Substituted piperazines as CGRP antagonists
The present invention relates to new CGRP-antagonists of general formula I wherein R 1 , R 2 , R 3 , R a , R b , R c , X, Y and Z are defined as mentioned hereinafter, the individual diastereomers, the individual enantiomers and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, medicaments containing these compounds, the use thereof and processes for the preparation thereof.
1. A compound of the formula I
wherein
X denotes C—H, or C—Cl,
Y, Z independently of one another each denote CH,
(a) R 1 denotes H,
R 2 denotes R 2.1 —C 0-1 -alkylene,
R 2.1 denotes a group selected from
and
A denotes —O—, —S—, —S(O)— or —S(O 2 )—; or
(b) R 1 denotes H,
R 2 denotes R 2.1 —CH 2 — and
R 2.1 denotes a group
or
(c) R 1 and R 2 together with the carbon atom to which they are attached denote a C 4-6 -cycloalkyl group which is spirocyclically linked in each case to an oxetane or tetrahydropyran ring; or
(d) R 1 and R 2 together with the carbon atom to which they are attached denote a group
and
R 3 denotes H, —C(O)—O—C 1-4 -alkyl or a C 1-6 -alkyl group which may be substituted by 1, 2, 3, 4 or 5 fluorine atoms,
R a denotes H, F, —OCH 3 or —OCF 3 ,
R b denotes H, F, —OCH 3 or —OCF 3 , and
R c denotes H, F, —OCH 3 or —OCF 3 ,
or a physiologically acceptable salt thereof.
2. A compound of the formula I according to claim 1 , wherein
X, Y, Z in each case denote C—H,
(a) R 1 denotes H and
R 2 denotes a group selected from
or
(b) R 1 and R 2 together with the carbon atom to which they are attached denote a group selected from
and
R 3 denotes H, —C(O)—O—C 1-4 -alkyl or a C 1-6 -alkyl group which may be substituted by 1, 2, 3, 4 or 5 fluorine atoms,
R a denotes H, F, —OCH 3 or —OCF 3 ,
R b denotes H, F, —OCH 3 or —OCF 3 , and
R c denotes H, F, —OCH 3 or —OCF 3 ,
or a physiologically acceptable salt thereof.
3. A compound of the formula I according to claim 1 , wherein
X, Y, Z in each case denotes C—H,
R 1 denotes H,
R 2 denotes a group selected from
R 3 denotes H, —C(O)—O—C 1-4 -alkyl or a C 1-6 -alkyl group which may be substituted by 1, 2, 3, 4 or 5 fluorine atoms,
R a denotes H, F, —OCH 3 or —OCF 3 ,
R b denotes H, F, —OCH 3 or —OCF 3 , and
R c denotes H, F, —OCH 3 or —OCF 3 ,
or a physiologically acceptable salt thereof.
4. A compound of the formula I according to claim 1 , wherein
X, Y, Z in each case denote C—H,
R 1 denotes H,
R 2 denotes a group
R 3 denotes H, —C(O)—O—C 1-4 -alkyl or a C 1-6 -alkyl group which may be substituted by 1, 2, 3, 4 or 5 fluorine atoms,
R a denotes H, F, —OCH 3 or —OCF 3 ,
R b denotes H, F, —OCH 3 or —OCF 3 , and
R c denotes H, F, —OCH 3 or —OCF 3 ,
or a physiologically acceptable salt thereof.
5. A compound of the formula I according to claim 1 , wherein
X, Y, Z in each case denote C—H,
R 1 and R 2 together with the carbon atom to which they are attached denote a group selected from
R 3 denotes H, —C(O)—O—C 1-4 -alkyl or a C 1-6 -alkyl group which may be substituted by 1, 2, 3, 4 or 5 fluorine atoms,
R a denotes H, F, —OCH 3 or —OCF 3 ,
R b denotes H, F, —OCH 3 or —OCF 3 , and
R c denotes H, F, —OCH 3 or —OCF 3 ,
or a physiologically acceptable salt thereof.
6. A compound of the formula I according to claim 1 , wherein
in each case denote C—H,
R 1 and R 2 together with the carbon atom to which they are attached denote a group
R 3 denotes H, —C(O)—O—C 1-4 -alkyl or a C 1-6 -alkyl group which may be substituted by 1, 2, 3, 4 or 5 fluorine atoms,
R a denotes H, F, —OCH 3 or —OCF 3 ,
R b denotes H, F, —OCH 3 or —OCF 3 , and
R c denotes H, F, —OCH 3 or —OCF 3 ,
or a physiologically acceptable salt thereof.
7. A compound of the formula I according to claim 1 , wherein
X, Y, Z in each case denote C—H,
R 1 and R 2 together with the carbon atom to which they are attached denote a group
R 3 denotes H, —C(O)—O—C 1-4 -alkyl or a C 1-6 -alkyl group which may be substituted by 1, 2, 3, 4 or 5 fluorine atoms,
R a denotes H, F, —OCH 3 or —OCF 3 ,
R b denotes H, F, —OCH 3 or —OCF 3 , and
R c denotes H, F, —OCH 3 or —OCF 3 ,
or a physiologically acceptable salt thereof.
8. A compound of the formula Ia
wherein
X denotes C—H, or C—Cl,
Y, Z independently of one another each denote CH,
(a) R 1 denotes H,
R 2 denotes R 2.1 —C 0-1 -alkylene,
R 2.1 denotes a group selected from
and
A denotes —O—, —S—, —S(O)— or —S(O 2 )—; or
(b) R 1 denotes H,
R 2 denotes R 2.1 —CH 2 — and
R 2.1 denotes a group
or
(c) R 1 and R 2 together with the carbon atom to which they are attached denote a C 4-6 -cycloalkyl group which is spirocyclically linked in each case to an oxetane or tetrahydropyran ring; or
(d) R 1 and R 2 together with the carbon atom to which they are attached denote a group
and
R 3 denotes H or CH 3 ,
or a physiologically acceptable salt thereof.
9. A compound of formula I according to claim 1 , wherein
X denotes CH,
Y denotes CH and
Z denotes CH,
or a physiologically acceptable salt thereof.
10. A compound of formula Ia according to claim 8 , wherein,
R 3 denotes H or CH 3 ,
X denotes CH,
Y denotes CH and
Z denotes CH,
or a physiologically acceptable salt thereof.
11. A compound of the formula I according to claim 1 , selected from the group consisting of:
No.
Structure
(1)
(1a)
(1b)
(3)
(5)
(7)
(9)
(11)
(13)
(14)
(15)
(16)
(17)
(18)
(19)
(20)
(21)
(22)
(23)
or a physiologically acceptable salt thereof.
12. A pharmaceutical composition comprising a compound according to claim 1 , or a salt thereof, and a carrier or diluent.
13. A method for treating migraine or cluster headache which comprises administering to a host suffering from the same a therapeutically effective amount of a compound according to claim 1 , or a physiologically acceptable salt thereof.