Substituted sulfonamide compounds
Substituted sulfonamide compounds with bradykinin receptor (B1R) modulating activity; processes for the preparation thereof, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat or inhibit pain and/or other disorders and/or disease states.
1. A substituted sulfonamide derivative of the general formula I
wherein
m represents 1, 2 or 3
n represents 1 or 2
p represents 1,
R 1 represents thienyl, phenyl, benzyl, phenethyl, pyridyl, or pyridyl linked via a —CH 2 —or —CH 2 —CH 2 —chain, in each case unsubstituted or mono- or poly-substituted,
R 2 represents OH, OC 1-6 -alkyl or F,
R 3 represents aryl or heteroaryl, in each case unsubstituted or mono- or poly-substituted;
R 4 and R 4a independently of one another represent H, C 1-6 -alkyl, in each case saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; F; Cl; aryl, in each case unsubstituted or mono- or poly-substituted; or aryl linked via a C 1-3 -alkyl chain and in each case unsubstituted or mono- or poly-substituted;
Z represents O;
R 5 and R 5a independently of one another represent H; or C 1-6 -alkyl, in each case saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; OH, OC 1-6 -alkyl, F, Cl, phenoxy or benzyloxy;
R 6 represents H; C 1-6 -alkyl, in each case saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; C 3-8 -cycloalkyl, saturated or unsaturated, unsubstituted or mono- or poly-substituted; aryl or heteroaryl, unsubstituted or mono- or poly-substituted; aryl or C 3-8 -cycloalkyl linked via a C 1-3 -alkyl chain;
Q denotes —CH 2 —, —CH 2 —CH 2 —, or
wherein represents a single bond or a double bond;
in the form of a pure stereoisomer or a mixture of stereoisomers in any mixing ratio; or
a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein said compound is in the form of a pure enantiomer or diastereomer.
3. A compound according to claim 1 , wherein said compound is in the form of a racemic mixture.
4. A compound according to claim 1 , wherein
m represents 1, 2 or 3
n represents 1 or 2
p represents 1,
R 1 represents thienyl, phenyl, benzyl, phenethyl, pyridyl, or pyridyl linked via a —CH 2 —or —CH 2 —CH 2 - chain, in each case unsubstituted or mono- or poly-substituted,
R 2 represents OH, OC 1-6 -alkyl or F,
R 3 represents aryl or heteroaryl, in each case unsubstituted or mono- or poly-substituted;
R 4 and R 4a independently of one another represent H, C 1-6 -alkyl, in each case saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; F; Cl; aryl, in each case unsubstituted or mono- or poly-substituted; or aryl linked via a C 1-3 -alkyl chain and in each case unsubstituted or mono- or poly-substituted;
Z represents O;
R 5 and R 5a independently of one another represent H; or C 1-6 -alkyl, in each case saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; OH, OC 1-6 -alkyl, F, Cl, phenoxy or benzyloxy;
R 6 represents H; C 1-6 -alkyl, in each case saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; C 3-8 -cycloalkyl, saturated or unsaturated, unsubstituted or mono- or poly-substituted; aryl or heteroaryl, unsubstituted or mono- or poly-substituted; aryl or C 3-8 -cycloalkyl linked via a C 1-3 -alkyl chain; or Cl 1-6 -alkyl;
Q denotes —CH 2 —, —CH 2 —CH 2 —, or
wherein represents a single bond or a double bond;
wherein
“alkyl substituted” and “cycloalkyl substituted” denotes replacement of one or more hydrogen radicals by F, Cl, Br, I, —CN, NH 2 , NH—C 1-6 -alkyl, NH—C 1-6 -alkyl-OH, C 1-6 -alkyl, N(C 1-6 -alkyl) 2 , N(C 1-6 -alkyl-OH) 2 , NO 2 , SH, S—C 1-6 -alkyl, S-benzyl, O—C 1-6 -alkyl, OH, O—C 1-6 -alkyl-OH, ═O, O-benzyl, C(═O)C 1-6 -alkyl, CO 2 H, CO 2 —C 1-6 -alkyl, phenyl or benzyl;
“aryl substituted” and “heteroaryl substituted” denotes replacement one or more times, e.g. two, three or four times, of one or more hydrogen atoms of the ring system by F, Cl, Br, I, CN, NH 2 , NH—C 1-6 -alkyl, NH—C 1-6 -alkyl-OH, N(C 1-6 -alkyl) 2 , N(C 1-6 -alkyl-OH) 2 , NO 2 , SH, S—C 1-6 -alkyl, OH, O—C 1-6 -alkyl, O—C 1-6 alkyl-OH, C(═O)C 1-6 -alkyl, CO 2 H, CH 2 SO 2 -phenyl, CO 2 —C 1-6 -alkyl, OCF 3 , CF 3 ,
C 1-6 -alkyl, phenyl, pyridyl, thienyl or furyl.
5. A compound according to claim 1 , wherein R 3 denotes phenyl, naphthyl, thienyl or benzothiophene, in each case unsubstituted or mono- or poly-substituted.
6. A compound according to claim 1 , wherein
R 6 denotes H, methyl, ethyl, n-propyl, isobutyl, cyclopropyl, cyclopropyl linked via a C 1-3 -alkyl chain, or benzyl.
7. A compound according to claim 1 , wherein R 4 and R 4a each represent H.
8. A compound according to claim 1 , wherein R 5 and R 5a each represent H.
9. A compound according to claim 1 , wherein
m represents 1,
n represents 1 or 2
R 4 , R 4a , R 5 and R 5a each represent H, and
Z represents O;
or
m represents 2,
Z represents O,
n represents 1, and
R 4 and R 4a , R 5 and R 5a each represent H.
10. A compound according to claim 1 , wherein R 2 denotes OH.
11. A compound according to claim 1 , wherein R 3 denotes 2,6-dimethyl-4-methoxyphenyl.
12. A compound according to claim 1 , selected from the group consisting of:
1 N-{2-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-2-oxo-ethoxy]-ethyl}-N-ethyl-4-methoxy-2,3,6-trimethyl-phenylsulfonamide
2 2,4,6-trichloro-N-{2-[2-(4′-hydroxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-2-oxo-ethoxy]-ethyl}-N-methyl-phenylsulfonamide
3 N-(2-(2-(4-hydroxy-4-(pyridin-3-yl)piperidin-1-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylphenylsulfonamide hydrochloride
4 N-{2-[2-(4′-hydroxy-3′,4′,5′,6-tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl)-2-oxo-ethoxy]-ethyl}-4-methoxy-2,6,N-trimethyl-phenylsulfonamide
5 2,4,6-trichloro-N-(2-(2-(4-hydroxy-4-(pyridin-3-yl)piperidin-1-yl)-2-oxoethoxy)ethyl)-N-methylphenylsulfonamide hydrochloride
6 2,4,6-trichloro-N-{2-[2-(4′-hydroxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl)-2-oxo-ethoxy]-ethyl}-N-methyl-phenylsulfonamide
7 1-(4-benzyl-4-hydroxy-piperidin-1-yl)-2-[1-(4-methoxy-2,3,6-trimethyl-phenylsulfonyl)-pyrrolidin-3-yloxy]-ethanone
8 1-(4-benzyl-4-hydroxy-piperidin-1-yl)-2-[1-(4-methoxy-2,3,6-trimethyl-phenylsulfonyl)-piperidin-4-yloxy]-ethanone
9 N-{2-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-2-oxo-ethoxy]-ethyl}-2,4,6-trichloro-N-methyl-phenylsulfonamide
10 2,6-dichloro-N-{2-[2-(4′-hydroxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl)-2-oxo-ethoxy]-ethyl}-N-methyl-phenylsulfonamide
11 1-(4-benzyl-4-hydroxy-piperidin-1-yl)-2-[1-(4-methoxy-2,3,6-trimethyl-phenylsulfonyl)-piperidin-3-yloxy]-ethanone
12 2-[1-(3,4-dichloro-phenylsulfonyl)-piperidin-2-ylmethoxy]-1-(4′-hydroxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-ethanone
13 N-benzyl-N-{2-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-2-oxo-ethoxy]-ethyl}-4-methoxy-2,3,6-trimethyl-phenylsulfonamide
16 N-{2-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-2-oxo-ethoxy]-ethyl}-3,4-dimethoxy-N-methyl-phenylsulfonamide
20 N-{2-[2-(4′-hydroxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl)-2-oxo-ethoxy]-ethyl}-N-methyl-4-trifluoromethoxy-phenylsulfonamide
28 N-{2-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-2-oxo-ethoxy]-ethyl}-4-methoxy-N-methyl-phenylsulfonamide
38 N-{2-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-2-oxo-ethoxy]-ethyl}-N-methyl-3-trifluoromethyl-phenylsulfonamide
39 N-{2-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-2-oxo-ethoxy]-ethyl}-N-methyl-phenylsulfonamide
41 N-{2-[2-(4′-hydroxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl)-2-oxo-ethoxy]-ethyl}-3,4-dimethoxy-N-methyl-phenylsulfonamide
42 N-{2-[2-(4′-hydroxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl)-2-oxo-ethoxy]-ethyl}-4-methoxy-N-methyl-phenylsulfonamide
43 N-{2-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-2-oxo-ethoxy]-cyclohexyl}-3,4-dichloro-N-methyl-phenylsulfonamide
61 N-(2-(2-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2-oxoethoxy)ethyl)-5-fluoro-N,2-dimethylphenylsulfonamide
62 N-{2-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-2-oxo-ethoxy]-ethyl}-5-fluoro-2,N-dimethyl-phenylsulfonamide
69 N-benzyl-N-{2-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-2-oxo-ethoxymethyl]-thiophen-3-yl}-3,4-dichloro-phenylsulfonamide
70 3,5-difluoro-N-{2-[2-(4′-hydroxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl)-2-oxo-ethoxy]-ethyl}-N-methyl-phenylsulfonamide
71 2,5-difluoro-N-{2-[2-(4′-hydroxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl)-2-oxo-ethoxy]-ethyl}-N-methyl-phenylsulfonamide
86 N-{2-[2-(4-hydroxy-4-thiophen-2-yl-piperidin-1-yl)-2-oxo-ethoxy]-ethyl}-4-methoxy-2,6,N-trimethyl-phenylsulfonamide
88 N-{2-[2-(4-hydroxy-3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1-yl)-2-oxo-ethoxy]-ethyl}-4-methoxy-2,6,N-trimethyl-phenylsulfonamide
93 N-(2-(2-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2-oxoethoxy)ethyl)-3,5-difluoro-N-methylphenylsulfonamide
97 5-fluoro-N-{2-[2-(4′-hydroxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl)-2-oxo-ethoxy]-ethyl}-2,N-dimethyl-phenylsulfonamide
102 5-chloro-thiophene-2-sulfonic acid {2-[2-(4′-hydroxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-2-oxo-ethoxy]-ethyl}-methyl-amide
103 5-chloro-thiophene-2-sulfonic acid {2-[2-(4′-hydroxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl)-2-oxo-ethoxy]-ethyl}-methyl-amide
104 2,4-dichloro-N-(2-(2-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2-oxoethoxy)ethyl)-N,6-dimethylphenylsulfonamide
105 2,4-dichloro-N-(2-(2-(4-hydroxy-4-phenylpiperidin-1-yl)-2-oxoethoxy)ethyl)-N,6-dimethylphenylsulfonamide
106 N-{2-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-2-oxo-ethoxy]-ethyl}-2,4-dichloro-6,N-dimethyl-phenylsulfonamide
130 N-benzyl-N-(2-(2-(4-hydroxy-4-(pyridin-3-yl)piperidin-1-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylphenylsulfonamide
132 N-(2-(2-(4-hydroxy-4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylphenylsulfonamide
133 N-(2-(3-(4-hydroxy-4-(pyridin-3-yl)piperidin-1-yl)-3-oxopropoxy)ethyl)-4-methoxy-N,2,6-trimethylphenylsulfonamide
136 N-(2-(2-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylphenylsulfonamide
137 N-(2-(2-(4-hydroxy-4-phenylpiperidin-1-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylphenylsulfonamide
139 N-cyclopropyl-N-(2-(2-(4-hydroxy-4-(pyridin-3-yl)piperidin-1-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylphenylsulfonamide
140 N-(2-(2-(4-hydroxy-4-(2-(pyridin-3-yl)ethyl)piperidin-1-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylphenylsulfonamide
141 N-(2-(2-(4-(3-fluorophenyl)-4-hydroxypiperidin-1-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylphenylsulfonamide
143 N-(2-(2-(4-hydroxy-4-(pyridin-3-yl)piperidin-1-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylphenylsulfonamide
148 N-(2-(2-(4-hydroxy-4-(pyridin-3-yl)piperidin-1-yl)-2-oxoethoxy)ethyl)-N,2-dimethylnaphthalene-1-sulfonamide
149 4-chloro-N-(2-(2-(4-hydroxy-4-(pyridin-3-yl)piperidin-1-yl)-2-oxoethoxy)ethyl)-N,2,5-trimethylphenylsulfonamide
150 4-chloro-N-(2-(2-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2-oxoethoxy)ethyl)-N,2,5-trimethylphenylsulfonamide
151 N-(2-(2-(4-(4-bromophenyl)-4-hydroxypiperidin-1-yl)-2-oxoethoxy)ethyl)-4-chloro-N,2,5-trimethylphenylsulfonamide
152 4-chloro-N-(2-(2-(4-hydroxy-4-phenylpiperidin-1-yl)-2-oxoethoxy)ethyl)-N,2,5-trimethylphenylsulfonamide
153 N-(2-(2-(4-benzyl-4-hydroxypiperidin-1-yl)-2-oxoethoxy)ethyl)-4-chloro-N,2,5-trimethylphenylsulfonamide
154 4-chloro-N-(2-(2-(4-hydroxy-4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-2-oxoethoxy)ethyl)-N,2,5-trimethylphenylsulfonamide
191 N-benzyl-N-(2-(2-(4-benzyl-4-hydroxypiperidin-1-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylphenylsulfonamide
198 2,4-dichloro-N-(2-(2-(4-hydroxy-4-(pyridin-2-yl)piperidin-1-yl)-2-oxoethoxy)ethyl)-N,6-dimethylphenylsulfonamide
199 2,4-dichloro-N-(2-(2-(4-hydroxy-4-(pyridin-3-yl)piperidin-1-yl)-2-oxoethoxy)ethyl)-N,5-dimethylphenylsulfonamide
205 N-(2-(2-(4-(4-bromophenyl)-4-hydroxypiperidin-1-yl)-2-oxoethoxy)ethyl)-N-(cyclopropylmethyl)-4-methoxy-2,3,6-trimethylphenylsulfonamide
206 N-(cyclopropylmethyl)-N-(2-(2-(4-hydroxy-4-phenylpiperidin-1-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylphenylsulfonamide
207 N-(2-(2-(4-benzyl-4-hydroxypiperidin-1-yl)-2-oxoethoxy)ethyl)-N-(cyclopropylmethyl)-4-methoxy-2,3,6-trimethylphenylsulfonamide
208 N-(cyclopropylmethyl)-N-(2-(2-(4-hydroxy-4-(3-(trifluoromethyl)phenyl)-piperidin-1-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylphenyl-sulfonamide
209 N-(2-(2-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylphenylsulfonamide
210 N-(2-(2-(4-(4-bromophenyl)-4-hydroxypiperidin-1-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylphenylsulfonamide
211 N-(2-(2-(4-benzyl-4-hydroxypiperidin-1-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylphenylsulfonamide
212 N-(2-(2-(4-hydroxy-4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylphenylsulfonamide
237 N-(2-(2-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydroxypiperidin-1-yl)-2-oxoethoxy)ethyl)-N-(cyclopropylmethyl)-4-methoxy-2,3,6-trimethylphenyl-sulfonamide
238 N-(2-(2-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydroxypiperidin-1-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylphenylsulfonamide
240 N-(cyclopropylmethyl)-N-(2-(2-(4-hydroxy-4-(pyridin-3-yl)piperidin-1-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylphenylsulfonamide
241 N-(2-(2-(4-hydroxy-4-(pyridin-3-yl)piperidin-1-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylphenylsulfonamide
256 N-(2-(2-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2-oxoethoxy)ethyl)-N,2,5-trimethylthiophene-3-sulfonamide
257 N-(2-(2-(4-(4-bromophenyl)-4-hydroxypiperidin-1-yl)-2-oxoethoxy)ethyl)-N,2,5-trimethylthiophene-3-sulfonamide
258 N-(2-(2-(4-hydroxy-4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-2-oxoethoxy)ethyl)-N,2,5-trimethylthiophene-3-sulfonamide
259 N-(2-(2-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydroxypiperidin-1-yl)-2-oxoethoxy)ethyl)-N,2,5-trimethylthiophene-3-sulfonamide
260 2,5-dichloro-N-(2-(2-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2-oxoethoxy)ethyl)-N-methylthiophene-3-sulfonamide
261 N-(2-(2-(4-(4-bromophenyl)-4-hydroxypiperidin-1-yl)-2-oxoethoxy)ethyl)-2,5-dichloro-N-methylthiophene-3-sulfonamide
262 2,5-dichloro-N-(2-(2-(4-hydroxy-4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-2-oxoethoxy)ethyl)-N-methylthiophene-3-sulfonamide
263 2,5-dichloro-N-(2-(2-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydroxypiperidin-1-yl)-2-oxoethoxy)ethyl)-N-methylthiophene-3-sulfonamide
268 N-(cyclopropylmethyl)-N-(2-(2-(4-hydroxy-4-(thiophen-2-yl)piperidin-1-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylphenylsulfonamide
269 N-(2-(2-(4-hydroxy-4-(thiophen-2-yl)piperidin-1-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylphenylsulfonamide
275 N-(2-(3-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-3-oxopropoxy)ethyl)-4-methoxy-N,2,6-trimethylphenylsulfonamide
276 N-(2-(3-(4-hydroxy-4-phenylpiperidin-1-yl)-3-oxopropoxy)ethyl)-4-methoxy-N,2,6-trimethylphenylsulfonamide
277 N-(2-(3-(4-benzyl-4-hydroxypiperidin-1-yl)-3-oxopropoxy)ethyl)-4-methoxy-N,2,6-trimethylphenylsulfonamide
278 N-(2-(3-(4-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydroxypiperidin-1-yl)-3-oxopropoxy)ethyl)-4-methoxy-N,2,6-trimethylphenylsulfonamide.
13. A process for preparing a substituted sulfonamide compound according to claim 1 , said process comprising:
reacting a carboxylic acid corresponding to formula G with a primary or secondary amine corresponding to formula S:
in the presence of a dehydrating agent, or in the presence of a coupling reagent, and an organic base in organic solvent.
14. A method according to claim 13 , wherein the dehydrating agent is selected from the group consisting of sodium sulfate, magnesium sulfate and phosphorus oxide; the coupling agent is CDI or polymer-bonded DCC, TBTU, EDCI, PyBOP or PFPTFA; HOAt or HOBt is added; the organic base is selected from the group consisting of DIPEA and pyridine, and the organic solvent is selected from the group consisting of THF, methylene chloride, diethyl ether, dioxane, DMF and acetonitrile.
15. A pharmaceutical composition comprising a compound according to claim 1 and at least one pharmaceutically acceptable carrier, additive or auxiliary substance.