Azaindole derivatives, process for their preparation, and their use as antitumor agents

• US 6,486,322 B1
• Filed: 10/02/2001
• Issued: 11/26/2002
• Est. Priority Date: 06/19/2000
• Status: Expired due to Fees

• Current Assignee: Pharmacia Italia SPA (Pfizer Inc.)
• Original Assignee: Pharmacia Italia SPA (Pfizer Inc.)
• Inventors: Brasca, Maria Gabriella, Varasi, Mario, Pevarello, Paolo, Traquandi, Gabriella, Longo, Antonio, Orsini, Paolo, Vulpetti, Anna, Pittalà, Valeria
• Primary Examiner(s): DENTZ, BERNARD I
• Application Number:
  US09/968,042
• Publication Number:
  US 20030004350A1
• Time in Patent Office: 420 Days
• Field of Search: 546/113
• US Class Current: 546/113
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Novel 1H-pyrrolo[2,3-b]pyridines which are represented by formula (I):

wherein R is a hydrogen or halogen atom or a group selected from —CN, —OH, —OCOR₄, —(CH₂)_nNH₂, —(CH₂)_nNHR₄, —(CH₂)_nNHCOR₄, —(CH₂)_nNHCONR₄R₅, —(CH₂)_nNHCOOR₄, or —(CH₂)_nNHSO₂R₄, wherein n is either 0 or 1, R₄ and R₅ are as described in the specification; R₁ is hydrogen or an optionally substituted alkyl group; R₂ is an optionally substituted group selected from alkyl or aryl; R₃ is hydrogen or a group selected from —CONR₄R₅, —COOR₄, —CONHOR₄, —SO₂NHR₄, alkylsulphonylaminocarbonyl or perfluorinated alkylsulphonylaminocarbonyl; or a pharmaceutically acceptable salt thereof, are disclosed.

These compounds are useful for treating cell proliferative disorders associated with an altered cell dependent kinase activity.

Claims

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

wherein

R is;

a halogen atom or

selected from the group consisting of —

CN, —

OH, —

OCOR₄, —

(CH₂)_nNH₂, —

(CH₂)_nNHR₄, —

(CH₂)_nNHCOR₄, —

(CH₂)_nNHCONR₄R₅, —

(CH₂)_nNHCOOR₄, and —

(CH₂)_nNHSO₂R₄,

wherein n is either 0 or 1, and wherein

R₄ and R₅ are, independently from each other, hydrogen or an optionally substituted group selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl or, taken together to the nitrogen atom to which they are bonded, form an optionally substituted heterocyclyl group; and

wherein R₁ is optionally substituted alkyl, comprising;

reacting a compound of formula (VII);

 

with

a) methylmagnesium iodide, thus obtaining a compound of formula (VIII);

 

and

b) reacting the compound of formula (VIII) with a compound of formula (IX);

2. A compound of formula (II):

wherein

R is;

a halogen atom or

is selected from the group consisting of —

CN, —

OH, —

OCOR₄, —

(CH₂)_nNH₂, —

(CH₂)_nNHR₄, —

(CH₂)_nNHCOR₄, —

(CH₂)_nNHCONR₄R₅, —

(CH₂)_nNHCOOR₄, and —

(CH₂)_nNHSO₂R₄,

wherein n is either 0 or 1, and wherein

R₄ and R₅ are, independently from each other, hydrogen or an optionally substituted group selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl or, taken together to the nitrogen atom to which they are bonded, form an optionally substituted heterocyclyl group; and

R₁ is hydrogen or an optionally substituted alkyl group,

provided that when R₁ is hydrogen, then R is not hydroxy, amino or ureido and

provided that when R₁ is chloromethyl or dimethylaminomethyl, then R is not a chlorine atom at position 6.

3. The compound of claim 2, wherein R is a halogen atom.

4. The compound of claim 2, wherein R is selected from the group consisting of —

CN, —

OH, —

OCOR₄, —

(CH₂)_nNH₂, —

(CH₂)_nNHR₄, —

(CH₂)_nNHCOR₄, —

(CH₂)_nNHCONR₄R₅, —

(CH₂)_nNHCOOR₄, and —

(CH₂)_nNHSO₂R₄; and

n=1.

5. The compound of claim 2, wherein R is selected from the group consisting of —

CN, —

OH, —

OCOR₄, —

(CH₂)_nNH₂, —

(CH₂)_nNHR₄, —

(CH₂)_nNHCOR₄, —

(CH₂)_nNHCONR₄R₅, —

(CH₂)_nNHCOOR₄, and —

(CH₂)_nNHSO₂R₄; and

n=0.

6. The compound of claim 2, wherein R is selected from the group consisting of —

CN, —

OH, —

OCOR₄, —

(CH₂)_nNH₂, —

(CH₂)_nNHR₄, —

(CH₂)_nNHCOR₄, —

(CH₂)_nNHCONR₄R₅, —

(CH₂)_nNHCOOR₄, and —

(CH₂)_nNHSO₂R₄; and

R₄ and R₅ are, independently from each other, an optionally substituted group selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl or, taken together to the nitrogen atom to which they are bonded, form an optionally substituted heterocyclyl group.

7. The compound of claim 2, wherein R₁ is alkyl.

8. The compound of claim 2, wherein R₂ is a substituted alkyl group.

9. The compound of claim 2, wherein R₁ is hydrogen.

18. A process for preparing a compound of formula (II) as defined in claim 2, wherein R₁ is hydrogen, comprising:

reacting a compound of formula (VII);

with a suitable formylating agent, wherein R is as defined in claim 2.

19. The process of claim 18, wherein said formylating agent is hexmethylenetetramine.

10. A compound of formula (II):

wherein

R is;

a halogen atom or

is selected from the group consisting of —

CN, —

OH, —

OCOR₄, —

(CH₂)_nNH₂, —

(CH₂)_nNHR₄, —

(CH₂)_nNHCOR₄, —

(CH₂)_nNHCONR₄R₅, —

(CH₂)_nNHCOOR₄, and —

(CH₂)_nNHSO₂R₄,

wherein n is either 0 or 1, and wherein

R₄ and R₅ are, independently from each other, hydrogen or an optionally substituted group selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl or, taken together to the nitrogen atom to which they are bonded, form an optionally substituted heterocyclyl group; and

R₁ is an optionally substituted alkyl group,

with the proviso that when R is chlorine at position 6, then R₁ is not methyl substituted with chlorine or methyl substituted with dimethylamino.

11. The compound of claim 10, wherein R is a halogen atom.

12. The compound of claim 10, wherein R is selected from the group consisting of —

CN, —

OH, —

OCOR₄, —

(CH₂)_nNH₂, —

(CH₂)_nNHR₄, —

(CH₂)_nNHCOR₄, —

(CH₂)_nNHCONR₄R₅, —

(CH₂)_nNHCOOR₄, and —

(CH₂)_nNHSO₂R₄; and

n=1.

13. The compound of claim 10, wherein R is selected from the group consisting of —

CN, —

OH, —

OCOR₄, —

(CH₂)_nNH₂, —

(CH₂)_nNHR₄, —

(CH₂)_nNHCOR₄, —

(CH₂)_nNHCONR₄R₅, —

(CH₂)_nNHCOOR₄, and —

(CH₂)_nNHSO₂R₄; and

n=0.

14. The compound of claim 10, wherein R is selected from the group consisting of —

CN, —

OH, —

OCOR₄, —

(CH₂)_nNH₂, —

(CH₂)_nNHR₄, —

(CH₂)_nNHCOR₄, —

(CH₂)_nNHCONR₄R₅, —

(CH₂)_nNHCOOR₄, and —

(CH₂)_nNHSO₂R₄; and

R₄ and R₅ are, independently from each other, an optionally substituted group selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl or, taken together to the nitrogen atom to which they are bonded, form an optionally substituted heterocyclyl group.

15. The compound of claim 14, wherein R is —

CN, —

OCOR₄, (CH₂)_nNHCOR₄, —

(CH₂)_nNHCONR₄R₅, —

(CH₂)_nNHCOOR₄, or —

(CH₂)_nNHSO₂R₄.

16. The compound of claim 10, wherein R₁ is alkyl.

17. The compound of claim 10, wherein R₁ is substituted alkyl.