- FUSED PYRIMIDINE COMPOUNDS, COMPOSITIONS AND MEDICINAL APPLICATIONS THEREOF
-
The present disclosure relates to a class of fused pyrimidine compounds of Formula I, their stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, and hydrates thereof. The present disclosure also relates to a process of preparation of these fused pyrimidine compounds, and to pharmaceutical compositions containing them.
- -
-
Paragraph 0216
(2021/04/02)
-
- Ultrasound promoted environmentally benign, highly efficient, and chemoselective N-tert-butyloxycarbonylation of amines by reusable sulfated polyborate
-
The sulfated polyborate catalyzed an efficient and chemoselective N-tert-butyloxycarbonylation of amines under ultrasonic irradiation is developed. A broad substrate scope has been demonstrated for N-Boc protection of various primary/secondary amines. It allows converting several aliphatic/aryl/heteroaryl amines, amino alcohol, aminoester, and chiral amines to their N-Boc-protected derivatives under solvent-free conditions with excellent yields. The protocol has several advantages such as easy catalyst, and product isolation, short reaction time, excellent yields, outstanding chemoselectivity, and catalyst recyclability, among others. This makes the process practicable, economical, and environmentally benign.
- Pise, Ashok S.,Ingale, Ajit P.,Dalvi, Navnath R.
-
supporting information
p. 3768 - 3780
(2021/10/26)
-
- Nanoceria as an efficient and green catalyst for the chemoselective N-tert-butyloxycarbonylation of amines under the solvent-free conditions
-
Nanocerium oxide mediated an efficient and green protocol has been described for the chemoselective N-tert-butyloxycarbonylation of amines under the solvent-free conditions at ambient temperature. Various aliphatic, aromatic and heteroaromatic amines were protected using developed protocol and several functional groups such as alcohol, phenol and ester were well tolerated under these conditions. The rapid reaction rate, mild conditions, very good functional group tolerance, excellent yield, solvent-free, easy recovery products and excellent catalyst recyclability are the advantages of this protocol. This makes the protocol feasible, economical and environmentally benign.
- Garad, Dnyaneshwar N.,Ingale, Ajit P.,Shinde, Sandeep V.,Ukale, Dattatraya
-
supporting information
p. 1656 - 1668
(2021/04/05)
-
- Sulfated tungstate: A highly efficient, recyclable and ecofriendly catalyst for chemoselective N-tert butyloxycarbonylation of amines under the solvent-free conditions
-
Sulfated tungstate catalyzed an efficient and ecofriendly protocol has been described for the chemoselective N-tert-butyloxycarbonylation of amines under the solvent-free conditions at room temperature. The variety of functionalized aliphatic, aromatic and heteroaromatic amines efficiently undergoes the N-tert-butyloxycarbonylation under the developed protocol. The aminoalcohol, aminophenol, aminoester as well as various chiral amines underwent the chemoselective N-Boc protection under the optimized reaction condition. The rapid reaction rate, mild conditions, very good functional group tolerance, excellent yield, solvent-free, easy recovery products and excellent catalyst recyclability are the advantages of this protocol. This makes the protocol feasible, economical and environmentally benign.
- Ingale, Ajit P.,Shinde, Sandeep V.,Thorat, Nitin M.
-
supporting information
p. 2528 - 2543
(2021/07/02)
-
- SUBSTITUTED AMIDE COMPOUNDS USEFUL AS FARNESOID X RECEPTOR MODULATORS
-
Disclosed are compounds of Formula (I): or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof, wherein Q is: (i) halo, cyano, hydroxyl, NRxRx, C(O)OH, C(O)NH2, C1-6 alkyl substituted with zero to 6 R1a, or P(O)R1cR1c; or (ii) L R1; and A, X1, X2, X3, X4, Z1, Z2, R1, R1a, R1c, R2, R3a, R3b, Rx, L, a, b, and d are defined herein. Also disclosed are methods of using these compounds to modulate the activity of farnesoid X receptor (FXR); pharmaceutical compositions comprising these compounds; and methods of treating a disease, disorder, or condition associated with FXR dysregulation, such as pathological fibrosis, transplant rejection, cancer, osteoporosis, and inflammatory disorders, by using the compounds and pharmaceutical compositions.
- -
-
Page/Page column 119; 120
(2020/08/28)
-
- N-alkyl-hydroxybenzoyl anilide hydroxamates as dual inhibitors of HDAC and HSP90, downregulating IFN-γ induced PD-L1 expression
-
Novel dual inhibitors of histone deacetylase (HDAC) and heat-shock protein 90 (HSP90) are synthesized and evaluated. These compounds are endowed with potent HDAC and HSP90 inhibitory activities with IC50 values in nanomolar range with Compound 20 (HDAC IC50 = 194 nM; HSP90α IC50 = 153 nM) and compound 26 (HDAC IC50 = 360 nM; HSP90α IC50 = 77 nM) displaying most potent HDAC and HSP90α inhibitory activities. Both of these compounds induce HSP70 expression and down regulate HSP90 client proteins which play important roles in the regulation of survival and invasiveness in cancer cells. In addition, compounds 20 and 26 induce acetylation of α-tubulin and histone H3. Significantly, compounds 20 and 26 could effectively reduce programmed death-ligand 1 (PD-L1) expression in IFN-γ treated lung H1975 cells in a dose dependent manner. These findings suggest that dual inhibition of HDAC and HSP90 that can modulate immunosuppressive ability of tumor area may provide a better therapeutic strategy for cancer treatment in the future.
- Mehndiratta, Samir,Lin, Mei-Hsiang,Wu, Yi-Wen,Chen, Chun-Han,Wu, Tung-Yun,Chuang, Kuo-Hsiang,Chao, Min-Wu,Chen, Yi-Ying,Pan, Shiow-Lin,Chen, Mei-Chuan,Liou, Jing-Ping
-
-
- Tert-Butyl(3-cyano-4,6-dimethylpyridin-2-yl)carbonate as a green and chemoselective N-tert-butoxycarbonylation reagent
-
The use of tert-butyl(3-cyano-4,6-dimethylpyridin-2-yl)carbonate as a chemoselective tert-butoxycarbonylation reagent for aromatic and aliphatic amines has been demonstrated. To gain insight into this reaction, in situ React IR technology was used to confirm the effectivity and chemoselectivity of this novel Boc reagent. The reaction was carried out chemoselectively in high yield under mild, environment-friendly conditions and was completed quickly within 1 hour. Simultaneously, the Boc carrier was easily recyclable, and has great application prospects for industrial production.
- Du, Fangyu,Zhou, Qifan,Fu, Yang,Zhao, Hanqi,Chen, Yuanguang,Chen, Guoliang
-
supporting information
p. 6549 - 6554
(2019/05/04)
-
- COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASE 4 POLYPEPTIDES
-
The present disclosure relates to bifunctional compounds, which find utility as modulators of Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4); the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hppel-Lindau, cereblon, ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
- -
-
Paragraph 1646-1647
(2019/06/07)
-
- Chemoselective: N-tert -butyloxycarbonylation of amines in glycerol
-
A catalyst-free, efficient and green protocol has been developed for the chemoselective N-Boc protection of amines by using glycerol as a solvent at room temperature. A variety of functionalized amines, such as aliphatic, aromatic as well as heteroaromatic were protected using the developed protocol. N-tert-Butyloxycarbonylation derivatives were formed without the formation of isocyanate, urea, N,N-di-t-Boc, or oxazolidinone as side products. The operational simplicity, cleaner reaction, rapid reaction convergence, functional group tolerance, excellent yield, high selectivity, catalyst-free feature and solvent recyclability are the distinct advantages of this protocol. Owing to these merits, this protocol is feasible, economical and environmentally benign.
- Ingale, Ajit P.,More, Vishal K.,Gangarde, Uddhav S.,Shinde, Sandeep V.
-
supporting information
p. 10142 - 10147
(2018/06/18)
-
- [TPA][Pro] ionic liquid as efficient reaction medium for N-tert-Boc protection of amines
-
A facile and efficient N-tert-Boc protection of amines is described by the reaction of various primary, secondary, benzylic and aryl amines with di-tert-butyl dicarbonate in the ionic liquid [TPA][Pro] at room temperature. All the N-tert-butylcarbamates are afforded in excellent yields. A catalyst-free method was developed and the ionic liquid [TPA][Pro] can be recovered and reused for several times without loss of its activity.
- Vijaya Durga,Rambabu,Srinivasa Reddy,Hari Babu
-
p. 1313 - 1316
(2017/05/02)
-
- NITROGENOUS HETEROCYCLIC DERIVATIVES AND THEIR APPLICATION IN DRUGS
-
The invention relates to the field of medicine, discloses new nitrogen heterocyclic derivatives, preparation method thereof and as medicament in particular as the treatment and prevention of treating tissue fibrosis of the medicament. The invention also discloses a pharmaceutically acceptable compound of the present invention comprise a pharmaceutical composition and methods for using the composition for the treatment of the human or animal tissue fibrosis of diseases, in particular for treating the human or animal renal interstitial fibrosis, glomerular sclerosis, hepatic fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, skin fibrosis, after the operation of adhering, benign prostate hypertrophy, bone-myocardial, scleroderma, multiple sclerosis, pancreas fibrosis, liver cirrhosis, myosarcoma, neurofibromatosis, interstitial pulmonary fibrosis, diabetic nephropathy, Alzheimer's disease or vascular fibrosis disease in use. (by machine translation)
- -
-
Paragraph 133; 134
(2018/06/01)
-
- Carbazole and Carboline Compounds for Use in the Diagnosis, Treatment, Alleviation or Prevention of Disorders Associated with Amyloid or Amyloid-Like Proteins
-
The present invention relates to novel compounds that can be employed in the diagnosis, treatment, alleviation or prevention of a group of disorders and abnormalities associated with amyloid proteins and amyloid-like proteins, such as Alzheimer's disease. Precursors for the preparation of the compounds according to the present invention are also provided.
- -
-
Paragraph 0749; 0750; 0751; 0752;
(2017/01/23)
-
- BENZODIAZEPINE DERIVATIVES AS CCK2/GASTRIN RECEPTOR ANTAGONISTS
-
The invention relates to benzodiazepine derivatives of formula (A) useful as CCK2/gastrin receptor antagonists, their preparation and their use in the treatment or prevention of disorders associated with CCK2/gastrin receptors, disorders caused by or associated with hypergastrinaemia, and gastric acid-related disorders.
- -
-
Page/Page column 59; 63; 64
(2016/03/26)
-
- Ligand-Promoted Meta-C-H Arylation of Anilines, Phenols, and Heterocycles
-
Here we report the development of a versatile 3-acetylamino-2-hydroxypyridine class of ligands that promote meta-C-H arylation of anilines, heterocyclic aromatic amines, phenols, and 2-benzyl heterocycles using norbornene as a transient mediator. More than 120 examples are presented, demonstrating this ligand scaffold enables a wide substrate and coupling partner scope. Meta-C-H arylation with heterocyclic aryl iodides as coupling partners is also realized for the first time using this ligand. The utility for this transformation for drug discovery is showcased by allowing the meta-C-H arylation of a lenalidomide derivative. The first steps toward a silver-free protocol for this reaction are also demonstrated.
- Wang, Peng,Farmer, Marcus E.,Huo, Xing,Jain, Pankaj,Shen, Peng-Xiang,Ishoey, Mette,Bradner, James E.,Wisniewski, Steven R.,Eastgate, Martin D.,Yu, Jin-Quan
-
supporting information
p. 9269 - 9276
(2016/08/05)
-
- Nitrogenous Heterocyclic Derivatives And Their Application In Drugs
-
The present invention relates to the field of medicine, provided herein are novel nitrogenous heterocyclic compounds, their preparation methods and their uses as drugs, especially for treatment and prevention of tissue fibrosis. Also provided herein are pharmaceutically acceptable compositions comprising the nitrogenous heterocyclic compounds and the uses of the compositions in the treatment of human or animal tissue fibrosis, especially for human or animal renal interstitial fibrosis, glomerular sclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, dermatofibrosis, postsurgical adhesion, benign prostatic hyperplasia, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myosarcoma, neurofibroma, pulmonary interstitial fibrosis, diabetic nephropathy, alzheimer disease or vascular fibrosis.
- -
-
Paragraph 0579
(2015/03/31)
-
- Development of first lead structures for phosphoinositide 3-kinase-c2γ inhibitors
-
The importance of complete elucidation of the biological functions of phosphoinositide 3-kinases (PI3K) was realized years ago. They generate 3-phosphoinositides, which are known to function as important second messengers in many inter- and intracellular signaling pathways. However, the functional role of class II PI3Ks is still unclear. Herein, we describe the synthesis of a panel of compounds that were tested against all eight mammalian PI3K-isoforms. We found inhibitors with some selectivity for class II PI3K-C2γ and also compounds with preferred inhibition of class II PI3K-C2β, providing structural leads to develop selective tool compounds.
- Freitag, Anne,Prajwal, Prajwal,Shymanets, Aliaksei,Harteneck, Christian,Nürnberg, Bernd,Sch?chtele, Christoph,Kubbutat, Michael,Totzke, Frank,Laufer, Stefan A.
-
supporting information
p. 212 - 221
(2015/03/03)
-
- CARBAZOLE AND CARBOLINE COMPOUNDS FOR USE IN THE DIAGNOSIS, TREATMENT, ALLEVIATION OR PREVENTION OF DISORDERS ASSOCIATED WITH AMYLOID OR AMYOLID-LIKE PROTEINS
-
The present invention relates to novel compounds that can be employed in the diagnosis, treatment, alleviation or prevention of a group of disorders and abnormalities associated with amyloid proteins and amyloid-like proteins, such as Alzheimer's disease. Precursors for the preparation of the compounds according to the present invention are also provided.
- -
-
Page/Page column 157
(2015/08/06)
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- HETEROARYL COMPOUNDS AND USES THEREOF
-
The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.
- -
-
Paragraph 0688
(2015/07/02)
-
- NITROGENOUS HETEROCYCLIC DERIVATIVES AND THEIR APPLICATION IN DRUGS
-
The present invention relates to the field of medicine, provided herein are novel nitrogenous heterocyclic compounds, their preparation methods and their uses as drugs, especially for treatment and prevention of tissue fibrosis. Also provided herein are pharmaceutically acceptable compositions comprising the nitrogenous heterocyclic compounds and the uses of the compositions in the treatment of human or animal tissue fibrosis, especially for human or animal renal interstitial fibrosis, glomerular sclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, dermatofibrosis, postsurgical adhesion, benign prostatic hyperplasia, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myosarcoma, neurofibroma, pulmonary interstitial fibrosis, diabetic nephropathy, alzheimer disease or vascular fibrosis.
- -
-
Paragraph 00313
(2014/02/15)
-
- 6-AMINOINDOLE DERIVATIVES AS TRP CHANNEL ANTAGONISTS
-
The invention is concerned with the compounds of formula (I) and pharmaceutically acceptable salts thereof. In addition, the present invention relates to methods of manufacturing and using the compounds of formula (I) as well as pharmaceutical composition
- -
-
Page/Page column 12
(2014/05/07)
-
- N-Protection of amines using pyridinium 2,2,2-trifluoroacetate ionic liquid as an efficient and reusable catalyst
-
A simple, green, and efficient method for the N-tert-butoxycarbonylation of amines by pyridinium 2,2,2-trifluoroacetate ([Py][OTf]) as an efficient and reusable catalyst is reported. In general, electron donating groups on aryl group give rise to the higher yields than electron withdrawing groups. Clean reaction, short reaction times, high yields, reusability of catalyst, and easy preparation of it are some advantages of this work.
- Karimian, Somaye,Tajik, Hassan
-
p. 218 - 220
(2014/02/14)
-
- HETEROARYL COMPOUNDS AND USES THEREOF
-
The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.
- -
-
Paragraph 0439; 0443
(2014/07/08)
-
- PURINONE COMPOUNDS AS KINASE INHIBITORS
-
Disclosed herein are compounds that form covalent bonds with Bruton's tyrosine kinase (Btk). Also described are irreversible inhibitors of Btk. In addition, reversible inhibitors of Btk are also described. Also disclosed are pharmaceutical compositions th
- -
-
Paragraph 0715; 0716
(2013/08/14)
-
- Zinc chloride promoted efficient and facile BOC protection of amines
-
Amines are efficiently protected as their BOC derivatives under mild reaction conditions when reacted with BOC anhydride in presence of ZnCl2. The present method is applicable to a variety of amines including aliphatic, aromatic as well as heteroaromatic amines. This protocol appears to be competitive and in some cases superior to previously reported procedures that work under basic conditions.
- Arifuddin, M.,Lakshmikant, N.,Rajasekar, N.,Shinde, D. B.
-
p. 1168 - 1172,5
(2020/08/31)
-
- HETEROCYCLIC COMPOUND AND USE THEREOF
-
A compound represented by formula (I) or a salt thereof, which has a potent Raf inhibitory activity. In formula (I), R1 represents an optionally substituted C1-6 alkyl, etc.; X represents —O— or —NR2— (wherein R2 represents a hydrogen atom or a C1-6 alkyl); Y represents a group represented by formula 2 (2ii or 2ii) (wherein ring A represents an optionally substituted benzene ring; Z represents a group represented by (1) —NR3CO—W1—, (2) —NR3CO—W1—O—, (3) —NR3CO—W1—O—W2—, (4) —NR3CO—W1—S—, (5) —NR3CO—W1—NR4—, (6) —NR3COO—, (7) —NR3COO—W1—, (8) —NR3CO—CO—, or (9) —NR3CONR4— (wherein R3 and R4 each represents a hydrogen atom, etc., and W1 and W2 each represents an optionally substituted C1-6 alkylene, etc.); and R5 represents an optionally substituted five- or six-membered ring group.
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-
Page/Page column 34
(2011/10/12)
-
- Ferric chloride-promoted efficient and facile BOC protection of amines
-
Amines are efficiently protected as their tertiary butyloxycarbonyl (BOC) derivatives under mild reaction condition when reacted with (BOC)2O in the presence of FeCl3. The present method is applicable to a variety of amines including aliphatic, aromatic, and hetero aromatic amines.
- Tasneem,Rajanna
-
experimental part
p. 715 - 719
(2011/04/12)
-
- Helix persistence and breakdown in oligoureas of metaphenylenediamine: Apparent diastereotopicity as a spectroscopic marker of helix length in solution
-
Oligomeric ureas derived from m-phenylenediamine with chain lengths of up to seven urea linkages were made by iterative synthetic pathways. Three families were synthesized: 4 and 20, bearing a terminal chiral sulfinyl group; 24, bearing a terminal rotatio
- Clayden, Jonathan,Lemiegre, Loic,Morris, Gareth A.,Pickworth, Mark,Snape, Timothy J.,Jones, Lyn H.
-
supporting information; experimental part
p. 15193 - 15202
(2009/03/12)
-
- An efficient and chemoselective Br?nsted acidic ionic liquid-catalyzed N-Boc protection of amines
-
The first report of a Br?nsted acidic ionic liquid, 1-methylimidazolium tetrafluoroborate [(HMIm)BF4], catalyzed efficient and chemoselective N-Boc protection of various amines using (Boc)2O is presented. Optically pure amino alcohols and amino acid esters were converted efficiently to their corresponding optically pure N-Boc derivatives. The reported method is mild, solvent-free and has the advantages of both homogeneous and heterogeneous catalysis with high product yields, selectivity and ease of product separation.
- Sunitha, Sadula,Kanjilal, Sanjit,Reddy, P. Srinivasa,Prasad, Rachapudi B.N.
-
p. 2527 - 2532
(2008/09/19)
-
- Optimization of 1,3,4-benzotriazepine-based CCK2 antagonists to obtain potent, orally active inhibitors of gastrin-mediated gastric acid secretion
-
Starting from a novel, achiral 1,3,4-benzotriazepine-based CCK2 receptor antagonist, a process of optimization has afforded further compounds of this type that maintain the nanomolar affinity for recombinant, human CCK2 receptors and high selectivity over
- McDonald, Iain M.,Black, James W.,Buck, Ildiko M.,Dunstone, David J.,Griffin, Eric P.,Harper, Elaine A.,Hull, Robert A. D.,Kalindjian, S. Barret,Lilley, Elliot J.,Linney, Ian D.,Pether, Michael J.,Roberts, Sonia P.,Shaxted, Mark E.,Spencer, John,Steel, Katherine I. M.,Sykes, David A.,Walker, Martin K.,Watt, Gillian F.,Wright, Laurence,Wright, Paul T.,Xun, Wei
-
p. 3101 - 3112
(2008/02/09)
-
- Metasubstituted thiazolidinones, their manufacture and use as a drug
-
This invention involves thiazolidinone of general formula (I) and its creation and use as inhibitors of polo like kinase (PLK) for the treatment of various diseases.
- -
-
Page/Page column 40
(2010/11/25)
-
- Facile N-tert-butoxycarbonylation of amines using La(NO3)3·6H2O as a mild and efficient catalyst under solvent-free conditions
-
Facile N-tert-butoxycarbonylation of amines is described by the treatment of various primary, secondary, benzylic and aryl amines with di-tert-butyl dicarbonate in the presence of catalytic amounts of La(NO3)3·6H2O under solvent-free conditions at room temperature to afford N-tert-butylcarbamates in excellent yields.
- Suryakiran,Prabhakar,Reddy, T. Srikanth,Rajesh,Venkateswarlu
-
p. 8039 - 8042
(2007/10/03)
-
- A highly chemoselective Boc protection of amines using sulfonic-acid-functionalized silica as an efficient heterogeneous recyclable catalyst
-
A facile and versatile method for the chemoselective Boc protection of amines has been developed by a treatment with (Boc)2O in the presence of sulfonic-acid-functionalized silica as a catalyst. The method is general for the preparation of N-Boc derivatives of aliphatic (acyclic and cyclic), aromatic, and heteroaromatic amines; primary and secondary amines; aminols, amino-esters; and sulfonamides. The catalyst works under heterogeneous conditions and can be recycled.
- Das, Biswanath,Venkateswarlu, Katta,Krishnaiah, Maddeboina,Holla, Harish
-
p. 7551 - 7556
(2008/02/08)
-
- Copper(II) tetrafluoroborate as a novel and highly efficient catalyst for N-tert-butoxycarbonylation of amines under solvent-free conditions at room temperature
-
Commercially available copper(II) tetrafluoroborate hydrate was found to be a highly efficient catalyst for chemoselective N-tert-butoxycarbonylation of amines with di-tert-butyl dicarbonate under solvent-free conditions and at room temperature. Various aromatic amines were protected as their N-tert-butyl carbamates in high yields and in short times. No competitive side reactions such as isocyanate, urea, and N,N-di-t-Boc formation was observed. Chemoselective N-tert-butoxycarbonylation was achieved with substrates bearing OH and SH groups. Chiral α-amino acid esters afforded the corresponding N-t-Boc derivatives in excellent yields.
- Chankeshwara, Sunay V.,Chakraborti, Asit K.
-
p. 1087 - 1091
(2007/10/03)
-
- Novel, achiral 1,3,4-benzotriazepine analogues of 1,4-benzodiazepine-based CCK2 antagonists that display high selectivity over CCK1 receptors
-
A series of 1,3,4-benzotriazepine-based CCK2 antagonists have been devised by consideration of the structural features that govern CCK receptor affinity and the receptor subtype selectivity of 1,4-benzodiazepine- based CCK2 antagonists. In contrast to the latter compounds, these novel 1,3,4-benzotriazepines are achiral, yet they display similar affinity for CCK2 receptors to the earlier molecules and are highly selective over CCK1 receptors.
- McDonald, Iain M.,Austin, Carol,Buck, Ildiko M.,Dunstone, David J.,Griffin, Eric,Harper, Elaine A.,Hull, Robert A. D.,Kalindjian, S. Barret,Linney, Ian D.,Low, Caroline M. R.,Pether, Michael J.,Spencer, John,Wright, Paul T.,Adatia, Trushar,Bashall, Alan
-
p. 2253 - 2261
(2007/10/03)
-
- 1, 3, 4-BENZOTRIAZEPIN-2-ONE SALTS AND THEIR USE AS CCK RECEPTOR LIGANDS
-
This invention relates to pharmaceutically acceptable salts of compounds of formula (I) wherein: W is N or N+-O-; R2 is an optionally substituted C1 to C18 hydrocarbyl group wherein up to three C atoms may optionally be replaced by N, O and/or S atoms. R3 is -(CR11R12)m-X-(CR13R14)p-R9; m is 0, 1, 2, 3 or 4; p is 0, 1 or 2; X is a bond, -CR15=CR16-, -C≡C-, C(O)NH, NHC(O), C(O)NMe, NMeC(O), C(O)O, NHC(O)NH, NHC(O)O, OC(O)NH, NH, O, CO, SO2, SO2NH, C(O)NHNH, R9 is H ; C1 to C6 alkyl ; or phenyl, naphthyl, pyridyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolinyl, isoindolinyl, indolyl, isoindolyl or 2-pyridonyl substituted with -L-Q. R4 is an optionally substituted C1 to C18 hydrocarbyl group wherein up to three C atoms may optionally be replaced by N, O and/or S atoms ; and Such salts are useful, for example, for the treatment of gastrin related disorders.
- -
-
-
- BENZOTRIAZEPINE DERIVATIVES AND THEIR USE AS GASTRIN AND CHOLECYSTOKININ RECEPTOR LIGANDS
-
This invention relates to a compound of formula (I). The compound is useful for the treatment of gastrin related disorders.
- -
-
Page/Page column 24
(2010/02/09)
-
- N-aryl N′-hydroxyguanidines, a new class of NO-donors after selective oxidation by nitric oxide synthases: Structure-activity relationship
-
The formation of nitric oxide (NO) was followed during the oxidation of 37 N-hydroxyguanidines or related derivatives, including 18 new N-aryl N′ -hydroxyguanidines, by recombinant inducible nitric oxide synthase (NOS II). Several N-aryl N′-hydroxyguanidines bearing a relatively small, electron-donating para subtituent, such as H, F, Cl, CH3, OH, OCH3, and NH2, led to NO formation rates between 8 and 41% of that of NO formation from the natural NOS substrate, Nω-hydroxy-L-arginine (NOHA). The characteristics of these reactions were very similar to those previously reported for the oxidation of NOHA by NOS: (i) the strict requirement of NOS containing (6R)-5,6,7,8-tetrahydro-L-biopterin, reduced nicotinamide adenine dinucleotide phosphate, and O2 for the oxidation to occur, (ii) the formation of NO and the corresponding urea in a 1:1 molar ratio, and (iii) a strong inhibitory effect of the classical NOS inhibitors such as Nω-nitro-L-arginine and S-ethyl-iso-thiourea. Structure-activity relationship studies showed that two structural factors are crucial for NO formation from compounds containing a C=NOH function. The first one is the presence of a monosubstituted N-hydroxyguanidine function, since disubstituted N-hydroxyguanidines, amidoximes, ketoximes, and aldoximes failed to produce NO. The second one is the presence of a N-phenyl ring bearing a relatively small, not electron-withdrawing para substituent that could favorably interact with a hydrophobic cavity close to the NOS catalytic site. The kcat value for NOS II-catalyzed oxidation of N-parafluorophenyl N′-hydroxyguanidine was 80% of that found for NOHA, and its kcat/Km value was only 9-fold lower than that of NOHA. Interestingly, the Km value found for NOS II-catalyzed oxidation of N-(3-thienyl) N′-hydroxyguanidine was 25 μM, almost identical to that of NOHA. Recombinant NOS I and NOS III also oxidize several N-aryl N′-hydroxyguanidines with the formation of NO, with a clearly different substrate specificity. The best substrates of the studied series for NOS I and NOS III were N-(para-hydroxyphenyl) and N-(meta-aminophenyl) N′-hydroxyguanidine, respectively. Among the studied compounds, the para-chlorophenyl and paramethylphenyl derivatives were selective substrates of NOS II. These results open the way toward a new class of selective NO donors after in situ oxidation by each NOS family.
- Renodon-Cornière, Axelle,Dijols, Sylvie,Perollier, Céline,Lefevre-Groboillot, David,Boucher, Jean-Luc,Attias, Roger,Sari, Marie-Agnes,Stuehr, Dennis,Mansuy, Daniel
-
p. 944 - 954
(2007/10/03)
-
- NOVEL AMIDE COMPOUNDS
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A compound of the formula (I):R1-A-X-NHCO-Y-R2 ???whereinR1 is heterocyclic group which may have suitable substituents, or phenyl which may have suitable substituents,R2 is condensed phenyl which may have suitable substituents, phenyl which may have suitable substituents, or thienyl which may have suitable substituents,A is a group of the formula:-(CH2)t-(O)m- or in which R3 and R4 are each hydrogen or linked together to form imino,R5 is hydrogen or lower alkyl,t is 0, 1 or 2,p, m and n are each 0 or 1,X is phenylene which may have suitable substituents, or bivalent heterocyclic group containing nitrogen which may have suitable substituents,Y is bond, lower alkylene, or lower alkenylene, and a salt thereof.
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- Gastrin and cholecystokinin receptor ligands
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Compounds of formula (I) and their pharmaceutically acceptable salts are ligands at gastrin and/or cholecystokinin receptors. X and Y are independently ═N—, —N(R5)—═CH—, —S— or —O—. n is from 1 to 4; R1is H or C1to C1
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- Chemoselective conversion of azides to t-butyl carbamates and amines
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Azides were converted to the corresponding carbamates using a system of 20 mol% of decaborane (B10H14) and 20 weight% of 10% Pd/C in methanol in the presence of di-tert-butyl dicarbonate at rt in high yields and to the corresponding amines using a system of 10 mol% of decaborane and 20 weight% of 10% Pd/C in methanol in the absence of di-tert-butyl dicarbonate at rt in high yields.
- Jung, Yeon Joo,Chang, Yu Mi,Lee, Ji Hee,Yoon, Cheol Min
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p. 8735 - 8739
(2007/10/03)
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- Acetamidine derivatives and their use as inhibitors for the nitric oxide synthase
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A class of acetamidine derivatives of general formula (I) STR1 wherein R1 is hydrogen, C1-6 hydrocarbyl group optionally substituted by halo, halo, nitro, cyano or a group XR3 wherein X is oxygen, C(O)m wherein m is 1 or 2, S(O)n wherein n is 0, 1 or 2, or a group NR4 wherein R4 is hydrogen or C1-6 alkyl; and R3 is hydrogen, C1-6 alkyl, or a group NR5 R6 wherein R5 and R6 are independently hydrogen or C1-6 alkyl, provided that R3 is not NR5 R6 when X is oxygen or S(O)n; R1a and R1b are independently selected from hydrogen and halo; R2 is a C1-14 hydrocarbyl group which may optionally contain one or two heteroatoms, the group R2 being optionally substituted by one or more groups independently selected from halo; N3 ; nitro; CF3 ; ZR7 wherein Z is oxygen, C(O)m' wherein m' is 1 or 2, S(O)n' wherein n' is 0, 1 or 2, or a group NR8 wherein R8 is hydrogen or C1-6 alkyl and R7 is hydrogen, C1-6 alkyl or a group NR9 R10 wherein R9 and R10 are independently hydrogen or C1-6 alkyl; or R2 is substituted by a group (a) STR2 wherein R11 has a definition the same as for R1 ; with the proviso that when R1 is a C1-6 alkyl group and R2 is a C1-14 hydrocarbyl substituted by two groups ZR7 wherein one group ZR7 is CO2 H, the other group ZR7 is not NH2; and salts thereof, methods for the manufacture thereof, and therapies, particularly inhibtion of nitric oxide synthase, is disclosed.
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- Synthesis and biological activity of a novel series of nonsteroidal, peripherally selective androgen receptor antagonists derived from 1,2- dihydropyridono[5,6-g]quinolines
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A new nonsteroidal antiandrogenic pharmacophore has been discovered using cell-based cotransfection assays with human androgen receptor (hAR). This series of AR antagonists is structurally characterized by a linear tricyclic 1,2-dihydropyridono[5,6-g]quinoline core. Analogues inhibit AR- mediated reporter gene expression and bind to AR as potently as or better than any known AR antagonists. Several analogues also showed excellent in vivo activity in classic rodent models of AR antagonism, inhibiting growth of rat ventral prostate and seminal vesicles, without accompanying increases in serum gonadotropin and testosterone levels, as is seen with other AR antagonists. Investigations of structure - activity relationships surrounding this pharmacophore resulted in molecules with complete specificity for AR, antagonist activity on an AR mutant commonly observed in prostate cancer patients, and improved in vivo efficacy. Molecules based on this series of compounds have the potential to provide unique and effective clinical opportunities for treatment of prostate cancer and other androgen-dependent diseases.
- Hamann, Lawrence G.,Higuchi, Robert I.,Zhi, Lin,Edwards, James P.,Wang, Xiao-Ning,Marschke, Keith B.,Kong, James W.,Farmer, Luc J.,Jones, Todd K.
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p. 623 - 639
(2007/10/03)
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- N-phenylamidines as selective inhibitors of human neuronal nitric oxide synthase: Structure-activity studies and demonstration of in vivo activity
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Selective inhibition of the neuronal isoform of nitric oxide synthase (NOS) compared to the endothelial and inducible isoforms may be required for treatment of neurological disorders caused by excessive production of nitric oxide. Recently, we described N-(3-(aminomethyl)benzyl)acetamidine (13) as a slow, tight-binding inhibitor, highly selective for human inducible nitric oxide synthase (iNOS). Removal of a single methylene bridge between the amidine nitrogen and phenyl ring to give N-(3- (aminomethyl)phenyl)acetamidine (14) dramatically altered the selectivity to give a neuronal selective nitric oxide synthase (nNOS) inhibitor. Part of this large shift in selectivity was due to 14 being a rapidly reversible inhibitor of iNOS in contrast to the essentially irreversible inhibition of iNOS observed with 13. Structure-activity studies revealed that a basic amine functionality tethered to an aromatic ring and a sterically compact amidine are key pharmacophores for this class of NOS inhibitors. Maximal nNOS inhibition potency was achieved with N-(3-(aminomethyl)phenyl)-2- furanylamidine (77) (K(i-nNOS) = 0.006 μM; K(i-eNOS) = 0.35 μM; K(i-iNOS) = 0.16 μM). Finally, α-fluoro-N-(3-(aminomethyl)phenyl)acetamidine (74) (K(i- nNOS) = 0.011 μM; K(i-eNOS) = 1.1 μM; K(i-iNOS) = 0.48 μM) had excellent brain penetration and inhibited nNOS in a rat brain slice assay as well as in the rat brain (cerebellum) in vivo. Thus, N-phenylamidines should be useful in validating the role of nNOS in neurological disorders.
- Collins, Jon L.,Shearer, Barry G.,Oplinger, Jeffrey A.,Lee, Shuliang,Garvey, Edward P.,Salter, Mark,Duffy, Claire,Burnette, Thimysta C.,Furfine, Eric S.
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p. 2858 - 2871
(2007/10/03)
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- DEVELOPMENT OF NEW DNA-BINDING AND CLEAVING MOLECULES: DESIGN, SYNTHESIS AND ACTIVITY OF A BISDIAZONIUM SALT
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The bisdiazonium compound 1 has been shown to cleave DNA at concentrations as low as 0.1 μM.Evidence is presented to indicate that 1 is binding to the minor groove of DNA, and that binding may be responsible for its effectiveness as a DNA cleaving reagent
- Arya, Dev P.,Warner, Philip M.,Jebaratnam, David J.
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p. 7823 - 7826
(2007/10/02)
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