- COMPOSITIONS AND METHODS USING THE SAME FOR TREATMENT OF NEURODEGENERATIVE AND MITOCHONDRIAL DISEASE
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The present disclosure is directed, in part, to compounds, or pharmaceutically acceptable salts thereof, for the treatment and/or prevention of neurodegenerative disease and/or mitchonodrial disease including Parkinson's disease and Leigh's disease.
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Page/Page column 138; 139
(2015/09/22)
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- INHIBITORS OF PI3K-DELTA AND METHODS OF THEIR USE AND MANUFACTURE
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The invention is directed to Compounds of Formula I: and pharmaceutically acceptable salts or solvates thereof, as well as methods of making and using the compounds.
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Page/Page column 124-125
(2012/04/04)
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- Scale-up of microwave-assisted reactions in a multimode bench-top reactor
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An evaluation of a new bench-top microwave batch reactor that uses a single 1 L reaction vessel is presented. Several microwave-assisted organic reactions have been scaled-up, including Newman Kwart and Diels-Alder reactions, Pd-catalyzed cross-couplings, heterocycle synthesis, aromatic substitution, and a Knoevenagel condensation. A range of different solvents (high and low microwave absorbing), varying reaction times (4 s up to 2 h), and temperatures (120-250 °C) have been explored in these investigations. For all studied transformations, it was possible to perform a direct scale-up (up to 720 mL reaction volume) without changing the previously optimized reaction conditions achieved in a laboratory-scale single-mode microwave instrument (2-20 mL processing volume), obtaining similar isolated product yields. A scalability up to 360-fold, when moving from 3 mmol up to 1.08 mol, was demonstrated, and isolated product yields up to 300 g (2.5 mol scale) in a single run could be accomplished, providing the potential for a kilogram output per day for specific transformations by performing multiple sequential runs.
- Dallinger, Doris,Lehmann, Hansjoerg,Moseley, Jonathan D.,Stadler, Alexander,Kappe, C. Oliver
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experimental part
p. 841 - 854
(2012/06/18)
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- Scale-up of organic reactions in a pharmaceutical kilo-lab using a commercial microwave reactor
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A range of pharmaceutically relevant reactions were investigated for scale-up in a kilo-lab environment using a commercial batch microwave reactor. Typical scale-up issues are discussed, taking into account the specific limitations of microwave heating in large-scale experiments. Examples of scale-up from 15 mL to 1 L are presented and demonstrate that the synthesis of compounds on greater than 100 g scale is feasible in one batch. Aided by this new technology reaction times have been significantly reduced and the productivity of our scale-up laboratory has been enhanced. Production rates of several hundred grams per day were achieved using microwave technology. The article concludes with a brief discussion of advantages and disadvantages of this type of batch microwave reactor.
- Lehmann, Hansjoerg,Lavecchia, Luigi
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experimental part
p. 650 - 656
(2011/08/05)
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- Novel 8-arylated purines as inhibitors of glycogen synthase kinase
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A series of 8-arylated purine derivatives bearing either an aniline or an alkyl amide at position 6 were found to inhibit glycogen synthase kinase-3,with good selectivity over ten kinases. Molecular modeling studies indicated that the most active compounds (8a and 8e),adopt a planar conformation,close to the shape of AMPPNP in the crystal structure of GSK-3. These compounds are stabilized by hydrophobic contacts between the 8-aromatic group and the protein adenine pocket and by electrostatic contacts.
- Ibrahim, Nada,Mouawad, Liliane,Legraverend, Michel
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scheme or table
p. 3389 - 3393
(2010/08/06)
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- Imidazolo-, oxazolo-, and thiazolopyrimidine modulators of TRPV1
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Certain TRPV1-modulating imidazolo-, oxazolo-, and thiazolopyrimdine compounds are described. The compounds may be used in pharmaceutical compositions and methods for treating disease states, disorders, and conditions mediated by TRPV1 activity, such as pain, arthritis, itch, cough, asthma, or inflammatory bowel disease.
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Page/Page column 18
(2009/07/03)
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- Imidazolopyrimidine modulators of TRPV1
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Certain TRPV1-modulating imidazolopyrimidine compounds are described. The compounds may be used in pharmaceutical compositions and methods for treating disease states, disorders, and conditions mediated by TRPV1 activity, such as pain, arthritis, itch, cough, asthma, or inflammatory bowel disease.
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Page/Page column 10
(2009/07/03)
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- SUBSTITUTED PIPERIDINES CONTAINING A HETEROARYLAMIDE OR HETEROARYLPHENYL MOIETY
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The invention provides compounds of the formula (I) having PKA and PKB kinase inhibiting compounds of the formula (I): GP 1 J T 2 J N 4 R N H (I) or salts, solvates, tautomers or N-oxides thereof, wherein (1) GP is a group GP1: HET 2a a Q G (HNCO)f 7 (R )x N * (GP1) (2) GP is a group GP2: 10 (R )r O 2a a QG (CH2)w N V H N * (GP2) wherein HET is a monocyclic or bicyclic heterocyclic group containing up to 4 heteroatom ring members; the ring V is a monocyclic or bicyclic heteroaryl group of 5 to 10 ring members; and J1, J2, R4, R7, R10, Q2a, Ga, x, w and f are as defined in the claims
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Page/Page column 116
(2008/12/06)
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- Heteroaryl compounds useful as inhibitors of E1 activating enzymes
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This invention relates to compounds that inhibit E1 activating enzymes, pharmaceutical compositions comprising the compounds, and methods of using the compounds. The compounds are useful for treating disorders, particularly cell proliferation disorders, including cancers, inflammatory and neurodegenerative disorders; and inflammation associated with infection and cachexia.
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Page/Page column 114
(2008/06/13)
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- PHARMACEUTICAL COMPOUNDS
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The invention provides a compound having the formula (I): or salts, solvates, tautomers or N-oxides thereof, wherein T is N or CR5; J1-J2 is N=C(R6), (R7)C=N, (R8)N-C(O), (R8)2C-C(O), N=N or (R7)C=C(R6); A is an optionally substituted saturated C1-7 hydrocarbon linker group having a maximum chain length of 5 atoms extending between R1 and NR2R3 and a maximum chain length of 4 atoms extending between E and NR2R3, one of the carbon atoms in the linker group being optionally replaced by oxygen or nitrogen; E is a monocyclic or bicyclic carbocyclic or heterocyclic group or an acyclic group X-G wherein X is CH2, O, S or NH and G is a C1-4 alkylene chain wherein one of the carbon atoms is optionally replaced by O, S or NH; R1 is hydrogen or an aryl or heteroaryl group; R2 and R3 are each hydrogen, optionally substituted C1-4 hydrocarbyl or optionally substituted C1-4 acyl; or NR2R3 forms an imidazole group or a saturated monocyclic heterocyclic group having 4-7 ring members; or NR2R3 and A together form a saturated monocyclic heterocyclic group having 4-7 ring members which is optionally substituted by C1-4 alkyl; or NR2R3 and the adjacent carbon atom of linker group A together form a cyano group; or R1, A and NR2R3 together form a cyano group; and R4, R5, R6, R7 and R8 are each independently selected from hydrogen and various substituents as defined in the claims, wherein the compound is for use in: (a) the treatment or prophylaxis of a disease or condition in which the modulation (e.g. inhibition) of ROCK kinase or protein kinase p70S6K is indicated; and/or (b) the treatment of a subject or patient population in which the modulation (e.g. inhibition) of ROCK kinase or protein kinase p70S6K is indicated.
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Page/Page column 115
(2008/06/13)
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- PHARMACEUTICAL COMPOUNDS
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The invention provides compounds of the formula (I): or salts, solvates, tautomers or N-oxides thereof, wherein J1-J2 is CH=CH, N=CH, CH=N, HN-C(O) or CH2CO; T is N or CH and GP is as defined in the claims. The compounds have activity as inhibitors of PKA and PKB kinases and are useful in the treatment of cancers.
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Page/Page column 92-93
(2008/06/13)
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- ORTHO- CONDENSED PYRIDINE AND PYRIMIDINE DERIVATIVES (E. G. PURINES) AS PROTEIN KINASES INHIBITORS
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The invention provides a compound for use in the prophylaxis or treatment of a disease state or condition mediated by protein kinase B, the compound having the formula (I): or salts, solvates, tautomers or N-oxides thereof, wherein T is N or CR5; J1-J2 is N=C(R6), (R7)C=N, (R8)N-C(O), (R8)2C-C(O), N=N or (R7)C=C(R6); A is an optionally substituted saturated C1-7 hydrocarbon linker group having a maximum chain length of 5 atoms extending between R1 and NR2R3 and a maximum chain length of 4 atoms extending between E and NR2R3, one of the carbon atoms in the linker group being optionally replaced by oxygen or nitrogen; E is a monocyclic or bicyclic carbocyclic or heterocyclic group or an acyclic group X-G wherein X is CH2, O, S or NH and G is a C1-4 alkylene chain wherein one of the carbon atoms is optionally replaced by O, S or NH; R1 is hydrogen or an aryl or heteroaryl group; R2 and R3 are each hydrogen, optionally substituted C1-4 hydrocarbyl or optionally substituted C1-4 acyl; or NR2R3 forms an imidazole group or a saturated monocyclic heterocyclic group having 4-7 ring members; or NR2R3 and A together form a saturated monocyclic heterocyclic group having 4-7 ring members which is optionally substituted by C1-4alkyl; or NR2R3 and the adjacent carbon atom of linker group A together form a cyano group; or R1, A and NR2R3 together form a cyano group; and R4, R5, R6, R7 and R8 are each independently selected from hydrogen and various substituents as defined in the claims.
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Page/Page column 115-116
(2008/06/13)
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- An efficient one-pot synthesis of 6-alkoxy-8,9-dialkylpurines via reaction of 5-amino-4-chloro-6-alkylaminopyrimidines with N,N-dimethylalkaneamides and alkoxide ions
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The synthesis of a number of new 6-alkoxy-8,9-(disubstituted)purines has been accomplished by the cyclization of the corresponding intermediate 5-amino-4-chloro-6-(alkylamino)pyrimidines promoted by alkoxides and various N,N-dimethyl amides, where the latter act as solvent-reagents. By this three-component condensation reaction we are able to introduce an alkyl group in the 8 position of the purine ring with the concomitant nucleophilic replacement of the 6-chloro group with an alkoxy moiety.
- Baraldi, Pier Giovanni,Broceta, Asier Unciti,Infantas, Maria Josè Pineda De Las,Mochun, Juan Josè Dìaz,Espinosa, Antonio,Romagnoli, Romeo
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p. 7607 - 7611
(2007/10/03)
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- Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists
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Substituted Imidazo-fused 6-membered heterocycles of structural formula: STR1 wherein A, B, C, and D are independently carbon atoms or nitrogen atoms are angiotensin II antagonists useful in the treatment of hypertension and congestive heart failure.
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- SUBSTITUTED IMIDAZO-FUSED 6-MEMBERED HETEROCYCLCES AS ANGIOTENSIN II ANTAGONISTS
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Substituted Imidazo-fused 6-membered heterocycles of structural formula: STR1 wherein A, B, C, and D are independently carbon atoms or nitrogren atoms are angiotensin II antagonists useful in the treatment of hypertension and congestive heart failure.
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- Kinetics of the Multistage Reactions of 6-Substituted Purine Nucleosides with Aqueous Alkalies
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Reactions of some 6-substituted 9-(β-D-ribofuranosyl)purines with aqueous sodium hydroxide have been studied by liquid chromatography.The main reaction pathway for the decomposition of 6-chloro, 6-methyl and 6-methylthio derivatives has been shown to consist of three consecutive reactions: an attack of hydroxide ion on C8 atom with rapid subsequent openingof the imidazole ring and anomerization of the glycone moiety, deformylation of the resulting 5-formamido-4-ribosylaminopyrimidines, and clevage of the N-glicosidic bond.With the 6-chloro derivative, the first step is irreversible, while with the 6-methyl and 6-methylthio derivatives, recyclization to purine ribosides competes with the deformylation of 5-formamido-4-ribosylaminopyrimidines. 6-Chloro- and 6-methylthio-9-(β-D-ribofuranosyl)purines also yield some inosine, but this reaction is of minor importance.In contrast, 6-methoxy-9-(β-D-ribofuranosyl)purine is converted quantitatively to inosine.The rate constants for the different partial reactions have been determined at several concentrations of hydroxide ion.The kinetic data, and those reported earlier for adenosine and 9-(β-D-ribofuranosyl)purine, have been used to evaluate the susceptibility of the consecutive steps to the polar nature of the 6-substituent.
- Loennberg, Harri,Kaeppi, Rainer,Lehikoinen, Pertti,Oivanen, Mikko
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- Mechanisms for the Solvolytic Decompositions of Nucleoside Analogues. IX. Pathways for the Alkyline Hydrolysis of 6-Substituted 9-(1-Ethoxyethyl)purines
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A few 6-substituted 9-(1-ethoxyethyl)purines have been prepared and the rates of their base-catalyzed hydrolysis were measured by UV spectroscopy.The product mixtures were fractionated by preparative TLC and characterized by NMR and UV spectroscopy.The results obtained suggest that the alkaline cleavage of 9-(1-ethoxyethyl)purines generally proceeds by nucleophilic attack of hydroxide ion on C8 of the purine moiety, resulting in formation of appropriate 4,5-diaminopyrimidine and 8-methylpurine as final products.With 6-methoxy, 6-methylthio, and 6-chloro derivatives nucleophilic attack of hydroxide ion of C6 giving 9-(1-ethoxyethyl)hypoxanthine competes with this reaction.
- Loennberg, Harri,Lehikoinen, Pertti,Neuvonen, Kari
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p. 707 - 712
(2007/10/02)
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