- A convergent process for the preparation of adamantane 11-β-HSD-1 inhibitors
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A convergent, scalable process was developed for the synthesis of adamantane 11-β-hydroxysteroid dehydrogenase-1 inhibitors E-4-(2-methyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl) propionylamino)adamantane-1-carboxylic acid (1) and E-4-(2-methyl-2-(4-(5- (trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propionylamino)-adamantane-1- carboxamide (2) to rapidly deliver material for development. The process was high yielding and provided 1 in 52% overall yield over six total steps with a five-step longest linear sequence and 2 in 45% overall yield over seven total steps with a six-step longest linear sequence. A process to prepare active pharmaceutical ingredient (API) of >99% purity at the kilogram scale has been developed under tight delivery timelines.
- Becker, Calvin L.,Engstrom, Kenneth M.,Kerdesky, Francis A.,Tolle, John C.,Wagaw, Seble H.,Wang, Weifeng
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Read Online
- Photodecarboxylation of Adamantane Amino Acids Activated by Phthalimide
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Adamantane α-, β-, and δ-amino acids activated by phthalimide (i.e., 3–6) were synthesized, and their photochemical reactivities were investigated. Amino acid derivatives 3–6 underwent a photoinduced electron transfer (PET) and decarboxylation reaction sequence, most probably through a triplet excited state. The decarboxylations of the β-amino acid derivatives were succeeded by cyclization reactions that afforded complex polycyclic molecules with potential biological interest. The adamantyl radical that is produced by the photoinduced decarboxylation could be trapped by alkenes or oxygen to deliver adducts or alcohols, respectively. The photodecarboxylation process was shown to be more efficient under acetone sensitization conditions (with quantum yields, Φ = 0.02–0.5) than upon direct excitation, and the reactivity was dependent on the chain length (intramolecular distance) between the electron donor (carboxylate) and acceptor (phthalimide in the triplet excited state) of the derivative. The formation of different radicals, that is, the 1- or 2-adamantyl intermediate, probably does not affect the overall rate of the decarboxylation This current report provides a better understanding of photodecarboxylation and the rational design of molecular systems to undergo photoinduced decarboxylation and cyclization reactions.
- Mandi?, Leo,Mlinari?-Majerski, Kata,Griesbeck, Axel G.,Basari?, Nikola
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p. 4404 - 4414
(2016/09/14)
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- Design of pyrazolo-pyrimidines as 11β-HSD1 inhibitors through optimisation of molecular electrostatic potential
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The inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a potentially attractive mechanism for the treatment of obesity and other elements of the metabolic syndrome. A series of pyrazolo-pyrimidine inhibitors of this enzyme were identified from directed library synthesis. Knowledge of how these compounds bind to the enzyme and the key hydrogen-bonding interactions was used to design further compounds. The hydrogen-bond acceptor strength was calculated from the molecular electrostatic potential using quantum mechanical theory. Compounds were designed to modulate the acceptor strength, thus optimising the potency and other drug-like properties. Compounds with enhanced CNS penetration were designed through further modification of the electrostatic potential and the hydrogen-bond properties.
- Robb, Graeme R.,Boyd, Scott,Davies, Christopher D.,Dossetter, Alexander G.,Goldberg, Frederick W.,Kemmitt, Paul D.,Scott, James S.,Swales, John G.
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supporting information
p. 926 - 934
(2015/05/27)
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- A COMPOUND FOR INHIBITING 11B-HYDROXY STEROID DEHYDROGENASE 1, AND A PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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Disclosed are a novel compound or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition including the same for inhibiting human 11-β-hydroxy steroid dehydrogenase type 1 (11β-HSD1). The disclosed compound and the pharmaceutical composition including the same for inhibiting human 11-β-hydroxy steroid dehydrogenase type 1 (11β-HSD1) are excellent in activity and solubility, and is more efficient in formulation and transfer.
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Paragraph 0228-0229
(2014/08/06)
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- A COMPOUND FOR INHIBITING 11BETA-HYDROXY STEROID DEHYDROGENASE 1, AND A PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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Disclosed are a novel compound or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition including the same for inhibiting human 11-beta-hydroxy steroid dehydrogenase type 1 (11beta-HSD1). The disclosed compound and the pharmaceutical composition including the same for inhibiting human 11-beta-hydroxy steroid dehydrogenase type 1 (11beta-HSD1) are excellent in activity and solubility, and is more efficient in formulation and transfer.
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Paragraph 405-407
(2013/03/26)
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- A COMPOUND FOR INHIBITING HUMAN 11-β-HYDROXY STEROID DEHYDROGENASE TYPE 1, AND A PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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The present invention relates to a novel compound, or a stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for human-11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) comprising the same. The invention provides a compound, which has excellent activity and solubility and is more efficiently formulated and delivered, and a pharmaceutical composition for human-11-beta-hydroxysteroid dehydrogenase type 1 comprising the same.
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Page/Page column 118
(2012/10/08)
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- 2, 4 -DIAMINOPYRIMIDINE DERIVATIVES AS PROTEIN KINASE INHIBITORS
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The present invention relates to novel pyrimide derivatives of formula (I): that are useful as kinase inhibitors. More particularly, the present invention relates to novel pyrimidine compounds, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative disorders.
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Page/Page column 89
(2012/05/20)
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- 2,4-DIAMINOPYRIMIDINE COMPOUND
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[Problem] Provided is a compound which is useful as an active ingredient for a pharmaceutical having a PKCθ inhibition activity, particularly a pharmaceutical composition for inhibiting acute rejection occurring in transplantation. [Means for Solution] Th
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Page/Page column 40; 77; 84
(2011/06/24)
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- TETRAHYDROQUINOXALINE UREA DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
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The present invention relates to tetrahydroquinoxaline urea derivatives, to their preparation and to their therapeutic application.
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Page/Page column 40
(2011/02/15)
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- TROPANE UREA DERIVATIVES, PREPARATION THEREOF AND THERAPEUTIC APPLICATION THEREOF AS MODULATORS OF THE ACTIVITY OF 11BETAHSD1
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The invention relates to tropane urea derivatives of general formula (I) and to the application thereof as modulators of the activity of 11β-hydroxysteroid dehydrogenose type 1 (11βHSD1).
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Page/Page column 11
(2011/12/13)
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- COMPOUND HAVING 11 ?-HSD1 INHIBITORY ACTIVITY
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The present invention provides compounds having excellent 11β-HSD1 inhibitory activity. A compound represented by the following formula (I): [wherein X1 represents an oxygen atom, or the formula -(CR11R12)p-, etc., Y1 represents a hydrogen atom, a hydroxyl group, etc., Z1 represents an oxygen atom or the formula -(NR14)-, R1 represents a hydrogen atom, a halogen atom, a cyano group, a C1-4 alkyl group, a C1-4 alkyl group substituted with 1 to 3 halogen atoms, a C1-4 alkoxy group, a C1-4 alkoxycarbonyl group, a carboxyl group, a carbamoyl group, or an amino group, and m represents an integer of 1 or 2, and R2 represents a hydrogen atom or a C1-4 alkyl group, and n represents an integer of 1 or 2].
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Page/Page column 12
(2010/04/25)
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- INHIBITORS OF THE 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1 ENZYME
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A compound of formula (I) or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof. Methods of inhibiting 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme. Methods of treating non-insulin dependent type 2 diabetes, ins
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Page/Page column 47
(2008/06/13)
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- INHIBITORS OF THE 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1 ENZYME
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The present invention relates to compounds which are inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme. The present invention further relates to the use of inhibitors of 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme for the treatme
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Page/Page column 54-55
(2008/06/13)
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- Metabolic stabilization of substituted adamantane
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The present invention is directed to the method of increasing the metabolic stability of adamantane containing compounds that are inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 (11-beta-HSD-1) enzyme. The stability is achieved by substitutions of the adamantane ring.
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Page/Page column 5; 6
(2008/06/13)
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- Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
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The present invention relates to compounds that are inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme. The present invention further relates to the use of inhibitors of 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme for the treatment of non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome and other diseases and conditions that are mediated by excessive glucocorticoid action.
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Page/Page column 24
(2008/06/13)
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