Azaquinazoline derivatives

• US 20050038047A1
• Filed: 08/13/2004
• Published: 02/17/2005
• Est. Priority Date: 08/14/2003
• Status: Abandoned Application

• Current Assignee: Cedric Poinsard, Graham Nigel Maw, Karl Richard Gibson, Paul John Edwards, Simon John Mantell
• Original Assignee: Cedric Poinsard, Graham Nigel Maw, Karl Richard Gibson, Paul John Edwards, Simon John Mantell
• Inventors: Edwards, Paul John, Maw, Graham Nigel, Gibson, Karl Richard, Mantell, Simon John, Poinsard, Cedric
• Application Number:
  US10/917,690
• Publication Number:
  US 20050038047A1
• Time in Patent Office: Days
• US Class Current: 514/264.110
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention relates to certain novel 6-amino-7-azaquinazoline derivatives and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives. One important use is in the treatment of pain.

Claims

1. A compound of formula (I):

2. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein X is methylene or a bond.

3. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein R¹ is (i) C₅-C₈ cycloalkyl optionally substituted with one or more substituents selected from halo and C₁-C₆ alkyl, wherein one of the methylene (—

CH₂—

) groups of said C₅-C₈ cycloalkyl may optionally be replaced by an —

O—

group and wherein said C₅-C₈ cycloalkyl, whether modified as indicated above or not, may be optionally benzo-fused;

or (ii) pyridyl optionally substituted by one or more C₁-C₆ alkyl groups;

with the proviso that R¹ may not be optionally substituted pyridyl when X is a bond.

4. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein R² is —

OR⁴ or —

NR⁴R⁵ and R⁴ is C₁-C₅ alkyl or C₅-C₆ cycloalkyl, said C₁-C₅ alkyl and C₅-C₆ cycloalkyl being optionally substituted by one or more groups selected from Het¹, Het², —

OR⁷—

NR⁷R⁷ and —

NR⁷SO₂R⁷ and optionally having one methylene (—

CH₂—

) group replaced by an —

O—

group and said C₅-C₆ cycloalkyl, whether modified as indicated above or not, being optionally benzo-fused and R⁵ is H;

or in the case where R² is —

NR⁴R⁵, R⁴ and R⁵ when taken together with the nitrogen atom to which they are attached, form a saturated heterocylic group selected from azetidinyl, piperdinyl and piperazinyl, wherein said heterocyclic group is optionally substituted on a ring carbon atom by one ore more groups selected from —

OR⁷—

(C₁-C₆ alkylene)-NR⁷R⁷ and halo and optionally substituted on a ring nitrogen atom by —

COR⁷.

5. A compound of formula (I), as claimed in claim 1, which is:

2-{2-[4-(indan-2-ylamino)-pyrido[3,4-d]pyrimidin-6-ylamino]-ethoxy}-ethanol;

N*4*-cycloheptyl-N*6*-(3-dimethylamino-propyl)-pyrido[3,4-d]pyrimidine-4,6-diamine;

or

cycloheptyl-[6-(2-morpholin-4-yl-ethoxy)-pyrido[3,4-d]pyrimidin-4-yl]-amine;

or a pharmaceutically acceptable salt or solvate thereof.

6. A pharmaceutical formulation including a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1 and a pharmaceutically acceptable excipient.

7. A method of treating pain in a mammal, including a human being, including administering to said mammal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1.

8. A combination of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1 and a second pharmacologically active compound.

9. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein:

X is a bond or C₁-C₃ alkylene;

R¹ is (a) C₃-C₈ cycloalkyl optionally substituted with one or more substituents selected from halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy and cyano, wherein one or two of the methylene (—

CH₂—

) groups of said C₃-C₈ cycloalkyl may optionally be replaced by an —

NR³—

, —

O—

or —

S(O)_n—

group and wherein said C₃-C₈ cycloalkyl, whether modified as indicated above or not, may be optionally benzo-fused, said benzo-fused portion being optionally substituted by one or more substituents selected from halo, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₁-C₆ alkoxy and cyano;

or

(b) Het²;

with the proviso that R¹ may not be Het² when X is a bond;

R² is —

OR⁴ or —

NR⁴R⁵;

R³ is H, C₁-C₆ alkyl or C₃-C₈ cycloalkyl;

R⁴ is C₁-C₆ alkyl or C₃-C₈ cycloalkyl, said C₁-C₆ alkyl and C₃-C₈ cycloalkyl being optionally substituted by one or more R⁶ groups and optionally having one methylene group (—

CH₂—

) replaced by an —

NR³—

, —

O—

or —

S(O)_n-group and said C₃-C₈ cycloalkyl, whether modified as indicated above or not, being optionally benzo-fused, said benzo-fused portion being optionally substituted by one or more substituents selected from halo, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₁-C₆ alkoxy and cyano; and

R⁵ is H, C₁-C₆ alkyl or C₃-C₈ cycloalkyl;

or, in the case where R² is —

NR⁴R⁵, R⁴ and R⁵, taken together, with the nitrogen atom to which they are attached, form a saturated heterocyclic group selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepinyl or diazapinyl, wherein said heterocyclic group is optionally substituted on a ring carbon atom by one or more R⁶ groups, optionally substituted on a ring nitrogen atom by one or more R⁹ groups and optionally benzo-fused, said benzo-fused portion being optionally substituted by one or more substituents selected from halo, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₁-C₆ alkoxy and cyano;

R⁶ is Het¹, Het², —

OR⁷, —

SR⁷, —

SOR⁸, —

SO₂R⁸, —

NR⁷R⁷, —

COR⁷, —

OCOR⁷, —

SCOR⁷,

—

NR⁷COR⁷, —

NR⁷SO₂R⁸, —

COOR⁷, —

COSR⁷, —

CONR⁷R⁷, —

OCOOR⁸, OCOSR⁸,

—

OCONR⁷R⁷, —

NR⁷COOR⁷, —

NR⁷COSR⁷, —

NR⁷CONR⁷R⁷, oxo, halo, —

CN, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or aryl;

each R⁷ is independently selected from H, C₁-C₆ alkyl and C₃-C₈ cycloalkyl;

each R⁸ is independently selected from C₁-C₆ alkyl and C₃-C₈ cycloalkyl;

R⁹ is C-linked Het¹, C-linked Het², —

SO₂R⁸, —

COR⁷, —

COOR⁸, —

COSR⁸, —

CONR⁷R⁷, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or aryl;

n is 0, 1 or 2;

Het¹ is a 3- to 8-membered, saturated or partially unsaturated heterocyclic group comprising one or two ring members selected from —

NR¹⁰—

, —

O— and

—

S(O)_n—

, said heterocyclic group being optionally substituted on a ring carbon atom by one or more substituents selected from oxo, halo, —

R⁸ or —

OR⁸ and optionally benzo-fused, said benzo-fused portion being optionally substituted by one or more substituents selected from halo, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₁-C₆ alkoxy and cyano;

R¹⁰ is H, C₁-C₆ alkyl or C₃-C₈ cycloalkyl, —

COR⁸, —

SO₂R⁸ or a bond to the group which is substituted with Het¹;

Het² is a 5-membered aromatic heterocyclic group comprising either (a) 1 to 4 nitrogen atoms, (b) one oxygen or one sulphur atom or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen atoms or a 6-membered aromatic heterocyclic group comprising 1 or 2 nitrogen atoms, said 5- or 6-membered heterocyclic group being optionally substituted by one or more substituents selected from halo, —

NR⁷R⁷, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₁-C₆ alkoxy and cyano and optionally benzo-fused, said benzo-fused portion being optionally substituted by one or more substituents selected from halo, —

NR⁷R⁷, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₁-C₆ alkoxy and cyano; and

aryl is phenyl or naphthyl optionally substituted by one or more substituents selected from halo, —

NR⁷R⁷, C₁-C₆ alkyl C₃-C₈ cycloalkyl, C₁-C₆ alkoxy and cyano.

10. A compound of formula (II):