US 7,462,600 B2
Macrolides
Louis S. Chupak, Old Saybrook, Conn. (US); Mark E. Flanagan, Gales Ferry, Conn. (US); Takushi Kaneko, Guilford, Conn. (US); Thomas V. Magee, Mystic, Conn. (US); Mark C. Noe, Mystic, Conn. (US); and Usa Reilly, West Haven, Conn. (US)
Assigned to Pfizer Inc, New York, N.Y. (US)
Filed on Dec. 21, 2005, as Appl. No. 11/313,523.
Claims priority of provisional application 60/638097, filed on Dec. 21, 2004.
Claims priority of provisional application 60/717530, filed on Sep. 14, 2005.
Prior Publication US 2006/0135447 A1, Jun. 22, 2006
Int. Cl. A61K 31/70 (2006.01); C07H 17/08 (2006.01)
U.S. Cl. 514—29  [536/7.4] 30 Claims
 
1. A compound of the formula:

OG Complex Work Unit Drawing
wherein:
diradical 1 is absent;
diradical 2 is >CH(R6);
diradical 3 is >C(O), >CH(OC(O)R14), >CH(OC(O)N(R14)R15), >CH(OC(O)OR14), >CH(OC(O)CH(N(R14)R15)(CRaRb)nAr), >CH(OC(O)CH(N(R14)R15)R14), >CH(OC(O)C(═NOR14)(CRaRb)nAr), >CH(OC(O)C(═NOR14)R14), >CH(OC(O)(CRaRb)nAr), >CH(OC(O)(CRaRb)nN(CRaRb)nAr)R14), or:

OG Complex Work Unit Drawing
wherein n is an integer from 0 to 5;
diradical 4 is >O or >NR10, with the proviso that when diradical 3 is not >C(O), diradical 4 is >O;
diradical 5 is >C(O);
diradical 6 is methylene;
diradical 7 is methylene;
R1 is H;
R2 is (a) 9-10 membered heterocyclic or carbocyclic, or (b) 4-6 membered heterocyclic or carbocyclic, wherein (b) can be substituted by 4-6 membered heterocyclic or carbocyclic; and R2 can be substituted by 1 to 2 of: SO2R11, hydroxy-substituted (C1-C3)alkyl, (C1-C3)alkyl, CN, CHO, nitro, F, Cl, Br, CF3, OCF3, OCHF2, CHF2, hydroxy, (C1-C3)alkoxy-(C1-C3)alkoxy, oxo, (C1-C3)alkanoyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or (C1-C3)alkoxy optionally substituted by CN;
R3 is methyl;
R4 is H or F, with the proviso that when diradical 3 is not >C(O), R4 is H;
R5 is ethyl;
R6 is H or methyl;
R10 is H or (C1-C6)alkyl;
each R11 and R12 is independently (a) H, (C1-C12)alkyl, (C2-C12)alkenyl, (C2-C12)alkynyl, any of which, except H, can have one carbon replaced by —NH—, —N(CH3)—, —N(4-10 membered carbo- or heterocyclic), —O—, —S—, —S(O)2—, or —S(O)2—, and wherein the foregoing R11 and R12, together with the atom to which they are attached, can form a 3 to 8 membered ring, or (b) 9-10 membered heterocyclic, 9-10 membered carbocyclic, 4-6 membered heterocyclic, or 4-6 membered carbocyclic, wherein any of (a) and (b), except H, can independently be substituted by 1 to 3 of: F, Cl, OH, (C1-C3)alkoxy, (C1-C3)alkoxy-(C1-C3)alkoxy, oxo, (C1-C3)alkyl, halo-substituted (C1-C3)alkyl, or (C1-C3)alkoxy-(C1-C3)alkyl;
each R14 and R15 is independently H or (C1-C10)alkyl; wherein the alkyl can be substituted by 1 to 3 of the Group S substituents; independently wherein 1 to 2 carbons of the alkyl can be replaced by Group T diradicals; and independently wherein each R14/R15 pair can, together with the atom to which they are attached, form a 3 to 8 membered ring;
R17 is OR19, —C(O)(C1-C6 alkyl), or —C(O)(4-10 membered carbo- or heterocyclic);
R19 is H, 4-10 membered carbo- or heterocyclic, —(C1-C6)alkyl, or —(C1-C6)alkyl-(4-10 membered carbo- or heterocyclic), any of which can have one alkyl carbon replaced by —NH—, —N(CH3)—, —N(4-10 membered carbo- or heterocyclic), —O—, —S—, —S(O)—, or —(O)2—; and independently which, except H, can be substituted by 1 to 3 of: F, Cl, OH, (C1-C3)alkoxy, (C1-C3)alkoxy-(C1-C3)alkoxy, oxo, (C1-C3)alkyl, halo-substituted (C1-C3)alkyl, or (C1-C3)alkoxy-(C1-C3)alkyl;
each Ra and Rb is independently H or (C1-C6)alkyl; wherein the alkyl can be substituted by 1 to 3 of the Group S substituents; independently wherein 1 to 2 carbons of the alkyl can be replaced by Group T diradicals; and independently wherein each Ra/Rb pair together with the carbon to which they are attached can form a 3 to 10 membered ring;
each Ar is independently (a) 9-10 membered heterocyclic, (b) 9-10 membered carbocyclic, (c) 4-6 membered heterocyclic, or (d) 4-6 membered carbocyclic, wherein (c) or (d) can be substituted by 4-6 membered heterocyclic or 4-6 membered carbocyclic; wherein any of the foregoing Ar ring systems can be substituted by 1 to 3 of the Group S substituents;
the Group S substituents are: nitro, halo, hydroxy, CF3, OCF3, OCHF2, CHF2, CN, CHO, (C1-C3)alkoxy-(C1-C3)alkoxy, (C1-C3)alkoxy-(C1-C3)alkyl, oxo, (C1-C10)alkanoyl, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, 4-10 membered heterocyclic or carbocylic, hydroxy-substituted (C1-C6)alkyl, —C(O)R11, —C(O)(4-10 membered heterocyclic), —C(O)(4-10 membered carbocyclic), —C(O)2(4-10 membered heterocyclic), —O(4-10 membered carbocyclic), —O(4-10 membered heterocyclic), —C(O)2(4-10 membered carbocyclic), —C(O)OR11, —OC(O)R11, —C(O)NR11R12, —OC(O)NR11R12, —NR11R12, —SO2NR11R12, —S(O)pR11, wherein p is 0 to 2, and (C1-C10)alkoxy optionally substituted by CN; and in cases where the Group S substituent substitutes a non-aromatic carbon, Group S can also be ═N—NR11R12, ═N-(4-10 membered heterocyclic), ═N-(4-10 membered carbocyclic), ═N—NHC(O)R11, ═N—NHC(O)NR11R12, —N(R11)SO2R12, or ═N—R17; wherein any of the heterocyclic and carbocyclic groups can be substituted by Cl, F, (C1-C10)alkyl, (C1-C10)alkoxy, oxo, or CN; and
the Group T diradicals are: —O—, —S—, —S(O)—, —S(O)2—, —N((C1-C6)alkyl)-, —NH—, —C(O)—, —OC(O)—, —C(O)—, —N(Ar)—, and —OC(O)O—.