Arylsulfonylmethyl or arylsulfonamide substituted aromatic compounds suitable for treating disorders that respond to modulation of the dopamine D3 receptor
View Patent ↗The present invention relates to aromatic compounds of the formula I wherein Ar is phenyl or an aromatic 5- or 6-membered C-bound heteroaromatic radical, wherein Ar may carry 1 radical R a and wherein Ar may also carry 1 or 2 radicals R b ; X is N or CH; Y is O, S, —CH═N—, —CH═CH— or —N═CH—; A is CH 2 , O or S; E is CR 6 R 7 or NR 3 ; R 1 is C 1 -C 4 -alkyl, C 3 -C 4 -cycloalkyl, C 3 -C 4 -cycloalkylmethyl, C 3 -C 4 -alkenyl, fluorinated C 1 -C 4 -alkyl, fluorinated C 3 -C 4 -cycloalkyl, fluorinated C 3 -C 4 -cycloalkylmethyl, fluorinated C 3 -C 4 -alkenyl, formyl or C 1 -C 3 -alkylcarbonyl; R 1a is H, C 2 -C 4 -alkyl, C 3 -C 4 -cycloalkyl, C 3 -C 4 -alkenyl, fluorinated C 1 -C 4 -alkyl, fluorinated C 3 -C 4 -cycloalkyl, or R 1a and R 2 together are (CH 2 ) n with n being 2 or 3, or R 1a and R 2a together are (CH 2 ) n with n being 2 or 3; R 2 and R 2a are independently of each other H, CH 3 , CH 2 F, CHF 2 or CF 3 ; R 3 is H or C 1 -C 4 -alkyl; R 6 , R 7 independently of each other are selected from H, C 1 -C 2 -alkyl and fluorinated C 1 -C 2 -alkyl; and the physiologically tolerated acid addition salts thereof. The invention also relates to the use of a compound of the formula I or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for the treatment of a medical disorder susceptible to treatment with a dopamine D3 receptor ligand.
1. An aromatic compound of the formula I
wherein
Ar is phenyl or an aromatic 5- or 6-membered C-bound heteroaromatic radical, wherein Ar is substituted with 1 radical R a , wherein
R a is selected from the group consisting of C 2 -C 6 alkyl, fluorinated C 2 -C 6 alkyl, fluorinated C 3 -C 6 cycloalkyl, fluoromethyl, difluoromethyl, fluoromethoxy, difluoromethoxy, C 1 -C 6 hydroxyalkyl and a 3- to 7-membered heterocyclic radical, wherein the 3- to 7-membered heterocyclic radical is optionally substituted with 1, 2, 3 or 4 radicals selected from the group consisting of halogen, cyano, OH, oxo, CN, and C 1 -C 6 alkyl;
X is CH;
Y is —CH═CH—;
A is CH 2 ;
E is NR 3 ;
R 1 is selected from the group consisting of C 1 -C 4 -alkyl, C 3 -C 4 -cycloalkyl, C 3 -C 4 -cycloalkylmethyl, C 3 -C 4 -alkenyl, fluorinated C 1 -C 4 -alkyl, fluorinated C 3 -C 4 -cycloalkyl, fluorinated C 3 -C 4 -cycloalkylmethyl, fluorinated C 3 -C 4 -alkenyl, formyl and C 1 -C 3 alkylcarbonyl;
R 1a is selected from the group consisting of H, C 2 -C 4 -alkyl, C 3 -C 4 -cycloalkyl, C 3 -C 4 -alkenyl, fluorinated C 1 -C 4 -alkyl, and fluorinated C 3 -C 4 -cycloalkyl, or R 1a and R 2 together are (CH 2 ) n wherein n is 2 or 3, or R 1a and R 2a together are (CH 2 ) n with n being 2 or 3;
R 2 and R 2a are each independently selected from the group consisting of H, CH 3 , CH 2 F, CHF 2 and CF 3 ;
R 3 is H or C 1 -C 4 -alkyl;
or a physiologically tolerated acid addition salt thereof.
2. The compound as claimed in claim 1 , wherein
R 1 is selected from the group consisting of C 2 -C 4 -alkyl, C 3 -C 4 -alkenyl, fluorinated C 1 -C 4 -alkyl, and C 1 -C 3 -alkylcarbonyl;
R 1a is hydrogen or C 2 -C 4 -alkyl, or R 1a and R 2 together are (CH 2 ) 3 , or R 1a and R 2a together are (CH 2 ) 3 .
3. The compound as claimed in claim 1 , wherein the radical R a is selected from the group consisting of isopropyl, (R)-1-fluoroethyl, (S)-1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (R)-1-fluoropropyl, (S)-1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 1,1-difluoropropyl, 2,2-difluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, (R)-2-fluoro-1-methylethyl, (S)-2-fluoro-1-methylethyl, (R)-2,2-difluoro-1-methylethyl, (S)-2,2-difluoro-1-methylethyl, (R)-1,2-difluoro-1-methylethyl, (S)-1,2-difluoro-1-methylethyl, (R)-2,2,2-trifluoro-1-methylethyl, (S)-2,2,2-trifluoro-1-methylethyl, 2-fluoro-1-(fluoromethyl)ethyl, 1-(difluoromethyl)-2,2-difluoroethyl, 1-fluoro-1-methylethyl cyclopropyl, 1 fluorocyclopropyl, (R)-2,2-difluorocyclopropyl, (S)-2,2-difluorocyclopropyl (R)-, and (S)-2-fluorocyclopropyl.
4. The compound as claimed in claim 1 , wherein the radical R a is selected from the group consisting of 4-morpholinyl, 4-thiomorpholinyl, 4-(1,1-dioxo)thiomorpholinyl, piperazin-1-yl, 4-methylpiperazin-1-yl, azetidin-1-yl, 2-methylazetidin-1-yl, (S)-2-methylazetidin-1-yl, (R)-2-methylazetidin-1-yl, 3-fluoroazetidin-1-yl, 3-methoxyazetidin-1-yl, 3-hydroxyazetidin-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, (S)pyrrolidin-2-yl, (R)-pyrrolidin-2-yl, pyrrolidin-3-yl, (S)-pyrrolidin-3-yl, (R)-pyrrolidin-3-yl, 2-fluoropyrrolidin-1-yl, (S)-2-fluoropyrrolidin-1-yl, (R)-2-fluoropyrrolidin-1-yl, 3-fluoropyrrolidin-1-yl, (S)-3-fluoropyrrolidin-1-yl, (R)-3-fluoropyrrolidin-1-yl, 2,2-difluoropyrrolidin-1-yl, 3,3-difluoropyrrolidin-1-yl, 2-methylpyrrolidin-1-yl, (S)-2-methylpyrrolidin-1-yl, (R)-2-methylpyrrolidin-1-yl, 3-methylpyrrolidin-1-yl, (S)-3-methylpyrrolidin-1-yl, (R)-3-methylpyrrolidin-1-yl, 1-methylpyrrolidin-2-yl, (S)-1-methylpyrrolidin-2-yl, (R)-1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-3-yl, (S)-1-methylpyrrolidin-3-yl, (R)-1-methylpyrrolidin-3-yl, 2,2-dimethylpyrrolidin-1-yl, 3,3-dimethylpyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxo-oxazolidin-3-yl, piperidin-1-yl, 2-methylpiperidin-1-yl, (S)-2-methylpiperidin-1-yl, and (R)-2-methylpiperidin-1-yl.
5. The compound as claimed in claim 1 , wherein Ar is substituted by one radical R a , which is selected from the group consisting of CHF 2 , CH 2 F, OCHF 2 , and OCH 2 F.
6. The compound as claimed in claim 1 , wherein Ar is substituted by one radical R a , which is selected from 5- or 6-membered heteroaromatic radicals having as ring members 1 heteroatom selected from O, S, and N, and which optionally further contains 1, 2 or 3 nitrogen atoms as ring members, and wherein the 5- or 6-membered heteroaromatic radical is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen, OH, CN, and C 1 -C 6 -alkyl.
7. The compound as claimed in claim 6 , wherein Ar is substituted by one heteroaromatic radical R a , which is selected from the group consisting of furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, and tetrazolyl, wherein the heteroaromatic radical is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen and C 2 -C 4 -alkyl.
8. The compound as claimed in claim 1 , wherein Ar is phenyl.
9. The compound as claimed in claim 1 , wherein Ar is phenyl that is substituted by a radical R a in the 4-position of the phenyl ring.
10. The compounds as claimed in claim 1 , wherein R 1 is n-propyl, fluorinated linear C 2 -C 3 -alkyl, or 1-propen-3-yl.
11. The compound as claimed in claim 1 , wherein R 1a is hydrogen.
12. The compounds as claimed in claim 1 , wherein R 1a is n-propyl or 1-propen-3-yl.
13. The compounds as claimed in claim 1 , wherein either R 1a and R 2 or R 1a and R 2a form a moiety (CH 2 ) n with n being 2 or 3.
14. The compound as claimed in claim 1 of the formula Ia
wherein R 1 , R 1a , R 2 , R 2a , R 3 , E and Ar have the meanings given in claim 1 or a physiologically tolerated acid addition salt thereof.
15. The compound of the formula Ia and the physiologically tolerated acid addition salts thereof as claimed in claim 14 , wherein R 2 and R 2a are hydrogen, Ar is 4-difluoromethoxyphenyl, and R 1 is n-propyl, fluorinated linear C 2 -C 3 -alkyl, or 1-propen-3-yl.
16. The compound as claimed in claim 15 , wherein R 1a is hydrogen.
17. The compound as claimed in claim 15 , wherein R 1 is propyl.
18. The compound as claimed in claim 1 , wherein R 2 and R 2a are hydrogen.
19. The compound as claimed in claim 18 , wherein Ar is 4-difluoromethoxyphenyl.
20. The compound as claimed in claim 18 , wherein R 1 is n-propyl, fluorinated linear C 2 -C 3 -alkyl, or 1-propen-3-yl.
21. The compound as claimed in claim 18 , wherein R 1a is hydrogen.
22. A compound selected from the group consisting of:
(R)—N-[7-(4-Isopropylbenzenesulfonylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-propionamide;
(R)-4-Isopropyl-N-((R)-7-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)benzenesulfonamide;
4-Isopropyl-N-((R)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide;
(R)—N-[5-(4-Isopropyl-benzenesulfonylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-propionamide;
(R)-4-Isopropyl-N-(6-propylamino-5,6,7,8-tetrahydro-naphthalen-1-yl)-benzenesulfonamide;
N—((R)-6-Allylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)-4-isopropyl-benzenesulfonamide;
N—((S)-6-Allylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)-4-isopropyl-benzenesulfonamide;
4-Isopropyl-N-((S)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide;
N—((S)-6-Allylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)-4-isopropyl-N-methylbenzenesulfonamide;
4-Isopropyl-N-methyl-N-((S)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)benzenesulfonamide;
N-((4aS,10bS)-4-Allyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-8-yl)-4-isopropylbenzenesulfonamide;
N-((4aS,10bS)-4-Allyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-9-yl)-4-isopropylbenzenesulfonamide;
N-((4aS,10bS)-4-Allyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-7-yl)-4-isopropylbenzenesulfonamide;
trans-4-Isopropyl-N-(1-propionyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinolin-7-yl)benzenesulfonamide;
trans-4-Isopropyl-N-(1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinolin-7-yl)benzenesulfonamide;
N—((R)-6-Dipropylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)-4-isopropyl-benzenesulfonamide;
N—((S)-6-Dipropylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)-4-isopropyl-benzenesulfonamide;
4-Oxazol-5-yl-N-((S)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)benzenesulfonamide;
5-Oxazol-5-yl-thiophene-2-sulfonic acid ((S)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)amide;
5-Isoxazol-5-yl-thiophene-2-sulfonic acid ((S)-6-propylamino-5,6,7,8-tetrahydronaphthalen-2-yl)amide;
N—((S)-6-Propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)-4-(2,2,2-trifluoro-1-methyl-ethyl)benzenesulfonamide racemate;
N—((S)-6-Propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)-4-((R)-2,2,2-trifluoro-1-methylethyl)-benzenesulfonamide;
N—((S)-6-Propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)-4-((S)-2,2,2-trifluoro-1-methylethyl)-benzenesulfonamide;
5-Isoxazol-3-yl-thiophene-2-sulfonic acid ((S)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)amide;
4-((R)-3-Fluoro-pyrrolidin-1-yl)-N-((S)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)benzenesulfonamide;
4-Morpholin-4-yl-N-((S)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)benzenesulfonamide;
4-Difluoromethoxy-N-((S)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)benzenesulfonamide;
N—((S)-6-Propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)-4-(2,2,2-trifluoroethyl)benzenesulfonamide;
4-(2,2-Difluoro-cyclopropyl)-N-((S)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)benzenesulfonamide;
N—((S)-6-Propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)-4-pyrrolidin-1-ylbenzenesulfonamide;
4-(3-Fluoro-propyl)-N-((S)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)benzenesulfonamide;
5-Propyl-thiophene-sulfonic acid ((S)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)amide;
4-((S)-2-Fluoro-1-methyl-ethyl)-N-((S)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)benzenesulfonamide;
4-((R)-2-Fluoro-1-methyl-ethyl)-N-((S)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)benzenesulfonamide;
4-(1-Methyl-1H-pyrazol-4-yl)-N-((S)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)benzenesulfonamide;
4-(3-Fluoro-propyl)-N-((R)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)benzenesulfonamide;
4-(2-Fluoro-ethyl)-N-((R)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)benzenesulfonamide;
4-(1-Hydroxy-1-methyl-ethyl)-N-((S)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)benzenesulfonamide;
4-(1-Fluoro-1-methyl-ethyl)-N-((S)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)benzenesulfonamide;
N—((S)-6-Ethylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)-4-isopropyl-benzenesulfonamide;
N—[(S)-6-(2-Fluoro-ethylamino)-5,6,7,8-tetrahydro-naphthalen-2-yl]-4-isopropylbenzenesulfonamide;
N—[(S)-6-(3-Fluoro-propylamino)-5,6,7,8-tetrahydro-naphthalen-2-yl]-4-isopropylbenzenesulfonamide;
N—((S)-6-Ethylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)-4-(2-oxo-pyrrolidin-1-yl)benzenesulfonamide;
N—((S)-6-Ethylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)-4-pyrrolidin-1-yl benzenesulfonamide;
4-((S)-2-Fluoro-1-methyl-ethyl)-N-((R)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)benzenesulfonamide;
N—((R)-6-Propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)-4-(2,2,2-trifluoro-1-methylethyl)benzenesulfonamide;
4-Difluoromethoxy-N-((R)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)benzenesulfonamide;
N—((S)-6-Propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)-4-pyrazol-1-yl benzenesulfonamide;
4-(2,2-Difluoro-1-methyl-ethyl)-N-((S)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-y1)benzenesulfonamide;
4-Oxazol-5-yl-N-((R)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)benzenesulfonamide;
5-Oxazol-5-yl-thiophene-2-sulfonic acid ((R)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)amide; and
4-(2,2-Difluoro-1-methyl-ethyl)-N-((R)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)benzenesulfonamide;
or a physiologically tolerated acid addition salt thereof.
23. The compound 4-difluoromethoxy-N-((S)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)benzenesulfonamide or a physiologically tolerated acid addition salt thereof.
24. The compound 4-difluoromethoxy-N-((S)-6-propylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)benzenesulfonamide, hydrochloride.
25. A pharmaceutical composition comprising at least one compound of the formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1 , optionally together with at least one physiologically acceptable carrier or auxiliary substance.