US 7,906,537 B2Granted

Substituted p-diaminobenzene derivatives

AssigneeH. Lundbeck A/S

InventorsNikolay Khanzhin, Mario Rottlander, Andreas Ritzen, William P. Watson

Life of this patent

Estimating the term…

Abstract

The present invention relates to aniline derivatives of the general formula I or pharmaceutically acceptable salts thereof and their use.

Claims19

Dependent claims

A substituted p-diaminobenzene derivative of the general formula I

wherein:
s is 0 or 1;
U is O, S, SO2, SONR11, or CONR11;
wherein:
R11 is hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6 -alk(en/yn)yl;
or
R2 and R11 taken together with the nitrogen atom form a 5-8 membered saturated or unsaturated ring, which optionally contains 1, 2 or 3 further heteroatoms;
q is 0 or 1;
X is CO or SO2;
with the proviso that q is 0 when X is SO2;
Z is O or S;
R1 is hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6 -alk(en/yn)yl, acyl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8 -cycloalk(en)yl-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo -C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en) yl or cyano-C3-8 -cycloalk(en)yl-C1-6-alk(en/yn)yl;
R2 is hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6 -alk(en/yn)yl, Ar, Ar—C1-6-alk(en/yn)yl, Ar—C3-8-cycloalk(en)yl, Ar—C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, acyl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk (en)yl, hydroxy-C3-8 -cycloalk(en)yl-C1-6-alk(en/yn)yl, halogen, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk (en)yl, halo -C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano, cyano-C1-6-alk(en/yn)yl, cyano-C3-8cycloalk(en)yl, cyano-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, NR10R10′—C1-6-alk(en/yn)yl, NR10R10′—C3-8 -cycloalk(en)yl or NR10R10′—C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl;
wherein:
R10 and R10′ are each independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl or cyano-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl;
or
R10 and R10′ taken together with the nitrogen atom form a 5-8 membered saturated or unsaturated ring, which optionally contains 1, 2 or 3 further heteroatoms;
with the proviso that:
when R2 is halogen or cyano, then s is 0;
and
when s is 1 and R2 is a hydrogen atom or acyl, then U is O or S;
R3 is C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, heterocycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, C1-6-alk(en/yn)yl-heterocycloalk(en)yl, heterocycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy-C3-8-cycloalk(en)yl, C1-6-alk(en/yn)yloxy-heterocycloalk(en)yl, C1-6-alk(en/yn)yloxy-carbonyl-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy-carbonyl-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yloxy -carbonyl-C1-6-alk(en/yn)yl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy -heterocycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, hydroxy-C1-6-alk(en/yn)yl -C3-8-cycloalk(en)yl, hydroxy-C1-6-alk(en/yn)yl-heterocycloalk(en)yl, halo -C3-8-cycloalk(en)yl, halo-heterocycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, halo -C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, halo-C1-6-alk(en/yn)yl-heterocycloalk(en)yl, cyano-C1-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl, cyano-heterocycloalk(en)yl, cyano-C3-8-cycloalk(en)yl -C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, cyano-C1-6-alk(en/yn)yl -heterocycloalk(en)yl, acyl-C1-6-alk(en/yn)yl, acyl-C3-8-cycloalk(en)yl, acyl-heterocycloalk(en)yl, acyl-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, acyl-C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, acyl-C1-6-alk(en/yn)yl-heterocycloalk(en)yl, NR12R12′, optionally substituted NR12R12′-C1-6-alk(en/yn)yl, optionally substituted NR12R12′-C3-8-alk(en/yn)yl, or optionally substituted NR12R12′-C3-8-alk(en/yn)yl-C1-6-alk(en/yn)yl;
wherein:
R12 and R12′ are each independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar, Ar—C1-6-alk(en/yn)yl, Ar—C3-8-cycloalk(en)yl, Ar—C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar-heterocycloalk(en)yl, Ar-oxy-C1-6-alk(en/yn)yl, Ar-oxy-C3-8-cycloalk(en)yl, Ar-oxy-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar-oxy -heterocycloalk(en)yl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl, or cyano -C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl;
or
R12 and R12′ taken together with the nitrogen atom form a 5-8 membered saturated or unsaturated ring, which optionally contains 1, 2 or 3 further heteroatoms;
with the proviso that when R3 is NR12R12′ then q is 0;
and
Y is a group of formula XXXXI:
wherein:
“|” represents a bond attaching the group represented by Y to the carbon atom;
V is C or CH;
and
k is 0, 1, 2 or 3;
and
each R5 is independently C1-6-alk(en/yn)yl, C3-8-cycloalk (en)yl, C3-8-cycloalk(en) yl-C1-6-alk(en/yn)yl, Ar, Ar—C1-6-alk(en/yn)yl, Ar—C3-8-cycloalk(en)yl, Ar—C3-8-cycloalk (en)yl-C1-6-alk(en/yn)yl , Ar-oxy, Ar-oxy-C1-6alk(en/yn)yl, Ar-oxy-C3-8-cycloalk(en)yl, C1-6-alk (en/yn)yl -heterocycloalk(en)yl, Ar-oxy-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, acyl, C1-6-alk (en/yn)yloxy, C3-8-cycloalk(en)yloxy, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)yloxy-carbonyl, halogen, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, —CO—NR6R6′, cyano, cyano-C1-6-alk(en/yn)yl, cyano-C3-8-cycloalk (en)yl, cyano-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, NR7R7′, S—R8 or SO2R8;
or
two adjacent R5 groups taken together with the aromatic group form a 5-8 membered ring, which optionally contains one or two heteroatoms;
wherein:
R6 and R6′ are each independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl or Ar;
R7 and R7′ are each independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar, heterocycloalk(en)yl-C1-6-alk (en/yn)yl, heterocycloalk(en)yl-C3-8-cycloalk(en)yl, heterocycloalk(en)yl-C3-8-cycloalk(en)yl-C1-6-alk (en/yn)yl, heterocycloalk(en)yl-Ar or acyl;
or
R7 and R7′ taken together with the nitrogen atom form a 5-8 membered saturated or unsaturated ring which optionally contains 1, 2 or 3 further heteroatoms;
and
R8 is hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar or —NR9R9′;
wherein:
R9 and R9′ are each independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl;
or salts thereof.

45 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/550,448Filed 18 Mar 2004 · us provisional application
Priority: DK 20030044121 Mar 2003
Published: US 2006/0183791 A117 Aug 2006
Granted: 15 Mar 2011
Term ends: Not estimatedThe source records don’t support an estimate.

Classification51 codes

C07D 333/28
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61P 21/02
Drugs for disorders of the muscular or neuromuscular system: muscle relaxants, e.g. for tetanus or cramps
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/02
Drugs for disorders of the nervous system: for peripheral neuropathies

Family

Application60/456,698Us provisional application · filed 21 Mar 2003
US 2006/0183791 A1Pre-grant publication · published 17 Aug 2006
US 7,906,537 B2This patent

From the US filing history. Foreign family members aren’t listed.

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A substituted p-diaminobenzene derivative of the general formula I

wherein:
s is 0 or 1;
U is O, S, SO2, SONR11, or CONR11;
wherein:
R11 is hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6 -alk(en/yn)yl;
or
R2 and R11 taken together with the nitrogen atom form a 5-8 membered saturated or unsaturated ring, which optionally contains 1, 2 or 3 further heteroatoms;
q is 0 or 1;
X is CO or SO2;
with the proviso that q is 0 when X is SO2;
Z is O or S;
R1 is hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6 -alk(en/yn)yl, acyl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8 -cycloalk(en)yl-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo -C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en) yl or cyano-C3-8 -cycloalk(en)yl-C1-6-alk(en/yn)yl;
R2 is hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6 -alk(en/yn)yl, Ar, Ar—C1-6-alk(en/yn)yl, Ar—C3-8-cycloalk(en)yl, Ar—C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, acyl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk (en)yl, hydroxy-C3-8 -cycloalk(en)yl-C1-6-alk(en/yn)yl, halogen, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk (en)yl, halo -C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano, cyano-C1-6-alk(en/yn)yl, cyano-C3-8cycloalk(en)yl, cyano-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, NR10R10′—C1-6-alk(en/yn)yl, NR10R10′—C3-8 -cycloalk(en)yl or NR10R10′—C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl;
wherein:
R10 and R10′ are each independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl or cyano-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl;
or
R10 and R10′ taken together with the nitrogen atom form a 5-8 membered saturated or unsaturated ring, which optionally contains 1, 2 or 3 further heteroatoms;
with the proviso that:
when R2 is halogen or cyano, then s is 0;
and
when s is 1 and R2 is a hydrogen atom or acyl, then U is O or S;
R3 is C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, heterocycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, C1-6-alk(en/yn)yl-heterocycloalk(en)yl, heterocycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy-C3-8-cycloalk(en)yl, C1-6-alk(en/yn)yloxy-heterocycloalk(en)yl, C1-6-alk(en/yn)yloxy-carbonyl-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy-carbonyl-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yloxy -carbonyl-C1-6-alk(en/yn)yl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy -heterocycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, hydroxy-C1-6-alk(en/yn)yl -C3-8-cycloalk(en)yl, hydroxy-C1-6-alk(en/yn)yl-heterocycloalk(en)yl, halo -C3-8-cycloalk(en)yl, halo-heterocycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, halo -C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, halo-C1-6-alk(en/yn)yl-heterocycloalk(en)yl, cyano-C1-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl, cyano-heterocycloalk(en)yl, cyano-C3-8-cycloalk(en)yl -C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, cyano-C1-6-alk(en/yn)yl -heterocycloalk(en)yl, acyl-C1-6-alk(en/yn)yl, acyl-C3-8-cycloalk(en)yl, acyl-heterocycloalk(en)yl, acyl-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, acyl-C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, acyl-C1-6-alk(en/yn)yl-heterocycloalk(en)yl, NR12R12′, optionally substituted NR12R12′-C1-6-alk(en/yn)yl, optionally substituted NR12R12′-C3-8-alk(en/yn)yl, or optionally substituted NR12R12′-C3-8-alk(en/yn)yl-C1-6-alk(en/yn)yl;
wherein:
R12 and R12′ are each independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar, Ar—C1-6-alk(en/yn)yl, Ar—C3-8-cycloalk(en)yl, Ar—C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar-heterocycloalk(en)yl, Ar-oxy-C1-6-alk(en/yn)yl, Ar-oxy-C3-8-cycloalk(en)yl, Ar-oxy-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar-oxy -heterocycloalk(en)yl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl, or cyano -C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl;
or
R12 and R12′ taken together with the nitrogen atom form a 5-8 membered saturated or unsaturated ring, which optionally contains 1, 2 or 3 further heteroatoms;
with the proviso that when R3 is NR12R12′ then q is 0;
and
Y is a group of formula XXXXI:
wherein:
“|” represents a bond attaching the group represented by Y to the carbon atom;
V is C or CH;
and
k is 0, 1, 2 or 3;
and
each R5 is independently C1-6-alk(en/yn)yl, C3-8-cycloalk (en)yl, C3-8-cycloalk(en) yl-C1-6-alk(en/yn)yl, Ar, Ar—C1-6-alk(en/yn)yl, Ar—C3-8-cycloalk(en)yl, Ar—C3-8-cycloalk (en)yl-C1-6-alk(en/yn)yl , Ar-oxy, Ar-oxy-C1-6alk(en/yn)yl, Ar-oxy-C3-8-cycloalk(en)yl, C1-6-alk (en/yn)yl -heterocycloalk(en)yl, Ar-oxy-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, acyl, C1-6-alk (en/yn)yloxy, C3-8-cycloalk(en)yloxy, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)yloxy-carbonyl, halogen, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, —CO—NR6R6′, cyano, cyano-C1-6-alk(en/yn)yl, cyano-C3-8-cycloalk (en)yl, cyano-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, NR7R7′, S—R8 or SO2R8;
or
two adjacent R5 groups taken together with the aromatic group form a 5-8 membered ring, which optionally contains one or two heteroatoms;
wherein:
R6 and R6′ are each independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl or Ar;
R7 and R7′ are each independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar, heterocycloalk(en)yl-C1-6-alk (en/yn)yl, heterocycloalk(en)yl-C3-8-cycloalk(en)yl, heterocycloalk(en)yl-C3-8-cycloalk(en)yl-C1-6-alk (en/yn)yl, heterocycloalk(en)yl-Ar or acyl;
or
R7 and R7′ taken together with the nitrogen atom form a 5-8 membered saturated or unsaturated ring which optionally contains 1, 2 or 3 further heteroatoms;
and
R8 is hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar or —NR9R9′;
wherein:
R9 and R9′ are each independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl;
or salts thereof.

45 more elements

Facts

Application

10/550,448Filed 18 Mar 2004 · us provisional application

Priority

DK 20030044121 Mar 2003

Published

US 2006/0183791 A117 Aug 2006

Granted

15 Mar 2011

Term ends

Not estimatedThe source records don’t support an estimate.

Classification51 codes

C07D 333/28
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61P 21/02
Drugs for disorders of the muscular or neuromuscular system: muscle relaxants, e.g. for tetanus or cramps
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/02
Drugs for disorders of the nervous system: for peripheral neuropathies