- 4-SUBSTITUTED PYRANO[3,4,B]PYRAZINE KAPPA AGONISTS FOR TREATING DRUG DEPENDENCY
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1-Phenylacetyl-8-aminohexahydro-2H-pyrano[3,4-b]pyrazines of formula I are disclosed. The compounds are kappa ligands and are useful to treat drug dependency.
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Paragraph 045; 047
(2020/12/29)
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- THERAPEUTICALLY ACTIVE BICYCLIC-SULPHONAMIDES AND PHARMACEUTICAL COMPOSITIONS
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Pharmaceutical compounds have a bicyclic-sulphonamide structure and pharmaceutical compositions including the compounds may be used in therapy as brain-cell-death protectants and may be used, for example, in the treatment of chronic neurodegenerative diseases. The compounds are active as inhibitors of N-acylethanolamine-hydrolysing acid amidase (NAAA) and may be used for the therapeutic treatment and prevention of pain and inflammatory disorders and other disorders which benefit from the modulation of fatty acid ethanolamides, particularly palmitoylethanolamide (PEA).
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Paragraph 0082
(2019/05/18)
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- FXR receptor agonist
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The present invention discloses an FXR receptor agonist, belongs to the technical field of medicine, and particularly relates to a compound represented by a formula (I), a pharmaceutically acceptablesalt, an ester or a stereoisomer thereof, wherein R, R, R, M, L, L1, W, A , B, Q, m and n are defined in the specification. The present invention further relates to a preparation method of the compound, a pharmaceutical preparation, and applications in preparation of drugs for treatment and/or prevention of nonalcoholic fatty liver disease, primary biliary cirrhosis, lipid metabolism disorder, diabetic complication, malignant tumors and other related diseases mediated by FXR receptors. The formula I is defined in the specification.
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Paragraph 0324; 0326; 0327; 0328
(2019/02/10)
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- PYRANO[3,4-B]PYRAZINE KAPPA OPIOID RECEPTOR LIGANDS FOR TREATING ADDICTION, PRURITUS, PAIN, AND INFLAMMATION
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l-Phenylacetyl-8-aminohexahydro-2H-pyrano[3,4-b]pyrazines of formula Formula (I) are disclosed. The compounds are kappa ligands and are useful to treat drug dependency, pruritus, pain, and inflammation.
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Paragraph 059
(2019/06/23)
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- SUBSTITUTED BRIDGED DIAZEPANE DERIVATIVES AND USE THEREOF
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The present application relates to novel imidazopyridinyl-or imidazopyrimidinyl-substituted, bridged 1,4-diazepane derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of respiratory disorders including, sleep-related respiratory disorders such as obstructive sleep apnoeas and central sleep apnoeas and snoring.
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Page/Page column 64
(2019/01/07)
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- Discovery of the oxazabicyclo[3.3.1]nonane derivatives as potent and orally active GPR119 agonists
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The design and synthesis of two conformationally restricted oxazabicyclo octane derivatives as GRP119 agonists is described. Derivatives of scaffold C, with syn configuration, have the best overall profiles with respect to solubility and in vivo efficacy. Compound 25a was found to have extremely potent agonistic activity and was orally active in lowering blood glucose levels in a mouse oral glucose tolerance test at a dose of 0.1 mg/kg.
- Dai, Xing,Stamford, Andrew,Liu, Hong,Neustadt, Bernard,Hao, Jingsong,Kowalski, Tim,Hawes, Brian,Xu, Xiaoying,Baker, Hana,O'Neill, Kim,Woods, Morgan,Tang, Huadong,Greenlee, William
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p. 5291 - 5294
(2015/11/09)
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- 9H-Carbazole-1-carboxamides as potent and selective JAK2 inhibitors
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The discovery, synthesis, and characterization of 9H-carbazole-1-carboxamides as potent and selective ATP-competitive inhibitors of Janus kinase 2 (JAK2) are discussed. Optimization for JAK family selectivity led to compounds 14 and 21, with greater than 45-fold selectivity for JAK2 over all other members of the JAK kinase family.
- Zimmermann, Kurt,Sang, Xiaopeng,Mastalerz, Harold A.,Johnson, Walter L.,Zhang, Guifen,Liu, Qingjie,Batt, Douglas,Lombardo, Louis J.,Vyas, Dinesh,Trainor, George L.,Tokarski, John S.,Lorenzi, Matthew V.,You, Dan,Gottardis, Marco M.,Lippy, Jonathan,Khan, Javed,Sack, John S.,Purandare, Ashok V.
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p. 2809 - 2812
(2015/06/08)
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- USE OF ISOQUINOLONES FOR PREPARING DRUGS, NOVEL ISOQUINOLONES AND METHOD FOR SYNTHESISING SAME
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The use of isoquinolones for preparing drugs, including novel isoquinolones as well as their synthesis method. In particular, isoquinolone derivatives used in the treatment of pathological angiogenesis, and more particularly of cancer.
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Paragraph 0611; 0612
(2013/04/24)
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- METHODS AND INTERMEDIATES FOR PREPARING PHARMACEUTICAL AGENTS
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Methods and intermediates useful for preparing a compound of formula I and salts thereof.
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Page/Page column 61; 62
(2013/08/15)
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- Iron-mediated and -catalyzed metalative cyclization of electron- withdrawing-group-substituted alkynes and alkenes with grignard reagents
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Treatment of ethyl (E)-5,5-bis[(benzyloxy)methyl]-8-(N,N-diethylcarbamoyl)- 2-octen-7-ynoate with an iron reagent generated from FeCl2 and tBuMgCl in a ratio of 1:4 (abbreviated as FeCl2/4 tBuMgCl) afforded ethyl [4,4-bis[(benzyloxy)methyl]-2-[(E)-(N,N-diethylcarbamoyl)methylene] cyclopent-1-yl]acetate in good yield. Deuteriolysis of an identical reaction mixture afforded the bis-deuterated product ethyl [4,4-bis[(benzyloxy)methyl]-2- [(E)-(N,N-diethylcarbamoyl)deuteriomethylene]cyclopent-1-yl]deuterioacetate, thus confirming the existence of the corresponding dimetalated intermediate. The latter intermediate can react with halogens or aldehydes to facilitate further synthetic transformations. The amount of FeCl2 was reduced to catalytic levels (10 mol% relative to enyne), and catalytic cyclizations of this sort proceeded with yields comparable to those of the aforementioned stoichiometric reactions. The cyclization of diethyl (E,E)-2,7-nonadienedioate with a stoichiometric amount of FeCl2/4 tBuMgCl, followed by the addition of sBuOH as a proton source, afforded a mixture of 2-(ethoxycarbonyl)- 3-bicyclo[3.3.0]octanone and its enol form in good yield. The use of aldehyde or ketone in place of sBuOH afforded 2-(ethoxycarbonyl)-3-bicyclo[3.3.0]octanone, which has an additional hydroxyalkyl side chain. Additionally, the metalation of a carbon-carbon unsaturated bond in N,N-diethyl-5,5-bis[(benzyloxy)methyl]-7,8- epoxy-2-octynamide or (E)-3,3-dimethyl-6-(N,N-diethylcarbamoyl)-5-hexenyl p-toluenesulfonate with FeCl2/4 tBuMgCl or FeCl2/4 PhMgBr was followed by an intramolecular alkylation with an epoxide or alkyl p-toluenesulfonate to afford 5,5-bis[(benzyloxy)methyl]-3-[(E)-(N,N- diethylcarbamoyl)methylene]-1-cyclohexanol or N,N-diethyl(3,3- dimethylcyclopentyl)acetamide after hydrolysis. In both cases, the remaining metalated portion α to the amide group was confirmed by deuteriolysis and could be utilized for an alkylation with methyl iodide.
- Hata, Takeshi,Sujaku, Shiro,Hirone, Naoki,Nakano, Kirihiro,Imoto, Junsuke,Imade, Haduki,Urabe, Hirokazu
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supporting information; scheme or table
p. 14593 - 14602
(2012/02/04)
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- BICYCLIC HETEROCYCLE DERIVATIVES AND METHODS OF USE THEREOF
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The present invention relates to Bicyclic Heterocycle Derivatives, compositions comprising a Bicyclic Heterocycle Derivative, and methods of using the Bicyclic Heterocycle Derivatives for treating or preventing obesity, diabetes, a metabolic disorder, a cardiovascular disease or a disorder related to the activity of GPR119 in a patient.
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Page/Page column 196
(2009/05/30)
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- N-Bridged bicyclic sulfonamides as inhibitors of γ-secretase
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The structural modification of a series of [3.3.1] bicyclic sulfonamide based γ-secretase inhibitors is described. Appropriate substitution on the bicyclic scaffold provides a significant increase in the metabolic stability of the compounds resulting in an improved in vivo metabolic profile.
- Bowers, Simeon,Probst, Gary D.,Truong, Anh P.,Hom, Roy K.,Konradi, Andrei W.,Sham, Hing L.,Garofalo, Albert W.,Wong, Karina,Goldbach, Erich,Quinn, Kevin P.,Sauer, John-Michael,Wallace, William,Nguyen, Lan,Hemphill, Susanna S.,Bova, Michael P.,Basi, Guriqbal S.
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scheme or table
p. 6952 - 6956
(2010/06/16)
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- MODULATORS OF PHARMACOKINETIC PROPERTIES OF THERAPEUTICS
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The present application provides for a compound of Formula I, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, compositions containing such compounds, therapeutic methods that include the administration of such compounds, and therapeutic methods and include the administration of such compounds with at least one additional therapeutic agent.
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Page/Page column 215-216
(2008/06/13)
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- RHO KINASE INHIBITORS
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Substituted amide and urea derivatives useful as inhibitors of Rho kinase are described, which inhibitors can be useful in the treatment of various disorders such as cardiovascular diseases, cancer, neurological diseases, renal diseases, bronchial asthma, erectile dysfunction and glaucoma.
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Page/Page column 142-143; 145
(2008/12/07)
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- PROCESS FOR THE SAFE OZONOLYSIS OF ORGANIC COMPOUNDS IN FLAMMABLE SOLVENTS
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An improved process for the safe ozonolysis of unsaturated, organic carbon compounds having one or more olefinic or aromatic double bonds in the molecule in flammable solvents for the preparation of mono- or biscarbonyl or hydroxy compounds, in which ozonolysis is carried out with the use of an ozone-carrying inert gas/O2 stream, in which the oxygen concentration in the inert gas/O2 stream is above the known limiting oxygen concentration of the homogeneous fuel/gas mixtures and below the safety-critical limiting oxygen concentration of the heterogeneous mixture of the liquid fuel and oxygen-containing gas which is dependent on the reaction conditions and at which ignition and flame propagation no longer take place.
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Page/Page column 22-23
(2008/12/06)
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- BRIDGED N-CYCLIC SULFONAMIDO INHIBITORS OF GAMMA SECRETASE
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The invention provides N-cyclic sulfonamido compounds and salts of Formula (I): wherein A is as described in the specification and R1 and R2combine to form a [3.3.1] or a [3.2.1] ring system, where the nitrogen is attached to the two bridgehead carbons, and the [3.3.1] or [3.2.1] ring systems are optionally fused with an heteroaryl or heterocycloalkyl ring. Compounds of Formula (I) are useful in treating or preventing cognitive disorders, such as Alzheimer's Disease. The invention also encompasses pharmaceutical compositions comprising compounds of Formula I, methods of treating cognitive disorders, such as Alzheimer's disease, and the intermediates useful in preparing the compounds of Formula (I).
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Page/Page column 74
(2010/11/26)
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- COMPOSITIONS USEFUL AS INHIBITORS OF PROTEIN KINASES
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The present invention relates to compounds useful of inhibitors of protein kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.
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Page/Page column 211-212
(2010/02/11)
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- Samarium diiodide-induced intramolecular pinacol coupling of dinitrones: Synthesis of cyclic cis-vicinal diamines
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Pinacol coupling of alkyl dinitrones mediated by SmI2 was achieved in the presence of a proton source allowing the synthesis of cyclic vicinal diamines with good cis-selectivity. The Royal Society of Chemistry 2005.
- Ebran, Jean-Philippe,Hazell, Rita G.,Skrydstrup, Troels
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p. 5402 - 5404
(2007/10/03)
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- Synthetic entry to functionalised morpholines and [1,4]-oxazepanes via reductive amination reactions of carbohydrate derived dialdehydes
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Synthetic entry to functionalised morpholines and [1,4]-oxazepanes by reductive amination reactions between amines and carbohydrate derived dialdehydes is described. The rapid synthesis of functionalised morpholines and [1,4]-oxazepanes displaying up to three stereocentres, by reductive amination reactions between carbohydrate derived dialdehydes and a range of amines, is described.
- Clark, Stuart M.,Osborn, Helen M. I.
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p. 3643 - 3652
(2007/10/03)
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- 5-HT4 receptor agonists
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Compounds of formula (I) and pharmaceutically acceptable salts thereof are selective agonists for 5-HT4 receptors. STR1 wherein Ak is a C3 -C6 alkyl group, and R is a C2 -C6 alkyl group, a C3 -C6 alkenyl group, a C3 -C6 alkynyl group, a C3 -C7 cycloalkyl group or a C3 -C6 cycloalkylmethyl group.
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- Peptide compounds, in particular LHRH-antagonists
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The invention concerns LHRH antagonists of the general formula (I),X-X 1 -X 2 -X 3 -L-Ser-L-Tyr-X 6 -L-Leu-X 8 -L-Pro-X 10 (I)The invention concerns LHRH antagonists of the general formula (I), in which X is an acyl group, X 1 is a D-Nal, X 2 is D-(4-Cl)-Phe, X 3 is D-(3)-Pal, X 6 is D-Cit or D-Neu, X 8 is L-Arg or L-Neu, at least one of the groups X 6 and X 8 being a Neu, and X 10 is D-Ala-NH 2, Neu being a group of formula (II), (IV), (IX) or (X), wherein W is one of the group (a)-(d). The invention includes drugs containing a compound of formula (I), plus the usual auxiliaries and carriers. These drugs are suitable for use in cases of carcinoma of the prostate and in endometriosis, as well as for fertility control.
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- Oxazabicyclo derivatives and their use as 5-HT4 receptor agonists
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Oxazabicyclo derivatives of formula (I): wherein the variable groups are as defined in the specification, which are useful as 5-HT? receptor agonist for the treatment of digestive tract diseases.
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- Synthesis and Antitumor Activity of Isodoxorubicin Analogues
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The synthesis and biological activity of the new 4-demethoxyanthracyclines 15, 22, and 23 are reported.They were obtained from synthetic 9-deacetyl-9-(hydroxymethyl)-4-demethoxydaunomycinone (isopropylidene derivative 9) and from 4-azido- or 4-amino-2,4,6-trideoxy-L-lyxo-hexoses.Anthracycline 22 (hydrochloride salt), the most active compound in the series, was slightly more potent than doxorubicin in vitro against three cell lines (L1210, HT29, A549).It was found to exhibit similar antitumor activity in vivo (iv route) against L1210 leukemia, but was less activethan doxorubicin against three human tumors in a subrenal capsule assay (LX, A549, and HT29).
- Florent, Jean-Claude,Gaudel, Gilbert,Monneret, Claude,Hoffmann, Dieter,Kraemer, Hans-Peter
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p. 1364 - 1368
(2007/10/02)
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- REACTION OF 3-HETERO-1,5-DIALDEHYDES WITH tert-BUTYL CYANOACETATE
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The reaction of thiodiglycolaldehyde and diglycolaldehyde with tert-butyl cyanoacetate yields derivatives of tetrahydrothiopyran and tetrahydropyran, respectively.Similar reactions of diglycolaldehyde derivatives having a furan nucleus at the α-position yield D-xylo (major) and L-arabino (minor) C-pyranosyl derivatives.Starting from α-(S)-methoxy-α'-(R)-hydroxymethyldiglycolaldehyde, D-gluco and D-manno glycosides were obtained, the relative proportions of which depended on the time of reaction.In addition to the 1:1 addition products, minor products corresponding to 1:2 (dialdehyde: active methylene compound) addition were isolated.
- Aparicio, F. J. Lopez,Gonzalez, F. Santoyo,Mendoza, P. Garcia,Mateo, F. Hernandez,Martinez, J. A. Dominguez
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- Intensely potent morpholinyl anthracyclines
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3'-Deamino-3'-(3-cyano-4-morpholinyl)doxorubicin is a new analogue that is 100 to 1000 times more potent than doxorubicin against tumors in cell culture or in mice, that is active by intraperitoneal, intravenous, or oral dosing, and that does not produce chronic myocardial lesions in mice. This analogue was encountered in studies on the reductive alkylation of doxorubicin and daunorubicin with 2,2'-oxybis[acetaldehyde], which constructs a morpholino ring incorporating the amino N. The morpholinyl nitrile byproducts are separated by virtue of their nonbasicity from the expected morpholino derivatives. The 13-dihydro and 5-imino derivatives are also described in this important new class of anthracyclines.
- Acton,Tong,Mosher,Wolgemuth
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p. 638 - 645
(2007/10/02)
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- An Asymmetric Synthesis of 2,4-Dimethylvalerolactone and Mevalonolactone using Chiral Binaphthyldiamine Derivatives
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Axially dissymmetric binaphthyldiamine derivatives formed by asymmetric ring opening of the cyclic anhydrides (3) and (4) ring close on hydrolysis to give (-)-cis-2,4-dimethylvalerolactone (6) and (-)-mevalonolactone (7) in 92percent and 58percent enantiomeric excess (e.e.), respectively; similarly the derivative of the racemic cyclic anhydride (+/-)-(3) ring closes to give (-)-trans-2,4-dimethylvalerolactone with 74percent e.e.
- Kawakami, Yukio,Hiratake, Jun,Yamamoto, Yukio,Oda, Jun'ichi
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p. 779 - 781
(2007/10/02)
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- SYNTHESIS AND STRUCTURES OF SOME DIGLYCOLALDEHYDE THIOACETALS
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Diglycolaldehyde (2,2'-oxybisacetaldehyde, 1a) reacts with thiols under conditions similar to those for monosaccharides.The nature of the reaction products depends on the degree of α-substitution of the thiol.The acyclic dithioacetal 2a was the only product isolated when methanethiol was used, but mixtures of acyclic dithioacetals, cis-2,6-bis(alkylthio)-1,4-dioxanes, and trans-2,6-bis(alkylthio)-1,4-dioxanes were obtained when ethanethiol, 1-propanethiol, and 2-propanethiol were used.From 1a and 2-methylpropane-2-thiol the acyclic dithioacetal 2e and the cis (7) and trans (8) stereoisomers of 3,5-bis(tert-butylthio)-1,4-oxathiane were isolated.On the other hand, when diglycolaldehyde bis(dialkyl acetals) (9a-d) or 2,6-di-isopropoxy-1,4-dioxane (10) were treated with primary or secondary thiols in acid media, the acyclic dithioacetals were isolated as the only products.The acyclic dithioacetal 2e and the oxathiane derivatives 7 and 8 were obtained when 9a-d or 10 were treated with 2-methylpropane-2-thiol under the above conditions.
- Aparicio, F. J. Lopez,Benitez, F. Zorrilla,Gonzales, F. Santoyo
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- Enhanced Antitumor Properties of 3'-(4-Morpholinyl) and 3'-(4-Methoxy-1-piperidinyl) Dervatives of 3'-Deaminodaunorubicin
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Reductive N,N-dialkylation of daunorubicin with 2,2'-oxydiacetaldehyde and NaBH3CN occurred in two steps without interruption and with cyclization to form 3'-(4-morpholinyl)-3'-deaminodaunorubicin.This derivative retained the antitumor efficacy of doxorubicin against mouse leukemia P388 but at one-fortieth the dose; hence, it is the most potent anthracycline analogue synthesized so far.The 4-methoxy-1-piperidinyl derivative, similarly prepared with 3-methoxyglutaraldehyde, showed improved efficacy against P388, though at normal doses.Results with a series of analogues indicate that incorporation of the N in the new ring and the presence of an ether O at the 4-position are critical for enhanced activity.
- Mosher, Carol W.,Wu, Helen Y.,Fujiwara, Allan N.,Acton, Edward M.
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