- Preparation method for (1S,4S)-2,5-diazabicyclo[2.2.1]heptane or (1S,4S)-2,5-diazabicyclo [2.2.1]octane derivative
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The invention discloses a preparation method for a (1S,4S)-2,5-diazabicyclo[2.2.1]heptane or (1S,4S)-2,5-diazabicyclo [2.2.1]octane derivative. The method comprises the following steps: subjecting a hydroxyl group of five-component or six-component N-heterocycle to sulfonylation by using a sulfonylation reagent; then subjecting sulfonate to a substitution reaction of SN2 by using an azide; simultaneously reducing an azido group and an ester group by using a reduction reaction; and finally, carrying out ring closure so as to obtain the derivative. The synthesis route of the preparation method has higher selectivity compared with the prior art; reaction steps are reduced; cost for raw materials and time cost are saved; product yield is substantially higher than product yield in the prior art; and the preparation method can easily realize purification and enlarged production and reduce discharging of waste.
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Paragraph 0070; 0072; 0073
(2017/06/02)
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- A inhibiting DPP-IV compounds and intermediates
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Provided are compounds as presented in formulas IA or IB or pharmaceutically acceptable salts thereof, the preparation method therefor, and uses thereof. Also provided are the intermediates of the compounds and the preparation method therefor. The compounds of the present invention can effectively inhibit DPP-IV activity. Compared to the commercial available medicine, Januvia, compound 1 exhibits strong inhibition against DPP4, but has lower activity inhibition against other DPP family members (DPP2, DPP8, and DPP9). Hence the compound of the present invention can not only effectively inhibit DPP4 from exhibiting medicinal activity, but also lower the activity inhibition against other members of the DPP family, reduce toxic side effect, and have better medicinal safety.
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Paragraph 0206-0209
(2016/10/20)
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- An improved synthesis of (lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptane
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An improved and efficient method for synthesis of (lS,4S)-2-oxa-5- azabicyclo[2.2.1]heptane (1) from trans-4-hydroxy-l-proline was developed. Using benzyloxycarbonyl (Cbz) as protection group of amine, the reactions were in mild conditions, and the title compound 1 was accomplished in six steps in overall yield of 70%.
- Zhang, Dong-Feng,Li, Peng,Lin, Zi-Yun,Huang, Hai-Hong
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p. 479 - 481
(2014/03/21)
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- Discovery and synthesis of HIV integrase inhibitors: Development of potent and orally bioavailable N-methyl pyrimidones
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The human immunodeficiency virus type-1 (HIV-1) encodes three enzymes essential for viral replication: a reverse transcriptase, a protease, and an integrase. The latter is responsible for the integration of the viral genome into the human genome and, therefore, represents an attractive target for chemotherapeutic intervention against AIDS. A drug based on this mechanism has not yet been approved. Benzyl-dihydroxypyrimidine-carboxamides were discovered in our laboratories as a novel and metabolically stable class of agents that exhibits potent inhibition of the HIV integrase strand transfer step. Further efforts led to very potent compounds based on the structurally related N-Me pyrimidone scaffold. One of the more interesting compounds in this series is the 2-N-Me-morpholino derivative 27a, which shows a CIC95 of 65 nM in the cell in the presence of serum. The compound has favorable pharmacokinetic properties in three preclinical species and shows no liabilities in several counterscreening assays.
- Gardelli, Cristina,Nizi, Emanuela,Muraglia, Ester,Crescenzi, Benedetta,Ferrara, Marco,Orvieto, Federica,Pace, Paola,Pescatore, Giovanna,Poma, Marco,Ferreira, Maria Del Rosario Rico,Scarpelli, Rita,Homnick, Carl F.,Ikemoto, Norihiro,Alfieri, Anna,Verdirame, Maria,Bonelli, Fabio,Paz, Odalys Gonzalez,Taliani, Marina,Monteagudo, Edith,Pesci, Silvia,Laufer, Ralph,Felock, Peter,Stillmock, Kara A.,Hazuda, Daria,Rowley, Michael,Summa, Vincenzo
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p. 4953 - 4975
(2008/03/14)
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- Synthesis, biological evaluation, and pharmacokinetic study of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives as VLA-4 antagonists
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A series of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives were synthesized and evaluated for their activity as VLA-4 antagonists. Of 22 compounds synthesized, 19 compounds showed potent activity with low nanomolar IC50 values. In addition, the representative compounds 11o and 11p with a hydroxy group in the pyrrolidine ring showed moderate plasma clearance in rats (11o, 30 ml/min/kg and 11p, 21 ml/min/kg) and in dogs (11o, 12 ml/min/kg and 11p, 9 ml/min/kg).
- Chiba, Jun,Takayama, Gensuke,Takashi, Tohru,Yokoyama, Mika,Nakayama, Atsushi,Baldwin, John J.,McDonald, Edward,Moriarty, Kevin J.,Sarko, Christopher R.,Saionz, Kurt W.,Swanson, Robert,Hussain, Zahid,Wong, Angela,MacHinaga, Nobuo
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p. 2725 - 2746
(2007/10/03)
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- BICYCLIC UNSATURATED TERTIARY AMINE COMPOUND
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The present invention provides a bicyclic unsaturated tertiary amine compound capable of inhibiting the production of inflammatory cytokines.A compound of the following formula (1): (wherein, A represents pyrrole or pyrazole, R1 represents an aryl group or a heteroaryl group which may be substituted, R2 represents a heteroaryl group which may be substituted, and R3 represents an indolizine group), or a pharmacologically acceptable salt thereof, a pharmacologically acceptable ester thereof or other pharmacologically acceptable derivative thereof.
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Page/Page column 88
(2010/02/11)
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- Optimal N-caps for N-terminal helical templates: Effects of changes in H-bonding efficiency and charge
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A family of efficient helix-initiating N-terminal caps X-Hel is introduced that expand the scope and versatility of the previously reported reporting conformational template Ac-Hel, (Kemp, D. S.; Allen, T. J.; Oslick, S. J. Am. Chem. Soc. 1995, 117, 6641-6657) and a working principle for predicting cap performance is described, based on structurally specific intramolecular hydrogen bond formation. Replacement of the N-acetyl by urethane, urea, or sulfonamide generated less efficient polypeptide helix inducers. The N-formyl cap is found to be equivalent to the N-acetyl and may provide more convenient quantitative helix reporting properties. Anionic N-caps derived from the series X = -O2C-(CH2)n-CO, 0 ≤ n ≤ 3, are superior to N-acetyl, as are N-acylglycyl and N-acyl-β-aspartyl. The latter pair of caps permit introduction of the X-Hel functionality within a polypeptide chain, allowing control of helicity of a peptide sub-sequence. Applications of these capping functions are discussed. This work has been focused primarily on immediate practical goals directed toward enhancing the maximum helicity of isolated short to medium-sized peptides in aqueous solution, but its developing concepts and working hypotheses are likely to significantly enhance our understanding at a chemical level of the protein folding problem.
- Maison,Arce,Renold,Kennedy,Kemp
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p. 10245 - 10254
(2007/10/03)
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- Synthesis of (2R,3R,4S)-2-hydroxymethylpyrrolidine-3,4-diol from (2S)-3,4-dehydroproline derivatives
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(2R,3R,4S)-2-Hydroxymethylpyrrolidine-3,4-diol (1,4-dideoxy-1,4-imino-D-ribitol) was synthesized in five steps from N-protected (2S)-3,4-dehydroproline methyl esters.The stereoselective reaction of osmium tetraoxide with dehydroproline derivatives gave hi
- Goli, Deepa M.,Cheesman, Bruce V.,Hassan, Mohamed E.,Lodaya, Rita,Slama, James T.
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p. 219 - 242
(2007/10/02)
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- The preparation of (S)-3,4-dehydroproline from (2S,4R)-4-hydroxyproline
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(2S,4R)-N-benzyloxycarbonyl-4-tosyloxyproline methyl ester, readily prepared from commercially available (2S,4R)-N-benzyloxycarbonyl-4-hydroxyproline, was converted to (S)-3,4-dehydroproline of high enantiomeric purity by a process which involved a highly regioselective phenylselenoxide elimination to introduce the olefinic function.
- Rueeger, Heinrich,Benn, M. H.
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p. 2918 - 2920
(2007/10/02)
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