- MACROCYCLIC COMPOUNDS FOR THE TREATMENT OF MEDICAL DISORDERS
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Compounds, methods of use, and processes for making inhibitors of complement factor D or a pharmaceutically acceptable salt or composition thereof are provided. The inhibitors described herein target factor D and inhibit or regulate the complement cascade. The inhibitors of factor D described herein reduce excessive activation of complement.
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Page/Page column 453; 480; 481; 482
(2020/03/29)
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- Photoinduced Olefin Diamination with Alkylamines
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Vicinal diamines are ubiquitous materials in organic and medicinal chemistry. The direct coupling of olefins and amines would be an ideal approach to construct these motifs. However, alkene diamination remains a long-standing challenge in organic synthesis, especially when using two different amine components. We report a general strategy for the direct and selective assembly of vicinal 1,2-diamines using readily available olefin and amine building blocks. This mild and straightforward approach involves in situ formation and photoinduced activation of N-chloroamines to give aminium radicals that enable efficient alkene aminochlorination. Owing to the ambiphilic nature of the β-chloroamines produced, conversion into tetra-alkyl aziridinium ions was possible, thus enabling diamination by regioselective ring-opening with primary or secondary amines. This strategy streamlines the preparation of vicinal diamines from multistep sequences to a single chemical transformation.
- Angelini, Lucrezia,Govaerts, Sebastian,Hampton, Charlotte,Leonori, Daniele,Malet-Sanz, Laia,Ruffoni, Alessandro
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supporting information
p. 15021 - 15028
(2020/06/17)
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- Divergent Access to Histone Deacetylase Inhibitory Cyclopeptides via a Late-Stage Cyclopropane Ring Cleavage Strategy. Short Synthesis of Chlamydocin
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A unified step-economical strategy for accessing histone deacetylase inhibitory peptides is proposed, based on the late-stage installation of multiple zinc-binding functionalities via the cleavage of the strained cyclopropane ring in the common pluripoten
- Elek, Gábor Zoltán,Koppel, Kaur,Zubrytski, Dzmitry M.,Konrad, Nele,J?rving, Ivar,Lopp, Margus,Kananovich, Dzmitry G.
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supporting information
p. 8473 - 8478
(2019/10/16)
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- Conformation-constrained entirely-synthetic macrocyclic compounds
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The invention relates to conformation-constrained entirely-synthetic macrocyclic compounds. A conformation-constrained, space-defined 12-30-member macrocyclic system (I) which is as shown in the description comprises three different constitution units: an aromatic template a, a confor1ation regulator b and a spaced part c, which are illustrated in the description and the claims. The macrocyclic compounds (I) can be easily prepared according to a parallel synthesis method or a combinatorial chemistry method, and are designed for realizing interaction with a specific biological target. Particularly, the compounds show agonistic or antagonistic activity to the following matters: a motilin receptor (MR), a 5-hydroxytryptamine receptor (5-HT2B receptor) of a subtype 5-HT2B, and a prostaglandin F2alpha receptor (FP receptor). Thus, the compounds are effectively used for treating gastrointestinal tract hypomotility disorder such as diabetic gastroparesis and constipation-predominant irritable bowel syndrome, CNS-related diseases such as migraine, schizophrenia, psychosis and depression, ocular hypertension such as glaucoma-related ocular hypertension, and premature delivery.
- -
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Paragraph 0782; 1408
(2016/10/07)
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- CONFORMATIONALLY CONSTRAINED, SYNTHETIC MACROCYCLIC COMPOUNDS
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PROBLEM TO BE SOLVED: To provide a novel macrocyclic compound showing agonistic or antagonistic activity on a motilin receptor, a serotonin receptor and a prostaglandin F2A receptor. SOLUTION: This invention provides a macrocyclic compound incorporating building blocks A, B and C, represented by formula (I). The compound is useful for the treatment of motility disorders of the gastrointestinal tract, CNS-related disease and ocular hypertension. COPYRIGHT: (C)2015,JPO&INPIT
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Paragraph 0106; 0111
(2016/10/10)
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- Diastereoselective synthesis of cyclic β2,3-amino acids utilizing 4-substituted-1,3-oxazinan-6-ones
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The 4-substituted-1,3-oxazinan-6-one scaffold is a versatile synthon enabling access to a diverse array of β-amino acid derivatives. In this study, the synthetic utility of the 1,3-oxazinan-6-one is expanded to include the diastereoselective synthesis of
- Sleebs, Brad E.,Nguyen, Nghi H.,Hughes, Andrew B.
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p. 6275 - 6284
(2013/07/27)
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- CONFORMATIONALLY CONSTRAINED, FULLY SYNTHETIC MACROCYCLIC COMPOUNDS
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Conformationally restricted, spatially defined 12-30 membered macrocyclic ring systems of formulae Ia and Ib are constituted by three distinct molecular parts: Template A, conformation Modulator B and Bridge C. These macrocycles Ia and Ib are readily manufactured by parallel synthesis or combinatorial chemistry in solution or on solid phase. They are designed to interact with a variety of specific biological target classes, examples being the agonistic or antagonistic activity on G-protein coupled receptors (GPCRs), ion channels and signal transduction pathways. In particular, these macrocycles act as antagonists of the motilin receptor, the FP receptor and the purinergic receptors P2Y1, as modulators of the serotonin receptor of subtype 5-HT2B, as blockers of the voltage-gated potassium channel Kv1.3 and as inhibitors of the β-catenin-dependent “canonical” Wnt pathway. Thus they are showing great potential as medicaments for a variety of diseases.
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Page/Page column 116
(2012/11/07)
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- CONFORMATIONALLY CONSTRAINED, FULLY SYNTHETIC MACROCYCLIC COMPOUNDS
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Conformationally restricted, spatially defined 12-30 membered macrocyclic ring systems of type (I) are constituted by three distinct building blocks: an aromatic template a, a conformation modulator b and a spacer moiety c as detailed in the description and the claims. Macrocycles of type (I) are readily manufactured by parallel synthesis or combinatorial chemistry. They are designed to interact with specific biological targets. In particular, they show agonistic or antagonistic activity on the motilin receptor (MR receptor), on the serotonin receptor of subtype 5-HT2B (5-HT2B receptor), and on the prostaglandin F2 ? receptor (FP receptor). They are thus potentially useful for the treatment of hypomotility disorders of the gastrointestinal tract such as diabetic gastroparesis and constipation type irritable bowl syndrome; of CNS related diseases like migraine, schizophrenia, psychosis or depression; of ocular hypertension such as associated with glaucoma and preterm labour.
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Page/Page column 187; 398
(2011/02/24)
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- Straightforward synthesis of chiral silylated amino acids through hydrosilylation
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A method using hydrosilylation of unsaturated amino acids was developed and optimised to obtain silylated amino acids. The platinum (Bu4N) 2PtCl6 complex was identified as the best catalyst, and the procedure tolerated dif
- Marchand, Damien,Martinez, Jean,Cavelier, Florine
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experimental part
p. 3107 - 3112
(2009/05/11)
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- Asymmetric eschenmoser-claisen rearrangement for anti-β-substituted γ,δ-unsaturated amino acids
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Optically active anti-β-substituted γ,δ-unsaturated amino acids are important synthetic building blocks in organic synthesis and for peptidomimetics. A novel asymmetric Eschenmoser-Claisen rearrangement with use of a C2-symmetric chiral auxiliary was developed to generate this type of amino acid. Excellent diastereoselectivities and high enantioselectivities (87-93% ee) were obtained after the chiral auxiliary was removed via iodolactonization/zinc reduction.
- Qu, Hongchang,Gu, Xuyuan,Liu, Zhihua,Min, Byoung J.,Hruby, Victor J.
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p. 3997 - 4000
(2008/02/11)
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- Compounds and Compositions as Channel Activating Protease Inhibitors
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The invention provides compounds and pharmaceutical compositions thereof, which are useful for modulating channel activating proteases, and methods for, using such compounds to treat, ameliorate or prevent a condition associated with a channel activating protease, including but not limited to prostasin, PRSS22, TMPRSS11 (e.g., TMPRSS11B, TMPRSS11E), TMPRSS2, TMPRSS3, TMPRSS4 (MTSP-2), matriptase (MTSP-1), CAP2, CAP3, trypsin, cathepsin A, or neutrophil elastase.
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Page/Page column 32
(2008/06/13)
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- Diastereoselective cationic tandem cyclizations to N-heterocyclic scaffolds: Total synthesis of (-)-dysibetaine PP
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Herein, we report a short and diastereoselective synthesis of the natural product (-)-dysibetaine PP. The key step in the synthetic sequence is a novel highly diastereoselective tandem-cyclization reaction of an enantiomerically pure dipeptide. This cyclization methodology is applied in the synthesis of a broader range of N-heterocyclic scaffolds.
- IJzendoorn, Denis R.,Botman, Peter N. M.,Blaauw, Richard H.
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p. 239 - 242
(2007/10/03)
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- NOVEL LACTAMS AND USES THEREOF
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This invention relates to novel compounds having formula (I) to their pharmaceutical compositions and to their methods of use. These novel compounds inhibit secretase and thereby inhibit the production of amyloid ? protein, thereby acting to prevent the formation of neurological deposits of amyloid protein. The present invention relates to the treatment of neurological disorders related to amyloid ? - protein production such as Alzheimer's disease.
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- Use of hydrolases for the synthesis of cyclic amino acids
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The synthesis of several cyclic amino acids that have all the necessary structural features to make them ideal scaffolds for use in medicinal chemistry is described. A key step in each synthesis is the use of hydrolase enzymes to define a chiral centre. I
- Lloyd, Richard C.,Lloyd, Michael C.,Smith, Mark E. B.,Holt, Karen E.,Swift, Jonathan P.,Keene, Philip A.,Taylor, Stephen J. C.,McCague, Raymond
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p. 717 - 728
(2007/10/03)
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- Chemoenzymatic synthesis of the four diastereoisomers of 4-hydroxypipecolic acid from N-acetyl-(R,S)-allylglycine: Chiral scaffolds for drug discovery
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All four diastereoisomers of 4-hydroxypipecolic acid were prepared in a form conveniently protected for drug discovery applications with the use of industrially scaleable methodology. Resolution of the racemic starting material using proprietary acylases followed by an acyliminium ion cyclisation gave diastereomeric mixtures of 4-formyloxypipecolic acid, which were differentiated using an enzyme-catalysed hydrolysis. The products were separated by partition, and by following a sequence of straightforward chemical steps, the individual stereoisomers of the protected 4-hydroxypipecolates were crystallized to optical purity in 100 g quantities.
- Lloyd, Richard C.,Smith, Mark E. B.,Brick, Dean,Taylor, Stephen J. C.,Chaplin, David A.,McCague, Raymond
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p. 762 - 766
(2013/09/06)
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- Synthesis and evaluation of novel substrates and inhibitors of N-succinyl-LL-diaminopimelate aminotransferase (DAP-AT) from Escherichia coli
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N-Succinyl-LL-diaminopimelate aminotransferase (DAP-AT) (EC 2.6.1.17), a key enzyme in the bacterial pathway to L-lysine, was purified to near homogeneity (1500-fold) in five steps from wild type Escherichia coli ATCC 9637. This pyridoxal phosphate (PLP)
- Cox, Russell J.,Sherwin, William A.,Lam, Lister K. P.,Vederas, John C.
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p. 7449 - 7460
(2007/10/03)
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- Structure-Activity Study of 5-Substituted 1-Carbobenzoxy-2-iminohydantoins as Potential Anticonvulsant Agents
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On the basis of our previous findings, a series of 5-substituted 2-iminohydantoins has been synthesized and tested for anticonvulsant activity to better understand the SAR of 2-iminohydantoins.Among the compounds tested, (S)-(+)-1-carbobenzoxy-2-iminohydantoin analogs with ethyl (6)-, n-propyl (7a)-, isopropyl (8)-, allyl (9)-, and sec-butyl (11)-substituted groups at the C5 of the iminohydanotin ring provided the best activities against the MES test with ED50 values in the range of 52-74 mg/kg.All of the above compounds except 8 also showed activity against the scMET test with ED50 values in the range of 141-223 mg/kg.All significantly active compounds (1, 6, 7a, 8, 9, and 11) possesed aliphatic hydrocarbon side chains of two- to three-carbon lengths at the C5 position.All of the compounds with no or minimal activity had either shorter or longer side chains.The compounds substituted at the C5 position by aryl groups, arylalkyl groups, or alkyl and arylalkyl groups containing heteroatoms also showed no activity against the MES and scMET tests.The results suggested that the C5 side chain with the correct stereochemistry in 2-iminohydantoins provides optimal anticonvulsant activity when the side chains are aliphatic hydrocarbons with a lenght, ignoring branchingg, of two to three carbons.
- Sun, Zhong-Yue,Kwon, Chul-Hoon,Wurpel, John N. D.
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p. 2841 - 2845
(2007/10/02)
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- Porcine Pancreatic Lipase Catalyzed Enantioselective Hydrolysis of Esters of N-Protected Unusual Amino Acids
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Porcine pancreatic lipase catalyzed the highly enantioselective hydrolysis of a kind of α-substituted carboxylic esters, i.e., the 2,2,2-trifluoroethyl esters of the N-benzyloxycarbonyl derivatives of unusual amino acids.
- Miyazawa, Toshifumi,Iwanaga, Hitoshi,Ueji, Shinichi,Yamada,Takashi,Kuwata, Shigeru
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p. 2219 - 2222
(2007/10/02)
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- Optical Resolution of Unusual Amino-Acids by Lipase-catalysed Hydrolysis
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The 2-chloroethyl esters of the N-benzyloxycarbonyl (Z) derivatives of several unusual amino-acids are converted by Aspergillus niger lipase into enantiomerically enriched Z-amino-acids with fairly high optical purities, the L-enantiomers being preferentially hydrolysed.
- Miyazawa, Toshifumi,Takitani, Tadanori,Ueji, Shinichi,Yamada, Takashi,Kuwata, Shigeru
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p. 1214 - 1216
(2007/10/02)
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- Conversion of Serine β-Lactones to Chiral α-Amino Acids by Copper-Containing Organolithium and Organomagnesium Reagents
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A method for the synthesis of optically pure α-amino acids has been developed.Mono- and di-N-protected α-amino-β-lactones 3a (L, R1=H, R2=COOCH2Ph (Z)), 3b (D, R1=H, R2=Z), 3c (L, R1=CH2Ph, R2=Z), and 3d (D, R1=CH2Ph, R2=Z) are readily produced by cyclization of the corresponding serine derivatives 2 under modified Mitsunobu conditions without loss of optical purity.Stereochemical integrity was demonstrated by conversion of 3 to 2-methoxy-2-(trifluoromethyl)phenylacetate esters 6 and analysis by HPLC, (19)F NMR, and (1)H NMR.Reaction of 3 with organolithium-derived cuprate reagents (R2CuLi or R2Cu(CN)Li2) at low temperature produces N-protected α-amino acids by attack at the β-methylene group.Yields of di-N-protected amino acids are generally higher (ca. 50-75percent), but some decrease in enantiomeric excess (ee) can occur (0-27percent).In contrast, the mono-N-protected β-lactones 3a and 3b give slightly lower yields (ca. 44-62percent) but negligible decrease in ee (0-1.7percent) with the exception of Ph2Cu(CN)Li2 (67percent loss of ee).However, the use of Cu(I)-catalyzed Grignard (RMgCl) additions gives better yields (44-83percent), complete retention of optical purity ( 99.4percent), and fewer side products.Reductive removal of the protecting groups in a single step (H2/Pd-C or Na/NH3) affords the free α-amino acids in 91-99percent yield.Their stereochemical purity was determined by conversion to the corresponding N-(-)-camphanoyl methyl esters and analysis by gas chromatography and (1)H NMR spectroscopy.
- Arnold, Lee D.,Drover, John C. G.,Vederas, John C.
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p. 4649 - 4659
(2007/10/02)
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- SYNTHESIS OF NICOTIANAMINE AND A RELATED COMPOUND, DERIVATIVES OF AZETIDINE-2-CARBOXYLIC ACID
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The synthesis of nicotianamine (1) and a related compound (2) - amino acid derivatives having the azetidine ring - was achieved by reductive coupling of L-aspartic-β-semialdehyde derivatives with L-azetidine-2-carboxylic acid methyl ester.
- Fushiya, Shinji,Nakatsuyama, Shuichi,Sato, Yoshikazu,Nozoe, Shigeo
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p. 819 - 822
(2007/10/02)
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