US 2006/0148818 A1Published application

Novel tetraydrospiro(piperdine-2,7'- pyrrolo{3,2-b}pyridine derivatives and novel in-dole derivatives useful in the treatment of 5-ht6 receptor-related disorders

OwnerGary Johansson, Peter Brandt +2inventors

InventorsGary Johansson, Peter Brandt, Graeme Dykes, Bjorn Nilsson

Life of this patent

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Abstract

The present invention relates to compounds of formula (I): Formula (I) wherein U, P, W1, W2, W3, v, Y, Z, Rm, and Rm′ are as described herein, to pharmaceutical compositions comprising the compounds, to processes for their preparation, as well as to the use of the compounds for the preparation of a medicament against 5-HT6 receptor-related disorders.

Claims24

Dependent claims

A compound of the Formula (I)

wherein:
v is 1 or 2 and P is selected from a substituent of Formula (II) and Formula (III);
or P may also be selected from H or C1-6-alkyl provided that Rm is selected from
—NHSO2R11, —SO2NR8R11 or —S(O)eR11, wherein R11 is selected from aryl and heteroaryl and where e is 0, 1, 2 or 3, v is 1 and Rm′ is H;
represents a single bond or a double bond, with the proviso that both represent double bonds or that both represent single bonds;
W1, W2, W3, Z and Y are each a carbon atom;
or
one of W1, W2, W3, Z and Y is a nitrogen atom, while the remainder being carbon atoms,
provided that both in Formula (I) represent single bonds;
U is selected from CHR4, CR4 and CR4R4′, provided that when the dotted line connecting W1 and U is a double bond, then U is CR4;
and further provided that when the dotted line connecting W1 and U is a single bond, then U is selected from CHR4 and CR4R4′;
R1 is selected from:
(a) C1-6-alkyl,
(b) C1-6-alkoxy-C1-6-alkyl,
(c) C3-6-alkenyl,
(d) hydroxy-C1-6-alkyl,
(e) halo-C1-6-alkyl,
(f) aryl,
(g) arylcarbonylmethyl,
(h) aryl-C2-6-alkenyl,
(i) aryl-C1-6-alkyl,
(j) C3-7-cycloalkyl,
(k) heteroaryl,
(l) 4-piperidinyl,
(m) N-substituted 4-piperidinyl, wherein the substituents are selected from C1-6-alkyl, aryl, heteroaryl, aryl-C1-6-alkyl and heteroaryl-C1-6-alkyl,
(n) heteroaryl-C1-6-alkyl,
wherein any heteroaryl or aryl residue, alone or as part of another group, is optionally substituted, independently, in one or more positions with substituents having the values as defined for Rm and Rm′;
Rm and Rm′ are each independently selected from:
(a) hydrogen,
(b) halogen,
(c) C1-6-alkyl,
(d) hydroxy,
(e) C1-6-alkoxy,
(f) C2-6-alkenyl,
(g) phenyl,
(h) phenoxy,
(i) benzyloxy,
(j) benzoyl,
(k) —OCF3,
(l) —CN,
(m) hydroxy-C1-6-alkyl,
(n) halo-C1-6-alkyl,
(o) —NR10R10,
(p) —NO2,
(q) —CONR10R10,
(r) —NHSO2R11,
(s) —NR8COR11,
(t) —SO2NR8R11,
(u)—C(═O)R11,
(v) C1-6-alkoxycarbonyl,
(w) —S(O)eR11, wherein e is 0, 1, 2 or 3,
(x) —SCF3,
(y) —CHF═CH2,
(aa) —OCF2H, or
(ab) ethynyl;
and with the proviso that, Rm, is attached to a carbon atom in ring B;
and
with the further proviso that when one of W1, W2 and W3 in Formula (I) is a nitrogen atom and both represent single bonds the said nitrogen atom is attached to Rm, wherein Rm is selected from hydrogen or C1-4-alkyl and v is 1;
and
with the further proviso that when W1, W2 and W3 in Formula (I) are each a carbon atom and both represent single bonds, Rm is selected from hydrogen or methyl;
and
with the further proviso that when Rm or Rm′, as substituents on ring A and B in Formula (I), are selected from phenyl, phenoxy, benzyloxy and benzoyl, the phenyl or aryl ring thereof may be optionally substituted by C1-4-alkyl, halogen, C1-4-alkoxy, C1-4-alkylthio, trifluoromethyl, hydroxymethyl or cyano;
wherein Rm and R4 may be linked to each other to form a fused substituent of Formula (IV) provided that Rm is attached to W1:
when U is CR4 or CHR4, R4 is a group selected from:
wherein:
n=0, 1, or 2,
o=1 or 2,
p=1, 2, 3, or 4,
r=2 or 3,
s=1, 2 or 3;
when U is CHR4, R4 is additionally selected from the following groups:
wherein:
n=0,1 or 2,
o=1 or 2,
t=2, 3 or 4,
r=2 or 3,
s=1, 2 or 3;
wherein X is selected from O, NR8 and S;
wherein R5 is independently a group selected from:
(a) hydrogen,
(b) C1-6-alkyl,
(c) 2-cyanoethyl,
(d) hydroxy-C2-6-alkyl,
(e) C3-6-alkenyl,
(f) C3-6-alkynyl,
(g) C3-7-cycloalkyl,
(h) C3-7-cycloalkyl-C1-4-alkyl,
(i) C1-6-alkoxy-C2-6-alkyl,
(j) aryl-C1-6-alkyl,
(k) heteroaryl-C1-6-alkyl,
(l) 3,3,3-trifluoropropyl,
wherein any aryl and heteroaryl residue may be optionally substituted with C1-4-alkyl, halogen, C1-4-alkoxy, C1-4-alkylthio, trifluoromethyl or cyano;
R6 is selected from:
(a) hydrogen,
(b) C1-4-alkyl,
(c) hydroxy-C1-4-alkyl,
(d) C1-4-alkoxy-C1-4-alkyl,
(e) halo-C1-4-alkyl,
(f) —NR8R8, provided that the said —NR8R8 group is not attached to a carbon atom adjacent to a ring nitrogen atom,
(g) —CO—NR8R8;
(h) hydroxy, provided that the said hydroxy group is not attached to a carbon atom adjacent to a ring nitrogen atom;
R7 is selected from:
(a) hydrogen,
(b) C1-4-alkyl,
(c) hydroxy-C1-4-alkyl, or
(d) C1-4-alkoxy-C1-4-alkyl,
(e) hydroxy, provided that the said hydroxy group is not attached to a carbon atom adjacent to a heterocyclic ring nitrogen atom and that the said hydroxy group is attached to a heterocyclic ring not substituted with oxo;
R8 is each independently selected from:
(a) hydrogen, or
(b) C1-6-alkyl,
R9 is selected from:
(a) hydrogen,
(b) C1-4-alkyl, wherein one or two groups may be present at any carbon atom, or when two groups are present at the same carbon atom they may together form a cyclopropane ring,
(c) hydroxy-C1-4-alkyl,
(d) C1-4-alkoxy-C1-4-alkyl,
(e) halo-C1-4-alkyl,
R10 is each independently selected from:
(a) hydrogen,
(b) C1-6-alkyl,
(c) hydroxy-C2-4-alkyl,
(d) C3-7-cycloalkyl, or
(e) C1-4-alkoxy-C2-4-alkyl,
wherein the two R10 groups together with the nitrogen to which they are attached form a heterocyclic ring;
and when the two R10 groups form a piperazine ring, the nitrogen of the piperazine ring that allows the substitution may be substituted with a group selected from R5;
R11 is selected from:
(a) C1-6-alkyl,
(b) aryl, or
(c) heteroaryl,
wherein aryl and heteroaryl may be optionally substituted with C1-4-alkyl, halogen, C1-4-alkoxy, C1-4-alkylthio, trifluoromethyl, hydroxymethyl or cyano;
R12 is selected from:
(a) hydrogen, or
(b) methyl;
when U is R4R4′, R4 and R4 are linked to each other to form a heterocyclic ring selected from pyrrolidine or piperidine, wherein the N atom may be substituted by a group selected from R5;
and pharmaceutically acceptable salts, hydrates, solvates, geometrical isomers, tautomers, optical isomers, and prodrug forms thereof.

131 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/536,603Filed 20 Oct 2004
Priority: SE 0302760420 Oct 2003
Published: 6 Jul 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification23 codes

C04B 35/632
Using additives specially adapted for forming the products , e.g.. binder binders: organic additives
A61P 1/14
Drugs for disorders of the alimentary tract or the digestive system: prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics,…
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics

Family

No related US applications are recorded in the indexed filing history.

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Abstract

A compound of the Formula (I)

wherein:
v is 1 or 2 and P is selected from a substituent of Formula (II) and Formula (III);
or P may also be selected from H or C1-6-alkyl provided that Rm is selected from
—NHSO2R11, —SO2NR8R11 or —S(O)eR11, wherein R11 is selected from aryl and heteroaryl and where e is 0, 1, 2 or 3, v is 1 and Rm′ is H;
represents a single bond or a double bond, with the proviso that both represent double bonds or that both represent single bonds;
W1, W2, W3, Z and Y are each a carbon atom;
or
one of W1, W2, W3, Z and Y is a nitrogen atom, while the remainder being carbon atoms,
provided that both in Formula (I) represent single bonds;
U is selected from CHR4, CR4 and CR4R4′, provided that when the dotted line connecting W1 and U is a double bond, then U is CR4;
and further provided that when the dotted line connecting W1 and U is a single bond, then U is selected from CHR4 and CR4R4′;
R1 is selected from:
(a) C1-6-alkyl,
(b) C1-6-alkoxy-C1-6-alkyl,
(c) C3-6-alkenyl,
(d) hydroxy-C1-6-alkyl,
(e) halo-C1-6-alkyl,
(f) aryl,
(g) arylcarbonylmethyl,
(h) aryl-C2-6-alkenyl,
(i) aryl-C1-6-alkyl,
(j) C3-7-cycloalkyl,
(k) heteroaryl,
(l) 4-piperidinyl,
(m) N-substituted 4-piperidinyl, wherein the substituents are selected from C1-6-alkyl, aryl, heteroaryl, aryl-C1-6-alkyl and heteroaryl-C1-6-alkyl,
(n) heteroaryl-C1-6-alkyl,
wherein any heteroaryl or aryl residue, alone or as part of another group, is optionally substituted, independently, in one or more positions with substituents having the values as defined for Rm and Rm′;
Rm and Rm′ are each independently selected from:
(a) hydrogen,
(b) halogen,
(c) C1-6-alkyl,
(d) hydroxy,
(e) C1-6-alkoxy,
(f) C2-6-alkenyl,
(g) phenyl,
(h) phenoxy,
(i) benzyloxy,
(j) benzoyl,
(k) —OCF3,
(l) —CN,
(m) hydroxy-C1-6-alkyl,
(n) halo-C1-6-alkyl,
(o) —NR10R10,
(p) —NO2,
(q) —CONR10R10,
(r) —NHSO2R11,
(s) —NR8COR11,
(t) —SO2NR8R11,
(u)—C(═O)R11,
(v) C1-6-alkoxycarbonyl,
(w) —S(O)eR11, wherein e is 0, 1, 2 or 3,
(x) —SCF3,
(y) —CHF═CH2,
(aa) —OCF2H, or
(ab) ethynyl;
and with the proviso that, Rm, is attached to a carbon atom in ring B;
and
with the further proviso that when one of W1, W2 and W3 in Formula (I) is a nitrogen atom and both represent single bonds the said nitrogen atom is attached to Rm, wherein Rm is selected from hydrogen or C1-4-alkyl and v is 1;
and
with the further proviso that when W1, W2 and W3 in Formula (I) are each a carbon atom and both represent single bonds, Rm is selected from hydrogen or methyl;
and
with the further proviso that when Rm or Rm′, as substituents on ring A and B in Formula (I), are selected from phenyl, phenoxy, benzyloxy and benzoyl, the phenyl or aryl ring thereof may be optionally substituted by C1-4-alkyl, halogen, C1-4-alkoxy, C1-4-alkylthio, trifluoromethyl, hydroxymethyl or cyano;
wherein Rm and R4 may be linked to each other to form a fused substituent of Formula (IV) provided that Rm is attached to W1:
when U is CR4 or CHR4, R4 is a group selected from:
wherein:
n=0, 1, or 2,
o=1 or 2,
p=1, 2, 3, or 4,
r=2 or 3,
s=1, 2 or 3;
when U is CHR4, R4 is additionally selected from the following groups:
wherein:
n=0,1 or 2,
o=1 or 2,
t=2, 3 or 4,
r=2 or 3,
s=1, 2 or 3;
wherein X is selected from O, NR8 and S;
wherein R5 is independently a group selected from:
(a) hydrogen,
(b) C1-6-alkyl,
(c) 2-cyanoethyl,
(d) hydroxy-C2-6-alkyl,
(e) C3-6-alkenyl,
(f) C3-6-alkynyl,
(g) C3-7-cycloalkyl,
(h) C3-7-cycloalkyl-C1-4-alkyl,
(i) C1-6-alkoxy-C2-6-alkyl,
(j) aryl-C1-6-alkyl,
(k) heteroaryl-C1-6-alkyl,
(l) 3,3,3-trifluoropropyl,
wherein any aryl and heteroaryl residue may be optionally substituted with C1-4-alkyl, halogen, C1-4-alkoxy, C1-4-alkylthio, trifluoromethyl or cyano;
R6 is selected from:
(a) hydrogen,
(b) C1-4-alkyl,
(c) hydroxy-C1-4-alkyl,
(d) C1-4-alkoxy-C1-4-alkyl,
(e) halo-C1-4-alkyl,
(f) —NR8R8, provided that the said —NR8R8 group is not attached to a carbon atom adjacent to a ring nitrogen atom,
(g) —CO—NR8R8;
(h) hydroxy, provided that the said hydroxy group is not attached to a carbon atom adjacent to a ring nitrogen atom;
R7 is selected from:
(a) hydrogen,
(b) C1-4-alkyl,
(c) hydroxy-C1-4-alkyl, or
(d) C1-4-alkoxy-C1-4-alkyl,
(e) hydroxy, provided that the said hydroxy group is not attached to a carbon atom adjacent to a heterocyclic ring nitrogen atom and that the said hydroxy group is attached to a heterocyclic ring not substituted with oxo;
R8 is each independently selected from:
(a) hydrogen, or
(b) C1-6-alkyl,
R9 is selected from:
(a) hydrogen,
(b) C1-4-alkyl, wherein one or two groups may be present at any carbon atom, or when two groups are present at the same carbon atom they may together form a cyclopropane ring,
(c) hydroxy-C1-4-alkyl,
(d) C1-4-alkoxy-C1-4-alkyl,
(e) halo-C1-4-alkyl,
R10 is each independently selected from:
(a) hydrogen,
(b) C1-6-alkyl,
(c) hydroxy-C2-4-alkyl,
(d) C3-7-cycloalkyl, or
(e) C1-4-alkoxy-C2-4-alkyl,
wherein the two R10 groups together with the nitrogen to which they are attached form a heterocyclic ring;
and when the two R10 groups form a piperazine ring, the nitrogen of the piperazine ring that allows the substitution may be substituted with a group selected from R5;
R11 is selected from:
(a) C1-6-alkyl,
(b) aryl, or
(c) heteroaryl,
wherein aryl and heteroaryl may be optionally substituted with C1-4-alkyl, halogen, C1-4-alkoxy, C1-4-alkylthio, trifluoromethyl, hydroxymethyl or cyano;
R12 is selected from:
(a) hydrogen, or
(b) methyl;
when U is R4R4′, R4 and R4 are linked to each other to form a heterocyclic ring selected from pyrrolidine or piperidine, wherein the N atom may be substituted by a group selected from R5;
and pharmaceutically acceptable salts, hydrates, solvates, geometrical isomers, tautomers, optical isomers, and prodrug forms thereof.

131 more elements

Facts

Application

10/536,603Filed 20 Oct 2004

Priority

SE 0302760420 Oct 2003

Published

6 Jul 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification23 codes

C04B 35/632
Using additives specially adapted for forming the products , e.g.. binder binders: organic additives
A61P 1/14
Drugs for disorders of the alimentary tract or the digestive system: prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics,…
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics