- SS-AMINO ACID DERIVATIVE, KINASE INHIBITOR AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME, AND USE OF THE SAME
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A compound represented by Formula (I), a pharmaceutically acceptable salt or ester, hydrate, solvate or crystalline form thereof is provided: The compound represented by Formula (I) is a β-amino acid derivative, and in Formula (I): X is a single bond or O; Y is NH or C=O; Z is C=O, C=S, NH, W is C or N; A is a single bond, O, OH, OCH2, a heterocycle or N3; R1 is H or F; R2 is H, F, OH, CF3, CH2OH, CHO or ; R3 is H; n is 0 or 1; and m is 0 or 1.
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Paragraph 0061; 0096-0097
(2021/07/08)
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- Nitroxide derivative of ROCK kinase inhibitor
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The invention provides a small molecular compound of a NO donor. The small molecular compound is characterized in that the small molecular compound is a compound shown represented by structural formula I shown in the description, or a stereoisomer, a geometrical isomer, a tautomer, a racemate, a deuterated isotope derivative, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof; and in the formula I, ring A is a substituted or unsubstituted heteroaromatic ring, X is selected from (CH2)n, n is selected from 0, 1, 2 and 3, R is a substituent group of terminal -O-NO2, R is selected from hydrogen, a hydroxyl group, halogen, an amino group, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group and a substituted or unsubstituted heteroalkyl group, and R and R are respectively and independently selected from hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted naphthenic base or an amino protecting group, or R and R are connected to form a substituted or unsubstituted cyclic heteroalkyl group. The compound has a high-activity inhibition effect on ROCK kinase.
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Paragraph 0064-0068; 0073-0074
(2020/06/17)
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- IMIDAZOLE-BASED ANTICANCER AGENTS AND DERIVATIVES THEREOF, AND METHODS OF MAKING AND USING SAME
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Imidazole-based anticancer agents and derivatives thereof, as well as methods of making and methods of using the same, are described. The imidazole-based anticancer agents are HDAC inhibitor compounds having a 1-(1H-imidazol-2-yl)ethan-1-one or 1-(1H-imidazol-2-yl)ethane-1- thione moiety.
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Paragraph 00152-00153
(2019/03/05)
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- Asymmetric Synthesis of Netarsudil: A New Therapeutic for Open-Angle Glaucoma
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The asymmetric synthesis of a Rho kinase/norepinephrine transport inhibitor, netarsudil, the active component in the recently FDA-approved product Rhopressa, is described herein. This concise six-step synthetic route utilizes the 2,4-dimethylbenzoate ester of a phenylacetic acid as the backbone of the β-amino acid's framework. A chiral enolate of the Evans auxiliary, (R)-4-benzyloxazolidin-2-one, is used to direct the formation of the (S)-stereocenter by incorporating the N -Boc-protected β-amino methyl arm with high diastereoselectivity (96:4 dr) using N -Boc-1-aminomethylbenzotriazole as the electrophile. Uniquely, 2,2,2-trichloro-1,1-dimethylethyl chloroformate is used as a non-racemizing activating agent for the coupling reaction between the chiral (S)- N -Boc-protected 2,4-dimethylbenzoyloxymethyl phenyl propanoic acid and 6-aminoisoquinoline to provide N -Boc-protected netarsudil in good yield and excellent enantiomeric purity (63%, 98% ee). Final acidic deprotection and recrystallization provides netarsudil (>99% ee), an ophthalmic agent used for the treatment of patients with open-angle glaucoma.
- Delong, Mitchell A.,Sturdivant, Jill M.
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p. 953 - 959
(2019/02/10)
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- Identification of Novel Triazole-Based Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors Endowed with Antiproliferative and Antiinflammatory Activity
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Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme involved in the recycling of nicotinamide to maintain adequate NAD levels inside the cells. It has been postulated to be a pharmacological target, as it is overexpressed in cancer cells as well as in inflammatory diseases. We describe the synthesis and characterization of a novel class of one-digit nanomolar NAMPT inhibitors based on in vitro characterization. The most active compound tested, 30c, displayed activity in xenograft and allograft models, strengthening the potential of NAMPT inhibitors as antitumoral drugs. Furthermore, in the present contribution we describe the ability of 30c to significantly improve the outcome of colitis in mice. Given that this is the first report of an effect of NAMPT inhibitors in colitis, this result paves the way for novel applications for this class of compounds.
- Travelli, Cristina,Aprile, Silvio,Rahimian, Reza,Grolla, Ambra A.,Rogati, Federica,Bertolotti, Mattia,Malagnino, Floriana,Di Paola, Rosanna,Impellizzeri, Daniela,Fusco, Roberta,Mercalli, Valentina,Massarotti, Alberto,Stortini, Giorgio,Terrazzino, Salvatore,Del Grosso, Erika,Fakhfouri, Gohar,Troiani, Maria Pia,Alisi, Maria Alessandra,Grosa, Giorgio,Sorba, Giovanni,Canonico, Pier Luigi,Orsomando, Giuseppe,Cuzzocrea, Salvatore,Genazzani, Armando A.,Galli, Ubaldina,Tron, Gian Cesare
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p. 1768 - 1792
(2017/03/17)
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- PROCESS FOR THE PREPARATION OF KINASE INHIBITORS AND INTERMEDIATES THEREOF
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Described are processes for the synthesis of certain compounds, useful for treating diseases, e.g. eye disease, such as glaucoma and ocular hypertension, in a subject.
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Paragraph 00106
(2017/06/12)
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- Process for the preparation of kinase inhibitors and intermediates thereof
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Described are processes for the synthesis of certain compounds, useful for treating diseases, e.g. eye disease, such as glaucoma and ocular hypertension, in a subject.
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Page/Page column 35
(2017/05/31)
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- 2-PHENYL-3H-IMIDAZO[4,5-B]PYRIDINE DERIVATES USEFUL AS INHIBITORS OF MAMMALIAN TYROSINE KINASE ROR1 ACTIVITY
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A compound of formula (I′) or (I′′) or a pharmaceutically acceptable salt thereof. The compound is an inhibitor of mammalian kinase enzyme activity, including ROR1 tyrosine kinase activity and may be used in the treatment of disorders associated with such activity.
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Page/Page column 112
(2016/09/22)
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- OPTIONALLY FUSED HETEROCYCLYL-SUBSTITUTED DERIVATIVES OF PYRIMIDINE USEFUL FOR THE TREATMENT OF INFLAMMATORY, METABOLIC, ONCOLOGIC AND AUTOIMMUNE DISEASES
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Disclosed are compounds active towards nuclear receptors, pharmaceutical compositions containing the compounds and use of the compounds in therapy.
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Page/Page column 180
(2016/03/19)
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- 3,3-DIFLUORO-PIPERIDINE DERIVATIVES AS NR2B NMDA RECEPTOR ANTAGONISTS
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Disclosed are chemical entities of Formula (I): wherein X, Y, Z, R1, R3, R4 and R5 are defined herein, as NR2B subtype selective receptor antagonists. Also disclosed are pharmaceutical compositions comprising a chemical entity of Formula (I), and methods of treating various diseases and disorders associated with NR2B antagonism, e.g., diseases and disorders of the CNS, such as depression, by administering a chemical entity of Formula (I).
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Paragraph 0224
(2016/09/22)
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- "INHIBITORS OF NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE, COMPOSITIONS, PRODUCTS AND USES THEREOF"
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Compounds of formula (I): able to inhibit nicotinamide phosphoribosyltransferase. The disclosure also relates to the use of compounds of formula (I) for treatment of pathological conditions in which NAMPT inhibition might be beneficial, such as acute and chronic inflammation, cancer and metabolic disorders.
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Page/Page column 59; 67
(2014/11/13)
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- COMPOUNDS HAVING MUSCARINIC RECEPTOR ANTAGONIST AND BETA2 ADRENERGIC RECEPTOR AGONIST ACTIVITY
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The present invention relates to compounds acting both as muscarinic receptor antagonists and beta2 adrenergic receptor agonists, to processes for their preparation, to compositions comprising them, to therapeutic uses and combinations with other pharmaceutical active ingredients.
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Page/Page column 74; 75
(2014/06/24)
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- SUBSTITUTED TRICYCLIC COMPOUNDS WITH ACTIVITY TOWARDS EP1 RECEPTORS
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The present invention belongs to the field of EP1 receptor ligands. More specifically it refers to compounds of general formula (I) having great affinity and selectivity for the EP1 receptor. The invention also refers to the process for their preparation, to their use as medicament for the treatment and/or prophylaxis of diseases or disorders mediated by the EP1 receptor as well as to pharmaceutical compositions comprising them.
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Page/Page column 46; 47
(2013/10/22)
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- DUAL-ACTION INHIBITORS AND METHODS OF USING SAME
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Provided are compounds, compositions, and methods for treating diseases and conditions wherein an inhibitor of a kinase, such as rho kinase (ROCK), and an inhibitor of one or more of the monoamine transporters, such as NET or SERT, act in concert to improve the condition.
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Page/Page column 54
(2010/11/17)
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- BEZOTHIAZOL DERIVATIVES AS BETA2 ADRENORECEPTOR AGONISTS
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The present invention relates to compounds according to formula (I) , a process for preparing them, the intermediate compounds of the process and the use of the compounds in the manufacture of a medicament for use in treating diseases such as ARDS, pulmonary emphysema, bronchitis, bronchiectasis, COPD, asthma and rhinitis. The compounds are beta2 adrenoreceptor agonists.
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Page/Page column 68
(2008/06/13)
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- Arylacetamide κ opioid receptor agonists with reduced cytochrome P450 2D6 inhibitory activity
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Some κ opioid receptor agonists of the arylacetamide class, for example, ICI 199441 (1), were found to strongly inhibit the activity of cytochrome P450 2D6 (CYP2D6) (1: CYP2D6 IC50 = 26 nM). Certain analogs bearing a substituted sulfonylamino group, for example, 13, were discovered to have significantly reduced CYP2D6 inhibitory activity (13: CYP2D6 IC50 > 10 μM) while displaying high affinity toward the cloned human κ opioid receptor, good κ/δ and κ/μ selectivity, and potent in vitro and in vivo agonist activity.
- Le Bourdonnec, Bertrand,Ajello, Christopher W.,Seida, Pamela R.,Susnow, Roberta G.,Cassel, Joel A.,Belanger, Serge,Stabley, Gabriel J.,DeHaven, Robert N.,DeHaven-Hudkins, Diane L.,Dolle, Roland E.
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p. 2647 - 2652
(2007/10/03)
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- Sulfonylamino phenylacetamide derivatives and methods of their use
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Sulfonylamino phenylacetamide derivatives of the general formula are disclosed. Pharmaceutical compositions containing the compounds and methods for their use are also disclosed. In certain embodiments, the compounds of the invention that, preferably: (1) bind with high affinity to κ opioid receptors; (2) display good opioid receptor selectivity of κ versus μ and κ versus δ; and (3) do not substantially inhibit cytochrome P450 enzymatic activity, in particular CYP2D6, CYP2C9 and CYP3A4.
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