1000045-28-2

Upstream product

• 112031-55-7 5,6-di-O-benzyl-3-deoxy-1,2-O-isopropylidene-α-D-glucofuranoside 
• 1056674-30-6 (2S,5S)-2-((R)-1,2-bis(benzyloxy)ethyl)-5-methoxytetrahydrofuran 
• 1056674-18-0 methyl 5,6-di-O-benzyl-3-deoxy-α-D-glucofuranoside 
• 100-39-0 benzyl bromide 
• 1067648-38-7 imidazole-1-carbothioic acid O-(5-(1,2-bisbenzyloxyethyl)-2-methoxytetrahydrofuran-3-yl) ester 
• 1056674-40-8 (3S,5S)-5-((R)-1,2-bis(benzyloxy)ethyl)-3-isopropyldihydrofuran-2(3H)-one 
• 1079398-63-2 methyl 5,6-di-O-benzyl-3-deoxy-D-glucofuranoside 
• 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 
• 1056674-45-3 (3S,5S)-5-((R)-1,2-dihydroxyethyl)-3-isopropyldihydrofuran-2(3H)-one 
• 89358-30-5 benzyl (2E)-4-bromobut-2-en-1-yl ether 
• 1187941-31-6 C₂₆H₃₁NO₄ 
• 1000045-24-8 (2S,4E)-6-(benzyloxy)-2-isopropylhex-4-enoic acid 
• 145589-03-3 (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one 

Downstream Products

• 1067648-89-8 (2S,4S,5S)-5-azido-6-benzyloxy-4-hydroxy-2-isopropyl-hexanoic acid ((S)-1-benzylcarbamoyl-2-methyl-butyl)-amide 
• 1056674-63-5 (2S,4S,5S)-5-azido-6-benzyloxy-4-hydroxy-2-isopropyl-hexanoic acid ((S)-1-benzylcarbamoyl-2-methyl-propyl)amide 
• 1056676-15-3 (2S,4S,5S)-5-azido-6-benzyloxy-4-hydroxy-2-isopropyl-hexanoic acid ((1S,2S)-1-benzylcarbamoyl-2-methyl-butyl)-amide 
• 1056676-05-1 [(S)-2-benzyloxy-1-((2S,4S)-4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-ethyl]-carbamic acid tert-butyl ester 
• 1000048-12-3 (2S,4S,5S)-5-amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-4-hydroxy-N-(trans-4-hydroxycyclohexyl)-2-isopropylhexanamide fumarate 
• 1000048-01-0 (2S,4S,5S)-5-amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-4-hydroxy-2-isopropyl-N-(tetrahydro-2H-pyran-4-yl)hexanamide fumarate 
• 1000048-32-7 (2S,4S,5S)-5-amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-4-hydroxy-2-isopropyl-N-(pyridin-2-yl)hexanamide fumarate 
• 1000048-38-3 (2S,4S,5S)-5-amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-4-hydroxy-2-isopropyl-N-(pyridin-3-yl)hexanamide fumarate 
• 1000048-41-8 (2S,4S,5S)-5-amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-4-hydroxy-2-isopropyl-N-(pyridin-4-yl)hexanamide fumarate 
• 1436430-24-8 methyl 5-[(tert-butoxycarbonyl)amino]-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-2,3,5,6-tetradeoxy-2-propan-2-yl-L-lyxo-hexonate 
• 1436430-26-0 tert-butyl (4S,5S)-4-{[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]methyl}-5-[(2S)-2-(methoxycarbonyl)-3-methylbutyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate 
• 1436430-30-6 (2S)-2-{[(4S,5S)-3-(tert-butoxycarbonyl)-4-{[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]methyl}-2,2-dimethyl-1,3-oxazolidin-5-yl]methyl}-3-methylbutanoic acid 
• 1436430-33-9 tert-butyl (4S,5S)-4-{[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]methyl}-5-{(2S)-2-[(3-hydroxyadamantan-1-yl)carbamoyl]-3-methylbutyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate 
• 1000045-29-3 N-{(1S)-2-hydroxy-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide 

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.

Efficient synthesis of 5-amino-6-dialkylamino-4-hydroxypentanamide derivatives for renin inhibitors

We report an efficient synthetic method for 5-amino-6-dialkylamino-4- hydroxypentanamide derivatives using Shi Asymmetric Epoxidation and the ring opening of N-(2-nitrobenzenesulfonyl)aziridine with hindered secondary amine as key steps. The Japan Institute of Heterocyclic Chemistry.

The P1 N-isopropyl motif bearing hydroxyethylene dipeptide isostere analogues of aliskiren are in vitro potent inhibitors of the human aspartyl protease renin

Novel nonpeptide small molecule renin inhibitors bearing an N-isopropyl P1 motif were designed based on initial lead structures 1 and aliskiren (2). (P3-P1)-Benzamide derivatives such as 9a and 34, as well as the corresponding P1 basic tertiary amine derivatives 10 and 35 were found to display low nanomolar inhibition against human renin in vitro.

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].

ASPARTYL PROTEASE INHIBITORS

The invention provides compounds of the formula (I) wherein A is selected from the partial structures A1, A2 and A3; Ry and Ry' are both hydrogen, or Ry and Ry' together with the nitrogen atom to which they are attached form a cyclic amine such as morpholine, piperidine, piperazine or pyrrolidine; L is NHNH, CH2NH, O or S; Y is NH, NHNH, NHC(=O), S(=O)2NH, NHS(=O)2, CH2, CH2NH, O, S or S(=0)p; Q is aryl or heterocyclyl; Z is O, S, NRa or S(=0)p; m is O, 1 or 2; n is O, 1, 2 or 3; p is independently 1 or 2; q is 0 or 1; Ra is H or C1-C4alkyl; R1 is hydrogen, C1-C6alkyl, C3-C7cycloalkylC0-C3alkyl, arylC0-C3alkyl or heterocyclylC0-C3alkyl, R4'' is H or C1-C6alkyl; or R4' and R4'' together with the carbon atom to which they are attached define a C3-C6cycloalkyl; W is H, C1-C6alkyl, C3-C7ycycloalkyl, aryl or heterocyclyl; or a pharmaceutically acceptable salt, hydrate or N-oxide thereof. The compounds of the invention are inhibitors of aspartyl proteases such as renin and are among other things useful for the treatment of conditions associated with activities of the RAS, such as hypertension, heart failure and renal insufficiency.

NEW COMPOUNDS

The invention provides compounds of the formula I wherein Q is aryl or heterocyclyl any of which is optionally substituted; Z is O, S, NRa or S(=O)p; Y is NH, NHNH, CH2NH, O, S or S(=O)p; n is 0, 1, 2 or 3; m is 0, 1 or 2; p is 1 or 2; Ra is H or C1-C4alkyl; R1 is hydrogen, C1-C6alkyl, C0-C3alkanediylC3-C7cycloalkyl, C0-C3alkanediylaryl or C0- C3alkanediylheterocyclyl; R2 is hydrogen or C1-C6alkyl; X' is hydrogen, fluoro, hydroxy, amino or C1-C6alkoxy; X" is hydrogen, or when X' is fluoro, then X" may also be fluoro; R3is C1-C6alkyl; R4' is C1-C6alkyl; R4" is H or C1-C6alkyl; or R4' and R4" together with the carbon atom to which they are attached define a C3-C6cycloalkyl; W is C1-C6alkyl, C3-C7cycloalkyl, aryl or heterocyclyl any of which is optionally substituted; or a pharmaceutically acceptable salt, hydrate or N-oxide thereof. The compounds of the invention are inhibitors of aspartyl proteases such as renin and are among other things useful for the treatment of conditions associated with activities of the RAS, such as hypertension, heart failure and renal insufficiency.

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.