14347-25-2

Upstream product

• 14347-08-1 1-[4-Phenylmethoxy-3-[(methylsulfonyl)amino]phenyl]ethanone 
• 100-39-0 benzyl bromide 
• 14347-05-8 4-benzyloxy-3-nitroacetophenone 
• 6322-56-1 4'-hydroxy-3'-nitroacetophenone 
• 14347-15-0 1-[4-phenylmethoxy-3-aminophenyl]ethanone 

Downstream Products

• 170687-82-8 N-{2-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]phenyl}methane sulfonamide 
• 116814-70-1 N-[[4-[4-[[6-[[2-Hydroxy-2-[4-hydroxy-3-[(methylsulphonyl)amino]phenyl]ethyl]amino]hexyl]oxy]butyl]phenyl]methyl]pentanamide, benzoate (salt) 
• 116814-76-7 N,N-Dipropyl-4-[3-[[6-[[2-hydroxy-2-[4-hydroxy-3-[(methylsulphonyl)amino]phenyl]ethyl]amino]hexyl]oxy]propyl]benzamide, benzoate (salt) 
• 861448-71-7 N-[2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]methane sulfonamide 
• 861448-79-5 (3-{2-[(2R)-2-(4-benzyloxy-3-methanesulfonylaminophenyl)-2-(tert-butyldimethylsilanyloxy)ethylamino]-2-methylpropyl}phenyl)acetic acid methyl ester 
• 861448-88-6 methyl (3-{2-[((2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetate 

Relevant academic research and scientific papers

Development of an enabling route to PF-00610355: A novel inhaled β2-adrenoreceptor agonist

The initial route used to prepare PF-00610355 (8) for early clinical development is described. Through careful choice of solvent, an efficient, telescoped route to carboxylic acid 23 was developed, affording this late-stage intermediate in 80% yield over 4 steps. Deprotection of 23 to give sodium salt 24a and coupling with amine 6·HCl afforded the desired API. Effective synthetic routes to two of the starting materials, chiral bromide 1 and amine 6, are also described.

Beta 3 agonists. Part 1: Evolution from inception to BMS-194449

Screening of the BMS collection identified 4-hydroxy-3-methylsulfonanilidoethanolamines as full beta 3 agonists. Substitution of the ethanolamine nitrogen with a benzyl group bearing a para hydrogen bond acceptor promoted β3 selectivity. SAR elucidation established that highly selective β3 agonists were generated upon substitution of Cα with either benzyl to form (R)-1,2-diarylethylamines or with aryl to generate 1,1-diarylmethylamines. This latter subset yielded a clinical candidate, BMS-194449 (35).

4-Aminopiperidine ureas as potent selective agonists of the human β3-Adrenergic receptor

The preparation and structure-activity relationships (SARs) of potent agonists of the human β3-adrenergic receptor (AR) derived from a 4-aminopiperidine scaffold are described. Examples combine human β3-AR potency with selectivity over human β1-AR and/or human β2-AR agonism. Compound 29s was identified as a potent (EC50 = 1 nM) and selective (greater than 400-fold over β1- with no β2-AR agonism) full β3-AR agonist with in vivo activity in a transgenic mouse model of thermogenesis.

CATECHOLAMINE SURROGATES USEFUL AS BETA 3 AGONISTS

Compounds of the formula STR1 and pharmaceutically acceptable salts thereof. These compounds are beta three adrenergic receptor agonists and are useful, therefore for example, in the treatment of diabetes, obesity and gastrointestinal diseases.

Catecholamine surrogates useful as β3 agonists

Compounds of the formula STR1 or pharmaceutically acceptable salts thereof wherein: A is a bond, --(CH 2) n -- or --CH(B)--, where n is an integer of 1 to 3 and B is --CN, --CON(R 9)R 9'' or --CO 2 R 7 ;R 1 is lower alkyl, aryl or arylalkyl;R 2 is hydrogen, hydroxy, alkoxy, --CH 2 OH, cyano, --C(O)OR 7, --CO 2 H, --CONH 2, tetrazole, --CH 2 NH 2 or halogen; STR2 R 3 is hydrogen, alkyl, heterocycle or R 4 is hydrogen, alkyl or B;R 5, R 5'', R 8, R 8'' or R 8"" are independently hydrogen, alkoxy, lower alkyl, halogen, --OH, --CN, --(CH 2) n NR 6 COR 7, --CON(R 6)R 6'', --CON(R 6)OR 6'', --CO 2 R 6, --SR 7, --SOR 7, --SO 2 R 7, --N(R 6)SO 2 R 1, --N(R 6)R 6'', --NR 6 COR 7, --OCH 2 CON(R 6)R 6'', --OCH 2 CO 2 R 7 or aryl; orR 5 and R 5'' or R 8 and R 8'' may together with the carbon atoms to which they are attached form an aryl or heterocycle;R 6 and R 6'' are independently hydrogen or lower alkyl; andR 7 is lower alkyl;R 9 is hydrogen, lower alkyl, alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl; or R 9 and R 9'' may together with the nitrogen atom to which they are attached form a heterocycle; with the proviso that when A is a bond or --(CH 2) n and R 3 is hydrogen or unsubstituted alkyl, then R 4 is B or substituted alkyl. These compounds are beta 3 adrenergic receptor agonists and are useful, therefore for example, in the treatment of diabetes, obesity and gastrointestinal diseases.

Synthesis and Structure-Activity Relationships among α-Adrenergic Receptor Agonists of the Phenylethanolamine Type

Nineteen arylethanolamine derivatives related to norepinephrine were prepared and tested for α-adrenergic stimulant activity.In one series the analogues possess a p-hydroxy function, while the meta position is substituted by methyl, ethyl, isopropyl, cyclohexyl, fluoro, chloro, iodo, carboxy, carbomethoxy, and methylsulfamido groups.The other series is meta hydroxylated with the para position substituted by the same groups.The influence of these groups upon the α-adrenergic activity is discussed, and the compounds are compared to octopamine, normetanephrine,norepinephrine, and norphenylephrine.It has been found that the introduction of an isopropyl, cyclohexyl, and fluoro group in the meta position of octopamine improves its affinity by three, five, and six times, respectively, whereas when these groups are introduced in the para position of norphenylephrine their effects are always detrimental.The most active compound, α-(aminomethyl)-(4-fluoro-3-hydroxyphenyl)methanol (44), has about one-hundreth the affinity and the same intrinsic activity as norepinephrine.