- RET INHIBITORS, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
-
Provided herein are a RET inhibitor, a pharmaceutical composition thereof and uses thereof. In particular, provided is a compound having Formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof. Provided is a pharmaceutical composition comprising the compound, and uses of the compound and pharmaceutical composition thereof for the preparation of a medicament, in particular for treatment and prevention of RET-related diseases and conditions, including cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.
- -
-
Paragraph 00230; 00398
(2020/07/05)
-
- C-3 NOVEL TRITERPENONE WITH C-17 REVERSE AMIDE DERIVATIVES AS HIV INHIBITORS
-
The present invention relates to C-3 novel triterpenone with C-17 reverse amide compounds of Formula (I); and pharmaceutically acceptable salts thereof, wherein ring Formula (II), R1, R2, R3, R4, R5, R6, R7, 'n' and 'm' are as defined in Formula (I). The invention also relates to C-3 novel triterpenone with C-17 reverse amide derivatives, related compounds, and pharmaceutical compositions useful for the therapeutic treatment of viral diseases and particularly HIV mediated diseases.
- -
-
Page/Page column 62
(2018/03/06)
-
- Novel indanone derivatives as MAO B/H3R dual-targeting ligands for treatment of Parkinson's disease
-
The design of multi-targeting ligands was developed in the last decades as an innovative therapeutic concept for Parkinson's disease (PD) and other neurodegenerative disorders. As the monoamine oxidase B (MAO B) and the histamine H3 receptor (H3R) are promising targets for dopaminergic regulation, we synthetized dual-targeting ligands (DTLs) as non-dopaminergic receptor approach for the treatment of PD. Three series of compounds were developed by attaching the H3R pharmacophore to indanone-related MAO B motifs, leading to development of MAO B/H3R DTLs. Among synthesized indanone DTLs, compounds bearing the 2-benzylidene-1-indanone core structure showed MAO B preferring inhibition capabilities along with nanomolar hH3R affinity. Substitution of C5 and C6 position of the 2-benzylidene-1-indanones with lipophilic substituents revealed three promising candidates exhibiting inhibitory potencies for MAO B with IC50 values ranging from 1931 nM to 276 nM and high affinities at hH3R (Ki 50 = 276 nM, hH3R Ki = 6.5 nM) showed highest preference for MAO B over MAO A (SI > 36). Interestingly, IC50 determinations after preincubation of enzyme and DTLs revealed also nanomolar MAO B potency for 3e (MAO B IC50 = 232 nM), a structural isomer of 3f, and 3d (MAO B IC50 = 541 nM), suggesting time-dependent inhibition modes. Reversibility of inhibition for all three compounds were confirmed by dilution studies in excess of substrate. Thus, indanone-substituted derivatives are promising lead structures for the design of MAO B/hH3R DTLs as novel therapeutic approach of PD therapy.
- Affini, Anna,Hagenow, Stefanie,Zivkovic, Aleksandra,Marco-Contelles, Jose,Stark, Holger
-
p. 487 - 497
(2018/02/28)
-
- Isoflavone amide type derivative, preparation method and medical application thereof
-
The invention relates to the field of medicinal chemistry, and relates to an isoflavone amide type derivative, a preparation method and a medical application thereof, in particular to an isoflavone amide type derivative with the general formula (I), a preparation method thereof, medicine compositions including the isoflavone amide type derivative and a medical application thereof, especially an application of the isoflavone amide type derivative as a medicine for preventing or curing hyperlipemia, obesity or type II diabetes. The general formula (I) is shown in the description.
- -
-
Paragraph 0016; 0080; 0081; 0082; 0083; 0084; 0085
(2016/10/10)
-
- ASK1 INHIBITING PYRROLOPYRIMIDINE DERIVATIVES
-
This invention relates to pyrrolopyrimidine derivatives of formula (I): where R1, X, p, R4, R2and R3are as defined herein, and their use as pharmaceuticals.
- -
-
Page/Page column 42
(2012/06/30)
-
- NOVEL HETEROCYCLYL COMPOUNDS
-
The invention is concerned with novel heterocyclyl compounds of formula (I) wherein A, X, Y1, Y2, Y3, R3, R4, R5, R6, R7, R8, R9, R10, m, n and p are as defined in the description and in the claims, as well as physiologically acceptable salts thereof. These compounds are antagonists of CCR2 receptor, CCR5 receptor and/or CCR3 receptor and can be used as medicaments.
- -
-
Page/Page column 25
(2010/02/17)
-
- NOVEL MCH RECEPTOR ANTAGONISTS
-
The present invention relates to a melanin concentrating hormone antagonist compound of formula (I): wherein R1, Ra, Rb, R2, L1, R3, R4 and R5 are as defined, or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture of diasteromers thereof useful in the treatment, obesity and related diseases.
- -
-
Page/Page column 45-47
(2008/06/13)
-
- 3- Or 4-monosubstituted phenol derivatives useful as H3 ligands
-
The invention relates to 3- or 4-monosubstituted phenol derivatives and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives. Said 3- or 4-monosubstituted phenol derivatives are H3 ligands and are useful in numerous diseases, disorders and conditions, in particular inflammatory, allergic and respiratory diseases, disorders and conditions.
- -
-
Page/Page column 38
(2010/02/14)
-
- Preparation and in vitro pharmacology of 5-HT4 receptor ligands. Partial agonism and antagonism of metoclopramide analogous benzoic esters
-
Alicyclic ester analogues of the gastroprokinetic benzamide metoclopramide (1) and its ester congener SDZ 205557 (2), a 5-HT4 receptor antagonist, were prepared by O-alkylation of 4-amino-5-chloro-2-methoxybenzoate with N-(2-chloroethyl) substituted alicyclic amines. The bromo and iodo analogue of compound 13b (2-(1-piperidinyl)ethyl 4-amino-5-chloro-2-methoxybenzoate) were obtained by halogenation of dechloro-13b with N-halogenated succinimides. The series was evaluated in functional in vitro assays with regard to affinity for serotoninergic 5-HT4, 5-HT3 and muscarinic M3 receptors. The affinities for 5-HT3 and M3 receptors were below 6.0 (pK(B) or pA2). On 5-HT4 receptors in guinea-pig ileal longitudinal muscle and rat oesophagus, the majority of compounds revealed partial 5-HT4 receptor agonism susceptible to blockade by SDZ 205557, a reference 5-HT4 receptor antagonist (pK(B) = 7.25-7.73 (guinea-pig ileum) and 7.09-7.43 (rat oesophagus)). The relative agonist potency was in the range of 5-303% (5-HT: 100%). Compound 13b and its bromo analogue 17 were the most potent esters of the series. The enantiomers of 13g ((R)- and (S)-2-(2-methyl-1-piperidinyl)ethyl 4-amino-5-chloro-2-methoxybenzoate) interacted stereoselectively with 5-HT4 receptors and displayed enantiomeric potency ratios (R)/(S) of 4.3-8.7. There was an excellent correlation between (a) antagonist affinity on guinea-pig ileum and rat oesophagus, (b) relative agonist potency on guinea-pig ileum and rat oesophagus, and (c) between antagonist affinity and relative agonist potency within each assay (r2 > 0.91). The new compounds may serve as academic tools in evaluating the functional role of 5-HT4 receptors. The selective partial 5-HT4 receptor agonists presented in this paper may be useful to restore physiological motility and secretion in the gut with reduced or absent propensity to elicit tachycardia and desensitization of the intestinal target receptor.
- Elz,Keller
-
p. 585 - 594
(2007/10/03)
-
- Introduction of Pharmacorphoric Groups into Polycyclis Systems. Part 3. Amine Derivatives of Adamantane and Diaza-adamantane
-
Methods for introducing various pharmacophoric amine-containing substituents into the adamantane system have been investigated.These include β- and α-aminoalkyloxyimino, β-aminoalkylidine, β-hydroxyethylamino, and β-phenylethylamino.Aminoalkoxyimines were prepared by alkylation of the anion of adamantanone oxime with the corresponding aminoalkyl chloride, and a 2-aminoethylidene derivative was prepared by Witting reaction of 2-dimethylaminoethyltriphenylphosphonium bromide with adamantanone.The reaction of 6-hydroxy-7-methyl-6-phenyladamantane-2,4-dione with aqueous sodium cyanide has been shown to be both regio- and stereo-selective, only the C-2 carbonyl group reacting from the most hindered direction.This is possibly due to stabilisation of the cyanohydrin by hydrogen bonding between the hydroxy and C-4 carbonyl groups.When trimethyl cyanide was used in place of sodium cyanide, the reaction remained regioselective but, in the absence of hydrogen bond stabilisation, the stereoselectivity was lost and two trimethylsilyloxy cyanides were isolated, epimeric at C-2.The stereochemistry of one epimer has been determined by X-ray crystallography, details of which are reported here.Hydrogenation of the trimethylsilyloxy cyanides then gave the corresponding β-hydroxyamine, isolated as the hydrochloride.Finally 5,7-diphenyl-1,3-diaza-adamantan-6-one was prepared by a literature method and converted, with difficulty, into the oxime which was reduced by RedAl to the corresponding amine.
- Hickmott, Peter W.,Wood, Simon,Murray-Rust, Peter
-
p. 2033 - 2038
(2007/10/02)
-
- Method of manufacturing ketones
-
The invention relates to a method for the manufacture of ketones which comprises oxidizing an n-olefin in the presence of a catalyst containing palladium, copper, a halogen, and at least one of specific tertiary amines.
- -
-
-
- Substituted N-arylanilines
-
N-Arylanilines, further substituted on nitrogen by aroyl, aralkanoyl or aralkyl groups, and wherein one of the aryl groups has a 3- or 4-(aminoalkoxy)substituent, having hypocholesteremic activity, are prepared by a series of O-alkylation, N-acylation or -alkylation, and reduction reactions starting from the appropriate hydroxydiarylamines or benzyl ethers thereof.
- -
-
-