Isomannide derivatives as inhibitors of soluble epoxide hydrolase

A compound of formula (I), a stereoisomeric form thereof, or a physiologically tolerable salt of any of the foregoing,

• wherein
• R1 is
• —(C1-C4)-alkylene-(C3-C12)-cycloalkyl, wherein said cycloalkyl is a ring system containing 3 to 12 carbon atoms in mono-, bi- or tricycles or bridged rings, and wherein said cycloalkyl is mono-, di-, tri- or tetrasubstituted independently of one another by R2,
• —(C1-C4)-alkylene-aryl, wherein said aryl is an aromatic hydrocarbon radical containing from 6 to 14 carbon atoms depending on the number of carbon atoms in one, two or three rings, and wherein said alkylene or aryl is independently from each other mono-, di- or trisubstituted independently of one another by R3,
• —(C1-C4)-alkylene-heterocyclyl, wherein said heterocyclyl is a ring system containing 4 to 15 ring carbon atoms, wherein depending on the ring size one, two, three or four of the 4 to 15 ring carbon atoms are independently replaced by nitrogen, oxygen or sulfur atoms, and wherein said alkylene or heterocyclyl is independently from each other unsubstituted or mono-, di- or trisubstituted independently of one another by R4,
• -cyclopropyl-heterocyclyl, wherein said heterocyclyl is a ring system containing 4 to 15 ring carbon atoms, wherein depending on the ring size one, two, three or four of the 4 to 15 ring carbon atoms are independently replaced by nitrogen, oxygen or sulfur atoms, and wherein said heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R4,
• -heterocyclyl, wherein said heterocyclyl is a ring system containing 4 to 15 ring carbon atoms, wherein depending on the ring size one, two, three or four of the 4 to 15 ring carbon atoms are independently replaced by nitrogen, oxygen or sulfur atoms, and wherein said heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R4,
• -aryl, wherein said aryl is an aromatic hydrocarbon radical containing from 6 to 14 carbon atoms depending on the number of carbon atoms in one, two or three rings, and wherein said aryl is mono-, di- or trisubstituted independently of one another by R3, or
• —(C3-C12)-cycloalkyl, wherein said cycloalkyl is a ring system containing 3 to 12 carbon atoms in mono-, bi- or tricycles or bridged rings, and wherein said cycloalkyl is mono-, di-, tri- or tetrasubstituted independently of one another by R2;
• X is
• —O-aryl, wherein said aryl is an aromatic hydrocarbon radical containing from 6 to 14 carbon atoms depending on the number of carbon atoms in one, two or three rings, and wherein said aryl is mono-, di- or trisubstituted independently of one another by R6,
• —O-heterocyclyl, wherein said heterocyclyl is a ring system containing 4 to 15 ring carbon atoms, wherein depending on the ring size one, two, three or four of the 4 to 15 ring carbon atoms are independently replaced by nitrogen, oxygen or sulfur atoms, and wherein said heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R7,
• —(C1-C4)-alkyl-R17, wherein said alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R17,
• —(C1-C4)-alkyl-aryl, wherein said aryl is an aromatic hydrocarbon radical containing from 6 to 14 carbon atoms depending on the number of carbon atoms in one, two or three rings, and wherein said aryl is mono-, di- or trisubstituted independently of one another by R8,
• —(C1-C4)-alkyl-heterocyclyl, wherein said heterocyclyl is a ring system containing 4 to 15 ring carbon atoms, wherein depending on the ring size one, two, three or four of the 4 to 15 ring carbon atoms are independently replaced by nitrogen, oxygen or sulfur atoms, and wherein said heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R7,
• —(CH═CH)-aryl, wherein said aryl is an aromatic hydrocarbon radical containing from 6 to 14 carbon atoms depending on the number of carbon atoms in one, two or three rings, and wherein said aryl is mono-, di- or trisubstituted independently of one another by R8,
• —(CH═CH)-heterocyclyl, wherein said heterocyclyl is a ring system containing 4 to 15 ring carbon atoms, wherein depending on the ring size one, two, three or four of the 4 to 15 ring carbon atoms are independently replaced by nitrogen, oxygen or sulfur atoms, and wherein said heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R7,
• —(C≡C)-aryl, wherein said aryl is an aromatic hydrocarbon radical containing from 6 to 14 carbon atoms depending on the number of carbon atoms in one, two or three rings, and wherein said aryl is mono-, di- or trisubstituted independently of one another by R8,
• —(C≡C)-heterocyclyl, wherein said heterocyclyl is a ring system containing 4 to 15 ring carbon atoms, wherein depending on the ring size one, two, three or four of the 4 to 15 ring carbon atoms are independently replaced by nitrogen, oxygen or sulfur atoms, and wherein said heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R7,
• —CN,
• —O—(C1-C3)-fluoroalkyl,
• —O—C(O)-heterocyclyl, wherein said heterocyclyl is selected from the group consisting of imidazolyl, morpholinyl, oxadiazolyl, piperazinyl, piperidinyl, pyrazinyl, pyridyl, pyrrolidinyl, tetrahydrofuranyl, tetrazolyl, thiazolyl, thiophenyl, and triazolyl, and wherein said heterocyclyl is mono-, di- or trisubstituted independently of one another by R7,
• —N(R10)heterocyclyl, wherein said heterocyclyl is selected from the group consisting of imidazolyl, morpholinyl, oxadiazolyl, piperazinyl, piperidinyl, pyrazinyl, pyridyl, pyrrolidinyl, tetrahydrofuranyl, tetrazolyl, thiazolyl, thiophenyl, and triazolyl, and wherein said heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R7,
• —S—(C1-C4)-alkyl-R17, wherein said alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R17,
• —S—(C3-C8)-cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R17,
• —SO2—(C3-C8)-cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R17,
• —O—SO2-aryl, wherein said aryl is an aromatic hydrocarbon radical containing from 6 to 14 carbon atoms depending on the number of carbon atoms in one, two or three rings, and wherein said aryl is mono-, di- or trisubstituted independently of one another by R8,
• —S-aryl, wherein said aryl is an aromatic hydrocarbon radical containing from 6 to 14 carbon atoms depending on the number of carbon atoms in one, two or three rings, and wherein said aryl is mono-, di- or trisubstituted independently of one another by R8,
• —S-heterocyclyl, wherein said heterocyclyl is a ring system containing 4 to 15 ring carbon atoms, wherein depending on the ring size one, two, three or four of the 4 to 15 ring carbon atoms are independently replaced by nitrogen, oxygen or sulfur atoms, and wherein said heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R7, or
• —S—(C1-C4)-alkyl, wherein said alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R18;
• R2, R3, R14, R17 and R18 are independent of one another, are identical or different, and are selected from the group consisting of a hydrogen atom, —(C1-C4)-alkyl, —OH, —(C1-C4)-alkyl-OH, halogen, —(C1-C3)-fluoroalkyl, —C(O)—OH, —C(O)—O—(C1-C4)-alkyl, —O—(C1-C4)-alkyl, —CN, —O—(C1-C3)-fluoroalkyl, —N(R10)-R21, —NH—C(O)—(C1-C4)-alkyl, —S—(C1-C4)-alkyl, —S(O)2—C1-C3)-alkyl, —(C1-C3)-alkyl —O—(C1-C3)-alkyl, phenyl, and —O—(C1-C4)-alkyl-phenyl;
• R6 is
• -aryl, wherein said aryl is an aromatic hydrocarbon radical containing from 6 to 14 carbon atoms depending on the number of carbon atoms in one, two or three rings, and wherein said aryl is mono-, di- or trisubstituted independently of one another by R10,
• —O-aryl, wherein said aryl is an aromatic hydrocarbon radical containing from 6 to 14 carbon atoms depending on the number of carbon atoms in one, two or three rings, and wherein said aryl is mono-, di- or trisubstituted independently of one another by R10,
• —(C1-C4)-alkylene-aryl, wherein said aryl is an aromatic hydrocarbon radical containing from 6 to 14 carbon atoms depending on the number of carbon atoms in one, two or three rings, and wherein said aryl is mono-, di- or trisubstituted independently of one another by R10,
• -heterocyclyl, wherein said heterocyclyl is selected from the group consisting of imidazolyl, morpholinyl, oxadiazolyl, piperazinyl, piperidinyl, pyrazinyl, pyridyl, pyrrolidinyl, tetrahydrofuranyl, tetrazolyl, thiazolyl, thiophenyl, and triazolyl, and wherein said heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R10,
• —O-heterocyclyl, wherein said heterocyclyl is selected from the group consisting of imidazolyl, morpholinyl, oxadiazolyl, piperazinyl, piperidinyl, pyrazinyl, pyridyl, pyrrolidinyl, tetrahydrofuranyl, tetrazolyl, thiazolyl, thiophenyl, and triazolyl, and wherein said heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R10,
• —C(O)-heterocyclyl, wherein said heterocyclyl is selected from the group consisting of imidazolyl, morpholinyl, oxadiazolyl, piperazinyl, piperidinyl, pyrazinyl, pyridyl, pyrrolidinyl, tetrahydrofuranyl, tetrazolyl, thiazolyl, thiophenyl, and triazolyl, and wherein said heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R10,
• —(C1-C4)-alkylene-heterocyclyl, wherein said heterocyclyl is selected from the group consisting of imidazolyl, morpholinyl, oxadiazolyl, piperazinyl, piperidinyl, pyrazinyl, pyridyl, pyrrolidinyl, tetrahydrofuranyl, tetrazolyl, thiazolyl, thiophenyl, and triazolyl, and wherein said heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R10,
• —O—(C1-C4)-alkylene-heterocyclyl, wherein said heterocyclyl is selected from the group consisting of imidazolyl, morpholinyl, oxadiazolyl, piperazinyl, piperidinyl, pyrazinyl, pyridyl, pyrrolidinyl, tetrahydrofuranyl, tetrazolyl, thiazolyl, thiophenyl, and triazolyl, and wherein said heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R10,
• —(C3-C8)-cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R10, or
• is selected from the group consisting of a hydrogen atom, —(C1-C4)-alkylene-N(R10)-R21, —C(O)—N(R10)-R20, —N(R10)-R21, —(C1-C4)-alkyl, —(C1-C4)-alkyl-CN, —(C1-C3)-fluoroalkyl, —O—(C1-C4)-alkyl, halogen, —C(O)—O—R10, —(C1-C3)-alkylene-C(O)—O—R10, —NH—C(O)—(C1-C4)-alkyl, —C(O)—(C1-C4)-alkyl, and —NO2;
• R4 and R7 are independent of one another, are identical or different, and are selected from the group consisting of a hydrogen atom, —(C1-C4)-alkyl, —O—(C1-C4)-alkyl, —(C1-C5)-alkyl-OH, halogen, —C(O)—O—R10, ═O , phenyl, —(C1-C3)-alkylene-C(O)—O—R10, —C(O)—N(R10)-R20, —N(R10)-R21, —CN, —(C1-C3)-fluoroalkyl, —(C1-C3)-alkyl-O—(C1-C3)-alkyl, —C(O)—(C1-C4)-alkyl, —C(O)—(C1-C3)-fluoroalkyl, and —C(O)—(C3-C8)-cycloalkyl,
• —C(O)-aryl, wherein said aryl is an aromatic hydrocarbon radical containing from 6 to 14 carbon atoms depending on the number of carbon atoms in one, two or three rings, and wherein said aryl is mono-, di- or trisubstituted independently of one another by R6,
• aryl, wherein said aryl is an aromatic hydrocarbon radical containing from 6 to 14 carbon atoms depending on the number of carbon atoms in one, two or three rings, and wherein said aryl is mono-, di- or trisubstituted independently of one another by R6,
• methanesulfonyl, or
• heterocyclyl, wherein said heterocyclyl is selected from the group consisting of imidazolyl, morpholinyl, oxadiazolyl, piperazinyl, piperidinyl, pyrazinyl, pyridyl, pyrrolidinyl, tetrahydrofuranyl, tetrazolyl, thiazolyl, thiophenyl, and triazolyl;
• R8 and R9 are independent of one another, are identical or different, and are selected from the group consisting of a hydrogen atom, halogen, —OH, —N(R10)-C(O)—R20, and —(C1-C4)-alkyl;
• R10 is a hydrogen atom, —(C1-C4)-alkyl or —O—(C1-C4)-alkyl;
• R11 is a hydrogen atom, —(C1-C4)-alkyl or benzyl;
• R12 is a hydrogen atom or
• R1 and R12 together with the nitrogen atom to which they are bonded form a four- to eight-membered monocyclic heterocyclic ring which, as well as the nitrogen atom, may additionally, according to the ring size, also contain one or two identical or different heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, wherein the four- to eight-membered monocyclic heterocyclic ring is mono-, di- or trisubstituted independently of one another by —(C1-C4)-alkyl or halogen;
• R20 is a hydrogen atom or —(C1-C4)-alkyl;
• and
• R21 is selected from the group consisting of a hydrogen atom, —(C1-C4)-alkyl, —C(O)—R20, —(C1-C4)-alkyl-heterocyclyl, wherein said heterocyclyl is selected from the group consisting of imidazolyl, morpholinyl, oxadiazolyl, piperazinyl, piperidinyl, pyrazinyl, pyridyl, pyrrolidinyl, tetrahydrofuranyl, tetrazolyl, thiazolyl, thiophenyl, and triazolyl, heterocyclyl, wherein said heterocyclyl is selected from the group consisting of imidazolyl, morpholinyl, oxadiazolyl, piperazinyl, piperidinyl, pyrazinyl, pyridyl, pyrrolidinyl, tetrahydrofuranyl, tetrazolyl, thiazolyl, thiophenyl, and triazolyl, and
• —(C3-C8)-cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R10.