Patent EA-005156-B1 (EA)
Title: 13-membered azalides and their use as antibiotic agents
Inventor: RAFKA ROBERT JOHN
IPC: A61K31/70
Filed: 1999-11-09
Abstract: 1. A compound of the formula 1 or a pharmaceutically acceptable salt thereof, wherein: R<1> is acetyl, 3-N, N-dimethylamino-2-propenoyl, 1-N-methyl-5-pyrazolyl, 3-pyrazolyl, 1-methyl-N-3-pyrazolyl, 1-N-benzyl-3-pyrazolyl, 1-N-(3-hydroxybenzyl)-3-pyrazolyl, 3-isoxazolyl, or R<2> is C1-C4 alkyl; R<3> is phenyl optionally substituted with halogen atoms; R<6> is hydrogen or methyl; R<7> hydrogen or benzyloxycarbonyl; R<8> is hydrogen; R<9> is or 4"-oxocladinosyl; and R<12> is -CH2N(hydrogen, C1-C10alkyl, C2-C10alkenyl or C2-C10alkynyl)(hydrogen, C1-C10alkyl, C2-C10 alkenyl or C2-C10alkynyl). 2. A compound of the formula 15 or a pharmaceutically acceptable salt thereof, wherein: R<1> is acetyl, 3-N, N-dimethylamino-2-propenoyl, 1-N-methyl-5-pyrazolyl, 3-pyrazolyl, 1-methyl-N-3-pyrazolyl, 1-N-benzyl-3-pyrazolyl, 1-N-(3-hydroxybenzyl)-3-pyrazolyl, 3-isoxazolyl, or R<2> is C1-C4alkyl; R<3> is phenyl optionally substituted with halogen atoms; R<6> is hydrogen or methyl; R<7> hydrogen or benzyloxycarbonyl; R<8> is hydrogen; R<9> is or 4"-oxocladinosyl; and R<10> is C2-C8 alkyl; R<11> is hydrogen or -OH; and R<15> is H or -CH2N(hydrogen, C1-C10alkyl, C2-C10alkenyl or C2-C10alkynyl)(hydrogen, C1-C10alkyl, C2-C10alkenyl or C2-C10alkynyl) except that when R<15> is H, R<10> is not ethyl. 3. The compound of claim 2 wherein R<1> is R<6> is H and R<9> is and cladinosyl. 4. The compound of claim 1 wherein R<1> is or 5. The compound of claim 2 having the formula 3 6. A compound having the formula 3 selected from the group consisting of: the compound wherein R<1> is acetyl and R<6> is hydrogen; the compound wherein R<1> is 3-N,N-dimethylamino-2-propenoyl and R<6> is hydrogen; the compound wherein R<1> is 3-pyrazolyl and R<6> is hydrogen; the compound wherein R<1> is acetyl and R<6> is methyl; the compound wherein R<1> is 3-N,N-dimethylamino-2-propenoyl and R<6> is methyl; the compound wherein R<1> is 3-pyrazolyl and R<6> is methyl; the compound wherein R<1> is 1-N-methy-3-pyrazolyl and R<6> is methyl; the compound wherein R<1> is 1-N-benzyl-3-pyrazolyl and R<6> is methyl; the compound wherein R<1> is 1-N-(3-hydroxybenzyl)-3-pyrazolyl and R<6> is methyl; the compound wherein R<1> is 2-(4-fluorophenyl)-3-pyrimidinyl and R<6> is methyl; the compound wherein R<1> is 2-(phenylamino)-3-pyrimidinyl and R<6> is methyl; and the compound wherein R<1> is 1-N-methy-5-pyrazolyl and R<6> is methyl. 7. A compound of the formula 14: or a pharmaceutically acceptable salt thereof, wherein: R<1> is , acetyl, 3-N,N-dimethylamino-2-propenoyl, , 1-N-methyl-5-pyrazolyl, 3-pyrazolyl, 1-methyl-N-3-pyrazolyl, 1-N-benzyl-3-pyrazolyl, 1-N-(3-hydroxybenzyl)-3-pyrazolyl, 3-isoxazolyl or ; R<3> is as defined in claim 1; R<7> is hydrogen; and R<13> and R<14> are, independently, hydrogen or C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl. 8. A compound of the formula 14: or a pharmaceutically acceptable salt thereof, wherein R<1> is , acetyl, 3-N,N dimethylamino-2-propenoyl, , 1-N-methyl-5-pyrazolyl, 3-pyrazolyl, 1-methyl-N-3-pyrazolyl, 1-N-benzyl-3-pyrazolyl, 1-N-(3-hydroxybenzyl)-3-izoxazolyl or ; R<10>, R<11> and R<3> are as defined in claim 2; R<7> is hydrogen; and R<13>and R<14> are, independently, hydrogen or C1-C10alkyl, C2-C10alkenyl or C2-C10alkynyl. 9. The compound of claim 7 or 8 wherein R<1> is or . 10. The compound of claim 1 or 2 in isolated or purified form. 11. A compound of the formula 2 or a pharmaceutically acceptable salt thereof, wherein: X is -C(O)- or -CH(OR<7>)-; R<2> is C1-C4 alkyl; R<7> is hydrogen; R<8> is hydrogen; R<9> is or 4"-oxocladinosyl; and R<5> is hydrogen or CH2N(hydrogen, C1-C10alkyl, C2-C10alkenyl or C2-C10alkynyl)(hydrogen, C1-C10alkyl, C2-C10alkenyl or C2-C10alkynyl). 12. The compound of claim 11 wherein R<9> is , and R<13> and R<14> are, independently, hydrogen or C1-C6alkyl, C2-C6 alkenyl or C2-C6alkynyl. 13. The compound of claim 11 in isolated or purified form. 14. A pharmaceutical composition useful 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 or 2 and a pharmaceutically acceptable carrier. 15. 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 or 2. 16. A pharmaceutical composition useful 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 10 and a pharmaceutically acceptable carrier. 17. 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 10. 18. A method of preparing a compound of the formula wherein R<1> is trans with respect to the methyl group at position 11 of formula 1, and is , acetyl, 3-N,N-dimethylamino-2-propenoyl, , 1-N-methyl-5-pyrazolyl, 3 pyrazolyl, 1-methyl-N-3-pyrazolyl, 1-N-benzyl-3-pyrazolyl, 1-N-(3-hydroxybenzyl)-3-pyrazolyl, 3isoxazolyl or ; R<2> is C1-C4alkyl; R<3> is phenyl optionally substituted with halogen atoms; R<6>, R<7> and R<8> are hydrogen; R<9> is or 4"-oxocladinosyl; and R<12> is H, CH2N(hydrogen, C1-C10alkyl, C2-C10alkenyl or C2-C10alkynyl)(hydrogen, C1-C10alkyl, C2-C10alkenyl or C2-C10alkynyl); which comprises the step of contacting a compound of the formula 5 wherein R<9>, is as defined in the compound of formula 1; R<10> is C2-C8alkyl; and R<11> is hydrogen or -OH; with an acid or a base to result in the formation of a compound of formula 1. 19. A method of preparing a compound of the formula 15 or a pharmaceutically acceptable salt thereof, wherein: R<1> is , acetyl, 3-N,N-dimethylamino-2-propenoyl, , 1-N-methyl-5-pyrazolyl, 3-pyrazolyl, 1-methyl-N-3-pyrazolyl, 1-N-benzyl-3-pyrazolyl, 1-N-(3-hydroxybenzyl)-3-pyrazolyl, 3-isoxazlyl or ; R<2> is C1-C4alkyl; R<3> is phenyl optionally substituted with halogen atoms; R<6> is hydrogen or methyl; R<7> is hydrogen; R<8> is hydrogen or methyl; R<9>is , or 4"-oxocladinosyl; R<10> is C2-C8alkyl; R<11> is hydrogen or -OH; and R<15> is H, CH2N(hydrogen, C1-C10alkyl, C2-C10alkenyl or C2-C10alkynyl)(hydrogen, C1-C10alkyl, C2-C10alkenyl or C2-C10alkynyl); which comprises the step of contacting a compound of the formula 5 wherein R<9>, R<10> and R<11> are defined above, with an acid or a base, to result in the formation of the compound of formula 15. 20. A method of preparing a compound of the formula 1 wherein R<1> is trans with respect to the methyl group at position 11 of formula 1, and is , acetyl, 3-N,N-dimethylamino-2-propenoyl, , 1-N-methyl-5-pyrazolyl, 3-pyrazolyl, 1-methyl-N-3-pyrazolyl, 1-N-benzyl-3-pyrazolyl, 1-N-(3-hydroxybenzyl)-3-pyrazolyl, 3 isoxazolyl or ; R<2> is C1-C4 alkyl; R<3> is phenyl substituted with halogen atoms; R<6>, R<7> and R<8> are hydrogen; R<9>is , or 4"-oxocladinosyl; and R<12> is H or CH2N(hydrogen, C1-C10alkyl, C2-C10alkenyl or C2-C10alkynyl)(hydrogen, C1-C10alkyl, C2-C10alkenyl or C2-C10alkynyl); which comprises the step of heating a compound of the formula 5 wherein R<9>, is as defined in the compound of formula 1; R<10> is C2-C8alkyl; and R<11> is hydrogen or -OH; in the presence of a solvent system, to result in the formation of the compound of formula 1. 21. A method of preparing a compound of the formula 15 or a pharmaceutically acceptable salt thereof, wherein: R<1> is , acetyl, 3-N,N-dimethylamino-2-propenoyl, , 1-N-methyl-5-pyrazolyl, 3-pyrazolyl, 1-methyl-N-3-pyrazolyl, 1-N-benzyl-3-pyrazolyl, 1-N-(3-hydroxybenzyl)-3-pyrazolyl, 3-isoxazolyl or ; R<2> is C1-C4alkyl; R<3> is phenyl optionally substituted with halogen atoms; R<6> is hydrogen or methyl; R<7> is hydrogen; R<8> is hydrogen; R<9> is , or 4''-oxocladinosyl; R<10> is C2-C8alkyl; R<11> is hydrogen or -OH; R<15> is H or CH2N(hydrogen, C1-C10alkyl, C2-C10alkenyl or C2-C10alkynyl)(hydrogen, C1-C10alkyl, C2-C10alkenyl or C2-C10alkynyl), which comprises the step of heating a compound of the formula 5 wherein R<9>, R<10> and R<11> are as defined above; in the presence of a solvent system, to result in the formation of the compound of formula 15. 22. A method of preparing a compound of the formula 15 or a pharmaceutically acceptable salt thereof, wherein: R<1> is ; R<2> is C1-C4alkyl; R<6> is hydrogen or methyl; R<7> is hydrogen; R<8> is hydrogen; R<9> is or 4"-oxocladinosyl; R<10> is C2-C8alkyl; R<11> is hydrogen or -OH; and R<15> is H or CH2N(hydrogen, C1-C10alkyl, C2-C10alkenyl or C2-C10alkynyl)(hydrogen, C1-C10alkyl, C2-C10alkenyl or C2-C10alkynyl), which comprises the step of contacting a compound of the formula 5 wherein R<9>, R<10> and R<11> are defined above, with an acid or a base, to result in the formation of the compound of formula 15. 23. A method of preparing a compound of the formula 15 or a pharmaceutically acceptable salt thereof, wherein: R<1> is ; R<2> is C1-C4alkyl; R<6> is hydrogen or methyl; R<7> is hydrogen; R<8> is hydrogen; R<9> is or 4"-oxocladinosyl; R<10> is C2-C8alkyl; R<11> is hydrogen or -OH; and R<15> is H or CH2N(hydrogen, C1-C10alkyl, C2-C10alkenyl or C2-C10alkynyl)(hydrogen, C1-C10alkyl, C2-C10alkenyl or C2-C10alkynyl), which comprises the step of heating a compound of the formula 5 wherein R<9>, R<10> and R<11> are as defined above; in the presence of a solvent system, to result in the formation of the compound of formula 15. 24. The method of any of claims 20, 21, or 23 wherein the solvent system comprises a solvent selected from the group consisting of lower alkanols, diethyl ether, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, metheylene chloride, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidinone, and mixtures thereof. 25. The method of any of claims 20, 21, or 23 wherein the solvent system further comprises a pr