Patent EA-002441-B1 (EA)
Title: 4"-substituted -9-deoxo -9a-aza-9a-homoerythromycin a derivatives
Inventor: BRONK BRIAN SCOTT
IPC: A61K31/70
Filed: 1998-05-29
Abstract: 1. A compound of the formula   or a pharmaceutically acceptable salt thereof, wherein: R<1> is H, hydroxy or methoxy; R<2> is hydroxy; R<3> is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkymyl, cyano, -CH2S(O)nR<5> wherein n is an integer ranging from 0 to 2, -CH2OR<8>, -CH2N(OR<9>)R<8>, -CH2NR<8>R<15>, -(CH2)m(C6-C10 aryl), or -(CH2)m(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the foregoing R<3> groups are optionally substituted by 1 to 3 R<16> groups; or R<2> and R<3> are taken together to form an oxazolyl ring as shown below   R<4> is H, -C(O)R<9>, -C(O)OR<9>, -C(O)nR<9>R<10>or a hydroxy protecting group; R<5> is -SR<8>, -(CH2)nC(O)R<8> wherein n is 0 or 1, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, -(CH2)m(C6-C10 aryl), or -(CH2)m(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the foregoing R<5> groups are optionally substituted by 1 to 3 R<16> groups; each R<6> and R<7> is independently H, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CH2)m(C6-C,0 aryl), or -(CH2)m(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4; each R<8> is independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, -(CH2)qCR<11>R<12>(CH2)rNR<13>R<14> wherein q and r are each independently an integer ranging from 0 to 3 except q and r are not both 0, -(CH2)m(C6-C10 aryl), or -(CH2)m(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the foregoing R<8> groups, except H, are optionally substituted by 1 to 3 R<16> groups; or where R<8> is as -CH2NR<8>R<15>, R<15> and R<8> may be taken together to form a 4-10 membered monocyclic or polycyclic saturated ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and N(R<8>)-, in addition to the nitrogen to which R<15> and R<8> are attached, said saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds, and said saturated and heteroaryl rings are optionally substituted by I to 3 R<16> groups; each R<9> and R<10> is independently H or C1-C6 alkyl; each R", R<12>, R<13> and R<14> is independently selected from H, C1-C10 alkyl, -(CH2)m(C6-C10 aryl), and -(CH2)m(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the foregoing R<11>, R<12>, R<13> and R<14> groups, except H, are optionally substituted by 1 to 3 R<16> groups; or R<11> and R<13> are taken together to form -(CH2)p- wherein p is an integer ranging from 0 to 3 such that a 4-7 membered saturated ring is formed that optionally includes 1 or 2 carboncarbon double or triple bonds; or R<13> and R<14> are taken together to form a 4-10 membered monocyclic or polycyclic saturated ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and -N(R<8>)-, in addition to the nitrogen to which R<13> and R<14> are attached, said saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds, and said saturated and heteroaryl rings are optionally substituted by 1 to 3 R<16> groups; R<15> is H, C1-C10 alkyl, C2-C10 alkenyl, or C2-C,0 alkynyl, wherein the foregoing R<15> groups are optionally substituted by 1 to 3 substituents independently selected from halo and -OR<9>. each R<16> is independently selected from halo, cyano, nitro, trifluoromethyl, azido, -C(O)R<17>, -C(O)0R<17>, -C(O)OR<17>, -OC(O)OR<17>, -NR<6>C(O)R<7>, C(O)nRR<7>, -NR<6>R<7>, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, -(CH2)m(C6-C10 aryl), and -(CH2)m(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein said aryl and heteroaryl subsituents are optionally substituted by 1 or 2 substituents independently selected from halo, cyano, nitro, trifluoromethyl, azido, -C(O)R<17>, -C(O)OR<17>, -C(O)OR<17>, -OC(O)OR<17>, -NR<6>C(O)R<7>, -C(O)nR<6>R<7>, -NR<6>R<7>, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy; each R<17> is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, -(CH2)m(C6-C10 aryl), and -(CH2)m(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4; with the proviso that R<8> is not H where R<3> is CH2S(O)nR<8>. 2. The compound of Claim 1 wherein R<4> is H, acetyl, or benzyloxycarbonyl. 3. The compound of Claim 2 wherein R<1> is hydroxy, R<2> is hydroxy, R<3> is -CH2NR<15>R<8> or -CH2SR<8>. 4. The compound of Claim 3 wherein R<3> is -CH2NR<15>R<8> and R<15> and R<8> are independently selected from H, C1-C10 alkyl, C2C10 alkenyl, and C2-C10 alkynyl, wherein the foregoing R<15> and R<8> groups, except H, are optionally substituted by 1 or 2 substituents independently selected from hydroxy, halo and C1-C6 alkoxy. 5. The compound of Claim 4 wherein R<15> and R<8> are each independently selected from H, methyl, ethyl, allyl, n-butyl, isobutyl, 2-methoxyethyl, cyclopentyl, 3-methoxypropyl, 3-ethoxypropyl, n-propyl, isopropyl, 2-hydroxyethyl, cyclopropyl, 2,2,2-trifluoroethyl, 2-propynyl, sec-butyl, tert-butyl, and n-hexyl. 6. The compound of Claim 2 wherein R<1> is hydroxy, R<2> is hydroxy, R is -CH2NHR<8>, and R<8> is -(CH2)m(C6-C10 aryl) wherein m is an integer ranging from 0 to 4. 7. The compound of Claim 6 wherein R<8> is phenyl or benzyl. 8. The compound of Claim 2 wherein R<1> is hydroxy, R<2> is hydroxy, R<3> is -CH2NR<15>R<8>, and R<15> and R<8> are taken together to form a 4-10 membered saturated ring. 9. The compound of Claim 8 wherein R<15> and R<8> are taken together to form a piperidino, trimethyleneimino, or morpholino ring. 10. The compound of Claim 2 wherein R<1> is hydroxy, R<2> is hydroxy, R<3> is -CH2NR<15>R<8>, and R<15> and R<8> are taken together to form a 5-10 membered heteroaryl ring optionally substituted by 1 or 2 C1-C6 alkyl groups. 11. The compound of Claim 10 wherein R<15> and R<8> are taken together to form a pyrrolidino, triazolyl, or imidazolyl ring wherein said heteroaryl groups are optionally substituted by 1 or 2 methyl groups. 12. The compound of Claim 2 wherein R<1> is hydroxy, R<2> is hydroxy, R<3> is -CH2SR<8>, and R<8> is selected from C1-C10 alkyl, C2-C10 alkenyl, and C2-C10 alkynyl, wherein said R<8> groups are optionally substituted by 1 or 2 substituents independently selected from hydroxy, halo and C1-C6 alkoxy. 13. The compound of Claim 12 wherein R<8> is methyl, ethyl, or 2-hydroxyethyl. 14. The compound of Claim 2 wherein R<1> is hydroxy, R<2> is hydroxy, and R<3> is selected from C1-C10 alkyl, C2-C10 alkenyl, and C2-C10 alkynyl, wherein said R<3> groups are optionally substituted by I or 2 substituents independently selected from hydroxy, -C(O)R<17>, -NRsR<7>, halo, cyano, acids, 5-10 membered heteroaryl, and C1-C6 alkoxy. 15. The compound of Claim 14 wherein R<3> is methyl, allyl, vinyl, ethynyl, 1-methyl-1-propenyl, 3-methoxy-I -propynyl, 3-dimethylamino-1-propynyl, 2-pyridylethynyl, 1-propynyl, 3-hydroxy-1-propynyl, 3-hydroxy-1-propenyl, 3-hydroxypropyl, 3-methoxy-1-propenyl, 3-methoxypropyl, I -propynyl, n-butyl, ethyl, propyl, 2-hydroxyethyl, azidomethyl, formylmethyl, 6-cyano-1-pentynyl, 3-dimethylamino-1-propenyl, or 3-dimethylaminopropyl. 16. The compound of Claim 2 wherein R<1> is hydroxy, R<2> is hydroxy, and R is -(C H2)m(5-10 membered heteroaryl) wherein m is an integer ranging from 0 to 4. 17. The compound of Claim 16 wherein R<3> is 2-thienyl, 2-pyridyl, 1-methyl-2-imidazolyl, 2-furyl, or 1-methyl-2-pyrro. 18. The compound of Claim 2 wherein R<1> is hydroxy, R<2> is hydroxy, and R is -(CH2)m(C6-C10 aryl) wherein m is an integer ranging from 0 to 4. 19. The compound of Claim 18 wherein R<3> is phenyl. 20. The compound of Claim 2 wherein R<2> and R<3> are taken together to form an oxazolyl ring as shown below   21. The compound of Claim 2 wherein R<3> is selected from the following:   wherein X is O, S or -N(R<15>)-, R<9> and R<15> are as defined in Claim 1, and the -OR<9> group may be attached at any available carbon on the phenyl group. 22. A pharmaceutical composition for the treatment of a bacterial infection or a protozoa infection in a mammal, fish, or bird which comprises a therapeutically effective amount of a compound of Claim 1 and a pharmaceutically acceptable carrier. 23. A method of treating a bacterial infection or a protozoa infection in a mammal, fish, or bird which comprises administering to said mammal, fish or bird a therapeutically effective amount of a compound of Claim 1. 24. A method of preparing a compound of the formula   or a pharmaceutically acceptable salt thereof, wherein: R<1> is H, hydroxy or methoxy; R<2> is hydroxy; R<3> is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, cyano, -CH2S(O)nR<8> wherein n is an integer ranging from 0 to 2, -CH2OR<8>, -CH2N(OR<9>)R<8>, -CH2NR<8>R<15>, -(CH2)m(C6-C10 aryl), or -(CH2)m(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the foregoing R<3> groups are optionally substituted by 1 to 3 R<16> groups; or R<2> and R<3> are taken together to form an oxazolyl ring as shown below   R<4> is H, -C(O)R<9>, -C(O)OR<9>, -C(O)nR<9>R<10> or a hydroxy protecting group; R<5> is -SR<8>, -(CH2)nC(O)R<8> wherein n is 0 or 1, C,-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, -(CH2)m(C6-C10 aryl), or -(CH2)m(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the foregoing R<5> groups are optionally substituted by 1 to 3 R<16> groups; each R<6> and R<7> is independently H, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CH2)m(C6-C10 aryl), or -(CH2)m(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4; each R<8> is independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, (CH2)qCR<11>R<12>(CH2)rNR<13>R<14> wherein q and r are each independently an integer ranging from 0 to 3 except q and r are not both 0, -(CH2)m(C6-C10 aryl), or -(CH2)m(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the foregoi