PYRAZOLINE DERIVATIVES FOR THE TREATMENT OF TURBERCULOSIS

• US 20100179161A1
• Filed: 08/16/2006
• Published: 07/15/2010
• Est. Priority Date: 08/19/2005
• Status: Abandoned Application

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Schmitt, Stefan, Bandodkar, Balachandra Shankar
• Application Number:
  US12/063,740
• Publication Number:
  US 20100179161A1
• Time in Patent Office: Days
• US Class Current: 514/252.50
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 containing three or more hetero rings

Abstract

Compounds of the formula (I) and pharmaceutically acceptable salts or in vivo hydrolysable esters thereof, useful in the treatment of Mycobacterium tuberculosis (M.tb).

Claims

1. A compound of the formula (I)

wherein G₁ and G₂ are independently selected from C or N and the aromatic ring comprising them is further optionally substituted by one or two C_1-6 alkyl groups,

Y is O, N or C═

O,

R1 is H or C_1-6 alkyl,

R2 is H or C_1-6 alkyl;

C_6-10 aryl-C_1-6 alkyl-, C_6-10 heteroaryl-C_1-6 alkyl-, C_1-6 alkoxy, C_6-10 aryl-C_1-6 alkoxy-, C_6-10 heteroaryl-C_1-6 alkoxy-, or —

N substituted by one or two C_1-4 alkyl groups;

R3 is H, C_1-6 alkyl, C_6-10 aryl-C_1-6 alkyl-, or C_6-10 heteroaryl-C_1-6 alkyl-, C_1-6 alkoxy, C_6-10 aryl-C_1-6 alkoxy-, C_6-10 heteroaryl-C_1-6 alkoxy-, or —

N substituted by one or two C_1-4 alkyl groups;

R4 is H or C_1-6 alkyl, except where Y is O or C═

O then R4 is absent,

R5 is C_1-6 alkyl, C_5-10 aryl, C_5-10 heteroaryl, C_5-10 aryl-C_1-6 alkyl-, C_5-10 heteroaryl-C_1-6 alkyl, SO₂—

C_5-10 aryl or SO₂—

C_5-10 heteroaryl, C═

O—

C_5-10 aryl or C═

O—

C_5-10 heteroaryl, and when Y is C═

O then additionally —

NH—

C_5-10 aryl or —

NH—

C_5-10 heteroaryl,

wherein heteroaryl comprises 1-3 heteroatoms independently selected from N,O, or S and wherein each aryl or heteroaryl group is optionally substituted by 1-3 groups independently selected from C_1-6 alkyl, C_1-6 alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, halogen, hydroxy, NO₂, amino, di-C_1-6 alkylamino, phenyl or CN,

or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.

2. A compound as claimed in claim 1 or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof wherein Y is N and R5 is optionally substituted C(═

O)—

C_5-10 aryl or C(═

O)—

C_5-10 heteroaryl.

3. A compound as claimed in claim 1 or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof wherein Y is N and R5 is optionally substituted SO₂—

C_5-10 aryl or SO₂—

C_5-10 heteroaryl.

4. A compound as claimed in claim 1 or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof wherein Y is O and R5 is optionally substituted C_6-10 aryl-C_1-4 alkyl- or C_6-10 heteroaryl-C_1-4 alkyl-.

5. A compound as claimed in claim 1 or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof wherein R2 is C_1-4 alkyl.

7. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1-5, or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof, in combination with a pharmaceutically acceptable diluent or carrier

8. A method for the treatment of Mycobacterium tuberculosis which comprises administering to a human or animal an effective amount of a compound of formula (I) as claimed in any one of claims 1-5, or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof.

9. A process for the preparation of a compound of the formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof which process comprises:

where Y is N,

by reacting a compound of formula (II)

wherein R¹, R², R³, R⁴, G₁ and G₂ are as defined in relation to formula (I), with a compound of formula (III)

R5-SO₂—

Z 

 

(III)

wherein R⁵ is as defined in relation to formula (I), and

wherein Z is a leaving group, under appropriate reaction conditions;

or

(ii) where Y is C═

O, by reacting a compound of formula II as defined above, with a compound of formula (IV)

R⁵—

CO—

Z 

 

(IV)

wherein R⁵ is as defined in relation to formula (I), and

wherein Z is a leaving group, under appropriate reaction conditions;

or

(iii) Y is O, by reacting a compound of formula (V)

wherein R¹, R², R³, G₁ and G₂ are as defined in relation to formula (I),

wherein Z is a leaving group, with a compound of the formula (VI)

R⁵—

OH 

 

(VI)

wherein R⁵ is as defined in relation to formula (I), under appropriate reaction conditions;

and thereafter if desired or necessary converting any substituent group to another substituent group as defined.

6. (canceled)