Compounds
The present invention relates to new CGRP-antagonists of general formula I wherein U, V, X, Y, R 1 , R 2 , R 3 and R 4 are defined as in the description, the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof and the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, medicaments containing these compounds, their use and processes for preparing them.
1. A compound of the formula I
wherein
R 1 denotes a group of the formula IIa or IIb
and
R 2 denotes H or C 1-3 -alkyl, or
R 1 and R 2 together with the nitrogen atom to which they are bound denote a group of the formula IIIa or IIIb
G denotes C-R 1.1 or N,
T denotes N-R 1.2 or O,
R 1.1 independently of one another denote
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —CN, C 1-3 -alkyl-O—, —C(O)—O—C 1-3 -alkyl, C 2-4 -alkenyl, —C 2-4 -alkynyl, C 1-3 -alkyl-S—, cyclopropyl, —NH 2 , —COOH, —NH—C(O)—O—C 1-3 -alkyl, —NH—C(O)—C 1-3 -alkyl,
(c) a C 1-3 -alkyl group or C 1-3 -alkyl-O— group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 1.2 independently of one another denote
(a) H or
(b) C 1-3 -alkyl,
R 1.3 denotes
(a) H,
(b) F, —CN, C 1-3 -alkyl, —CO 2 —R 1.3.1 or
(c) a C 1-3 -alkyl group, wherein each methylene group may be substituted by up to two fluorine atoms and each methyl group may be substituted by up to three fluorine atoms,
R 1.3.1 denotes
(a) H, or
(b) C 1-6 -alkyl,
R 3 denotes
(a) H,
(b) C 1-6 -alkylene-R 3.1 ,
(c) a C 3-6 -cycloalkyl group substituted by one or two groups R 3.2 ,
(d) a C 5-7 -cycloalkenyl group substituted by one or two groups R 3.2 ,
(e) an aryl group substituted by one or two groups R 3.2 ,
(f) a heterocyclyl group substituted by one or two groups R 3.2 ,
(g) a C 5-7 -cycloalkyl group, which may be fused to an aryl or heteroaryl group and is additionally substituted by one or two groups R 3.2 ,
(h) a heteroaryl group substituted by one or two groups R 3.2 ,
(i) a C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, or
(j) a dicyclopropylmethyl group,
R 3.1 denotes
(a) H,
(b) an aryl group substituted by the groups R 3.1.1 and R 3.1.2 ,
(c) a heteroaryl group substituted by the groups R 3.1.1 and R 3.1.2 , or
(d) a C 2-4 -alkynyl group,
R 3.1.1 denotes
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —CN, —O—C 1-3 -alkyl, —O—C(O)—C 1-3 -alkyl, —NR 3.1.1.1 R 3.1.1.2 , —S(O) m —C 1-3 -alkyl, —NR 3.1.1.1 —C(O)—C 1-3 -alkyl, —C(O)—NR 3.1.1.1 R 3.1.1.2 , —C(O)—O—R 3.1.1.3 , —NR 3.1.1.1 —C(O)—O—C 1-3 -alkyl, —O—C(O)—NR 3.1.1.1 R 3.1.1.2 , or
(c) a C 1-3 -alkyl or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 3.1.1.1 denotes H, or C 1-3 -alkyl and
R 3.1.1.2 denotes H, or C 1-3 -alkyl, or
R 3.1.1.1 and R 3.1.1.2 together with the nitrogen atom to which they are bound also denote a group which is selected from morpholinyl, thiomorpholinyl, piperidinyl, piperidonyl, piperazinyl, pyrrolidinyl and azetidinyl, wherein the group may additionally be substituted by one or two substituents selected from F, —OH, —O—C 1-3 -alkyl, —OCF 3 , C 1-3 -alkyl and CF 3 ,
R 3.1.1.3 denotes H, or C 1-3 -alkyl,
R 3.1.2 denotes
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —CN, —O—C 1-3 -alkyl, or
(c) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, or
R 3.2 independently of one another denote
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —CN, —O—C 1-3 -alkyl, —O—C(O)—C 1-3 -alkyl, —NR 3.2.1 R 3.2.2 , —S(O) m —C 1-3 -alkyl, —NR 3.2.1 —C(O)—C 1-3 -alkyl, —C(O)—NR 3.2.1 R 3.2.2 , —C(O)—O—R 3.2.3 , —NR 3.2.1 —C(O)—O—C 1-3 -alkyl, —O—C(O)—NR 3.2.1 R 3.2.2 , or
(c) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 3.2.1 denotes H, or C 1-3 -alkyl and
R 3.2.2 denotes H, or C 1-3 -alkyl, or
R 3.2.1 and R 3.2.2 together with the nitrogen atom to which they are bound, also denote a group which is selected from morpholinyl, thiomorpholinyl, piperidinyl, piperidonyl, piperazinyl, pyrrolidinyl and azetidinyl, wherein the group may additionally be substituted by one or two substituents selected from F, —OH, —O—C 1-3 -alkyl, —OCF 3 , C 1-3 -alkyl and CF 3 ,
R 3.2.3 denotes H, or C 1-3 -alkyl,
R 4 denotes
(a) H,
(b) C 1-6 -alkylene—R 4.1 ,
(c) a C 3-6 -cycloalkyl group substituted by one or two groups R 4.2 ,
(d) a C 5-7 -cycloalkenyl group substituted by one or two groups R 4.2 ,
(e) an aryl group substituted by one or two groups R 4.2 ,
(f) a heterocyclyl group substituted by one or two groups R 4.2 ,
(g) a C 5-7 -cycloalkyl group, which may be fused to an aryl or heteroaryl group and is additionally substituted by one or two groups R 4.2 ,
(h) a heteroaryl group substituted by one or two groups R 4.2 ,
(i) a C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, or
(j) a dicyclopropylmethyl group,
R 4.1 denotes
(a) H,
(b) an aryl group substituted by the groups R 4.1.1 and R 4.1.2 ,
(c) a heteroaryl group substituted by the groups R 4.1.1 and R 4.1.2 , or
(d) a C 2-4 -alkynyl group,
R 4.1.1 denotes
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —CN, —O—C 1-3 -alkyl, —O—C(O)—C 1-3 -alkyl, —NR 4.1.1.1 R 4.1.1.2 , —S(O) m —C 1-3 -alkyl, —NR 4.1.1.1 —C(O)—C 1-3 -alkyl, —C(O)—NR 4.1.1.1 R 4.1.1.2 , —C(O)—O—R 4.1.1.3 , —NR 4.1.1.1 —C(O)—O—C 1-3 -alkyl, —O—C(O)—NR 4.1.1.1 R 4.1.1.2 , or
(c) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 4.1.1.1 denotes H, or C 1-3 -alkyl and
R 4.1.1.2 denotes H, or C 1-3 -alkyl, or
R 4.1.1.1 and R 4.1.1.2 together with the nitrogen atom to which they are bound also denote a group which is selected from morpholinyl, thiomorpholinyl, piperidinyl, piperidonyl, piperazinyl, pyrrolidinyl and azetidinyl, wherein the group may additionally be substituted by one or two substituents selected from F, —OH, —O—C 1-3 -alkyl, —OCF 3 , C 1-3 -alkyl and CF 3 ,
R 4.1.1.3 denotes H, or C 1-3 -alkyl,
R 4.1.2 denotes
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —CN, —O—C 1-3 -alkyl, or
(c) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, or
R 4.2 independently of one another denote
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —CN, —O—C 1-3 -alkyl, —O—C(O)—C 1-3 -alkyl, —NR 4.2.1 R 4.2.2 , —S(O) m —C 1-3 -alkyl, —NR 4.2.1 —C(O)—C 1-3 -alkyl, —C(O)—NR 4.2.1 R 4.2.2 , —C(O)—O—R 4.2.3 , —NR 4.2.1 —C(O)—O—C 1-3 -alkyl, —O—C(O)—NR 4.2.1 R 4.2.2 , or
(c) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 4.2.1 denotes H, or C 1-3 -alkyl and
R 4.2.2 denotes H, or C 1-3 -alkyl, or
R 4.2.1 and R 4.2.2 together with the nitrogen atom to which they are bound, also denote a group which is selected from morpholinyl, thiomorpholinyl, piperidinyl, piperidonyl, piperazinyl, pyrrolidinyl and azetidinyl, wherein the group may additionally be substituted by one or two substituents selected from F, —OH, —O—C 1-3 -alkyl, —OCF 3 , C 1-3 -alkyl and CF 3 ,
R 4.2.3 denotes H, or C 1-3 -alkyl, or
R 3 and R 4 together with the nitrogen atom to which they are bound denote:
(a) a saturated 5-, 6-, 7- or 9-membered heterocyclic group, which is substituted at a carbon atom by a group R 4.3 or by two groups R 4.3 and R 4.4 ,
(b) a saturated 5-, 6- or 7-membered heterocyclic group, which is substituted at two adjacent carbon atoms by in each case a group R 4.3 and R 4.4 ,
(c) a saturated 5-, 6- or 7-membered heterocyclic group, which is substituted at a carbon atom by a group R 4.3 or by two groups R 4.3 and R 4.4 and is additionally fused to a 5-, 6- or 7-membered cycloalkyl or heterocyclyl group, wherein the fused-on cycloalkyl or heterocyclyl group is substituted by 1, 2 or 3 groups R 4.5 ,
(d) a monounsaturated 5-, 6- or 7-membered heterocyclic group, which is substituted at a carbon atom by a group R 4.3 or by two groups R 4.3 and R 4.4 and is additionally fused to a phenyl group, wherein the fused-on phenyl group is substituted by 1, 2 or 3 groups R 4.5 ,
(e) a monounsaturated 5-, 6- or 7-membered heterocyclic group, which is substituted at a carbon atom by a group R 4.3 or by two groups R 4.3 and R 4.4 and additionally is fused to a 5- or 6-membered heteroaryl group, wherein the fused-on heteroaryl group is substituted by 1, 2 or 3 groups R 4.5 , or
(f) a heteroaryl group, which is substituted at 1, 2 or 3 carbon atoms by in each case a group R 4.5 ,
R 4.3 independently of one another denote
(a) H, C 1-3 -alkyl, HO—C 1-3 -alkylene-, C 2-6 -alkynyl, aryl, —C 1-3 -alkylene-R 4.3.1 , C 1-3 -alkyl-O—C(O)—, HO—C(O)—, F, —O—C 1-3 -alkyl, —OH, —CN, or
(b) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 4.3.1 denotes H, C 1-3 -alkyl-O—C(O)—, —NH 2 , (C 1-4 -alkyl)—NH—, (C 1-4 -alkyl) 2 N—, C 3-6 -cycloalkyl-, heterocyclyl, heteroaryl, or aryl,
R 4.4 denotes
(a) H, C 1-3 -alkyl, —OH, —O—C 1-3 -alkyl or
(b) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 4.3 and R 4.4 together with the carbon atoms to which they are bound, also denote a C 3-6 -cycloalkyl, C 5-6 -cycloalkenyl or heterocyclyl group,
R 4.5 independently of one another denote
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —O—C 1-3 -alkyl, —S(O) m —C 1-3 -alkyl, —NR 4.5.2 R 4.5.3 , —CN, —NO 2 , —C(O)—O—R 4.5.1 , —C(O)—NR 4.5.2 R 4.5.3 ,
(c) a C 1-3 -alkyl or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, or
(d) aryl, heteroaryl,
R 4.5.1 denotes H, or C 1-3 -alkyl,
R 4.5.2 denotes H, or C 1-3 -alkyl,
R 4.5.3 denotes H, or C 1-3 -alkyl, or
R 4.5.2 and R 4.5.3 together with the nitrogen atom to which they are bound also denote a group which is selected from morpholinyl, thiomorpholinyl, piperidinyl, piperidonyl, piperazinyl, pyrrolidinyl and azetidinyl, wherein the group may additionally be substituted by one or two substituents selected from F, —OH, —O—C 1-3 -alkyl, —OCF 3 , C 1-3 -alkyl and CF 3 ,
and,
the ring
denotes a group of the formula
or a tautomer or salt thereof.
2. A compound of the formula I according to claim 1 , wherein
R 1 denotes
R 1.1 denotes
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —CN, —O—C 1-3 -alkyl, —C(O)—O—C 1-3 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, C 1-3 -alkyl-S—, —NH 2 , or
(c) a C 1-3 -alkyl group or C 1-3 -alkyl-O—group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, and
R 1.2 denotes H or CH 3 and
R 2 denotes H or C 1-3 -alkyl,
or a tautomer or salt thereof.
3. A compound of the formula I according to claim 1 , wherein
R 1 and R 2 together with the nitrogen atom to which they are attached denote
and
R 11 denotes
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —CN, —O—C 1-3 -alkyl, —C(O)—O—C 1-3 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, C 1-3 -alkyl-S, —NH 2 , or
(c) a C 1-3 -alkyl group or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
or a tautomer or salt thereof.
4. A compound of the formula I according to claim 1 , wherein
R 1 denotes
R 1.1 denotes
(a) F, CH 3 , —OH, —O—CH 3 or
(b) CF 3 and
R 2 denotes H or C 1-3 -alkyl,
or a tautomer or salt thereof.
5. A compound of the formula I according to claim 1 , wherein
R 1 and R 2 together with the nitrogen atom to which they are attached denote
and
R 1.1 denotes
(a) F, CH 3 , —OH, —O—CH 3 or
(b) CF 3 ,
or a tautomer or salt thereof.
6. A compound of the formula I according to claim 1 , wherein
R 1 denotes
and
R 2 denotes H,
or a tautomer or salt thereof.
7. A compound of the formula I according to claim 1 , wherein
R 1 and R 2 together with the nitrogen atom to which they are attached denote
or a tautomer or salt thereof.
8. A compound of the formula I according to claim 1 , wherein
R 3 denotes
(a) H,
(b) C 1-6 -alkyl,
(c) a C 3-6 -cycloalkyl group substituted by one or two groups R 3.2 , or
(d) a C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 3.2 independently of one another denote
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —O—C 1-3 -alkyl, or
(c) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 4 denotes
(a) H,
(b) C 1-6 -alkylene-R 4.1 ,
(c) a C 3-6 -cycloalkyl group substituted by one or two groups R 4.2 ,
(d) a C 5-7 -cycloalkenyl group substituted by one or two groups R 4.2 ,
(e) an aryl group substituted by one or two groups R 4.2 ,
(f) a C 5-7 -cycloalkyl group which may be fused to an aryl group and is additionally substituted by one or two groups R 4.2 , or
(g) a heteroaryl group substituted by one or two groups R 4.2 ,
R 4.1 denotes
(a) H,
(b) a phenyl group substituted by the groups R 4.1.1 and R 4.1.2 ,
(c) a heteroaryl group substituted by the groups R 4.1.1 and R 4.1.2 , or
(d) a C 2-3 -alkynyl group,
R 4.1.1 denotes
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —CN, —O—C 1-3 -alkyl, —NR 4.1.1.1 R 4.1.1.2 , —S—C 1-3 -alkyl, —NR 4.1.1.1 —C(O)—C 1-3 -alkyl, —C(O)—NR 4.1.1.1 R 4.1.1.2 , —C(O)—O—R 4.1.1.3 , or
(c) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 4.1.1.1 denotes H, or C 1-3 -alkyl,
R 4.1.1.2 denotes H, or C 1-3 -alkyl, or
R 4.1.1.1 and R 4.1.1.2 together with the nitrogen atom to which they are bound also denote a group selected from morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, pyrrolidinyl and azetidinyl,
R 4.1.1.3 denotes H, or C 1-3 -alkyl,
R 4.1.2 denotes
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —O—C 1-3 -alkyl, or
(c) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, or
R 4.2 independently of one another denote
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —CN, —O—C 1-3 -alkyl, —NR 4.2.1 R 4.2.2 , —S—C 1-3 -alkyl, —NR 4.2.1 —C(O)—C 1-3 -alkyl, —C(O)—NR 4.2.1 R 4.2.2 , —C(O)—O—R 4.2.3 , or
(c) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 4.2.1 denotes H, or C 1-3 -alkyl and
R 4.2.2 denotes H, or C 1-3 -alkyl, or
R 4.2.1 and R 4.2.2 together with the nitrogen atom to which they are bound also denote a group which is selected from among morpholinyl, thiomorpholinyl, piperidinyl, piperidonyl, piperazinyl, pyrrolidinyl and azetidinyl, and which may additionally be substituted by one or two groups selected from among F, —OH, —O—C 1-3 -alkyl, —OCF 3 , C 1-3 -alkyl and CF 3 ,
R 4.2.3 denotes H, or C 1-3 -alkyl,
R 3 and R 4 together with the nitrogen atom to which they are bound denote:
(a) a saturated 5-, 6-, 7- or 9-membered heterocyclic group, which is substituted at a carbon atom by a group R 4.3 or by two groups R 4.3 and R 4.4 ,
(b) a saturated 5-, 6- or 7-membered heterocyclic group, which is substituted at two adjacent carbon atoms by in each case a group R 4.3 and R 4.4 ,
(c) a saturated 5-, 6- or 7-membered heterocyclic group which is substituted at a carbon atom by a group R 4.3 or by two groups R 4.3 and R 4.4 and is additionally fused to a 5-, 6- or 7-membered cycloalkyl- or heterocyclyl group, wherein the fused-on cycloalkyl or heterocyclyl group is substituted by 1, 2 or 3 groups R 4.5 ,
(d) a monounsaturated 5-, 6- or 7-membered heterocyclic group, which is substituted at a carbon atom by a group R 4.3 or by two groups R 4.3 and R 4.4 and is additionally fused to a phenyl group, wherein the fused-on phenyl group is substituted by 1, 2 or 3 groups R 4.5 ,
(e) a monounsaturated 5-, 6- or 7-membered heterocyclic group, which is substituted at a carbon atom a group R 4.3 or by two groups R 4.3 and R 4.4 and is additionally fused to a 5- or 6-membered heteroaryl group, wherein the fused-on heteroaryl group is substituted by 1, 2 or 3 groups R 4.5 , or
(f) a heteroaryl group which is substituted by a group R 4.5 at 1, 2 or 3 carbon atoms,
R 4.3 denotes H, C 1-3 -alkyl, phenyl, —C 1-3 -alkylene-R 4.3.1 , C 1-3 -alkyl-O—C(O)—, HO—C(O)—, F, —O—C 1-3 -alkyl, —OH, or —CN,
R 4.3.1 denotes H, C 1-3 -alkyl-O—C(O)—, —NH 2 , (C 1-4 -alkyl)—NH—, (C 1-4 -alkyl) 2 N—, or heterocyclyl,
R 4.4 denotes
(a) H, C 1-3 -alkyl, —OH, —O—C 1-3 -alkyl or
(b) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 4.3 and R 4.4 together with the carbon atoms to which they are bound also denote a C 3-6 -cycloalkyl, C 5-6 -cycloalkenyl or heterocyclyl group,
R 4.3 independently of one another denote
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —O—C 1-3 -alkyl, —NH 2 , —CN, —C(O)—O—R 4.5.1 , —C(O)—NR 4.5.2 R 4.5.3 ,
(c) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, or
(d) phenyl,
R 4.5.1 denotes H, or C 1-3 -alkyl,
R 4.5.2 denotes H, or C 1-3 -alkyl and
R 4.5.3 denotes H, or C 1-3 -alkyl,
or a tautomer or salt thereof.
9. A compound of the formula I according to claim 1 , wherein
R 3 denotes
(a) H,
(b) C 1-6 -alkyl,
(c) a C 3-6 -cycloalkyl substituted by one or two groups R 3.2 , or
(d) a C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 3.2 independently of one another denote
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —O—C 1-3 -alkyl, or
(c) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 4 denotes
(a) H,
(b) C 1-6 -alkylene-R 4.1 ,
(c) a C 3-6 -cycloalkyl group substituted by one or two groups R 4.2 ,
(d) a C 5-7 -cycloalkenyl group substituted by one or two groups R 4.2 ,
(e) an aryl group substituted by one or two groups R 4.2 or
(f) a C 5-6 -cycloalkyl group, which may be fused to a phenyl group and which is additionally substituted by one or two groups R 4.2 ,
R 4.1 denotes
(a) H or
(b) a phenyl group substituted by the groups R 4.1.1 and R 4.1.2 ,
R 4.1.1 denotes
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —O—C 1-3 -alkyl, —CN, —C(O)—O—R 4.1.1.3 , or
(c) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 4.1.1.3 denotes H, or C 1-3 -alkyl,
R 4.1.2 denotes
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —O—C 1-3 -alkyl, or
(c) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, or
R 4.2 independently of one another denote
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —O—C 1-3 -alkyl, —CN, —O—C(O)—C 1-3 -alkyl, or
(c) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 3 and R 4 together with the nitrogen atom to which they are bound denote:
(a) a saturated 5- or 6-membered heterocyclic group, which is substituted at a carbon atom by a group R 4.3 or by two groups R 4.3 and R 4.4 ,
(b) a saturated 5- or 6-membered heterocyclic group, which is substituted at two adjacent carbon atoms by a group R 4.3 and R 4.4 in each case,
(c) a saturated 5-, 6- or 7-membered heterocyclic group, which is substituted at a carbon atom by a group R 4.3 or by two groups R 4.3 and R 4.4 and is additionally fused to a 5-, 6- or 7-membered cycloalkyl or heterocyclyl group, wherein the fused-on cycloalkyl or heterocyclyl group is substituted by 1, 2 or 3 groups R 4.5 ,
(d) a monounsaturated 5-, 6- or 7-membered heterocyclic group, which is substituted at a carbon atom by a group R 4.3 or by two groups R 4.3 and R 4.4 and is additionally fused to a phenyl group, wherein the fused-on phenyl group is substituted by 1, 2 or 3 groups R 4.5 ,
(e) a monounsaturated 5-, 6- or 7-membered heterocyclic group, which is substituted at a carbon atom by a group R 4.3 or by two groups R 4.3 and R 4.4 and is additionally fused to a 5- or 6-membered heteroaryl group, wherein the fused-on heteroaryl group is substituted by 1, 2 or 3 groups R 4.5 and is selected from among
or
(f) a heteroaryl group, which is substituted in each case by a group R 4.5 at 1, 2 or 3 carbon atoms,
R 4.3 denotes H, C 1-3 -alkyl, phenyl, —C 1-3 -alkylene-R 4.3.1 , C 1-3 -alkyl-O—C(O)—, HO—C(O)—, F, —O—C 1-3 -alkyl, —OH, or —CN,
R 4.3.1 denotes H, C 1-3 -alkyl-O—C(O)—, —NH 2 , (C 1-4 -alkyl)—NH—, (C 1-4 -alkyl) 2 N—, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or azetidinyl,
R 4.4 denotes
(a) H, C 1-3 -alkyl, —OH, —O—C 1-3 -alkyl, or
(b) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 4.3 and R 4.4 together with the carbon atoms to which they are bound also denote a C 3-6 -cycloalkyl or heterocyclyl group, and
R 4.5 independently of one another denote
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —O—C 1-3 -alkyl, —NH 2 , —CN,
(c) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, or
(d) phenyl,
or a tautomer or salt thereof.
10. A compound of the formula I according to claim 1 , wherein
R 3 denotes
(a) H,
(b) C 1-6 -alkyl,
(c) a C 3-6 -cycloalkyl group substituted by one or two groups R 3.2 or
(d) a C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 3.2 independently of one another denote
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —O—C 1-3 -alkyl, or
(c) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 4 denotes
(a) H,
(b) C 1-6 -alkylene-R 4.1 ,
(c) a C 3-6 -cycloalkyl group substituted by one or two groups R 4.2 ,
(d) a C 5-7 -cycloalkenyl group substituted by one or two groups R 4.2 ,
(e) a phenyl group substituted by one or two groups R 4.2 or
(f) a C 5-6 -cycloalkyl group, which may be fused to a phenyl group and is additionally substituted by one or two groups R 4.2 ,
R 4.1 denotes
(a) H or
(b) a phenyl group substituted by the groups R 4.1.1 and R 4.1.2 ,
R 4.1.1 denotes
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —O—C 1-3 -alkyl, —CN, —C(O)—O—R 4.1.1.3 , or
(c) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 4.1.1.3 denotes H, or C 1-3 -alkyl,
R 4.1.2 denotes
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —O—C 1-3 -alkyl, or
(c) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, or
R 4.2 denotes
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —O—C 1-3 -alkyl, —CN, or
(c) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, or
R 3 and R 4 together with the nitrogen atom to which they are bound denote:
(a) a saturated 5- or 6-membered heterocyclic group, which is selected from among piperidinyl, piperidinonyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl and pyrrolidinonyl, and which is substituted at a carbon atom by a group R 4.3 or by two groups R 4.3 and R 4.4 ,
(b) a saturated 5- or 6-membered heterocyclic group, which is selected from among piperidinyl, piperidinonyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl and pyrrolidinonyl, and which is substituted at two adjacent carbon atoms by a group R 4.3 and R 4.4 in each case,
(c) a saturated 5-, 6- or 7-membered heterocyclic group, which is selected from among piperidinyl, piperidinonyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, pyrrolidinonyl, azepanyl, diazepanyl, diazepanonyl and oxazepanyl, and which is substituted at a carbon atom by a group R 4.3 or by two groups R 4.3 and R 4.4 and is additionally fused to a 5-, 6- or 7-membered cycloalkyl or heterocyclyl group, which is selected from among piperidinyl, piperidinonyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, pyrrolidinonyl, azepanyl, diazepanyl, diazepanonyl and oxazepanyl, wherein the fused-on cycloalkyl or heterocyclyl group is substituted by 1, 2 or 3 groups R 4.5 ,
(d) a monounsaturated 5-, 6- or 7-membered heterocyclic group, which is selected from among
and which is substituted at a carbon atom by a group R 4.3 or by two groups R 4.3 and R 4.4 and is additionally fused to a phenyl group, while the fused-on phenyl group is substituted by 1, 2 or 3 groups R 4.5 ,
(e) a monounsaturated 5-, 6- or 7-membered heterocyclic group, which is selected from among
and which is substituted at a carbon atom by a group R 4.3 or by two groups R 4.3 and R 4.4 and is additionally fused to a 5- or 6-membered heteroaryl group, while the fused-on heteroaryl group is substituted by 1, 2 or 3 groups R 4.3 and is selected from among
or
(f) a heteroaryl group, which is selected from among indole, isoindole, azaindole, indazole and benzimidazole, and which is substituted by a group R 4.5 at 1, 2 or 3 carbon atoms,
R 4.3 denotes H, C 1-3 -alkyl, phenyl, —C 1-3 -alkylene-R 4.3.1 , C 1-3 -alkyl-O—C(O)—, HO—C(O)—, F, —O—C 1-3 -alkyl, —OH, or —CN,
R 4.3.1 denotes H, C 1-3 -alkyl-O—C(O)—, —NH 2 , (C 1-4 -alkyl)—NH—, (C 1-4 -alkyl) 2 N—, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or azetidinyl,
R 4.4 denotes
(a) H, C 1-3 -alkyl, —OH, —O—C 1-3 -alkyl or
(b) a C 1-3 -alkyl or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 4.3 and R 4.4 together with the carbon atoms to which they are bound also denote a C 3-6 -cycloalkyl group or a heterocyclyl group which is selected from among azetidinyl, pyrrolidinyl, piperidinyl and azepanyl, and
R 4.5 independently of one another denote
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —O—C 1-3 -alkyl, —NH 2 , —CN,
(c) a C 1-3 -alkyl or —O—C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, or
(d) phenyl,
or a tautomer or salt thereof.
11. A compound of the formula I according to claim 1 , wherein
R 3 denotes
(a) H,
(b) C 1-3 -alkyl or
(c) a C 1-3 -alkyl group, wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, and
R 4 denotes H, cyclopropyl or a group selected from
R 3 and R 4 together with the nitrogen atom to which they are attached denote a group selected from
or a tautomer or salt thereof.
12. A compound of the formula I according to claim 1 , wherein
R 3 and R 4 together with the nitrogen atom to which they are attached denote a monounsaturated 5-membered heterocyclic group which is substituted at a carbon atom by a group R 4.3 or by two groups R 4.3 and R 4.4 and is additionally fused to a phenyl group, while the fused-on phenyl group is substituted by 1, 2 or 3 groups R 4.5 ,
R 4.3 denotes H, C 1-3 -alkyl, phenyl, —C 1-3 -alkylene-R 4.3.1 , C 1-3 -alkyl-O—C(O)—, HO—C(O)—, F, —O—C 1-3 -alkyl, —OH, or —CN,
R 4.3.1 denotes H, C 1-3 -alkyl-O—C(O)—, —NH 2 , (C 1-4 -alkyl)—NH—, (C 1-4 -alkyl) 2 N—, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or azetidinyl,
R 4.4 denotes
(a) H, C 1-3 -alkyl, —OH, —O—C 1-3 -alkyl or
(b) a C 1-3 -alkyl or —O—C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, or
R 4.3 and R 4.4 together with the carbon atom to which they are attached also denote a C 3-6 -cycloalkyl group or a heterocyclyl group which is selected from among azetidinyl, pyrrolidinyl, piperidinyl and azepanyl, and
R 4.5 independently of one another denote
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —O—C 1-3 -alkyl, —NH 2 , —CN,
(c) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, or
(d) phenyl,
or a tautomer or salt thereof.
13. A compound of the formula I according to claim 1 , wherein
R 3 and R 4 together with the nitrogen atom to which they are attached denote a group of the formula IVa or IVb
R 4.3 denotes H, C 1-3 -alkyl, phenyl, —C 1-3 -alkylene-R 4.3.1 , C 1-3 -alkyl-O—C(O)—, HO—C(O)—, F, —O—C 1-3 -alkyl, —OH, or —CN,
R 4.3.1 denotes H, C 1-3 -alkyl-O—C(O)—, —NH 2 , (C 1-4 -alkyl)—NH—, (C 1-4 -alkyl) 2 N—, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or azetidinyl,
R 4.4 denotes
(a) H, C 1-3 -alkyl, —OH, —O—C 1-3 -alkyl or
(b) a C 1-3 -alkyl- or —O—C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, or
R 4.3 and R 4.4 together with the carbon atom to which they are attached also denote a C 3-6 -cycloalkyl group or a heterocyclyl group which is selected from among azetidinyl, pyrrolidinyl, piperidinyl and azepanyl, and
R 4.5 independently of one another denote
(a) H,
(b) halogen, C 1-3 -alkyl, —OH, —O—C 1-3 -alkyl, —NH 2 , —CN, NO 2 ,
(c) a C 1-3 -alkyl or —O—C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, or
(d) phenyl,
or a tautomer or salt thereof.
14. A compound of the formula I according to claim 1 , wherein
R 3 and R 4 together with the nitrogen atom to which they are attached denote a group selected from
or a tautomer or salt thereof.
15. A compound of the formula I according to claim 1 , wherein
R 1 denotes
R 2 denotes H,
R 3 denotes
(a) H,
(b) C 1-3 -alkyl or
(c) a C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, and
R 4 denotes H, cyclopropyl or a group selected from
or
R 3 and R 4 together with the nitrogen atom to which they are attached denote a group selected from
and the ring
denotes a group selected from
or a tautomer or salt thereof.
16. A compound of the formula I according to claim 1 , wherein
R 1 and R 2 together with the nitrogen atom to which they are attached denote a group selected from
R 3 and R 4 together with the nitrogen atom to which they are attached denote a group selected from
and the ring
denote a group selected from
or a tautomer or salt thereof.
17. A compound of according to claim 1 selected from the group consisting of:
No.
Structure
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11)
(12)
(13)
(14)
(15)
(16)
(17)
(18)
(19)
(32)
(33)
(34)
(35)
(36)
(37)
(38)
(39)
(40)
(41)
(43)
(44)
(45)
(46)
(47)
(48)
(49)
(50)
(51)
(52)
(55)
(56)
(57)
(58)
(59)
(60)
(61)
(62)
(63)
(64)
(65)
(66)
(67)
(68)
(69)
(70)
(71)
or a salt thereof.
18. A physiologically acceptable salt of a compound according to any one of claims 1 to 14 and 15 to 17 .
19. A pharmaceutical composition comprising a compound according to any one of claim 1 to 14 and 15 to 17 , or a physiologically acceptable salt thereof, and a carrier or diluent.
20. A method of treating tension, migraine or cluster headache which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound according to any one of claim 1 to 14 and 15 to 17 , or a physiologically acceptable salt thereof.