116779-08-9

Upstream product

• 17159-79-4 ethyl 4-oxocyclohexane-1-carboxylate 
• 108-95-2 phenol 

Relevant academic research and scientific papers

Symmetrical bis(heteroarylmethoxyphenyl)alkylcarboxylic acids as inhibitors of leukotriene biosynthesis

Symmetrical bis(quinolylmethoxyphenyl)alkylcarboxylic acids were investigated as inhibitors of leukotriene biosynthesis and 4,4-bis(4-(2-quinolylmethoxy)phenyl)pentanoic acid sodium salt (47·Na) met our design parameters for a drug candidate (ABT-080). This compound was readily synthesized in three steps from commercially available diphenolic acid. Against intact human neutrophils, 47·Na inhibited ionophore-stimulated LTB4 formation with an IC50 = 20 nM. In zymosan-stimulated mouse peritoneal macrophages producing both LTC4 and PGE2, 47·Na showed 9000-fold selectivity for inhibition of LTC4 (IC50 = 0.16 nM) over PGE2 (IC50 = 1500 nM). Preliminary pharmacokinetic evaluation in rat and cynomolgus monkey demonstrated good oral bioavailability and elimination half-lives of 9 and 5 h, respectively. Pharmacological evaluation of leukotriene inhibition with oral dosing was demonstrated in a rat pleural inflammation model (ED50 = 3 mg/kg) and a rat peritoneal passive anaphylaxis model (LTB4, ED50 = 2.5 mg/kg; LTE4, ED50 = 1.0 mg/kg). In a model of airway constriction induced by antigen challenge in actively sensitized guinea pigs, 47·Na dosed orally blocked bronchoconstriction with an ED50 = 0.4 mg/kg, the most potent activity we have observed for any leukotriene inhibitor in this model. The mode of inhibitory action of 47·Na occurs at the stage of 5-lipoxygenase biosynthesis as it blocks both leukotriene pathways leading to LTB4 and LTC4 but not PGH2 biosynthesis. However, 47·Na does not inhibit 5-lipoxygenase catalysis in a broken cell enzyme assay; therefore it is likely that 47·Na acts as a FLAP inhibitor.

Bis-(Heteroarylmethoxyphenyl)cycloalkyl carboxylates as inhibitors of leukotriene biosynthesis

Compounds having the structure STR1 where m is an integer of from one to nine; n is an integer of from one to four; W is selected from substituted or unsubstituted quinolyl, benzothiazolyl, or quinoxalyl, X is selected from C1-6 alkylene, C2-6 alkenylene and C2-6 alkynylene; Y is selected from halogen, C1-6 alkyl and C1-6, alkoxy; and Z is selected from --C(O)B; --C(R2)2 --O--N=A--C(O)B; and --C(R2)=N--O--A--C(O)B where A is C1-6 alkylene and B is --OH, --O--M+, --OD where D is a metabolically cleavable group, --OR6 where R6 is hydrogen or C1-6 alkyl, --NR6 R7 where R7 is hydrogen, C1-6 alkyl, hydroxy or C1-6 alkoxy, or where R6 and R7 taken together form a five to eight membered ring optionally containing one heteroatom selected from nitrogen, oxygen or sulfur, are inhibitors of leukotriene biosynthesis.

Process for the preparation of 4'-hydroxybiphenyl-4-carboxyl acid

A process for the preparation of 4'-hydroxybiphenyl-4-carboxylic acid by reacting a cyclohexanone-4-carboxylic acid compound with phenol in the presence of an acid catalyst, and then subjecting the resulting 4,4-bis(4-hydroxyphenyl)cyclohexanecarboxylic acid compound to decomposition and dehydrogenation reactions in the presence of a base and a dehydrogenation catalyst. The aforesaid cyclohexanone-4-carboxylic acid compound is obtained by catalytically hydrogenating a 4-hydroxybenzoic acid compound in a secondary alcohol or tertiary alcohol solvent, and the reaction mixture thus obtained is directly used for the reaction with phenol.