- Enantioselective Desymmetrization of 2-Aryl-1,3-propanediols by Direct O-Alkylation with a Rationally Designed Chiral Hemiboronic Acid Catalyst That Mitigates Substrate Conformational Poisoning
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Enantioselective desymmetrization by direct monofunctionalization of prochiral diols is a powerful strategy to prepare valuable synthetic intermediates in high optical purity. Boron acids can activate diols toward nucleophilic additions; however, the design of stable chiral catalysts remains a challenge and highlights the need to identify new chemotypes for this purpose. Herein, the discovery and optimization of a bench-stable chiral 9-hydroxy-9,10-boroxarophenanthrene catalyst is described and applied in the highly enantioselective desymmetrization of 2-aryl-1,3-diols using benzylic electrophiles under operationally simple, ambient conditions. Nucleophilic activation and discrimination of the enantiotopic hydroxy groups on the diol substrate occurs via a defined chairlike six-membered anionic complex with the hemiboronic heterocycle. The optimal binaphthyl-based catalyst 1g features a large aryloxytrityl group to effectively shield one of the two prochiral hydroxy groups on the diol complex, whereas a strategically placed "methyl blocker"on the boroxarophenanthrene unit mitigates the deleterious effect of a competing conformation of the complexed diol that compromised the overall efficiency of the desymmetrization process. This methodology affords monoalkylated products in enantiomeric ratios equal or over 95:5 for a wide range of 1,3-propanediols with various 2-aryl/heteroaryl groups.
- Estrada, Carl D.,Ang, Hwee Ting,Vetter, Kim-Marie,Ponich, Ashley A.,Hall, Dennis G.
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supporting information
(2021/04/07)
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- OXIDATIVE COUPLING OF ARYL BORON REAGENTS WITH SP3-CARBON NUCLEOPHILES, AND AMBIENT DECARBOXYLATIVE ARYLATION OF MALONATE HALF-ESTERS VIA OXIDATIVE CATALYSIS
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Described herein are methods of oxidative coupling of aryl boron reagents with sp3-carbon nucleophiles, and ambient decarboxylative arylation of malonate half-esters via oxidative catalysis.
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Paragraph 0478; 0512
(2018/07/29)
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- Ambient Decarboxylative Arylation of Malonate Half-Esters via Oxidative Catalysis
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We report decarboxylative carbonyl α-arylation by coupling of arylboron nucleophiles with malonic acid derivatives. This process is enabled by the merger of aerobic oxidative Cu catalysis with decarboxylative enolate interception reminiscent of malonyl-CoA reactivity in polyketide biosynthesis. This method enables the synthesis of monoaryl acetate derivatives containing electrophilic functional groups that are incompatible with existing α-arylation reactivity paradigms. The utility of the reaction is demonstrated in drug intermediate synthesis and late-stage functionalization.
- Moon, Patrick J.,Yin, Shengkang,Lundgren, Rylan J.
-
supporting information
p. 13826 - 13829
(2016/11/06)
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- SUBSTITUTED AROMATIC COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS FOR THE PREVENTION AND TREATMENT OF OSTEOPOROSIS
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The present invention concerns the use of compounds for preventing and/or treating osteoporosis, for stimulating bone formation, for stimulating bone remodeling, for stimulating the differentiation and mineralization of osteoblasts, for inhibiting bone resorption and for modulating serum level of adiponectin in a subject. These uses have been found for compounds represented by Formula I and pharmaceutically acceptable salts thereof. wherein A is C5 alkyl, C6 alkyl, C5 alkenyl, C6 alkenyl, C(O)-(CH2)n-CH3 or CH(OH)-(CH2)n-CH3 wherein n is 3 or 4; R1 is H, F or OH; R2 is H, F, OH, C6 alkyl, C5 alkenyl, C6 alkenyl, C(O)-(CH2)n-CH3 or CH(OH)-(CH2)n-CH3 wherein n is 3 or 4; R3 is H, F, OH or CH2Ph; R4 is H, F, or OH; Q is 1) (CH2)mC(O)OH wherein m is 1 or 2, 2) CH(F)-C(O)OH, 3) CF2-C(O)OH or 4) C(O)-C(O)OH.
- -
-
Paragraph 0099; 00100
(2016/05/02)
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- SUBSTITUTED AROMATIC COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS FOR TISSUE SELF-REPAIR AND REGENERATION
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Described herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, or combinations thereof, as well as uses thereof. Such uses include promoting tissue self-repair or tissue regeneration of an organ, stimulating the generation of tissue growth, modulating (e.g. increasing) the level of a tissue-repair marker, treating physical injury in an organ, tissue, or cell, promoting wound healing as well as anti-aging applications. Corresponding compositions, methods and uses are also described. Formula I wherein A is C5 alkyl, C6 alkyl, C5 alkenyl, C6 alkenyl, C(0)-(CH2)n-CH3 or CH(OH)-(CH2)n-CH3 wherein n is 3 or 4; R1 is H, F of OH; R2 is H, F, OH, C5 alkyl, C6 alkyl, C5 alkenyl, C6 alkenyl, C(0)-(CH2)n-CH3 or CH(OH)-(CH2)n-CH3 wherein n is 3 or 4; R3 is H, F, OH, or CH2Ph; R4 is H, F or OH; Q is 1) (CH2),C(0)OH wherein m is 1 or 2 2) CH(CH3)C(0)OH, 3) C(CH3)2C(0)OH, 4) CH(F)-C(0)OH, 5) CF2-C(0)OH or 6) C(0)-C(0)OH.
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Paragraph 0094
(2016/06/13)
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- HETEROCYCLIC INHIBITORS OF THE SODIUM CHANNEL
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The invention relates to compounds useful in treating conditions associated with voltage-gated ion channel function, particularly conditions associated with sodium channel activity. More specifically, the invention concerns heterocyclic compounds (e.g., compounds according to any of Formulas (l)-(ll l) or Compounds (1 )-(65) of Table 1 ) that are that are useful in treatment of conditions such as epilepsy, cancer, pain, migraine, Parkinson's Disease, mood disorders, schizophrenia, psychosis, tinnitus, amyotropic lateral sclerosis, glaucoma, ischaemia, spasticity disorders, obsessive compulsive disorder, restless leg syndrome and Tourette syndrome.
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Page/Page column 77
(2015/09/28)
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- Synthesis of α-aryl esters and nitriles: Deaminative coupling of α-aminoesters and α-aminoacetonitriles with arylboronic acids
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Transition-metal-free synthesis of α-aryl esters and nitriles using arylboronic acids with α-aminoesters and α-aminoacetonitriles, respectively, as the starting materials has been developed. The reaction represents a rare case of converting C(sp3)-N bonds into C(sp3)-C(sp2) bonds. The reaction conditions are mild, demonstrate good functional-group tolerance, and can be scaled up. Touch base: A transition-metal-free protocol for the synthesis of α-aryl esters and nitriles by deaminative coupling is presented. Strong bases and transition-metal catalysts are not needed. The new synthetic method uses readily available starting materials and demonstrates wide substrate scope.
- Wu, Guojiao,Deng, Yifan,Wu, Chaoqiang,Zhang, Yan,Wang, Jianbo
-
supporting information
p. 10510 - 10514
(2016/02/18)
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- Substituted phenylimidazopyrazoles and their use
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The present application relates to novel 1-phenyl-1H-imidazo[1,2-b]pyrazole derivatives, to processes for their preparation, to their use 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 angiogenic disorders and hyperproliferative disorders, where neovascularization plays a role, such as, for example, neoplastic disorders and tumour disorders. Such treatments can be carried out as monotherapy or else in combination with other medicaments or further therapeutic measures.
- -
-
Paragraph 1328; 1329; 1330
(2013/07/31)
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- SUBSTITUTED PYRIMIDINES
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Disclosed are substituted pyrimidines useful as HIF prolyl hydroxylase inhibitors to treat anemia and like conditions.
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Page/Page column 99
(2013/04/10)
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- HETEROCYCLIC INHIBITORS OF GLUTAMINASE
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The invention relates to the heterocyclic compounds of Formula (I) as defined further herein, and pharmaceutical preparations thereof. The invention further relates to methods of treating cancer, immunological or neurological diseases using the heterocyclic compounds of the invention.
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Page/Page column 136
(2013/06/06)
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- SUBSTITUTED PYRIMIDINES
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The present invention relates to substituted pyrimidines useful as HIF prolyl hydroxylase inhibitors to treat anemia and like conditions.
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Page/Page column 99
(2013/04/10)
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- COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF CANCER
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New uses for phenylketone carboxylate compounds and substituted aromatic compounds of Formula I, Formula I.1, Formula I.2, Formula IA, Formula IB, Formula IC and Formula II and their pharmaceutical acceptable salts for the treatment of cancer. The use of
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Page/Page column 29
(2012/08/07)
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- COFERONS AND METHODS OF MAKING AND USING THEM
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The present invention is directed to a monomer useful in preparing therapeutic compounds. The monomer includes one or more pharmacophores which potentially binds to a target molecule with a dissociation constant of less than 300 μM and a linker element connected to the pharmacophore. The linker element has a molecular weight less than 500 daltons, is connected, directly or indirectly through a connector, to the pharmacophore.
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Page/Page column 228
(2012/12/13)
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- Discovery and optimization of a biphenylacetic acid series of prostaglandin D2 receptor DP2 antagonists with efficacy in a murine model of allergic rhinitis
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Biphenylacetic acid (5) was identified through a library screen as an inhibitor of the prostaglandin D2 receptor DP2 (CRTH2). Optimization for potency and pharmacokinetic properties led to a series of selective CRTH2 antagonists. Compounds demonstrated potency in a human DP2 binding assay and a human whole blood eosinophil shape change assay, as well as good oral bioavailability in rat and dog, and efficacy in a mouse model of allergic rhinitis following oral dosing.
- Scott, Jill M.,Baccei, Christopher,Bain, Gretchen,Broadhead, Alex,Evans, Jilly F.,Fagan, Patrick,Hutchinson, John H.,King, Christopher,Lorrain, Daniel S.,Lee, Catherine,Prasit, Peppi,Prodanovich, Pat,Santini, Angelina,Santini, Brian A.
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scheme or table
p. 6608 - 6612
(2011/12/04)
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- SUBSTITUTED AROMATIC COMPOUNDS AND PHARMACEUTICAL USES THEREOF
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The present invention relates to substituted aromatic compounds of Formula (I) and their pharmaceutical uses. Particular aspects of the invention relate to the use of those compounds in the prevention and/or treatment of various diseases and conditions in subjects, including the prevention or treatment of (i) blood disorders, (ii) renal disorders, nephropathies, or renal disorder complications; (iii) inflammatory-related diseases; and/or (iv) oxidative stress related disorders.
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Page/Page column 39-40
(2010/11/18)
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- SALTS OF 3-PENTYLPHENYLACETIC ACID AND PHARMACEUTICAL USES THEREOF
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The present invention relates to salts of 3-pentylphenylacetic acid and their pharmaceutical uses. Particular aspects of the invention relate to the use of those salts in the prevention and/or treatment of various diseases and conditions in subjects, including the prevention and treatment of (i) blood disorders, (ii) renal disorders and renal disorder complications; (iii) inflammatory-related diseases; and/or (iv) oxidative stress related disorders.
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Page/Page column 26-27
(2010/11/18)
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- ANTAGONISTS OF LYSOPHOSPHATIDIC ACID RECEPTORS
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Described herein are compounds that are antagonists of lysophosphatidic receptor(s). Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods of using such antagonists, alone and in combination with other compounds, for treating LPA-dependent or LPA-mediated conditions or diseases.
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Page/Page column 20
(2010/06/22)
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- A COMBINATION OF NIACIN AND A PROSTAGLANDIN D2 RECEPTOR ANTAGONIST
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The present invention is directed to a pharmaceutical composition comprising Niacin or a pharmaceutically acceptable salt, solvate or N-oxide thereof, or a nicotinic acid receptor agonist, and a compound of formula (I) as defined herein, or an N-oxide thereof, or an ester prodrug thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and its use for treating atherosclerosis, dyslipidemia, diabetes or a related condition while reducing substantial flushing.
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Page/Page column 204
(2008/06/13)
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- SUBSTITUTED AZACYCLOALKANES USEFUL FOR TREATING CNS CONDITIONS
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The invention relates to substituted azacycloalkaπe compounds useful in treating conditions of the Central Nervous System (CNS); a pharmaceutical composition comprising same; a method of treating such conditions and of treating conditions in which inhibition of beta-secretase is indicated.
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Page/Page column 73
(2008/06/13)
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- 6-Substituted pyridoindolone derivatives, production and therapeutic use thereof
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Compounds of formula: and pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein R1, R2, R3, R4, and R5, have the meanings given in the description; pharmaceutical compositions comprising said compounds; and processes for preparing said compounds and methods of use thereof.
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Page/Page column 12
(2010/11/27)
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- 2, 6-SUBSTITUTED-4-MONOSUBSTITUTEDAMINO-PYRIDIMIDINE AS PROSTAGLANDIN D2 RECEPTOR ANTAGONISTS
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The present invention is directed a compound of Formula (I) as defined herein, a pharmaceutical composition comprising a pharmaceutically effective amount of one or more compounds according to Formula (I) in admixture with a pharmaceutically acceptable carrier, and a method of treating a patient suffering from a PGD2-mediated disorder including, but not limited to, allergic disease (such as allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma and food allergy), systemic mastocytosis, discorders accompanied by systemic mast cell activation, anaphylaxis shock, bronchoconstriction, bronchitis, urticaria, eczema, diseases accompanied by itch (such as atopic dermatitis and urticaria), diseases (such as cataract, retinal detachment, inflammation, infection and sleeping disorders) which is generated secondarily as a result of behavior accompanied by itch (such as scratching and beating), inflammation, chronic obstructive pulmonary diseases, ischemic reperfusion injury, cerebrovascular accident, chronic rheumatoid arthritis, pleurisy, ulcerative colitis and the like by administering to said patient a pharmaceutically effective amount of a compound according to Formula (I).
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Page/Page column 205
(2008/06/13)
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- Imidazo-fused oxazolo[4,5-b]pyridine and imidazo-fused thiazolo[4,5-b]pyridine based tricyclic compounds and pharmaceutical compositions comprising same
-
The present invention provides for pyrazolopurine-based tricyclic compounds having the formula (I), wherein R1, R2, R3, and R6 are as described herein. The present invention further provides pharmaceutical compositions comprising such compounds, as well as the use of such compounds for treating inflammatory and immune diseases.
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Page/Page column 29
(2010/11/30)
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- CaSR ANTAGONIST
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The present invention provides a compound having a calcium-sensitive receptor antagonistic action, a pharmaceutical composition containing the compound, particularly a calcium receptor antagonist and a therapeutic drug for osteoporosis. A compound represented by the following formula (1), a pharmaceutically acceptable salt thereof or an optically active form thereof: wherein each symbol is as defined in the description.
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Page/Page column 50
(2008/06/13)
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- PROSTAGLANDIN DERIVATIVE
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A prostaglandin derivative represented by the formula: (I) wherein R1 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an alkenyl group having 2 to 4 carbon atoms; X represents an ethylene group, a trimethylene group, a vinylene group, an ethynylene group or a group represented by the formula: -SCH2-; R2 and R3 independently represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms which is substituted by an alkoxy group having 1 to 6 carbon atoms, a phenyl group, a substituted phenyl group, a furyl group or a thienyl group, or a pharmaceutically acceptable salt thereof or a hydrate of the derivative or salt. These compounds show a satisfactory level of anti-inflammatory effect while minimizing the cAMP production-enhancing effect and is provided for reducing the adverse side effects that may be caused by an EP4 agonist.
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Page/Page column 13
(2010/11/25)
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- Pyridoindolone derivatives substituted in the 3-position by a phenyl, their preparation and their application in therapeutics
-
The present invention relates to pyridoindolone derivatives substituted in the 3-position by a phenyl of general formula (I): to processes for preparing the same and to their use in therapeutics.
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Page/Page column 9-10
(2010/02/15)
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- Method for treating glaucoma
-
Methods of using prostaglandin agonists for the reduction of intraocular pressure, and accordingly glaucoma.
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- O- or S- substituted tetrahydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity
-
Compounds of the formula where the symbols have the meaning described in the application, have retinoid-like or retinoid antagonist-like biological activity.
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Page column 70
(2010/11/29)
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- Prevention of loss and restoration of bone mass by certain prostaglandin agonists
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Prostaglandin agonists of formula (I), in which, for example, A is a sulphonyl or acyl group, B is N or CH, M contains a ring and K and Q are linking groups, methods of using such prostaglandin agonists, pharmaceutical compositions containing such prostaglandin agonists and kits useful for the treatment of bone disorders including osteoporosis. STR1
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-
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- Method for inhibiting gene expression promoted by AP1 protein with RAR beta selective retinoids and method for treatment of diseases and conditions with such retinoids
-
Retinoid compounds which repress expression of the gene promoted by AP1 protein but which do not significantly activate expression of the genes having RA-responsive elements in their promoter region through RAR alpha and RAR GAMMA receptor subtypes, are u
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-
-
- AMP deaminase inhibitors. 3. SAR of 3-(carboxyarylalkyl)coformycin aglycon analogues
-
N3-Substituted coformycin aglycon analogues with improved AMP deaminase (AMPDA) inhibitory potency are described. Replacement of the 5-carboxypentyl substituent in the lead AMPDA inhibitor 3-(5-carboxypentyl)-3,6,7,8- tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol (2) described in the previous article with various carboxyarylalkyl groups resulted in compounds with 10- 100-fold improved AMPDA inhibitory potencies. The optimal N3 substituent had m-carboxyphenyl with a two-carbon alkyl tether. For example, 3-[2-(3-carboxy- 5-ethylphenyl)ethyl]-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol (43g) inhibited human AMPDA with a K(i) = 0.06 μM. The compounds within the series also exhibited > 1000-fold specificity for AMPDA relative to adenosine deaminase.
- Kasibhatla, Srinivas Rao,Bookser, Brett C.,Probst, Gary,Appleman, James R.,Erion, Mark D.
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p. 1508 - 1518
(2007/10/03)
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- Acetylenes disubstituted with a 5-amino or substituted 5-amino substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity
-
Compounds of the formula STR1 having retinoid like biological activity.
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