Patent EA-003579-B1 (EA)
Title: Nodulisporic acid derivatives
Inventor: MEINKE PETER T
IPC: A01N47/12
Filed: 1996-03-15
Abstract: 1. A compound having the formula I: wherein R1 is (1) hydrogen, R2 and R4 are independently OR<a>, OC(O)NR<c>R<d>; or R1 and R2 represent =O, =NOR<a>; R3 is OH; R5 and R6 are hydrogen; or R5 and R6 together represent -O-; R7 is (1) CHO, or (2) the fragment R8 is (1) hydrogen, (2) OR<a>; R9 is (1) hydrogen, (2) OR<a>; R10 is (1) C(O)OR<b>, (2) C(O)NR<c>R<d>, (3) C(O)NR<c>NR<c> R<d> - - - represents a single or a double bond; R<a> is (1) hydrogen, (2) optionally substituted C1-C10 alkyl, R<b> is (1) hydrogen, (2) optionally substituted aryl, (3) optionally substituted C1-C10 alkyl, (4) optionally substituted C3-C10 alkenyl, (5) optionally substituted C3-C10 alkynyl, (6) optionally substituted C3-C15 cycloalkyl, (7) optionally substituted 5- to 10-membered heterocycle containing from 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen; where the substituents on the groups R<b> (1) -(7) are from groups independently selected from: (i) hydroxy, (ii) C1-C6alkyl, (iii) oxo, (iv) SO2NR<g>R<h>, (v) hydroxy C1-C6 alkyl, (vi) C1-C12 alkoxy, (vii) hydroxy C1-C6 alkoxy, (viii) amino C1-C6 alkoxy, (ix) cyano, (x) mercapto, (xi) C1-C6 alkyl-S(O)m, (xii) C3-C7 cycloalkyl optionally substituted with 1 to 4 groups independently selected from R<e>, (xiii) halogen, (xiv) C1-C5 alkanoyloxy, (xv) C(O)NR<g>R<h>, (xvi) NR<g>R<h>, (xvii) 5 to 9-membered heterocycle, which may be saturated or partially unsaturated, containing from 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 to 5 groups independently selected from R<e>, (xviii) optionally substituted aryl, wherein the aryl substituents are 1,2-methylenedioxy or 1 to 5 groups independently selected from R<e>, (xix) C1-C5 perfluoroalkyl; R<c> and R<d> are independently selected from R<b>; or R<c> and R<d> together with the N to which they are attached form a 3- to 10 membered ring containing 0 to 2 additional heteroatoms selected from O, S(O)m, and N, optionally substituted with 1 to 3 groups independently selected from R<g>, hydroxy; R<e> is (1) halogen, (2) C1-C7 alkyl, (3) C1-C3 perfluoroalkyl, (4) -S(O)mR, (5) nitro, (6) RO(CH2)v-, (7) optionally substituted aryl where the substituents are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy, R<g> and R<h> are independently (1) hydrogen, (2) C1-C6 alkyl optionally substituted with hydroxy, amino, (3) aryl optionally substituted with halogen, 1,2-methylenedioxy, C1-C7 alkoxy, C1-C7 alkyl or C1-C3 perfluoroalkyl, (4) aryl C1-C6 alkyl, wherein the aryl is optionally substituted with C1-C3 perfluoroalkyl or 1,2-methylenedioxy; (5) C1-C5 alkoxycarbonyl, (6) C1-C5 alkanoyl, (7) aryl C1-C5 alkoxycarbonyl, (8) aminocarbonyl, (9) C1-C5 mon- or di-alkylaminocarbonyl or R<g> and R<h> together with the N to which they are attached form a 3- to 7 membered ring containing 0 to 2 additional heteroatoms selected from O, S(O)m, and N, optionally substituted with groups independently selected from R<e>; R is (1) hydrogen, (2) C1-C3 perfluoroalkyl, (3) C1-C6alkyl, (4) optionally substituted aryl C0-C6 alkyl, where the aryl substituents are independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, and hydroxy; m is 0 to 2; and v is 0 to 3; or a pharmaceutically acceptable salt thereof excluding nodulisporic acid, 29,30-dihydro-20,30-oxa-nodulisporic acid, and 31-hydroxy-20,30-oxa-29,30,31,32-tetrahydro-nodulisporic acid, provided that aryl is mono- and bicyclic aromatic and heteroaromatic ring containing from 0 to 5 heteroatoms independently selected from N, O and S, or benzocondensed cycloalkyl, benzocondensed cycloalkenyl and benzocondensed heterocyclic groups. 2. A compound of Claim 1 wherein R1 is hydrogen, R8 and R9 are independently (1) H, (2) OR<a>; R10 is (1) C(O)OR<b>, (2) C(O)NR<c>R<d>, (3) C(O)NR<c>NR<c>R<d> R<a> is (1) hydrogen, (2) optionally substituted C1-C10 alkyl, R<b> is (1) hydrogen, (2) optionally substituted aryl, (3) optionally substituted C1-C10 alkyl, (4) optionally substituted C3-C10 alkenyl, (5) optionally substituted C3-C10 alkynyl, (6) optionally substituted C3-C15 cycloalkyl, (7) optionally substituted 5- to 10-membered heterocycle containing from 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen; where the substituents on the groups R<b> (1) -(7) are independently selected from: (i) hydroxy, (ii) C1-C6alkyl, (iii) oxo, (iv) SO2NR<g>R<h>, (v) hydroxy C1-C6 alkyl, (vi) C1-C12 alkoxy, (vii) hydroxy C1-C6 alkoxy, (viii) amino C1-C6 alkoxy, (ix) cyano, (x) mercapto, (xi) C1-C6 alkyl-S(O)m, (xii) C3-C7 cycloalkyl optionally substituted with 1 to 4 groups independently selected from R<e>, (xiii) halogen, (xiv) C1-C5 alkanoyloxy, (xv) C(O)NR<g>R<h>, (xvi) NR<g>R<h>, (xvii) 5 to 6-membered heterocycle, which may be saturated or partially unsaturated, containing from 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 to 5 groups independently selected from R<e>, (xviii) optionally substituted aryl, wherein the aryl substituents are 1,2-methylenedioxy or 1 to 5 groups independently selected from R<e>, (xix) C1-C5 perfluoroalkyl; R<e> is (1) halogen, (2) C1-C3 alkyl, (3) C1-C3 perfluoroalkyl, (4) -S(O)mR, (5) RO(CH2)v-, (6) optionally substituted aryl where the substituents are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy, R<g> and R<h> are independently (1) hydrogen, (2) C1-C6 alkyl optionally substituted with hydroxy, amino, (3) aryl optionally substituted with halogen, 1,2-methylenedioxy, C1-C7 alkoxy, C1-C7 alkyl or C1-C3 perfluoroalkyl, (4) aryl C1-C6 alkyl, wherein the aryl is optionally substituted with C1-C3 perfluoroalkyl or 1,2-methylenedioxy; (5) C1-C5 alkoxycarbonyl, (6) C1-C5 alkanoyl, (7) aryl C1-C5 alkoxycarbonyl, (8) aminocarbonyl, (9) C1-C5 mon- or di-alkylaminocarbonyl or R<g> and R<h> together with the N to which they are attached form a 5- to 6 membered ring containing 0 to 2 additional heteroatoms selected from O, S(O)m, and N, optionally substituted with groups independently selected from R<e>; R is (1) hydrogen, (2) C1-C3 perfluoroalkyl, (3) C1-C4 alkyl, (4) optionally substituted aryl C0-C4 alkyl, where the aryl substituents are independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, and hydroxy; and all other groups are as defined in Claim 1. 3. A compound of Claim 1 wherein R1 is hydrogen, R8 and R9 are independently (1) H, (2) OH; R10 is (1)C(O)OR<b>, (2) C(O)NR<c>R<d>, (3) C(O)NR<c>NR<c>R<d> R<a> is (1) hydrogen, (2) optionally substituted C1-C4 alkyl, R<b> is (1) hydrogen, (2) optionally substituted aryl, (3) optionally substituted C1-C6 alkyl, (4) optionally substituted C3-C6 alkenyl, (5) optionally substituted C3-C6 alkynyl, (6) optionally substituted C5-C6 cycloalkyl, (7) optionally substituted 5- to 10-membered heterocycle containing from 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen; where the substituents on the groups R<b> are independently selected from: (i) hydroxy, (ii) C1-C3 alkyl, (iii) oxo, (iv) SO2NR<g>R<h>, (v) hydroxy C1-C4 alkyl, (vi) C1-C4 alkoxy, (vii) hydroxy C1-C4 alkoxy, (viii) amino C1-C4 alkoxy, (ix) cyano, (x) mercapto, (xi) C1-C4 alkyl-S(O)m, (xii) C5-C6 cycloalkyl optionally substituted with 1 to 4 groups independently selected from R<e>, (xiii) halogen, (xiv) C1-C3 alkanoyloxy, (xv) C(O)NR<g>R<h>, (xvi) NR<g>R<h>, (xvii) 5 to 6-membered heterocycle, which may be saturated or partially unsaturated, containing from 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 to 5 groups independently selected from R<e>, (xviii) optionally substituted aryl, wherein the aryl substituents are 1,2-methylenedioxy or 1 to 5 groups independently selected from R<e>, (xix) C1-C5 perfluoroalkyl; R<e> is (1) halogen, (2) C1-C3 alkyl, (3) C1-C3 perfluoroalkyl, (4) -S(O)mR, (5) RO(CH2)v-, (6) optionally substituted aryl where the substituents are from 1 to 3 of halogen, C1-C3 alkyl, C1-C3 alkoxy, or hydroxy, R<g> and R<h> are independently (1) hydrogen, (2) C1-C6 alkyl optionally substituted with hydroxy, amino, (3) aryl optionally substituted with halogen, 1,2-methylenedioxy, C1-C7 alkoxy, C1-C7 alkyl or C1-C3 perfluoroalkyl, (4) aryl C1-C6 alkyl, wherein the aryl is optionally substituted with C1-C3 perfluoroalkyl or 1,2-methylenedioxy; (5) C1-C5 alkoxycarbonyl, (6) C1-C5 alkanoyl, (7) aryl C1-C5 alkoxycarbonyl, (8) aminocarbonyl, (9) C1-C5 mono- or di-alkylaminocarbonyl or R<g> and R<h> together with the N to which they are attached form a 5- to 6 membered ring containing 0 to 2 additional heteroatoms selected from O, S(O)m, and N, optionally substituted with groups independently selected from R<e>; R is (1) hydrogen, (2) C1-C3 perfluoroalkyl, (3) C1-C4 alkyl, (4) optionally substituted aryl C0-C6 alkyl, where the aryl substituents are independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, and hydroxy; and all other groups are as defined in claim 1. 4. A compound of Claim 1 wherein R7 is CHO. 5. A compound of Claim 1 wherein R7 is a fragment wherein R10 is (1)C(O)OR<b>, (2) C(O)NR<c>R<d>, (3) C(O)NR<c>NR<c>R<d> and groups R<8>, R<9>, R<b>, R<c> and R<d> are as defined in Claim 1. 6. A compound of Claim 5 wherein R10 is C(O)OR<b>, R<b> is (1) hydrogen, (2)optionally substituted aryl, (3) optionally substituted C1-C6 alkyl, (4) optionally substituted C3-C6 alkenyl, (5) optionally substituted C3-C6 alkynyl, (6) optionally substituted C3-C6 cycloalkyl, (7) optionally substituted 5- to 6-membered heterocycle containing from 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen; and where the substituents on the groups R<b> are independently selected from: (i) hydroxy, (ii) C1-C3 alkyl, (iii) oxo, (iv) SO2NR<g>R<h>, (v) hydroxy C1-C4 alkyl, (vi) C1-C12 alkoxy, (vii) hydroxy C1-C4 alkoxy, (viii) amino C1-C4 alkoxy, (ix) cyano, (x) C1-C4 alkyl-S(O)m, (xi) C5-C6 cycloalkyl optionally s