[(1E claim 1 ,4S)-4-(1-ethylcyclobutyl)-4-hydroxy-1-buten-1-yl]-3-hydroxycyclopentyl}-5-heptenoyl]oxy}butyl 3-(pentadecyloxy)benzoate claim 1 , 2-{[(5Z)-7-{(1R claim 1 ,2R claim 1 ,3R claim 1 ,5R)-5-chloro-2-[(1E claim 1 ,4S)-4-(1-ethylcyclobutyl)-4-hydroxy-1-buten-1-yl]-3-hydroxycyclopentyl}-5-heptenoyl]oxy}ethyl 3-(dodecyloxy)benzoate claim 1 , 2-{[(5Z)-7-{(1R claim 1 ,2R claim 1 ,3R claim 1 ,5R)-5-chloro-2-[(1E claim 1 ,4S)-4-(1-ethylcyclobutyl)-4-hydroxy-1-buten-1-yl]-3-hydroxycyclopentyl}-5-heptenoyl]oxy}ethyl 3-(tetradecyloxy)benzoate claim 1 , 2-{[(5Z)-7-{(1R claim 1 ,2R claim 1 ,3R claim 1 ,5R)-5-chloro-2-[(1E claim 1 ,4S)-4-(1-ethylcyclobutyl)-4-hydroxy-1-buten-1-yl]-3-hydroxycyclopentyl}-5-heptenoyl]oxy}ethyl 3-(hexadecyloxy)benzoate claim 1 , 2-{[(5Z)-7-{(1R claim 1 ,2R claim 1 ,3R claim 1 ,5R)-5-chloro-2-[(1E claim 1 ,4S)-4-(1-ethylcyclobutyl)-4-hydroxy-1-buten-1-yl]-3-hydroxycyclopentyl}-5-heptenoyl]oxy}ethyl 3-(octadecyloxy)benzoate claim 1 ...

Method for producing pkrostaglandin

The present invention provides a method for producing a compound represented by Formula (1a), (1b), or (1c), comprising a step of reducing a compound represented by Formula (3) in the presence of a metal complex represented by Formula (5), an inorganic base, and a solvent under a hydrogen atmosphere to obtain a compound represented by Formula (4). In the formula, Ar 1 is an aryl group, each Are is independently a phenyl group or the like, W is a biphenyl group or the like, Z is an ethylene group that is substituted with a phenyl group or the like, and L is a chlorine atom or if Z has a phenyl group or a C 1-3 alkoxyphenyl group, L is one of carbon atoms constituting the phenyl group or the C 1-3 alkoxyphenyl group.

Compositions comprising a prostaglandin for treating neuropsychiatric conditions

The present invention relates to methods and compositions for the treatment of neuropsychiatric conditions (e.g., bipolar disorder) by administration of prostaglandin or prostaglandin derivatives (e.g., latanoprost) to a subject (e.g., a human).

NITRIC OXIDE DONATING DERIVATIVES OF LATANOPROST FREE ACID

The present invention relates to 15-nitrooxyderivatives of latanoprost and 15-nitrooxyderivatives of latanoprost free acid, their use for the treatment of glaucoma and ocular hypertension and formulation containing 15-nitrooxyderivatives of latanoprost and 15-nitrooxyderivatives of latanoprost free acid. 2. A compound of formula (I) according to claim 1 , whereinR is —CH(CH3)2 andRa is A1): —(CHR1)-NH—(C═O)—(CH2)m-[O—(CH2)n]p-(CH—ONO2)q-CH2-ONO2whereinR1 is —H or —CH3,p is 1 or 0,q is 1 or 0,m is an integer ranging from 1 to 10;n is an integer ranging from 1 to 6.4. A compound of formula (I) according to claim 1 , wherein R is —CH(CH3)2 andRa is A2): —(CH2)2-NH—(C═O)—(CH2)m-[O—(CH2)n]p-(CH—ONO2)q-CH2-ONO2whereinp is 1 or 0,q is 1 or 0,m is an integer ranging from 1 to 10;n is an integer ranging from 1 to 6.6. A compound of formula (I) according to claim 1 , wherein R is —CH(CH3)2 andRa is A3): —(CH2)m-[O—(CH2)n]p-(CH—ONO2)q-CH2-ONO2whereinp is 1 or 0,q is 1 or 0,m is an integer ranging from 1 to 10;n is an integer ranging from 1 to 6.8. A compound of formula (I) according to claim 1 , wherein R is —H.12. A compound of formula (I) according to claim 1 , selected from the following group of compounds:(Z)-isopropyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-(3-(6-(nitrooxy)hexanamido) propanoyloxy)-5-phenylpentyl)cyclopentyl)hept-5-enoate (Compound (1));(Z)-isopropyl 7-((1R,2R,3R,5S)-2-((3R)-3-(3-(5,6-bis(nitrooxy)hexanamido) propanoyloxy)-5-phenylpentyl)-3,5-dihydroxycyclopentyl)hept-5-enoate (Compound (2));(Z)-isopropyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-(3-(2-(2-(nitrooxy)ethoxy)acetamido)propanoyloxy)-5-phenylpentyl)cyclopentyl)hept-5-enoate (Compound (3));(Z)-isopropyl 7-((1R,2R,3R,5S)-2-((3R)-3-(3-(3-(2,3-bis(nitrooxy)propoxy) propanamido)propanoyloxy)-5-phenylpentyl)-3,5-dihydroxycyclopentyl)hept-5-enoate (Compound (4));(Z)-isopropyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-(2-(6-(nitrooxy)hexanamido)acetoxy)-5-phenylpentyl)cyclopentyl)hept-5-enoate (Compound ( ...

NITRIC OXIDE DONATING DERIVATIVES OF FLUPROSTENOL

The present invention relates to 15-nitrooxyderivatives of fluprostenol, their use for the treatment of glaucoma and ocular hypertension and formulation containing 15-nitrooxy derivatives of fluprostenol. 2. A compound of formula (I) according to claim 1 , wherein Ra is selected from{'sup': '1', 'sub': 2', 'm', '2', 'n', 'p', '2', 'q', '2', '2, 'A1): —(CHR)—NH—(C═O)—(CH)—[O—(CH)]—(CH—ONO)—CH—ONO, and'}{'sub': 2', 'm', '2', 'n', 'p', '2', 'q', '2', '2, 'A3): —(CH)—[O—(CH)]—(CH—ONO)—CH—ONO.'}3. A compound of formula (I) according to claim 2 , wherein R is —CH(CH)and{'sup': '1', 'sub': 2', 'm', '2', 'n', 'p', '2', 'q', '2', '2, 'Ra is A1): —(CHR)—NH—(C═O)—(CH)—[O—(CH)]—(CH—ONO)—CH—ONO'}wherein{'sup': '1', 'sub': '3', 'Ris H or CH,'}p is 1 or 0,q is 1 or 0,m is an integer ranging from 1 to 10;n is an integer ranging from 1 to 6.5. A compound of formula (I) according to claim 2 , wherein R is —CH(CH)and{'sub': 2', 'm', '2', 'n', 'p', '2', 'q', '2', '2, 'Ra is A3): —(CH)—[O—(CH)]—(CH—ONO)—CH—ONO'}whereinp is 1 or 0,q is 1 or 0,m is an integer ranging from 1 to 10;n is an integer ranging from 1 to 6.7. A compound of formula (I) according to claim 3 , wherein R is —H.8. A compound of formula (I) according to selected from the following group of compounds:(Z)-isopropyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-(2-(6-(nitrooxy) hexanamido) acetoxy)-4-(3-(trifluoromethyl)phenoxy)but-1-enyl)cyclopentyl)hept-5-enoate (Compound (5));(Z)-isopropyl 7-((1R,2R,3R,5S)-2-((3R,E)-3-(2-(5,6-bis(nitrooxy)hexanamido)acetoxy)-4-(3-(trifluoromethyl)phenoxy)but-1-enyl)-3,5-dihydroxycyclopentyl)hept-5-enoate (Compound (6));(Z)-isopropyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-(2-(2-(2-(nitrooxy)ethoxy) acetamido)acetoxy)-4-(3-(trifluoromethyl)phenoxy)but-1-enyl)cyclopentyl)hept-5-enoate (Compound (7));(Z)-isopropyl 7-((1R,2R,3R,5S)-2-((3R,E)-3-(2-(3-(2,3-bis(nitrooxy)propoxy) propanamido)acetoxy)-4-(3-(trifluoromethyl)phenoxy)but-1-enyl)-3,5-dihydroxycyclopentyl)hept-5-enoate (Compound (8 ...

METHOD FOR THE PURIFICATION OF PROSTAGLANDINS

The present invention provides a method for the purification of a prostaglandin by supercritical fluid chromatography, said method comprising the use of a stationary phase and a mobile phase comprising carbon dioxide, provided that when the stationary phase is unmodified silica gel, the prostaglandin is not luprostiol. The invention also provides prostaglandins obtainable by the method. 1. A latanoprost composition comprising C11-beta isomer of latanoprost in an amount greater than 0% and less than 0.03% , and containing less than 0.03% C15R-Trans isomer of latanoprost , less than 0.05% C15S-Trans isomer of latanoprost , and less than 0.03% C15S-Cis isomer of latanoprost.2. A latanoprost composition comprising C11-beta isomer of latanoprost in an amount greater than 0% and less than 0.03% , and containing less than 0.03% C15R-Trans isomer of latanoprost , less than 0.05% C15S-Trans isomer of latanoprost , and less than 0.03% C15S-Cis isomer of latanoprost , after 11 months storage at freezer temperature.3. C11-beta isomer of latanoprost.4. A latanoprost composition comprising C11-beta isomer of latanoprost in an amount greater than 0% and less than 0.03%.5. A latanoprost composition comprising at C11-beta isomer of latanoprost in an amount greater than 0% and less than 0.03% , after 11 months storage at freezer temperature.6. A composition according to claim 1 , wherein the latanopost composition is at least 99% chemically pure.7. A composition according to claim 1 , wherein the latanopost composition is at least 99.5% chemically pure.8. A composition according to claim 1 , wherein the latanopost composition is at least 99.8% chemically pure.9. A composition according to claim 1 , wherein the latanopost composition is at least 99% isometrically pure.10. A composition according to claim 1 , wherein the latanopost composition is at least 99.5% isometrically pure.11. A composition according to claim 1 , wherein the latanopost composition is at least 99.8% isometrically ...

METHOD FOR PREPARING TREPROSTINIL AND INTERMEDIATE THEREFOR

The present invention relates to a cost-effective and efficient method for preparing treprostinil with high purity, and an intermediate therefor. 2. The method according to claim 1 , wherein the conversion of an alkyl halide or alkenyl tin of formula (3) to its cuprate in step (i) is carried out by adding methyl lithium (MeLi) or t-butyl lithium claim 1 , and copper cyanide (CuCN).3. The method according to claim 1 , wherein the methenylation in step (ii) is carried out using a Nysted reagent.4. The method according to claim 1 , wherein the deprotection in step (iii) is carried out under an acidic condition.5. The method according to claim 1 , wherein the conversion in step (iv) is carried out using 1 claim 1 ,1-carbonyldiimidazole.6. The method according to claim 1 , wherein the deprotection in step (v) is carried out using a fluoride (F) compound.7. The method according to claim 1 , wherein the intramolecular Friedel-Crafts allylic alkylation in step (vi) is carried out using a palladium catalyst and a ligand.8. The method according to claim 7 , wherein the palladium catalyst is bis(dibenzylideneacetone)palladium(0) claim 7 , and the ligand is triphenylphosphine.9. The method according to claim 1 , wherein the hydrogenation in step (vii) is carried out using Pd/C under a basic condition.10. The method according to claim 1 , wherein the alkylation in step (viii) is carried out in the presence of a base.11. The method according to claim 1 , wherein the hydrolysis in step (ix) is carried out in the presence of a base.13. The compound of formula (8) according to claim 12 , wherein{'img': {'@id': 'CUSTOM-CHARACTER-00007', '@he': '2.12mm', '@wi': '3.56mm', '@file': 'US20190119205A1-20190425-P00007.TIF', '@alt': 'custom-character', '@img-content': 'character', '@img-format': 'tif'}, 'represents a single bond between carbon atoms,'}{'sub': '1', 'Rrepresents chlorine,'}{'sub': '5', 'Y represents α-OR:β-H,'}{'sub': '5', 'Rrepresents hydrogen or a hydroxyl protecting group, ...

PROCESS FOR THE PREPARATION OF A NITRIC OXIDE DONATING PROSTAGLANDIN ANALOGUE

The present invention relates to a process for preparing the hexanoic acid, 6-(nitrooxy)-, (1S,2E)-3-[(1R,2R,3S,5R)-2-[(2Z)-7-(ethylamino)-7-oxo-2-hepten-1-yl]-3,5-dihydroxycyclopentyl]-1-(2-phenylethyl)-2-propen-1-yl ester of formula (I). 2. The process according to wherein step 1) is carried out at a temperature ranging from 0° C. to room temperature in an aprotic organic solvent.3. The process according to wherein the aprotic organic solvent is methyltertbutyl ether.4. The process according to wherein in step 1) the molar ratio of compound (II) to 6-(nitrooxy)hexanoyl chloride (IVa) is from 1:1.4 to 1:1.6 and the molar ratio of compound (II) to 4-dimethylaminopyridine preferably is from 1:2.0 to 1:2.4.5. The process according to wherein in step 4) the inorganic base is potassium hydroxide.6. The process according to wherein step 4) is carried out in a solvent selected from methanol claim 1 , ethanol or isopropanol.7. The process according to wherein the solvent is methanol.8. The process according to wherein step 5) is carried out in dichloromethane.9. The process according to wherein in step 6) the concentration of the formic acid in water (HO+HCOOH) is 0.1% w/w.10. The process according to wherein in step 6) the chromatographic fractions containing the compound (Vila) are extracted with CHCl claim 1 , dried and the solvent is evaporated.11. The process according to wherein step 7) is carried out in dichloromethane and the chlorinating agent is oxalyl chloride.12. The process according to wherein the 6-(nitrooxy)hexanoyl chloride obtained in step 7) is used without further purification.15. A pharmaceutical formulation containing hexanoic acid claim 1 , 6-(nitrooxy)- claim 1 , (1S claim 1 ,2E)-3-[(1R claim 1 ,2R claim 1 ,3S claim 1 ,5R)-2-[(2Z)-7-(ethylamino)-7-oxo-2-hepten-1-yl]-3 claim 1 ,5-dihydroxycyclopentyl]-1-(2-phenylethyl)-2-propen-1-yl ester of formula (I) and at least a pharmaceutically acceptable excipient claim 1 , wherein hexanoic acid claim 1 , 6-( ...

NOVEL PROCESSES FOR THE PREPARATION OF PROSTAGLANDIN AMIDES

The subject of the invention is process for the preparation of the prostaglandin amides of the general formula I, 3. Process according to claim 2 , characterized in that dimethyl ether claim 2 , diethyl ether claim 2 , diisopropyl ether are used as ether-type solvents.4. Process according to claim 2 , characterized in that ethyl-acetate claim 2 , methyl-acetate claim 2 , isopropyl-acetate are used as ester-type solvents.5. Process according to claim 2 , characterized in that crystallisation is performed between (−)30° C. and 30° C.6. Process according to claim 2 , characterized in that the suspension of crystals is stirred 1-24 hours.7. Process according to claim 2 , characterized by that the crystal suspension is filtered and washed with ether type solvent.8. Process according to claim 2 , characterized in that the filtered crystals are dried under vacuum between 25-50° C.9. Process according to claim 2 , characterized in that diethyl-ether and diisopropyl ether are used as ether-type solvents.10. Process according to claim 2 , characterized in that isopropyl-acetate are used as ester-type solvents.11. Process according to claim 2 , characterized in that crystallisation is performed between 0-25° C.12. Process according to claim 2 , characterized in that the suspension of crystals is stirred 8 hours.13. Process according to claim 2 , characterized by that the crystal suspension is filtered and washed with diisopropyl ether.14. Process according to claim 2 , characterized in that the filtered crystals are dried under vacuum between 35-40° C. This application is a Divisional of copending application Ser. No. 14/123,497, filed on Jan. 29, 2014, which was filed as PCT International Application No. PCT/HU2012/000045 on May 25, 2012, which claims the benefit under 35 U.S.C. §119(a) to Patent Application No. P11 00291, filed in Hungary on Jun. 2, 2011 and Patent Application No. P11 00292, filed in Hungary on Jun. 2, 2011, all of which are hereby expressly incorporated by ...

NOVEL PROSTAGLANDIN DERIVATIVE

The present invention relates to a novel prostaglandin derivative having an alkynyl group on ω-chain, particularly, a novel prostaglandin derivative having a double bond at the 2-position and an alkynyl group on the ω-chain and a medicament containing the compound as an active ingredient. 119-. (canceled)21: The compound or pharmaceutically acceptable salt of claim 20 , wherein Y is CH.22: The compound or pharmaceutically acceptable salt of claim 20 , wherein Ris —CH═CZ(COX).23: The compound or pharmaceutically acceptable salt of claim 20 , wherein Ris —CH—CZZ(COX).24: The compound or pharmaceutically acceptable salt of claim 20 , wherein n is 1.25: The compound or pharmaceutically acceptable salt of claim 20 , wherein A-B is a carbon-carbon double bond.26: The compound or pharmaceutically acceptable salt of claim 20 , wherein Ris a hydrogen atom and Ris an alkyl group having 1 to 3 carbon atoms.27: The compound or pharmaceutically acceptable salt of claim 20 , wherein Ris a cycloalkyl group having 3 to 5 carbon atoms.28: The compound or pharmaceutically acceptable salt of claim 20 , wherein X is OR.29: A cyclodextrin clathrate compound claim 20 , comprising the compound or pharmaceutically acceptable salt of .30: A medicament claim 20 , comprising the compound or pharmaceutically acceptable salt of .31: A method of treating a blood flow disorder claim 30 , the method comprising administering the medicament of claim 30 , as a prophylactic or therapeutic agent claim 30 , to a subject in need thereof.32: The method of claim 31 , wherein the blood flow disorder is a blood flow disorder of a nerve.33: The method of claim 32 , wherein the blood flow disorder of the nerve is a blood flow disorder associated with spinal canal stenosis.34: The method of claim 31 , wherein the blood flow disorder is a blood flow disorder of a peripheral artery claim 31 , skin or brain.35: The method of claim 34 , wherein the blood flow disorder is a blood flow disorder of a peripheral artery ...

NOVEL PROCESSES FOR THE PREPARATION OF PROSTAGLANDIN AMIDES

The subject of the invention is process for the preparation of the prostaglandin amides of the general formula I, 2. Crystal form II. prepared by the process according to claim 1 , characterized in that its melting point is between 72-78° C.3. Crystal form II. prepared by the process according to claim 1 , characterized in that on the basis of DSC investigation the endothermic peak is between 72-79° C. and its melting heat is higher than 75 J/g.4. Process according to claim 1 , characterized in that 20-60 mass % amount of protic solvent is applied.5. Process according to claim 1 , characterized in that alcohols and/or water are used as protic solvents.6. Process according to claim 5 , characterized in that methanol or ethanol is used as alcohol.7. Process according to claim 5 , characterized in that water is used as protic solvent.8. Process according to claim 1 , characterized in that 2000-8000 mass % amount of ether-type solvent is applied.9. Process according to claim 1 , characterized in that dimethyl ether claim 1 , diethyl ether claim 1 , diisopropyl ether are used as ether-type solvents.10. Process according to claim 1 , characterized in that stirring or scratching claim 1 , or both are applied as mechanical effect.11. Process according to claim 1 , characterized in that the added solvent is removed by drying.12. Process according to claim 4 , characterized in that drying is performed in vacuum claim 4 , at a temperature between (−) 60° C. and 70° C.13. Process according to claim 8 , characterized in that drying is performed at a temperature between 0-(−)50° C. by passing through nitrogen gas.14. Process according to claim 1 , characterized in that 35 mass % amount of protic solvent is applied. This application is a Divisional of copending application Ser. No. 14/123,497, filed on Jan. 29, 2014, which was filed as PCT International Application No. PCT/HU2012/000045 on May 25, 2012, which claims the benefit under 35 U.S.C. §119(a) to Patent Application No. P11 ...

Process to prepare treprostinil, the active ingredient in remodulin®

This present invention relates to an improved process to prepare prostacyclin derivatives. One embodiment provides for an improved process to convert benzindene triol to treprostinil via salts of treprostinil and to purify treprostinil.

Compound And Method

A compound of formula (I): (I) wherein Y is, Z is OR, NRRSR, S(0)RS0R, Ris H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, CO—R, or a protecting group, and Ris optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or alkoxyl; a process for making a compound of formula (I); and a process for making a prostaglandin or a prostaglandin analogue using a compound of formula (I). 4. (canceled)6. The process according to claim 5 , wherein the acidic co-catalyst is added to the reaction mixture after the chiral secondary amine catalyst has been added.7. (canceled)11. The process according to claim 5 , wherein the acidic co-catalyst has the structure [α][β] wherein [α] is a cation selected from [BnNH] claim 5 , [BnNH] claim 5 , [pyridinium] claim 5 , [2 claim 5 ,2′-bipyridinium] claim 5 , [2 claim 5 ,2′:6′ claim 5 ,2″-terpyridinium] claim 5 , [morpholinium] and [thiomorpholinium] claim 5 , and [β] is an anion selected from [F] claim 5 , [Cl] claim 5 , [Br] claim 5 , [I] claim 5 , [OCOCF] claim 5 , [BF] claim 5 , [OCOCHCl] claim 5 , and [O—CH-2 claim 5 ,4-(NO)].12. The process according to claim 11 , wherein the acidic co-catalyst comprises [BnNH][OCOCF].14. (canceled)16. A process for making a prostaglandin or a prostaglandin analogue claim 1 , which uses a compound of formula (I) as defined in as a reactant. The present invention relates to a compound of formula (I) as defined below, a process for making a compound of formula (I), and a process for making a prostaglandin or a prostaglandin analogue using a compound of formula (I).Prostaglandins are hormone-like chemical messengers that regulate a host of physiological ...

NOVEL PROSTAMIDES FOR THE TREATMENT OF GLAUCOMA AND RELATED DISEASES

Disclosed herein are compositions comprising an amide related to a prostaglandin and a biogenic amine. Other aspects relate to certain chemical compounds, pharmaceutical compositions, and methods of treating glaucoma. 110.-. (canceled)1420.-. (canceled) This application is continuation of U.S. application Ser. No. 14/137,000, filed Dec. 20, 2013, which is a continuation application of U.S. application Ser. No. 11/573,692, filed Jun. 12, 2007, now U.S. Pat. No. 8,648,213, issued Feb. 11, 2014, which is a national stage application under 35 U.S.C. §371 of PCT application PCT/US2005/035748, filed on Oct. 4, 2005, which claims the benefit of provisional application No. 60/616,780, filed on Oct. 6, 2004, the disclosures of which are hereby incorporated by reference in their entireties and serve as the basis of a priority and/or benefit claim for the present application.Field of the InventionThe present invention relates to novel amides related to prostaglandins as potent ocular hypotensives that are particularly suited for the management of glaucoma and related diseases.Description of Related ArtOcular hypotensive agents are useful in the treatment of a number of various ocular hypertensive conditions, such as post-surgical and post-laser trabeculectomy ocular hypertensive episodes, glaucoma, and as presurgical adjuncts.Glaucoma is a disease of the eye characterized by increased intraocular pressure. On the basis of its etiology, glaucoma has been classified as primary or secondary. For example, primary glaucoma in adults (congenital glaucoma) may be either open-angle or acute or chronic angle-closure. Secondary glaucoma results from pre-existing ocular diseases such as uveitis, intraocular tumor or an enlarged cataract.The underlying causes of primary glaucoma are not yet known. The increased intraocular tension is due to the obstruction of aqueous humor outflow. In chronic open-angle glaucoma, the anterior chamber and its anatomic structures appear normal, but drainage ...

ANTI-CONSTIPATION COMPOSITION

An object of the present invention is to provide an anti-constipation composition containing a halogenated-bi-cyclic compound as an active ingredient in a ratio of bi-cyclic/mono-cyclic structure of at least 1:1. The halogenated-bi-cyclic compound is represented by Formula (I): 2. The pharmaceutical composition according to claim 1 , further comprising a compound which is a mono-cyclic tautomer of formula (I) claim 1 ,wherein in the composition a ratio of bi-cyclic to mono-cyclic structure is at least 1:1.3. The pharmaceutical composition according to claim 1 , further comprising a compound which is a mono-cyclic tautomer of formula (I) claim 1 ,wherein in the composition a ratio of bi-cyclic/mono-cyclic structure is at least 20:1.5. The pharmaceutical composition according to claim 4 , further comprising a compound which is a mono-cyclic tautomer of formula (I) claim 4 ,wherein in the composition a ratio of bi-cyclic/monocyclic structure is at least 1:1.6. The pharmaceutical composition according to claim 5 , wherein the ratio of bi-cyclic/mono-cyclic structure is at least 20:1.7. The pharmaceutical composition of according to claim 1 , wherein Z is a sulfur atom or a nitrogen atom.8. The pharmaceutical composition according to claim 4 , wherein Z is a sulfur atom or a nitrogen atom.9. The pharmaceutical composition according to claim 4 , wherein the medium chain fatty acid triglyceride is present in an amount of 1-1 claim 4 ,000 claim 4 ,000 parts by weight based on one part by weight of the bi-cyclic structure.10. The pharmaceutical composition according to claim 9 , wherein the medium chain fatty acid triglyceride is present in an amount of 5-500 claim 9 ,000 parts by weight based on one part by weight of the bi-cyclic structure.11. The pharmaceutical composition according to claim 9 , wherein the medium chain fatty acid triglyceride is present in an amount of 10-200 claim 9 ,000 parts by weight based on one part by weight of the bi-cyclic structure.12. The ...

METHOD FOR PREPARING LATANOPROSTENE BUNOD, AND INTERMEDIATE THEREFOR

The present invention relates to a process for preparing latanoprostene bunod and an intermediate therefor. In accordance with the preparation process of the present invention, latanoprostene bunod can be efficiently and cost-effectively prepared while reducing side reactions. 2. The process according to claim 1 , wherein the esterification of step (i) is carried out in the presence of a base.3. The process according to claim 2 , wherein the base is potassium carbonate.4. The process according to claim 1 , wherein the nitration of step (ii) is carried out using silver nitrate (AgNO).6. The process according to claim 5 , wherein the hydrolysis is carried out using lithium hydroxide monohydrate. The present invention relates to a process for preparing latanoprostene bunod and an intermediate therefor. More particularly, the present invention relates to a cost-effective and efficient process for preparing latanoprostene bunod, and an intermediate therefor.Latanoprostene bunod of the following formula (1) (4-(nitrooxy)butyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate) is an active pharmaceutical ingredient (API) of Vesneo® which is a medicine for glaucoma.U.S. Pat. No. 7,273,946 discloses a process for preparing latanoprostene bunod by preparing 4-bromobutyl nitrate using tetrahydrofuran as a starting material and subjecting it to combination reaction with latanoprost acid, as shown in the following reaction scheme 1. However, the preparation process has the danger of using strong acids in the synthesis of 4-bromobutyl nitrate, and the risk of explosion due to rapid heat generation in dropwise addition of sulfuric acid into nitric acid solution. Further, the bromide produced by the combination reaction reacts with the nitrate of latanoprostene bunod, which causes the problem of producing a large amount of by-products.It is an object of the present invention to provide an efficient and cost-effective process for preparing ...

PROSTAGLANDIN F2 ALPHA DERIVATIVES FOR DECREASING INTRAOCULAR PRESSURE

The invention relates to clinical chemistry, in particular, to new biologically active compounds amide derivatives of prostaglandin F2α. These compounds have low cytotoxicity and are capable of stimulating formation of endogenous nitrogen oxide in mammal cells. Synthesis of such compounds promotes expansion of nomenclature of biologically active derivatives of prostaglandin F2α capable of reducing intraocular pressure. 2. Compounds of claim 1 , wherein salt with pharmaceutically acceptable cations is produced in the presence of free carboxyl group.3. Compounds of claim 1 , capable of reducing intraocular pressure. The invention relates to clinical chemistry, in particular, to new biologically active compounds—amide derivatives of prostaglandin F.Prostaglandins are the family of multifunctional biologically active substances synthesized in organism from arachidonic acid by means of cyclooxygenase (COX). These oxidized fatty acids are autocrine and paracrine lipid mediators, and they are characterized by broad-spectrum of physiological activity, for example, combination of dilatator (bronchi smooth muscles), constrictor (gastrointestinal tract smooth muscles), antiaggregatory (platelets), hypo- or hypertensive activities [Nicolau A. In: Bioactive Lipids (Eds. Nicolau A., Kokotos J.) II Bridgewater: Oily Press, 2004. —197 p]. Prostaglandin Fis formed in organism as a result of arachidonic acid oxidative metabolism caused by cyclooxygenase at the first stage and by reductase—at the second stage of biosynthesis [Smith W. L., Marnett L. J., DeWitt D. L. Prostaglandin and thromboxane biosynthesis//Pharmacology & Therapeutics. 1991, V. 49(3), P. 153-179]. It is G-protein coupled receptor FP endogenous ligand, which activation results in intracellular calcium mobilization [Toh H, Ichikawa A, Narumiya S. Molecular evolution of receptors for eicosanoids.//FEBS Lett. 1995, V. 361, P. 17-21].Prostaglandins are used for treatment of hypertension, thrombosis, asthma, gastric and ...

Preservative-free Treprostinil Devices

Embodiments include a system including a sealed prefilled drug-reservoir. The drug-reservoir may include a unit dosage of treprostinil in a sterile fluid composition. The composition may not include an antimicrobial preservative. The treprostinil may be present at a dosage of between 0.1 mg/mL and 25 mg/mL. In addition, the treprostinil may be treprostinil sodium Furthermore, the composition may include sodium chloride. The composition may also include a sodium ion from sodium chloride in a concentration from 3000 to 4500 ppm. The composition may not include metacresol.

Processes and intermediates for the preparations of isomer free prostaglandins

Novel processes for the preparation of a compound of Formula I-2 substantially free of the 5,6-trans isomer: wherein R 2 , R 3 and R 4 are as defined in the specification are provided. Novel intermediates for the preparations of isomer free Prostaglandins and derivatives thereof are also provided.

SYNTHESIS OF DELTA 12-PGJ3 AND RELATED COMPOUNDS

In one aspect, the present invention provides novel derivatives of Δ-PGJand modular synthetic pathways to obtaining Δ-PGJand derivatives thereof. In some aspects, the present derivatives of Δ-PGJare useful as chemotherapeutic agents. The present disclosure also describes compositions of these derivatives as well as methods of use of the derivatives thereof. 46.-. (canceled)7. The compound of claim 1 , wherein Yis O.8. The compound of claim 1 , wherein Yis N—OH or N—OMe.9. The compound of claim 8 , wherein Yis N—OMe.1095.-. (canceled)97. The compound of claim 96 , wherein Ais alkenediyl.98. (canceled)99. The compound of claim 96 , wherein z is 1 claim 96 , 2 claim 96 , 3 claim 96 , or 4.100101.-. (canceled)102. The compound of claim 96 , wherein Xis O.103. The compound of claim 96 , wherein Xis alkenyl.104. (canceled)107. A pharmaceutical composition comprising a compound of and an excipient.108. (canceled)109. The pharmaceutical composition of claim 107 , wherein the composition is formulated for oral claim 107 , topical claim 107 , intraarterial claim 107 , intraperitoneal claim 107 , or intravenous administration.110114-. (canceled)115. A method of treating a disease or disorder in a patient in need thereof comprising administering to the patient a pharmaceutically effective amount of a compound or composition of or a pharmaceutically acceptable salt or optical isomer thereof.116. The method of claim 115 , wherein the disease is cancer.117118.-. (canceled)119. The method of claim 116 , wherein the cancer is leukemia.120130.-. (canceled)132293.-. (canceled)295434.-. (canceled) This application claims the benefit of U.S. Provisional Application 61/882,093, filed on Sep. 25, 2013, U.S. Provisional Application 61/897,681, filed on Oct. 30, 2013, U.S. Provisional Application 61/920,302, filed on Dec. 23, 2013, U.S. Provisional Application 61/954,295, filed on Mar. 17, 2014, and U.S. Provisional Application 61/979,276, filed on Apr. 14, 2014, the entire contents of each ...

Preservative-free Treprostinil Formulations and Methods and Devices for Use with Same

This invention provides for a unit dosage form of treprostinil at a dosage of between 0.1 mg/mL and 25 mg/mL in a sterile fluid composition formulated for subcutaneous or intravenous injection, which composition does not comprise an antimicrobial preservative. Selectively activatable patch-pump assemblies comprising a sealed prefilled drug-reservoir containing the unit dosage form is described as are methods for reducing pain at a site of subcutaneous or intravenous infusion of treprostinil in a subject in need thereof, and methods of reducing irritation, inflammation or a combination thereof at a site of subcutaneous or intravenous infusion of treprostinil in a subject in need thereof. The invention also provides a method of treating pulmonary hypertension, and methods for treating, or reducing the severity or reducing the pathogenesis of Pulmonary arterial hypertension (PAH) in a subject making use of the compositions as herein described. 1. A unit dosage form of treprostinil in a sterile fluid composition formulated for subcutaneous or intravenous injection , wherein said composition does not comprise an antimicrobial preservative , and said treprostinil is present at a dosage of between 0.1 mg/mL and 25 mg/mL.2. The unit dosage form of claim 1 , wherein said composition does not comprise metacresol.3. The unit dosage form of claim 1 , wherein said treprostinil is treprostinil sodium.4. The unit dosage form of claim 3 , wherein the sodium ion concentration ranges from 3000-4500 ppm.5. The unit dosage form of claim 1 , wherein said composition provides for a maximal volume of injection which does not exceed 10 mL for single use.6. A selectively activatable patch-pump assembly comprising a sealed prefilled drug-reservoir containing the unit dosage form of claim 1 ,7. Treprostinil in a sterile fluid composition formulated for subcutaneous or intravenous injection claim 1 , for use in reducing pain at a site of subcutaneous or intravenous infusion of treprostinil in ...

TROMETHAMINE SALT OF BIMATOPROST ACID IN CRYSTALLINE FORM 1, METHODS FOR PREPARATION, AND METHODS FOR USE THEREOF

The present invention provides tromethamine salt of (Z)-7-[3,5-Dihydroxy-2-((E)-3-hydroxy-5-phenyl-pent-1-enyl)-cyclopentyl]-hept-5-enoic acid in crystalline Form 1 and amorphous form. This compound is may also be referred to as “tromethamine salt of bimatoprost acid.” The invention crystalline form is useful for solid ocular implant or topical formulations, utilized in the treatment of various ocular conditions, such as, for example, ocular hypertension. 2. The crystalline Form 1 of having the X-ray powder diffraction pattern as shown in .3. The crystalline form of having a melting enthalpy from about 103.6 J/g to about 119.9 J/g.4. The crystalline form of having a melting temperature within the range of about 104-110° C.5. The crystalline form of having a melting temperature of about 105° C.6. The crystalline form of having a melting temperature of about 105.6° C.7. A pharmaceutical composition comprising a therapeutically effective amount of tromethamine salt of bimatoprost acid in crystalline Form 1.8. The pharmaceutical composition of wherein the tromethamine salt of bimatoprost acid in crystalline Form 1 is in a pharmaceutically acceptable carrier.9. The pharmaceutical composition of claim 7 , wherein the pharmaceutical composition is a suspension claim 7 , solution claim 7 , foam claim 7 , gel claim 7 , cream claim 7 , ointment claim 7 , emulsion claim 7 , or lotion.10. The pharmaceutical composition of claim 9 , wherein the suspension is a gel suspension claim 9 , a gel-based micro-suspension claim 9 , or a nano-suspension.11. The pharmaceutical composition of claim 7 , wherein the pharmaceutical composition is a solid dosage form.12. The pharmaceutical composition of for the treatment of elevated intraocular pressure claim 7 , glaucoma claim 7 , or localized fat reduction claim 7 , or for promotion of hair growth.13. A method for treating ocular hypertension comprising administering to a subject in need thereof a therapeutically effective amount of ...

PROCESS FOR THE PREPARATION OF CARBOPROST AND ITS TROMETHAMINE SALT

The subject of the invention is a novel process for the preparation of Carboprost tromethamine salt where alkylation the enone of the general formula (II) is carried out in the presence of a chiral auxiliary in aprotic solvent with a Grignard reagent. The methyl ester epimers of formula (VII) are separated by gravity silicagel chromatography and the salt formation is carried out by using solid tromethamine base. 2. Process as defined in claim 1 , comprising that as Grignard reagent methylmagnesium chloride or methylmagnesium bromide claim 1 , preferably methylmagnesium bromide is applied.3. Process as defined in claim 2 , comprising that methylmagnesium bromide is applied in 3-4 molar equivalent claim 2 , preferably 3.5 molar equivalent amount.4. Process as defined in claim 1 , comprising that as chiral auxiliary a complex-forming chiral auxiliary material is used.5. Process as defined in claim 4 , comprising that as complex-forming chiral auxiliary material (S)-Taddol is applied.6. Process as defined in claim 5 , comprising that (S)-Taddol is used in 1 molar equivalent amount.7. Process as defined in claim 1 , comprising that as R protecting group ether- claim 1 , silyl ether- claim 1 , benzyl- claim 1 , substituted benzyl- claim 1 , or acyl-groups are applied.8. Process as defined in claim 7 , comprising that as R protecting group -p-phenylbenzoyl group is applied.9. Process as defined in claim 1 , comprising that as aprotic organic solvent ethers claim 1 , as diethyl ether claim 1 , methyl tertiary-butyl ether claim 1 , diisopropyl ether claim 1 , tetrahydrofuran claim 1 , methyltetrahydrofuran claim 1 , dimethoxyethane; aromatic hydrocarbons claim 1 , as benzene claim 1 , toluene claim 1 , xylene; halogenated solvents claim 1 , as dichloromethane claim 1 , or the mixture of these solvents are applied.10. Process as defined in claim 9 , comprising that as solvent claim 9 , toluene is applied.11. Process as defined in claim 1 , comprising that methylation is ...

Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension

Prostaglandins

The invention relates to a novel process for the preparation of 13,14-dihydro-15(R)-17-phenyl-18,19,20-trinor-PGF2α isopropyl ester of formula (I), wherein R stands for saturated or unsaturated straight, branched or cyclic C1-7 alkyl or phenyl or benzyl group. The process of the invention comprises reducing the oxo group on the side chain of the compound of formula (VII), transforming the obtained 3,3a,4,5,6,6a-hexahydro-2-oxo-4-[5'-phenyl-3'(R)-hydroxypent-1'-enil]-5-(4'-phenylbenzoxyloxy)-2H-cyclopenta[b]furan of formula (VI) by hydrogenation to 3,3a,4,5,6,6a-hexahydro-2-oxo-4-[5'-phenyl-3'(R)-hydroxy-1'-pentyl]-5-(4'-phenylbenzoyloxy)-2H-cyclopenta[b]furan of formula (V) reducing the compound of formula (V) to 3,3a,4,5,6,6a-hexahydro-2-hydroxy-4-[5'-phenyl-3'(R)-hydroxy-1'-pentyl]-5-(4'-phenylbenzoyloxy)-2H-cyclopenta[b]furan of formula (IV), removing the protective group from the compound of formula (IV) to obtain 3,3a,4,5,6,6a-hexahydro-2,5-dihydroxy-4-[5'-phenyl-3'(R)-hydroxy-1'-pentyl]-2H-cyclopenta[b]furan of formula (III) then transforming the compound of formula (III) obtained to 13,14-dihydro-15(R)-17-phenyl-18,19,20-trinor-PGF2α of formula (II) by using 4-carboxybutyl-triphenylphosphonium halide and finally, transforming the compound of formula (II) with a compound of the general formula R-X- wherein R has the same meaning as stated above, X is halogen sulphate, mesyl, tosyl or any suitable group to 13,14-dihydro-15(R)-17-phenyl-18,19,20-trinor-PGF2α esters of general formula (I).

Production of cyclopentenylheptanoic acid derivatives

Cyclopentenyl heptanoic acid derivatives having the formula: wherein R is hydrogen or C, to C 4 alkyl and -(A)-is: wherein M is hydrogen or triorganosilyl, are prepared by reacting a compound having the formula: wherein X is halogen, with a compound having the formula: The derivatives belong to the pharmacologically -active class of compounds called "prostagfandins".

Microbiological reduction of PGA2 and 15-epi PGA2

Reduction of 7(2-[(3R and 3S)-3-hydroxy-1-octenyl]-5-oxo-3-cyclopenten-1-yl)-5-heptenoic acid by microorganisms of the genera Streptomyces, Pseudomonas and Corynebacterium is disclosed. The products 7-(2-[(3R)-3-hydroxy-1-octenyl]-5-oxo-cyclopentyl)-5-heptenoic acid(11-deoxy-15-epi-PGE 2 ), which is novel, and 7-(2-[(3S)-3-hydroxy-1-octenyl]-5-oxo-3-cyclopentyl)-5-heptenoic acid(11-deoxy-PGE 2 ), respectively, are useful as intermediates for the synthesis of other physiologically active ingredients.

Synthesis of prostanoids

The presently disclosed subject matter provides a method of synthesizing prostaglandins and prostaglandin analogs comprising the ring closing metathesis of compounds of Formula (I). Also provided are novel compounds of Formula (I) and Formula (II). In addition to their use as synthetic intermediates in the presently disclosed methods, compounds of Formula (II) can be used as prostaglandin and/or prostaglandin analog prodrugs.

Use of certain prostaglandin analogues to treat glaucoma and ocular hypertension

Certain D series prostaglandin analogues are effective in lowering intra ocular pressure and are useful in the treatment of glaucoma and ocular hypertension. Also disclosed are opthalmic, pharmaceutical compositions comprising such prostaglandin analogues and their use.

Difluoroprostaglandin derivatives and their use

A fluorine-containing prostaglandin derivative of the formula (1) or a salt thereof, and a medicine containing it, particularly, as a preventive or therapeutic medicine for an eye disease: wherein A is a vinylene group or the like, R 1 is an aryloxyalkyl group or the like, R 2 and R 3 are hydrogen atoms or the like, and Z is OR 4 , therein OR 4 is a hydrogen atom or an alkyl group or the like.

Solid phase and combinatorial synthesis of benzodiazepine compounds on a solid support

Methods, compositions, and devices for synthesis of therapeutically useful compounds. The invention provides a rapid approach for combinatorial synthesis and screening of libraries of derivatives of therapeutically important classes of compounds such as benzodiazepines, prostaglandins and β-turn mimetics. In order to expediently synthesize a combinatorial library of derivatives based upon these core structures, general methodology for the solid phase synthesis of these derivatives is also provided. This disclosure thus also describes an important extension of solid phase synthesis methods to nonpolymeric organic compounds.

13,14-Didehydro-PG analogs

This invention comprises certain analogs of the prostaglandins in which the double bond between C-13 and C-14 is replaced by a triple bond. Also provided in this invention, are novel chemical processes and novel chemical intermediates useful in the preparation of the above prostaglandin analogs. These prostaglandin analogs exhibit prostaglandin-like activity, and are accordingly useful for the same pharmacological purposes as the prostaglandins. Among these purposes are blood pressure lowering, labor induction at term, reproductive-cycle regulation, gastric antisecretory action, and the like.

前列腺素衍生物

7-THIAPROSTAGLANDINE AND METHOD FOR THE PRODUCTION THEREOF

New process for preparing high purity prostaglandins

Sett att framstella nya 11-desoxi-prostaglandin-f?712-derivat

Process for the preparation of 16-fluoro-16,17-didehydro prostanoids

ANALOGS OF PROSTANIC ACIDS AND THE PROCESS FOR THEIR PRODUCTION

Process of preparing derivatives of prostacycline or their epimers

1. Способ получени  производных простдциклина обшей формулы ,iH А-С-В или их эпимеров, где R -водород, щелочной металл или низший алкил; 1 -водород или метил ; --СН -СН--, транс-СН СНА у-, транс-1-н сн- ; 1((СКл},-СУ( или --С(Р В цикле гюгексил; 1 и R - одинаковые или разные, водород или этил, о т л И ч а ю щ и и с   тем, что соединение общей формулы ОН -J . ) и R2имеют указанные знагде А, В У и одинаковые или разчени , R ные, водород или защитна  группа тетрагидропйранил или триметилсилил, подвергают взаимодействию, в среде органического растворител  в инертной атмосфере при lO-ЗОс в присутствии сильного основани  с 1-6-кратным мол рным количеством соединени  общей формулы . {СбН5)зР-Ш2-О 1 ,в Hai 41 I-Ч41ЛПТ 6 JOOR где в - водород, метил или этил; Hal - бром или иод, 6 и затем, когда К водоррд, -этерифицируют диазометаном при 0-30°С, а когда R и R 5 - защитна  группа, последние отщепл ют с получением соедиО ) нени  общей формулы ОН а S но соов А-С-В КО R2 где R ,. А и В имеют указанные значени / R - метил или. этил, которое :бромируют или иодируют в присутствии инертного растворител  и при необходимости в присутствии акцептора кислоты при 0-30 с и ииклизуют в соединение общей формулы .где t, Я , А и В имеют указанные значени  ; X - бром или иод, и от полученного соединени  фбрмулы У при 0-90°С отщепл ют галоид-водо 1. A process for the preparation of prostadcycline derivatives of the general formula iH A-C-B or their epimers, where R is hydrogen, alkali metal or lower alkyl; 1 is hydrogen or methyl; --CH -CH--, trans-CHA CHA y-, trans-1-nn-; 1 ((CKl}, - SU (or –C (P in the hegexyl cycle; 1 and R are the same or different, hydrogen or ethyl), and with the fact that the compound of the general formula OH is J.) and R2 have the indicated values where A, B Y and the same or different, R are hydrogen, or the protective group of tetrahydropyranyl or trimethylsilyl, is reacted in an organic solvent medium in an inert atmosphere at 0-30 ° C in the ...

用于制备无异构体的前列腺素的方法和中间体

本申请涉及用于制备无异构体的前列腺素的方法和中间体。本发明提供用于制备实质上不含5,6‑反式异构体的式I‑2化合物的新颖方法： 其中 R 2 、R 3 和R 4 如说明书中所定义。本发明还提供用于制备无异构体的前列腺素和其衍生物的新颖中间体。

Process for preparing heterocyclic compounds and isomers thereof

Heterocyclic compds. of formula (I) are new, where R1 is H, an alcohol residue in the form up on ester, or a pharmaceutically compatible cation; R2 is H or methyl; A is -CH2-CH2- or trans-CH=CH-; and B is C5-7 alkyl of formula -CR3R4-(CH2)3-CH3 (where R3 and R4 are H or (m)ethyl or cyclohexyl opt. 4-substd. by (m)ethyl. (I) have good thrombocyte aggregation inhibiting activity in humans and also in external circulatory systems.

Prostaglandin derivatives

Preparation of prostaglandin-like compounds

174; an improved process to prepare treprostinil the active ingredient in remodulin174;

본 발명은 프로스타시클린 유도체의 개선된 제조 방법에 관한 것이다. 한 가지 구체예는 트레프로스티닐의 염에 의해 벤즈인덴 트리올을 트레프로스티닐로 전환시키고, 트레프로스티닐을 정제하는 개선된 방법을 제공한다. The present invention relates to an improved process for the preparation of prostacyclin derivatives. One embodiment provides an improved method of converting benzindentiol to treprostinil by the salt of treprostinil and purifying the treprostinil.

Substituted cyclopentanes, possessing prostaglandin activity

FIELD: chemistry. SUBSTANCE: invention relates to novel analogues of 11,15,19-trihydroxy-9-halo-prostaglandin and their application as eye hypotensive medications, medications for treatment of glaucoma, as well as for improvement of hair growth or improvement of hair outlook, namely to compounds of formula , where dash and dash line stands for presence or absence of bond; Y has from 1 to 14 carbon atoms and is functional group of carboxylic acid or its ester; X represents halogen; Z represents -OH; each of R 1 is independently CH 2 , or, if R 1 forms double bond with other R 1 , both are CH, and each R is independently -H. EFFECT: increased efficiency of compound application. 11 cl, 2 tbl, 2 dwg РОССИЙСКАЯ ФЕДЕРАЦИЯ (19) RU (11) 2 505 530 (13) C2 (51) МПК C07C 405/00 (2006.01) ФЕДЕРАЛЬНАЯ СЛУЖБА ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ (12) ОПИСАНИЕ ИЗОБРЕТЕНИЯ К ПАТЕНТУ (21)(22) Заявка: 2010135795/04, 03.02.2009 (24) Дата начала отсчета срока действия патента: 03.02.2009 (73) Патентообладатель(и): Аллерган, Инк. (US) R U Приоритет(ы): (30) Конвенционный приоритет: 02.02.2009 US 12/363,996 05.02.2008 US 61/026,179 (72) Автор(ы): БЁРК Роберт М. (US) (43) Дата публикации заявки: 20.03.2012 Бюл. № 8 2 5 0 5 5 3 0 2 5 0 5 5 3 0 R U (56) Список документов, цитированных в отчете о поиске: DATABASE CAS on STN, реферат статьи Steffenrud S. et al. "Metabolism of prostaglandin E analogs in the guinea pig liver mitochondrial fraction", "Biochemical Medicine", 1984, 32, p.161-180, RN 93800-38-5. DE 2228154 A, 28.12.1972. US 2005/070516 A1, 31.03.2005. EP 0116358 A1, 22.08.1984. WO 2007/060453 A, 31.05.2007. US 6410591 B1, 25.06.2002. WO (см. прод.) (85) Дата начала рассмотрения заявки PCT на национальной фазе: 06.09.2010 (86) Заявка PCT: US 2009/032943 (03.02.2009) (87) Публикация заявки РСТ: WO 2009/100057 (13.08.2009) Адрес для переписки: 191002, Санкт-Петербург, а/я 5, ООО "Ляпунов и партнеры", пат.пов. Ю.В.Кузнецовой (54) ЗАМЕЩЕННЫЕ ЦИКЛОПЕНТАНЫ, ОБЛАДАЮЩИЕ ПРОСТАГЛАНДИНОВОЙ ...

The method of obtaining derivatives of prostanocarboxylic acid

DERIVATIVES OF 5-THIA-ω-SUBSTITUTED PHENYLPROSTAGLANDIN E, METHODS FOR ITS PREPARING, PHARMACEUTICAL COMPOSITION

FIELD: organic chemistry, medicine, pharmacy. SUBSTANCE: invention relates to new derivatives of prostaglandins, namely, to 5-thia-ω-substituted phenylprostaglandin E of the formula (I) -ω- wherein is OH or R 1 -alkoxy-group; C 1-6 is oxygen or halogen atom; R 2 is hydrogen atom or OH; R 3 and R 4a mean independently hydrogen atom or R 4b -alkyl; C 1-4 is phenyl substituted with R 5 -alkoxy-C 1-4 -alkyl, C 1-4 -alkenyloxy-C 2-4 -alkyl, phenyloxy-C 1-4 -alkyl and others. Compounds of the formula (I) can bind tightly with C 1-4 -receptors (especially with receptors of subtype PGE 2 ). Therefore, these compounds are useful for prophylaxis and/or treatment of immunologic diseases (autoimmune diseases, such as amyotrophic lateral sclerosis, disseminated sclerosis, Sjogren's syndrome, chronic rheumoarthrosis, exanthematous (systemic) erythematosus and others, rejections after organs transplantation and others), asthma, pathology in bones formation, death of nerve cells, lung damage, liver injury, acute hepatitis, renal insufficiency, hypertension, myocardium ischemia, nephritis, general inflammatory response syndrome, burns pain, sepsis, hemophagus-syndrome, macrophages activation, Still's disease, Kawasaki's disease systemic granulomatosis, nonspecific ulcerous colitis, Crohn's disease, hypercytokinemia in dialysis, multiple organs injury, shock and others. Except for, receptor of subtype EP 4 relates to sleep disorder and blood platelet aggregation. Therefore, it is believed that proposed compounds are useful in prophylaxis and/or treatment of above indicated diseases. EFFECT: improved preparing method, valuable medicinal properties of compounds. 21 cl, 4 tbl, 5 sch, 37 ex 5 О0сСсс ПЧ сэ ")2у“” 2 220 135 (° С2 57 М” С 07С 405/00, А 61 К 31/557, 47140 РОССИЙСКОЕ АГЕНТСТВО ПО ПАТЕНТАМ И ТОВАРНЫМ ЗНАКАМ 12) ОПИСАНИЕ ИЗОБРЕТЕНИЯ К ПАТЕНТУ РОССИЙСКОЙ ФЕДЕРАЦИИ (21), (22) Заявка: 2001101470/04, 14.07.1999 (71) Заявитель: ОНО ФАРМАСЬЮТИКАЛ КО. ЛТД. (.Р) (24) ...

3-hydroxybutyric acid polymers

An improved process to prepare treprostinil, the active ingredient in remodulin®

본 발명은 프로스타시클린 유도체의 개선된 제조 방법에 관한 것이다. 한 가지 구체예는 트레프로스티닐의 염에 의해 벤즈인덴 트리올을 트레프로스티닐로 전환시키고, 트레프로스티닐을 정제하는 개선된 방법을 제공한다.

Method of producing 16-fluorine-15,17-didihydroprostanoids of general formula i

16-Fluoro-16,17-didehydro prostanoids of formula: <IMAGE> wherein R is 1)-OH or -OR', wherein R' is C1-C6 alkyl optionally substituted by phenyl, monocycloalkyl or a heteromonocylic ring; <IMAGE> wherein each of R'' and R''' is, independently, hydrogen; C1-C6 alkyl; phenyl; or a heteromonocyclic ring; or R'' and R''', together with the nitrogen atom to which they are linked, form a heteromonocyclic ring -W-(CH2)n-X where W is -O- or -NH-, n is an integer of 1 to 4 and X represents a group -OR' or a group <IMAGE> or 4) -NHSO2-R<IV>, wherein R<IV> is C1-C4 alkyl, phenyl or phenyl substituted by C1-C4 alkyl; one of R1 and R2 is hydrogen and the other is hydroxy or R1 or R2, taken together, form an oxo group; one of R3 and R4 is hydrogen and the other is hydroxy or R3 and R4 are both hydrogen or, taken together, form an oxo group; one of R5 and R6 is hydroxy and the other is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or phenyl; m is zero or an integer of 1 to 3; R7 is C1-C6 alkyl; C3-C7 monocycloalkyl; unsubstituted phenyl or phenyl substituted by one or more substituents chosen from C1-C4 alkyl; C1-C4 alkoxy, tri-halo-C1-C4-alkyl, halogen, <IMAGE> wherein each of R<V> and R<VI> is, independently, hydrogen, C1-C4 alkyl or phenyl; or R7 is a heteromonocyclic ring optionally substituted by one or more of halogen, C1-C4 alkyl, C1-C4 alkoxy, phenyl and phenoxy; A is trans -CH = CH-, -CH2-CH2- or -C IDENTICAL C-, and the symbol @ represents a single bond or a cis double bond; with the condition that R3 and R4 do not form an oxo group when R1 and R2 form an oxo group; and the pharmaceutically or veterinarily acceptable salts thereof; are useful as luteolytic, anti-ulcer and anti-neoplastic agents and can inhibit platelet aggregation.

Processes for the preparation of isomer free prostaglandins

本发明提供用于制备实质上不含5,6-反式异构体的式I-2化合物的新颖方法： 其中 R 2 、R 3 和R 4 如说明书中所定义。本发明还提供用于制备无异构体的前列腺素和其衍生物的新颖中间体。

therapeutic substituted cyclopentanes

therapeutic compounds

DERIVATIVES OF 10,10-DIALKYLPANOPANIC ACID TO REDUCE THE INTERNAL EYE PRESSURE

ÐÎÑÑÈÉÑÊÀß ÔÅÄÅÐÀÖÈß (19) RU (11) 2005 129 072 (13) A (51) ÌÏÊ C07C 405/00 (2006.01) ÔÅÄÅÐÀËÜÍÀß ÑËÓÆÁÀ ÏÎ ÈÍÒÅËËÅÊÒÓÀËÜÍÎÉ ÑÎÁÑÒÂÅÍÍÎÑÒÈ, ÏÀÒÅÍÒÀÌ È ÒÎÂÀÐÍÛÌ ÇÍÀÊÀÌ (12) ÇÀßÂÊÀ ÍÀ ÈÇÎÁÐÅÒÅÍÈÅ (21), (22) Çà âêà: 2005129072/04, 06.02.2004 (71) Çà âèòåëü(è): ÀËËÅÐÃÀÍ, ÈÍÊ. (US) (30) Ïðèîðèòåò: 11.02.2003 US 10/365,369 04.02.2004 US 10/772,720 (85) Äàòà ïåðåâîäà çà âêè PCT íà íàöèîíàëüíóþ ôàçó: 20050912 (74) Ïàòåíòíûé ïîâåðåííûé: Êóçíåöîâà Þëè Âëàäèìèðîâíà (87) Ïóáëèêàöè PCT: WO 2004/071428 (26.08.2004) Àäðåñ äë ïåðåïèñêè: 191002, Ñàíêò-Ïåòåðáóðã, à/ 5, ÎÎÎ "Ë ïóíîâ è ïàðòíåðû", ïàò.ïîâ. Þ.Â.Êóçíåöîâîé (54) ÏÐÎÈÇÂÎÄÍÛÅ 10,10-ÄÈÀËÊÈËÏÐÎÑÒÀÍÎÂÎÉ ÊÈÑËÎÒÛ ÄËß ÑÍÈÆÅÍÈß R U (57) Ôîðìóëà èçîáðåòåíè 1. Ïðèìåíåíèå ñîåäèíåíè ôîðìóëû I äë ïðîèçâîäñòâà ëåêàðñòâà äë ëå÷åíè ãëàçíîé ãèïåðòåíçèè èëè ãëàóêîìû ó ìëåêîïèòàþùåãî A 2 0 0 5 1 2 9 0 7 2 A ÂÍÓÒÐÈÃËÀÇÍÎÃÎ ÄÀÂËÅÍÈß ãäå ïóíêòèðíûå ëèíèè óêàçûâàþò íà íàëè÷èå èëè îòñóòñòâèå ñâ çè, çàøòðèõîâàííûé êëèí îáîçíà÷àåò α-êîíôèãóðàöèþ (âíèç îò ïëîñêîñòè ëèñòà), à ñïëîøíîé òðåóãîëüíèê îáîçíà÷àåò β -êîíôèãóðàöèþ (ââåðõ îò ïëîñêîñòè ëèñòà);  ïðåäñòàâë åò ñîáîé ïðîñòóþ, äâîéíóþ èëè òðîéíóþ êîâàëåíòíóþ ñâ çü; n ðàâíî 0-6; Õ ïðåäñòàâë åò ñîáîé CH2, S èëè Î; Y ïðåäñòàâë åò ñîáîé ëþáóþ ôàðìàöåâòè÷åñêè ïðèåìëåìóþ ñîëü ïî ãðóïïå CO2Í, ëèáî ãðóïïó CO2R, CONR2, CONHCH2CH2OH, CON(CH2CH2OH)2, CH2OR, P(O)(OR)2, CONRSO2R, SONR2 èëè Ñòðàíèöà: 1 RU 2 0 0 5 1 2 9 0 7 2 (86) Çà âêà PCT: US 2004/003433 (06.02.2004) R U (43) Äàòà ïóáëèêàöèè çà âêè: 27.02.2006 Áþë. ¹ 6 (72) Àâòîð(û): ÄÎÍÄ ßðèâ (US), ÍÃÓÅÍ Äæåðåìèà Õ. (US) A 2 0 0 5 1 2 9 0 7 2 R U Ñòðàíèöà: 2 A ãäå Y ïðåäñòàâë åò ñîáîé CO2R èëè ëþáóþ ôàðìàöåâòè÷åñêè ïðèåìëåìóþ ñîëü ïî ãðóïïå CO2Í. 4. Ïðèìåíåíèå ïî ï.3, ãäå R 6 ïðåäñòàâë åò ñîáîé Ñ6-10àðèë èëè Ñ3-10ãåòåðîàðèë, ãäå îäèí èëè áîëåå àòîìîâ óãëåðîäà çàìåùåíû N, Î èëè S, è óêàçàííûå ãðóïïèðîâêè ìîãóò 2 0 0 5 1 2 9 0 7 2 ãäå À ïðåäñòàâë åò ñîáîé CO2Í èëè CO2Ìå; D ïðåäñòàâë åò ñîáîé ïðîñòóþ, äâîéíóþ èëè òðîéíóþ êîâàëåíòíóþ ñâ çü; Å ïðåäñòàâë åò ñîáîé ...

Nitric oxide donating derivatives of prostaglandins

The present invention relates to nitrooxyderivatives of tafluprost acid, their use for the treatment of glaucoma and ocular hypertension and formulation containing nitrooxyderivatives of tafluprost acid.

Processes and intermediates for the preparations of isomer free prostaglandins

5,6-트랜스 이성질체를 실질적으로 함유하지 않는 화학식 Ⅰ-2의 화합물: 의 제조를 위한 신규한 방법이 제공되며, 상기 식에서, , R 2 , R 3 및 R 4 는 본 명세서에 정의된 바와 같다. 이성질체 무함유 프로스타글란딘 제조를 위한 신규한 중간체 및 그 유도체도 제공된다. A compound of Formula I-2 that is substantially free of the 5,6-trans isomer: A novel process is provided for the preparation of , R 2 , R 3 and R 4 are as defined herein. Novel intermediates and derivatives thereof for the preparation of isomer-free prostaglandins are also provided.

THERAPEUTIC SUBSTITUTED CYCLOPENTANES

1. Соединение формулы ! ! где Y представляет собой ! или ; ! или его фармацевтически приемлемая соль, ! где пунктирная линия показывает наличие или отсутствие связи. ! 2. Соединение по п.1 формулы ! ! или его фармацевтически приемлемая соль. ! 3. Соединение по п.1 формулы !! или его фармацевтически приемлемая соль. ! 4. Соединение по п.3 формулы ! ! или его фармацевтически приемлемая соль. ! 5. Соединение по п.1 формулы ! ! или его фармацевтически приемлемая соль. ! 6. Способ лечения облысения, включающий введение соединения по п.1 млекопитающему, нуждающемуся в таком лечении. (19) РОССИЙСКАЯ ФЕДЕРАЦИЯ RU (11) 2010 141 793 (13) A (51) МПК C07C 405/00 (2006.01) ФЕДЕРАЛЬНАЯ СЛУЖБА ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ (12) ЗАЯВКА НА ИЗОБРЕТЕНИЕ (21)(22) Заявка: 2010141793/04, 17.03.2009 (71) Заявитель(и): Аллерган, Инк. (US) Приоритет(ы): (30) Конвенционный приоритет: 18.03.2008 US 61/037,625 16.03.2009 US 12/404,753 (85) Дата начала рассмотрения заявки PCT на национальной фазе: 18.10.2010 A (87) Публикация заявки РСТ: WO 2009/117388 (24.09.2009) Адрес для переписки: 191002, Санкт-Петербург, а/я 5, ООО "Ляпунов и партнеры", пат.пов. Ю.В.Кузнецовой R U (57) Формула изобретения 1. Соединение формулы A 2 0 1 0 1 4 1 7 9 3 (54) ТЕРАПЕВТИЧЕСКИЕ ЗАМЕЩЕННЫЕ ЦИКЛОПЕНТАНЫ где Y представляет собой или ; или его фармацевтически приемлемая соль, где пунктирная линия показывает наличие или отсутствие связи. 2. Соединение по п.1 формулы Ñòð.: 1 ru 2 0 1 0 1 4 1 7 9 3 (86) Заявка PCT: US 2009/037355 (17.03.2009) R U (43) Дата публикации заявки: 27.04.2012 Бюл. № 12 (72) Автор(ы): ДОНДЕ Ярив (US), БЁРК Роберт М. (US), НГУЙЕН Джеремиа Х. (US) или его фармацевтически приемлемая соль. 3. Соединение по п.1 формулы A или его фармацевтически приемлемая соль. 6. Способ лечения облысения, включающий введение соединения по п.1 млекопитающему, нуждающемуся в таком лечении. A R U 2 0 1 0 1 4 1 7 9 3 2 0 1 0 1 4 1 7 9 3 или его фармацевтически приемлемая соль. 5. Соединение по п.1 формулы R U или ...

Cis-13-PGF2.sub.α analogs

This invention comprises certain analogs of the prostaglandins in which the double bond between C-13 and C-14 is of the cis configuration. Also provided in this invention, are novel chemical processes and novel chemical intermediates useful in the preparation of the above prostaglandin analogs. These prostaglandin analogs exhibit prostaglandin-like activity, and are accordingly useful for the same pharmacological purposes as the prostaglandins. Among these purposes are blood pressure lowering, labor induction at term, reproductive-cycle regulation, gastric antisecretory action, and the like.

Ophthalmic composition for topical treatment of glaucoma or elevated intraocular pressure containing a prostaglandin derivative

Composition and method for promoting hair growth

본 발명은, 두 개의 헤테로 원자를 15 위치에 갖는 프로스타글란딘 화합물을 그 활성 성분으로 함유하는, 포유류에서의 육모 촉진용 조성물 및 방법을 제공한다.

Method for preparing stable prostaglandine pharma ceuticals

Difluoroprostaglundin Derivatives and their use

式(1)的含氟前列腺素衍生物(或其盐)和含该衍生物的药物,尤其是预防或治疗眼病的药物。式中,A表示1,2－亚乙烯基等,R 1 表示芳氧基烷基等,R 2 和R 3 表示氢原子等,Z表示－OR 4 (其中OR 4 是氢原子或烷基)等。

Methods and intermediates for producing isomer-free prostaglandins

THERAPEUTIC SUBSTITUTED CYCLOPENTANES TO REDUCE IN-ORGAL PRESSURE

1. Соединение, имеющее формулугде пунктирная линия обозначает наличие или отсутствие связи;Y представляет собой функциональную группу органической кислоты, или ее амид или сложный эфир; или Y представляет собой тетразолильную функциональную группу;А представляет собой -(CH)-Ar-(CH)O-, где Ar представляет собой тиофенил или тиазолил, сумма m и о равна 1, 2, 3 или 4,одна группа -СН- может быть заменена атомом S, и одна группа -СН-СН- может быть заменена группой -СН=СН-;Uвыбрано из группы, состоящей из: -Н, =O, -F, -CI, -CFи -CN,Uвыбрано из группы, состоящей из: -Н, =O и -ОН; иВ представляет собой тиофенил, замещенный или незамещенный фенил или пиридинил, причем каждый из заместителей в группе В, если присутствует, представляет собой Cl, F, Br, I или Cалкил,при условии, что если Uпредставляет собой =O, то Uне обозначает -ОН или -Н.2. Применение соединения по п. 1 для уменьшения внутриглазного давления. РОССИЙСКАЯ ФЕДЕРАЦИЯ (19) RU (11) (13) 2014 105 895 A (51) МПК A61K 31/5575 (2006.01) ФЕДЕРАЛЬНАЯ СЛУЖБА ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ (12) ЗАЯВКА НА ИЗОБРЕТЕНИЕ (21)(22) Заявка: 2014105895/15, 19.02.2014 (71) Заявитель(и): Аллерган, Инк. (US) Приоритет(ы): (30) Конвенционный приоритет: (72) Автор(ы): ОЛД Дэвид В. (US), НГО Винх Экс. (US), ХОЛОБОСКИ Марк (US), ПОСНЕР Мари Ф. (US) (43) Дата публикации заявки: 27.08.2015 Бюл. № 24 R U (57) Формула изобретения 1. Соединение, имеющее формулу A 2 0 1 4 1 0 5 8 9 5 A (54) ТЕРАПЕВТИЧЕСКИЕ ЗАМЕЩЕННЫЕ ЦИКЛОПЕНТАНЫ ДЛЯ УМЕНЬШЕНИЯ ВНУТРИГЛАЗНОГО ДАВЛЕНИЯ 2 0 1 4 1 0 5 8 9 5 Адрес для переписки: 191002, Санкт-Петербург, а/я 5, ООО "Ляпунов и партнеры" R U 03.07.2007 US 60/947,904 (62) Номер и дата подачи первоначальной заявки, из которой данная заявка выделена: 2010103149 02.02.2010 где пунктирная линия обозначает наличие или отсутствие связи; Y представляет собой функциональную группу органической кислоты, или ее амид или сложный эфир; или Y представляет собой тетразолильную функциональную группу; А представляет собой -(CH2)m- ...

Process for producing intermediate for 13,14-didehydroprostaglandin e

1010- 1010-dialkyl prostanoic acid derivatives as agents for lowering intraocular pressure

본 발명은 고안압증 또는 녹내장이 있는 동물에 치료학적으로 유효한 양의 화학식 I의 화합물을 투여하는 것을 포함하는 고안압증 및 녹내장을 처치하는 방법을 제공한다; 여기서, 점선은 결합이 있거나 없는 것을 나타내고, 빗금선은 α배열(아래)을 나타내고, 검은 삼각형은 β배열(위)을 나타내며; B는 단일, 이중 또는 삼중 공유 결합이고; n은 0-6이고, X는 CH 2 , S 또는 O이고; Y는 C0 2 H의 약리학적으로 허용가능한 염, 또는 C0 2 R, CONR 2 , CONHCH 2 CH 2 0H, CON(CH 2 CH 2 0H) 2 , CH 2 0R, P(O)(OR) 2 , CONRS0 2 R, SONR 2 , 또는 화학식 Ia이고; R은 H, C 1-6 알킬 또는 C 2-6 알케닐이고; R 2 및 R 3 는 동일하거나 상이한 C 1-6 직선형 알킬이고, 서로 결합하여 이들이 보통 부착되는 탄소를 포함하는 고리를 형성할 수 있다. The present invention provides a method of treating ocular hypertension and glaucoma comprising administering to a animal with ocular hypertension or glaucoma a therapeutically effective amount of a compound of formula (I); Here, the dotted line indicates the presence or absence of a bond, the hatched line indicates the α array (bottom), and the black triangle indicates the β array (top); B is a single, double or triple covalent bond; n is 0-6 and X is CH 2 , S or O; Y is a pharmacologically acceptable salt of C0 2 H, or C0 2 R, CONR 2 , CONHCH 2 CH 2 0H, CON (CH 2 CH 2 0H) 2 , CH 2 0R, P (O) (OR) 2 , CONRS0 2 R, SONR 2 , or Formula Ia; R is H, C 1-6 alkyl or C 2-6 alkenyl; R 2 and R 3 are the same or different C 1-6 straight alkyl and can be combined with each other to form a ring comprising the carbon to which they are normally attached.

Method of producing derivatives of 16-phenoxyprostatrienic acid in the form of their stereoisomers or a mixture of stereoisomers

This invention relates to a process for making a compound of formula I in the form of a stereoisomer or mixture thereof, wherein R is hydrogen, lower alkyl; X is hydrogen, halo, trifluoromethyl, lower alkyl or lower alkoxy, and the wavy lines represent the a or β configuration with the proviso that when one wavy line is α the other is β, or a pharmaceutically acceptable, non-toxic salt of the compound wherein R is hydrogen; novel intermediates useful for preparing these compounds; processes for making the intermediates; and a stereoisomer of the compound of formula I wherein R is methyl and X is hydrogen and a process for making same.

Therapeutical novel (3,2,0)bicycloheptanone oxime ether

(57)【要約】本公報は電子出願前の出願データであるた め要約のデータは記録されません。

Prostaglandin derivatives

用式(1)表示的前列腺素衍生物、其药学上可允许的盐或其水合物,(式中,X表示卤原子、R 1 表示氢原子、C 1－10 的烷基或C 3－10 的环烷基、m表示0～5的整数、Y是用式(Ⅱ)表示的基(式中,R 2 表示C 3－10 的环烷基、用C 1－4 的烷基取代的C 3－10 的环烷基、用C 3－10 的环烷基取代的C 1－4 的烷基、C 1－10 的烷基、C 2－10 的烯基、C 2－10 的炔基或交联环式烃基。)或用式(Ⅲ)表示的基(式中,n表示1～8的整数)。

Stabilization of 13,14-dihydro-15-keto-prostaglandins

Derivatives of 10,10-dialkylprostanic acid used for intraocular decompression

FIELD: medicine; pharmacology. SUBSTANCE: invention describes application of derivatives of 10,10-dialkylprostanic acid as effective ophthalmic antihypertensive agents. Animal suffering from ocular hypertension or glaucoma is introduced with therapeutically effective amount of composition of general formula : where dotted line indicates presence or absence of bond, cross-hatch wedge designates α-configuration and solid triangle designates β-configuration; B is simple, double or triple covalent bond; n - 0-6; X - CH 2 , S or O; Y is any pharmaceutically acceptable salt of group CO 2 H, or group CO 2 R, CONR 2 , CONHCH 2 CH 2 OH, CON (CH 2 CH 2 OH) 2 , CH 2 OR, P(O)(OR) 2 , CONRSO 2 R, CONR 2 or of formula Ia; R - H, C 1-6 alkyl or C 2-6 alkenyl; R 2 and R 3 represent C 1-6 normal alkyl which can be same or another, and can be connected with each other so that to form ring including carbon atom to which both of them are connected. EFFECT: invention provides higher efficiency of composition and method of treatment. 52 cl, 1 ex, 2 tbl, 8 dwg ÐÎÑÑÈÉÑÊÀß ÔÅÄÅÐÀÖÈß (19) RU (11) 2 336 081 (13) C2 (51) ÌÏÊ A61K 31/557 (2006.01) C07C 401/00 (2006.01) ÔÅÄÅÐÀËÜÍÀß ÑËÓÆÁÀ ÏÎ ÈÍÒÅËËÅÊÒÓÀËÜÍÎÉ ÑÎÁÑÒÂÅÍÍÎÑÒÈ, ÏÀÒÅÍÒÀÌ È ÒÎÂÀÐÍÛÌ ÇÍÀÊÀÌ (12) ÎÏÈÑÀÍÈÅ ÈÇÎÁÐÅÒÅÍÈß Ê ÏÀÒÅÍÒÓ (21), (22) Çà âêà: 2005129072/04, 06.02.2004 (72) Àâòîð(û): ÄÎÍÄ ßðèâ (US), ÍÃÓÅÍ Äæåðåìèà Õ. (US) (24) Äàòà íà÷àëà îòñ÷åòà ñðîêà äåéñòâè ïàòåíòà: 06.02.2004 (73) Ïàòåíòîîáëàäàòåëü(è): ÀËËÅÐÃÀÍ, ÈÍÊ. (US) R U (30) Êîíâåíöèîííûé ïðèîðèòåò: 11.02.2003 US 10/365369 04.02.2004 US 10/772720 (43) Äàòà ïóáëèêàöèè çà âêè: 27.02.2006 2 3 3 6 0 8 1 (45) Îïóáëèêîâàíî: 20.10.2008 Áþë. ¹ 29 (56) Ñïèñîê äîêóìåíòîâ, öèòèðîâàííûõ â îò÷åòå î ïîèñêå: US 5034413 À, 23.07.1991. US 4117014 À, 26.09.1978. US 4994274 À, 19.02.1991. (85) Äàòà ïåðåâîäà çà âêè PCT íà íàöèîíàëüíóþ ôàçó: 12.09.2005 2 3 3 6 0 8 1 R U (87) Ïóáëèêàöè PCT: WO 2004/071428 (26.08.2004) C 2 C 2 (86) Çà âêà PCT: US 2004/003433 (06.02.2004) Àäðåñ äë ïåðåïèñêè: 191002, ...

Process for preparing prostaglandineea and certain derivatives

Compositions and methods for using ester derivatives of bimatoprost

FIELD: medicine; pharmaceuticals. SUBSTANCE: present invention relates to a compound with structural formula (I) or its pharmaceutically acceptable salt or enantiomer; where R 1 is hydrogen or R la C(O)-; R 2 is hydrogen or a R 2a C(O)-; R 3 is hydrogen or a R 3a C(O)-; R la , R 2a and R 3a independently are unsubstituted with C 1 -C 10 alkyl; and R 4 and R 5 independently represent hydrogen or unsubstituted with C 1 -C 10 alkyl; however provided that at least one of R 1 , R 2 and R 3 is not hydrogen. EFFECT: bimatoprost derivatives are effective for treatment of such diseases or disorders, as high intraocular pressure, hair loss, inflammatory diseases and disorders of skin. 10 cl, 6 tbl, 16 dwg, 18 ex РОССИЙСКАЯ ФЕДЕРАЦИЯ (19) RU (11) (13) 2 599 249 C2 (51) МПК C07C 405/00 (2006.01) A61K 31/5575 (2006.01) A61P 17/14 (2006.01) A61Q 7/00 (2006.01) ФЕДЕРАЛЬНАЯ СЛУЖБА ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ (12) ОПИСАНИЕ (21)(22) Заявка: ИЗОБРЕТЕНИЯ К ПАТЕНТУ 2013141849/04, 13.02.2012 (24) Дата начала отсчета срока действия патента: 13.02.2012 Приоритет(ы): (30) Конвенционный приоритет: (43) Дата публикации заявки: 27.03.2015 Бюл. № 9 (45) Опубликовано: 10.10.2016 Бюл. № 28 (73) Патентообладатель(и): АЛЛЕРГАН, ИНК. (US) (85) Дата начала рассмотрения заявки PCT на национальной фазе: 16.09.2013 2 5 9 9 2 4 9 (56) Список документов, цитированных в отчете о поиске: WO 2009/136281 А1, 12.11.2009;WO 2007/037849 А2, 05.04.2007;WO 2008/094675 А2, 07.08.2008;WO 03/066008 А1, 14.08.2003. RU 2252212 С2, 20.05.2005. R U 14.02.2011 US 61/442,400 (72) Автор(ы): ВУДВАРД Дэвид Ф. (US), ВАНГ Дженни В. (US), ГАРСТ Майкл Е. (US), БЕРК Роберт М. (US), ГЭК Тодд С. (US), ПОЛОСО Неил Дж. (US) (86) Заявка PCT: 2 5 9 9 2 4 9 R U C 2 C 2 US 2012/024881 (13.02.2012) (87) Публикация заявки PCT: WO 2012/112451 (23.08.2012) Адрес для переписки: 191002, Санкт-Петербург а/я 5, ООО "Ляпунов и партнеры" (54) КОМПОЗИЦИИ И СПОСОБЫ ПРИМЕНЕНИЯ СЛОЖНОЭФИРНЫХ ПРОИЗВОДНЫХ БИМАТОПРОСТА (57) Реферат: Настоящее ...

An improved process to prepare treprostinil, the active ingredient in Remodulin

本发明涉及制备前列环素衍生物的改良方法。一种实施方式提供通过曲前列素的盐将苯并茚三元醇转化为曲前列素的改良方法并且提供纯化曲前列素的改良方法。

LACENTIVE COMPOSITION

Prostaglandin Derivatives

본 발명은 하기 화학식 I로 표시되는 프로스타글란딘 유도체, 그의 제약상 허용되는 염 또는 그의 수화물에 관한 것이다. 본 발명은 우수한 프로스타글란딘 D 2 양태의 효능제 활성 및 수면 유발 작용을 갖는 신규한 프로스타글란딘 유도체를 제공한다. The present invention relates to prostaglandin derivatives represented by the following formula (I), pharmaceutically acceptable salts thereof or hydrates thereof. The present invention provides novel prostaglandin derivatives having good agonist activity and sleep triggering action in a prostaglandin D 2 embodiment. <화학식 I> <Formula I> 식 중, In the formula, X는 α, 또는 β 치환의 할로겐 원자를 나타내고, X represents a halogen atom of α or β substitution, Y는 에틸렌기, 비닐렌기 또는 에티닐렌기를 나타내고, Y represents an ethylene group, a vinylene group, or an ethynylene group, A는 식 O(CH 2 ) n , A is of the formula O (CH 2 ) n , 식 S(O) p (CH 2 ) n , Formula S (O) p (CH 2 ) n , 식 O(CH 2 ) q O(CH 2 ) r , Formula O (CH 2 ) q O (CH 2 ) r , 식 O(CH 2 ) q S(O) p (CH 2 ) r , Formula O (CH 2 ) q S (O) p (CH 2 ) r , 식 S(O) p (CH 2 ) q S(O) p (CH 2 ) r 또는 Formula S (O) p (CH 2 ) q S (O) p (CH 2 ) r or 식 S(O) p (CH 2 ) q O(CH 2 ) r Formula S (O) p (CH 2 ) q O (CH 2 ) r (각 식 중, n은 1 내지 5의 정수를 나타내며, p는 0, 1 또는 2를 나타내며, q는 1 내지 3의 정수를 나타내고, r은 O 또는 1을 나타냄)으로 나타내는 기를 표시하고, R 1 은 C 3-10 시클로알킬기, C 1-4 알킬C 3-10 시클로알킬기, C 3-10 시클로알킬C 1-4 알킬기, C 5-10 알킬기, C 5-10 알케닐기, C 5-10 알키닐기 또는 가교 환식 탄화수소기를 나타내며, R 2 는 수소 원자, C 1-10 알킬기 또는 C 3-10 시클로알킬기를 나타내고, m은 0, 1 또는 2를 나타낸다. In each formula, n represents an integer of 1 to 5, p represents 0, 1 or 2, q represents an integer of 1 to 3, r represents O or 1, and R is represented by R 1 is C 3-10 cycloalkyl group, C 1-4 alkyl C 3-10 cycloalkyl group, C 3-10 cycloalkylC 1-4 alkyl group, C 5-10 alkyl group, C 5-10 alkenyl group, C 5-10 An alkynyl group or a crosslinked cyclic hydrocarbon group is represented, R 2 represents a hydrogen atom, a C 1-10 alkyl group or a C 3-10 cycloalkyl group, and m represents 0, 1 or 2. 프로스타글란딘 유도체, 수면 유발 작용 Prostaglandin Derivatives, Sleep-Inducing Actions

METHOD OF SYNTHESIS OF 13,14-DIHYDRO-15(R)-17-PHENYL-18,19,20-TRINOR-PGF2α ESTER

Использование в качестве лекарственных препаратов широкого спектра действия. Сущность: продукт - сложные эфиры 13,14-дигидро-15(R)-17-фенил-18,19,20-тринор PGF2 α формулы I, который получают восстановлением оксогруппы в боковой цепи соответствующего лактона формулы VII, после чего проводят гидрирование полученного продукта VI до 3,3a,4,5,6,6a-гексагидро-2-оксо-4-[5'-фенил- 3'(R)-гидрокси-1'-пентил] -5-(4'-фенилбензоилокси)-2H-циклопента [b] фурана формулы V, после чего 2-оксогруппу соединения V восстанавливают до IV, после чего после ряда стадий: снятия защитной группы, размыкания цикла и алкилирования, получают продукт I. 3 с. и 7 з. п. ф-лы. с;660с ПЧ Го РОССИЙСКОЕ АГЕНТСТВО ПО ПАТЕНТАМ И ТОВАРНЫМ ЗНАКАМ (19) (51) МПК ВИ” 2 099 325 ' 13) Сл С 07С 405/00 12) ОПИСАНИЕ ИЗОБРЕТЕНИЯ К ПАТЕНТУ РОССИЙСКОЙ ФЕДЕРАЦИИ (21), (22) Заявка: 93004874/04, 23.02.1993 (30) Приоритет: 24.06.1991 НЦ 2092/91 (46) Дата публикации: 20.12.1997 (56) Ссылки: ОЕ, патент, 2234709, кл. С 07 С 405/00, 1973. \!О, патент, 9002553, кл. С 07 С 1717100, 1990. (86) Заявка РСТ: НУ 92/00025 (19.06.92) (71) Заявитель: Каби Фармациа АБ ($Е), Хиноин Дьедьсер Еш Ведьесети Термекек Дьяра РТ (НЦ) (72) Изобретатель: Йожеф Иванич[НУ], Тибор Сабо[Ну], Иштван Хермец НЦ], Дюла Далмади[НУ], Йожефней Иванич[НУ], Габорней Ковач[НУ], Ресюл Бахрам[5Е] (73) Патентообладатель: Каби Фармациа АБ (3Е), Хиноин Дьедьсер Еш Ведьесети Термекек Дьяра РТ (НЦ) (54) СПОСОБ ПОЛУЧЕНИЯ ЭФИРОВ 13,14-ДИГИДРО-15(К)-17-ФЕНИЛ-18,19,20-ТРИНОР РСЕ2 а 13,14-ДИГИДРО-15(В)-17-ФЕНИЛ-18,19,20-ТРИНОР РСЕ2о СОЕДИНЕНИЯ. (57) Реферат: Использование в качестве лекарственных препаратов широкого спектра действия. Сущность: продукт - сложные эфиры 13,14-дигидро-15(К)-1 7-фенил-18,19,20-трино р РСЕ2“ формулы | который получают восстановлением оксогруппы в боковой цепи соответствующего лактона формулы УП, после чего проводят гидрирование полученного продукта М до 3,3а,4,5,6,ба-гексагидро-2-оксо-4-[5'-фенил- 3'(В)-гидрокси-1"-пентил] -5-(4 ...

Compositions and process