Pyridinecarboxamides, useful-plant-protecting composition comprising them and processes for their preparation and their use

Compounds of the formula (I), or salts thereof, in which R 1 to R 4 are as defined in formula (I) of claim 1 are suitable as useful-plant-protecting agents for reducing or preventing harmful effects of agrochemicals on the useful plants and their method of preparation are described.

PRODUCTION METHOD OF INTERMEDIATE COMPOUND FOR SYNTHESIZING MEDICAMENT

The present invention relates to a novel method for preparing a compound of formula (2) as the intermediate, which can be effectively used for preparation of a compound of formula (1) exhibiting good inhibitory activity against dipeptidyl peptidase IV enzyme. 3. The method according to claim 1 , wherein Pis t-butyl group claim 1 , and Pis methyl or ethyl group.4. The method according to claim 1 , wherein GO is triflate claim 1 , mesylate claim 1 , tosylate claim 1 , besylate or nonaflate.5. The method according to claim 1 , wherein R3 and R4 are hydrogen claim 1 , and R5 and R6 are fluorine.6. The method according to claim 2 , wherein in step (a) C-Ctrialkylamine is used as the base.7. The method according to claim 2 , wherein in step (b) acetic acid is used as the acid.8. The method according to claim 2 , wherein in the case of the compound of formula (2a) wherein Pis Boc and Pis t-butyl claim 2 , the hydrolysis of said step (c) is conducted under the basic condition to selectively remove only Pamong the protecting groups Pand Pto provide the compound of formula (2).9. The method according to claim 8 , wherein aqueous sodium hydroxide solution is used as the base.11. The method according to claim 10 , wherein in step (a) the reduction is conducted using NaBH.12. The method according to claim 10 , wherein in step (b) the Gcompound is selected from the group consisting of trifluoromethane sulfonic acid anhydride (TfO) claim 10 , trifluoromethane sulfonyl chloride (TfCl) claim 10 , methanesulfonyl chloride (MsCl) claim 10 , toluenesulfonyl chloride (TsCl) claim 10 , bromobenzenesulfonyl chloride (BsCl) claim 10 , (CF(CF)SO)F and (CF(CF)SO)O.14. The method according to claim 13 , wherein Pis Boc claim 13 , Pis i-propyl group or t-butyl group claim 13 , and GO is triflate or nonaflate.17. The method according to claim 16 , wherein Pis Boc claim 16 , and Pis i-propyl or t-butyl.18. The method according to claim 16 , wherein in step (a) chloroformate or BocO is used as ...

ANTI-INFLAMMATORY AGENTS

Disclosed herein are methods of preventing or treating inflammatory diseases using 3-aminolactam compounds, each with aromatic “tail groups”. Compounds as defined by formulae (I) and (I′), and the medical uses of the compounds, are described herein. 3. (canceled)4. (canceled)6. A compound of{'claim-ref': {'@idref': 'CLM-00002', 'claim 2'}, ','}provided that the compound is not selected from the group consisting of: (S)-3-(4′-methoxybenzoylamino)-caprolactam, (S)-3-(4′-methylbenzoylamino)-caprolactam, (S)-3-(3′-trifluoromethylbenzoylamino)-caprolactam, (S)-3-(2′-carboxybenzoyl-amino)-caprolactam, and (S)-3-(3′,4′,5′-trimethoxybenzoylamino)-caprolactam.7. A pharmaceutical composition comprising claim 5 , as active ingredient claim 5 , a compound as defined in claim 5 , or a pharmaceutically acceptable salt thereof claim 5 , and at least one pharmaceutically acceptable excipient and/or carrier.8. The compound according to claim 1 , wherein n=2.9. The compound according to claim 1 , wherein n=3.10. The compound according to claim 1 , wherein X is haloalkyl.11. The compound according to claim 2 , wherein the compound is selected from the group consisting of:(S)-3-(4′-methylbenzoylamino)-caprolactam, and(S)-3-(3′,5′-dimethylbenzoylamino)-caprolactam,and pharmaceutically acceptable salts thereof.12. A compound according to claim 2 , selected from the group consisting of:(S)-3-fluoro-N-(2-oxopiperidin-3-yl)benzamide,(S)-2-fluoro-N-(2-oxopiperidin-3-yl)benzamide,(S)-4-fluoro-N-(2-oxopiperidin-3-yl)benzamide,(S)—N-(2-oxopiperidin-3-yl)-4-(trifluoromethyl)benzamide,(S)—N-(2-oxopiperidin-3-yl)-3-(trifluoromethyl)benzamide,(S)—N-(2-oxopiperidin-3-yl)-2-(trifluoromethyl)benzamide,(S)-2,3-difluoro-N-(2-oxopiperidin-3-yl)benzamide,(S)-2,4-difluoro-N-(2-oxopiperidin-3-yl)benzamide,(S)-2,5-difluoro-N-(2-oxopiperidin-3-yl)benzamide,(S)-2,6-difluoro-N-(2-oxopiperidin-3-yl)benzamide,(S)-3,4-difluoro-N-(2-oxopiperidin-3-yl)benzamide,(S)-3,5-difluoro-N-(2-oxopiperidin-3-yl)benzamide,(S)-3 ...

Alpha-AminoCycloLactam Ligands for G-Protein Coupled Receptors, and Methods of Using Same

The invention relates to the generation of a library of compounds enriched in agonist and antagonists for members of the G-protein coupled class of receptors (GPCRs). 4. A library composed of claim 1 , or enriched in claim 1 , library elements which are compounds according to .5. A method of screening in an assay claim 4 , a library according to claim 4 , to identify agent(s) which modulate signalling through GPCRs.6. The method according to claim 5 , wherein the agent(s) identified are antagonists at one or more GPCRs.7. The method according to claim 5 , wherein the agent(s) identified are agonists at one or more GPCRs.8. The method according to claim 5 , wherein the GPCR is selected from the group consisting of adrenalin receptors claim 5 , endothelin receptors claim 5 , chemokine receptors claim 5 , EDG receptors claim 5 , VIP/PECAP receptors claim 5 , dopamine receptors claim 5 , serotonin receptors claim 5 , purine receptors claim 5 , metabotropic glutamate receptors claim 5 , acetyl choline receptors claim 5 , C5a receptors claim 5 , fMLP receptors claim 5 , glucagon or GLP receptors claim 5 , NPY receptors claim 5 , MSH receptors claim 5 , glycoprotein hormone receptors claim 5 , protease activated receptors (PARs) claim 5 , somatostatin receptors claim 5 , angiotensin receptors claim 5 , cholecystokinin receptors claim 5 , and melatonin receptors. This application is a continuation of application Ser. No. 13/193,274, now U.S. Pat. No. 8,389,279, which is a continuation of application Ser. No. 11/574,656, now U.S. Pat. No. 8,008,289, which is the U.S. national stage of PCT/GB2005/003134, filed Aug. 10, 2005 and published in English as WO 2006/024815 A1 on Mar. 9, 2006, which claims the benefit of priority under 35 U.S.C. §119 to United Kingdom application serial no. 0419517.8, filed Sep. 2, 2004, all of which applications and publications are incorporated herein by reference.The invention relates to the generation of a library of compounds enriched in agonist ...

ANTI-INFLAMMATORY AGENTS

Disclosed herein are methods of preventing or treating inflammatory diseases using sulfonamide analogs of 3-aminolactam compounds, each with aromatic “tail groups”. Compounds as defined by formulae (I) and (I′), and the medical uses of the compounds, are described herein. 3. (canceled)4. (canceled)5. A compound according to claim 1 , with the proviso that:{'sub': 2', '6', '1', '7', '1', '7, 'when n =3, then at least one of C-Con the phenyl ring is substituted with a group other than halogen, C-Calkyl, or C-Chaloalkyl; and'}when n =1, 2 or 3, then{'sub': 2', '6, 'Cor Con the phenyl ring are other than hydrogen or fluorine, or'}{'sub': 3', '1', '6, 'Con the phenyl ring is other than hydrogen, halogen, C-Calkyl,'}{'sub': 1', '6', '1', '6, 'C-Calkoxy, or C-Chaloalkyl, or'}{'sub': 4', '1', '6', '1', '6', '1', '6, 'Con the phenyl ring is other than hydrogen, halogen, C-Calkyl, C-Calkoxy, C-Chaloalkyl, amino, aminoalkyl or aminodialkyl, or'}{'sub': '5', 'Con the phenyl ring is other than hydrogen or halogen;'}provided that the compound is neither of:3-(2′-carboxybenzenesulfonylamino)-tetrahydropyridin-2-one, and (R)-3-(4′-methylbenzenesulfonylamino)-caprolactam.6. A compound of claim 2 , with the proviso that:{'sub': 2', '6', '1', '7', '1', '7, 'when n=3, then at least one of C-Con the phenyl ring is substituted with a group other than halogen, C-Calkyl, or C-Chaloalkyl; and'}when n =1, 2 or 3, then{'sub': 2', '6, 'Cor Con the phenyl ring are other than hydrogen or fluorine, or'}{'sub': 3', '1', '6', '1', '6', '1', '6, 'Con the phenyl ring is other than hydrogen, halogen, C-Calkyl, C-Calkoxy, or C-Chaloalkyl, or'}{'sub': 4', '1', '6', '1', '6', '1', '6, 'Con the phenyl ring is other than hydrogen, halogen, C-Calkyl, C-Calkoxy, C-Chaloalkyl, amino, aminoalkyl or aminodialkyl, or'}{'sub': '5', 'Con the phenyl ring is other than hydrogen or halogen;'}provided that the compound is not one of the group consisting of:(S)-3-(4′-methylbenzenesulfonylamino)-tetrahydropyridin-2-one ...

Method To Prepare beta-Functionalized Aliphatic Esters

The invention pertains to a new route to prepare β-functionalized carboxylic acid esters in a one-pot reaction, by reacting an olefinic acid ester in the presence of a catalyst system, comprising a Rh(I)-complex, together with an aryl boron or a diamine as nucleophilic compounds, and under oxygen-free conditions and elevated temperatures.

BETA-LACTAMASE INHIBITORS

Substituted bicyclic beta-lactams of Formula I: 2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein bond a is a single bond and X is —CH— or —CHCH—.3. The compound according to or claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris OSOM.4. The compound according to claim 6 , or a pharmaceutically acceptable salt thereof claim 6 , wherein Ris OSOH.5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris C(O)N(R)R.6. The compound according to claim 5 , or a pharmaceutically acceptable salt thereof claim 5 , wherein Ris HetA claim 5 , CH-HetA claim 5 , CHCH-HetA claim 5 , CH(CH)-HetA claim 5 , or CH(CHOH)-HetA.7. The compound according to claim 6 , or a pharmaceutically acceptable salt thereof claim 6 , wherein HetA is an optionally fused claim 6 , saturated heterocyclic ring selected from the group consisting of azetidinyl claim 6 , pyrrolidinyl claim 6 , oxopyrrolidinyl claim 6 , piperidinyl claim 6 , piperazinyl claim 6 , tetrahydropyranyl claim 6 , tetrahydrothiopyranyl claim 6 , morpholinyl claim 6 , 1 claim 6 ,1-dioxidotetrahydrothiopyranyl claim 6 , azepanyl claim 6 , oxazepanyl claim 6 , azocanyl claim 6 , and azabicyclo[3.1.0]cyclohexyl claim 6 , wherein the heterocyclic is optionally substituted with 1 or 2 (CH)N(R)Rand optionally substituted with 1 or 2 (CH)R.9. The compound according to claim 8 , or a pharmaceutically acceptable salt thereof claim 8 , wherein T is H claim 8 , CH claim 8 , pyrrolidin-3-yl claim 8 , piperidin-4-yl claim 8 , (CH)OCH claim 8 , (CH)OH claim 8 , (CH)F claim 8 , (CH)-piperidinyl claim 8 , (CH)-pyrrolidinyl; and T′ is H claim 8 , F claim 8 , O—Calkyl claim 8 , OH claim 8 , NH claim 8 , N(H)CH claim 8 , N(CH).10. The compound according to claim 5 , or a pharmaceutically acceptable salt thereof claim 5 , wherein Ris HetB.11. The compound according to claim 12 , or a pharmaceutically acceptable salt thereof ...

Psyllid Attractants and Their Uses

The present specification discloses psyllid attractants, compositions comprising such attractants, lures, traps and other devices using such attractants, methods and uses to attract, capture and/or kill psyllids using such attractants, compositions and/or lures, traps and/or other devices, and methods and uses for monitoring a psyllid population using such attractants, compositions and/or lures, traps and/or other devices. 156-. (canceled)62. The compound of claim 57 , wherein the compound has a binding affinity for a psyllid OBP or SAP having an equilibrium dissociation constant of less than 0.500 nM claim 57 , less than 0.450 nM claim 57 , less than 0.400 nM claim 57 , less than 0.350 nM claim 57 , less than 0.300 nM claim 57 , less than 0.250 nM claim 57 , less than 0.200 nM claim 57 , less than 0.150 nM claim 57 , less than 0.100 nM claim 57 , or less than 0.050 nM.63. A composition comprising one or more of the compounds as defined in .64. The composition of claim 57 , wherein the composition is a liquid composition claim 57 , a semi-solid composition claim 57 , or a solid composition.65. A device comprising one or more of the compounds as defined in .66. A method of capturing psyllids claim 57 , the method comprising using one or more of the compounds as defined in to attract the psyllids to a device claim 57 , thereby capturing the psyllids.67. A method of killing psyllids claim 57 , the method comprising using one or more of the compounds as defined in to attract the psyllids to a device claim 57 , thereby killing the psyllids.68. A method of monitoring a psyllid population claim 57 , the method comprising a) using one or more of the compounds as defined in to attract psyllids to a device claim 57 , thereby capturing the psyllids; b) counting the psyllids to determine a number of captured psyllids; and c) performing a statistical analysis on the number of captured psyllids in order to determine the psyllid population claim 57 , thereby monitoring the psyllid ...

VINYL-ARYL DERIVATIVES FOR INFLAMMATION AND IMMUNE-RELATED USES

The invention relates to compounds that are useful as immunosuppressive agents and for treating and preventing inflammatory conditions, allergic disorders, and immune disorders. 2. The compound of claim 1 , wherein Y is substituted with one to two substituents.3. The compound of claim 2 , wherein the one to two substituents are each independently a lower alkyl or a halo.4. The compound of claim 3 , wherein Y is a difluorophenyl.5. The compound of claim 4 , wherein Y is 2 claim 4 ,6-difluorophenyl.6. The compound of claim 1 , wherein L is —NHCH— claim 1 , —CHNH— claim 1 , —NH—C(O)— claim 1 , or —C(O)—NH—.7. The compound of claim 6 , wherein L is —NHC(O)—.8. The compound of claim 1 , wherein Ris selected from the group consisting of a halo claim 1 , an optionally substituted alkyl claim 1 , an optionally substituted alkenyl claim 1 , an optionally substituted alkynyl claim 1 , an optionally substituted cycloalkyl claim 1 , an optionally substituted cycloalkenyl claim 1 , an optionally substituted heterocyclyl claim 1 , an optionally substituted aryl claim 1 , an optionally substituted heteroaryl claim 1 , an optionally substituted aralkyl claim 1 , and an optionally substituted heteraralkyl.9. The compound of claim 8 , wherein Ris selected from the group consisting of halo claim 8 , and an optionally substituted lower alkyl.10. The compound of claim 1 , wherein Xis CHand Xis NR.11. The compound of claim 1 , wherein Xis CHand Xis NR.12. The compound of claim 1 , wherein Xand Xare both CH or both N.13. (canceled)14. The compound of claim 1 , wherein Xis N and Xis CH.15. (canceled)16. The compound of claim 1 , whereinY is a difluorophenyl;L is —NHC(O)—;{'sub': '1', 'Ris selected from the group consisting of halo and an optionally substituted lower alkyl; and'}m is 0.1830-. (canceled)3247-. (canceled)4959-. (canceled)6176-. (canceled)77. A pharmaceutical composition claim 1 , comprising a pharmaceutically acceptable carrier and a compound of .78. The pharmaceutical ...

QUINONE COMPOUNDS FOR TREATING APE1 MEDIATED DISEASES

The invention described herein pertains to compounds and compositions for treating Ape1 mediated diseases. In particular, the invention described herein pertains to quinone compounds and pharmaceutical compositions containing them for treating Ape1 mediated diseases. 2. The compound of wherein each Ris alkoxy.3. The compound of wherein Rrepresents optionally substituted benzo.4. (canceled)5. The compound of wherein R is alkyl or heteroalkyl claim 1 , each of which is optionally substituted.6. The compound of wherein R is optionally substituted alkyl.7. (canceled)8. The compound of wherein R is alkoxy.9. The compound of wherein R is alkylthio.10. The compound of wherein R is halo.11. The compound of wherein each Ris optionally substituted alkyl.12. (canceled)13. The compound of wherein one Ris polyhydroxyalkyl.14. The compound of wherein both Rare taken together with the attached nitrogen to form an optionally substituted heterocycle selected from the group consisting of pyrrolidine claim 1 , piperidine claim 1 , piperazine claim 1 , morpholine claim 1 , pyrrolidinone claim 1 , piperidinone claim 1 , piperazinone claim 1 , and morpholinone.15. (canceled)16. The compound of wherein at least one Ris hydrogen.17. The compound of wherein at least one Ris alkyl.18. The compound of wherein both Rare alkyl.19. The compound of wherein both Rare taken together with the attached nitrogen and oxygen to form an optionally substituted heterocycle selected from the group consisting of oxazolidine claim 1 , oxazine claim 1 , oxazapine claim 1 , oxazolidinone claim 1 , oxazinone claim 1 , and oxazapinone.20. The compound of wherein X is optionally substituted alkylene.21. The compound of wherein X is an epoxy alkylene.22. The compound of wherein X is optionally substituted alkenylene.2324-. (canceled)25. A pharmaceutical composition comprising one or more compounds of .2627-. (canceled)28. A method for treating a disease responsive to Ape1 inhibition in a host animal claim 1 , the ...

PHOTOSTABLE COMPOUNDS, ABSORBING COMPOUNDS AND USES THEREOF

The present invention describes compounds and uses thereof in applications relating to absorption of electromagnetic energy. Preferred compounds are double bond-containing cyclic compounds capable of absorbing electromagnetic radiation energy and having improved photostability due to the presence and location of one or more fluorine groups in relation to the double bond of the ring. 2. The compound of wherein R′ is selected from Cto Calkenyl claim 1 , Cto Calkynyl claim 1 , Cto Caryl claim 1 , Cto Cheteroaryl claim 1 , Cto Caroyl claim 1 , Cto Calkenone claim 1 , Cto Ccycloalkenyl claim 1 , Cto Ccycloalkenone claim 1 , or Cto Cheterocyclic claim 1 , all of which groups may be substituted or unsubstituted.3. (canceled)5. (canceled)6. The compound of wherein A is a six-membered nitrogen heterocycle comprising at one double bond claim 4 , which nitrogen heterocycle may be further substituted or unsubstituted.7. The compound of wherein A is a six-membered nitrogen heterocycle comprising one double bond and having the carbon atom to which W is attached also attached to a double bonded ring carbon claim 4 , which nitrogen heterocycle may be further substituted or unsubstituted.9. The compound of wherein Rand Rare independently selected from Cto Calkyl claim 8 , Cto Calkenyl or Cto Calkoxy claim 8 , each of which groups may be substituted or unsubstituted.1012-. (canceled)13. The compound of wherein at least one of Rand Rare fluorine or wherein Rand Rcombine to form a 6-membered ring with one or more fluorine substituents on the ring.14. (canceled)15. The compound of wherein Ris selected from halo claim 1 , Cto Calkyl claim 1 , Cto Calkenyl claim 1 , C-Caryl claim 1 , C-Cheteroaryl claim 1 , Cto Calkanone claim 1 , C-Ccycloalkyl claim 1 , C-Ccycloalkanone claim 1 , C-Ccycloalkenyl claim 1 , Cto Calkanoyl claim 1 , Cto Calkanoyloxy claim 1 , Cto Calkoxycarbonyl claim 1 , Cto Ccarbamoyl claim 1 , Cto Ccarboxyl claim 1 , haloalkyl claim 1 , N-alkyl claim 1 , N-aryl claim 1 , ...

SUBSTITUTED PYRIDOXINE-LACTAM CARBOXYLATE-SALTS

The present invention provides salt adducts comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5- to 7-membered lactam ring, optionally additionally substituted, methods of their preparation, and pharmaceutical compositions and medicaments comprising them. Salt adducts of the invention and compositions comprising them may be used to in the treatment of diseases or disorders associated with or inflicted by alcohol consumption, The present application is a continuation of application No. 13/056,943, filed Jan. 31, 2011, which was a National Stage of International Application No. PCT/IL2009/000741, filed Jul. 29, 2009, designating the United States and claiming priority from U.S. Provisional Patent Application No. 61/084,514, filed on Jul. 29, 2008. The foregoing applications are incorporated herein by reference in their entirety.The present invention relates to salt adducts comprising at least one pyridoxine or a derivative thereof and at least one carboxylated 5- to 7-membered lactam ring and uses thereof.Alcohol-induced liver diseases are a common disorder in modern communities and societies. For example, in Europe there are more than 45 million individuals showing signs of alcohol-related damage such as liver disease and myopathies. Chronic alcohol consumption increases hepatic accumulation of triglycerides and leads to hepatic steatosis, which is the earliest and most common response to severe alcohol intoxication.Thus, severe alcohol intoxication is a serious disease that should be treated with medication in order to reduce the damage to the human body of the alcohol intoxicated individual, For example, alcohol intoxication can be treated with metadoxine (pyridoxine L-2-pyrrolidone-5-carboxylate). Metadoxine is a salt of the corresponding anion of L-2-pyrrolidone-5-carboxylic acid (L-2-pyroglutamic acid) (1) and the protonated derivative of pyridoxine (vitamin B6) (2), having the following ...

METHOD FOR PRODUCING KAKEROMYCIN AND DERIVATIVES THEREOF

Provided is a production method of kakeromycin and a derivative thereof showing an antifungal activity and cytotoxicity and expected as a new antifungal agent or anticancer agent, by chemical synthesis. A production method of a compound represented by the formula (1): This patent application is a divisional of copending U.S. patent application Ser. No. 15/554,002, filed on Aug. 27, 2017, which the U.S. national phase of International Patent Application No. PCT/JP2016/055891, filed on Feb. 26, 2016, which claims the benefit of Japanese Patent Application No. 2015-039363, filed Feb. 27, 2015, the disclosures of which are incorporated herein by reference in their entireties for all purposes.The present invention relates to a production method of kakeromycin and a derivative thereof.In recent years, along with an increase in elderly people, progress of advanced medicine, immunodeficiency of late stage cancer patients and the like, infections with fungi have been increasing. These infections provide serious effects, often causing death. Since there are not many kinds of existing antifungal agents, and their toxicity is high, the mother nucleus of a new antifungal agent, which is different from that of conventional medicaments, has been desired. In addition, since the use of antifungal agents causes increased emergence of resistant bacteria, the development of a new medicament has been earnestly desired. While candin-based antifungal agents show low toxicity, since the molecular weight thereof is large, reactivity with serum poses problems. Azole-based antifungal agents have a problem in that administration at a high concentration is difficult in view of the toxicity thereof. Therefore, an effective, low-molecular-weight compound showing low reactivity with serum and low toxicity has been strongly desired.Conventionally, in search of a pharmaceutical product seed compound from microbial metabolites, terrestrial separation sources have been mainly harvested and subjected ...

METHOD FOR PRODUCING KAKEROMYCIN AND DERIVATIVES THEREOF

Provided is a production method of kakeromycin and a derivative thereof showing an antifungal activity and cytotoxicity and expected as a new antifungal agent or anticancer agent, by chemical synthesis. A production method of a compound represented by the formula (1): This patent application is a divisional of copending U.S. patent application Ser. No. 15/554,002, filed on Aug. 27, 2017, which the U.S. national phase of International Patent Application No. PCT/JP2016/055891, filed on Feb. 26, 2016, which claims the benefit of Japanese Patent Application No. 2015-039363, filed Feb. 27, 2015, the disclosures of which are incorporated herein by reference in their entireties for all purposes.The present invention relates to a production method of kakeromycin and a derivative thereof.In recent years, along with an increase in elderly people, progress of advanced medicine, immunodeficiency of late stage cancer patients and the like, infections with fungi have been increasing. These infections provide serious effects, often causing death. Since there are not many kinds of existing antifungal agents, and their toxicity is high, the mother nucleus of a new antifungal agent, which is different from that of conventional medicaments, has been desired. In addition, since the use of antifungal agents causes increased emergence of resistant bacteria, the development of a new medicament has been earnestly desired. While candin-based antifungal agents show low toxicity, since the molecular weight thereof is large, reactivity with serum poses problems. Azole-based antifungal agents have a problem in that administration at a high concentration is difficult in view of the toxicity thereof. Therefore, an effective, low-molecular-weight compound showing low reactivity with serum and low toxicity has been strongly desired.Conventionally, in search of a pharmaceutical product seed compound from microbial metabolites, terrestrial separation sources have been mainly harvested and subjected ...

METHOD FOR PRODUCING KAKEROMYCIN AND DERIVATIVES THEREOF

Provided is a production method of kakeromycin and a derivative thereof showing an antifungal activity and cytotoxicity and expected as a new antifungal agent or anticancer agent, by chemical synthesis. A production method of a compound represented by the formula (1): 1. A compound represented by the formula (6):whereinR is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,{'sup': '4', 'Ris an optionally substituted hydrocarbon group or an optionally substituted hydrocarbon-oxy group, and'}n is 0 or 1, This patent application is a divisional of copending U.S. patent application Ser. No. 15/554,002, filed on Aug. 27, 2017, which the U.S. national phase of International Patent Application No. PCT/JP2016/055891, filed on Feb. 26, 2016, which claims the benefit of Japanese Patent Application No. 2015-039363, filed Feb. 27, 2015, the disclosures of which are incorporated herein by reference in their entireties for all purposes.The present invention relates to a production method of kakeromycin and a derivative thereof.In recent years, along with an increase in elderly people, progress of advanced medicine, immunodeficiency of late stage cancer patients and the like, infections with fungi have been increasing. These infections provide serious effects, often causing death. Since there are not many kinds of existing antifungal agents, and their toxicity is high, the mother nucleus of a new antifungal agent, which is different from that of conventional medicaments, has been desired. In addition, since the use of antifungal agents causes increased emergence of resistant bacteria, the development of a new medicament has been earnestly desired. While candin-based antifungal agents show low toxicity, since the molecular weight thereof is large, reactivity with serum poses problems. Azole-based antifungal agents have a problem in that administration at a high concentration is difficult in view of the toxicity thereof. Therefore, an ...

NEW ARYLAMINOALCOHOL DERIVATIVES WITH ANTIPLASMODIAL ACTIVITY

The present invention relates to new arylaminoalcohol derivatives of formula (I), and to a method for the preparation of such compounds: I The invention also relates to the use of these compounds as medicaments, and in particular for the prevention and/or the treatment of parasitic diseases caused by apicomplexan parasites such as malaria and toxoplasmosis. Finally, the invention relates to pharmaceutical compositions containing such compounds of formula (I) as active principles. 2. Compound according to claim 1 , wherein the aromatic group Ar is substituted by an halogen atom claim 1 , and preferably by a fluorine atom.3. Compound according to claim 2 , wherein the aromatic group Ar is selected from the 4-fluoro-1-phenyl and 4-fluoro-1-naphtyl groups claim 2 , and preferably Ar is the 4-fluoro-1-phenyl group.4. Compound according to claim 1 , wherein the amino entity Am is a tetrahydropyridine entity.5. Compound according to claim 1 , wherein R is —NOor —F.6. Compound according to claim 1 , wherein R′ is —H or —CF.7. Compound according to claim 5 , wherein R═—NOand R′═—CF.9. Compound of formula (I) according to claim 1 , or one of its tautomeric claim 1 , racemic claim 1 , enantiomeric or polymorphic forms or pharmaceutically acceptable salts claim 1 , for its use as a medicament.10. Compound of formula (I) for its use according to claim 9 , for the prevention and/or the treatment of parasitic diseases involving apicomplexan parasites.11Plasmodium, Babesia, Toxoplasma, Neospora, Cryptosporidium, Theileria, SarcosystisEimeria.. Compound of formula (I) for its use according to claim 10 , wherein said apicomplexan parasites are selected from and12. Compound of formula (I) for its use according to for the prevention and/or the treatment of malaria.13. Compound of formula (I) for its use according to to for the prevention and/or the treatment of toxoplasmosis.14. Compound of formula (I) for its use according to for the prevention and/or the treatment of AIDS virus.15. A ...

METHOD FOR PRODUCING FLUOROVINYL AMIDE COMPOUND

An object of this disclosure provides a novel method for producing a fluorovinyl amide compound and the like. The object is achieved by a method for producing a compound represented by formula (1): 2. The production method according to claim 1 , wherein Rf is —F or perfluoroalkyl.3. The production method according to claim 1 , wherein Ris —H claim 1 , an alkyl group optionally substituted with one or more substituents claim 1 , or an aromatic ring group optionally substituted with one or more substituents.4. The production method according to claim 1 , wherein Ris —H claim 1 , an alkyl group optionally substituted with one or more substituents claim 1 , or an aromatic ring group optionally substituted with one or more substituents.5. The production method according to claim 1 , wherein either Ror Ris —H claim 1 , and the other is —H or an aromatic ring group optionally substituted with one or more substituents.6. The production method according to claim 1 , wherein Ris a halo group or a sulfonic acid ester group.7. The production method according to claim 1 ,wherein{'sup': ['b1', 'b', 'h'], 'claim-text': ['wherein', {'sup': 'h', '#text': 'Ris'}, 'an aliphatic hydrocarbyl group optionally substituted with one or more substituents,', 'wherein one or more heteroatoms selected from the group consisting of O, S, and Si may be inserted into the aliphatic hydrocarbyl group, or', 'an aromatic ring group optionally substituted with one or more substituents, and', {'sup': ['b', 'r', 'r'], '#text': 'Lis a single bond, —NR—, —O—, or —S—, and Ris —H or an alkyl group.'}], '#text': 'Ris -L-R,'}8. The production method according to claim 1 ,wherein{'sup': ['b2', 'b', 'h'], 'claim-text': ['wherein', {'sup': 'h', '#text': 'Ris'}, 'an aliphatic hydrocarbyl group optionally substituted with one or more substituents,', 'wherein one or more heteroatoms selected from the group consisting of O, S, and Si may be inserted into the aliphatic hydrocarbyl group, or', 'an aromatic ring group ...

PROCESS FOR PREPARING LACTAMS

The present invention relates to a method for preparing lactams using heterogeneous catalysis by hydrogenating at least one compound of the following formula (I), where A is a radical of the following formula (I′) or (II′): —CH(R)—CH(R)— (I′); or —CH(R)—CH(R)—CH(R)— (II′); where R, Rand Rare, independently from each other, H, OH, an alkyl radical, or a cycloalkyl radical; and R is H or a straight or branched alkyl radical having 1 to 20, preferably 1 to 10, and more preferably 1 to 4 carbon atoms. Said method is carried out at a pressure of less than 60 bars, preferably 10 to 50 bars, in the presence of a solid hydrogenation catalyst including at least two metals selected from the group of noble metals and transition metals, and an inert substance used as a support, wherein said compound of formula (I) can be used alone or as part of a mixture. 2. The process of claim 1 , wherein the hydrogenation is carried out in the absence of solvent.3. The process of claim 1 , wherein the hydrogenation is carried out in the liquid phase.4. The process of claim 1 , wherein R claim 1 , Rand Rrepresent H or a (C-C)alkyl radical.5. The process of claim 1 , wherein A is a radical of formula —CH—CH—CH(R′)— claim 1 , and R′ represents a (C-C)alkyl radical claim 1 , and preferably methyl or ethyl.6. The process of claim 1 , wherein R is H.7. The process of claim 1 , wherein the hydrogenation is carried out at a temperature greater than or equal to 105° C.9. The process of claim 1 , wherein the pressure is between 10 bar and 50 bar.10. The process of claim 1 , wherein R represents a linear or branched alkyl radical comprising from 1 to 10 carbon atoms.11. The process of claim 1 , wherein the hydrogenation catalyst is a mixture of at least two metals selected from the group consisting of ruthenium claim 1 , platinum claim 1 , palladium claim 1 , iridium and rhodium claim 1 , said mixture being supported by an inert substance.12. The process of claim 1 , wherein the hydrogenation catalyst ...

METHODS FOR ENANTIOSELECTIVE ALLYLIC ALKYLATION OF ESTERS, LACTONES, AND LACTAMS WITH UNACTIVATED ALLYLIC ALCOHOLS

The present disclosure provides methods for enantioselective synthesis of cyclic and acyclic α-quaternary carboxylic acid derivatives via nickel-catalyzed allylic alkylation. 113-. (canceled)15. The method of claim 14 , wherein:{'sub': '2', 'the Ni(0) source is Ni(COD);'}L is (S)—C3-TunePhos; andthe organic solvent is diethyl ether.16. The method of claim 14 , wherein:{'sub': '6', 'Ris methyl; and'}{'sub': '7', 'Ris methyl.'}17. (canceled)18. The method of claim 15 , wherein:{'sub': '6', 'Ris methyl; and'}{'sub': '7', 'Ris methyl.'}19. A method comprising{'claim-ref': {'@idref': 'CLM-00014', 'claim 14'}, 'preparing a compound of Formula (XI) according to ; and'}synthesizing a pharmaceutical agent from the compound of Formula (XI).21. The method of claim 20 , wherein:{'sub': '2', 'the Ni(0) source is Ni(COD);'}L is (S)—C3-TunePhos; andthe organic solvent is diethyl ether.22. The method of claim 20 , wherein:{'sub': '6', 'Ris methyl; and'}{'sub': '7', 'Ris methyl.'}23. The method of claim 21 , wherein:{'sub': '6', 'Ris methyl; and'}{'sub': '7', 'Ris methyl.'} This Application claims the benefit of U.S. Provisional Application 62/580,091, filed Nov. 1, 2017, the contents of which are hereby incorporated herein by reference.This invention was made with government support under Grant Nos. GM080269 awarded by the National Institutes of Health. The Government has certain rights in the invention.Synthetic methods for the generation of enantioenriched quaternary stereocenters are highly desirable given their prevalence as motifs in a wide variety of biologically active molecules of both natural and unnatural origin, and the pharmaceutical industries increasing recognition for the motif's applicability in drug design. Despite their importance, the number of highly enantioselective transformations that construct quaternary stereocenters under mild reaction conditions is limited, with respect to both cyclic and acyclic systems.Since 1965, transition metal-catalyzed allylic ...

BIOCATALYSTS AND METHODS FOR THE SYNTHESIS OF SUBSTITUTED LACTAMS

The present disclosure relates to transaminase polypeptides capable of aminating a dicarbonyl substrate, and polynucleotides, vectors, host cells, and methods of making and using the transaminase polypeptides. 1. An engineered polynucleotide encoding an engineered transaminase polypeptide comprising an amino acid sequence having at least 80% sequence identity to reference sequence SEQ ID NO:4 and at least an amino acid residue difference as compared to SEQ ID NO:4 at residue position X323.2. The engineered polynucleotide encoding an engineered polypeptide of claim 1 , in which X323 is selected from C claim 1 , E claim 1 , N claim 1 , and R.3. The engineered polynucleotide encoding an engineered polypeptide of claim 2 , wherein the amino acid sequence further comprises one or more residue differences as compared to SEQ ID NO:4 selected from: X42G; X54P; X54R; X69A; X69G; X69T; X122M; X124F; X124L; X124N; X124R; X126A; X126T; X150S; X152C; X152G; X152I; X152L; X152S; X156A; X156S; X156T; X157L; X165N claim 2 , X192A claim 2 , X193G claim 2 , X192H claim 2 , X192K claim 2 , X192N claim 2 , X193Q claim 2 , X192R claim 2 , and X192S.4. The engineered polynucleotide encoding an engineered polypeptide of claim 2 , wherein the amino acid sequence further comprises a combination of residue differences selected from:(a) X124W and X327L;(b) X209M and X300G;(c) X122F, X223V and X284A;(d) XI92A, X215H and X311T;(e) X62N, X124F, X126A and X136L;(f) X124W, X126A, X136L, X192A and X284A; and(g) X124W, X126A, X136L, X152R/X152L/X152I, and X192A.5. The engineered polynucleotide encoding an engineered polypeptide of claim 1 , in which the amino acid sequence further comprises at least one or more residue differences as compared to SEQ ID NO:4 selected from: X54A; X54L; X56D; X56E; X61G; X61W; X62A; X62L; X62N; X62S; X64C; X68I; X122F claim 1 , X122W; X122Y; X124K; X124M; X124S; X124W; X126C; X126I; X139E; X140K; X143V; X150L; X155I; X155L; X159G; X160L; X176C; X199L; X199V; X209F; ...

Methods of preparing hydroxylamine derivatives useful in the preparation of anti-infective agents

The present invention relates to processes for the preparation of N-protected 4-((2S,5R)-5-((benzyloxy)amino)piperidine-2-carboxamido)piperidine-1-carboxylates. Such compounds have application in the preparation of beta-lactamase inhibitors such as 7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamides and esters, in particular, the beta lactamase inhibitor, (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide. The present invention also encompasses intermediates useful in the disclosed processes and methods for their preparation.

SKIN WOUND HEALING AND SCAR REDUCTION WITH PROSTAGLANDIN EP4 AGONIST COMBINATIONS

A combination of a prostaglandin EP4 agonist and an effective amount of: a prostaglandin EP2 agonist, a skin growth factor, a small peptide, a small inhibitory RNA targeting excess chronic inflammation or fibrosis, a cytokine with beneficial anti-inflammatory activity, an adenosine A2a receptor agonist, an anti-oxidant, or a combination thereof, may be used to treat skin wounds or scars. 1. A method of treating a skin wound or a scar comprising administering an effective amount of a prostaglandin EP4 agonist and an effective amount of an additional compound selected from the group consisting of a prostaglandin EP2 agonist , a skin growth factor , a small peptide , a small inhibitory RNA targeting excess chronic inflammation or fibrosis , a cytokine with beneficial anti-inflammatory activity , an adenosine A2a receptor agonist , an anti-oxidant , or a combination thereof , to a mammal in need thereof.9. The method of claim 1 , comprising administering an effective amount of a prostaglandin EP4 agonist and an effective amount of a prostaglandin EP2 agonist.10. The method of claim 9 , wherein the prostaglandin EP4 agonist and the prostaglandin EP2 agonist are administered topically.11. The method of claim 9 , wherein the prostaglandin EP4 agonist and the prostaglandin EP2 agonist are administered orally.12. The method of claim 9 , wherein the prostaglandin EP4 agonist and the prostaglandin EP2 agonist are administered in a single composition.13. The method of claim 9 , wherein the prostaglandin EP4 agonist and the prostaglandin EP2 agonist are administered at least daily for about 1 day to about 30 days.16. The method of wherein the EP4 agonist and the additional compound are applied directly to the skin wound or the scar.17. The method of wherein the EP4 agonist and the additional compound are applied directly to the skin surrounding the skin wound or the scar.18. The method of wherein the EP4 agonist and the additional compound are applied to a surgical site from ...

Manufacture of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol

The present invention relates to a process for synthesis of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol abbreviated THIP, having the INN name gaboxadol, starting from pyrrolidin-2-one. The process comprises a new direct process to obtain the intermediate dimethyl 5-hydroxy-3,6-dihydropyridine-1,4(2H)-5 dicarboxylate or the intermediate diethyl 5-hydroxy-3,6-dihydropyridine-1,4(2H)-dicarboxylate. 127-. (canceled)29. The process according to claim 28 , wherein step (e) is carried out in toluene.30. The process according to claim 28 , wherein the reaction in step (e) is carried out at either a reflux temperature or at a temperature between 70° C. and 85° C.33. The process according to claim 31 , wherein the steps (b) claim 31 , (c) and (d) are carried out in toluene.34. The process according to claim 31 , wherein the base used in step (b) is triethylamine.35. The process according to claim 31 , wherein the compound of formula V is purified by washing with acidified water or by distillation or by a combination of these two purification strategies.36. The process according to claim 31 , wherein the compound of formula V is purified by thin-film distillation.39. The process according to claim 38 , wherein the compound of formula IIb is obtained by a one-pot synthesis. The present invention relates to a process for synthesis of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol abbreviated THIP, having the INN name gaboxadol, starting from pyrrolidin-2-one. The process comprises a new direct process to obtain the intermediate dimethyl 5-hydroxy-3,6-dihydropyridine-1,4(2H)-dicarboxylate or the intermediate diethyl 5-hydroxy-3,6-dihydropyridine-1,4(2H)-dicarboxylate.The compound 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol abbreviated THIP, having the INN name gaboxadol, was disclosed for the first time in EP Patent No. 0000338 and has the molecular structure depicted below.Gaboxadol is a GABAA receptor agonist with functional selectivity for the delta containing GABAA ...

SUBSTITUTED TETRACYCLINE COMPOUNDS

The present invention pertains, at least in part, to novel substituted tetracycline compounds. These tetracycline compounds can be used to treat numerous tetracycline compound-responsive states, such as bacterial infections and neoplasms, as well as other known applications for tetracycline compounds such as blocking tetracycline efflux and modulation of gene expression. 133-. (canceled)3565-. (canceled)66. The compound of claim 34 , wherein Ris methoxycarbonyl substituted alkynyl claim 34 , pyrazinyl claim 34 , methoxymethyl claim 34 , cyclopropyl claim 34 , methyl claim 34 , methoxymethyl substituted alkynyl claim 34 , amino substituted pyridinyl claim 34 , alkylcarbonyl claim 34 , arylcarbonyl claim 34 , pyrimidinyl claim 34 , oxazolyl claim 34 , pyrazolyl claim 34 , carboxylate claim 34 , pyridinyl claim 34 , thiazolyl claim 34 , substituted or unsubstituted thiophenyl claim 34 , piperidinylcarbonyl claim 34 , dialkylaminomethyl claim 34 , cyano claim 34 , substituted or unsubstituted arylthiocarbonyl claim 34 , deuterated alkylaminoalkyl claim 34 , substituted furanyl claim 34 , isoxolazolyl claim 34 , cyano substituted pyridinyl claim 34 , alkylcarbonylamino substituted pyridinyl claim 34 , dialkylamino substituted phenyl claim 34 , pyrrolidonylcarbonyl claim 34 , azepanylcarbonyl claim 34 , carboxylatecarbonyl claim 34 , alkylcarbonyl substituted phenyl claim 34 , aminocarbonyl substituted phenyl claim 34 , carboxylate substituted phenyl or piperazinylcarbonyl.6778-. (canceled)80258-. (canceled)259. A method for treating a tetracycline responsive state in a subject claim 34 , comprising administering to said subject an effective amount of a tetracycline compound of claim 34 , such that said subject is treated.260. The method of claim 259 , wherein said tetracycline responsive state is malaria.261. The method of claim 259 , wherein said tetracycline responsive state is a bacterial infection claim 259 , a viral infection claim 259 , or a parasitic infection. ...

FUCOSIDASE INHIBITORS

The present disclosure relates, in general, to compounds useful as inhibitors of fucosidase enzymes, and to methods and compositions for the treatment of tumors or cancers, such as liver disorders and liver tumors (e.g., hepatocellular carcinoma), with a compound as disclosed herein. 118-. (canceled)20. (canceled)21. The method of claim 19 , wherein the compound reduces tumor metastasis in a subject.2223-. (canceled)24. The method of claim 19 , wherein the treatment results in a decrease in tumor size in the subject.25. The method of claim 19 , wherein the treatment results in a reduction of alpha-fetoprotein levels in blood of the subject compared to levels before treatment.26. The method of claim 19 , wherein the compound is administered intravenously.27. The method of claim 26 , wherein the compound is administered via the hepatic artery.28. The method of claim 19 , wherein the compound is administered in combination with a second agent.29. The method of claim 28 , wherein the second agent is selected from the group consisting of a chemotherapeutic agent claim 28 , a cytotoxic agent claim 28 , a radioisotope claim 28 , an anti-viral agent claim 28 , an anti-fungal agent claim 28 , an anti-inflammatory agent and an antibody.30. The method of claim 29 , wherein the chemotherapeutic agent is selected from the group consisting of doxorubicin and 5-fluorouracil.31. The method of claim 29 , wherein the second agent is a cytotoxic agent.32. The method of claim 31 , wherein the cytotoxic agent is selected from the group consisting of mechlorethamine hydrochloride claim 31 , cyclophosphamide claim 31 , ifosfamide claim 31 , chlorambucil claim 31 , melphalan claim 31 , busulfan claim 31 , thiotepa claim 31 , carmustine claim 31 , lomustine claim 31 , dacarbazine and streptozocin.33. The method of claim 29 , wherein the second agent is a radioisotope.34. The method of claim 33 , wherein the radioisotope is selected from the group consisting of I claim 33 , I claim 33 , In ...

PROCESS FOR PRODUCING HETEROCYCLIC COMPOUND

The present invention provides a method of efficiently producing an optically active 6-(3-aminopiperidin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine derivative. The optically active piperidine-3-carboxamide or a derivative thereof, which is obtained by subjecting 1,4,5,6-tetrahydropyridine-3-carboxamide or a derivative thereof to an asymmetric reduction in the presence of a catalyst, is used as an intermediate. 2. The method according to claim 1 , wherein the organic metal complex is a transition metal complex.3. The method according to claim 2 , wherein the transition metal complex is a ruthenium complex.4. The method according to claim 3 , wherein the ruthenium complex is represented by the formula:{'br': None, 'sup': 'a', 'sub': '2', '[Ru(OCOR)L*]\u2003\u2003(VIII)'}wherein{'sup': 'a', 'sub': '1-3', 'Ris an optionally substituted Calkyl group; and'}{'sup': 'a', 'Lis a diphosphine ligand.'} This application is a divisional of U.S. application Ser. No. 15/125,299, which is the U.S. National Stage application of PCT/JP2015/057541, filed Mar. 13, 2015, which claims priority from Japanese application 2014-052809, filed Mar. 14, 2014.The present invention relates to a production method of an optically active 6-(3-aminopiperidin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine derivative which is useful as a dipeptidylpeptidase inhibitor, and various intermediates useful therefor, and production methods thereof.An optically active 6-(3-aminopiperidin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine derivative is known to be useful as a dipeptidylpeptidase inhibitor and an agent for the treatment of diabetes.Patent Document 1 discloses a method of producing a 6-(3-aminopiperidin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine derivative by reacting optically active 3-aminopiperidine with a 6-chloro-2,4-dioxo-1,2,3,4-tetrahydropyrimidine derivative.Patent Document 2 discloses a method of efficiently producing an optically active 8-(3-aminopiperidin-1-yl)xanthine derivative by ...

PROCESS FOR PRODUCING HETEROCYCLIC COMPOUND

The present invention provides a method of efficiently producing an optically active 6-(3-aminopiperidin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine derivative. 2. The method according to claim 1 , wherein the organic metal complex is a transition metal complex.3. The method according to claim 2 , wherein the transition metal complex is a ruthenium complex.4. The method according to claim 3 , wherein the ruthenium complex is represented by the formula:{'br': None, 'sup': a', 'a, 'sub': '2', '[Ru(OCOR)L]\u2003\u2003(VIII)'}wherein{'sup': 'a', 'sub': '1-3', 'Ris an optionally substituted Calkyl group; and'}{'sup': 'a', 'Lis a diphosphine ligand.'} The present invention relates to a production method of an optically active 6-(3-aminopiperidin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine derivative which is useful as a dipeptidylpeptidase inhibitor, and various intermediates useful therefor, and production methods thereof.An optically active 6-(3-aminopiperidin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine derivative is known to be useful as a dipeptidylpeptidase inhibitor and an agent for the treatment of diabetes.Patent Document 1 discloses a method of producing a 6-(3-aminopiperidin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine derivative by reacting optically active 3-aminopiperidine with a 6-chloro-2,4-dioxo-1,2,3,4-tetrahydropyrimidine derivative.Patent Document 2 discloses a method of efficiently producing an optically active 8-(3-aminopiperidin-1-yl)xanthine derivative by subjecting racemic 3-aminopiperidine to acylation with phthalic anhydride, subjecting the obtained 3-phthalimide piperidine to optical resolution with optically active tartaric acid, coupling the obtained optically resolved compound with a xanthine ring, and subjecting the obtained compound to deacylation.Patent Document 3 discloses a method of optically resolving racemic piperidine-3-carboxamide with optically active lactic acid.Patent Document 4 discloses a method of producing an optically ...

TETRAHYDROPYRIDINE DERIVATIVES AND THEIR USE AS ANTIBACTERIAL AGENTS

The present disclosure relates to a novel tetrahydropyridine derivative compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, methods for preparing the compounds, methods for inhibiting UDP-3-O—(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC), methods for treating Gram-negative bacterial infections, the use of the compounds for the preparation of therapeutic medicaments for treating Gram-negative bacterial infections, and pharmaceutical compositions for prevention or treatment of Gram-negative bacterial infections, which contain the compounds. The compounds represented by formula I, stereoisomers thereof or pharmaceutically acceptable salts thereof according to the present disclosure can exhibit excellent effects on the treatment bacterial infections. 2. The tetrahydropyridine compound claim 1 , a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to :wherein,n is 1 or 2;{'sub': '1', 'Ris C1-C6 alkyl;'}{'sub': '2', 'Ris C1-C6 alkyl;'}{'sub': '3', 'Ris hydrogen;'}L is aryl, heteroaryl or null, wherein at least one H of aryl or heteroaryl may be substituted with halogen, C1-C6 alkyl or C1-C6 haloalkyl;D is C≡C or null;E is C≡C or null;G is C1-C6 alkyl, C3-C7 cycloalkyl, 4-6 membered heterocycloalkyl, aryl or heteroaryl,{'sub': A', 'B', 'C, 'wherein at least one H of C1-C6 alkyl may be substituted with halogen, —NRR, —OH or —OR,'}{'sub': '2', 'at least one H of 4-6 membered heterocycloalkyl may be substituted with C1-C6 alkyl, —(C═O)—C1-C6 alkyl or —S(═O)—C1-C6 alkyl,'}{'sub': A', 'B', 'A', 'B', 'C', '2', '2', 'A', 'B, 'at least one H of aryl or heteroaryl may be substituted with C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkyl-NRR, halogen, nitro, cyano, —NRR, —OH, —OR, —S(═O)—C1-C6 alkyl or —S(═O)—NRR;'}{'sub': A', 'B', 'A', 'B, 'Rand Rare each independently hydrogen or C1-C6 alkyl, or Rand Rmay be linked together to form 4-6 membered ring, wherein the 4-6 membered ring may have O atom and at least one H ...

New Complexes of Ruthenium, Method for Their Preparation, and Their Application in Olefin Metathesis Reactions

The present invention provides new ruthenium complexes of Formula (1), which contain a chelate ring created by a halogen atom X. The invention concerns also a method for the preparation of the new ruthenium complexes and their application in metathesis reactions. 5. The method according to claim 4 , wherein the reaction is carried out in the presence of anhydrous halogen salts of copper(I) such as CuBr or CuCl in the presence of Brønsted acids such as HSO claim 4 , HCl claim 4 , HNO claim 4 , HPO claim 4 , sulphonated polymers (Nafion-H) claim 4 , or other acids bonded with a fixed substrate claim 4 , in a solvent.6. Method The method according to claim 4 , wherein the reaction is carried out at a temperature in the range of 0-120° C.7. The method according to claim 4 , wherein the reaction is carried out in a protic or aprotic solvent or a chlorinated solvent or in an aromatic hydrocarbon solvent claim 4 , or in mixtures thereof.8. The method according to claim 4 , wherein the reaction is carried out in a solvent such as methylene chloride and/or toluene.9. A method of using the ruthenium complexes of formula 1 comprising using the ruthenium complexes as (pre)catalysts in metathesis processes.10. The method according to claim 9 , wherein the ruthenium complexes are used as (pre)catalysts in ring-opening metathesis reactions claim 9 , homometathesis claim 9 , cross-metathesis claim 9 , metathesis of the alkene-alkyne (ene-yne) type claim 9 , ring-closing metathesis or ROMP-type polymerisation reactions. The invention concerns new ruthenium complexes which act as (pre)catalysts, a method for their preparation, and their application in olefin metathesis reactions. This invention is used in organic synthesis in a broad sense.In applications of olefin metathesis in organic synthesis, significant progress has been made in recent years. In the state of the art, a number of carbene complexes of ruthenium are known which act as (pre)catalysts and which display both high ...

PROCESSES OF MAKING AND CRYSTALLINE FORMS OF A MDM2 INHIBITOR

The present invention provides processes for making 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid as well as intermediates and processes for making the intermediates. Also provided are crystalline forms of the compound and the intermediates. 14. The process of wherein the dehydrating conditions are azeotropic distillation with toluene.19. The process of wherein the oxidation is accomplished using ozone.20. The process of wherein the oxidation is accomplished using ozone followed by Pinnick oxidation.25. The process of wherein the base is sodium tert-butoxide.26. The process of wherein the oxidation is accomplished using RuCland NaIO.38. The process of wherein the oxidizing agent is ozone and the acid is hydrochloric acid. The present invention provides processes for making 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (“Compound A” herein) as well as intermediates and processes for making the intermediates. Also provided are crystalline forms of the compound and the intermediates.p53 is a tumor suppressor and transcription factor that responds to cellular stress by activating the transcription of numerous genes involved in cell cycle arrest, apoptosis, senescence, and DNA repair. Unlike normal cells, which have infrequent cause for p53 activation, tumor cells are under constant cellular stress from various insults including hypoxia and pro-apoptotic oncogene activation. Thus, there is a strong selective advantage for inactivation of the p53 pathway in tumors, and it has been proposed that eliminating p53 function may be a prerequisite for tumor survival. In support of this notion, three groups of investigators have used mouse models to demonstrate that absence of p53 function is a continuous requirement for the maintenance of established tumors. When the investigators restored ...

CHEMICAL PROCESS FOR PREPARING PHENYLPIPERIDINYL INDOLE DERIVATIVES

The present invention relates to a method of synthesizing a compound of formula (I) also referred to as 4-(((2S,4S)-(4-ethoxy-1-(((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid, or a pharmaceutically acceptable salt thereof, and/or intermediates thereof, their use as pharmaceuticals and pharmaceutical compositions and the use of intermediates for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof. 116-. (canceled)18. The process of claim 17 , wherein the Lewis acid is selected from the group consisting of MgCl claim 17 , MgBr claim 17 , and MgIor mixtures thereof.19. The process of claim 17 , wherein the base is selected from the group consisting of N claim 17 ,N-diisopropylethylamine claim 17 , 1 claim 17 ,8-diazabicyclo[5.4.0]undec-7-ene claim 17 , 1 claim 17 ,4-diazabicyclo[2.2.2]octane claim 17 , or mixtures thereof.20. The process of claim 17 , wherein the aldehyde source is selected from the group consisting of formaldehyde claim 17 , paraformaldehyde claim 17 , and 2 claim 17 ,4 claim 17 ,6-trimethyl-1 claim 17 ,3 claim 17 ,5-trioxane.21. The process of claim 17 , wherein Pis selected from the group consisting of tert-butyloxycarbonyl (Boc) claim 17 , toluenesulfonyl (tosyl) claim 17 , and trifluoromethanesulfonyl.23. The process of claim 22 , wherein the Lewis acid is selected from the group consisting of MgCl claim 22 , MgBr claim 22 , and MgIor mixtures thereof.24. The process of claim 22 , wherein the base is selected from the group consisting of N claim 22 ,N-diisopropylethylamine claim 22 , 1 claim 22 ,8-diazabicyclo[5.4.0]undec-7-ene claim 22 , 1 claim 22 ,4-diazabicyclo[2.2.2]octane claim 22 , or mixtures thereof.25. The process of claim 22 , wherein the aldehyde source is selected from the group consisting of formaldehyde claim 22 , paraformaldehyde claim 22 , and 2 claim 22 ,4 claim 22 ,6-trimethyl-1 claim 22 ,3 claim 22 ,5-trioxane.26. The process of claim 22 , wherein Pis selected from the ...

PROCESS FOR MAKING CGRP RECEPTOR ANTAGONISTS

The disclosure encompasses a novel process for making piperidinone carboxamide indane and azainane derivatives, having less steps and improved yields as compared to previous synthetic methods for making these compounds, which are CGRP receptor antagonists, useful for the treatment of migraine. Conditions for an amide bond formation between an acid and amine include for example reacting the compounds of Formulae B (after salt break) and C with an amide coupling reagent and optionally an additive and an acid and/or a base in a non-reactive solvent. 2. The process according to where the compound of Formula B is coupled with a compound of Formula C after salt break by reacting the reagents with an amide coupling reagent in a non-reactive solvent to yield a compound of Formula I.3. The process according to wherein the amide coupling reagent is selected from the group consisting of EDC claim 2 , HATU claim 2 , T3P® and CDI claim 2 , and the non-reactive solvent is an organic/aqueous mixture selected from the group consisting of DCM/water claim 2 , iPAC/water claim 2 , acetonitrile/water claim 2 , acetone/water claim 2 , iPA/water and THF/water.4. The process according to further comprising an amide coupling reagent additive selected from the group consisting of HOBT and HOPO.5. The process according to wherein a salt of a compound of Formula C is coupled to the compound of Formula B.6. The process according to wherein the arylaldehyde derivative is selected from 2-hydroxybenzaldehyde claim 1 , 2-hydroxy-5-nitrobenzaldehyde and 2-hydroxy-3 claim 1 ,5-dichlorobenzaldehyde.8. The process according to wherein the electrophilic alkylating agent is R—OS(O)CFor R—OS(O)F claim 7 , or R—OS(O)R claim 7 , wherein Ris a polyfluorinated one to six membered carbon chain.9. The process according to wherein: Z is t-butyl-O—C(O)— claim 8 , deprotection is effected by reacting the compound of Formula D with a second acid claim 8 , the base is a lithium base claim 8 , the additive is an ...

N1-CYCLIC AMINE-N5-SUBSTITUTED BIGUANIDE DERIVATIVES, METHODS OF PREPARING THE SAME AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME

The present invention provides an N1-cyclic amine-N5-substituted biguanide derivative compound represented by Formula 1, a method of preparing the same and a pharmaceutical composition including the biguanide derivative or the pharmaceutically acceptable salt thereof as an active ingredient. The biguanide derivatives have an effect of inhibiting cancer cell proliferation, cancer metastasis and cancer recurrence by activation of AMPK, even when administered in a small dose compared with conventional drugs. 120-. (canceled)22. The compound of Formula 1 or the pharmaceutically acceptable salt thereof of claim 21 , wherein the compound of Formula 1 isN1-(3-methyl)piperidine-N5-(4-fluoro)phenyl biguanide;N1-(3-methyl)piperidine-N5-(4-bromo)phenyl biguanide;N1-(3-methyl)piperidine-N5-(4-chloro,3-trifluoromethyl)phenyl biguanide;N1-(3-methyl)piperidine-N5-(3-fluoro,4-trifluoromethyl)phenyl biguanide;N1-(3-methyl)piperidine-N5-(4-fluoro,3-trifluoromethyl)phenyl biguanide;N1-(2-methyl)piperidine-N5-(4-trifluoromethoxy)phenyl biguanide;N1-(2-methyl)piperidine-N5-(3-trifluoromethoxy)phenyl biguanide;N1-(2-methyl)piperidine-N5-(4-trifluoromethyl)phenyl biguanide;N1-(3-methyl)piperidine-N5-(3-fluoro,4-trifluoromethoxy)phenyl biguanide;N1-(2-methyl)piperidine-N5-(3-fluoro,4-trifluoromethoxy)phenyl biguanide;N1-(2-methyl)piperidine-N5-(4-chloro)phenyl biguanide;N1-(2-methyl)piperidine-N5-(4-fluoro,3-trifluoromethyl)phenyl biguanide;N1-(2-methyl)piperidine-N5-(3-trifluoromethyl)phenyl biguanide;N1-(2-methyl)piperidine-N5-(4-chloro,3-trifluoromethyl)phenyl biguanide;N1-(3-methyl)piperidine-N5-(4-trifluoromethyl)phenyl biguanide;N1-(3-methyl)piperidine-N5-(4-trifluoromethoxy) phenyl biguanide;N1-(3-methyl)piperidine-N5-(3-trifluoromethoxy)phenyl biguanide;N1-(3-methyl)piperidine-N5-(4-fluoro,3-trifluoromethyl)phenyl biguanide;N1-(3-methyl)piperidine-N5-(4-chloro)phenyl biguanide;N1-(3-methyl)piperidine-N5-(3-trifluoromethyl)phenyl biguanide;N1-(2,6-dimethyl)piperidine-N5-(4- ...

Method for producing n-alkoxycarbonylpiperidine derivative, and intermediate therefor

The object of the present invention is to provide a simple method for preparing an N-alkoxycarbonyl piperidine derivative. The object can be solved by a method for preparing a hydroxypiperidine derivative, comprising a step of: (A) reacting a piperidylidene acetic acid derivative represented by the formula (1): wherein R 1 is an aralkyl group which may have a substituent group, and R 2 is an alkyl group, with 4-hydroxypiperidine in the presence of base, to obtain a hydroxypiperidine derivative represented by the formula (2) or the formula (3): wherein R 1 is an aralkyl group which may have a substituent group.

METHOD FOR SYNTHESIZING LACTAM DERIVATIVES WITHOUT USE OF CATALYST

Disclosed is a simple synthesis method of lactam derivatives, comprising: with formamide functioning as both an amine source and a hydrogen source (hydrolyzed to produce formic acid), carrying out a cycloamination reaction on a raw material keto acid in the absence of a solvent or a catalyst to simply synthesize a lactam derivative. Compared with previous reports, the present disclosure has the following advantages: the time required for the reaction is greatly shortened, the selectivity is remarkably improved, a conversion rate of a keto acid derivative is greater than 99%, and the yield of the lactam derivative can reach 70% to 94%. 1. A method for synthesizing lactam derivatives without use of a catalyst , comprising: carrying out a direct addition reaction between a raw material keto acid derivative and formamide functioning as both an amine source and a hydrogen source in the absence of an organic solvent or a catalyst , and then carrying out formic acid reduction and ring-closure reaction to obtain a corresponding lactam derivative.2. The method for synthesizing lactam derivatives without use of a catalyst according to claim 1 , wherein the preparation of the lactam derivative is carried out in water claim 1 , the reaction system is a closed system claim 1 , and the reaction is carried out for 60 to 300 min at a temperature within a range of 140° C. to 180° C.3. The method for synthesizing lactam derivatives without use of a catalyst according to claim 1 , wherein a molar ratio of the keto acid derivative to the formamide to water is 1:5˜15:10˜40.4. The method for synthesizing lactam derivatives without use of a catalyst according to claim 1 , wherein the keto acid derivative comprises levulinic acid claim 1 , 3-(4-chlorobenzoyl)propionic acid claim 1 , 3-benzoylpropionic acid claim 1 , 3-(4-fluorobenzoyl)propionic acid claim 1 , 4-oxo-4-(2-thienyl)butanoic acid claim 1 , acetobutyric acid claim 1 , 4-(4-fluorobenzoyl)butyric acid claim 1 , 4-benzoylbutyric ...

Process for Making CGRP Receptor Antagonists

The invention encompasses a novel process for making piperidinone carboxamide indane and azainane derivatives, which are CGRP receptor antagonists useful for the treatment of migraine. 111-. (canceled)12. Crystalline (S)—N-((3S ,5S ,6R)-6-methyl-2-oxo-1-(2 ,2 ,2-trifluoroethyl)-5-(2 ,3 ,6-trifluorophenyl)piperidin-3-yl)-2′-oxo-1′ ,2′ ,5 ,7-tetrahydrospiro[cyclopenta[b]pyridine-6 ,3′-pyrrolo[2 ,3-b]pyridine]-3-carboxamide monohydrate.13. Crystalline (S)—N-((3S claim 12 ,5S claim 12 ,6R)-6-methyl-2-oxo-1-(2 claim 12 ,2 claim 12 ,2-trifluoroethyl)-5-(2 claim 12 ,3 claim 12 ,6-trifluorophenyl)piperidin-3-yl)-2′-oxo-1′ claim 12 ,2′ claim 12 ,5 claim 12 ,7-tetrahydrospiro[cyclopenta[b]pyridine-6 claim 12 ,3′-pyrrolo[2 claim 12 ,3-b]pyridine]-3-carboxamide monohydrate according to having a DSC extrapolated onset melting temperature of about 144° C. and a DSC peak melting temperature of about 175° C.14. Crystalline (S)—N-((3S claim 12 ,5S claim 12 ,6R)-6-methyl-2-oxo-1-(2 claim 12 ,2 claim 12 ,2-trifluoroethyl)-5-(2 claim 12 ,3 claim 12 ,6-trifluorophenyl)piperidin-3-yl)-2′-oxo-1′ claim 12 ,2′ claim 12 ,5 claim 12 ,7-tetrahydrospiro[cyclopenta[b]pyridine-6 claim 12 ,3′-pyrrolo[2 claim 12 ,3-b]pyridine]-3-carboxamide monohydrate according to having d-spacings determined by x-ray powder diffraction claim 12 , Cu K alpha claim 12 , of about 12.7 claim 12 , 8.9 claim 12 , 8.1 claim 12 , 7.4 claim 12 , 6.4 claim 12 , 5.2 claim 12 , 4.9 claim 12 , 4.8 and 4.0 angstroms.15. Crystalline (S)—N-((3S claim 12 ,5S claim 12 ,6R)-6-methyl-2-oxo-1-(2 claim 12 ,2 claim 12 ,2-trifluoroethyl)-5-(2 claim 12 ,3 claim 12 ,5-trifluorophenyl)piperidin-3-yl)-2′-oxo-1′ claim 12 ,2′ claim 12 ,5 claim 12 ,7-tetrahydrospiro[cyclopenta[b]pyridine-6 claim 12 ,3′-pyrrolo[2 claim 12 ,3-b]pyridine]-3-carboxamide. The official copy of the Sequence Listing is submitted concurrently with the specification as an ASCII formatted text file via EFS-Web, with a file name of “23236USPSP-SEQLIST-09MAY2012”, a ...

INTERMEDIATES FOR PREPARING CGRP RECEPTOR ANTAGONISTS

The invention encompasses a novel process for making piperidinone carboxamide indane and azainane derivatives, which are CGRP receptor antagonists useful for the treatment of migraine. 116-. (canceled) The official copy of the Sequence Listing is submitted concurrently with the specification as an ASCII formatted text file via EFS-Web, with a file name of “23236USPSP-SEQLIST-9 May 2012”, a creation date of May 9, 2012, and a size of 4,509 bytes. The Sequence Listing filed via EFS-Web is part of the Specification and is incorporated in its entirety by reference herein.This invention relates to a process for making piperidinone carboxamide indane and azainane derivatives, which are CGRP receptor antagonists useful for the treatment of migraine. This class of compounds is described in U.S. patent application Ser. Nos. 13/293,166 filed Nov. 10, 2011, 13/293,177 filed Nov. 10, 2011 and 13/293,186 filed Nov. 10, 2011, and PCT International Application Nos. PCT/US11/60081 filed Nov. 10, 2011 and PCT/US11/60083 filed Nov. 10, 2011.CGRP (Calcitonin Gene-Related Peptide) is a naturally occurring 37-amino acid peptide that is generated by tissue-specific alternate processing of calcitonin messenger RNA and is widely distributed in the central and peripheral nervous system. CGRP is localized predominantly in sensory afferent and central neurons and mediates several biological actions, including vasodilation. CGRP is expressed in alpha- and beta-forms that vary by one and three amino acids in the rat and human, respectively. CGRP-alpha and CGRP-beta display similar biological properties. When released from the cell, CGRP initiates its biological responses by binding to specific cell surface receptors that are predominantly coupled to the activation of adenylyl cyclase. CGRP receptors have been identified and pharmacologically evaluated in several tissues and cells, including those of brain, cardiovascular, endothelial, and smooth muscle origin.Based on pharmacological properties ...

PROCESSES OF MAKING AND CRYSTALLINE FORMS OF A MDM2 INHIBITOR

The present invention provides processes for making 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid as well as intermediates and processes for making the intermediates. Also provided are crystalline forms of the compound and the intermediates. 112-. (canceled)14. The process of claim 14 , wherein the dehydrating conditions are azeotropic distillation with toluene.16. (canceled)17. (canceled)1938.-. (canceled)39. The process of claim 18 , wherein the base is sodium tert-butoxide. The present invention provides processes for making 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)- 3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (“Compound A” herein) as well as intermediates and processes for making the intermediates. Also provided are crystalline forms of the compound and the intermediates.p53 is a tumor suppressor and transcription factor that responds to cellular stress by activating the transcription of numerous genes involved in cell cycle arrest, apoptosis, senescence, and DNA repair. Unlike normal cells, which have infrequent cause for p53 activation, tumor cells are under constant cellular stress from various insults including hypoxia and pro-apoptotic oncogene activation. Thus, there is a strong selective advantage for inactivation of the p53 pathway in tumors, and it has been proposed that eliminating p53 function may be a prerequisite for tumor survival. In support of this notion, three groups of investigators have used mouse models to demonstrate that absence of p53 function is a continuous requirement for the maintenance of established tumors. When the investigators restored p53 function to tumors with inactivated p53, the tumors regressed.p53 is inactivated by mutation and/or loss in 50% of solid tumors and 10% of liquid tumors. Other key members of the p53 pathway are also genetically or epigenetically altered in ...

USE OF TETRAHYDROPYRIDINES IN THE TREATMENT OF SODIUM CHANNEL RELATED DISEASE AND DISORDERS

The present invention provides a method of treating one or more sodium channel related diseases or disorders in an individual, including related symptoms. The method comprises administering to the individual a tetrahydropyridine derivative in an amount effective to treat sodium channel related diseases or disorders in individuals. These compounds are generally categorised as Ritalin related compounds. The present invention also provides compounds for use in the treatment of and also for use in the manufacture of a medicament for the treatment of sodium channel related diseases or disorders in an individual. A method is further provided for the preparation and isolation of the derivatives of the compound of the present invention. 2. The method according to claim 1 , wherein the R-bearing group is mono- claim 1 , di- claim 1 , or tri-substituted.3. The method according to claim 1 , wherein the compound is a threo-diastereomer claim 1 , a erythro-diastereomer or a mixture of the threo-diastereomer and the erythro-diastereomer.4. The method according to claim 1 , wherein R is one or more substituents selected from the group consisting of hydrogen claim 1 , halogens claim 1 , substituted or unsubstituted phenyls claim 1 , and adjacent rings which share a side with the R-bearing group.5. The method according to claim 1 , wherein R consists of chlorine substituents at positions 3 and 4.6. The method according to claim 1 , wherein R is a p-bromo.7. The method according to claim 1 , wherein R is a p-chloro.8. The method according to claim 1 , wherein R is a p-2-naphthyl.9. The method according to claim 1 , wherein R is an unsubstituted p-phenyl.12. The method according to claim 6 , wherein the compound comprises mixture of structures (2) and (3).13. The method according to claim 1 , wherein the compound is capable of inhibiting sodium channel conductance.14. The method according to claim 13 , wherein the sodium channels are voltage gated sodium channels.15. The method ...

RUTHENIUM POLYMERISATION CATALYSTS

Cis and trans ruthenium complexes that can be used as catalysts for ring opening metathesis polymerisation (ROMP) are described. The complexes are generally square pyramidal in nature, having two anionic ligands X. Corresponding cationic complexes where one or both of the anionic ligands X are replaced by a non-co-ordinating anionic ligand are also described. Polymers such as polydicyclopentadiene (PDCPD) can be prepared using the catalysts. 3. The method according to wherein the group A is an N-heterocyclic carbene.4. The method according to wherein the anionic ligands X are independently selected from the group consisting of halogen claim 1 , benzoate claim 1 , C-Ccarboxylates such as pivalate and trifluoroacetate claim 1 , C-Calkoxy claim 1 , phenoxy claim 1 , C-Calkyl thio groups claim 1 , tosylate claim 1 , mesylate claim 1 , brosylate claim 1 , trifluoromethane sulfonate claim 1 , phenylacetate and pseudo-halogens.5. The method according to wherein the groups Rand Rare H and aryl.6. The method according to wherein the groups Rand Rare fused to form a substituted or unsubstituted indenylidene moiety. The work leading to this invention has received funding from the European Research Council under the European Community's Seventh Framework Programme (FP7-NMP-2007-SMALL-1) “EUMET”/ERC grant agreement no. NMP2-SL-2009-211468.The present invention relates to the provision of ruthenium complexes, their manufacture and uses for example in catalysis, in particular in olefin metathesis reactions, including in Ring Opening Metathesis Polymerisation (ROMP).Olefin metathesis is considered as one of the most useful tools in organic chemistry. Since Grubbs reported the first generation ruthenium-catalyst (ref 1), numerous studies have been aimed at developing long life and more active catalysts and precatalysts. A breakthrough was the replacement of a phosphine ligand by a N-heterocyclic carbene (NHC), increasing the reactivity and stability of the corresponding complex (ref ...

METHOD FOR PRODUCING KAKEROMYCIN AND DERIVATIVES THEREOF

Provided is a production method of kakeromycin and a derivative thereof showing an antifungal activity and cytotoxicity and expected as a new antifungal agent or anticancer agent, by chemical synthesis. A production method of a compound represented by the formula (1): This patent application is a divisional of copending U.S. patent application Ser. No. 15/554,002, filed on Aug. 27, 2017, which the U.S. national phase of International Patent Application No. PCT/JP2016/055891, filed on Feb. 26, 2016, which claims the benefit of Japanese Patent Application No. 2015-039363, filed Feb. 27, 2015, the disclosures of which are incorporated herein by reference in their entireties for all purposes.The present invention relates to a production method of kakeromycin and a derivative thereof.In recent years, along with an increase in elderly people, progress of advanced medicine, immunodeficiency of late stage cancer patients and the like, infections with fungi have been increasing. These infections provide serious effects, often causing death. Since there are not many kinds of existing antifungal agents, and their toxicity is high, the mother nucleus of a new antifungal agent, which is different from that of conventional medicaments, has been desired. In addition, since the use of antifungal agents causes increased emergence of resistant bacteria, the development of a new medicament has been earnestly desired. While candin-based antifungal agents show low toxicity, since the molecular weight thereof is large, reactivity with serum poses problems. Azole-based antifungal agents have a problem in that administration at a high concentration is difficult in view of the toxicity thereof. Therefore, an effective, low-molecular-weight compound showing low reactivity with serum and low toxicity has been strongly desired.Conventionally, in search of a pharmaceutical product seed compound from microbial metabolites, terrestrial separation sources have been mainly harvested and subjected ...

PIPERIDINONE HERBICIDES

Disclosed are compounds of Formula 1, including all stereoisomers, N-oxides, and salts thereof: 2. The compound of wherein{'sup': 7', '10, 'sub': 1', '4', '1', '4', '2', '4', '2', '4', '2', '4', '2', '4', '1', '4', '2', '4', '2', '4', '2', '4', '3', '4', '3', '4', '1', '4', '1', '4', '2', '4', '2', '4', '3', '4', '3', '4', '3', '4', '1', '4', '1', '4', '1', '4', '1', '4', '1', '4', '1', '4', '2', '4', '2', '4', '1', '4', '1', '4', '1', '4', '2', '4', '2', '4', '5', '3', '4, 'each Rand Ris independently halogen, cyano, nitro, C-Calkyl, C-Chaloalkyl, C-Calkenyl, C-Chaloalkenyl C-Calkynyl, C-Chaloalkynyl, C-Cnitroalkyl, C-Cnitroalkenyl, C-Calkoxyalkyl, C-Chaloalkoxyalkyl, C-Ccycloalkyl, C-Chalocycloalkyl, C-Calkoxy, C-Chaloalkoxy, C-Calkenyloxy, C-Chaloalkenyloxy, C-Calkynyloxy, C-Chaloalkynyloxy, C-Ccycloalkoxy, C-Calkylthio, C-Chaloalkylthio, C-Calkylsulfinyl, C-Chaloalkylsulfinyl, C-Calkylsulfonyl, C-Chaloalkylsulfonyl, C-Calkylcarbonyl, C-Calkylcarbonyloxy, C-Calkylsulfonyloxy, C-Chaloalkylsulfonyloxy, C-Calkylamino, C-Cdialkylamino, formylamino, C-Calkylcarbonylamino, —SF, —SCN, C-Ctrialkylsilyl, trimethylsilylmethyl or trimethylsilylmethoxy; and'}{'sup': 9', '11, 'sub': 1', '2, 'each Rand Ris independently H or C-Calkyl.'}3. The compound of wherein{'sup': 1', '2, 'Yand Yare each O;'}{'sup': '1', 'sub': 1', '6, 'Ris H or C-Calkyl; and'}{'sup': 2', '3', '2A', '3A', '4', '5', '6, 'R, R, R, R, R, Rand Rare each H.'}4. The compound of wherein{'sup': '1', 'Ris H or Me.'}5. The compound of wherein{'sup': 1', '7, 'Qis a phenyl ring substituted with 1 to 3 substituents independently selected from R; and'}{'sup': 2', '10, 'Qis a phenyl ring substituted with 1 to 3 substituents independently selected from R.'}6. The compound of wherein{'sup': '7', 'sub': 1', '2', '1', '3', '1', '3, 'each Ris independently halogen, cyano, C-Calkyl, C-Chaloalkyl or C-Calkylsulfonyl; and'}{'sup': '10', 'sub': 1', '2', '1', '3', '1', '3, 'each Ris independently halogen, cyano, nitro, C-Calkyl, ...

PYRROLIDIN-2-ONE AND PIPERIDIN-2-ONE DERIVATIVES AS 11-BETA HYDROXYSTEROID DEHYDROGENASE INHIBITORS

The N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein 2. A compound according to wherein;n is 2;{'sub': 1-3', '1-4', '1-3', '1-4', '1-4', '1-3', '1-4', '1', '1-4', '1', '1-4', '1, 'L represents a Calkyl linker optionally substituted with one or two substituents selected from Calkyl, Calkyloxy-Calkyl-, hydroxy-Calkyl, hydroxy, Calkyloxy- or phenyl-Calkyl; in particular L represents a C-linker optionally substituted with Calkyl; preferably L represents a C-linker substituted with Calkyl, more preferably a C-linker substituted with methyl;'}{'sub': 1-2', '1-4', '1-4', '1', '1-4, 'M represents a direct bond or a Calkyl optionally substituted with one or two substituents selected from hydroxy, Calkyl or Calkyloxy-; preferably M represents a C-linker optionally substituted with Calkyl;'}{'sup': '1', 'sub': 1-4', '1-4', '1-4, 'Rrepresents hydrogen, hydroxy, halo, Calkyl, Calkyloxy-, or Calkyloxy substituted with halo;'}{'sup': 2', '1, 'sub': 1-4', '1-4', '1-4, 'Rrepresents hydrogen, halo, Calkyl, Calkyloxy- or Ar—Calkyloxy-;'}{'sup': '3', 'sub': 1-4', '1-4, 'Rrepresents hydrogen, halo, Calkyl, Calkyloxy- or cyano;'}{'sup': '4', 'sub': 1-4', '1-4, 'Rrepresents hydrogen, halo, Calkyl or Calkyloxy-;'}{'sup': 5', '2, 'sub': 1-4', '1-4, 'Rrepresents hydrogen, Calkyl or Ar—Calkyl; in particular hydrogen;'}{'sup': '6', 'sub': '1-4', 'Rrepresents hydrogen, halo, or Calkyloxy; in particular hydrogen, chloro, fluoro, bromo or methoxy;'}{'sup': '1', 'Arrepresents phenyl;'}{'sup': '2', 'Arrepresents phenyl or naphtyl.'}3. (canceled)4. A compound according to wherein Ris at the para position claim 1 , L represents a C-alkyl linker and M represents a C-linker.5. A compound according to wherein L represents a C-linker substituted with a Calkyl claim 1 , CalkyloxyCalkyl- claim 1 , hydroxyCalkyl- or phenylCalkyl- wherein said Calkyl claim 1 , CalkyloxyCalkyl- claim 1 , hydroxyCalkyl- or phenylCalkyl- is in the S- ...

SUBSTITUTED AMINOINDANE- AND AMINOTETRALINECARBOXYLIC ACIDS AND THE USE THEREOF

The present application relates to novel substituted aminoindane- and aminotetralinecarboxylic acids, to processes for preparation thereof, to the use thereof for treatment and/or prevention of diseases, and to the use thereof for production of medicaments for treatment and/or prevention of diseases, especially for treatment and/or prevention of cardiovascular and cardiopulmonary diseases. 5. (canceled)6. (canceled)7. (canceled)8. Medicament comprising a compound as defined in in combination with one or more inert claim 1 , nontoxic claim 1 , pharmaceutically suitable excipients.9. Medicament comprising a compound as defined in in combination with one or more further active compounds selected from the group consisting of organic nitrates claim 1 , NO donors claim 1 , cGMP-PDE inhibitors claim 1 , stimulators of guanylate cyclase claim 1 , antithrombotic agents claim 1 , hypotensive agents and lipid metabolism modifiers.10. (canceled)11. Method for treatment and/or prevention of heart failure claim 1 , angina pectoris claim 1 , hypertension claim 1 , pulmonary hypertension claim 1 , thromboembolic disorders claim 1 , ischaemias claim 1 , vascular disorders claim 1 , impaired microcirculation claim 1 , renal insufficiency claim 1 , fibrotic disorders and arteriosclerosis in humans and animals by administration of an effective amount of at least one compound as defined in to a human or animal in need thereof.12. A method for the treatment and/or prevention of heart failure claim 8 , angina pectoris claim 8 , hypertension claim 8 , pulmonary hypertension claim 8 , thromboembolic disorders claim 8 , ischaemias claim 8 , vascular disorders claim 8 , impaired microcirculation claim 8 , renal insufficiency claim 8 , fibrotic disorders and arteriosclerosis in humans and animals by administration of an effective amount of the medicament of to a human or animal in need thereof.13. A method for the treatment and/or prevention of heart failure claim 9 , angina pectoris claim 9 , ...

ENANTIOSELECTIVE SYNTHESIS OF ALPHA-QUATERNARY MANNICH ADDUCTS BY PALLADIUM-CATALYZED ALLYLIC ALKYLATION

This invention provides enantioenriched Mannich adducts with quaternary stereogenic centers and novel methods of preparing the compounds. Methods include the method for the preparation of a compound of formula (I): 163-. (canceled)65. The method of claim 64 , wherein the transition metal catalyst comprises a transition metal selected from palladium claim 64 , nickel claim 64 , and platinum.66. The method of claim 64 , wherein the transition metal catalyst further comprises a chiral ligand.67. The method of claim 64 , wherein the compound represented by formula (Ia) has about 80% ee or greater.68. The method of claim 64 , wherein the compound represented by formula (Ia) has about 85% ee or greater.69. The method of claim 64 , wherein the compound represented by formula (Ia) has about 90% ee or greater. This Application is a Continuation of U.S. patent application Ser. No. 14/972,475, filed Dec. 17, 2015, which claims the benefit of U.S. Provisional Application 62/093,982, filed Dec. 18, 2014, the contents of both of which are incorporated herein by reference.This invention was made with Government support under Grant Number R01GM080269, awarded by the National Institutes of Health. The Government has certain rights in the invention.The Mannich reaction, first discovered in the early 20th century, is among the most robust reactions known to produce nitrogen-containing compounds. In a classic intermolecular Mannich reaction, an aldehyde, an amine and an α-acidic carbonyl compound react to form a β-amino carbonyl compound. Recent progress in this area, including modified imine donors and well-explored catalyst systems, has made available a wide variety of asymmetric α-functionalizations of carbonyl compounds. However, to date, asymmetric Mannich-type reactions to establish α-quaternary carbonyl compounds have been limited to specialized substrate classes.There exists a need for methods that enable access to α-quaternary Mannich Adducts, particularly enantioselective ...

ENANTIOSELECTIVE SYNTHESIS OF alpha-QUATERNARY MANNICH ADDUCTS BY PALLADIUM-CATALYZED ALLYLIC ALKYLATION

This invention provides enantioenriched Mannich adducts with quaternary stereogenic centers and novel methods of preparing the compounds. Methods include the method for the preparation of a compound of formula (I): 2. (canceled)4. The compound of claim 3 , wherein the sum of m and n is 0 claim 3 , 1 claim 3 , 2 claim 3 , or 3.5. The compound of claim 3 , wherein each occurrence of A claim 3 , B claim 3 , C claim 3 , and D is each independently CR″R′″ or CR″.6. The compound of claim 5 , wherein each occurrence of A claim 5 , B claim 5 , C claim 5 , and D is CR″R′″; andR″ and R′″ are each independently selected for each occurrence from hydrogen, hydroxyl, halogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl, amino, alkoxy, aryloxy, and alkylamino.7. (canceled)8. The compound of claim 6 , wherein each occurrence of A claim 6 , B claim 6 , C claim 6 , and D is CH.9. The compound of claim 5 , wherein at least two adjacent occurrences of A claim 5 , B claim 5 , C claim 5 , and D are CR″.10. The compound of claim 9 , wherein A and B are each CR″ and m is 1; andR″ is independently selected for each occurrence from hydrogen, hydroxyl, halogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkenyl, amino, alkoxy, aryloxy, and alkylamino; orthe occurrence of R″ on A and the occurrence of R″ on B are taken together to form an optionally substituted aryl, heteroaryl, cycloalkenyl, or heterocycloalkenyl group.11. (canceled)12. (canceled)13. The compound of claim 3 , wherein at least one occurrence of A claim 3 , B claim 3 , C claim 3 , and D is NR′.14. The compound of claim 13 , wherein at least one occurrence of the remaining A claim 13 , B claim 13 , C claim 13 , and D is NR′ or O.15. The compound of claim 13 , wherein R′ represents independently for each occurrence hydrogen or optionally ...

PYRROLIDINYL DERIVATIVES AS 11-BETA HYDROXYSTEROID DEHYDROGENASE INHIBITORS

The N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein 2. A compound according to wherein;n is 1;{'sub': 1', '1-4, 'L represents a C-linker optionally substituted with one or two Calkyl substituents'}{'sub': '1-2', 'M represents a Calkanediyl'}{'sup': '3', 'sub': 1-4', '1-4, 'Rrepresents hydrogen, halo, Calkyl, Calkyloxy- or cyano;'}{'sup': '4', 'sub': 1-4', '1-4, 'Rrepresents hydrogen, halo, Calkyl or Calkyloxy-;'}{'sup': 5', '2, 'sub': 1-4', '1-4, 'Rrepresents hydrogen, Calkyl or Ar—Calkyl;'}{'sup': '6', 'sub': '1-4', 'Rrepresents hydrogen, halo, or Calkyloxy;'}{'sup': '1', 'Arrepresents phenyl;'}{'sup': '2', 'Arrepresents phenyl or naphthyl.'}3. (canceled)4. A compound according to wherein M represents a C-linker.5. A compound according to wherein L represents a C-linker substituted with a Calkyl claim 1 , wherein said Calkyl is in the S-configuration.6. A compound as claimed in wherein the compound is selected from the group consisting of:3-[(6-Chloro-1,3-benzodioxol-5-yl)methyl]-1-(1-phenylethyl)-2-pyrrolidinone;an N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof.7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and claim 1 , as active ingredient claim 1 , an effective 11β-HSD1 inhibitory amount of a compound as described in .8. A process of preparing a pharmaceutical composition as defined in claim 1 , characterized in that claim 1 , a pharmaceutically acceptable carrier is intimately mixed with an effective 11β-HSD1 inhibitory amount of a compound as described in .9. (canceled)10. A method for treating pathologies associated with excess cortisol formation claim 1 , comprising administering an effective amount of a compound as claimed in .11. The method of claim 10 , wherein the pathology associated with excess cortisol formation is selected from obesity claim 10 , diabetes claim 10 , obesity related cardiovascular ...

COMPOUNDS FOR INHIBITION OF FUNGAL TOXIN PRODUCTION

The invention relates to compounds, compositions, and methods that can inhibit the biosynthesis of mycotoxins. 2. The method of claim 1 , wherein the aryl contains about 6 to about 14 carbons in the ring portions of the aryl.3. The method of claim 1 , wherein the aryl is phenyl.4. The method of claim 1 , wherein the substituents on the aryl are each separately selected from the group consisting of hydroxy; halogen; lower alkyl; lower alkoxy; amino; and thiol.5. The method of claim 1 , wherein the substituents on the aryl are each separately hydroxy or and lower alkoxy.6. The method of claim 1 , wherein m is 2 claim 1 , 3 claim 1 , or 4.7. The method of claim 1 , wherein Z is oxo (═O) claim 1 , hydroxy claim 1 , or amino.8. The method of claim 1 , wherein Z is oxo (═O) claim 1 , and Y is a carbon atom.9. The method of claim 1 , wherein B is an aryl ring.10. The method of claim 1 , wherein B is phenyl.14. The compound of claim 13 , wherein the aryl contains about 6 to about 14 carbons in the ring portions of the aryl.15. The compound of claim 13 , wherein the aryl is phenyl.16. The compound of claim 13 , wherein the substituents on the aryl are each separately selected from the group consisting of hydroxy; halogen; lower alkyl; lower alkoxy; amino; and thiol.17. The compound of claim 13 , wherein the substituents on the aryl are each separately hydroxy or and lower alkoxy.18. The compound of claim 13 , wherein Z is oxo (═O) claim 13 , hydroxy claim 13 , or amino.19. The compound of claim 13 , wherein B is an aryl ring. Mycotoxins are toxins produced by fungi that contaminate grains and nuts. These toxins cause immunosuppressive, carcinogenic, cytotoxic and teratogenic effects in humans and animals who consume the contaminated grains and nuts. Aflatoxin, the most well-known mycotoxin, is produced by several species of the fungus and contaminates corn, tree nuts, cottonseed and peanuts in the southern and western United States. The FDA limits aflatoxin levels in food ...

SUBSTITUTED 3-PHENYLPROPYLAMINE DERIVATIVES FOR THE TREATMENT OF OPHTHALMIC DISEASES AND DISORDERS

The present invention relates generally to compositions and methods for treating neurodegenerative diseases and disorders, particularly ophthalmic diseases and disorders. Provided herein are substituted 3-phenylpropylamine derivative compounds and pharmaceutical compositions comprising said compounds. The subject compositions are useful for treating and preventing ophthalmic diseases and disorders, including age-related macular degeneration (AMD) and Stargardt's Disease. 2. The compound of claim 1 , wherein A is —O—.3. The compound of claim 1 , wherein A is —CH—.4. The compound of claim 1 , wherein Ris OH and Ris H.5. The compound of claim 1 , wherein Rand Rare both hydrogen.6. The compound of claim 1 , wherein Ris hydrogen and Ris C-Calkyl.7. The compound of claim 1 , wherein Ris hydrogen and Ris —C(═O)R.10. A compound claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , selected from the group consisting of:(R)-3-Amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol;3-Amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol;(1R)-3-Amino-1-(3-((tetrahydro-2H-pyran-3-yl)methoxy)phenyl)propan-1-ol;(R)-3-Amino-1-(3-(pyridin-4-ylmethoxy)phenyl)propan-1-ol;(R)-3-Amino-1-(3-(pyridin-3-ylmethoxy)phenyl)propan-1-ol;(R)-3-Amino-1-(3-(pyridin-2-ylmethoxy)phenyl)propan-1-ol;(1R)-3-amino-1-(3-((tetrahydro-2H-thiopyran-3-yl)methoxy)phenyl)propan-1-ol;(R)-3-Amino-1-(3-((tetrahydro-2H-thiopyran-4-yl)methoxy)phenyl)propan-1-ol;(R)-4-((3-(3-Amino-1-hydroxypropyl)phenoxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide;3-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide;(R)-1-(4-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)piperidin-1-yl)ethanone;(R)-3-Amino-1-(3-((6-methylpyridin-2-yl)methoxy)phenyl)propan-1-ol;(1R)-3-Amino-1-(3-((2,3-dihydrobenzofuran-2-yl)methoxy)phenyl)propan-1-ol;(1R)-3-Amino-1-(3-((tetrahydrofuran-2-yl)methoxy)phenyl)propan-1-ol;(R)-3-Amino-1-(3-(piperidin-4-ylmethoxy)phenyl)propan-1-ol;(R)-3-Amino-1-( ...

Method for preparing triacetone amine

An improved method is used for preparing triacetone amine while recycling the by-products. This involves treating the crude product from triacetone amine preparation, which leads to an increase in the content of compounds which react readily with ammonia. This method enables efficient recycling of the by-products formed in the synthesis of triacetone amine. 1. A method for preparing triacetone amine , comprising:(a) reacting acetone and ammonia in the presence of a first catalyst (K1) to give a first crude product (RP1) comprising triacetone amine, acetone, mesityl oxide and at least one by-product selected from the group consisting of diacetone alcohol, diacetone amine, acetonin, phorone and isophorone,(b) at least partially removing, by distillation, the acetone and/or the mesityl oxide from RP1,(c) adding ammonia and, optionally, further acetone, to the acetone and/or the mesityl oxide removed from RP1 in (b), and at least partially reacting the added ammonia with the acetone and/or the mesityl oxide in the presence of a second catalyst (K2) to give triacetone amine, as a result of which a second crude product (RP2) comprising triacetone amine is obtained, and(d) adding water to RP1 before and/or during the removing, by distillation, of the acetone and/or the mesityl oxide from RP1 in (b),wherein at least one of the by-products in RP1 is at least partially reacted with the water, andwherein at least one of the by-products in RP1 is at least partially cleaved into mesityl oxide and/or acetone.2. The method according to claim 1 , wherein claim 1 , in (d) claim 1 ,the water is added to RP1 during the removing, by distillation, of the acetone and/or the mesityl oxide from RP1 in (b),wherein at least one of the by-products in RP is at least partially reacted with the water, andwherein at least one of the by-products in RP1 is at least partially cleaved into mesityl oxide and/or acetone.3. The method according to claim 1 , wherein the at least partially removing claim ...

SUBSTITUTED BENZYLAMINE COMPOUNDS, THEIR USE IN MEDICINE, AND IN PARTICULAR THE TREATMENT OF HEPATITIS C VIRUS (HCV) INFECTION

The invention provides compounds of the formula (6): 2. A compound according to claim 1 , or a salt claim 1 , N-oxide or tautomer thereof claim 1 , wherein A is CH and E is CH.3. A compound according to claim 1 , or a salt claim 1 , N-oxide or tautomer thereof claim 1 , wherein Ris hydrogen.4. A compound according to claim 1 , or a salt claim 1 , N-oxide or tautomer thereof claim 1 , wherein Ris selected from:{'sub': 1-8', '1-8, 'sup': '6', 'an acyclic Chydrocarbon group optionally substituted with one substituent R, wherein one carbon atom of the acyclic Chydrocarbon group may optionally be replaced by a heteroatom O; and'}{'sup': '7a', 'a monocyclic carbocyclic or heterocyclic group of 3, 4, 5 or 6 ring members, of which 0, 1 or 2 are heteroatom ring members selected from O and N, the carbocyclic or heterocyclic group being optionally substituted with one or two substituents R.'}5. A compound according to claim 4 , or a salt claim 4 , N-oxide or tautomer thereof claim 4 , wherein Ris ethyl.6. A compound according to claim 1 , or a salt claim 1 , N-oxide or tautomer thereof claim 1 , wherein Ris selected from hydrogen and a group Rwherein Ris selected from a Calkyl group optionally substituted with a substituent R; cyclohexyl substituted with a substituent R; pyridine optionally substituted with a substituent R; and tetrahydroisoquinoline; wherein the substituent Ris selected from hydroxy; C(═O)NRR; piperidine; pyrrole and imidazole.7. A compound according to claim 6 , or a salt claim 6 , N-oxide or tautomer thereof claim 6 , wherein Ris a group Rwherein Ris a Calkyl group optionally substituted with a substituent R; wherein the substituent Ris selected from hydroxy and C(═O)NRR.8. A compound according to claim 6 , or a salt claim 6 , N-oxide or tautomer thereof claim 6 , wherein Ris hydrogen.9. A compound according to claim 1 , or a salt claim 1 , N-oxide or tautomer thereof claim 1 , wherein Ris fluorine.10. A compound according to claim 1 , or a salt claim 1 , N ...

GLYCOLACTAM COMPOUNDS, PROCESS FOR PREPARATION AND USES THEREOF

The present invention discloses compounds of Formula I, Wherein, R═R═R═R═R═R═R═Rand is selected from H, OBn, OH, CHOH, CHOH, CH; Ris selected front alkyl, substituted alkyl, hydroxyl alkyl, alkenyl, benzyl; process for preparation of N-alkylated glycolactain compounds of Formula I and their use for the synthesis of piperidine alkaloids and their analogues. 19-. (canceled)12. The compound as claimed in claim 10 , wherein said compound is:(4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-1-methylpiperidin-2-one(3a);(4R,5S,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-1-methylpiperidin-2-one(4a);(4R,5S,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-1-ethylpiperidin-2-one(5a);(4R,5S,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-1-ethylpiperidin-2-one(6a);(4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-1-propyl piperidine-2-one(7 a);(4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-1-propylpiperidin-2-one(8a);(4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-1-butylpiperidin-2-one(9a);(4R,5S,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-1-butylpiperidin-2-one(10a);(4R,5R,6R)-1-benzyl-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)piperidin-2-one(11a);(4R,5R,6R)-1-allyl-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)piperidin-2-one(12a);(4R,5S,6R)-1-allyl-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)piperdin-2-one(13a);(4R,5R,6R)-4,5-bis(benzyloxy)-1-(2-(benzyloxy)ethyl)-6-((benzyloxy)methyl)piperidin-2-one(14a);(4R,5S,6R)-4,5-bis(benzyloxy)-1-(2-(benzyloxy)ethyl)-6-((benzyloxy)methyl)piperidin-2-one(15a);(5S,6R)-5-(benzyloxy)-6-((benzyloxy)methyl)-1-methyl-5,6-dihydropyridin-2(1H)-one (16b);(5R,6R)-5-(benzyloxy)-6-((benzyloxy)methyl)-1-methyl-5,6-dihydropyridin-2(1H)-one(17b);(5S,6R)-5-(benzyloxy)-6-((benzyloxy)methyl)-1-ethyl-5,6-dihydropyridin-2(1H)-one(18b);(5R,6R)-5-(benzyloxy)-6-((benzyloxy)methyl)-1-ethyl-5,6-dihydropyridin-2(1H)-one(19b);(5S,6R)-5-(benzyloxy)-6-(benzyloxy)methyl)-1-propyl-5,6-dihydropyridin-2(1H)-one(20b);(5R,6R)-5-(benzyloxy)-6-((benzyloxy)methyl)-1-propyl-5,6 ...

Method for synthesizing cationic bleach activators via a single-bath reaction

The present invention provides a method for synthesizing cationic bleach activators via a single-bath reaction, comprising steps of: separately dissolving 4-chloromethylbenoyl chloride and lactam in its respective solvent, adding an acid-binding agent to the lactam solution, next adding dropwisely 4-chloromethylbenoyl chloride solution into the lactam/acid binding-agent solution, and finally adding tertiary amine to the solution above to make a reaction solution, which is further treated with mixing and refluxing. The washed and dried final product is TBLC cationic bleach activator. The method of the present invention greatly simplifies the synthesizing process and lowers the stringency of reaction conditions for preparing cationic bleach activators (TBLC). At the same time, the present method produces TBLC cationic bleach activators with high yields, making it a suitable option for industrial production of these bleach activators.

BIARYL LIGANDS

Embodiments of the present disclosure provide for biaryl ligands (also referred to herein as “biaryl compound”), biaryl complexes, methods of making biaryl compounds, methods of making single enantiomers of these biaryl compounds, methods of use (e.g., catalysis) and the like. 2. The composition of claim 1 , wherein the A ring is an aryl group claim 1 , each Ris a halogen claim 1 , and each Ris an aryl group.4. The composition of claim 3 , wherein each Ris halogen claim 3 , wherein two of Q1 claim 3 , Q2 claim 3 , Q3 claim 3 , Q4 claim 3 , and Q5 are N claim 3 , wherein X is C claim 3 , and wherein each Ris an aryl group.5. The composition of claim 4 , wherein Q2 and Q5 are N.6. The composition of claim 4 , wherein each Ris a phenyl group.7. The composition of claim 4 , wherein each Ris fluorine.9. The composition of claim 8 , wherein X is C claim 8 , wherein each Ris a phenyl group claim 8 , and wherein each Ris fluorine.14. A method of using a biaryl compound claim 8 , comprising:{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'sup': '3', 'using a biaryl compound selected from as a catalyst in a reaction selected from one of the following: an enantioselective transformation, an enantioselective Acoupling, an alkyne addition asymmetric allylic alkylation, and an addition to a aliphatic or an aromatic aldehyde.'} This application claims priority to U.S. provisional application entitled “BIARYL LIGANDS, METHODS OF MAKING BIARYL LIGANDS, AND METHODS OF USE THEREOF,” having Ser. No. 61/877,505 filed on Sep. 13, 2013, which is entirely incorporated herein by reference.This application claims priority to U.S. provisional application entitled “BIARYL LIGANDS, METHODS OF MAKING BIARYL LIGANDS, AND METHODS OF USE THEREOF,” having Ser. No. 61/881,480 filed on Sep. 24, 2013, which is entirely incorporated herein by reference.The development of new chiral ligands is essential for enantioselective catalysis and continues to be an important area at the forefront of organic ...

CYCLOALKENYL HYDROXAMIC ACID DERIVATIVES AND THEIR USE AS HISTONE DEACETYLASE INHIBITORS

The present invention provides compounds of formula (I): 2. The compound of claim 1 , wherein n is 0 claim 1 , 1 claim 1 , or and t is 0 claim 1 , 1 claim 1 , 2 claim 1 , or 3.315-. (canceled)1741-. (canceled)4347-. (canceled)49. The compound of claim 42 , wherein:{'sup': b', 'c', 'cc, 'one of Ror Ris attached to Rto form a fused ring; or'}{'sup': cc', 'c, 'Ris attached to Rto form a fused ring.'}50. The compound of claim 48 , wherein:{'sup': b', 'c', 'cc, 'one of Ror Ris attached to Rto form a fused ring; or'}{'sup': cc', 'e, 'Ris attached to Rto form a fused ring.'}5175-. (canceled)76. The compound of claim 48 , wherein Rand Rtaken together with the carbon atom to which they are attached form a spirocyclic ring.77151-. (canceled)153175-. (canceled)177187-. (canceled)189. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt claim 1 , solvate claim 1 , tautomer claim 1 , or prodrug thereof; and a pharmaceutical carrier claim 1 , diluent claim 1 , or excipient.190. A method of treating or preventing a disease claim 1 , disorder claim 1 , or condition in a subject comprising administering to the subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt claim 1 , solvate claim 1 , tautomer claim 1 , or prodrug thereof.191. The method of claim 190 , wherein the disease claim 190 , disorder claim 190 , or condition is selected from neurological disorder claim 190 , infectious disease claim 190 , inflammatory disease claim 190 , neoplastic disease claim 190 , autoimmune disease claim 190 , heteroimmune disease claim 190 , metabolic disease claim 190 , and a disease claim 190 , disorder claim 190 , or condition mediated by or linked to T-cell dysregulation.192211-. (canceled)212. A method of synthesizing a compound of claim 1 , or a pharmaceutically acceptable salt claim 1 , solvate claim 1 , tautomer claim 1 , or prodrug thereof.213. A kit containing ...

SUBSTITUTED 3-PHENYLPROPYLAMINE DERIVATIVES FOR THE TREATMENT OF OPHTHALMIC DISEASES AND DISORDERS

The present invention relates generally to compositions and methods for treating neurodegenerative diseases and disorders, particularly ophthalmic diseases and disorders. Provided herein are substituted 3-phenylpropylamine derivative compounds and pharmaceutical compositions comprising said compounds. The subject compositions are useful for treating and preventing ophthalmic diseases and disorders, including age-related macular degeneration (AMD) and Stargardt's Disease. 2. The compound of claim 1 , wherein A is —O—.3. The compound of claim 1 , wherein A is —CH—.4. The compound of claim 1 , wherein Ris OH and Ris H.5. The compound of claim 1 , wherein Rand Rare both hydrogen.6. The compound of claim 1 , wherein Ris hydrogen and Ris C-Calkyl.7. The compound of claim 1 , wherein Ris hydrogen and Ris —C(═O)R.10. A compound claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , selected from the group consisting of:(R)-3-Amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol;3-Amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol;(1R)-3-Amino-1-(3-((tetrahydro-2H-pyran-3-yl)methoxy)phenyl)propan-1-ol;(R)-3-Amino-1-(3-(pyridin-4-ylmethoxy)phenyl)propan-1-ol;(R)-3-Amino-1-(3-(pyridin-3-ylmethoxy)phenyl)propan-1-ol;(R)-3-Amino-1-(3-(pyridin-2-ylmethoxy)phenyl)propan-1-ol;(1R)-3-amino-1-(3-((tetrahydro-2H-thiopyran-3-yl)methoxy)phenyl)propan-1-ol;(R)-3-Amino-1-(3-((tetrahydro-2H-thiopyran-4-yl)methoxy)phenyl)propan-1-ol;(R)-4-((3-(3-Amino-1-hydroxypropyl)phenoxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide;3-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide;(R)-1-(4-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)piperidin-1-yl)ethanone;(R)-3-Amino-1-(3-((6-methylpyridin-2-yl)methoxy)phenyl)propan-1-ol;(1R)-3-Amino-1-(3-((2,3-dihydrobenzofuran-2-yl)methoxy)phenyl)propan-1-ol;(1R)-3-Amino-1-(3-((tetrahydrofuran-2-yl)methoxy)phenyl)propan-1-ol;(R)-3-Amino-1-(3-(piperidin-4-ylmethoxy)phenyl)propan-1-ol;(R)-3-Amino-1-( ...

MANUFACTURE OF 4,5,6,7-TETRAHYDROISOXAZOLO[5,4-C]PYRIDIN-3-OL

The present invention relates to a process for synthesis of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol abbreviated THIP, having the INN name gaboxadol, starting from pyrrolidin-2-one. The process comprises a new direct process to obtain the intermediate dimethyl 5-hydroxy-3,6-dihydropyridine-1,4(2H)-dicarboxylate or the intermediate diethyl 5-hydroxy-3,6-dihydropyridine-1,4(2H)-dicarboxylate. 4. The process according to claim 3 , wherein steps (b) claim 3 , (c) and (d) are carried out in toluene.5. The process according to claim 3 , wherein the base used in step (b) is triethylamine.6. The process according to claim 3 , wherein the compound of formula V is purified by thin-film distillation.7. The process according to claim 3 , wherein the compound of formula V is purified by washing with acidified water or by distillation or by a combination of these two purification strategies.9. The process according to claim 8 , wherein the anhydrous acid is anhydrous methanesulfonic acid.11. The process according to claim 10 , wherein the compound of formula IIb is obtained by a one-pot synthesis.14. The process according to claim 13 , further comprising the step of converting the compound of formula VIII to the compound of formula IX. This application is a divisional of U.S. application Ser. No. 15/559,630, (filed Sep. 19, 2017); which is a § 371 national stage entry of PCT/EP2016/056244 (filed on Mar. 22, 2016); which application claims priority to Danish Patent Application PA 2015 00181 (filed on Mar. 24, 2015), each of which applications is incorporated herein by reference in their entirety.The present invention relates to a process for synthesis of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol abbreviated THIP, having the INN name gaboxadol, starting from pyrrolidin-2-one. The process comprises a new direct process to obtain the intermediate dimethyl 5-hydroxy-3,6-dihydropyridine-1,4(2H)-dicarboxylate or the intermediate diethyl 5-hydroxy-3,6-dihydropyridine-1,4(2H)- ...

Biaryl ligands, methods of making biarlyl ligands, and methods of use thereof

Embodiments of the present disclosure provide for biaryl ligands (also referred to herein as “biaryl compound”), biaryl complexes, methods of making biaryl compounds, methods of making single enantiomers of these biaryl compounds, methods of use (e.g., catalysis), and the like.

Process For Synthesizing Fluorinated Cyclic Aliphatic Compounds

The present invention relates to a novel method for producing fluorinated cycloaliphatic compounds from the analogous aromatic compounds by hydrogenation with an Rh-carbene catalyst system. 1. Method for producing fluorinated cycloaliphatic compounds comprising the step of hydrogenation of an aromatic fluorine-containing precursor substance with a catalyst , comprising at least one rhodium atom and also at least one N-heterocyclic carbene ligand , in the presence of a reducing agent.2. Method according to claim 1 , wherein the N-heterocyclic carbene ligand comprises a compound selected from the group consisting of pyrrolidinylidenes claim 1 , pyrrolidenes claim 1 , imidazolylidenes claim 1 , imidazolidinylidenes claim 1 , piperidinylenes claim 1 , hexahydropyrimidinylenes and triazolylidenes.3. Method according to or claim 1 , wherein the N-heterocyclic carbene ligand comprises a pyrrolidinylidene compound in which claim 1 , in the α position both to the nitrogen and to the carbene claim 1 , there is no hydrogen.5. Method according to one of to claim 1 , wherein the amount of catalyst before the start of the reaction is ≥0.05 mol % to ≤5 mol % (based on the aromatic precursor substance at the start of the reaction).6. Method according to one of to claim 1 , wherein the method is carried out in an organic solvent.7. Method according to one of to claim 1 , wherein the method is carried out at a temperature of ≥0° C.8. Method according to one of to claim 1 , wherein the method is carried out using gaseous hydrogen as reducing agent and the Hpressure (at the start of the reaction) is ≥10 bar.9. Method according to one of to claim 1 , wherein the reaction time is ≥4 h to ≤2 d. The present invention relates to the field of fluorinated cycloaliphatic compounds. Such compounds have an important role in the pharmaceutical or agrochemistry sectors on account of the polarity of the C—F bond with simultaneous steric similarity to C—H bonds and other effects. Furthermore, ...

BIOCATALYSTS AND METHODS FOR THE SYNTHESIS OF SUBSTITUTED LACTAMS

The present disclosure relates to transaminase polypeptides capable of aminating a dicarbonyl substrate, and polynucleotides, vectors, host cells, and methods of making and using the transaminase polypeptides. 1. An engineered transaminase polypeptide comprising an amino acid sequence having at least 80% sequence identity to reference sequence SEQ ID NO:4 and at least an amino acid residue difference as compared to SEQ ID NO:4 at residue position X323.2. The engineered polypeptide of claim 1 , in which X323 is selected from C claim 1 , E claim 1 , N claim 1 , and R.3. The engineered polypeptide of claim 2 , wherein the amino acid sequence further comprises one or more residue differences as compared to SEQ ID NO:4 selected from: X42G; X54P; X54R; X69A; X69G; X69T; X122M; X124F; X124L; X124N; X124R; X126A; X126T; X150S; X152C; X152G; X1521; X152L; X152S; X156A; X156S; X156T; X157L; X165N claim 2 , X192A claim 2 , X193G claim 2 , X192H claim 2 , X192K claim 2 , X192N claim 2 , X193Q claim 2 , X192R claim 2 , and X192S.4. The engineered polypeptide of claim 2 , wherein the amino acid sequence further comprises a combination of residue differences selected from:(a) X124W and X327L;(b) X209M and X300G;(c) X122F, X223V and X284A;(d) XI92A, X215H and X311T;(e) X62N, X124F, X126A and X136L;(f) X124W, X126A, X136L, X192A and X284A; and(g) X124W, X126A, X136L, X152R/X152L/X1521, and X192A.5. The engineered polypeptide of claim 1 , in which the amino acid sequence further comprises at least one or more residue differences as compared to SEQ ID NO:4 selected from: X54A; X54L; X56D; X56E; X61G; X61W; X62A; X62L; X62N; X62S; X64C; X68I; X122F claim 1 , X122W; X122Y; X124K; X124M; X124S; X124W; X126C; X1261; X139E; X140K; X143V; X150L; X155I; X155L; X159G; X160L; X176C; X199L; X199V; X209F; X209M; X209Q; X209V; X223S; X223T; X223V; X227I; X282L claim 1 , X282V; X284A; X284P; X284S; X284T; and X284V.6. An engineered polynucleotide encoding the polypeptide of .7. A vector comprising ...

COMPOSITIONS AND METHODS FOR SELECTIVELY DEPLETING SENESCENT CELLS

The present disclosure provides compositions and methods for selectively killing senescent cells, wherein the composition comprises piperlongumine (PL) or derivative thereof. The selective killing of senescent cells may delay aging and/or treat age-related disorders. 2. The compound of claim 1 , wherein X is selected from the group consisting of C(O) and S(O).3. The compound of claim 1 , wherein Y is O.4. The compound of claim 1 , wherein Ris hydrogen.5. The compound of claim 1 , wherein n is an integer from 0-2.6. The compound of claim 1 , wherein X is selected from the group consisting of C(O) and S(O); Y is O; Ris hydrogen and n is an integer from 0-2.8. The compound of claim 1 , wherein Rand Rare hydrogen.9. The compound of claim 1 , wherein R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , Rare hydrogen.10. The compound of claim 1 , wherein Rand Rare hydrogen and R claim 1 , Rand Rare OR.12. The method of claim 11 , wherein the senescent cells are senescent due to replicative cellular senescence claim 11 , premature cellular senescence claim 11 , or therapy-induced senescence.13. The method of claim 11 , wherein the senescent cells are from an age-related pathology.15. The method of any of claim 14 , wherein the subject has a received DNA-damaging therapy.17. The method of claim 16 , wherein the age-related disease or condition is a degenerative disease or a function-decreasing disorder.19. The method of claim 11 , wherein the composition further comprises at least one inhibitor of one or more anti-apoptotic proteins in the Bcl-2 family.20. The method of claim 19 , wherein the inhibitor is ABT263. This application claims the priority of U.S. provisional application No. 62/027,572, filed Jul. 22, 2014, U.S. provisional application No. 62/087,499, filed Dec. 4, 2014 and U.S. provisional application No. 62/134,155, filed Mar. 17, 2015, each of which is hereby incorporated by reference in its entirety.This invention was made with government ...

ANTI-FOULANT FORMULATION FOR COMPRESSORS

Disclosed are compositions and methods for preventing or reducing polymer formation and polymer deposition in equipment used in petrochemical processes. An antifoulant composition includes a combination of one or more antioxidants; one or more antipolymerants; one or more dispersants; and one or more solvents. A method of preventing or reducing fouling of process equipment used in an industrial process is also described. The method includes introducing into the process equipment an antifoulant composition, the antifoulant composition comprising a combination of one or more antioxidants; one or more antipolymerants; one or more dispersants; and one or more solvents. 1. An antifoulant composition comprising: one or more antipolymerants;', 'one or more dispersants; and', 'one or more solvents., 'a combination of one or more antioxidants;'}2. The composition of claim 1 , wherein the antifoulant composition comprises from about 1 wt % to about 15 wt % antioxidant; about 1 wt % to about 15 wt % antipolymerant; about 50 wt % to about 95 wt % dispersant and about 10 wt % to about 50 wt % solvent.3. The composition of claim 1 , wherein the one or more antioxidants are selected from 1 claim 1 ,4-phenylenediamine claim 1 , alkylated or phenyl derivatives thereof claim 1 , and combinations thereof.4. The composition of claim 1 , wherein the antipolymerant is selected from 2 claim 1 ,2 claim 1 ,6 claim 1 ,6-tetramethylpiperidinyl-1-oxyl claim 1 , 1-hydroxy-2 claim 1 ,2 claim 1 ,6 claim 1 ,6-tetramethylpiperidine claim 1 , 4-hydroxy-2 claim 1 ,2 claim 1 ,6 claim 1 ,6-tetramethylpiperidinyl-1-oxyl claim 1 , 4-oxo-2 claim 1 ,2 claim 1 ,6 claim 1 ,6-tetramethylpiperidinyl-1-oxyl claim 1 ,1 claim 1 ,4-dihydroxy -2 claim 1 ,2 claim 1 ,6 claim 1 ,6-tetramethylpiperidine claim 1 , and 1-hydroxy-4-oxo-2 claim 1 ,2 claim 1 ,6 claim 1 ,6-tetramethylpiperidine claim 1 , or a combination thereof.5. The composition of claim 1 , wherein the dispersant is a blend of two or more fatty acid ...

ONE CLASS OF PYRAZOLONE COMPOUNDS AND USE THEREOF

Provided are a class of pyrazolone compounds and a use thereof. In particular, a compound represented by formula I is provided, wherein the definition of each variable group is as described in the description. The compounds of formula (I) have a direct AMPK-activating activity and can significantly promote the phosphorylation of AMPK and ACC of L6 myocytes and HepG2 cells in a dose-dependent manner. 2. The compound of claim 1 , wherein claim 1 ,{'sub': 1', '2', '2, 'claim-text': [{'sub': 2', '2, 'Ris selected from the group consisting of: H and methyl, or Ris none;'}, {'sub': 3', '3, 'Ris selected from the group consisting of: H, or Ris none;'}, {'sub': '4', 'Ris H or methyl;'}], 'Ris selected from the group consisting of: 6- to 12-membered aryl group or 5-10 membered heteroaryl group in which the hydrogen atoms on the group are optionally substituted with one or more substituents selected from the group consisting of: halogen, trifluoromethyl, C1-C4 alkyl, adamantyl, hydroxyl, amino, nitro, substituted or unsubstituted acetoxy group (AcO), carboxyl, C1-C4 alkoxy, cyano, substituted or unsubstituted phenyl, and —SO—NH;'}{'sub': 5', '2', 'n, 'claim-text': n1, n2, and n3 are 1; and/or', {'sub': 8', '8, 'X is O or NR, wherein Ris H or methyl.'}], 'Ris selected from the group consisting of: C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkylene-C3-C7 cycloalkyl and benzyl, wherein the hydrogen atoms on benzyl can be optionally substituted by one or more substituents selected from the group consisting of: hydroxy, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and C2-C4 alkylene; wherein the hydrogen atoms of two adjacent carbons on phenyl are optionally substituted by “—O—(CH)O—”, wherein n=1, 2 or 3;'}3. The compound of claim 1 , wherein claim 1 ,{'sub': 1', '2', '2, 'claim-text': {'sub': 8', '8, 'X is NR, wherein Ris 14 or methyl.'}, 'Ris aryl or heteroaryl selected from the group consisting of: phenyl and benzothiazolyl; in which the hydrogen atoms on ...

Methylene-cycloalkylacetate derivatives and their use in treatment of neurotropic conditions

Methylene-cycloalkylacetate compounds and derivatives thereof and their use in methods for treatment of neurotropic conditions.

PROCESSES OF MAKING AND CRYSTALLINE FORMS OF A MDM2 INHIBITOR

The present invention provides processes for making 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid as well as intermediates and processes for making the intermediates. Also provided are crystalline forms of the compound and the intermediates. 238.-. (canceled) The present invention provides processes for making 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (“Compound A” herein) as well as intermediates and processes for making the intermediates. Also provided are crystalline forms of the compound and the intermediates.p53 is a tumor suppressor and transcription factor that responds to cellular stress by activating the transcription of numerous genes involved in cell cycle arrest, apoptosis, senescence, and DNA repair. Unlike normal cells, which have infrequent cause for p53 activation, tumor cells are under constant cellular stress from various insults including hypoxia and pro-apoptotic oncogene activation. Thus, there is a strong selective advantage for inactivation of the p53 pathway in tumors, and it has been proposed that eliminating p53 function may be a prerequisite for tumor survival. In support of this notion, three groups of investigators have used mouse models to demonstrate that absence of p53 function is a continuous requirement for the maintenance of established tumors. When the investigators restored p53 function to tumors with inactivated p53, the tumors regressed.p53 is inactivated by mutation and/or loss in 50% of solid tumors and 10% of liquid tumors. Other key members of the p53 pathway are also genetically or epigenetically altered in cancer. MDM2, an oncoprotein, inhibits p53 function, and it is activated by gene amplification at incidence rates that are reported to be as high as 10%. MDM2, in turn, is inhibited by another tumor suppressor, p14ARF. It has ...

COMPOUNDS FOR INHIBITION OF FUNGAL TOXIN PRODUCTION

The invention relates to compounds, compositions, and methods that can inhibit the biosynthesis of mycotoxins. 2. The composition of claim 1 , further comprising a carrier.3. The composition of claim 1 , further comprising alcohol as a carrier or a solvent.4. The composition of claim 1 , further comprising ethanol as a carrier or a solvent.5. The composition of claim 1 , further comprising an emulsifier claim 1 , a dispersing agent claim 1 , thickening agent claim 1 , a surfactant claim 1 , a wetting agent of ionic or non-ionic type or a mixture of such agents6. The composition of claim 1 , wherein the compound(s) of formula IA claim 1 , IB claim 1 , or II are at a concentration of about 0.1 ppm to 500 ppm. This application is a continuation of U.S. application Ser. No. 15/316,647, filed Dec. 6, 2016, which is a U.S. National Stage Application filed under 35 U.S.C. § 371 from International Application No. PCT/US2015/034543, filed on Jun. 5, 2015, and published as WO 2015/188136 on Dec. 10, 2015, which applications claim the benefit of priority to U.S. Provisional Patent Application Ser. No. 62/008,673, filed Jun. 6, 2014, and which applications and publications are incorporated herein by reference in their entireties.Mycotoxins are toxins produced by fungi that contaminate grains and nuts. These toxins cause immunosuppressive, carcinogenic, cytotoxic and teratogenic effects in humans and animals who consume the contaminated grains and nuts. Aflatoxin, the most well-known mycotoxin, is produced by several species of the fungus and contaminates corn, tree nuts, cottonseed and peanuts in the southern and western United States. The FDA limits aflatoxin levels in food and feed to 20 ppb, due to its carcinogenic capabilities. Aflatoxin, together with hepatitis C, is associated with high levels of liver cancer in Southeast Asia. Deoxynivalenol, a mycotoxin common in wheat and barley in the U.S. Midwest, is produced by several species on grain crops, has immunosuppressive ...

A PROCESS FOR SYNTHESIS OF PIPERIDINE ALKALOIDS

The present invention discloses a process for synthesis of piperidine alkaloids selected from fagomine, 4-epi-fagomine and nojirimycin from tri-O-benzyl-D-glucal or tri-O-benzyl-D-galactal.

CYCLIC AMIDINE COMPOUNDS FOR THE TREATMENT OF AUTOIMMUNE DISEASE

The present invention relates to compounds of formula (I), wherein R, Rand Rare as described herein, and their pharmaceutically acceptable salt, enantiomer or diastereomer thereof, and compositions including the compounds and methods of using the compounds as antagonist of TLR7 and/or TLR8 and/or TLR9 in the treatment of autoimmune diseases as well as auto-inflammation diseases.

Novel method for synthesizing key intermediate of apixaban

The invention relates to a method for synthesizing an intermediate of Apixaban comprising reacting a compound of formula I with 5-chloro-valeryl chloride in the presence of inorganic base in an inert solvent to obtain a compound of formula II, with the reaction formula of (A), wherein R is selected from nitro group and the group (B). The method is mild in reaction condition, simple in operation, easy in purification, inexpensive in production cost, environmental-friendly, and suitable for industrial production.

SUBSTITUTED PYRIDAZINES AS SKELETAL MUSCLE MODULATORS

Provided are compounds of Formula I: 2: The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein m is 0.3: The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein m is 1.4: The compound of claim 3 , or a pharmaceutically acceptable salt thereof claim 3 , wherein Rand Rare each hydrogen.517-. (canceled)18: The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris phenyl optionally substituted with 1 claim 1 , 2 claim 1 , 3 claim 1 , 4 or 5 substituents selected from the group consisting of halogen claim 1 , CN claim 1 , oxo claim 1 , OR claim 1 , OC(O)R claim 1 , OC(O)OR claim 1 , OC(O)NRR claim 1 , NRR claim 1 , NRC(O)R claim 1 , NRC(O)OR claim 1 , NRC(O)NRR claim 1 , NRC(O)C(O)NRR claim 1 , NRC(S)R claim 1 , NRC(S)OR claim 1 , NRC(S)NRR claim 1 , NRC(NR)NRR claim 1 , NRS(O)R claim 1 , NRSOR claim 1 , NRSONRR claim 1 , C(O)R claim 1 , C(O)OR claim 1 , C(O)NRR claim 1 , C(S)R claim 1 , C(S)OR claim 1 , C(S)NRR claim 1 , C(NR)NRR claim 1 , SR claim 1 , S(O)R claim 1 , SOR claim 1 , SONRR claim 1 , Calkyl claim 1 , Chaloalkyl claim 1 , Calkenyl claim 1 , Calkynyl claim 1 , Ccycloalkyl claim 1 , Ccycloalkenyl claim 1 , 3-8 membered heterocycloalkyl claim 1 , 3-8 membered heterocycloalkenyl claim 1 , Caryl claim 1 , Caralkyl claim 1 , and 5-10 membered heteroaryl claim 1 , wherein each of the Calkyl claim 1 , Calkenyl claim 1 , Calkynyl claim 1 , Ccycloalkyl claim 1 , Ccycloalkenyl claim 1 , 3-8 membered heterocycloalkyl claim 1 , 3-8 membered heterocycloalkenyl claim 1 , Caryl claim 1 , Caralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 claim 1 , 2 claim 1 , 3 claim 1 , 4 or 5 Rsubstituents.19: The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris 5-10 membered heteroaryl optionally substituted with 1 claim 1 , 2 claim 1 , 3 claim 1 , 4 or 5 substituents selected from the group consisting of halogen ...

PROCESSES OF MAKING AND CRYSTALLINE FORMS OF A MDM2 INHIBITOR

The present invention provides processes for making 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid as well as intermediates and processes for making the intermediates. Also provided are crystalline forms of the compound and the intermediates. 122.-. (canceled)25. The process of wherein the base is sodium tert-butoxide.26. The process of wherein the oxidation is accomplished using RuCland NaIO.2938.-. (canceled) The present invention provides processes for making 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (“Compound A” herein) as well as intermediates and processes for making the intermediates. Also provided are crystalline forms of the compound and the intermediates.p53 is a tumor suppressor and transcription factor that responds to cellular stress by activating the transcription of numerous genes involved in cell cycle arrest, apoptosis, senescence, and DNA repair. Unlike normal cells, which have infrequent cause for p53 activation, tumor cells are under constant cellular stress from various insults including hypoxia and pro-apoptotic oncogene activation. Thus, there is a strong selective advantage for inactivation of the p53 pathway in tumors, and it has been proposed that eliminating p53 function may be a prerequisite for tumor survival. In support of this notion, three groups of investigators have used mouse models to demonstrate that absence of p53 function is a continuous requirement for the maintenance of established tumors. When the investigators restored p53 function to tumors with inactivated p53, the tumors regressed.p53 is inactivated by mutation and/or loss in 50% of solid tumors and 10% of liquid tumors. Other key members of the p53 pathway are also genetically or epigenetically altered in cancer. MDM2, an oncoprotein, inhibits p53 function, and it is activated ...

BIARYL LIGANDS, METHODS OF MAKING BIARYL LIGANDS, AND METHODS OF USE THEREOF

Embodiments of the present disclosure provide for biaryl ligands (also referred to herein as “biaryl compound”), biaryl complexes, methods of making biaryl compounds, methods of making single enantiomers of these biaryl compounds, methods of use (e.g., catalysis), and the like. 5. The composition of claim 4 , wherein the A ring is an aryl group claim 4 , each Ris a halogen claim 4 , and each Ris an aryl group. This application a continuation application of U.S. patent application Ser. No. 15/021,053 entitled “BIARYL LIGANDS, METHODS OF MAKING BIARYL LIGANDS, AND METHODS OF USE THEREOF,” filed on Mar. 10, 2016, which is the 35 U.S.C. § 371 national stage application of PCT Application No. PCT/US2014/055356, filed Sep. 12, 2014. PCT Application No. PCT/US2014/055356 claims priority to U.S. Provisional Patent Application No. 61/877,505 entitled “BIARYL LIGANDS, METHODS OF MAKING BIARYL LIGANDS, AND METHODS OF USE THEREOF,” filed on Sep. 13, 2013, and the PCT Application also claims priority to U.S. Provisional Patent Application No. 61/881,480 entitled “BIARYL LIGANDS, METHODS OF MAKING BIARYL LIGANDS, AND METHODS OF USE THEREOF,” filed on Sep. 24, 2013, all of which are entirely incorporated herein by reference.The development of new chiral ligands is essential for enantioselective catalysis and continues to be an important area at the forefront of organic synthesis. Of particular importance are new ligands that introduce fundamental changes in the chiral backbone and/or unique modes of coordination.Embodiments of the present disclosure provide for biaryl ligands (also referred to herein as “biaryl compound”), biaryl complexes, methods of making biaryl compounds, methods of making single enantiomers of these biaryl compounds, methods of use (e.g., catalysis), and the like.One exemplary composition, among others, includes: a single biaryl enantiomer of the following structure:wherein the A ring is selected from a benzenoid, a 5 or 6-membered heteroaromatic ring, or an ...

SYNTHESIS OF UV ABSORBING COMPOUNDS

A method of synthesis is provided to obtain a range of UV absorbing compounds. The method broadly involves (a) the reduction of a glutarimide or its reaction with a carbon nucleophile; (b) when step (a) is a reduction, exposing the product of step (a) to an acidic environment to form a cyclic amide; (c) reducing the product of step (a) or step (b) to form a corresponding enamine; and subjecting the enamine product of step (c) to an acylation. 2. The method of wherein the compound is a cyclic enaminoketone compound claim 1 , or salt thereof.4. The method of wherein Ris selected from the group consisting of Cto Calkyl claim 3 , Cto Calkenyl claim 3 , Cto Calkynyl claim 3 , Cto Calkanoyl and Cto Ccarbamoyl claim 3 , benzyl claim 3 , benzoyl and phenyl.5. (canceled)6. The method of wherein Ris selected from the group consisting of Cto Calkyl claim 3 , benzyl claim 3 , phenyl claim 3 , heteroaryl and Cto Ccycloalkyl.7. (canceled)8. The method of wherein Rand Rare independently selected from the group consisting of hydrogen claim 3 , hydroxyl claim 3 , Cto Calkyl claim 3 , Cto Calkoxy and Cto Calkanoyl.9. (canceled)10. The method of wherein R claim 3 , Rand Rare independently selected from the group consisting of hydrogen claim 3 , Cto Calkyl claim 3 , Cto Calkanoyl and Cto Calkoxy.11. (canceled)12. The method of wherein the compound of formula I is selected from the group consisting of 1-(1-isobutyl-4 claim 3 ,4-dimethyl-1 claim 3 ,4 claim 3 ,5 claim 3 ,6-tetrahydropyridin-3-yl)propan-1-one claim 3 , 1-(1-tert-butyl-4 claim 3 ,4-dimethyl-1 claim 3 ,4 claim 3 ,5 claim 3 ,6-tetrahydropyridin-3-yl)octan-1-one and acidic salts thereof.13. The method of further comprising the step of forming a hydrochloride acid addition salt of the compound of formula I.14. (canceled)19. (canceled)20. The method of wherein the exposure to an acidic environment in step (b) occurs during work up of the reaction mixture of the reduction reaction of step (a).2124.-. (canceled)25. The method of ...

PROCESSES OF MAKING AND CRYSTALLINE FORMS OF A MDM2 INHIBITOR

The present invention provides processes for making 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid as well as intermediates and processes for making the intermediates. Also provided are crystalline forms of the compound and the intermediates. 15-. (canceled)712-. (canceled)14. The process of claim 14 , wherein the dehydrating conditions are azeotropic distillation with toluene.16. (canceled)17. (canceled)1938-. (canceled)39. The process of claim 18 , wherein the base is sodium tert-butoxide. The present invention provides processes for making 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (“Compound A” herein) as well as intermediates and processes for making the intermediates. Also provided are crystalline forms of the compound and the intermediates.p53 is a tumor suppressor and transcription factor that responds to cellular stress by activating the transcription of numerous genes involved in cell cycle arrest, apoptosis, senescence, and DNA repair. Unlike normal cells, which have infrequent cause for p53 activation, tumor cells are under constant cellular stress from various insults including hypoxia and pro-apoptotic oncogene activation. Thus, there is a strong selective advantage for inactivation of the p53 pathway in tumors, and it has been proposed that eliminating p53 function may be a prerequisite for tumor survival. In support of this notion, three groups of investigators have used mouse models to demonstrate that absence of p53 function is a continuous requirement for the maintenance of established tumors. When the investigators restored p53 function to tumors with inactivated p53, the tumors regressed.p53 is inactivated by mutation and/or loss in 50% of solid tumors and 10% of liquid tumors. Other key members of the p53 pathway are also genetically or epigenetically ...

Process Scheme for the Production of Optimal Quality Distillate for Olefin Production

Systems and processes for hydrotreating, splitting, and extracting a gasoil feed to produce a saturate-rich feedstock for olefin pyrolysis are provided. A gasoil feed is provided to a hydrotreating section to produce an ultralow sulfur distillate (ULSD) stream. The ULSD stream is provided to a splitter section to produce a light distillate stream and a heavy bottom stream. The light distillate stream is provided to an extraction section to produce an aromatic-rich extract phase and a saturate-rich raffinate phase. The raffinate phase is mixed with the heavy bottom stream to produce an olefin pyrolysis feedstock having a reduced BMCI as compared to the gasoil feed stream and the ULSD stream. 1. A system , comprising:a hydrotreating section operable to hydrotreat a gasoil feed with a hydrotreating catalyst in the presence of hydrogen to produce an ultralow sulfur distillate (ULSD) stream comprising less than 10 parts-per-million weight (ppmw) sulfur and less than 10 ppmw nitrogen;a separation section operable to separate the ULSD stream into a light distillate stream and a heavy bottom stream, wherein aromatics in the light distillate stream comprise at least 50% by weight monoaromatics and the aromatics in the heavy bottom stream comprise no more than 15% by weight monoaromatics; andan extraction section operable to extract an extract phase and a raffinate phase from the light distillate stream, the raffinate phase comprising at least 50% by weight saturated hydrocarbons and no more than 15% by weight aromatics.2. The system of claim 1 , wherein the light distillate stream has a true boiling point (TPB) in the range of 140° C. to about 300° C.3. The system of claim 1 , wherein the heavy bottom stream has a true boiling point (TPB) in the range of 300° C. to about 400° C.4. The system of claim 1 , comprising a mixing apparatus operable to mix the raffinate phase with the heavy bottom stream to produce the feedstock for olefin pyrolysis claim 1 , wherein a Bureau of ...

Cytotoxic Actin-Targeting Compounds

A class of compounds useful in pharmaceutical compositions and methods for treating or preventing cancer is described. Analogs of Mycalolide B have been prepared and tested in breast and ovarian cancer cell lines. The compounds show utility for inhibition of survival and proliferation of tumor cells. The compounds have been shown to disrupt actin. 3. A pharmaceutical composition claim 1 , comprising an effective amount of a compound of Formula (1) of .4. The pharmaceutical composition of claim 1 , wherein the compound of Formula (1) comprises compound 4a claim 1 , 4b claim 1 , 4c claim 1 , 4d claim 1 , 4e claim 1 , 4f claim 1 , 4g claim 1 , 4h claim 1 , 11 claim 1 , 12 claim 1 , MA-02-058 claim 1 , MA-02-047 claim 1 , MA-02-044 claim 1 , MA-02-046 of claim 1 , or a pharmaceutically acceptable salt thereof.5. The pharmaceutical composition of claim 3 , further comprising a pharmaceutically acceptable vehicle.6. The pharmaceutical composition of claim 3 , for the treatment and/or mitigation of cancer.7. The pharmaceutical composition of claim 6 , wherein the cancer is metastatic cancer.8. The pharmaceutical composition of claim 7 , wherein the metastatic cancer is breast cancer claim 7 , ovarian cancer claim 7 , lung cancer claim 7 , pancreatic cancer claim 7 , melanoma claim 7 , colorectal cancer claim 7 , kidney cancer claim 7 , cervical cancer claim 7 , testicular cancer claim 7 , or liver cancer.9. The pharmaceutical composition of for suppressing metastatic cancer cell motility claim 7 , survival claim 7 , or both claim 7 , comprising the pharmaceutical composition of claim 7 , and a pharmaceutically acceptable vehicle.10. The pharmaceutical composition of claim 3 , further comprising one or more antineoplastic agent(s).11. The pharmaceutical composition of claim 3 , wherein the pharmaceutical composition further comprises a protein or a glycosaminoglycan.12. The pharmaceutical composition of claim 11 , wherein the protein is an antibody claim 11 , hemoglobin ...

MIXED DISULFIDE CONJUGATES OF THIENOPYRIDINE COMPOUNDS AND USES THEREOF

This invention is in the field of medicinal chemistry. In particular, the invention relates to mixed disulfide conjugates of thienopyridine compounds, and their use as therapeutics for the treatment, amelioration, and prevention of cardiovascular diseases. 126-. (canceled)29. The compound of claim 27 , wherein R3 is Chlorine or Fluorine.33. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable carrier.34. The pharmaceutical composition of claim 33 , wherein said pharmaceutical composition is configured for intravenous administration.35. A method of treating claim 27 , ameliorating claim 27 , or preventing a cardiovascular disease in a patient comprising administering to said patient a therapeutically effective amount of the compound of .36. The method of claim 35 , wherein said administration is selected from the group consisting of oral administration and intravenous administration.37. The method of claim 35 , wherein said cardiovascular disease is selected from the group consisting of coronary artery disease claim 35 , peripheral vascular disease claim 35 , atherothrombosis claim 35 , and cerebrovascular disease.38. The method of claim 35 , wherein said compound reduces aggregation of platelets.39. The method of claim 38 , wherein said reduces aggregation of said platelets occurs through irreversible binding to P2Yreceptors.40. The method of claim 38 , wherein said reduces aggregation of said platelets occurs through blocking ADP receptors.41. The method of claim 38 , wherein said compound is capable of producing active thienopyridine metabolites in the presence of endogenous glutathione without the need for bioactivation by P450s.42. The method of claim 38 , further comprising co-administration of at least one agent selected from the group consisting of a HMG-CoA reductase inhibitor claim 38 , an ACE Inhibitor claim 38 , a Calcium Channel Blocker claim 38 , a Platelet Aggregation Inhibitor claim 38 , a Polyunsaturated Fatty Acid ...

Novel intermediate and polymorphs of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetra hydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide and process thereof

The present invention provides a novel intermediate as well as novel polymorphs of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide compound represented by the following structural formula-1 and processes for their preparation. 120-. (canceled)23. The process according to claim 22 , wherein the solvent is selected from hydrocarbon solvents claim 22 , chloro solvents claim 22 , ester solvents claim 22 , ether solvents claim 22 , alcoholic solvents claim 22 , ketone solvents claim 22 , polar aprotic solvents claim 22 , polar solvents or mixtures thereof claim 22 , preferably polar aprotic solvents.24. The process according to claim 22 , wherein claim 22 , lithium carbonate and alkali metal halide are employed individually in molar proportions ranging from 0.2 to 1 equivalents per one mole of compound of formula-5; the solvent is employed in an amount ranging from 2 to 10 volumes per 1 gm of compound of formula-5; and the temperature ranges from 0° C. to 130° C.28. The process according to claim 27 , wherein claim 27 , the morpholine is employed in molar proportions ranging from 1 to 10 equivalents per one mole of compound of formula-6 the solvent is employed in an amount ranging from 1 to 10 volumes per 1 gm of compound of formula-6; and the temperature is 0° C. to 140° C.30. The process according to claim 29 , wherein claim 29 , the base is employed in molar proportions ranging from 1 to 3 equivalents per one mole of compound of formula-6; the solvent is used in an amount ranging from 2 to 10 volumes per 1 gm of compound of formula-6; and the temperature ranges from 0° C. to 100° C.31. The process according to claim 21 , wherein claim 21 , the compound of formula-1 is prepared by the process comprising:{'b': '2', '(a) preparing the compound of formula-6 according to claim-,'}(b) reacting the compound of formula-6 with morpholine in toluene to provide 1-(4-iodophenyl)-3-morpholino-5,6- ...

ANTI-FOULANT FORMULATION FOR COMPRESSORS

Disclosed are compositions and methods for preventing or reducing polymer formation and polymer deposition in equipment used in petrochemical processes. An antifoulant composition includes a combination of one or more antioxidants; one or more antipolymerants; one or more dispersants; and one or more solvents. A method of preventing or reducing fouling of process equipment used in an industrial process is also described. The method includes introducing into the process equipment an antifoulant composition, the antifoulant composition comprising a combination of one or more antioxidants; one or more antipolymerants; one or more dispersants; and one or more solvents. 1. A method of preventing or reducing fouling of process equipment used in an industrial process comprising: one or more antioxidants;', 'one or more antipolymerants;', 'one or more dispersants; and', 'one or more solvents., 'introducing into the process equipment an antifoulant composition, the antifoulant composition comprising a combination of2. The method of claim 1 , wherein the introducing is upstream of a gas compressor or an inter-cooler in the process.3. The method of claim 1 , wherein the industrial process is an antifoulant process.4. The method of claim 1 , wherein the antifoulant composition comprises from about 1 wt % to about 15 wt % antioxidant; about 1 wt % to about 15 wt % antipolymerant; about 50 wt % to about 95 wt % dispersant and from about 10 wt % to about 50 wt % solvent in the total antifoulant composition.5. The method of claim 1 , wherein the one or more antioxidants are selected from 1 claim 1 ,4-phenylenediamine claim 1 , alkylated or phenyl derivatives thereof claim 1 , and combinations thereof.6. The method of claim 1 , wherein the antipolymerant is selected from 2 claim 1 ,2 claim 1 ,6 claim 1 ,6-tetramethylpiperidinyl-1-oxyl claim 1 , 1-hydroxy-2 claim 1 ,2 claim 1 ,6 claim 1 ,6-tetramethylpiperidine claim 1 , 4-hydroxy-2 claim 1 ,2 claim 1 ,6 claim 1 ,6- ...

N1-Cyclic Amine-N5-Substituted Biguanide Derivatives, Methods of Preparing the Same and Pharmaceutical Composition Comprising the Same

The present invention provides an N1-cyclic amine-N5-substituted biguanide derivative compound represented by Formula 1, a method of preparing the same and a pharmaceutical composition including the biguanide derivative or the pharmaceutically acceptable salt thereof as an active ingredient. The biguanide derivatives have an effect of inhibiting cancer cell proliferation, cancer metastasis and cancer recurrence by activation of AMPK, even when administered in a small dose compared with conventional drugs. 2. The compound of Formula 1 or the pharmaceutically acceptable salt thereof of claim 1 ,{'sub': 1', '2', '4-5', '4-5, 'wherein Rand Rare taken together with nitrogen to which they are attached to form Cheterocycloalkene having 5 to 6 ring atoms or Cheterocycloalkyl having 5 to 6 ring atoms; and'}{'sub': 3', '1-6', '1-2, 'Ris hydrogen; Calkyl; phenyl; or Calkyl substituted with phenyl,'}{'sub': 4-5', '1-6, 'wherein the Cheterocycloalkene is unsubstituted or substituted with Calkyl,'}{'sub': 4-5', '1-6, 'the Cheterocycloalkyl is substituted with 1 to 4 Calkyl groups, and'}{'sub': 1-6', '1-6', '1-6', '1-6, 'the phenyl is unsubstituted or substituted with at least one non-hydrogen substituent selected from the group consisting of halogen, hydroxy, Calkyl, Calkoxy, Chaloalkyl, and Chaloalkoxy.'}3. The compound of Formula 1 or the pharmaceutically acceptable salt thereof of claim 1 ,{'sub': 1', '2', '4-5', '4-5, 'wherein Rand Rare taken together with nitrogen to which they are attached to form Cheterocycloalkene having 5 to 6 ring atoms or Cheterocycloalkyl having 5 to 6 ring atoms; and'}{'sub': 3', '1-6', '1-2, 'Ris hydrogen; Calkyl; phenyl; or Calkyl substituted with phenyl,'}{'sub': 4-5', '1-2, 'wherein the Cheterocycloalkene is unsubstituted or substituted with Calkyl,'}{'sub': 4-5', '1-2, 'the Cheterocycloalkyl is substituted with one or two Calkyl groups, and'}{'sub': 1-2', '1-2', '1-2, 'the phenyl is unsubstituted or substituted with at least one non-hydrogen ...

CYCLOALKENYL HYDROXAMIC ACID DERIVATIVES AND THEIR USE AS HISTONE DEACETYLASE INHIBITORS

The present invention provides compounds of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein W, X, n, s, t, and Ra are as described herein. The present invention relates generally to selective inhibitors of histone deacetylase and to methods of making and using them. 2. The compound of claim 1 , wherein n is 0 claim 1 , 1 claim 1 , or 2 claim 1 , and t is 0 claim 1 , 1 claim 1 , 2 claim 1 , or 3.315-. (canceled)1718-. (canceled)2031-. (canceled)3341-. (canceled)4347-. (canceled)49. The compound of claim 42 , wherein:{'sup': b', 'c', 'cc, 'one of Ror Ris attached to Rto form a fused ring; or'}{'sup': cc', 'e, 'Ris attached to Rto form a fused ring.'}50. The compound of claim 48 , wherein:{'sup': b', 'c', 'cc, 'one of Ror Ris attached to Rto form a fused ring; or'}{'sup': cc', 'e, 'Ris attached to Rto form a fused ring.'}5175-. (canceled)76. The compound of claim 48 , wherein Rand Rtaken together with the carbon atom to which they are attached form a spirocyclic ring.77151-. (canceled)153175-. (canceled)177187-. (canceled)189. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt claim 1 , solvate claim 1 , tautomer claim 1 , or prodrug thereof; and a pharmaceutical carrier claim 1 , diluent claim 1 , or excipient.190. A method of treating or preventing a disease claim 1 , disorder claim 1 , or condition in a subject comprising administering to the subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt claim 1 , solvate claim 1 , tautomer claim 1 , or prodrug thereof.191. The method of claim 190 , wherein the disease claim 190 , disorder claim 190 , or condition is selected from neurological disorder claim 190 , infectious disease claim 190 , inflammatory disease claim 190 , neoplastic disease claim 190 , autoimmune disease claim 190 , heteroimmune disease claim 190 , metabolic disease claim 190 , and a ...

USE OF TETRAHYDROPYRIDINES IN THE TREATMENT OF SODIUM CHANNEL RELATED DISEASE AND DISORDERS

The present invention provides a method of treating one or more sodium channel related diseases or disorders in an individual, including related symptoms. The method comprises administering to the individual a tetrahydropyridine derivative in an amount effective to treat sodium channel related diseases or disorders in individuals. These compounds are generally categorised as Ritalin related compounds. The present invention also provides compounds for use in the treatment of and also for use in the manufacture of a medicament for the treatment of sodium channel related diseases or disorders in an individual. A method is further provided for the preparation and isolation of the derivatives of the compound of the present invention. 2. The method according to claim 1 , wherein the R-bearing group is mono- claim 1 , di- claim 1 , or tri-substituted.3. The method according to claim 1 , wherein the compound is a threo-diastereomer claim 1 , a erythro-diastereomer or a mixture of the threo-diastereomer and the erythro-diastereomer.4. The method according to claim 1 , wherein R is one or more substituents selected from the group consisting of hydrogen claim 1 , halogens claim 1 , substituted or unsubstituted phenyls claim 1 , and adjacent rings which share a side with the R-bearing group.5. The method according to claim 1 , wherein R consists of chlorine substituents at positions 3 and 4.6. The method according claim 1 , wherein R is selected from the group p-bromo claim 1 , p-chloro claim 1 , p-2-naphthyl claim 1 , and p-phenyl.79-. (canceled)12. The method according to claim 6 , wherein the compound comprises mixture of structures (2) and (3).13. The method according to claim 1 , wherein the compound is capable of inhibiting sodium channel conductance.14. The method according to claim 13 , wherein the sodium channels are voltage gated sodium channels.15. The method according to claim 1 , wherein the compound is capable of inhibiting serotonin receptors and reducing the ...

IONIZABLE COMPOUNDS AND COMPOSITIONS AND USES THEREOF

This invention includes ionizable compounds, and compositions and methods of use thereof. The ionizable compounds can be used for making nanoparticle compositions for use in biopharmaceuticals and therapeutics. More particularly, this invention relates to compounds, compositions and methods for providing nanoparticles to encapsulate active agents, such as nucleic acid agents, and to deliver and distribute the active agents to cells, tissues, organs, and subjects. 2. The compound of claim 1 , wherein alkyl is C(1-6)alkyl claim 1 , hydroxyalkyl claim 1 , is hydroxyl[C(1-6)alkyl] claim 1 , and aminoalkyl is amino[C(1-6)alkyl].3. The compound of claim 1 , Rand Rare independently for each occurrence a C(14-18) alkyl group claim 1 , or a C(14-18) alkenyl group.4. The compound of claim 1 , wherein Q is O claim 1 , wherein n claim 1 , m and p are each 1 claim 1 , and q is zero.30. A composition comprising an ionizable compound and a pharmaceutically acceptable carrier.31. The composition of claim 30 , wherein the composition comprises nanoparticles.32. A pharmaceutical composition comprising an ionizable compound claim 30 , an active agent claim 30 , and a pharmaceutically acceptable carrier.33. The composition of claim 32 , wherein the ionizable compound is from 15 mol % to 40 mol % of the lipids of the composition.34. The composition of claim 32 , wherein the composition comprises nanoparticles.35. The composition of claim 32 , wherein the active agent is one or more RNAi molecules.36. The composition of claim 32 , wherein the active agent is one or more RNAi molecules selected from small interfering RNAs (siRNA) claim 32 , double stranded RNAs (ddRNA) that are Dicer substrates claim 32 , microRNAs (miRNA) claim 32 , short hairpin RNAs (shRNA) claim 32 , DNA-directed RNAs (ddRNA) claim 32 , Piwi-interacting RNAs (piRNA) claim 32 , repeat associated siRNAs (rasiRNA) claim 32 , and modified forms thereof.37. A composition for use in distributing an active agent for treating ...

Process Scheme for the Production of Optimal Quality Distillate for Olefin Production

Systems and processes for hydrotreating, splitting, and extracting a gasoil feed to produce a saturate-rich feedstock for olefin pyrolysis are provided. A gasoil feed is provided to a hydrotreating section to produce an ultralow sulfur distillate (ULSD) stream. The ULSD stream is provided to a splitter section to produce a light distillate stream and a heavy bottom stream. The light distillate stream is provided to an extraction section to produce an aromatic-rich extract phase and a saturate-rich raffinate phase. The raffinate phase is mixed with the heavy bottom stream to produce an olefin pyrolysis feedstock having a reduced BMCI as compared to the gasoil feed stream and the ULSD stream.

PROCESS FOR PREPARING INTERMEDIATE OF ANTI-TUMOR DRUG NIRAPARIB AND INTERMEDIATE THEREOF

Disclosed is a process for preparing an intermediate of anti-tumor drug niraparib and an intermediate thereof. The present invention discloses a process for preparing compound f, which comprises conducting a cyclization reaction of compound e in a solvent and in the presence of a base to give compound f. The process of the present invention does not involve the steps of catalytic reduction or catalytic coupling reaction of precious metals and chiral separation, which has advantages such as low equipment requirements, simple operation, favorable industrial production, avoiding waste liquid containing heavy metals and phosphorus, low cost and high product ee value. 7. The process for preparing compound f as defined in claim 6 , wherein claim 6 , further comprising a recrystallization treatment after completion of the cyclization reaction; the solvent for recrystallization is an ethers solvent claim 6 , a nitriles solvent claim 6 , an esters solvent claim 6 , a mixed solvent of an ethers solvent and an alkanes solvent claim 6 , a mixed solvent of a nitriles solvent and an alkanes solvent claim 6 , or a mixed solvent of an esters solvent and an alkanes solvent.9. The process for preparing compound f as defined in claim 8 , wherein claim 8 , in the process for preparing compound e claim 8 , the solvent is a haloalkanes solvent and/or an esters solvent claim 8 , preferably dichloromethane and/or isopropyl acetateand/or, the condensing agent is N,N′-carbonyldiimidazole or 2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate.10. The process for preparing compound f as defined in claim 8 , wherein claim 8 , the process for preparing compound e comprises mixing a mixed solution of the acidic salt of compound c or compound c claim 8 , compound d and the solvent claim 8 , and a mixed solution of the condensing agent and the solvent at −5 to 5° C. to conduct the reaction claim 8 , preferably claim 8 , the mixed solution of the condensing agent and the ...

Process for the polymerization of unsaturated polyalkylpiperidines.

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1,230,319. 4 - Carboxy - 2 - piperidone and its esters. ALLIED CHEMICAL CORP. 28 Nov., 1969 [26 Feb., 1969], No. 58424/69. Heading C2C. [Also in Division C3] The invention comprises 4 - carboxy - 2 - piperidone. The acid and its esters may be prepared by reacting a dialkyl ester of itaconic acid with hydrogen cyanide at -40‹ to +50‹ C. to give the dialkyl ester of cyanomethyl succinic acid which is catalytically cyclohydrogenated to give a 4 - alkoxycarbonyl - 2 - piperidone and optionally converting this to the free acid by saponification and acidification.

Procede de polymerisation de polyalkylpiperidines insaturees, polymeres ainsi obtenus et composes insatures de cette classe, composition les contenant et leur utilisation comme stabilisants

L'invention concerne un procédé pour polymériser des amines à empêchement stérique éthyléniquement insaturées du type polyalkylpipéridine, éventuellement avec d'autres monomères insaturés.Le procédé comporte l'utilisation d'un catalyseur du type métallocène. L'invention concerne également les polymères et copolymères ainsi obtenus, ainsi que certaines polyalkylpipéridines insaturées monomères. Ces composés monomères ou polymères peuvent être utilisés pour stabiliser une matière organique, notamment un polymère synthétique tel qu'un polymère thermoplastique, contre les effets nuisibles de l'oxygène, de la chaleur et/ ou de la lumière actinique, et l'invention concerne donc aussi une composition comprenant une matière organique et un ou plusieurs de ces composés comme stabilisants.Domaine d'application : Stabilisation des matières organiques.

Procedimiento para polimerizar polialquilpiperidinas insaturadas.

Procedimiento para polimerizar polialquilpiperidinas insaturadas. Se describe un proceso de polimerización de aminas insaturadas e impedidas estéricamente del tipo de las polialquilpiperidinas (HALS) con intervención de un catalizador metaloceno, nuevos polímeros resultantes de dicho proceso y nuevas HALS insaturadas. Los nuevos compuestos monoméricos o copolímeros pueden emplearse con ventaja para la estabilización de materiales orgánicos contra el deterioro provocado por la luz, el oxígeno y/o el calor.

Pyrrolidonyl acrylate block polymers

Pyrrolidonyl acrylate block polymers having formula (I), wherein n has a value of 1 to 3; X and X' are dissimilar and each is hydrogen or methyl; y and z each have a value of from 1 to 40, except that at least one of y and z is greater than 1 and R is hydrogen or methyl; preparation of said polymers and uses of said polymers.

POLYALIPIPIPERIDINE POLYMERIZATION PROCEDURE

The method of obtaining-substituted esters of 1,2,3,6-tetrahydro-4-pyridylmethylcarboxylic acid

Methods and compositions for using non-ionic contrast agents to reduce the risk of clot formation in diagnostic procedures

In accordance with the present invention a novel method and composition for using nonionic contrast media to reduce the risk of clot formation in a diagnostic procedure is disclosed. Novel compositions for such method are also disclosed. The present method comprises employing a triiodinated phenyl contrast agent having a heterocyclic group or a dimeric triiodinated phenyl contrast agent having one or more heterocyclic groups.

Process for polymerizing unsaturated polyalkypiperidines

3-aminopyperidine derivatives and methods for production thereof

FIELD: organic chemistry. SUBSTANCE: invention relates to improved method for production of 3-aminopyperidine derivatives of formula Ib useful in production of protein kinases, wherein R 1 is C 1 -C 6 -alkyl; R 2 is hydrogen, C 1 -C 6 -alkyl; R 3 is hydrogen, C 1 -C 6 -alkyl; R 13 is phenyl; n = 1-4. Said method includes reduction of compound of formula II, , wherein R 14 is C 1 -C 6 -alkyl with reducing agent. EFFECT: improved method for production of 3-aminopyperidine derivatives. 7 cl, 3 dwg, 2 ex ÐÎÑÑÈÉÑÊÀß ÔÅÄÅÐÀÖÈß RU (19) (11) 2 309 147 (13) C2 (51) ÌÏÊ C07D 211/56 (2006.01) ÔÅÄÅÐÀËÜÍÀß ÑËÓÆÁÀ ÏÎ ÈÍÒÅËËÅÊÒÓÀËÜÍÎÉ ÑÎÁÑÒÂÅÍÍÎÑÒÈ, ÏÀÒÅÍÒÀÌ È ÒÎÂÀÐÍÛÌ ÇÍÀÊÀÌ (12) ÎÏÈÑÀÍÈÅ ÈÇÎÁÐÅÒÅÍÈß Ê ÏÀÒÅÍÒÓ (21), (22) Çà âêà: 2005115500/04, 10.11.2003 (72) Àâòîð(û): ÐÈÏÈÍ Äýâèä Ãàðîëüä Áðàóí (US) (24) Äàòà íà÷àëà îòñ÷åòà ñðîêà äåéñòâè ïàòåíòà: 10.11.2003 (73) Ïàòåíòîîáëàäàòåëü(è): ÏÔÀÉÇÅÐ ÏÐÎÄÀÊÒÑ ÈÍÊ. (US) R U (30) Êîíâåíöèîííûé ïðèîðèòåò: 21.11.2002 US 60/428,324 (43) Äàòà ïóáëèêàöèè çà âêè: 20.01.2006 (45) Îïóáëèêîâàíî: 27.10.2007 Áþë. ¹ 30 2 3 0 9 1 4 7 2 3 0 9 1 4 7 R U (85) Äàòà ïåðåâîäà çà âêè PCT íà íàöèîíàëüíóþ ôàçó: 20.05.2005 C 2 C 2 (56) Ñïèñîê äîêóìåíòîâ, öèòèðîâàííûõ â îò÷åòå î ïîèñêå: US 5559128 À, 24.09.1996. ÅÐ 0111864 À, 27.06.1984. WO 99/00368 À1, 02.01.1999. Duhamel et al. Synthesis of Bicyclic Azaenones via a Lewis Acid Catalysed Michaeltype Addition with Silyl Enol Ethers bearing a Nitrogen Atom. Tetrahedron. Letters. Vol. 34, No. 24, pp.3863-3866, 1993. WO 01/81347 À, 01.11.2001. JP 2002201192 À, 16.07.2002. RU 2105001 C1, 20.02.1998. (86) Çà âêà PCT: IB 03/05151 (10.11.2003) (87) Ïóáëèêàöè PCT: WO 2004/046112 (06.06.2004) Àäðåñ äë ïåðåïèñêè: 129010, Ìîñêâà, óë. Á.Ñïàññêà , 25, ñòð.3, ÎÎÎ "Þðèäè÷åñêà ôèðìà Ãîðîäèññêèé è Ïàðòíåðû", ïàò.ïîâ. Å.Å.Íàçèíîé, ðåã. ¹ 517 (54) ÏÐÎÈÇÂÎÄÍÛÅ 3-ÀÌÈÍÎÏÈÏÅÐÈÄÈÍÀ È ÑÏÎÑÎÁÛ ÈÕ ÏÎËÓ×ÅÍÈß (57) Ðåôåðàò: Èçîáðåòåíèå îòíîñèòñ ê óñîâåðøåíñòâîâàííîìó ñïîñîáó ïîëó÷åíè ïðîèçâîäíûõ 3-àìèíîïèïåðèäèíà - ñîåäèíåíèé ôîðìóëû (Ib), ...

3-aminopyperidine derivatives and methods for production thereof

FIELD: organic chemistry. SUBSTANCE: invention relates to improved method for production of 3-aminopyperidine derivatives of formula Ib useful in production of protein kinases, wherein R 1 is C 1 -C 6 -alkyl; R 2 is hydrogen, C 1 -C 6 -alkyl; R 3 is hydrogen, C 1 -C 6 -alkyl; R 13 is phenyl; n = 1-4. Said method includes reduction of compound of formula II, , wherein R 14 is C 1 -C 6 -alkyl with reducing agent. EFFECT: improved method for production of 3-aminopyperidine derivatives. 7 cl, 3 dwg, 2 ex ÐÎÑÑÈÉÑÊÀß ÔÅÄÅÐÀÖÈß RU (19) (11) 2 309 147 (13) C9 (51) ÌÏÊ C07D 211/56 (2006.01) ÔÅÄÅÐÀËÜÍÀß ÑËÓÆÁÀ ÏÎ ÈÍÒÅËËÅÊÒÓÀËÜÍÎÉ ÑÎÁÑÒÂÅÍÍÎÑÒÈ, ÏÀÒÅÍÒÀÌ È ÒÎÂÀÐÍÛÌ ÇÍÀÊÀÌ (12) ÑÊÎÐÐÅÊÒÈÐÎÂÀÍÍÎÅ ÎÏÈÑÀÍÈÅ ÈÇÎÁÐÅÒÅÍÈß Ê ÏÀÒÅÍÒÓ Ïðèìå÷àíèå: áèáëèîãðàôè îòðàæàåò ñîñòî íèå ïðè ïåðåèçäàíèè (21), (22) Çà âêà: 2005115500/04, 10.11.2003 (72) Àâòîð(û): ÐÈÏÈÍ Äýâèä Ãàðîëüä Áðàóí (US) (24) Äàòà íà÷àëà îòñ÷åòà ñðîêà äåéñòâè ïàòåíòà: 10.11.2003 (73) Ïàòåíòîîáëàäàòåëü(è): ÏÔÀÉÇÅÐ ÏÐÎÄÀÊÒÑ ÈÍÊ. (US) R U (30) Êîíâåíöèîííûé ïðèîðèòåò: 21.11.2002 US 60/428,324 (43) Äàòà ïóáëèêàöèè çà âêè: 20.01.2006 Îïóáëèêîâàíî íà CD-ROM: MIMOSA RBI 2007/30D 2 3 0 9 1 4 7 (45) Îïóáëèêîâàíî: 27.10.2007 RBI200730D (15) Èíôîðìàöè î êîððåêöèè: Âåðñè êîððåêöèè ¹ 1 (W1 C2) 2 3 0 9 1 4 7 R U (56) Ñïèñîê äîêóìåíòîâ, öèòèðîâàííûõ â îò÷åòå î ïîèñêå: US 5559128 À, 24.09.1996. ÅÐ 0111864 À, 27.06.1984. WO 99/00368 À1, 02.01.1999. Duhamel et al. Synthesis of Bicyclic Azaenones via a Lewis Acid Catalysed Michaeltype Addition with Silyl Enol Ethers bearing a Nitrogen Atom. Tetrahedron. Letters. Vol. 34, No. 24, pp.3863-3866, 1993. WO 01/81347 À, 01.11.2001. JP 2002201192 À, 16.07.2002. RU 2105001 C1, 20.02.1998. C 9 C 9 (48) Êîððåêöè îïóáëèêîâàíà: 20.03.2008 Áþë. ¹ 8/2008 (85) Äàòà ïåðåâîäà çà âêè PCT íà íàöèîíàëüíóþ ôàçó: 20.05.2005 (86) Çà âêà PCT: IB 03/05151 (10.11.2003) (87) Ïóáëèêàöè PCT: WO 2004/046112 (06.06.2004) Àäðåñ äë ïåðåïèñêè: 129010, Ìîñêâà, óë. Á.Ñïàññêà , 25, ñòð.3, ÎÎÎ "Þðèäè÷åñêà ôèðìà Ãîðîäèññêèé è ...

Method of producing vincubine

Triacetonamine hydrochloride is provided as a compound for use as a cytostatic agent and the invention provides pharmaceutical compositions containing triacetonamine hydrochloride together with a pharmaceutically acceptable carrier or diluent therefor. The invention also provides a method for the preparation of triacetonamine hydrochloride by forming a mixture of acetone, ammonia and a dehydrating agent; allowing the mixture to stand for 3-7 days and separating off the upper layer from the reaction mixture and removing excess solvent therefrom by distillation; successively acidifying and basifying the residue, optionally with an intermediate filtration step; taking the triacetonamine so formed up in an apolar organic solvent and then drying and removing the solvent by distillation; dissolving the resulting triacetonamine in acetone and contacting it with hydrogen chloride to form the hydrochloride which may be separated out by cooling the acetone solution and further purified by recrystallization from acetone.

Intermediates for optically active derivatives of piperidine and method for production thereof

FIELD: organic chemistry. SUBSTANCE: invention relates to the field of organic chemistry, namely to a method for producing a compound by the formula IV, including the following stages: stage 1 of producing a compound by the formula II by combining a compound by the formula I with a compound by the formula V-1 or V-2; stage 2 of producing a compound by the formula III by reacting a compound by the formula II with a base; and stage 3 of producing a compound by the formula IV by reacting a compound by the formula III with di-tert-butyl dicarbonate. The invention also relates to an intermediate compound by the formula II and to a method for producing compounds by the formula II and formula III. EFFECT: development of a method for producing a highly pure optically active compound by the formula IV used as an intermediate in the pharmaceutical and chemical industries, allowing to produce said compound industrially with high yield by using commercially available reagents and solvents. 14 cl, 8 ex РОССИЙСКАЯ ФЕДЕРАЦИЯ (19) RU (11) (13) 2 752 477 C1 (51) МПК C07D 211/74 (2006.01) A61K 31/45 (2006.01) ФЕДЕРАЛЬНАЯ СЛУЖБА ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ (12) ОПИСАНИЕ ИЗОБРЕТЕНИЯ К ПАТЕНТУ (52) СПК C07D 211/74 (2021.05); A61K 31/45 (2021.05) (21)(22) Заявка: 2020122729, 07.12.2018 (24) Дата начала отсчета срока действия патента: Дата регистрации: 28.07.2021 11.12.2017 KR 10-2017-0169227 (73) Патентообладатель(и): ХК ИННО.Н КОРПОРЕЙШН (KR) (45) Опубликовано: 28.07.2021 Бюл. № 22 (56) Список документов, цитированных в отчете о поиске: WO 2013021052 A1, 14.02.2013. WO 2011159852 A1, 22.12.2011. WO 2013116491 A1, 08.08.2013. SU 606310 A1, 23.05.1984. (85) Дата начала рассмотрения заявки PCT на национальной фазе: 13.07.2020 (86) Заявка PCT: 2 7 5 2 4 7 7 R U (87) Публикация заявки PCT: WO 2019/117550 (20.06.2019) C 1 C 1 KR 2018/015559 (07.12.2018) 2 7 5 2 4 7 7 Приоритет(ы): (30) Конвенционный приоритет: R U 07.12.2018 (72) Автор(ы): КВОН Дже Хон (KR), КИМ Ын Сон (KR), ЛИ Хёк У ( ...

PROCEDURE FOR THE PREPARATION OF 4-ARIL-3-HYDROXIMETHYLPIPERIDINS.

UN PROCEDIMIENTO DE PRODUCCION DE UN PIPERIDINCARBINOL REPRESENTADO POR LA FORMULA GENERAL (2) QUE CONSISTE EN REDUCIR EL ISOMERO TRANS DE UN COMPUESTO REPRESENTADO POR LA FORMULA GENERAL (1): DONDE R{SUP,1} ES UN ATOMO DE HIDROGENO, UN GRUPO ALQUILO INFERIOR O UN GRUPO ARALQUILO, R{SUP,2} ES UN ATOMO DE HIDROGENO, UN GRUPO ALQUILO INFERIOR, UN GRUPO ARILO O UN GRUPO ARALQUILO, Y X ES UN ATOMO DE HIDROGENO, UN ATOMO DE HALOGENO, UN GRUPO ALQUILO, ARILO, ARALQUILO, ALCOXI, DIALQUILAMINO, ALQUILTIO, ARILTIO O C{SUB,M}F{SUB,2M+1 }, DONDE M ES UN ENTERO COMPRENDIDO ENTRE 1 Y 20. A PROCEDURE FOR THE PRODUCTION OF A PIPERIDINCARBINOL REPRESENTED BY THE GENERAL FORMULA (2) THAT CONSISTS IN REDUCING THE TRANS ISOMERO OF A COMPOSITE REPRESENTED BY THE GENERAL FORMULA (1): WHERE R {SUP, 1} IS A HYDROGEN ATOM, A RENTED GROUP BOTTOM OR AN ARALQUILO GROUP, R {SUP, 2} IS A HYDROGEN ATOM, A LOWER RENT GROUP, AN ARILO GROUP OR AN ARALQUILO GROUP, YX IS A HYDROGEN ATOM, A HALOGEN ATOM, A RENT GROUP, AQUIL , ALCOXI, DIALQUILAMINO, ALQUILTIO, ARILTIO OC {SUB, M} F {SUB, 2M + 1}, WHERE M IS A WHOLE UNDERSTANDED BETWEEN 1 AND 20.

Method of producing 5r-[(benzyloxy)amino]piperidine-2s-carboxylic acid or derivative thereof

FIELD: chemistry. SUBSTANCE: present application relates to methods of producing 5R-[(benzyloxy)amino]piperidine-2S-carboxylic acid or derivatives thereof environmentally friendly. Method employs L-glutamic acid as a starting material, wherein it is first subjected to esterification reaction in the presence of an acid reagent, and then sequentially reacting with 2-halogenoacetate and a means for introducing a protective group for an N atom or with a means of introducing a protective group for an N atom and 2-haloacetate under basic conditions to obtain compound IV; then obtained compound IV is subjected to intramolecular condensation to form a ring under the action of a strong base to obtain a protective-group-for-atom-piperidin-5-one-2S-carboxylate (V). Obtained compound V is used to obtain 5R-[(benzyloxy)amino]piperidine-2S-carboxylic acid (or its ester) via one of the following paths. Path 1: compound V is subjected to removal of a protective group, condensation with benzyloxyamine hydrochloride, reduction of imine-chiral separation, neutralization and hydrolysis; path 2: compound V is subjected to hydrolysis, removal of the protective group, condensation with benzyloxyamine hydrochloride, reduction of imine-chiral separation and neutralization; path 3: compound V is condensed with benzyloxy amine hydrochloride, reduced imine-chiral separation, deprotection, neutralization and hydrolysis. EFFECT: all said paths can be realized using a "single-reactor" method. 19 cl, 2 dwg, 26 ex РОССИЙСКАЯ ФЕДЕРАЦИЯ (19) RU (11) (13) 2 730 006 C1 (51) МПК C07D 211/02 (2006.01) C07D 211/60 (2006.01) C07D 211/68 (2006.01) C07B 57/00 (2006.01) C07D 211/78 (2006.01) C07D 471/08 (2006.01) ФЕДЕРАЛЬНАЯ СЛУЖБА ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ (12) ОПИСАНИЕ ИЗОБРЕТЕНИЯ К ПАТЕНТУ (52) СПК C07D 211/02 (2020.02); C07D 211/60 (2020.02); C07D 211/68 (2020.02); C07B 57/00 (2020.02); C07D 211/78 (2020.02); C07D 471/08 (2020.02) (21)(22) Заявка: 2019121138, 06.03.2018 06.03.2018 Дата ...