- INHIBITORS OF APOL1 AND METHODS OF USING SAME
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The disclosure provides at least one entity chosen from compounds of formula (I), solid state forms of the same, compositions comprising the same, and methods of using the same, including use in treating focal segmental glomerulosclerosis (FSGS) and/or non-diabetic kidney disease (NDKD).
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- HETEROARYL(HETEROCYCLYL)METHANOL COMPOUNDS USEFUL IN THE TREATMENT OF HYPERGLYCAEMIA
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There is herein provided a compound of formula I (I) or a pharmaceutically acceptable salt thereof, wherein the ring comprising Q1 to Q5, R1, m, X1 and ring A have meanings as provided in the description.
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Page/Page column 53
(2020/10/09)
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- HETEROCYCLYL(PHENYL)METHANOL COMPOUNDS USEFUL IN THE TREATMENT OF HYPERGLYCAEMIA
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There is herein provided a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X, R1, R2, R3, ring A, n and y have meanings as provided in the description.
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Page/Page column 53
(2020/10/09)
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- LACTAM COMPOUNDS AS EP4 RECEPTOR-SELECTIVE AGONISTS FOR USE IN THE TREATMENT OF EP4-MEDIATED DISEASES AND CONDITIONS
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Disclosed herein are compounds of formula (I) wherein L1, L2, L3, L4, R1, R4, R5, R6, and s are as defined in the specification. Compounds of formula (I) are EP4 agonists useful in the treatment of glaucoma, osteoporosis, bone fracture, periodontal bone loss, orthopedic implant, alopecia, neuropathic pain, and related disorders. Pharmaceutical compositions and methods of treating conditions or disorders are also described.
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- NOVEL INDOLE DERIVATIVES AND THEIR USE IN NEURODEGENERATIVE DISEASES
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The present invention relates to indole compounds, and pharmaceutically acceptable compositions thereof, useful as antagonists of P2X7, and for the treatment of P2X7-related disorders.
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- Chiral-Substituted Poly-N-vinylpyrrolidinones and Bimetallic Nanoclusters in Catalytic Asymmetric Oxidation Reactions
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A new class of poly-N-vinylpyrrolidinones containing an asymmetric center at C5 of the pyrrolidinone ring were synthesized from l-amino acids. The polymers, particularly 17, were used to stabilize nanoclusters such as Pd/Au for the catalytic asymmetric oxidations of 1,3- and 1,2-cycloalkanediols and alkenes, and Cu/Au was used for C-H oxidation of cycloalkanes. It was found that the bulkier the C5 substituent in the pyrrolidinone ring, the greater the optical yields produced. Both oxidative kinetic resolution of (±)-1,3- and 1,2-trans-cycloalkanediols and desymmetrization of meso cis-diols took place with 0.15 mol % Pd/Au (3:1)-17 under oxygen atmosphere in water to give excellent chemical and optical yields of (S)-hydroxy ketones. Various alkenes were oxidized with 0.5 mol % Pd/Au (3:1)-17 under 30 psi of oxygen in water to give the dihydroxylated products in >93% ee. Oxidation of (R)-limonene at 25 °C occurred at the C-1,2-cyclic alkene function yielding (1S,2R,4R)-dihydroxylimonene 49 in 92% yield. Importantly, cycloalkanes were oxidized with 1 mol % Cu/Au (3:1)-17 and 30% H2O2 in acetonitrile to afford chiral ketones in very good to excellent chemical and optical yields. Alkene function was not oxidized under the reaction conditions. Mechanisms were proposed for the oxidation reactions, and observed stereo- and regio-chemistry were summarized.
- Hao, Bo,Gunaratna, Medha J.,Zhang, Man,Weerasekara, Sahani,Seiwald, Sarah N.,Nguyen, Vu T.,Meier, Alex,Hua, Duy H.
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supporting information
p. 16839 - 16848
(2017/01/10)
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- METHODS, SYSTEMS, AND COMPOSITIONS FOR PROMOTING BONE GROWTH
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The present invention relates to novel bone compositions for locally delivering a therapeutic agent to the site of a bone defect. Therapeutic agents may promote repair of the bone defect and/or treat conditions or disorders such as pain, inflammation, cancer, and infection. The compositions include calcium phosphate cements and a demineralized bone matrix or a collagen sponge. The compositions are useful for implantation in a patient at the site of a bone defect.
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- CARBONITRILE DERIVATIVES AS SELECTIVE ANDROGEN RECEPTOR MODULATORS
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The present invention relates to a compound of Formula 1, 2 or 3: I II III wherein A is N or -CR0--, where R0 is hydrogen, C1-C6 linear or branched chain alkyl, etc., Z is -CRe --, or, -N--, where Re is hydrogen, C1 -C6 linear or branched chain alkyl, etc.; R1 is hydrogen, C1 -C6 linear or branched chain alkyl, etc.; R2 are independently hydrogen or C1-C6 linear or branched chain alkyl; R3 and R4 are independently hydrogen, C1C6 linear or branched chain alkyl, etc.;. R5 and R6 are independently hydrogen or C1-C6 linear or branched chain alkyl, etc.; R8 is hydrogen, C1 -C6 linear or branched chain alkyl, etc.; R9 and R10 are independently hydrogen or C1- C6 linear or branched chain alkyl, etc.; Q is --CO--, --(CH2)q--, --(CHRs)q--, or -(CRsRt)q- -, where Rs and Rt are independently C1-C6 linear or branched chain alkyl, aryl, alkylaryl, heteroaryl or alkylheteroaryl; where q is 0, 1, 2, or 3; and, where n is 0, 1, 2, 3, 4 or 5; or, a pharmaceutically acceptable salt thereof, for the treatment of certain diseases, particularly those affected or mediated by the androgen receptor; to compbinations comprising such compounds with a second pharmaceutically active ingredient; to compositions containing such combinations; and to such combinations for the treatment of various diseases, particularly, those affected or mediated by the androgen receptor.
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- LACTAM COMPOUNDS AS EP4 RECEPTOR-SELECTIVE AGONISTS FOR USE IN THE TREATMENT OF EP4-MEDIATED DISEASES AND CONDITIONS
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Disclosed herein are compounds of formula (I) wherein L 1 , L 2 , L 3 , L 4 , R 1 , R 4 , R 5 , R 6 , and s are as defined in the specification. Compounds of formula (I) are EP 4 agonists useful in the treatment of glaucoma, osteoporosis, bone fracture, periodontal bone loss, orthopedic implant, alopecia, neuropathic pain, and related disorders. Pharmaceutical compositions and methods of treating conditions or disorders are also described.
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- Structural prerequisites for receptor binding of helicokinin I, a diuretic insect neuropeptide from helicoverpa zea
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In insects essential physiological processes such as muscle activity or water balance are controlled by neuropeptides. However, owing to their metabolic instability and adverse physicochemical properties peptides are unsuited as crop protection agents. Helicokinin I, a diuretic neuropeptide of cotton pest Helicoverpa zea represents a most promising target for the design of neuropeptide mimetics. Several helicokinin analogues containing scaffolds with varying rigidity and different orientations of the N- and C-terminal peptide chains were synthesized and tested for receptor binding. Additional conformational analyses by NMR spectroscopy in a membrane-mimicking environment together with MD simulations provide a deeper insight into the structural requirements for receptor binding and explain the remarkable activity of a macrocyclic helicokinin I derivative. A delicate balance of rigidity and flexibility makes the difference between activity and inactivity. Detailed conformational studies of analogues of the diuretic insect-neuropeptide helicokinin I containing diverse cyclic scaffolds with different flexibility and orientation of the N- and C-termini provide a better understanding of the structural requirements for receptor binding. Copyright
- Van, Chien Tran,Zdobinsky, Tino,Seebohm, Guiscard,Nennstiel, Dirk,Zerbe, Oliver,Scherkenbeck, Juergen
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p. 2714 - 2725
(2014/05/06)
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- DIFLUOROLACTAM COMPOSITIONS FOR EP4-MEDIATED OSTEO RELATED DISEASES AND CONDITIONS
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Disclosed herein are compositions and methods of treating osteroporosis, bone fracture, bone loss, and increasing bone density by administration of compounds of formula (I) or compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier, wherein L1, L2, L4, R1, R4, R5, R6, and s are as defined in the specification.
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- LACTAM COMPOUNDS AS EP4 RECEPTOR-SELECTIVE AGONISTS FOR USE IN THE TREATMENT OF EP4-MEDIATED DISEASES AND CONDITIONS
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Disclosed herein are compounds of formula (I) wherein L1, L2, L3, R1, R4, R5, and R6 are as defined in the specification. Compounds of formula (I) are EP4 agonists useful in the treatment of glaucoma, osteoporosis, bone fracture, periodontal bone loss, orthopedic implant, alopecia, neuropathic pain, and related disorders. Pharmaceutical compositions and methods of treating conditions or disorders are also described.
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- Synthesis of 3-guaninyl- and 3-adeninyl-5-hydroxymethyl-2-pyrrolidinone nucleosides
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l- And d-glutamic acids, as well as trans-4-hydroxy-l-proline, are converted to the corresponding 3-guaninyl-5-hydroxymethyl-2-pyrrolidinone (4) or 3-adeninyl-5-hydroxymethyl-2-pyrrolidinone (5) nucleoside analog. The protecting group used to block the lactam nitrogen in key intermediates has a significant effect on the diastereoselectivity of the coupling reaction with adenine or guanine.
- Saleh, Abdullah,D'Angelo, John G.,Morton, Martha D.,Quinn, Jesse,Redden, Kendra,Mielguz, Rafal W.,Pavlik, Christopher,Smith, Michael B.
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p. 5574 - 5583
(2011/10/02)
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- NOVEL COMPOUNDS AS CANNABINOID RECEPTOR LIGANDS
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Disclosed herein are compounds of formula (I) wherein R1, R2, R3, R25a, R26a, X, and n are as defined in the specification. Pharmaceutical compositions comprising such compounds, and methods of treating conditions and disorders using such compounds and pharmaceutical compositions are also described
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Page/Page column 23
(2009/10/06)
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- PYRROLIDIN-2-ON DERIVATIVES AS EP4 RECEPTOR AGONISTS
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This invention relates to potent selective agonists of the EP4 subtype of prostaglandin E2 receptors having structural formula (I), their use or a formulation thereof in the treatment of glaucoma and other conditions which are related to elevated intraocular pressure in the eye of a patient. This invention further relates to the use of the compounds of this invention for mediating the bone modeling and remodeling processes of the osteoblasts and osteoclasts.
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- 1,5-DISTRIBUTED PYRROLID-2-ONE DERIVATIVES FOR USE AS EP4 RECEPTOR AGONISTS IN THE TREATMENT OF EYE DISEASES SUCH AS GLAUCOMA
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This invention relates to potent selective agonists of the EP4 subtype of prostaglandin E2 receptors of formula (I), their use or a formulation thereof in the treatment of glaucoma and other conditions which are related to elevated intraocular pressure in the eye of the patient.
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- Chiral non-racemic bis(vicinal 1,2-diamines): 4,5-diamino-N-(3,4-diaminobutyl)pentanamide tetrahydrochloride, N,N'-bis[3,4-bis(t-butoxycarbonylamino)butyl]urea and N,N'-bis[3,4-bis(t-butoxycarbonylamino)butyl]hexanamide
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The reaction of (R) or (S)-N4,N5-bis(t-butoxycarbonyl)-4,5-diaminopentanoic acid (6) with (R) or (S)-N3,N4-bis(t-butoxycarbonyl)-3,4-diaminobutylisocyanate (8) catalyzed by 4-dimethylamino pyridine (DMAP), leads to the synthesis of (R,R), (S,S), (R,S) and (S,R) isomeric amides (11 a-d). The addition of adipic acid monomethyl ester to (R) or (S) isocyanate, followed by saponification, acidification and subsequent reaction with the second molecule of (R) or (S) isocyanate allows isolation of the (R,R), (S,S) and the meso isomers of N,N'-bis[3,4-bis(t-butoxycarbonylamino)butyl]hexanediamide (17). Removal of protecting groups with HCl/EtOH affords chiral non-racemic molecules having two free vicinal diamine units.
- Altman,Beck
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p. 13309 - 13320
(2007/10/02)
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- A NOVEL APPROACH TO THE ASYMMETRIC SYNTHESIS OF MANZAMINE A. CONSTRUCTION OF THE TETRACYCLIC ABCE RING SYSTEM
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The enantiomerically pure tetracyclic ABCE subunit of manzamine A has been constructed by an intramolecular Diels-Alder reaction of the vinylogous imide 13 to give the ABC tricyclic core 14; elaboration of 14 into 16 followed by a novel olefin metathesis reaction to form the azocine ring then delivered the tetracycle 17.
- Martin, Stephen F.,Liao, Yusheng,Wong, Yueling,Rein, Tobias
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p. 691 - 694
(2007/10/02)
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- Efficient total synthesis of AI-77-B, a gastroprotective substance from Bacillus pumilus AI-77
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First total synthesis of AI-77-B (1), a gastroprotective substance from Bacillus pumilus AI-77, was achieved in a stereoselective and convergent manner. In this synthesis, the dihydroisocoumarin part 2 was constructed in one step through 1,2-addition of the benzylic anion 17b to Boc-L-leucinal 7b. The hydroxy amino acid 4 was elaborated from (R)-glutamic acid in a highly stereoselective manner. Condensation of 2·HCl and 4, intramolecular Pinner reaction, followed by mild hydrolysis afforded AI-77-B (1).
- Hamada,Hara,Kawai,Kohno,Shioiri
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p. 8635 - 8652
(2007/10/02)
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- 12. Approaches to the Synthesis of Cytochalasans; Part 9: A Versatile Concept Leading To All Structural Types of Cytochalasans
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Starting from D-glutamic acid (5), the bicyclic compounds 4a and 4b were synthesized via 17 (Schemes 1 and 2).The reaction leading to 4g and 4h with LiCuPh2 was not successful.But treatment of the N-protected model lactams 19, 21, and 22 with Li2Cu(CN)Ph2 gave the amino ketones 24, 26, and 26, respectively (Scheme 3).The desired compound 23 was obtained from 20.Conversion of the unprotected lactams 28, 31, and 32 gave the phenyl derivative 34 in excellent yields.Ester 35 was transformed to the α-amino-γ-oxo-acid derivative 36.This conversion opens a novel access to this type of compounds.
- Ackermann, Jean,Matthes, Michael,Tamm, Christoph
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p. 122 - 132
(2007/10/02)
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- Stereoselectivity of muscarinic receptors in vivo and in vitro for oxotremorine analogues. N-[4-(Tertiary amino)-2-butynyl]-5-methyl-2-pyrrolidones
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The enantiomers of three 5-methyl-2-pyrrolidone analogues of the muscarinic agent oxotremorine were synthesized. The pyrrolidine derivative (R)-13 was an antagonist to carbachol in the guinea pig ileum and also showed central and peripheral antimuscarinic activity in vivo. It was more potent and more selective than atropine in antagonizing the central effects of 1. The dimethylamino analogue (R)-14 and the trimethylammonium salt (R)-15 were potent agonists in the guinea pig ileum. (R)-14 showed both central muscarinic (hypothermia) and central antimuscarinic activity (antagonism of oxotremorine-induced tremor) in vivo. The R enantiomers of 13-15 were considerably more potent than the S enantiomers in vivo and in vitro irrespective of whether agonist or antagonist activity was measured. From a comparison of the contribution of the methyl group at the chiral center to the overall affinities it is suggested that agonists and antagonists in this series bind in an essentially identical manner to the muscarinic receptor.
- Amstutz,Ringdahl,Karlen,Roch,Jenden
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p. 1760 - 1765
(2007/10/02)
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- Heterocyclic Prostaglandins. V. Synthesis of (12R,15S)-(-)-11-Deoxy-8-azaprostaglandin E1 and Related Compounds
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The synthesis of (12R,15S)-(-)-11-deoxy-8-azaprostaglandin E1 ((R)-1a) and three diastereomers ((R)-2a, (S)-1a, and (S)-2a) starting from optically active pyroglutamic acid ((R)-3 and (S)-3) is reported.Esterification of (R)-3 and NaBH4 reduction gave (R)-(-)-5-hydroxymethyl-2-pyrrolidinone ((R)-5).Ethoxyethylation of (R)-5 and N-alkylation with methyl 7-bromoheptanoate, followed by acid treatment, provided (R)-hydroxymethyl pyrrolidinone ((R)-8).The Collins oxidation of (R)-8 gave (R)-(-)-methyl 7-(5-formyl-2-oxo-1-pyrrolidine)heptanoate ((R)-9), which served as a key intermediate.The Wittig reaction of (R)-9 and dimethyl 2-oxoheptylphosphonate gave the (R)-enone ((R)-10a) which was converted to the (12R,15S)-enol ((R)-11a) and (12R,15R)-enol ((R)-12a) by NaBH4 reduction.Alkaline hydrolysis of (R)-11a and (R)-12a gave (R)-1a and (R)-2a in high yields.Similarly, the (S)-aldehyde ((S)-9) was prepared from (S)-3 and converted to the (12S,15S)-acid ((S)-1a) and (12S,15R)-acid ((S)-2a) by the same sequence of reactions used for the (R)-series.Some (12R,15S)-acid derivatives ((R)-1b-g) with a modified ω-chain were also synthesized.These analogs ((R)-1b-g) were also prepared from (R)-9 via synthetic sequences similar to that described above.Keywords - heterocyclic prostaglandin; (12R,15S)-(-)-11-deoxy-8-azaprostaglandin E1; (12R,15R)-(-)-11-deoxy-8-azaprostaglandin E1; (12S,15S)-(+)-11-deoxy-8-azaprostaglandin E1; (12S,15R)-(+)-11-deoxy-8-azaprostaglandin E1; (R)-(-)-methyl 7-(5-formyl-2-oxo-1-pyrrolidine)heptanoate; (S)-(+)-methyl 7-(5-formyl-2-oxo-1-pyrrolidine)heptanoate
- Saijo, Shigeyoshi,Wada, Masao,Himizu, Jun-ichi,Ishida, Akihiko
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p. 1449 - 1458
(2007/10/02)
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