Patent EA-003928-B1 (EA)
Title: Novel 8a- and 9a-15-membered lactams
Inventor: LAZAREVSKI GORJANA
IPC: A61K31/7048
Filed: 2000-04-19
Abstract: 1. Novel 15-membered 8a- and 9a-lactams from the class of 6-O-methyl-erythromycin A of the general formula (I) their pharmaceutically acceptable addition salts with inorganic or organic acids and their hydrates, wherein A stands for NH group and B simultaneously stands for C=O group, or A stands for C=O group and B simultaneously stands for NH group, R<1> stands for OH group, L-cladinosyl group of formula (II) or R<1> stands for a group of formula (III), wherein Y stands for hydrogen, C1-C6alkyl, C1-C6alkyl group with at least one incorporated O, N or S atom or Y stands for (CH2)n-Ar, wherein (CH2)n stands for alkyl and n is 1-10, with or without incorporated O, N or S atoms, and Ar stands for a 5-10-membered monocyclic or bicyclic aromatic ring containing 0-3 O, N or S atoms, which is unsubstituted or substituted with 1-3 groups representing halogen, OH, OMe, NO2, NH2, amino- C1-C3alkyl or amino-C1-C3dialkyl, CN, SO2NH2, C1-C3alkyl, or R<1> together with R<2> stands for ketone, R<2> stands for hydrogen or together with R<1> stands for ketone, R<3> stands for hydrogen or C1-C4alkanoyl group, R<4> stands for hydrogen or together with R<5> stands for ketone, R<5> stands for OH, NH2, amino-C1-C3 alkyl or amino-C1-C3dialkyl, O(CH2)n-Ar or S(CH2)n-Ar, wherein (CH2)n and Ar have the above meanings, or together with R<4> stands for ketone, with proviso that when R<5> stands for OH, R<1> does not stand for L-cladinosyl group of formula (II), R<6> stands for hydrogen, C1-C6 alkyl, C1-C6 alkyl group with at least one incorporated O, N or S atom, or (CH2)n-Ar group, wherein (CH2)n and Ar have the above meanings, with proviso that when R<6> stands for H, R<1> does not stand for L-cladinosyl group of formula (II), or R<5> and R<6> together with intervening atoms form an additional ring of formula (IV) wherein Z stands for CH2, C=O, C(NH), SO, SO2, CH2CO, COCH2, CH2CH2CO, COCH2CH2 or CH2CH2, and X stands for hydrogen, C1-C3alkyl, NH2, amino-C1-C3alkyl or amino-C1-C3dialkyl or (CH2)n-Ar group, wherein (CH2)n and Ar have the above meanings. 2. A compound according to claim 1, characterized in that A stands for NH and B simultaneously stands for C=O group, R<1> stands for L-cladinosyl group of formula (II) and R<2>, R<3> and R<4> are mutually the same and stand for hydrogen, R<5> and R<6> together with intervening atoms form an additional ring of formula (IV), wherein Z stands for CH2, C=O, C(NH), SO, SO2, CH2CO, COCH2, CH2CH2CO, COCH2CH2 or CH2CH2, and X stands for hydrogen, C1-C3alkyl, NH2, amino-C1-C3alkyl or amino-C1-C3dialkyl or (CH2)n-Ar group, wherein (CH2)n and Ar have the meanings given in claim 1. 3. A compound according to claim 2, characterized in that A stands for NH group and B simultaneously stands for C=O group, R<1> stands for L-cladinosyl group of formula (II) and R<2>, R<3> and R<4> are mutually the same and stand for hydrogen, R<5> and R<6> together with intervening atoms form an additional ring of formula (IVb), wherein Z stands for C=O group. 4. A compound according to claim 1, characterized in that A stands for C=O group and B simultaneously stands for NH group, R<1> stands for L-cladinosyl group of formula (II) and R<2>, R<3> and R<4> are mutually the same and stand for hydrogen, R<5> and R<6> together with intervening atoms form an additional ring of formula (IV), wherein Z stands for CH2, C=O, C(NH), SO, SO2, CH2CO, COCH2, CH2CH2CO, COCH2CH2 or CH2CH2, and X stands for hydrogen, C1-C3alkyl, NH2, amino-C1-C3alkyl or amino-C1-C3dialkyl or (CH2)n-Ar group, wherein (CH2)n and Ar have the meanings given in claim 1. 5. A compound according to claim 4, characterized in that A stands for C=O group and B simultaneously stands for NH group, R<1> stands for L-cladinosyl group of formula (II) and R<2>, R<3> and R<4> are mutually the same and stand for hydrogen, R<5> and R<6> together with intervening atoms form an additional ring of formula (IVb), wherein Z stands for C=O group. 6. A compound according to claim 1, characterized in that A stands for NH group and B simultaneously stands for C=O group, R<1> stands for OH and R<2>, R<3> and R<4> are mutually the same and stand for hydrogen, R<5> and R<6> together with intervening atoms form an additional ring of formula (IV), wherein Z stands for CH2, C=O, C(NH), SO, SO2, CH2CO, COCH2, CH2CH2CO, COCH2CH2 or CH2CH2, and X stands for hydrogen, C1-C3alkyl, NH2, amino-C1-C3alkyl or amino-C1-C3-dialkyl or (CH2)n-Ar group, wherein (CH2)n and Ar have the meanings given in claim 1. 7. A compound according to claim 6, characterized in that A stands for NH group and B simultaneously stands for C=O group, R<1> stands for OH and R<2>, R<3> and R<4> are mutually the same and stand for hydrogen, R<5> and R<6> together with intervening atoms form an additional ring of formula (IVb), wherein Z stands for C=O group. 8. A compound according to claim 1, characterized in that A stands for NH group and B simultaneously stands for C=O group, R<1> stands for OH, and R<2> and R<4> are mutually the same and stand for hydrogen, R<3> stands for C1-C4alkanoyl group, R<5> and R<6> together with intervening atoms form an additional ring of formula (IVb), wherein Z stands for C=O group. 9. A compound according to claim 8, characterized in that A stands for NH group and B simultaneously stands for C=O group, R<1> stands for OH, and R<2> and R<4> are mutually the same and stand for hydrogen, R<3> stands for acetyl group, R<5> and R<6> together with intervening atoms form an additional ring of formula (IVb), wherein Z stands for C=O group. 10. A compound according to claim 1, characterized in that A stands for C=O group and B simultaneously stands for NH group, R<1> stands for OH and R<2>, R<3> and R<4> are mutually the same and stand for hydrogen, R<5> and R<6> together with intervening atoms form an additional ring of formula (IV), wherein Z stands for CH2, C=O, C(NH), SO, SO2, CH2CO, COCH2, CH2CH2CO, COCH2CH2 or CH2CH2, and X stands for hydrogen, C1-C3alkyl, NH2, amino-C1-C3alkyl or amino-C1-C3-dialkyl or (CH2)n-Ar group, wherein (CH2)n and Ar have the meanings given in claim 1. 11. A compound according to claim 10, characterized in that A stands for C=O group and B simultaneously stands for NH group, R<1> stands for OH and R<2>, R<3> and R<4> are mutually the same and stand for hydrogen, R<5> and R<6> together with intervening atoms form an additional ring of formula (IV), wherein Z stands for C=O group. 12. A compound according to claim 1, characterized in that A stands for C=O group and B simultaneously stands for NH group, R<1> stands for OH, R<2> and R<4> are mutually the same and stand for hydrogen, R<3> stands for C1-C3alkanoyl group, R<5> and R<6> together with intervening atoms form an additional ring of formula (IVb), wherein Z stands for C=O group. 13. A compound according to claim 12, characterized in that A stands for C=O group and B simultanously stands for NH group, R<1> stands for OH, R<2> and R<4> are mutually the same and stand for hydrogen, R<3> stands for acetyl group, R<5> and R<6> together with intervening atoms form an additional ring of formula (IVb), wherein Z stands for C=O group. 14. A compound according to claim 1, characterized in that A stands for NH group and B simultaneously stands for C=O group, R<1> stands for a group of formula (III), wherein Y stands for hydrogen, C1-C6alkyl, C1-C6alkyl group with at least one incorporated O, N or S atom, or Y stands for (CH2)n-Ar, wherein (CH2)n stands for alkyl and n is 1-10, without or with incorporated O, N or S atoms, and Ar stands for a 5-10-membered monocyclic or bicyclic aromatic ring comprising 0-3 O, N or S atoms which is unsubstituted or substituted with 1-3 groups representing halogen, OH, OMe, NO2, NH2, amino-C1-C3alkyl or amino-C1-C3dialkyl, CN, SO2NH2, C1-C3alkyl, R<2>, R<3> and R<4> are mutually the same and stand for hydrogen, R<5> and R<6> together with intervening atoms form an additional ring of formula (IV), wherein Z stands for CH2, C=O, C(NH), SO, SO2, CH2CO, COCH2, CH2CH2CO, COCH2CH2 or CH2CH2, and X stands for hydrogen, C1-C3alkyl, NH2, amino-C1-C3alkyl or amino-C1-C3dialkyl or (CH2)n-Ar group, wherein (CH2)n and Ar have the above meanings. 15. A compound according to claim 14, characterized in that A stands for NH group and B simultaneously stands for C=O group, R<1> stands for a group of formula (III) wherein Y stands for (CH2)n-Ar, wherein (CH2)n stands for alkyl and n is 1 and Ar stands for 6-membered monocyclic aromatic ring substituted para-position with groups, having values NO2, OCH3, NH2, OH, CL, SO2NH2, NHCH3, N (CH3)2, CH3, R2, R3 and R4 are mutually the same and stand for hydrogen, R5 and R6 together with intervening atoms form an additional ring of formula (IVb), wherein Z stands for C=O. 16. A compound according to claim 1, characterized in that A stands for C=O group and B simultaneously stands for NH group, R<1> stands for a group of formula (III), Y stands for hydrogen, C1-C6alkyl, C1-C6alkyl group with at least one incorporated O, N or S atom, or Y stands for (CH2)nAr, wherein (CH2)n stands for alkyl and n is 1-10, without or with incorporated O, N or S atoms, and Ar stands for 5-10-membered monocyclic or bicyclic aromatic ring comprising 0-3 O, N or S atoms which is unsubstituted or substituted with 1-3 groups representing halogen, OH, OMe, NO2, NH2, amino-C1-C3alkyl or amino-C1-C3dialkyl, CN, SO2NH2, C1-C3alkyl, R<2>, R<3> and R<4> are mutually the same and stand for hydrogen, R<5> and R<6> together with intervening atoms form an additional ring of formula (IV), wherein Z stands for CH2, C=O, C(NH), SO, SO2, CH2CO, COCH2, CH2CH2CO, COCH2CH2 or CH2CH2, and X stands for hydrogen, C1-C3alkyl, NH2, amino-C1-C3alkyl or amino-C1-C3dialkyl or (CH2)n-Ar group, wherein (CH2)n and Ar have the above meanings. 17. A compound according to claim 16, characterized in that A stands for C=O group and B simultaneously stands for NH group, R<1> stands for a group of formula (III) wherein Y stands for (