Quaternary ammonium diphenylmethyl compounds useful as muscarinic receptor antagonists

A process for preparing a compound of formula I:

• in salt or zwitterionic form, wherein:
• a and b are independently 0 or an integer of from 1 to 5;
• each Rl and R2 is independently selected
• from —C1-4alkyl, —C2-4alkenyl, —C2-4alkynyl, —C3-6cycloalkyl, cyano, halo, —ORa, —CH2OH, —COOH, —C(O)—O—C1-4alkyl, —C(O)NRbRc, —SRa, —S(O)Ra, —S(O)2Ra, and —NRbRc;
• where each Ra is independently selected from hydrogen, —C1-4alkyl, —C2-4alkenyl, —C2-4alkynyl and —C3-6cycloalkyl;
• each Rb and Rc is independently selected from hydrogen, —C1-4alkyl, —C2-4alkenyl, —C2-4alkynyl, and —C3-6cycloalkyl;
• or Rb and Rc together with the nitrogen atom to which they are attached form a C3-6heterocycle;
• or two adjacent Rl groups or two adjacent R2 groups are joined together to form —C3-6alkylene, —C2-4alkylene-O— or —O—C1-4alkylene-O—;
• R3 is selected from —C(O)NR3aR3b, —C(O)O—C1-4alkyl, —CN, —CH2OH, and —CH2NH2;
• where R3a and R3b are independently selected from hydrogen, —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, —C3-6cycloalkyl, —C6-10aryl, —C2-9heteroaryl, —C3-6heterocycle, and —(CH2)1-2—R3c, where R3c is selected from —OH, —O—C1-6alkyl, —C3-6cycloalkyl, —C6-10aryl, —C2-9heteroaryl, and —C3-6heterocycle;
• or R3a and R3b together with the nitrogen atom to which they are attached form a C3-6heterocycle optionally containing one additional heteroatom selected from nitrogen, oxygen, and sulfur;
• c is 0 or an integer of from 1 to 3;
• each R4 is independently fluoro or —C1-4alkyl;
• d is 1 or 2, and depicts an optional double bond;
• R5 is selected from —C1-6alkyl, —CH2—C2-6alkenyl, —CH2—C2-6alkynyl, and —CH2COR5a;
• where R5a is selected from —OH, —O—C1-6alkyl, and —NR5bR5c;
• and R5b and R5a are independently selected from H and —C1-6alkyl;
• Q is selected from —C0-5alkylene-Q′-C0-1alkylene-, wherein Q′ is selected from —CH2—, —CH═CH—, —C≡C—, —O—, —S—, —S(O)—, —SO2—, —SO2—NRQ1-, —NRQ1—SO2—, —C(O)—, —OC(O)—, —C(O)O—, —NRQ1C(O)—, —C(O)NRQ1-, NRQ2—C(O)—NRQ3-, —NRQ2—C(S)—NRQ3-, —C═N—O—, —S—S—, and —C(═N—O—RQ4)—, where RQ1 is hydrogen or —C1-4alkyl, RQ2 and RQ3 are independently selected from hydrogen, —C1-4alkyl, and —C3-6cycloalkyl, or RQ2 and RQ3 are taken together to form —C2-4alkylene or —C2-3alkenylene, and RQ4 is —C1-4alkyl or benzyl;
• e is 0 or an integer of from 1 to 5;
• each R6 is independently selected from halo, —C1-4alkyl, —C0-4alkylene-OH, cyano, —C0-2alkylene-COOH, —C(O)O—C1-4alkyl, —O—C1-4alkyl, —S—C1-4alkyl, —NH—C(O)—C1-4alkyl, —N(C1-4alkyl)2, and —N+(O)O;
• wherein each alkyl, alkenyl, alkylene, alkynyl and cycloalkyl group in R1-3, R3a-3c, R4-6, and Ra-c is optionally substituted with 1 to 5 fluoro atoms;
• wherein each alkyl, alkenyl, and alkynyl group in R5 is optionally substituted with 1 to 2 substituents independently selected from —O—C1-6alkyl, —OH and phenyl;
• each cycloalkyl, aryl, heteroaryl and heterocycle group in R1-2, R3a-3c, and Ra-c is optionally substituted with 1 to 3 substituents independently selected from —C1-4alkyl, —C2-4alkenyl, —C2-4alkynyl, cyano, halo, —O—C1-4alkyl, —S—C1-4alkyl, —S(O)(C1-4alkyl), —S(O)2(C1-4alkyl), —NH2, —NH(C1-4alkyl) and —N(C1-4alkyl)2, wherein each alkyl, alkenyl and alkynyl group is optionally substituted with 1 to 5 fluoro substituents;
• and each —CH2— group in Q is optionally substituted with 1 or 2 substituents independently selected from —C1-2alkyl, —OH and fluoro;
• or a pharmaceutically acceptable salt thereof, comprising:
• (a) reacting a compound of formula II:
• with a compound of formula III:
• where L1 represents a leaving group, to produce a compound of formula IV:
• and reacting the compound of formula IV with an organic halide containing an R5 group;
• or
• (b) reacting a compound of formula V:
• with a compound of formula III;
• or
• (c) reacting a compound of formula V with a compound of formula VI:
• where L2 represents a leaving group, to produce a compound of formula VII:
• and reacting the compound of formula VII with a compound of formula VIII:
• wherein L3 represents a leaving group, and Q′, A and B are defined as:
• Q′
• A
• B
• —CH2—
• —CH3
• L3-alkylene-
• —CH═CH—
• H
• L3-alkenylene-
• —C≡C—
• H
• L3-alkynylene-
• —O—
• -L3
• HO—
• —S—
• -L3
• HS—
• —SO2—NRQ1—
• —SO2—OH or —SO2Cl
• RQ1HN—
• —NRQ1—SO2—
• —NHRQ1
• HOO2S—
• —OC(O)—
• —OH
• HO(O)C—
• —C(O)O—
• —C(O)OH or —C(O)Cl
• HO—
• —NRQ1C(O)—
• —NHRQ1
• HO(O)C—or
• Cl(O)C—
• —NRQ2—C(O)—NRQ3—
• —N═C═O
• H2N—
• where RQ2 and RQ3
• are H
• —NRQ2—C(S)—NRQ3—
• —N═S═O
• H2N—
• where RQ2 and RQ3
• are H
• —C═N—O—
• —CHO
• H2NO—
• —S—S—
• —SH
• HS—
• and recovering the product in salt or zwitterionic form.