- Design and development of novel thiazole-sulfonamide derivatives as a protective agent against diabetic cataract in Wistar rats via inhibition of aldose reductase
-
In recent years, ALR2 (aldose reductase) inhibitors have attracted attention for their effective ability to reduce the progression of diabetes-associated cataracts. Therefore, in the present article, we intended to develop novel thiazole-sulfonamide hybrids as a potent inhibitor of ALR2. These molecules significantly inhibited the ALR2 level in the rat lenses homogenate, where the most potent compound 7b showed activity comparable to sorbinil as standard. In Wistar rats, compound 7b improved the insulin level and body weight of the experimental animal together with a reduction in the glucose output. Compound 7b showed a significant reduction in the expression of ALR2 in rat lenses in western blot analysis.
- Yin, Liang,Zhang, Mingxue,He, Tiangeng
-
-
- Substituted 2-thioxothiazolidin-4-one derivatives showed protective effects against diabetic cataract via inhibition of aldose reductase
-
In an effort to develop a new class of potent aldose reductase inhibitors against diabetic cataracts, a series of novel 2-thioxothiazolidine-4-one derivatives was synthesized in excellent yields via a facile synthetic route. These compounds were tested against aldehyde (ALR1) and aldose reductase (ALR2) enzymes, where they showed considerable inhibitory activity. Among the tested derivatives, compound 6e showed selective and excellent inhibition of ALR2 over ALR1. The experimental diabetes was induced by the intraperitoneal administration of streptozotocin in male Wistar rats. Compound 6e showed positive modulation of body weight, blood glucose, and blood insulin levels in diabetic rats. Compound 6e also showed ALR2 inhibition as evidenced by Western blot analysis in lens homogenates of Wistar rats having cataract. The docking study of 6e was also performed inside the active site of ALR2 to enumerate the key contacts for inhibitory activity.
- Huang, Wanrong,Zhang, Yue,Liang, Xu,Yang, Lichun
-
-
- Catalytic Transfer Hydrodebenzylation with Low Palladium Loading
-
A highly-efficient catalytic system for hydrodebenzylation reaction is described. The cleavage of O-benzyl and N-benzyl protecting groups was performed using an uncommonly low palladium loading (0.02–0.3 mol%; TON up to 5000) in a relatively short reaction time. The approach was used for a variety of substrates including pharmaceutically important precursors, and gram-scale deprotection reaction was shown. Transfer conditions together with easy-to-make Pd/C catalyst are the key features of this debenzylation scheme. (Figure presented.).
- Yakukhnov, Sergey A.,Ananikov, Valentine P.
-
supporting information
p. 4781 - 4789
(2019/09/16)
-
- Method for preparing 4-Boc-aminopiperidine
-
The invention discloses a method for preparing 4-Boc-aminopiperidine. The method includes: allowing N-benzyl-4-piperidone to have reaction with ortho-formate in an alcoholic solution under acid catalysis to form ketal, allowing the ketal to have reaction with tert-butyl carbamate to generate imine, and subjecting the imine to Pd/C catalytic hydrogenation reduction to obtain the 4-Boc-aminopiperidine. The method is short in synthesizing route, easy in raw material obtaining, cheap, simple to operate, high in reaction yield, easy in product separation and purification and promising in application prospect.
- -
-
Paragraph 0024; 0026; 0027; 0029; 0030; 0032; 0033; 0035
(2018/04/15)
-
- Design and development of a novel chalcone derivative as an anticholinesterase inhibitor for possible treatment of dementia
-
Background: Cognitive decline (e.g., memory loss), which mainly occurs in the elderly, is termed dementia. In the present study, we intended to explore the cholinesterase inhibitory activity of some novel synthesized chalcones, together with their effect on β-amyloid anti-aggregation. Material/Methods: A novel class of chalcone derivatives have been synthesized and characterized by FT-IR,1H-NMR,13C-NMR, and mass and elemental analysis. These derivatives were later used for the determination of acetylcholinesterase (AChE) inhibitory and β-amyloid anti-aggregation activity. Results: The results of the study showed that among the developed compounds, 8g inhibits AChE more prominently than BuChE, as suggested by a selectivity index (SI) of 2.88. Furthermore, the most potent compound, 8g, showed considerable action in inhibition of β-secretase and Aβ aggregation, but not as prominent as that of curcumin as a standard. Conclusions: In conclusion, our study revealed a novel class of chalcone derivatives as a selective inhibitor of AChE with considerably action against β-secretase and Aβ aggregation. Our results may be useful in developing AD drug therapy and warrant further investigation to generate more advanced analogues.
- Zhao, Fu-Chun,Wu, Yan,Song, Xiao-Jie
-
p. 3311 - 3317
(2017/07/17)
-
- ANTIMICROBIAL COMPOSITIONS, METHODS OF USE, AND METHODS OF TREATMENT OF INFECTIONS
-
The present disclosure provides compositions including a compound (e.g., compounds A-D), pharmaceutical compositions including the compound, methods of treatment of a condition (e.g., an infection) or disease, methods of treatment using compositions or pharmaceutical compositions, and the like.
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Page/Page column 33
(2016/12/22)
-
- Synthesis, characterization, and DGAT1 inhibition of new 5-piperazinethiazole and 5-piperidinethiazole analogs
-
In this study, a novel series of 5-piperazinethiazole 2,2-dimethylbutanoic acid and 5-piperidinethiazole 2,2-dimethylbutanoic acid derivatives have been synthesized. Structures of the newly synthesized compounds have been elucidated using 1H-NMR, 13C-NMR, high-resolution mass spectroscopy, and high-performance liquid chromatographic analysis. The synthesized derivatives have been evaluated in vitro for their ability to inhibit the enzyme diacylglycerol acyltransferase 1 responsible for triglyceride biosynthesis.
- Kadam, Kishorkumar S.,Gandhi, Thirumanavelan,Reddy, M. Maheshkumar,Gupte, Amol,Sharma, Rajiv
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p. 802 - 814
(2015/05/13)
-
- Autotaxin inhibitors
-
The present invention relates to novel compounds that are autotaxin inhibitors, processes for their preparation, pharmaceutical compositions and medicaments containing them and to their use in diseases and disorders mediated by autotaxin.
- -
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Page/Page column
(2014/06/25)
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- Structure-activity relationship exploration of Kv1.3 blockers based on diphenoxylate
-
Diphenoxylate, a well-known opioid agonist and anti-diarrhoeal agent, was recently found to block Kv1.3 potassium channels, which have been proposed as potential therapeutic targets for a range of autoimmune diseases. The molecular basis for this Kv1.3 blockade was assessed by the selective removal of functional groups from the structure of diphenoxylate as well as a number of other structural variations. Removal of the nitrile functional group and replacement of the C-4 piperidinyl substituents resulted in several compounds with submicromolar IC50 values.
- Nguyen, William,Howard, Brittany L.,Jenkins, David P.,Wulff, Heike,Thompson, Philip E.,Manallack, David T.
-
supporting information
p. 7106 - 7109
(2013/01/15)
-
- Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists
-
Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays a role in metabolic and CNS disorders. The modeling-supported design, synthesis and multi-parameter optimization (biological activity, solubility, metabolic stability, hERG) of novel quinazoline derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified. Clusters of refined hMCHR1 homology models derived from the X-ray structure of the β2-adrenergic receptor, including extracellular loops, were developed and used to guide the design.
- Sasmal, Sanjita,Balaji, Gade,Kanna Reddy, Hariprasada R.,Balasubrahmanyam,Srinivas, Gujjary,Kyasa, Shivakumar,Sasmal, Pradip K.,Khanna, Ish,Talwar, Rashmi,Suresh,Jadhav, Vikram P.,Muzeeb, Syed,Shashikumar, Dhanya,Harinder Reddy,Sebastian,Frimurer, Thomas M.,Rist, ?ystein,Elster, Lisbeth,H?gberg, Thomas
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scheme or table
p. 3157 - 3162
(2012/06/04)
-
- Collection of traceable compounds and uses thereof
-
The use of a collection of compounds of general formula (I), wherein: n is 0 or 1; p represents an integer between 1 and 6; r represents an integer between 1 and 12; R1 and R′1 represent in particular a hydrogen atom; R2 represents an amino acid side chain or an amino acid derivative; R3 represents a group derived from a carboxylic acid, bearing a basic entity; R4 represents in particular an alkyl group containing 1 to 10 carbon atoms; and A represents a hydrogen atom, a protecting group or a tracing group, in particular a fluorophor, a coloring agent or a quencher, for determining, through binding studies, ligands of receptors whose ligand is unknown or whose ligand useful for carrying out specific affinity binding assays is unknown.
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- NAPHTHALENYLOXYPROPENYL DERIVATIVES HAVING INHIBITORY ACTIVITY AGAINST HISTONE DEACETYLASE AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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The present invention discloses novel naphthalenyloxypropenyl derivatives useful for inhibiting the enzyme activity of histone deacetylase, leading effective suppression of cancer cell proliferation
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Page/Page column 33; 34; 76; 77; 162-164
(2008/12/05)
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- ALKYLCARBAMOYL NAPHTHALENYLOXY- OCTENOYLHYDROXYAMIDE DERIVATIVES HAVING INHIBITORY ACTIVITY AGAINST HISTONE DEACETYLASE AND PREPARATION THEREOF
-
This invention discloses a novel alkylcarbamoyl naphthalenyloxy octenoylhydroxyamide derivative of formula (1) useful for inhibiting the enzyme activity of histone deacetylase, which leads to effective suppression of the cancer cell proliferation, a method for preparing same and a pharmaceutical composition comprising same.
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Page/Page column 18
(2010/11/27)
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- PYRAZOLE COMPOUNDS HAVING CANNABINOID RECEPTOR (CB1) ANTAGONIZING ACTIVITY
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The present invention relates to a pyrazole compound having potent CB1-antagonizing activity, having the following formula [I]: wherein R1 and R2 are the same or different and an optionally substituted aryl group etc., R3 is an alkyl group etc., E is one of the following groups of the formula (i) to (iv): Q1 is a single bond, an alkylene group or a group of the formula: -N(R7)-, R7 is a hydrogen atom or an alkyl group, Q2 is a single bond, an oxygen atom or an alkylene group, R4 is a cycloalkyl group, a group of the formula: -N(R5)(R6) etc., one of R5 and R6 is a hydrogen atom or an alkyl group and the other is an alkyl group, a group of the formula: -N(R8)(R9) etc., D is an oxygen atom etc., RA1 is an amino group etc., RA2 is an optionally substituted aliphatic heterocyclic group, R is an alkyl group optionally substituted by one to three halogen atom(s) etc., one of R8 and R9 is a hydrogen atom or an alkyl group and the other is an alkyl group etc., or a pharmaceutically acceptable salt thereof.
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Page/Page column 117
(2008/06/13)
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- CHEMOKINE RECEPTOR ANTAGONISTS
-
A compound of formula (I) or a pharmaceutically acceptable salt or prodrug ester thereof, wherein the variants R, R9, Z, X, Q and Y are defined in the specification.
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Page/Page column 26; 30
(2010/02/13)
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- Heteroaryloxy propanolamines, preparation method and pharmaceutical compositions containing same
-
Compounds of formula (I): where X is N or CH; A represents a group of formula (a) or (b) R1 represents hydrogen or an —NH2, —NR3R4, —NR3CO(C1-C4)Alk or —NR3SO2(C1-C4)Alk group;R2 represents hydrogen, a halogen or a (C1-C4)Alk, (C1-C4)alkoxy, —COOH, —COO(C1-C4)Alk, —CN, —CONR3R4, —NO2, —SO2NR3R4 or —NHSO2(C1-C4)Alk;m and n each represent 0, 1 or 2;R3 and R4 each represent hydrogen or a (C1-C4)Alk group;Y1 and Y2 each represent NH or O;and their salts or solvates, a process for their preparation and the pharmaceutical compositions comprising them.
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Page/Page column 7; 9
(2008/06/13)
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- 2-ALKOXY-6-AMINO-5-HALOGENO-N-(1-SUBSTITUTED-4-PIPERIDINYL)PYRIDINE-3-CARBOXAMIDE DERIVATIVE AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME
-
PROBLEM TO BE SOLVED: To provide a compound exhibiting high affinity for serotonin 4 receptor and useful as a digestive tract motion promoting agent or digestive tract function ameliorating agent. SOLUTION: The compound is represented by the formula(I), or an acid addition salt thereof and an intermediate thereof are provided. In formula(I), R1 is a halogen atom; R2 is H or a lower alkyl; R3 is H, a lower alkyl or the like; R4 is a lower alkyl; A is a group represented by the formula: Z-N(Q1)(Q2) or CO-R5, wherein Z is CO, CS or the like; Q1 and Q2 are each H, a lower alkyl or the like, or joined together with the nitrogen atom to which Q1 and Q2 are bound to form a pyrrolidine ring, piperidine ring or the like; and R5 is H, a lower alkyl, lower alkoxy, lower alkoxycarbonyl or the like.
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Page/Page column 23
(2010/02/11)
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- HETEROCYCLIC UREA DERIVATIVES FOR THE TREATMENT OF PAIN
-
Compounds of formula (I): or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein: P, P’, R1, R2, n, p, q, r, and s are as defined in the specification, processes for preparing such compounds, pharmaceutical compositions comprising such compounds and their use in therapy.
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-
-
- UREA COMPOUNDS ACTIVE AS VANILLOID RECEPTOR ANTAGONISTS FOR THE TREATMENT OF PAIN
-
Certain compounds of formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, P, P', n, p, q, r and s are as defined in the specification, a process for preparing such compounds, a pharmaceutical composition comprising such compounds and the use of such compounds in medicine.
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-
-
- Synthesis of new glycyrrhetinic acid (GA) derivatives and their effects on tyrosinase activity
-
To synthesize glycyrrhetinic acid (GA) derivatives (3, 4, 5, 10, 13, 14, 15, and 16), we first removed the ketonic group in the C-11 position, and the carboxylic function at the C-30 position was kept intact, reduced to an alcohol, or transformed to an aldehyde corresponding derivatives 10 and 13. Glycyrrhetinic acid (GA) derivatives (3, 4, 5, 15, and 16) were coupled with 4-amino piperpyridine derivatives (12 and 14) and 4-fluorobenzyl bromide at C-30 carboxylic acid position of glycyrrhetinic acid. In subsequent tyrosinase assays, we found that GA derivatives 4, 5, and 16 were not active at early time points, but strongly inhibited tyrosinase activity at late time points. Of the GA derivatives examined, derivative 5 was most active, with an IC50 value of 50 μM after 2 h reaction. IC50 values of derivatives 4 and 16 were 120 and 170 μM, respectively. Further kinetic data indicated that these derivatives are slow-binding inhibitors of tyrosinase. The time-dependent inhibition was reversed when vitamin C or kojic acid was used, that is, both compounds showed active inhibition at early time points. These results suggest that GA derivatives are much more stable than vitamin C or kojic acid, although their intrinsic inhibitory potentials are relatively low. Higher stability and activity suggest that GA derivative 5 might be a useful candidate for skin whitening. copy; 2003 Published by Elsevier Ltd.
- Um, Soo-Jong,Park, Myoung-Soon,Park, Si-Ho,Han, Hye-Sook,Kwon, Youn-Ja,Sin, Hong-Sig
-
p. 5345 - 5352
(2007/10/03)
-
- Substituted pyridazines having cytokine inhibitory activity
-
There are disclosed compounds of formula (I) and pharmaceutically acceptable salts thereof which exhibit utility for the treatment of cytokine mediated diseases such as arthritis.
- -
-
-
- NITROGENOUS FIVE-MEMBERED RING COMPOUNDS
-
The present invention is to provide an aliphatic nitrogen-containing 5-membered ring compound represented by the formula [I] : wherein symbols in the formula have the following meanings;A: -CH2- or -S-,B: CH or N,R1: H, a lower alkyl group, etc.,X: a single bonding arm, -CO-, -Alk-CO-, -COCH2-, -Alk-O-, -O-CH2-, -SO2-, -S-, -COO-, -CON(R3)-, -Alk-CON(R3)-, -CON(R3)CH2-, -NHCH2-, etc.,R3: hydrogen atom or a lower alkyl group,Alk: a lower alkylene group, andR2: (1) a cyclic group which may be substituted, (2) a substituted amino group, etc., provided that when X is -CO-, then B is N, or a pharmaceutically acceptable salt thereof.
- -
-
-
- Novel compounds
-
The invention provides compounds of general formula (I) wherein m, n, Q, Z1, Z2, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
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-
-
- Pyridine compounds
-
A compound selected from those of formula (I): wherein: W represents optionally substituted naphthyl, n represents an integer from 2 to 3 inclusive, Z represents a single bond, A represents nitrogen, Q represents nitrogen, M, together with the carbon of pyridyl to which it is bonded, represents thieno, furo, pyrrolo or oxopyrrolo, Its optical isomers and pharmaceutically-acceptable acid or base additional salts thereof, and Medicinal products containing the same which are useful in the treatment of CNS disorders. It being understood that “aryl” is phenyl, naphthyl, dihydronaphthyl, or tetrahydronaphthyl.
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-
-
- NOVEL QUINAZOLINE DERIVATIVES
-
Quinazoline derivatives represented by the general formula (1) or a pharmaceutically acceptable salt thereof in said formula R1is nitro or halogen; R2and R4are each hydrogen, C1-4alkyl, carboxyl, or C2-5alkoxycarbonyl; R3is hydrogen, amino, optionally substituted C1-4alkyl, C1-4alkanoyl, or C2-5alkoxycarbonyl; W is carbon or nitrogen; and m is 0 to 2.
- -
-
-
- An improved synthesis of butyl 4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidineacetate (AU-224)
-
A new and facile route for the synthesis of the novel gastrointestinal prokinetic butyl 4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidineacetate (1b), which exhibited potent gastro- and colon-prokinetic activities by oral administration without significant side effects, was established. The key intermediate, butyl 4-amino-1-piperidineacetate (16), was prepared from commercially available 4-amino-1-benzylpiperidine (2) in a high yield with four steps. Compound 1b was prepared by condensation of commercially available 4-amino-5-choloro-2-methoxybenzoic acid (7) with 16 in 84% yield. This improved synthetic route was appropriate for large-scale synthesis of 1b.
- Sakaguchi, Jun,Higashi, Taijiro,Azuma, Takahiro,Suzuki, Tomio,Iwasaki, Nobuhiko,Kondo, Noriyuki,Nagata, Osamu,Kato, Hideo,Hanaoka, Miyoji
-
p. 788 - 790
(2007/10/03)
-
- 2-alkylidene hydroxycumaranone derivatives
-
Compounds of the formula wherein R,R′, A,B,T and x have the meaning given in the specification possess uPA (urokinase-type plasminogen activator) antagonist activity and can be employed as antitumor and/or antimetastatic agents.
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-
- Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 4: Synthesis and structure-activity relationships for 1-[N-(methyl)-N-(phenylsulfonyl)amino]-2-(phenyl)-4-(4-(N-(alkyl)-N- (benzyloxycarbonyl)amino)piperidin-1-yl)butanes
-
(2S)-2-(3-Chlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro (2,3-dihydrobenzthiophene-3,4′-piperidin-1′-yl)]butane S-oxide (1b) has been identified as a potent CCR5 antagonist having an IC50 = 10 nM. Herein, structure-activity relationship studies of non-spiro piperidines are described, which led to the discovery of 4-(N-(alkyl)-N-(benzyloxycarbonyl)amino)piperidine derivatives (3-5) as potent CCR5 antagonists.
- Finke, Paul E.,Oates, Bryan,Mills, Sander G.,MacCoss, Malcolm,Malkowitz, Lorraine,Springer, Martin S.,Gould, Sandra L.,DeMartino, Julie A.,Carella, Anthony,Carver, Gwen,Holmes, Karen,Danzeisen, Renee,Hazuda, Daria,Kessler, Joseph,Lineberger, Janet,Miller, Michael,Schleif, William A.,Emini, Emilio A.
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p. 2475 - 2479
(2007/10/03)
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- Process for the preparation of chemical compounds
-
An improved and efficient synthesis for the preparation of 2-amino-6-[(4-aminopiperidin-1-yl]methyl]pyridine, an intermediate compound in the preparation of muscarinic M3 receptor antagonists, includes as a final step the removal of trimethylacetyl and an amino protecting group from 2-trimethylacetyl-amino-6-[(4-protected aminopiperidin-1-yl)methyl]pyridine.
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- 3-piperidyl-4-oxoquinazoline derivatives and pharmaceutical compositions comprising the same
-
3-piperidyl-4-oxoquinazoline derivatives are provided, which is represented by the formula (I): wherein R represents an amino group or a cyclic amino group such as dibenzoazepine, each of which is substituted with a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or the like, n is an integer of 1 to 3, R3and R4independently represents a hydrogen atom, a lower alkyl group, or the like, or a pharmaceutically acceptable salt thereof. Compounds (I) of the present invention have excellent MTP-inhibitory activity. Thus, these compounds not only inhibit formation of LDL that is a cause of arteriosclerotic diseases but also regulate TG, cholesterol, and lipoproteins such as LDL in the blood and regulate cellular lipids through regulation of MTP activity. They can also be used as a new type of preventive or therapeutic agents for hyperlipemia or arteriosclerotic diseases. Furthermore, they can be used as therapeutic or preventive agents for pancreatitis, obesity, hypercholesterolemia, and hypertriglyceridemia.
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- 1-[(1-Substituted-4-piperidinyl)methyl]-4-piperidine derivative, process for producing the same, medicinal compositions containing the same and intermediates of these compounds
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Compound of the formula (I): STR1wherein Ar is a group of the following formula (Ar-1) or (Ar-2): STR2A is a group of the formula:--Z--N(Q 1)(Q 2), --CO--R 7or--(CH 2)p--CH(R 8)--COR 9,or a pharmaceutically acceptable acid addition salt thereof, a process for preparing the same, a pharmaceutical composition containing the same, and intermediates therefor. The compounds of the present invention show a potent affinity for 5-HT 4 receptors, and they are useful as a gastrointestinal motility enhancer or a gastrointestinal prokinetic agent.
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- N-acyl cyclic amine derivatives
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The invention relates to compounds represented by the general formula [I][wherein Ar means an aryl group or a heteroaryl group which may have a substitutive group selected from a group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group; R1 means a C3-C6 cycloalkyl group which is substitutable with a fluorine atom; R2 and R4 mean hydrogen atoms, groups represented by -(A1)m-NH-B or the like; R3 and R5 mean hydrogen atoms, C1-C6 aliphatic hydrocarbon groups or the like which are substitutable with a lower alkyl group(s); n means 0 or 1; and X means an oxygen atom or a sulfur atom]. Compounds according to the invention, since they not only have potent selective antagonistic activity against muscarinic M3 receptors but also exhibit excellent oral activity, durability of action and pharmacokinetics, are very useful as safe and effective remedies against respiratory, urinary and digestive diseases with little adverse side effects.
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- 1-(3-Cyanobenzylpiperidin-4-yl)-5-methyl-4-phenyl-1,3-dihydroimidazol- 2-one: A selective high-affinity antagonist for the human dopamine D4 receptor with excellent selectivity over ion channels
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After the requirement of pseudocycle formation in the ureas 3 and 7 for hD4 binding and selectivity was confirmed, structural hybridization with the known hD4 ligand 2 led to the design and identification of the lead 4-(2- oxo-1,3-dihydroimidazol-2-yl)piperidine 8. Optimization studies were carried out on 8 with the aim of achieving 1000-fold selectivity for hD4 over all other receptors while retaining the good pharmacokinetic properties of the lead. After initial preparation of 8 as a minor component in a low-yielding reaction, a novel and regioselective 'four-step/one-pot' procedure was developed which proved to be applicable to rapid investigation of the SAR of the 1,3-dihydroimidazol-2-one ring. Various changes to substituents attached to the 3-, 4-, or 5-position of the 1,3-dihydroimidazol-2-one core of 8 did not significantly improve selectivity for hD4 over hD2 and hD3. Greater selectivity (> 1000-fold) was ultimately achieved by meta substitution of the benzyl group of 8 with various substituents. Compounds 28, 31, and 32 all possess the required selectivity for hD4 over the other dopamine subtypes, but only 32 has > 1000-fold selectivity over all the key counterscreens we tested against. Compound 32 is an antagonist at hD4 and has a good pharmacokinetic profile in the rat, with excellent estimated in vivo receptor occupancy, thus making it a potentially useful pharmacological tool to investigate the role of the D4 receptor.
- Carling, Robert W.,Moore, Kevin W.,Moyes, Christopher R.,Jones, Elizabeth A.,Bonner, Katrine,Emms, Frances,Marwood, Rosemary,Patel, Shil,Patel, Smita,Fletcher, Alan E.,Beer, Margaret,Sohal, Bindi,Pike, Andrew,Leeson, Paul D.
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p. 2706 - 2715
(2007/10/03)
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- Piperazine derivatives, medicaments comprising these compounds, their use and processes for their preparation
-
The present invention relates to piperazine derivatives of the general formula STR1 in which Ra, Y1 to Y3 and E are defined herein, tautomers thereof, stereoisomers thereof, including their mixtures, and salts thereof, and in particular physiologically tolerated salts thereof with inorganic or organic acids or bases. These compounds have valuable pharmacological properties, such as aggregation-inhibiting activity. This invention also relates to medicaments comprising these compounds and to processes for the preparation of these compounds.
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- Low molecular weight peptidomimetic growth hormone secretagogues
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The present invention comprises growth hormone releasing peptides/peptidomimetics (GHRP) capable of causing release of growth hormone from the pituitary. Compositions containing the GHRP's of this invention are used to promote growth in mammals either alone or in combination with other growth promoting compounds, especially IGF-1. In a method of this invention GHRP's in combination with IGF-1 are used to treat Type II diabetes. An exemplary compound of this invention is provided below. STR1
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- Inhibitors of microsomal triglyceride transfer protein and method
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Compounds are provided which inhibit microsomal triglyceride transfer protein and thus are useful for lowering serum lipids and treating atherosclerosis and related diseases. The compounds have the structure STR1 wherein R1 to R7, Q, X and Y are as defined herein.
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- Piperazine derivatives, pharmaceutical compositions containing these compounds, their use and processes for preparing them
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Piperazine derivatives useful in the treatment or prevention of inflammation, bone degradation, thrombosis and tumor metastasis. Exemplary species are: (a) ?4-trans-?3-?4-(4-Pyridyl)-piperazin-1-yl!propionyl!amino!-cyclohexanecarboxylic acid, (b) 3-?4-trans-?4-(4-Pyridyl)-piperazin-1-yl!carbonylamino!-cyclohexylpropionic acid, (c) 3-?4-trans-?4-(4-Pyridyl)-piperazin-1-yl!malonylamino!cyclohexylcarboxylic acid, (d) Methyl ?4-trans-?3-?4-(4-pyridyl)-piperazin-1-yl!-propionyl!-amino!cyclohexane carboxylate, (e) Methyl 3-?4-trans-?4-(4-pyridyl)-piperazin-1-yl!-carbonylamino!cyclohexyl propionate, (f) Methyl ?4-trans-?4-(4-pyridyl)-piperazin-1-yl!-malonylamino!-cyclohexyl carboxylate, (g) Cyclohexyl ?4-trans-??4-(4-pyridyl)-piperazin-1-yl!-acetyl!-amino!-cyclohexane carboxylate, and (h) Isobutyl ?4-trans-??4-(4-pyridyl)-piperazin-1-yl!-acetyl!-amino!-cyclohexane carboxylate.
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- Nucleic acids encoding microsomal trigyceride transfer protein
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Nucleic acid sequences, particularly DNA sequences, coding for all or part of the high molecular weight subunit of microsomal triglyceride transfer protein, expression vectors containing the DNA sequences, host cells containing the expression vectors, and methods utilizing these materials. The invention also concerns polypeptide molecules comprising all or part of the high molecular weight subunit of microsomal triglyceride transfer protein, and methods for producing these polypeptide molecules. The invention additionally concerns novel methods for preventing, stabilizing or causing regression of atherosclerosis and therapeutic agents having such activity. The invention concerns further novel methods for lowering serum liquid levels and therapeutic agents having such activity.
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- CARBOXAMIDE DERIVATIVES FOR TREATING ASTHMA
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The present invention concerns novel carboxamide derivatives of formula I, set out hereinbelow which antagonize the pharmacological actions of one of the endogenous neuropeptide tachykinins at the neurokinin 2 (NK2) receptor, making them useful whenever such antagonism is desired, such as in the treatment of asthma and related conditions. The invention also provides pharmaceutical compositions containing the novel carboxamide derivatives for use in such treatment, methods for their use, and processes and intermediates for the manufacture of the novel carboxamide derivatives. STR1
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- Carbostyril compounds connected via an oxyalkyl group with a piperidine ring and having pharmaceutical utility
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Carbostyril derivatives of Formula I: STR1 wherein: m is 0, 1, or 2; n is 0, 1, or 2; R1 is hydrogen or lower alkyl; R2 is hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy, aralkoxy, or acyloxy; R3 is hydrogen, halogen, lower alkyl, or lower alkoxy; R4 is hydrogen, hydroxy, lower alkyl, acyloxy, provided that when R4 is hydroxy or acyloxy, m and n are both 1; R5 is hydrogen or lower alkyl; and R6 is alkyl, hydroxyalkyl, alkoxyalkyl, or (dialkylamino)alkyl; and the pharmaceutically acceptable acid addition salts and N-oxides (at the carbostyril nitrogen) thereof, and compositions containing them, are useful in treating cardiovascular diseases, particularly arrhythmias. Methods of preparing intermediates, the compounds, their formulations and methods of treatment therewith are also disclosed.
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