US 6,586,452 B1Granted

C1 to C4 side chain modified nodulisporic acid analogs

AssigneeMerck & Co., Inc.

InventorsThomas Shih, Steven L. Colletti, Michael H. Fisher, Peter T. Meinke, Howard C. H. Kuo, Prasun K. Chakravarty, Matthew J. Wyvratt, Sriram Tyagarajan, Richard Berger

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Abstract

The present invention relates to novel nodulosporic acid derivatives, which are acaricidal, antiparasitic, insecticidal and anthelmintic agents.

Claims10

Dependent claims

A compound having the formula I:

wherein
represents a single or a double bond;
X—Y—Z is selected from the group:
each ring optionally substituted with 1 to 2 groups independently selected from C1-C4alkyl, phenyl, benzyl, CONRcRd and CO2Rb;
x is independently O or S;
the two R groups are independently H or C1-C5alkyl, or together complete a C3-C6 ring;
R1 is (1) hydrogen,
(2) optionally substituted C1-C10 alkyl,
(3) optionally substituted C2-C10 alkenyl,
(4) optionally substituted C2-C10 alkynyl,
(5) optionally substituted C3-C8 cycloalkyl,
(6) optionally substituted C5-C8 cycloalkenyl,
(7) optionally substituted aryl,
(8) 5- or 6-membered heterocycle containing from 1 to 4 heteroatoms independently selected from O, S and NRc,
where the substitutents on the alkyl, alkenyl, alkynyl are 1 to 3 groups selected from R′, the substituents on aryl is 1 to 3 groups selected from R″, and the substituents on cycloalkyl and cycloalkenyl are 1 to 3 groups independently selected from R″, oxo and thiono;
R2, R3, and R4 are independently ORa, OCO2Rb, OC(O)NRcRd;
or
R1+R2 represent ═O, ═NORa, ═N—NRcRd, ═CRaCO2Ra, ═CRaC(O)NRcRd, ═CRaCN, ═CRaC(O)Ra, or ═CRaRa;
R5 is (1) hydrogen,
(2) ORa or
R4+R5 represent ═O, ═NORa, ═N—NRcRd or ═CRaRa;
Ra is (1) H,
(2) optionally substituted C1-C10 alkyl,
(3) optionally substituted C3-C10 alkenyl,
(4) optionally substituted C3-C10 alkynyl,
(5) optionally substituted C3-C15 cycloalkyl,
(6) optionally substituted C5-C10 cycloalkenyl,
(7) optionally substituted aryl,
(8) optionally substituted heteroaryl,
(9) optionally substituted 3- to 10-membered heterocycle containing 1 to 4 heteroatoms selected from O, S and NRg,
(10) a benzene ring fused to a 4- to 8-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and NRg,
(11) a 4- or 8-membered heterocyclic ring with from 1 to 4 heteroatoms selected from O, S and NRg fused to a 4- or 8-membered heterocyclic ring with from 1 to 4 heteroatoms selected from O, S and NRg, and
where the substituents on the aryl, alkyl, alkenyl, alkynyl groups are 1 to 10 groups selected from R′;
the substituents on aryl, heteroaryl and benzene are 1 to 5 groups selected from R″;
and the substituents on cycloalkyl, cycloalkenyl and heterocycle are 1 to 10 groups selected from R″, oxo and thiono;
Rb is (1) a group selected from Ra,
(2) C2-C6 alkanoyl,
Rc and Rd are independently selected from Rb, hydroxy, C1-C5alkoxy, C1-C5alkoxycarbonyl, aminocarbonyl, C1-C5alkylaminocarbonyl and C1-C5dialkylaminocarbonyl;
or
Rcand Rd together with the N to which they are both attached form a 3- to 10-membered ring containing 0 to 2 additional heteroatoms selected from O, S(O)m, and NRg, said ring is optionally substituted with 1 to 5 groups independently selected from R″, thiono and oxo;
said ring is further optionally fused to a benzene ring optionally substituted with 1 to 3 groups selected from Re;
said ring is further optionally spiro fused to a C3-C7cycloalkyl ring;
Re is (1) halogen,
(2) C1-C7 alkyl,
(3) C1-C3 perfluoroalkyl,
(4) S(O)mRi,
(5) cyano,
(6) nitro,
(7) RiO(CH2)v—,
(8) RiCO2(CH2)v—,
(9) RiOCO(CH2)v,
(10) optionally substituted aryl where the substituents are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy,
(11) SO2NRiRi, or
(12) amino;
Rf is (1) H,
(2) C1-C5alkyl optionally substituted with 1 to 5 groups selected from halogen, cyano, hydroxy, C1-C3alkoxy, NRgRh, CO2Riand CONRgRh,
(3) C2-6alkenyl,
(4) C2-6alkynyl,
(5) C3-C6cycloalkyl,
(6) aryl optionally substituted with 1 to 4 groups independently selected from Re, or 2 adjacent substituents together form methylenedioxy, or
(7) aryl-C1-C3alkyl optionally substituted with 1 to 4 groups independently selected from Re, or 2 adjacent substituents together form methylenedioxy, or
two Rf groups together with the nitrogen atom to which they are attached form a a 3- to 10-membered ring containing 0 to 2 additional heteroatoms selected from O, S(O)m, and NRg, said ring is optionally substituted with 1 to 5 groups independently selected from R″, thiono and oxo;
said ring is further optionally fused to a benzene ring optionally substituted with 1 to 3 groups selected from Re;
said ring is further optionally spirofused to a C3-C7cycloalkyl ring;
Rg and Rh are independently
(1) hydrogen,
(2) C1-C10alkyl optionally substituted with 1 to 10 groups selected from hydroxy, amino, C(O)Ri, and CO2Ri,
(3) aryl optionally substituted with 1 to 5 groups selected from halogen, amino, 1,2-methylenedioxy, C1-C7 alkoxy, C1-C7 alkyl and C1-C3 perfluoroalkyl,
(4) aryl C1-C6 alkyl, wherein the aryl is optionally substituted with 1 to 5 groups selected from halogen, amino, 1,2-methylenedioxy, C1-C7 alkoxy, C1-C7 alkyl and C1-C3 perfluoroalkyl,
(5) C3-C7cycloalkyl optionally substituted with phenyl,
(6) C1-C5 alkanoyl,
(7) C1-C5 alkoxycarbonyl,
(8) aryl C1-C5 alkoxycarbonyl,
(9) aminocarbonyl,
(10) C1-C5 monoalkylaminocarbonyl
(11) C1-C5 dialkylaminocarbonyl;
or
Rg and Rh 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 NRi, optionally substituted with 1 to 3 groups independently selected from Re and oxo;
Riis (1) hydrogen,
(2) C1-C3 perfluoroalkyl,
(3) C1-C6 alkyl,
(4) optionally substituted aryl or optionally substituted aryl C1-C6 alkyl, where the aryl substituents are from 1 to 3 groups independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, and hydroxy;
Rz is ORa, OC(O)Ra, OC(O)ORb, OC(O)NRcRd, NRcC(O)Ra, NRcC(O)ORa, NRcC(O)NRcRd, NRcSO2Ra;
R′ is (1) halogen,
(2) cyano,
(3) nitro,
(4) C(O)Rf,
(5) CO2Rf,
(6) C(O)NRgRh,
(7) ORf,
(8) OC(O)Rf,
(9) OC(O)NRgRh,
(10) OC(O)ORf,
(11) SRf,
(12) S(O)mRf,
(13) SO2NRgRh,
(14) NRgRh,
(15) NRgC(O)Rf,
(16) NRgCO2Rf,
(17) NRgC(S)ORf,
(18) NRgC(O)NRgRh,
(19) C3-C7 cycloalkyl optionally substituted with 1 to 4 groups independently selected from Re,
(20) C5-C7 cycloalkenyl optionally substituted with 1 to 4 groups independently selected from Re,
(21) aryl optionally substituted with 1 to 4 groups independently selected from Re, or 2 adjacent substituents together form methylenedioxy,
(22) heteroaryl optionally substituted with 1 to 4 groups independently selected from Re,
(23) 5 to 9-membered heterocycle containing from 1 to 4 heteroatoms independently selected from O, S and NRg, and optionally substituted with 1 to 4 groups independently selected from Re,
R′ is (1) a group selected from R′,
(2) C1-C6 alkyl, optionally substituted with halogen, aryl, ORf and NRgRh,
(3) C2-6alkenyl,
(4) C2-6alkynyl;
m is 0 to 2;
n is 0 or 1;
and
v is 0 to 3;
or
a pharmaceutically acceptable salt thereof.

113 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/901,266Filed 9 Jul 2001 · us provisional application
Priority: 14 Jul 2000
Granted: 1 Jul 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 491/16
In which the condensed system contains three hetero rings: peri-condensed systems
A61K 31/407
Having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil: condensed with other…
A61P 33/10
Antiparasitic agents: anthelmintics
A61P 33/14
Antiparasitic agents: ectoparasiticides, e.g. scabicides

Family

Application60/218,398Us provisional application · filed 14 Jul 2000
US 6,586,452 B1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

The present invention relates to novel nodulosporic acid derivatives, which are acaricidal, antiparasitic, insecticidal and anthelmintic agents.

A compound having the formula I:

wherein
represents a single or a double bond;
X—Y—Z is selected from the group:
each ring optionally substituted with 1 to 2 groups independently selected from C1-C4alkyl, phenyl, benzyl, CONRcRd and CO2Rb;
x is independently O or S;
the two R groups are independently H or C1-C5alkyl, or together complete a C3-C6 ring;
R1 is (1) hydrogen,
(2) optionally substituted C1-C10 alkyl,
(3) optionally substituted C2-C10 alkenyl,
(4) optionally substituted C2-C10 alkynyl,
(5) optionally substituted C3-C8 cycloalkyl,
(6) optionally substituted C5-C8 cycloalkenyl,
(7) optionally substituted aryl,
(8) 5- or 6-membered heterocycle containing from 1 to 4 heteroatoms independently selected from O, S and NRc,
where the substitutents on the alkyl, alkenyl, alkynyl are 1 to 3 groups selected from R′, the substituents on aryl is 1 to 3 groups selected from R″, and the substituents on cycloalkyl and cycloalkenyl are 1 to 3 groups independently selected from R″, oxo and thiono;
R2, R3, and R4 are independently ORa, OCO2Rb, OC(O)NRcRd;
or
R1+R2 represent ═O, ═NORa, ═N—NRcRd, ═CRaCO2Ra, ═CRaC(O)NRcRd, ═CRaCN, ═CRaC(O)Ra, or ═CRaRa;
R5 is (1) hydrogen,
(2) ORa or
R4+R5 represent ═O, ═NORa, ═N—NRcRd or ═CRaRa;
Ra is (1) H,
(2) optionally substituted C1-C10 alkyl,
(3) optionally substituted C3-C10 alkenyl,
(4) optionally substituted C3-C10 alkynyl,
(5) optionally substituted C3-C15 cycloalkyl,
(6) optionally substituted C5-C10 cycloalkenyl,
(7) optionally substituted aryl,
(8) optionally substituted heteroaryl,
(9) optionally substituted 3- to 10-membered heterocycle containing 1 to 4 heteroatoms selected from O, S and NRg,
(10) a benzene ring fused to a 4- to 8-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and NRg,
(11) a 4- or 8-membered heterocyclic ring with from 1 to 4 heteroatoms selected from O, S and NRg fused to a 4- or 8-membered heterocyclic ring with from 1 to 4 heteroatoms selected from O, S and NRg, and
where the substituents on the aryl, alkyl, alkenyl, alkynyl groups are 1 to 10 groups selected from R′;
the substituents on aryl, heteroaryl and benzene are 1 to 5 groups selected from R″;
and the substituents on cycloalkyl, cycloalkenyl and heterocycle are 1 to 10 groups selected from R″, oxo and thiono;
Rb is (1) a group selected from Ra,
(2) C2-C6 alkanoyl,
Rc and Rd are independently selected from Rb, hydroxy, C1-C5alkoxy, C1-C5alkoxycarbonyl, aminocarbonyl, C1-C5alkylaminocarbonyl and C1-C5dialkylaminocarbonyl;
or
Rcand Rd together with the N to which they are both attached form a 3- to 10-membered ring containing 0 to 2 additional heteroatoms selected from O, S(O)m, and NRg, said ring is optionally substituted with 1 to 5 groups independently selected from R″, thiono and oxo;
said ring is further optionally fused to a benzene ring optionally substituted with 1 to 3 groups selected from Re;
said ring is further optionally spiro fused to a C3-C7cycloalkyl ring;
Re is (1) halogen,
(2) C1-C7 alkyl,
(3) C1-C3 perfluoroalkyl,
(4) S(O)mRi,
(5) cyano,
(6) nitro,
(7) RiO(CH2)v—,
(8) RiCO2(CH2)v—,
(9) RiOCO(CH2)v,
(10) optionally substituted aryl where the substituents are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy,
(11) SO2NRiRi, or
(12) amino;
Rf is (1) H,
(2) C1-C5alkyl optionally substituted with 1 to 5 groups selected from halogen, cyano, hydroxy, C1-C3alkoxy, NRgRh, CO2Riand CONRgRh,
(3) C2-6alkenyl,
(4) C2-6alkynyl,
(5) C3-C6cycloalkyl,
(6) aryl optionally substituted with 1 to 4 groups independently selected from Re, or 2 adjacent substituents together form methylenedioxy, or
(7) aryl-C1-C3alkyl optionally substituted with 1 to 4 groups independently selected from Re, or 2 adjacent substituents together form methylenedioxy, or
two Rf groups together with the nitrogen atom to which they are attached form a a 3- to 10-membered ring containing 0 to 2 additional heteroatoms selected from O, S(O)m, and NRg, said ring is optionally substituted with 1 to 5 groups independently selected from R″, thiono and oxo;
said ring is further optionally fused to a benzene ring optionally substituted with 1 to 3 groups selected from Re;
said ring is further optionally spirofused to a C3-C7cycloalkyl ring;
Rg and Rh are independently
(1) hydrogen,
(2) C1-C10alkyl optionally substituted with 1 to 10 groups selected from hydroxy, amino, C(O)Ri, and CO2Ri,
(3) aryl optionally substituted with 1 to 5 groups selected from halogen, amino, 1,2-methylenedioxy, C1-C7 alkoxy, C1-C7 alkyl and C1-C3 perfluoroalkyl,
(4) aryl C1-C6 alkyl, wherein the aryl is optionally substituted with 1 to 5 groups selected from halogen, amino, 1,2-methylenedioxy, C1-C7 alkoxy, C1-C7 alkyl and C1-C3 perfluoroalkyl,
(5) C3-C7cycloalkyl optionally substituted with phenyl,
(6) C1-C5 alkanoyl,
(7) C1-C5 alkoxycarbonyl,
(8) aryl C1-C5 alkoxycarbonyl,
(9) aminocarbonyl,
(10) C1-C5 monoalkylaminocarbonyl
(11) C1-C5 dialkylaminocarbonyl;
or
Rg and Rh 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 NRi, optionally substituted with 1 to 3 groups independently selected from Re and oxo;
Riis (1) hydrogen,
(2) C1-C3 perfluoroalkyl,
(3) C1-C6 alkyl,
(4) optionally substituted aryl or optionally substituted aryl C1-C6 alkyl, where the aryl substituents are from 1 to 3 groups independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, and hydroxy;
Rz is ORa, OC(O)Ra, OC(O)ORb, OC(O)NRcRd, NRcC(O)Ra, NRcC(O)ORa, NRcC(O)NRcRd, NRcSO2Ra;
R′ is (1) halogen,
(2) cyano,
(3) nitro,
(4) C(O)Rf,
(5) CO2Rf,
(6) C(O)NRgRh,
(7) ORf,
(8) OC(O)Rf,
(9) OC(O)NRgRh,
(10) OC(O)ORf,
(11) SRf,
(12) S(O)mRf,
(13) SO2NRgRh,
(14) NRgRh,
(15) NRgC(O)Rf,
(16) NRgCO2Rf,
(17) NRgC(S)ORf,
(18) NRgC(O)NRgRh,
(19) C3-C7 cycloalkyl optionally substituted with 1 to 4 groups independently selected from Re,
(20) C5-C7 cycloalkenyl optionally substituted with 1 to 4 groups independently selected from Re,
(21) aryl optionally substituted with 1 to 4 groups independently selected from Re, or 2 adjacent substituents together form methylenedioxy,
(22) heteroaryl optionally substituted with 1 to 4 groups independently selected from Re,
(23) 5 to 9-membered heterocycle containing from 1 to 4 heteroatoms independently selected from O, S and NRg, and optionally substituted with 1 to 4 groups independently selected from Re,
R′ is (1) a group selected from R′,
(2) C1-C6 alkyl, optionally substituted with halogen, aryl, ORf and NRgRh,
(3) C2-6alkenyl,
(4) C2-6alkynyl;
m is 0 to 2;
n is 0 or 1;
and
v is 0 to 3;
or
a pharmaceutically acceptable salt thereof.

113 more elements

Facts

Application

09/901,266Filed 9 Jul 2001 · us provisional application

Priority

14 Jul 2000

Granted

1 Jul 2003

Term ends

Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 491/16
In which the condensed system contains three hetero rings: peri-condensed systems
A61K 31/407
Having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil: condensed with other…
A61P 33/10
Antiparasitic agents: anthelmintics
A61P 33/14
Antiparasitic agents: ectoparasiticides, e.g. scabicides