- COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF ANDROGEN RECEPTOR
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This disclosure pertains to compounds, the preparation thereof, and the use of these compounds in the treatment of prostate cancer, including metastatic and/or castrate-resistant prostate cancer, in subjects in need thereof.
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- SUBSTITUTED CONDENSED THIOPHENES AS MODULATORS OF STING
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A compound of formula (I), wherein: R1 is selected from (i) H, (ii) C3-6cycloalkyl, (iii) C3-7heterocyclyl optionally substituted with a group selected from: methyl and ester, and (iv) linear or branched C1-4alkyl optionally substituted with a group selected from: alkoxy, amino, amido, acylamido, acyloxy, alkyl carboxyl ester, alkyl carbamoyl, alkyl carbamoyl ester, phenyl, phosphonate ester, C3-7heterocyclyl optionally substituted with a group selected from methyl and oxo, and a naturally occurring amino acid, optionally N-substituted with a group selected from methyl, acetyl and boc; A1 is CRA or N; A2 is CRB or N; A3 is CRC or N; A4 is CRD or N; where no more than two of A1, A2, A3, and A4 may be N; one or two of RA, RB, RC, and RD, (if present) are selected from H, F, Cl, Br, Me, CF3, cyclopropyl, cyano, OMe, OEt, CH2OH, CH2OMe and CH2NMe2; the remainder of RA, RB, RC, and RD, (if present) are H; Y is O, NH or CH2; RY is selected from: (RYA) and (RYB).
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Page/Page column 127-128
(2019/12/04)
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- Imidazole-containing condensed tricyclic compound and application thereof
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The invention discloses an imidazole-containing condensed tricyclic compound adopting the structure as shown in the formula (I) or pharmaceutically acceptable salts, stereisomers or prodrug molecules thereof. The imidazole-containing condensed tricyclic compound has the IDO1 activity regulation function, can enhance T-cell activation through blocking immune checkpoints IDO1, is used for treating IDO1-mediated immunosuppression, and therefore, can become an effective medicine for treating malignant tumors. When used together with checkpoint protein anti-body drugs or other anti-cancer drugs, the imidazole-containing condensed tricyclic compound can enhance the anti-cancer effect. Meanwhile, the imidazole-containing condensed tricyclic compound has the potential of effectively treating IDO1 abnormity related immunosuppressive diseases and has a high application value.
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- NEW BICYCLIC DERIVATIVES HAVING BETA2 ADRENERGIC AGONIST AND M3 MUSCARINIC ANTAGONIST ACTIVITIES
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The present invention relates to novel compounds having β2 adrenergic agonist and M3 muscarinic antagonist dual activity, to pharmaceutical compositions containing them, to the process for their preparation and to their use in respiratory therapies.
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- PHARMACEUTICAL COMPOUNDS
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This invention relates to compounds that inhibit or modulate the activity of Chk-1 kinase. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds.
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Page/Page column 94; 151; 152
(2015/09/23)
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- Physiological activity of Chinese Lichen (Gyrophora esculenta) component, methyl 2,4-dihydroxy-6-methylbenzoate and the related compounds
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It was confirmed that there was a higher expression of antioxidant potential in methyl 2,4-dihydroxy-6-methylbenzoate (orsellinic acid methyl ester) (2), which was isolated from methanol extract oil of Chinese lichen Gyrophora esculenta rather than from commercialized ascorbic acid. Taking this into account, 4 types of compounds-(4-7) which are known to be related to compound (2)-have been synthesized by using 2,4-dihydroxy benzoic acid (3) as starting material. After that, some physiological activity tests on these compounds have been conducted in the following aspects: antioxidant potential, cytotoxicity, cytokine suppressant effect and histamine liberation inhibition and the effects have been evaluated, respectively. The result shows that (2) and methyl 2,4-dihydroxybenzoate (4) showed high radical expression in both antioxidant potential and histamine liberation inhibition. It was also found that none of these compounds expresses cytotoxicity.
- Wu, Shuhsien,Zhao, Zhendong,Okada, Yoshiharu,Watanabe, Yoshiyuki,Takahata, Toshiyuki,Inoue, Toshio,Otsubo, Eiji,Wang, Jing,Lu, Yanju,Nomura, Masato
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p. 702 - 708
(2014/06/09)
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- Piperidine-based heterocyclic oxalyl amides as potent p38α MAP kinase inhibitors
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The design and synthesis of a new class of p38α MAP kinase inhibitors based on 4-fluorobenzylpiperidine heterocyclic oxalyl amides are described. Many of these compounds showed low-nanomolar activities in p38α enzymatic and cell-based cytokine TNFα produc
- Mavunkel, Babu J.,Perumattam, John J.,Tan, Xuefei,Luedtke, Gregory R.,Lu, Qing,Lim, Don,Kizer, Darin,Dugar, Sundeep,Chakravarty, Sarvajit,Xu, Yong-jin,Jung, Joon,Liclican, Albert,Levy, Daniel E.,Tabora, Jocelyn
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scheme or table
p. 1059 - 1062
(2010/06/14)
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- AMINO ALCOHOL DERIVATIVE, MEDICINAL COMPOSITION CONTAINING THE SAME, AND USE OF THESE
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The present invention provides compounds represented by general formula (I): a prodrug thereof, or pharmaceutical acceptable salts thereof, wherein R1 is hydrogen or lower alkyl; each of R2 and R3 is independently hydrogen or lower alkyl; each of R4, R5 and R6 is independently hydrogen, halogen, lower alkyl or lower alkoxy; R7 is hydrogen or lower alkyl; R8 is hydrogen, halogen, lower alkyl, lower alkoxy, etc; R9 is -COR10, -A1-COR10, -O-A2-COR10, etc; Ar is optionally substituted phenyl or heteroaryl; and A is a bond, -OCH2-, etc, which exhibit potent and selective β3-adrenoceptor stimulating activities. The present invention also provides pharmaceutical compositions containing said compound, and uses thereof.
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Page/Page column 33
(2008/06/13)
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- AMINO ALCOHOL DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME, AND USE THEREOF
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The present invention provides compounds represented by general formula (I): or pharmaceutical acceptable salts thereof, wherein R1 and R2 are each hydrogen or lower alkyl; R3 R4, R5 and R6 are each hydrogen, halogen, lower alkyl or lower alkoxy; R7 and R8 are each hydrogen, halogen, lower alkyl, halo-lower alkyl, lower alkoxy, cycloalkyl, aryl, heteroaryl, cyano, a hydroxyl group, lower acyl, carboxy or the like; R9 is -C(O)-R10, -A1-C(O)-R10, -O-A2-C(O)-R10 or a tetrazol-5-yl group, which exhibit potent and selective β3-adrenoceptor stimulating activities. The present invention also provides pharmaceutical compositions containing said compound, and uses thereof.
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Page/Page column 27
(2008/06/13)
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- Hydroxy-methoxybenzoic methyl esters: Synthesis and antifeedant activity on the pine weevil, Hylobius abietis
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The pine weevil Hylobius abietis (L.) (Coleoptera: Curculionidae) feeds on the bark of coniferous seedlings and is the economically most important forestry restocking pest in large parts of Europe. Substances with an antifeedant effect may offer an environmentally friendly alternative to insecticides for the protection of planted seedlings. Bioassays were performed on commercial and synthetic methyl hydroxy-methoxybenzoates in order to determine their possible antifeedant activity. Two methyl hydroxy-methoxybenzoates were synthesized by esterification and mono-O-methylation of two dihydroxybenzoic acids. A regioselective protection-deprotection strategy was used in the synthetic pathway of the other non-commercial esters, esterification and selective pivaloylation of the less-hindered hydroxyl group of other commercial dihydroxybenzoic acids gave diester intermediates, which then were O-methylated before methanolysis of the pivaloyl group which yielded the desired non-commercial methyl hydroxy-methoxybenzoates. The five synthesized methyl hydroxy-methoxybenzoic esters were complemented with commercial samples of the five other isomers of methyl hydroxy-methoxybenzoate and spectrometric data were collected for the complete set of isomers. All ten isomers were tested for their antifeedant effect on the pine weevil. The effect varied considerably among the hydroxy-methoxybenzoic esters. Methyl 2-hydroxy-3-methoxybenzoate showed the highest effect and may thus be a candidate for practical use in pine weevil pest management.
- Legrand, Sacha,Nordlander, G?ran,Nordenhem, Henrik,Borg-Karlson, Anna-Karin,Unelius, C. Rikard
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p. 829 - 835
(2007/10/03)
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- Nonpeptide oxytocin antagonists: Potent, orally bioavailable analogs of L-371,257 containing A 1-R-(pyridyl)ethyl ether terminus
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Structure-activity studies on the oxytocin antagonist 1 (L-371,257) have identified a new series of high affinity, receptor-selective OT antagonists in which the N-acetyl-4-piperidinyl ether terminus in 1 has been replaced with a 1-(aryl)ethoxy group.
- Kuo, Michelle S.,Bock, Mark G.,Freidinger, Roger M.,Guidotti, Maribeth T.,Lis, Edward V.,Pawluczyk, Joseph M.,Perlow, Debra S.,Pettibone, Douglas J.,Quigley, Amy G.,Reiss, Duane R.,Williams, Peter D.,Woyden, Carla J.
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p. 3081 - 3086
(2007/10/03)
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- Development of orally active oxytocin antagonists: Studies on 1-(1-{4- [1-(2-methyl-1-oxidopyridin-3-ylmethyl)piperidin-4-yloxy].2methoxybenzoyl}- 4-yl)-1,4-dihydrobenz[d][1,3]oxazin-2-one (L-372,662) and related pyridines
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The previously reported oxytocin antagonist L-371,257 (2) has been modified at its acetylpiperidine terminus to incorporate various pyridine N- oxide groups. This modification has led to the identification of compounds with improved pharmacokinetics and excellent oral bioavailability. The pyridine N-oxide series is exemplified by L-372,662 (30), which possessed good potency in vitro (Ki = 4.1 nM, cloned human oxytocin receptor) and in vivo (intravenous AD50 = 0.71 mg/kg in the rat), excellent oral bioavailability (90% in the rat, 96% in the dog), good aqueous solubility (>8.5 mg/mL at pH 5.2) which should facilitate formulation for iv administration, and excellent selectivity against the human arginine vasopressin receptors. Incorporation of a 5-fluoro substituent on the central benzoyl ring of this class of oxytocin antagonists enhanced in vitro and in vivo potency but was detrimental to the pharmacokinetic profiles of these compounds. Although lipophilic substitution around the pyridine ring of compound 30 gave higher affinity in vitro, such substituents were a metabolic liability and caused shortfalls in vivo. Two approaches to prevent this metabolism, addition of a cyclic constraint and incorporation of trifluoromethyl groups, were examined. The former approach was ineffective because of metabolic hydroxylation on the constrained ring system, whereas the latter showed improvement in plasma pharmacokinetics in some cases.
- Bell, Ian M.,Erb, Jill M.,Freidinger, Roger M.,Gallicchio, Steven N.,Guare, James P.,Guidotti, Maribeth T.,Halpin, Rita A.,Hobbs, Doug W.,Homnick, Carl F.,Kuo, Michelle S.,Lis, Edward V.,Mathre, David J.,Michelson, Stuart R.,Pawluczy, Joseph M.,Pettibone, Douglas J.,Reiss, Duane R.,Vickers, Stanley,Williams, Peter D.,Woyden, Carla J.
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p. 2146 - 2163
(2007/10/03)
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- Safety-catch anchoring linkage for synthesis of peptide amides by Boc/Fmoc strategy
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2-Methoxy-4,4'-bis(methylthio)benhydrylamine (10) and the corresponding disulfoxide were prepared and tested as a model amide protecting groups for their stability toward acidic conditions. Subsequently, the novel 4-[4,4'-bis(methylsulfinyl)-2-oxy-(9-fluorenylmethyloxycarbonyl) benzhydrylamino]butanoic acid (SCAL) handle (9) has been prepared and applied to solid-phase peptide synthesis of C-terminal peptide amide using both 9-fluorenylmethyloxycarbonyl (Fmoc) and tert-butyloxycarbonyl (Boc) groups for N(α)-amino protection.
- Patek,Lebl
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p. 3891 - 3894
(2007/10/02)
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- Structure-activity relationships of arylimidazopyridine cardiotonics: Discovery and inotropic activity of 2-[2-methoxy-4-(methylsulfinyl)phenyl]-1H-imidazo[4,5-c]pyridine
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Recently several noncatecholamine, nonglycoside cardiotonic drugs have been discovered that possess both inotropic and vasodilator activities in experimental animals and man. Prototypical compounds include amrinone, sulmazole, and fenoximone. We investigated the structural requirements necessary for optimal inotropic activity in a series of molecules containing a heterocyclic ring fused to 2-phenylimidazole and discovered that 2-phenylimidazo[4,5-c]pyridines were generally 5-10-fold more potent than analogous 2-phenylimidazo[4,5-b]pyridines (e.g., sulmazole) or 8-phenylpurines. Furthermore, all imidazo[4,5-c]pyridine analogues we tested were orally active; in contrast, only one of the imidazo[4,5-b]pyridine derivatives, sulmazole, was significantly active. One of several highly active compounds in the [4,5-c] series was 50 (LY175326, 2-[2-methoxy-4-(methylsulfinyl)phenyl]-1H- imidazo[4,5-c]pyridine hydrochloride). The structure-activity relationship of this series is presented and compared to that of the imidazo[4,5-b]pyridine and purine series.
- Robertson,Beedle,Krushinski,Pollock,Wilson,Wyss,Hayes
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p. 717 - 727
(2007/10/02)
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- Methods of protection against emesis in mammals by administration of a heterocyclic benzamide
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The heterocyclic benzamides of this invention are particularly effective for the treatment of emesis in mammals. For example, when they are administered to dogs in relatively small dosage, they afford 100% protection against vomiting. They are also non-toxic in dosages for effecting complete control of vomiting.
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