1000050-95-2

Upstream product

• 1067648-41-2 2,3-dideoxy-2-methyl-D-glucono-1,4-lactone 
• 100-39-0 benzyl bromide 
• 1067648-38-7 imidazole-1-carbothioic acid O-(5-(1,2-bisbenzyloxyethyl)-2-methoxytetrahydrofuran-3-yl) ester 
• 1079398-63-2 methyl 5,6-di-O-benzyl-3-deoxy-D-glucofuranoside 
• 1067648-40-1 5,6-di-O-benzyl-2,3-dideoxy-2-methyl-D-glucono-1,4-lactone 
• 1056674-35-1 5,6-di-O-benzyl-2,3-dideoxy-D-glucono-1,4-lactone 
• 1067648-39-8 methyl 5,6-di-O-benzyl-2,3-dideoxy-D-glucofuranoside 
• 127949-92-2 (2R,4E)-6-(benzyloxy)-2-methylhex-4-enoic acid 
• 89358-30-5 benzyl (2E)-4-bromobut-2-en-1-yl ether 
• 1000050-92-9 (4S)-4-benzyl-3-[(2R,4E)-6-(benzyloxy)-2-methylhex-4-enoyl]-1,3-oxazolidin-2-one 

Downstream Products

• 1000050-97-4 (1R)-2-(benzyloxy)-1-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl methanesulfonate 
• 1000050-99-6 (3R,5S)-5-[(1S)-1-azido-2-(benzyloxy)ethyl]-3-methyldihydrofuran-2(3H)-one 

Relevant academic research and scientific papers

Lead optimization of 5-amino-6-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)- 4-hydroxyhexanamides to reduce a cardiac safety issue: Discovery of DS-8108b, an orally active renin inhibitor

With the aim to address an undesired cardiac issue observed with our related compound in the recently disclosed novel series of renin inhibitors, further chemical modifications of this series were performed. Extensive structure-activity relationships studies as well as in vivo cardiac studies using the electrophysiology rat model led to the discovery of clinical candidate trans-adamantan-1-ol analogue 56 (DS-8108b) as a potent renin inhibitor with reduced potential cardiac risk. Oral administration of single doses of 3 and 10 mg/kg of 56 in cynomolgus monkeys pre-treated with furosemide led to significant reduction of mean arterial blood pressure for more than 12 h.

Synthesis of potent BACE-1 inhibitors incorporating a hydroxyethylene isostere as central core

We herein describe the design and synthesis of a series of BACE-1 inhibitors incorporating a P1-substituted hydroxylethylene transition state isostere. The synthetic route starting from commercially available carbohydrates yielded a pivotal lactone intermediate with excellent stereochemical control which subsequently could be diversified at the P1-position. The final inhibitors were optimized using three different amines to provide the residues in the P2′-P3′ position and three different acids affording the residues in the P2-P3 position. In addition we report on the stereochemical preference of the P1′-methyl substituent in the synthesized inhibitors. All inhibitors were evaluated in an in vitro BACE-1 assay where the most potent inhibitor, 34-(R), exhibited a BACE-1 IC50 value of 3.1 nM.

CYCLIC AMINE COMPOUND

The present invention provides an excellent antihypertensive medicament. The medicament of the present invention comprises a compound having the general formula (I) and the like: [wherein R1: H, substitutable alkyl, substitutable alkenyl, substitutable cyclic hydrocarbon, substitutable heterocyclyl or the like; R2: H, substitutable alkyl, substitutable alkenyl, substitutable cycloalkyl or the like; R3, R4; H, substitutable alkyl, substitutable alkenyl, substitutable cycloalkyl or the like; R5, R6: H, substitutable alkyl, substitutable cycloalkyl, substitutable alkoxy or the like; R7, R8: H, substitutable alkyl, substitutable cycloalkyl or the like; X: the formula (II) or the like; A: substitutable cyclic hydrocarbon, substitutable heterocyclyl or the like; Y: a single bond, substitutable alkylene, substitutable alkenylene, -(CH2)a-X1-(CH2)b- (X1: the formula -NH-, -O- or the like; a, b: 0-5) or the like; B: substitutable cyclic hydrocarbon, substitutable heterocyclyl or the like].

AMIDE DERIVATIVES AS INHIBITORS OF ASPARTYL PROTEASES

The invention provides compounds of the formula (I). N-oxides, addition salts, quaternary amines, metal complexes, stereochemically isomeric forms and metabolites thereof, wherein W is H, C1-C6alkyl, C3-C6cycloalkyl, aryl or heterocyclyl; Q is aryl or heterocyclyl; A is a five or six membered saturated, partially unsaturated or aromatic ring; D is formula (II) or formula (III); and the other variables are as defined in the specification. The compounds of the invention are inhibitors of aspartyl proteases such as renin and BACE and are among other things useful for the treatment and/or prophylaxis of conditions associated with activities of the RAS, such as hypertension, heart failure and renal insufficiency and for the treatment and or prophylaxis of conditions associated with BACE activity such as of Alzheimer's disease.