- The identification and use of robust transaminases from a domestic drain metagenome
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Transaminases remain one of the most promising biocatalysts for use in chiral amine synthesis, however their industrial implementation has been hampered by their general instability towards, for example, high amine donor concentrations and organic solvent content. Herein we describe the identification, cloning and screening of 29 novel transaminases from a household drain metagenome. The most promising enzymes were fully characterised and the effects of pH, temperature, amine donor concentration and co-solvent determined. Several enzymes demonstrated good substrate tolerance as well as an unprecedented robustness for a wild-type transaminase. One enzyme in particular readily accepted IPA as an amine donor giving the same conversion with 2-50 equivalents, as well as being tolerant to a number of co-solvents, and operational in up to 50% DMSO-a characteristic as yet unobserved in a wild-type transaminase. This work highlights the value of using metagenomics for biocatalyst discovery from niche environments, and here has led to the identification of one of the most robust native transaminases described to date, with respect to IPA and DMSO tolerance.
- Leipold, Leona,Dobrijevic, Dragana,Jeffries, Jack W.E.,Bawn, Maria,Moody, Thomas S.,Ward, John M.,Hailes, Helen C.
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- Economical synthesis of tert-butyl (S)-3-aminopyrrolidine-1-carboxylate from L-aspartic acid
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3-Aminopyrrolidine building block was used as the intermediate for many pharmaceutically active substances. Starting from L-aspartic acid, optically active (S)-tert-butyl-3-aminopyrrolidine-1-carboxylate was synthesized, and the reaction conditions were optimized in each step. The procedure of each step was discussed in detail and could be useful for the industrial preparation. This process was featured by readily available starting material, mild reaction conditions, easy work-up, and economy.
- Han, Zhi-Jian,Li, Yang-Bing,Gu, Bao-Hong,Li, Yu-Min,Chen, Hao
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p. 2452 - 2456
(2018/10/20)
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- HETEROAROMATIC DERIVATIVES AND PHARMACEUTICAL APPLICATIONS THEREOF
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Disclosed are heteroaryl derivatives, pharmaceutical composition and uses in the manufacture of a medicine for treating respiratory diseases, especially for chronic obstructive pulmonary disease (COPD).
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- Aromatic heterocyclic derivatives and applications of aromatic heterocyclic derivatives in medicines
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The present invention discloses aromatic heterocyclic derivatives and applications of the aromatic heterocyclic derivatives in medicines, and specifically provides a class of aromatic heterocyclic compounds or stereoisomers, geometric isomers, tautomers, racemic bodies, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and pharmaceutical compositions containing the compounds. The present invention further discloses uses of the compounds or pharmaceutical compositions in drug preparation, wherein the drug is used for treatment of respiratory diseases, particularly chronic obstructive pulmonary disease (COPD).
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Paragraph 1340-1342
(2016/10/09)
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- Synthesis and evaluation of novel ligands for the histamine H4 receptor based on a pyrrolo[2,3-d]pyrimidine scaffold
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Starting from a known H4R ligand based on a pyrimidine skeleton, a series of novel analogues based on a pyrrolo[2,3-d]pyrimidine scaffold have been prepared. Whereas the original pyrimidine congener shows good affinity at hH4R (Ki = 0.5 μM), its lacks selectivity with a K i value for the hH3R of 1 μM. Within the newly synthesized pyrrolo[2,3-d]pyrimidines, several congeners show Ki values of less than 1 μM at the hH4R and show a much improved selectivity profile. Therefore, these series represent an interesting starting point for the discovery of novel hH4R ligands.
- Gao, Ling-Jie,Schwed, J. Stephan,Weizel, Lilia,De Jonghe, Steven,Stark, Holger,Herdewijn, Piet
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p. 132 - 137
(2013/02/23)
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- CARBAPENEM ANTIBACTERIALS WITH GRAM-NEGATIVE ACTIVITY
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The present invention provides β-methyl carbapenem compounds and pharmaceutical compositions useful in the treatment of bacterial infections and methods for treating such infections using such compounds and/or compositions. The invention includes administering an effective amount of a carbapenem compound or salt and/or prodrug thereof to a host in need of such a treatment.
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- Anti-infective compounds
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The present invention relates to small molecule compounds and their use in the treatment of bacterial infections, in particular Tuberculosis.
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- Mepyramine-JNJ7777120-hybrid compounds show high affinity to hH 1R, but low affinity to hH4R
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In literature, a synergism between histamine H1 and H 4 receptor is discussed. Furthermore, it was shown, that the combined application of mepyramine, a H1 antagonist and JNJ7777120, a H 4 receptor ligand leads to a synergistic effect in the acute murine asthma model. Thus, the aim of this study was to develop new hybrid ligands, containing one H1 and one H4 pharmacophor, connected by an appropriate spacer, in order to address both, H1R and H 4R. Within this study, we synthesized nine hybrid compounds, which were pharmacologically characterized at hH1R and hH4R. The new compounds revealed (high) affinity to hH1R, but showed only low affinity to hH4R. Additionally, we performed molecular dynamic studies for some selected compounds at hH1R, in order to obtain information about the binding mode of these compounds on molecular level.
- Wagner, Eva,Wittmann, Hans-Joachim,Elz, Sigurd,Strasser, Andrea
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supporting information; experimental part
p. 6274 - 6280
(2011/11/29)
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- NOVEL 7-SUBSTITUTED 3-CARBOXY-OXADIAZINO-QUINOLONE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION AS ANTI-BACTERIALS
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A subject of the invention is the compounds of formula (I): in which either R1 represents H, OH, NH2, —(CH2)m—NRaRb(m=0.1 or 2),Ra and Rb represent H, linear, branched or cyclic (C1 -C6) alkyl, (C3-C6) cycloalkyl-(C3-C6)— alkyl, Rc, S(O)2Rc, C(O)Rc, S(O)2Rd or C(O)Rd;or Ra and Rb with N form an Rc radical;Rc represents a saturated, unsaturated or 5- or 6-members aromatic ring, containing 1 to 4 heteroatoms chosen from N, O and S, optionally substituted;Rd represents a linear, branched or cyclic (C1-C6) alkyl, optionally substituted by 1 to 4 halogens;or R1 represents Rc or CHReRc or CHReRd;Re represents H, OH, NH2, NH—(C1-C6)-alk or N-(C1-C6)-alk2, or NH—(C1-C7)-acyl or NHRc;R2 represents H, (CH2)m—NRaRb, Rc, CHReRc or CHReRd, and R′2 represents H; it being understood that R1 and R2 cannot at the same time be H or that R1 and R2 or R2 and R1 cannot be one (CH2)m—NRaRb or Rc or H and the other one OH, or one H and the other one NH2, or one H and the other one (CH2)m—NRaRb in which Ra and Rb represent H or alkyl or C(O)Rd, in which Rd represents an unsubstituted alkyl or cycloalkyl; or R1 has the above definition except H and R2 and R′2 together represent gem dialkyl or alkyl-oxime, or R2 and R′2 represent respectively Rc or Rd and OH, NH2, NHRc or NHRf, Rf being a (C1-C7) acyl radical;or R1 represents H and R2 and R′2 together represent alkyl-oxime or one represents Rc and the other one represents OH, NH2, NHRc or NHRf;n is 0 or 1;R3 and R′3 represent H or (C1-C6) alkyl optionally substituted by 1 to 3 halogens or R3 represents (C1-C6) alkoxy carbonyl and R′3 represents H;R4 represents methyl optionally substituted by halogen;R5 represents H, (C1-C6) alkyl or (C7-C12) arylalkyl;R6 represents H, fluorine, NO2, CF3 or CN;in the form of enantiomers or mixtures, as well as their salts with acids and bases; their preparation and their application as anti-bacterials, in both human and veterinary medicine.
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Page/Page column 51
(2009/09/08)
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- N-substituted-azacyclylamines as histamine-3 antagonists
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The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the histamine-3 receptor.
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Page/Page column 23
(2010/11/28)
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- 3-AMINOPYRROLIDINES AS INHIBITORS OF MONOAMINE UPTAKE
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The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, which are useful for the inhibition of the uptake of one or more physiologically active monoamines (serotonin, norepinephrine, and dopamine).
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Page/Page column 61
(2008/06/13)
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- TREATMENT OF LEARNING DISABILITIES AND MOTOR SKILLS DISORDER WITH NOREPINEPHRINE REUPTAKE INHIBITORS
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Provided are methods and medicaments for treating a learning disability or a Motor Skills Disorder, comprising administering to a patient in need of such treatment an effective amount of a selective norepinephrine reuptake inhibitor.
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Page/Page column 221
(2010/02/11)
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- TREATMENT OF PERVASIVE DEVELOPMENTAL DISORDERS WITH NOREPINEPHRINE REUPTAKE INHIBITORS
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Provided are methods and medicaments for treating a Pervasive Developmental Disorder, comprising administering to a patient in need of such treatment an effective amount of a selective norepinephrine reuptake inhibitor.
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Page/Page column 224
(2010/02/11)
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- TREATMENT OF HOT FLASHES, IMPULSE CONTROL DISORDERS AND PERSONALITY CHANGE DUE TO A GENERAL MEDICAL CONDITION
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Selective norepinephrine reuptake inhibitors are useful for the prevention or treatment of hot flashes, vasomotor symptoms, impulse control disorders or personality change due to a general medical condition.
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Page/Page column 224
(2010/02/12)
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- PROCESS FOR PRODUCING 1-ALKOXYCARBONYL NITROGENOUS SATURATED HETEROCYCLIC DERIVATIVE
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A method for producing N-protected heterocyclic compounds such as 1-alkoxycarbonyl-3-aminopyrrolidines through position-selective reaction at the nitrogen atom that constitutes the hetero ring of a nitrogen-containing saturated heterocyclic compound having two nitrogen atoms such as 3-aminopyrrolidine. A dialkyl dicarbonate (ROCO-O-COOR) is reacted with a nitrogen-containing saturated heterocyclic compounds having two nitrogen atoms, at pH of from 9 to 14 to obtain a high-purity 1-alkoxycarbonyl nitrogen-containing saturated heterocyclic compound.
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- Sulfonyl derivatives
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Sulfonyl derivatives represented by general formula (I), salts of the same, and solvates of both: and application of them as drugs: [wherein R1is hydrogen, hydroxyl, nitro or the like; R2and R3are each independently hydrogen, halogeno or the like; R4and R5are each dependently hydrogen, halogeno or the like; Q1is an optionally substituted saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or the like; Q2is a single bond, oxygen or the like; Q3is, e.g., a group represented by formula (a): T1is carbonyl or the like; and X1and X2are each independently methylidyne or nitrogen]. These compounds exhibit potent Fxa inhibiting activities and serve as excellent anticoagulants which speedily exert satisfactory and persistent anti-thrombotic effects through oral administration and little cause adverse effects.
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- Inhibitors of prenyl-protein transferase
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The present invention is directed to macrocyclic compounds which inhibit prenyl-protein transferase (FTase) and the prenylation of the oncogene protein Ras. The invention is further directed to chemothera-peutic compositions containing the compounds of this invention and methods for inhibiting prenyl-protein transferase and the prenylation of the oncogene protein Ras.
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- Anthranilic acid derivatives as inhibitors of the cGMP-phosphodiesterase
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Compounds of formula (I) STR1where R 1 is hydrogen; R 2 is nitro, cyano or halo(lower)alkyl; R 3 is phenyl substituted with one or more substituents selected from halogen, cyano and lower alkoxy; A is a lower alkylene group; R 4 is a group CR 6 R 7 R 8 wherein R 6 and R 7 form, together with the carbon atom to which they are attached a cycloalkyl group optionally substituted with hydroxy, lower alkoxy or a lower alkanoylamino; and R 8 is hydrogen; its prodrug and a salt thereof.
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- Process for producing 1H-3-aminopyrrolidine and derivatives thereof
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A process for producing 1H-3-aminopyrrolidine and derivatives thereof is disclosed. The process is especially useful for producing optically active 1H-3-aminopyrrolidine and derivatives thereof and in this case comprises reacting an optically active amino-protected aspartic anhydride represented by the formula (1) with a primary amine represented by the formula R'NH2, subjecting the reaction product to cyclodehydration to obtain an optically active 1-aralkyl-3-(protected amino)pyrrolidine-2,5-dione compound represented by the formula (2), subsequently eliminating the protective group from the 3-position amino group of the compound represented by the formula (2) to obtain an optically active 1-aralkyl-3-aminopyrrolidine-2,5-dione compound represented by the formula (3), reducing the carbonyl groups of the compound represented by the formula (3) to obtain either an optically active 1-aralkyl-3-aminopyrrolidine compound represented by the formula (4) or a salt thereof with a protonic acid, and then subjecting the compound represented by the formula (4) or the salt thereof to hydrogenolysis to obtain an optically active 1H-3-aminopyrrolidine or a protonic acid salt thereof.
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- NOVEL SULFONYL DERIVATIVES
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Sulfonyl derivatives represented by the following general formula (I): Q1-Q2-T1-Q3-SO2-QA and drugs containing the same (wherein Q1 is an optionally substituted, saturated or unsaturated, five- or six-membered cyclic hydrocarbon group, a five- or six-membered heterocyclic group, or the like; Q2 is a single band, oxygen, sulfur, C1-C6 alkylene or the like; QA is optionally substituted arylalkenyl, heteroarylalkenyl or the like; and T1 is carbonyl or the like). These compounds have potent FXa-inhibitory effects and promptly exert satisfactory and persistent antithrombotic effects through oral administration, thus being useful as anticoagulant agents little accompanied with side effects.
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- Design and biological activity of (S)-4-(5-{[1-(3-Chlorobenzyl)-2-oxopyrrolidin-3-ylamino]methyl}imidazol-1- ylmethyl)benzonitrile, a 3-aminopyrrolidinone farnesyltransferase inhibitor with excellent cell potency
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The synthesis, structure-activity relationships, and biological properties of a novel series of imidazole-containing inhibitors of farnesyltransferase are described. Starting from a 3-amino-pyrrolidinone core, a systematic series of modifications provided 5h, a non-thiol, non-peptide farnesyltransferase inhibitor with excellent bioavailability in dogs. Compound 5h was found to have an unusually favorable ratio of cell potency to intrinsic potency, compared with other known FTIs. It exhibited excellent potency against a range of tumor cell lines in vitro and showed full efficacy in the K-rasB transgenic mouse model.
- Bell,Gallicchio,Abrams,Beshore,Buser,Culberson,Davide,Ellis-Hutchings,Fernandes,Gibbs,Graham,Hartman,Heimbrook,Homnick,Huff,Kassahun,Koblan,Kohl,Lobell,Lynch Jr.,Miller,Omer,Rodrigues,Walsh,Williams
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p. 2933 - 2949
(2007/10/03)
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