Pyrrolothiazine and pyrrolothiazepine compounds having serotonin-2 receptor antagonistic and alpha-1-blocking action

1. A process for preparing a compound of formula (Ia):

wherein

the ring P is:

and is a pyrrole ring represented by the following structure:

in which R is an alkyl group, a cycloalkyl group, a cycloalkyl-alkyl group or a substituted or unsubstituted aralkyl group;

A is a substituted or unsubstituted alkylene group, a substituted or unsubstituted alkenylene group or a substituted or unsubstituted alkynylene group;

Y is a group having the following formula:

in which

E 1 and E 2 each independently is a hydrogen atom or a lower alkyl group;

W represents CH, C═ or a nitrogen atom; with the provisos that:

when W represents CH, then m is 0 or 1 and B represents a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group, a group —C(OH)R 2 — in which R 2 represents a substituted or unsubstituted aryl group, a group —CHR 3 — in which R 3 represents a substituted or unsubstituted aryl group, or a substituted or unsubstituted cyclic or acyclic acetal group;

when W represents C═, then m is 1 and B is a group:

in which the double bond is coupled with W and R 4 represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group; and

when W represents a nitrogen atom, then m is 0 or 1 and B is a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group or a group —CHR 5 — in which R 5 represents a substituted or unsubstituted aryl group; and

D represents a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted aromatic heterocyclic group; and

l is 0 or 1;

which process comprises:

reacting a compound of formula (VI) with a compound of formula (II),

wherein:

the compound of formula (VI) is:

X—A—Y  (VI),

where

X is an eliminative group;

A and Y are defined above; and

wherein the compound of formula (II) is:

wherein the ring P and l are defined above.

2. A process for preparing a compound of formula (Ic):

wherein

the ring P is:

and is a pyrrole ring represented by the following structure:

in which R is an alkyl group, a cycloalkyl group, a cycloalkyl-alkyl group or a substituted or unsubstituted aralkyl group;

R 1 is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group;

A is a substituted or unsubstituted alkylene group, a substituted or unsubstituted alkenylene group or a substituted or unsubstituted alkynylene group;

Y′ represents a group

in which

E 1 and E 2 each independently is a hydrogen atom or a lower alkyl group;

W represents CH, C═ or a nitrogen atom; with the provisos that:

when W represents CH, then m is 0 or 1 and B′ represents a sulfonyl group, an alkylene group, an alkenylene group, a group —C(OH)R 2 — in which R 2 represents a substituted or unsubstituted aryl group, a group —CHR 3 — in which R 3 represents a substituted or unsubstituted aryl group, or a substituted or unsubstituted cyclic or acyclic acetal group;

when W represents C═, then m is 1 and B′ is a group:

in which the double bond is coupled with W and R 4 represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group; and

when W represents a nitrogen atom, then m is 0 or 1 and B′ is a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group or a group —CHR 5 — in which R 5 represents a substituted or unsubstituted aryl group; and

D represents a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted aromatic heterocyclic group; and

l is 0 or 1;

which process comprises:

reacting a compound of formula (VII) with a compound of formula (Ib),

wherein the compound of formula (VII) is:

NH 2 OR 1   (VII)

wherein R 1 is defined above; and the compound of formula (Ib) is:

wherein the ring P, A, Y′ and l are defined above.

3. A process for preparing a compound of formula (Id):

wherein

the ring P is:

and is a pyrrole ring represented by the following structure:

in which R is an alkyl group, a cycloalkyl group, a cycloalkyl-alkyl group or a substituted or unsubstituted aralkyl group;

A is a substituted or unsubstituted alkylene group, a substituted or unsubstituted alkenylene group or a substituted or unsubstituted alkynylene group;

Y′ represents a group

in which

E 1 and E 2 each independently is a hydrogen atom or a lower alkyl group;

W represents CH, C═ or a nitrogen atom; with the provisos that:

when W represents CH, then m is 0 or 1 and B′ represents a sulfonyl group, an alkylene group, an alkenylene group, a group —C(OH)R 2 — in which R 2 represents a substituted or unsubstituted aryl group, a group —CHR 3 — in which R 3 represents a substituted or unsubstituted aryl group, or a substituted or unsubstituted cyclic or acyclic acetal group;

when W represents C═, then m is 1 and B′ is a group:

in which the double bond is coupled with W and R 4 represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group; and

when W represents a nitrogen atom, then m is 0 or 1 and B′ is a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group or a group —CHR 5 — in which R 5 represents a substituted or unsubstituted aryl group; and

D represents a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted aromatic heterocyclic group; and

l is 0 or 1;

which process comprises:

reducing a compound of formula (Ib):

wherein the ring P, A, Y′ and l are defined above.

4. A process for preparing a compound of formula (Ie):

wherein

the ring P is:

and is a pyrrole ring represented by the following structure:

in which R is an alkyl group, a cycloalkyl group, a cycloalkyl-alkyl group or a substituted or unsubstituted aralkyl group;

R 1 is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group;

A is a substituted or unsubstituted alkylene group, a substituted or unsubstituted alkenylene group or a substituted or unsubstituted alkynylene group;

Y is a group having the following formula:

in which

E 1 and E 2 each independently is a hydrogen atom or a lower alkyl group;

W represents CH, C═ or a nitrogen atom; with the provisos that:

when W represents CH, then m is 0 or 1 and B represents a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group, a group —C(OH)R 2 — in which R 2 represents a substituted or unsubstituted aryl group, a group —CHR 3 — in which R 3 represents a substituted or unsubstituted aryl group, or a substituted or unsubstituted cyclic or acyclic acetal group;

when W represents C═, then m is 1 and B is a group:

in which the double bond is coupled with W and R 4 represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group; and

when W represents a nitrogen atom, then m is 0 or 1 and B is a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group or a group —CHR 5 — in which R 5 represents a substituted or unsubstituted aryl group; and

D represents a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted aromatic heterocyclic group; and

l is 0 or 1;

which process comprises:

reacting a compound of formula (VII):

NH 2 OR 1   (VII)

wherein R 1 is defined above, with a compound of formula (IV):

wherein X is an eliminative group, and the ring P, A and l are defined above,

thereby obtaining a compound represented by the following formula (VIII):

wherein the ring P, R 1 , A, X and l are defined above; and then

reacting the compound of formula (VIII) with a nitrogen-containing compound of formula (V):

H—Y  (V)

wherein Y is defined above.

5. A process for preparing a compound of formula (If):

wherein

the ring P is:

and is a pyrrole ring represented by the following structure:

in which R is an alkyl group, a cycloalkyl group, a cycloalkyl-alkyl group or a substituted or unsubstituted aralkyl group;

A is a substituted or unsubstituted alkylene group, a substituted or unsubstituted alkenylene group or a substituted or unsubstituted alkynylene group;

Y is a group having the following formula:

in which

E 1 and E 2 each independently is a hydrogen atom or a lower alkyl group;

W represents CH, C═ or a nitrogen atom; with the provisos that:

when W represents CH, then m is 0 or 1 and B represents a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group, a group —C(OH)R 2 — in which R 2 represents a substituted or unsubstituted aryl group, a group —CHR 3 — in which R 3 represents a substituted or unsubstituted aryl group, or a substituted or unsubstituted cyclic or acyclic acetal group;

when W represents C═, then m is 1 and B is a group:

in which the double bond is coupled with W and R 4 represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group; and

when W represents a nitrogen atom, then m is 0 or 1 and B is a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group or a group —CHR 5 — in which R 5 represents a substituted or unsubstituted aryl group; and

D represents a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted aromatic heterocyclic group; and

l is 0 or 1;

which process comprises:

reducing a compound of formula (IV):

wherein X is an eliminative group, and the ring P, A and l are defined above, thereby obtaining a compound of formula (IX):

wherein the ring P, A, X and l are defined above; and then reacting the compound of formula (IX) with a nitrogen-containing compound represented by the following formula (V):

H—Y  (V)

wherein Y is defined above.

6. A process for preparing a compound of formula (Ig):

wherein

the ring P is:

and is a pyrrole ring represented by the following structure:

in which R is an alkyl group, a cycloalkyl group, a cycloalkyl-alkyl group or a substituted or unsubstituted aralkyl group;

A is a substituted or unsubstituted alkylene group, a substituted or unsubstituted alkenylene group or a substituted or unsubstituted alkynylene group;

Y is a group having the following formula:

in which

E 1 and E 2 each independently is a hydrogen atom or a lower alkyl group;

W represents CH, C═ or a nitrogen atom; with the provisos that:

when W represents CH, then m is 0 or 1 and B represents a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group, a group —C(OH)R 2 — in which R 2 represents a substituted or unsubstituted aryl group, a group —CHR 3 — in which R 3 represents a substituted or unsubstituted aryl group, or a substituted or unsubstituted cyclic or acyclic acetal group;

when W represents C═, then m is 1 and B is a group:

in which the double bond is coupled with W and R 4 represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group; and

when W represents a nitrogen atom, then m is 0 or 1 and B is a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group or a group —CHR 5 — in which R 5 represents a substituted or unsubstituted aryl group; and

D represents a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted aromatic heterocyclic group; and

l is 0 or 1;

which process comprises:

subjecting to a dehydration treatment a compound of formula (IX):

wherein the ring P, A, and l are defined above, and X is an eliminative group, thereby obtaining a compound of formula (X):

wherein the ring P, A, X and l have the same meanings as defined above; and then reacting the compound of formula (X) with a nitrogen-containing compound of formula (V):

H—Y  (V)

wherein Y is defined above.

7. A process for the preparation of a pyrrolesulfonamide derivative represented by the following formula (Ig):

wherein

the ring P is:

and is a pyrrole ring represented by the following structure:

in which R is an alkyl group, a cycloalkyl group, a cycloalkyl-alkyl group or a substituted or unsubstituted aralkyl group;

A is a substituted or unsubstituted alkylene group, a substituted or unsubstituted alkenylene group or a substituted or unsubstituted alkynylene group;

Y is a group having the following formula:

in which

E 1 and E 2 each independently is a hydrogen atom or a lower alkyl group;

W represents CH, C═ or a nitrogen atom; with the provisos that:

when W represents CH, then m is 0 or 1 and B represents a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group, a group —C(OH)R 2 — in which R 2 represents a substituted or unsubstituted aryl group, a group —CHR 3 — in which R 3 represents a substituted or unsubstituted aryl group, or a substituted or unsubstituted cyclic or acyclic acetal group;

when W represents C═, then m is 1 and B is a group:

in which the double bond is coupled with W and R 4 represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group; and

when W represents a nitrogen atom, then m is 0 or 1 and B is a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group or a group —CHR 5 — in which R 5 represents a substituted or unsubstituted aryl group; and

D represents a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted aromatic heterocyclic group; and

l is 0 or 1;

which process comprises:

subjecting a compound of formula (If):

wherein the ring P, A, Y and l are defined above, to a dehydration treatment.

8. A compound represented by the following formula (II):

wherein

the ring P is:

and is a pyrrole ring represented by the following structure:

in which R is an alkyl group, a cycloalkyl group, a cycloalkyl-alkyl group or a substituted or unsubstituted aralkyl group; and

l is 0 or 1.

9. A compound of formula (XI):

the ring P is:

and is a pyrrole ring represented by the following structure:

in which R is an alkyl group, a cycloalkyl group, a cycloalkyl-alkyl group or a substituted or unsubstituted aralkyl group;

Z 1 is a hydrogen atom and Z 2 is not present when the bond represented by the dashed line is present, and Z 1 is hydrogen and Z 2 is hydroxyl when the bond represented by the dashed line is not present or Z 1 and Z 2 together to represent an oxygen atom or a group NOR 1 , where R 1 is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group;

A is a substituted or unsubstituted alkylene group, a substituted or unsubstituted alkenylene group or a substituted or unsubstituted alkynylene group;

X is an eliminative group; and

l is 0 or 1.

10. A process for preparing a compound of formula (IIa) or (IIa′):

wherein R represents an alkyl group, a cycloalkyl group, a cycloalkyl-alkyl group or a substituted or unsubstituted aralkyl group and l is 0 or 1;

which process comprises:

converting a 1-substituted-pyrrole-3-sulfonic acid or a salt thereof of formula (XII):

wherein M represents a hydrogen ion, an alkali metal ion, an alkaline earth metal ion or a quaternary ammonium ion, p is 1 when M is a hydrogen ion, an alkali metal ion or a quaternary ammonium ion or p is 2 when M is an alkaline earth metal ion, q is 0 or 1, and R has the same meaning as defined above,

into a compound represented by formula (XIII):

wherein X″ is a chlorine atom or a bromine atom;

thus causing glycine or β-alknine or a derivative thereof of formula (XIV):

NH 2 (CH 2 ) l CH 2 COOR 6   (XIV)

wherein R 6 represents a hydrogen atom or a carboxyl-protecting group,

to act, thereby obtaining a compound of formula (XV):

wherein R, R 6 and l are defined above; and then subjecting said compound to ring closure.

11. A process for preparing a compound of formula (IIa) or (IIa′):

wherein

R represents an alkyl group, a cycloalkyl group, a cycloalkyl-alkyl group or a substituted or unsubstituted aralkyl group and

l is 0 or 1;

which process comprises:

reacting a compound of formula (XVIa) or (XVIb):

R—X′″  (XVIa)

(RO) 2 SO 2   (XVIb)

wherein X′″ is an eliminative group and R is defined above,

with a compound of formula (IIb) or (IIb′):

wherein l is defined above.

12. A compound of formula (XV):

R represents an alkyl group, a cycloalkyl group, a cycloalkyl-alkyl group or a substituted or unsubstituted aralkyl group;

R 6 represents a hydrogen atom or a carboxyl-protecting group; and

l is 0 or 1.