Patent RU-2722720-C1 (RU)
Title: Class of bifunctional compounds with quaternary ammonium salt structure
Inventor: VEN SHOUMIN
IPC: C07D453/02
Filed: 2017-12-13
Granted: 2020-06-03
Abstract: FIELD: chemistry. 
     SUBSTANCE: invention relates to compounds of formula (I) with bifunctional structure of quaternary ammonium salt with agonist activity β 2 -adrenoreceptor and muscarinic receptor antagonist, a pharmaceutically acceptable salt thereof and an optical isomer, as well as a pharmaceutical composition, a method for production thereof and use thereof. In general formula (I) L is (4-10C) aryl or heteroaryl, where heteroatom heteroaryl is selected from N, O and S, and said groups can be unsubstituted or optionally substituted with one or more substitutes selected from halogen, -OR 1 , -SR 1 , -NR 1 R 2 , -NHCOR 1 , -CONR 1 R 2 , -CN, -NO 2 , -COOR 1 , -CF 3  and C 1 -C 4  unbranched or branched hydrocarbyl; W is independently selected from substituted or unsubstituted (3-6C) cycloalkyl, substitute selected from halogen, (1-4C) alkyl, (1-4C) alkoxy, alkoxyhydrocarbyl and heterocycle; R1 is a divalent group -(R 1a ) d -(A 1 ) e -(R 1b ) f -; where d, e and f are each independently selected from 0, 1, 2 or 3 and the number of adjacent atoms in the shortest chain between two nitrogen atoms, to which R 1  is attached, ranges from 3 to 14; R 1a  and R 1b  are each independently selected from (1-10C) alkylene, (2-10C) alkenylene, (1-4C) alkyleneoxy, alkyleneoxyalkyl, alkylene amido, alkyleneacyloxy and alkyleneamino, where each of alkylene, alkenylene, alkyleneoxy, alkyleneoxyalkyl, alkyleneamino, alkyleneacyloxy, alkylene amido is unsubstituted or substituted with substituents, independently selected from (1-4C) alkyl, chlorine, fluorine, hydroxy, phenyl and substituted phenyl, R 1a  and R 1b  can be identical or different; A 1  is independently selected from (3-7C) cycloalkylene, (2-7C) alkylene, (6-10C) arylene, (4-9C) heteroarylene and (3-8C) heterocycloalkylene, where cycloalkylene can be unsubstituted or substituted with 1–4 substitutes independently selected from (1-6C) alkyl; each of arylene, heteroarylene and heterocycloalkylene can be unsubstituted or substituted with 1–3 substitutes independently selected from halogen, (1-6C) alkyl, (1-6C) alkoxy, -S-(1-4C) alkyl, -S(O)-(1-4C) alkyl, -S(O)2-(1-4C) alkyl, -C(O)-O-(1-4C) alkyl, -NH-(1-4C) alkyl, -N=[(1-4C)alkyl] 2 , carboxy, nitro, cyano, amido, ester group, trifluoromethyl and trifluoromethoxy; R 2  is independently selected from -NHCHO, -CH 2 OH, -NH-; R 3  is independently selected from -H, -CH=CH-C(O)-, -OCH 2 C(O)-; provided that R 2  is independently selected from -NHCHO or -CH 2 OH, when R 3  is -H; provided that R 2  is -NH-, when R 3  is independently selected from -CH═CH-C(O)- or -OCH 2 C(O)-, and R 2 , R 3  and their carbon atoms are connected to form a ring; Y is selected from Br - , Cl - , I - , bicarbonate, carbonate, bisulphate, sulphate, nitrate, phosphate, hydrophosphate, dihydrophosphate, phosphite, formate, acetate, propionate, isobutyrate, methanesulphonate, p-toluenesulphonate, benzoate, oxalate, tartrate, fumarate, malonate, succinate, suberate, mandelate, phthalate, benzene sulphonate, citrate, glucuronate, galactonate and amino acid radical; and T is the position of hydroxy on the benzene ring and is selected from the ortho- or meta-position of R 2  on the benzene ring.  
     
       
     
     EFFECT: compounds of the present invention are characterized by high selectivity with respect to the M-receptor subtype and have a lower adverse reaction and lower toxic and side effects on the treatment of pulmonary diseases, such as COPD and asthma. 
     14 cl, 8 tbl, 158 ex