Pyrroloazepine derivatives
AssigneeSuntory Limited
InventorsAkira Mizuno, Makoto Shibata, Tomoe Iwamori, Tetsuo Shimamoto, Kyoko Nakanishi, Norio Inomata
Life of this patent
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Abstract
A method of effecting serotonin-2-receptor antagonism in a mammal in need thereof, which includes administering to the mammal an effective amount of the compound of the formula (I), or a pharmaceutically acceptable salt thereof: 1 wherein ring P, the dashed line, A, Y, Z1 and Z2 are defined herein.
Claims39
A pyrroloazepine derivative or a salt thereof, said pyrroloazepine derivative being represented by the following formula (I):
- 148
- wherein
- the ring p represented by
- 149
- means a pyrrole ring represented by the following structure:
- 150
- in which R1 represents an alkyl group, a cycloalkyl group, a cycloalkyl-alkyl group, a substituted or unsubstituted aralkyl group or a substituted or unsubstituted aryl group, and R2 represents a hydrogen atom or an alkyl group;
- the dashed line indicates the presence or absence of a bond;
- and, when the bond indicated by the dashed line is present, Z2 is not present and Z1 represents a hydrogen atom but, when the bond indicated by the dashed line is absent, Z1 and Z2 both represent hydrogen atoms;
- Z1 represents a hydrogen atom and Z2 represents a group OR3 in which R3 represents a hydrogen atom, a substituted or unsubstituted alkyl group or a substituted or unsubstituted aralkyl group;
- Z1 and Z2 both represent groups SR4 in which R4 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group or a substituted or unsubstituted aryl group;
- or Z1 and Z2 are combined together to represent an oxygen atom, a group NOR5 in which R5 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group or a substituted or unsubstituted aryl group, or a group
- 151
- in which
- L represents a substituted or unsubstituted ethylene group or a substituted or unsubstituted trimethylene group;
- A represents an alkylene group, an alkenylene group or an alkynylene group;
- and
- Y represents a group
- 152
- in which W represents CH, C═ or a nitrogen atom;
- and, when W represents CH, m stands for 0 or 1, n stands for 1 or 2, G represents an oxygen atom, a sulfur atom, a carbonyl group, a sulfinyl group, a sulfonyl group, an alkylene group, an alkenylene group, a group
- 153
- in which R6 represents a substituted or unsubstituted aryl group, a group
- 154
- in which R7 represents a hydroxyl group, an alkoxy group or an aralkyloxy group, or a substituted or unsubstituted cyclic or acyclic acetal group;
- when W represents C═, m stands for 1, n stands for 1 or 2, G represents a group
- 155
- in which the double bond is coupled with W and R8 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group;
- when W represents a nitrogen atom, m stands for 0 or 1, n stands for 2 or 3, and G represents a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group or a group —CHR9— in which R9 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group;
- E1 and E2 each independently represents a hydrogen atom or a lower alkyl group;
- and D represents a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted aromatic heterocyclic group.
A compound selected from 8-hydroxy-1-methyl-5-[3-(4-phenylpiperazin-1-yl)propyl]-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepin-4-one, 5-[3-[4-(3-fluorophenyl)piperazin-1-yl]propyl]-8-hydroxy-1-methyl-1,4,5, 6,7,8-hexahydropyrrolo[3,2-c]azepin-4-one, 8-hydroxy-5-[3-[4-(4-hydroxyphenyl)piperazin-1-yl]propyl]-1-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepin-4-one, 5-[3-[4-(4-chlorophenyl)piperazin-1-yl]propyl]-8-hydroxy-1-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepin-4-one, 5-[3-[4-(4-chlorophenyl)piperazin-1-yl]propyl]-8-methoxy-1-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepin-4-one, 5-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-1-methyl-1,4,5,6-tetrahydropyrrolo[3,2-c]azepin-4-one, 5-[3-[4-(4-chlorophenyl)piperazin-1-yl]propyl]-1-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepin-4-one, 5-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-1-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepin-4-one, or 5-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-8-hydroxy-1-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepin-4-one;
- or an optically active isomer thereof.
A process for the preparation of a pyrroloazepine derivative represented by the following formula (Ia):
- 157
- wherein A, the ring P and Y have the same meanings as defined above, which comprises:
- reacting a compound, which is represented by the following formula (III):
- X-A-X1 (III)
- wherein A has the same meaning as defined above and X and X1 represent the same or different eliminative groups, to a compound represented by the following formula (II):
- 158
- wherein the ring P has the same meaning as defined above, thereby obtaining a compound represented by the following formula (IV):
- 159
- wherein A, the ring P and X have the same meanings as defined above;
- and then
- reacting a nitrogen-containing compound represented by the following formula (V):
- H—Y (V)
- wherein Y has the same meaning as defined above.
A process for the preparation of a pyrroloazepine derivative represented by the following formula (Ia):
- 160
- wherein A, the ring P and Y have the same meanings as defined above, which comprises:
- reacting a compound, which is represented by the following formula (VI):
- X-A-Y (VI)
- wherein A, X and Y have the same meanings as defined above, to a compound represented by the following formula (II):
- 161
- wherein the ring P has the same meaning as defined above.
A process for the preparation of a pyrroloazepine derivative represented by the following formula (Ib):
- 162
- wherein A, the ring P and Y have the same meanings as defined above, and Z1′ and Z2′ both represents groups —SR4 in which R4 has the same meaning as defined above or are combined together to represent a group —S-L-S— in which L has the same meaning as defined above, which comprises:
- reacting a compound, which is represented by the following formula (VIIa) or (VIIb):
- 23 R4-SH HS-L-SH (VIIa) (VIIb)
- wherein L and R4 have the same meanings as defined above, to a compound represented by the following formula (II):
- 163
- wherein the ring P has the same meaning as defined above, thereby obtaining a compound represented by the following formula (VIII):
- 164
- wherein Z1′ and Z2′ have the same meanings as defined above;
- and then
- reacting a nitrogen-containing compound represented by the following formula (VI):
- X-A-Y (VI)
- wherein A, X and Y have the same meanings as defined above.
A process for the preparation of a pyrroloazepine derivative represented by the following formula (Id):
- 165
- wherein A, the ring P, Z1′ and Z2′ have the same meanings as defined above, and Y′ represents a group
- 166
- in which, when W represents CH, G′ represents an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, an alkylene group, an alkenylene group, a group
- 167
- in which R6 represents a substituted or unsubstituted aryl group, a group
- 168
- in which R7 represents a hydroxyl group, an alkoxy group or an aralkyloxy group, or a substituted or unsubstituted cyclic or acyclic acetal group;
- when W represents C═, G′ represents a group
- 169
- in which the double bond is coupled with W and R8—represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group;
- when W represents a nitrogen atom, G′ represents a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group or a group —CHR9— in which R9 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group;
- and D, E1, E2, m and n have the same meanings as defined above, which comprises:
- reacting a pyrroloazepine derivative, which is represented by the following formula (Ic):
- 170
- wherein A, the ring P and Y′ have the same meanings as defined above, with a compound represented by the following formula (VIIa) or (VIIb):
- 24 R4-SH HS-L-SH (VIIa) (VIIb)
- wherein L an R4 have the same meanings as defined above.
A process for-the preparation of a pyrroloazepine derivative represented by the following formula (Ie):
- 171
- wherein A, the ring P, R5 and Y have the same meanings as defined above, which comprises:
- reacting a hydroxylamine or a derivative thereof, which is represented by the following formula (IX):
- NH2OR5 (IX)
- wherein R5 have the same meaning as defined above, to a compound represented by the following formula (IV):
- 172
- wherein A, the ring P and X have the same meanings as defined above, thereby obtaining a compound represented by the following formula (X):
- 173
- wherein A, the ring P, R5 and X have the same meanings as defined above;
- and then
- reacting a nitrogen-containing compound represented by the following formula (V):
- H—Y (V)
- wherein Y has the same meaning as defined above.
A process for the preparation of a pyrroloazepine derivative represented by the following formula (If):
- 174
- wherein A, the ring P, R5 and Y′ have the same meanings as defined above, which comprises:
- reacting a hydroxylamine or a derivative thereof, which is represented by the following formula (IX):
- NH2OR5 (IX)
- wherein R5 has the same meaning as defined above, to a compound represented by the following formula (Ic):
- 175
- wherein A, the ring P and Y′ have the same meanings as defined above.
A process for the preparation of a pyrroloazepine derivative represented by the following formula (Ig):
- 176
- wherein A, the ring P and Y have the same meanings as defined above, which comprises:
- reducing a compound represented by the following formula (IV):
- 177
- wherein A, the ring P and X have the same meanings as defined above, thereby obtaining a compound represented by the following formula (XI):
- 178
- wherein A, the ring P and X have the same meanings as defined above;
- and then
- reacting a nitrogen-containing compound represented by the following formula (V):
- H—Y (V)
- wherein Y has the same meaning as defined above.
A process for the preparation of a pyrroloazepine derivative represented by the following formula (Ih):
- 179
- wherein A, the ring P and Y′ have the same meanings as defined above, which comprises:
- reducing a pyrroloazepine derivative represented by the following formula (Ic):
- 180
- wherein A, the ring P and Y′ have the same meanings as defined above.
A process for the preparation of a pyrroloazepine derivative represented by the following formula (Ii):
- 185
- wherein A, the ring P and Y have the same meanings as defined above, and R13 represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted aralkyl group, which comprises:
- reacting a compound, which is represented by the formula (XV):
- R13—X2 (XV)
- wherein R13 has the same meaning as defined above and X2 represents an eliminative group, to a compound represented by the following formula (XI):
- 186
- wherein A, the ring P and X have the same meanings as defined above, thereby obtaining a compound represented by the following formula (XVI):
- 187
- wherein A, the ring P, R13 and X have the same meanings as defined above;
- and then
- reacting a nitrogen-containing compound represented by the following formula (V):
- H—Y (V)
- wherein Y has the same meaning as defined above.
A process for the preparation of a pyrroloazepine derivative represented by the following formula (Ii):
- 188
- wherein A, the ring P, R13 and Y have the same meanings as defined above, which comprises:
- reacting a compound, which is represented by the following formula (XV):
- R13—X2 (XV)
- wherein R13 and X2 have the same meanings as defined above, to a compound represented by the following formula (Ig):
- 189
- wherein A, the ring P and Y have the same meanings as defined above.
A process for the preparation of a pyrroloazepine derivative represented by the following formula (Ij):
- 190
- wherein A, the ring P and Y have the same meanings as defined above, which comprises:
- subjecting a compound, which is represented by the following formula (XI):
- 191
- wherein A, the ring P and X have the same meanings as defined above, to dehydration treatment, thereby obtaining a compound represented by the following formula (XVII):
- 192
- wherein A, the ring P and X have the same meanings as defined above;
- and then
- reacting a nitrogen-containing compound represented by the following formula (V):
- H—Y (V)
- wherein Y has the same meaning as defined above.
A process for the preparation of a pyrroloazepine derivative represented by the following formula (Ij):
- 193
- wherein A, the ring P and Y have the same meanings as defined above, which comprises:
- subjecting a compound, which is represented by the following formula (Ig):
- 194
- wherein A, the ring P and Y have the same meanings as defined above, to dehydration treatment.
A process for the preparation of a pyrroloazepine derivative represented by the following formula (Ik):
- 195
- wherein A, the ring P and Y have the same meanings as defined above, which comprises:
- reducing a compound represented by the following formula (XVII):
- 196
- wherein A, the ring P and X have the same meanings as defined above, thereby obtaining a compound represented by the following formula (XVIII):
- 197
- wherein A, the ring P and X have the same meanings as defined above;
- and then
- reacting a nitrogen-containing compound represented by the following formula (V):
- H—Y (V)
- wherein Y has the same meaning as defined above.
A process for the preparation of a pyrroloazepine derivative represented by the following formula (Ik):
- 198
- wherein A, the ring P and Y have the same meanings as defined above, which comprises:
- reducing a compound represented by the following formula (Ij):
- 199
- wherein A, the ring P and Y have the same meanings as defined above.
An intermediate for the production of a pharmaceutical product, which is represented by the following formula (XIXa) or (XIXb):
- 200
- wherein R1′ represents a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkyl-alkyl group, a substituted or unsubstituted aralkyl group or a substituted or unsubstituted aryl group, and R2 has the same meaning as defined above.
An intermediate for the production of a pharmaceutical product, which is represented by the following formula (XX):
- 201
- wherein the dashed line, A, the ring P, X, Z1 and Z2 have the same meanings as defined above.
A process for the preparation of a pyrroloazepine derivative represented by the following formula (XIXa) or (XIXb):
- 202
- wherein R1′ and R2 have the same meanings as defined above, which comprises:
- reacting a β-alanine or a derivative thereof, which is represented by the following formula (XXII):
- NH2CH2CH2COOR14 (XXII)
- wherein R14 represents a hydrogen atom or a carboxyl-protecting group, to a pyrrole-3-carboxylic acid or a derivative thereof represented by the following formula (XXI):
- 203
- wherein Q represents a hydroxyl group, an alkoxy group or an eliminative group easily replaceable by an amino group, R1′ and R2 have the same meanings as defined above, thereby obtaining a compound represented by the following formula (XXIII):
- 204
- wherein R1′, R2 and R14 have the same meanings as defined above;
- and then
- subjecting said compound to ring closure.
A process for the preparation of a pyrroloazepine derivative represented by the following formula (IVa′) or (IVb′):
- 205
- wherein A, R1′ and R2 have the same meanings as defined above, and X3 represents a chlorine atom or a bromine atom, which comprises:
- reacting an N-substituted β-alanine or a derivative thereof, which is represented by the following formula (XXIV):
- X3-A-NHCH2CH2COOR14 (XXIV)
- wherein X3, A and R14 have the same meanings as defined above, to a pyrrole-3-carboxylic acid or a derivative thereof represented by the following formula (XXI):
- 206
- wherein R1′, R2 and Q have the same meanings as defined above, thereby obtaining a compound represented by the following formula (XXV):
- 207
- wherein A, R1′, R2, R14 and X3 have the same meanings as defined above;
- and then
- subjecting said compound to ring closure.
An intermediate for the production of a pharmaceutical product,-which is represented by the following formula (XXIII):
- 208
- wherein R1′, R2 and R14 have the same meanings as defined above.
An intermediate for the production of a pharmaceutical product, which is represented by the following formula (XXV):
- 211
- wherein A, R1′, R2, R14 and X3 have the same meanings as defined above.
Dependencies are inferred from the claim text.