- 5-[3-[PIPERAZIN-1-YL]-3-OXO-PROPYL]-IMIDAZOLIDINE-2,4-DIONE DERIVATIVES AS ADAMTS 4 AND 5 INHIBITORS FOR TREATING E.G. OSTEOARTHRITIS
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The present invention discloses 5-[3-[piperazin-l-yl]-3-oxo-propyl]-imidazolidine-2,4-dione derivatives according to Formula (I), wherein R1, R2, R3a, R3b, R6a, R6b, the subscript n and Cy are as defined herein. The present invention relates to compounds inhibiting ADAMTS 4 and 5 for the prophylaxis or treatment of inflammatory diseases or diseases involving degradation of cartilage or disruption of cartilage homeostasis, such as e.g. osteoarthritis.
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Paragraph 0290
(2018/01/15)
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- 5-[3-[PIPERIDIN-1-YL]-3-OXO-PROPYL]-IMIDAZOLIDINE-2,4-DIONE DERIVATIVES AS ADAMTS 4 AND 5 INHIBITORS FOR TREATING E.G. OSTEOARTHRITIS
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The present invention discloses 5-[3-[piperazin-l-yl]-3-oxo-propyl]-imidazolidine-2,4-dione derivatives according to Formula (I), wherein R1, R2, R3a, R3b, R6a, R6b, the subscript n and Cy are as defined herein. The present invention relates to compounds inhibiting ADAMTS 4 and 5 for the prophylaxis or treatment of inflammatory diseases or diseases involving degradation of cartilage or disruption of cartilage homeostasis, such as e.g. osteoarthritis.
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Paragraph 0269; 0270
(2018/01/15)
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- N-((HETEROARYLMETHYL)-HETEROARYL-CARBOXAMIDE DERIVATIVES AS PLASMA KALLIKREIN INHIBITORS
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The present invention provides a selection of compounds of formula (I): compositions comprising such compounds; the use of such compounds in therapy (for example in the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated); and methods of treating patients with such compounds.
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Page/Page column 42
(2016/06/14)
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- Design and Synthesis of Benzimidazoles As Novel Corticotropin-Releasing Factor 1 Receptor Antagonists
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Benzazole derivatives with a flexible aryl group bonded through a one-atom linker as a new scaffold for a corticotropin-releasing factor 1 (CRF1) receptor antagonist were designed, synthesized, and evaluated. We expected that structural diversity could be expanded beyond that of reported CRF1 receptor antagonists. In a structure-activity relationship study, 4-chloro-N2-(4-chloro-2-methoxy-6-methylphenyl)-1-methyl-N7,N7-dipropyl-1H-benzimidazole-2,7-diamine 29g had the most potent binding activity against a human CRF1 receptor and the antagonistic activity (IC50 = 9.5 and 88 nM, respectively) without concerns regarding cytotoxicity at 30 μM. Potent CRF1 receptor-binding activity in brain in an ex vivo test and suppression of stress-induced activation of the hypothalamus-pituitary-adrenocortical (HPA) axis were also observed at 138 μmol/kg of compound 29g after oral administration in mice. Thus, the newly designed benzimidazole 29g showed in vivo CRF1 receptor antagonistic activity and good brain penetration, indicating that it is a promising lead for CRF1 receptor antagonist drug discovery research.
- Mochizuki, Michiyo,Kori, Masakuni,Kobayashi, Katsumi,Yano, Takahiko,Sako, Yuu,Tanaka, Maiko,Kanzaki, Naoyuki,Gyorkos, Albert C.,Corrette, Christopher P.,Cho, Suk Young,Pratt, Scott A.,Aso, Kazuyoshi
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p. 2551 - 2566
(2016/04/10)
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- Discovery of a 7-arylaminobenzimidazole series as novel CRF1receptor antagonists
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A promising lead compound 1 of a benzimidazole series has been identified as a corticotropin-releasing factor 1 (CRF1) receptor antagonist. In this study, we focused on replacement of a 7-alkylamino group of 1, predicted to occupy a large lipophilic pocket of a CRF1receptor, with an aryl group. During the course of this examination, we established new synthetic approaches to 2,7-diarylaminobenzimidazoles. The novel synthesis of 7-arylaminobenzimidazoles culminated in the identification of compounds exhibiting inhibitory activities comparable to the alkyl analog 1. A representative compound, p-methoxyanilino analog 16g, showed potent CRF binding inhibitory activity against a human CRF1receptor and human CRF1receptor antagonistic activity (IC50?=?27?nM, 56?nM, respectively). This compound exhibited ex vivo125I-Tyr0(125I-CRF) binding inhibitory activity in mouse frontal cortex, olfactory bulb, and pituitary gland at 20?mg/kg after oral administration. In this report, we discuss the structure–activity-relationship of these 7-arylamino-1H-benzimidazoles and their synthetic method.
- Mochizuki, Michiyo,Kori, Masakuni,Kono, Mitsunori,Yano, Takahiko,Sako, Yuu,Tanaka, Maiko,Kanzaki, Naoyuki,Gyorkos, Albert C.,Corrette, Christopher P.,Aso, Kazuyoshi
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p. 4675 - 4691
(2016/09/13)
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- 17BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1 INHIBITORS FOR THE TREATMENT OF HORMONE-RELATED DISEASES
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The invention relates to the use of non-steroidal 17beta-hydroxysteroid dehydrogenase type 1 inhibitors for the treatment and prophylaxis of hormone-dependent, particularly estrogen-dependent, diseases.The invention further relates to suitable inhibitors and to a method for the production thereof.
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Page/Page column 13
(2010/08/18)
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- NOVEL HIV REVERSE TRANSCRIPTASE INHIBITORS
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The invention is related to compounds of Formula (I) or a pharmaceutically acceptable salt, solvate, ester, and/ or phosphonate thereof, compositions containing such compounds, and therapeutic methods that include the administration of such compounds.
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Page/Page column 422; 423
(2009/03/07)
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- Derivatives of 4-(n-azacycloalkyl) anilides as potassium channel modulators
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This invention provides a compound of formula IA where X═O or S; Y is O or S; q=1 or 0; and other substituents are defined herein. Such compounds can affect the opening of, or otherwise modulate, voltage-gated potassium channels. They are potentially usef
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Page/Page column 31
(2008/12/06)
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- BENZIMIDAZOLE COMPOUNDS
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There is provided a compound of the formula (1) wherein R1 is an optionally substituted C1-10 alkyl; R2 is H, or a C1-6 alkyl which may be substituted with 1 to 3 substituents; R3 is a 5- or 6-membered aromatic group which may be substituted with 1 to 5 substituents, wherein the 5- or 6-membered aromatic group may be fused with a 5- or 6- membered ring which may be substituted with 1 to 3 C1-6 alkyls; R4 is a hydrogen, a halogen, a hydroxy, a cyano, a C1-6 alkyl or a C1-6 alkoxy; Z is -O-, -S-, -SO-, -SO2-, or - NR5- wherein R5 is a hydrogen or a C1-6 alkyl; or a salt thereof or a prodrug thereof, which have CRF receptor antagonist activity and use thereof.
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Page/Page column 92
(2008/12/05)
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- RENIN INHIBITORS
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Disclosed are compounds of Formula (I) wherein the R, R1, R2, R3, X, Y, A, Q, E, and G are defined herein. These compounds bind to aspartic proteases to inhibit their activity and are useful in the treatment or amelioration of diseases associated with aspartic protease activity. Also disclosed are methods of use of the compounds of Formula I for ameliorating or treating aspartic protease related disorders in a subject in need thereof.
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Page/Page column 138
(2008/12/04)
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- RENIN INHIBITORS
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Described are compounds which bind to aspartic proteases to inhibit their activity. They are useful in the treatment or amelioration of diseases associated with aspartic protease activity. Also described are methods of use of the compounds described herein in ameliorating or treating aspartic protease related disorders in a subject in need thereof.
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Page/Page column 118
(2008/12/04)
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- Synthesis of novel diarylpyrimidine analogues of TMC278 and their antiviral activity against HIV-1 wild-type and mutant strains
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Novel diarylpyrimidines (DAPY), which represent next generation of non-nucleoside reverse transcriptase inhibitors (NNRTIs), were synthesized and their activities against human immunodeficiency virus type I (HIV-1) assessed. Modulations at positions 2 and
- Mordant, Celine,Schmitt, Benoit,Pasquier, Elisabeth,Demestre, Christophe,Queguiner, Laurence,Masungi, Chantal,Peeters, Anik,Smeulders, Liesbeth,Bettens, Eva,Hertogs, Kurt,Heeres, Jan,Lewi, Paul,Guillemont, Jerome
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p. 567 - 579
(2008/02/10)
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- SHIP 1 MODULATOR COMPOUNDS
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The present invention provides the use of pelorol analogs of Formula, ( I ) and pharmaceutical compositions thereof as modulators of SHIP 1 activity. A compound or a pharmaceutical composition of the present invention may be used for the treatment or prop
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Page/Page column 51-52
(2008/06/13)
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- ISOINDOLONE COMPOUNDS AND THEIR USE AS METABOTROPIC GLUTAMATE RECEPTOR POTENTIATORS
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The present invention is directed to compounds of formula (I), wherein R1 is a ring and n is a number from 1 to 8. The invention also relates to use of the compounds in therapy as metabotropic glutamate receptor modulators, particularly in neurological and psychiatric disorders.
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Page/Page column 61
(2008/06/13)
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- HIV INHIBITING 1,2,4-TRIAZIN-6-ONE DERIVATIVES
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The present invention relates to HIV replication inhibitors of formula (I) a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof, wherein ring A and ring B represent phenyl, pyridyl, pyridaz
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Page/Page column 61
(2008/06/13)
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- HIV REPLICATION INHIBITING PURINE DERIVATIVES
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The present invention relates to the use of a compound of formula (I) for the manufacture of a medicament for the prevention or the treatment of HIV infection wherein the compound of formula (I) is a compound of formula (I) a N-oxide, a pharmaceutically a
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Page/Page column 52
(2010/02/11)
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- A short and concise asymmetric synthesis of hamigeran B
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The interesting biological properties of the hamigerans wherein hamigeran B is a potent antiviral agent with low cytotoxicity to host cells make these deceptively simple looking structures challenging synthetic targets. A strategy to hamigeran B evolved wherein the three contiguous stereocenters are established ultimately from a Pd catalyzed asymmetric allylic alkylation (AAA). The latter involves an asymmetric allylation of a non-stabilized ketone enolate in 77% yield and 93% ee. By using this process, (S)-5-allyl-2-isopropyl-5- methyl-1-trifluoromethanesulfonyloxycyclopentene becomes available in four steps from 2-methylcyclopentanone. Introduction of the aryl unit by cross-coupling proceeded intermolecularly but failed intramolecularly. On the other hand, reductive removal of the triflate permitted a Heck reaction to effect intramolecular introduction of the aryl ring. The unusual conformational properties of this molecular architecture are revealed by the regioselectivity of the β-hydrogen elimination in the Heck reaction and the diastereoselectivity of the reduction establishing the stereochemistry of the carbon bearing the isopropyl group. The successful route consists of 15 steps from 2-methylcyclopentanone and dimethylorcinol illustrating the efficiency of the route based upon the Pd AAA.
- Trost, Barry M.,Pissot-Soldermann, Carole,Chen, Irwin
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p. 951 - 959
(2007/10/03)
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- SUBSTITUTED MORPHOLINE AND THIOMORPHOLINE DERIVATIVES
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The present invention relates to morpholine and thiomorpholine derivatives of the general formula I or pharmaceutically acceptable salts thereof and their use.
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Page/Page column 44-45
(2008/06/13)
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- 2-Amino-6-arylsulfonylbenzonitriles as non-nucleoside reverse transcriptase inhibitors of HIV-1
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A series of 2-amino-5-arylthiobenzonitriles (1) was found to be active against HIV-1. Structural modifications led to the sulfoxides (2) and sulfones (3). The sulfoxides generally showed antiviral activity against HIV-1 similar to that of 1. The sulfones, however, were the most potent series of analogues, a number having activity against HIV-1 in the nanomolar range. Structural-activity relationship (SAR) studies suggested that a meta substituent, particularly a meta methyl substituent, invariably increased antiviral activities. However, optimal antiviral activities were manifested by compounds where both meta groups in the arylsulfonyl moiety were substituted and one of the substituents was a methyl group. Such a disubstitution led to compounds 3v, 3w, 3x, and 3y having IC50 values against HIV-1 in the low nanomolar range. When gauged for their broad-spectrum antiviral activity against key non-nucleoside reverse transcriptase inhibitor (NNRTI) related mutants, all the di-meta-substituted sulfones 3u-z and the 2-naphthyl analogue 3ee generally showed single-digit nanomolar activity against the V106A and P236L strains and submicromolar to low nanomolar activity against strains E138K, V108I, and Y188C. However, they showed a lack of activity against the K103N and Y181C mutant viruses. The elucidation of the X-ray crystal structure of the complex of 3v (739W94) in HIV-1 reverse transcriptase showed an overlap in the binding domain when compared with the complex of nevirapine in HIV-1 reverse transcriptase. The X-ray structure allowed for the rationalization of SAR data and potencies of the compounds against the mutants.
- Chan,Hong,Hunter III,Orr,Cowan,Sherman,Sparks,Reitter,Andrews III,Hazen,St. Clair,Boone,Ferris,Creech,Roberts,Short,Weaver,Ott,Ren,Hopkins,Stuart,Stammers
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p. 1866 - 1882
(2007/10/03)
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