IP Library › Granted Patent US 7,153,854

Granted Patent B2

US 7,153,854 · App. 10/747,079 · Granted Dec 26, 2006

Pyrrolopyridazine derivatives

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 7,153,854
App. No.: 10/747,079
Granted: Dec 26, 2006
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The invention relates to compound of the formula (I) or its salt, in which R 1 , R 2 , R 3 and R 4 are as defined in the description, their use of as medicament, the process for their preparation and use for the treatment of PDE-IV or TNF-α mediated diseases

Claims (250)

1. A compound of the formula I or a pharmaceutically acceptable salt thereof, or a prodrug thereof:

wherein

R 1 is a phenyl, a pyrrolyl, an isooxazolyl, a furanyl, a thienyl, a lower alkyl optionally substituted by a lower alkoxy, a piperazinyl or a morpholinyl, wherein a lower alkoxy is optionally substituted by a cyclo(lower)alkyl or a pyridinyl,

R 2 is —(CH2)n-R 7 , wherein n is an integer which may range from 2 to 5, and R 7 is a carboxy or an esterified carboxy, and

R 7 is

(1) a hydrogen,

(2) a substituted aryl or an unsubstituted aryl,

(3) a substituted heterocyclic group or an unsubstituted heterocyclic group,

(4) a carboxy, a protected carboxy or CONR 10 R 11 ,

(5) an acyl or a halocarbonyl,

(6) a cyano,

(7) an amino, a protected amino, a or mono- or di(lower)alkylamino,

(8) a hydroxy, an aryloxy, an acyloxy or a lower alkyl optionally substituted by a hydroxy or an acyloxy,

(9) a lower alkylthio, a lower alkylsulfinyl or a lower alkylsulfonyl, or

(10) —O—R 12 ,

R 3 is (1) a phenyl optionally substituted by a lower alkyl, a cyclo(lower)alkyl, a lower alkoxy, a halogen, a cyano, or a carbamoyl; or (2) a pyridinyl substituted by a lower alkyl, a cyclo(lower)alkyl, a lower alkoxy, a carbamoyl or a halogen,

R 4 is a hydrogen, a halogen, a cyano, a carbamoyl, an acyl, a thiocyanate, a lower alkylthio, a lower alkenyl, a hydroxyl(lower)alkyl, a trihalo(lower)alkyl, or a lower alkyl,

R 10 and R 11 each independently represents a hydrogen, a lower alkylsulfonyl, a heterocyclic group, or a lower alkyl optionally substituted by a hydroxy, an alkoxy, a sulfo, a carboxy, a protected carboxy or —R 17

or alternatively R 10 and R 11 , together with a nitrogen atom to which they are attached, represent a N-containing heterocyclic group, and

R 12 and R 17 are each independently a group derived from a protected sugar or an unprotected sugar by removal of the hydroxy group therefrom.

2. The compound of claim 1 , wherein

R 4 is a lower alkyl.

3. The compound of claim 1 , which is

(1) 3-[7-Ethyl-2-methyl-3-(4-pyridinyl)-pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile,

(2) 3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile,

(3) 4-[7-Ethyl-2-methyl-3-(methylsulfonyl)-pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile,

(4) 3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzamide,

(5) Ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate,

(6) 2-{[4-(3-Chlorophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]methyl}-1,3-propanediol,

(7) 3-[4-(3-Chlorophenyl)-7-ethyl-2-phenyl-pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid,

(8) 5-[7-Ethyl-2-methyl-4-(6-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid,

(9) 5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid,

(10) 5-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid,

(11) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid,

(12) 3-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid,

(13) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid,

(14) Ethyl(2E)-3-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propenoate,

(15) 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid,

(16) 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid,

(17) 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic acid,

(18) 5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid,

(19) 5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid,

(20) 4-{4-(5-chloro-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoic acid,

(21) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic acid,

(22) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic acid,

(23) 5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid,

(24) 5-{4-(3-cyanophenyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid, or

a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , which is

(1) ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate,

(2) 3-[4-(3-Chlorophenyl)-7-ethyl-2-phenyl-pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid,

(3) 5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid,

(4) 5-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid,

(5) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid,

(6) 3-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid,

(7) 5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid,

(8) 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid,

(9) 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid,

(10) 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic acid,

(11) 5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid,

(12) 5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic acid,

(13) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic acid,

(14) 5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid, or

a pharmaceutically acceptable salt thereof.

5. A process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, or a prodrug thereof:

wherein

R 1 is (1) a carboxy or a protected carboxy,

(2) —CONR 5 R 6 ,

(3) a hydroxy or a lower alkoxy,

(4) an amino, a cyclo(lower)alkylamino or a mono- or di(lower)alkylamino optionally substituted by a lower alkoxy,

(5) a trihalo(lower)alkyl,

(6) a trihalo(lower)alkylsulfonyloxy or an arylsulfonylamino,

(7) a substituted lower alkyl or an unsubstituted lower alkyl,

(8) a substituted aryl or an unsubstituted aryl, or

(9) a substituted heterocyclic group or an unsubstituted heterocyclic group,

R 2 is R 7 or -(A 1 )p-X-A 2 -R 7 ,

wherein

p is an integer of 0 or 1

A 1 is a (C 1 –C 2 )alkylene or —CH═CH—;

A 2 is —(CH 2 )n- or —(CH═CH)m- wherein n is an integer which may range from 1 to 6, and m is an integer which may range from 1 to 3;

X is a single bond, —O—, —NR 8 —, —C(═O)—, —C(═NR 9 )— or a hydroxy(C 1 –C 2 )alkylene wherein R 8 is a hydrogen or a lower alkyl, and R 9 is a substituted N-containing heterocyclic group, an unsubstituted N-containing heterocyclic group, and

R 7 is

(1) a hydrogen,

(2) a substituted aryl or an unsubstituted aryl,

(3) a substituted heterocyclic group or an unsubstituted heterocyclic group,

(4) a carboxy, a protected carboxy or CONR 10 R 11 ,

(5) an acyl or a halocarbonyl,

(6) a cyano,

(7) an amino, a protected amino, a or mono- or di(lower)alkylamino,

(8) a hydroxy, an aryloxy, an acyloxy or a lower alkyl optionally substituted by a hydroxy or an acyloxy,

(9) a lower alkylthio, a lower alkylsulfinyl or a lower alkylsulfonyl, or

(10) —O—R 12 ,

R 1 and R 2 are combined together to form a lower alkylene or a lower alkenylene group which is optionally interrupted by an amino or a sulfonyl, and optionally fused with a benzene ring, and optionally substituted by the group consisting of a lower alkyl, a hydroxy, an oxo, and a lower alkoxy,

R 3 is a substituted aryl, an unsubstituted aryl, a substituted heterocyclic group, or an unsubstituted heterocyclic group,

R 4 is a hydrogen, a halogen, a cyano, a carbamoyl, an acyl, a thiocyanate, a lower alkylthio, a lower alkenyl, a hydroxyl(lower)alkyl, a trihalo(lower)alkyl, or a lower alkyl,

R 5 , R 6 , R 10 and R 11 each independently represents a hydrogen, a lower alkylsulfonyl, a heterocyclic group, or a lower alkyl optionally substituted by a hydroxy, an alkoxy, a sulfo, a carboxy, a protected carboxy or —R 17

or alternatively R 5 and R 6 , or R 10 and R 11 , together with a nitrogen atom to which they are attached, represent a N-containing heterocyclic group, and

R 12 and R 17 are each independently a group derived from a protected sugar or an unprotected sugar by removal of the hydroxy group therefrom,

the process comprising:

(1) reacting a compound (II) of formula

wherein R 3 and R 4 are as defined for formula (I) or a salt thereof with a compound (III) of formula

wherein R 1 and R 2 are as defined for formula (I) or a salt thereof to obtain a compound (I) of formula

wherein R 1 , R 2 , R 3 , and R 4 are as defined for formula (I) or a salt thereof, or

(2) reacting a compound (V) of formula

wherein R 4 is as defined for formula (I) or a salt thereof with a compound (VI) of formula

wherein R 1 , R 2 and R 3 are as defined for formula (I) or a salt thereof to obtain a compound (I) of formula

or a salt thereof.

6. A pharmaceutical composition comprising:

a compound of claim 1 in admixture with a pharmaceutically acceptable carrier.

7. The compound of claim 1 , wherein R 7 is

(1) a hydrogen,

(2) a substituted aryl or an unsubstituted aryl,

(3) a cyano,

(4) an amino, a protected amino, a or mono- or di(lower)alkylamino, or

(5) a lower alkylthio, a lower alkylsulfinyl or a lower alkylsulfonyl.

8. The compound of claim 3 , which is 3-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid or a pharmaceutically acceptable salt thereof.

9. A composition comprising the compound of claim 8 and a pharmaceutically acceptable carrier.

10. The compound of claim 4 , which is 3-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid.

11. A composition comprising the compound of claim 10 and a pharmaceutically acceptable carrier.

12. The process of claim 5 , where in the compound of formula (I)

R 1 is (1) a carboxy or a protected carboxy,

(2) —CONR 5 R 6 wherein R 5 and R 6 each independently represents a lower alkyl, or alternatively R 5 and R 6 , together with a nitrogen atom to which they are attached represents a saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s),

(3) a hydroxy or a lower alkoxy,

(4) an amino, a cyclo (lower) alkylamino, or a mono- or di(lower)alkylamino optionally substituted by a lower alkoxy,

(5) a trihalo(lower)alkyl,

(6) a trihalo(lower)alkylsulfonyloxy or an arylsulfonylamino,

(7) a lower alkyl optionally substituted by

(i) a halogen;

(ii) a carboxy;

(iii) a protected carboxy;

(iv) a cyano;

(v) a carbamoyl;

(vi) —OCONR 15 R 16

wherein R 15 and R 16 each independently represents a hydrogen, an aryl or a lower alkyl optionally substituted by an aryl, or R 15 and R 16 , together with the nitrogen atom to which they are attached, represents a saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) and also optionally containing an oxygen atom;

(vii) a lower alkylthio;

(viii) a lower alkylsulfonyl;

(ix) a lower alkylsulfonyloxy;

(x) a lower alkylsulfonylamino;

(xi) a mono- or di(lower)alkylamino optionally substituted by a hydroxy, a lower alkoxy, an aryloxy, or a substituted or an unsubstituted aryl;

(xii) an amino;

(xiii) an acylamino;

(xiv) a protected amino;

(xv) a hydroxy;

(xvi) an acyloxy;

(xvii) a cyclo(lower)alkyloxy;

(xviii) an aryloxy;

(xix) an aryl;

(xx) a saturated or unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 3 nitrogen atom(s) and also optionally containing an oxygen atom or a sulfur atom which is optionally substituted by a lower alkyl, a hydroxy(lower)alkyl, an aryl or an oxo; or

(xxi) a lower alkoxy optionally substituted by a carboxy, a protected carboxy, a hydroxy, a protected hydroxy, a lower alkoxy, a cyclo(lower)alkyl, a substituted aryl, an unsubstituted aryl, a saturated or an unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) optionally substituted by a lower alkyl, or —CONR 13 R 14

wherein R 13 and R 14 each independently represents a hydrogen or a lower alkyl optionally substituted by an aryl, or R 13 and R 14 , together with a nitrogen atom to which they are attached, represents a saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) and also optionally containing an oxygen atom,

(8) an aryl optionally substituted by the substituent(s) selected from the group consisting of a halogen, or

(9) a saturated or an unsaturated 5- or 6-membered heteromonocyclic group optionally substituted by a lower alkyl or a halogen,

R 2 is R 7 or -(A 1 )p-X-A 2 -R 7

wherein

p is 0 or 1;

A 1 is a (C 1 –C 2 )alkylene or —CH═CH—;

A 2 is —(CH 2 )n- or —(CH═CH)m- wherein n is an integer which may range from 1 to 6, and m is an integer which may range from 1 to 3;

X is a single bond, —O—, —NR 8 —, —C(═O)—, —C(═NR 9 )— or a hydroxy(C 1 –C 2 )alkylene; wherein R 8 is a hydrogen or a lower alkyl, and R 9 is a substituted pyrrolyl, or an unsubstituted pyrrolyl

R 7 is

(1) a hydrogen,

(2) an aryl optionally substituted by a lower alkoxy,

(3) an unsaturated heteromonocyclic group containing 1 to 2 nitrogen atom(s), (4) a carboxy, an esterified carboxy or —CONR 10 R 11 wherein R 10 and R 11 each independently represents a hydrogen, a lower alkylsulfonyl, an unsaturated heteromonocyclic group containing 1 to 2 nitrogen atom(s) or a lower alkyl optionally substituted by a hydroxy, an alkoxy, a carboxy, a protected carboxy, a sulfo or —R 17 , or alternatively R 10 and R 11 , together with a nitrogen atom to which they are attached, represents a saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) and also optionally containing an oxygen atom including a morpholinyl,

(5) an acyl or a halocarbonyl,

(6) a cyano,

(7) an amino, a protected amino or a mono- or di(lower)alkylamino,

(8) a hydroxy, an aryloxy, an acyloxy or a lower alkoxy optionally substituted by a hydroxy or an acyloxy,

(9) a lower alkylthio, a lower alkylsulfinyl or a lower alkylsulfonyl, or

(10) —O—R 12 ,

is represents by the following formula:

R 3 is (1) an aryl optionally substituted by at least one substituent(s) selected from the group consisting of

(i) a halogen,

(ii) a carboxy,

(iii) a protected carboxy,

(iv) a cyano,

(v) —CONR 15 R 16 wherein R 15 and R 16 each independently represents a hydrogen, a lower alkyl optionally substituted by a hydroxy,

(vi) a lower alkyl,

(vii) a cyclo(lower)alkyl,

(viii) a hydroxy(lower)alkyl,

(ix) a lower alkoxy,

(x) a trihalo(lower)alkyl,

(xi) an unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 2 nitrogen atom(s),

(xii) a lower alkylsulfonyl,

(xiii) a nitro,

(xiv) a sulfamoyl, and

(xv) a protected sulfamoyl; or

(2) a heterocyclic group selected from the group consisting of a pyridinyl, a pyrazinyl, an oxazolyl, an isooxazolyl, a furanyl, a thienyl, a quinolinyl, a benzofuranyl and a benzothienyl,

wherein said heterocyclic group is optionally substituted by at least one substituent(s) selected from the group consisting of (i) a lower alkyl, (ii) a cyclo(lower)alkyl, (iii) a lower alkoxy, (iv) an acyl, (v) an amino, (vi) a mono- or di(lower)alkylamino, (vii) a protected amino, (viii) a cyano, (ix) a carboxy, (x) a protected carboxy, (xi) —CONR 15 R 16

wherein R 15 and R 16 each independently represents a hydrogen, a lower alkyl optionally substituted by a hydroxy, (xii) a lower alkenyl optionally substituted by a lower alkoxy, (xiii) a halogen, (xiv) a lower alkylthio and (xv) a hydroxyl;

R 4 is a hydrogen, a halogen, a cyano, a carbamoyl, an acyl, a thiocyanate, a lower alkylthio, a lower alkenyl, a hydroxyl(lower)alkyl, a trihalo(lower)alkyl, or a lower alkyl,

R 12 and R 17 are each independently a group derived from a protected sugar, or an unprotected sugar by removal of a hydroxy group therefrom.

13. The process of claim 12 , where in the compound of formula (I) R 4 is a lower alkyl.

14. The process of claim 13 , where in the compound of formula (I) R 1 is

(1) a mono- or di(lower)alkylamino,

(2) a phenyl,

(3) a saturated or unsaturated 5 to 6 membered heteromonocyclic group selected from the group consisting of a pyrrolidinyl, a pyrrolyl, an oxazolyl, an isooxazolyl, a thiazolyl, a furanyl, a thienyl, and a pyridinyl, or

(4) a lower alkyl optionally substituted by (i) a lower alkoxy or (ii) a saturated 5- or 6-membered heteromonocyclic group selected from the group consisting of a piperazinyl and a morpholinyl, wherein the lower alkoxy is optionally substituted by a cyclo(lower)alkyl or a pyridinyl.

15. The process of claim 14 , where in the compound of formula (I) R 2 is R 7 or -A 2 -R 7 ,

wherein A 2 is —(CH2)n- or —(CH═CH)m-

wherein n is an integer which may range from 2 to 6, and m is an integer of 1 or 2, and

R 7 is a hydrogen, a lower alkyl sulfonyl, a carboxy, an esterified carboxy or a pyridinyl,

R 3 is (1) a phenyl optionally substituted by a lower alkyl, a cyclo(lower)alkyl, a lower alkoxy, a halogen, a cyano, or a carbamoyl; or

(2) a quinolinyl; or a pyridinyl substituted by a lower alkyl, a cyclo(lower)alkyl, a lower alkoxy, a carbamoyl or a halogen.

16. The process of claim 15 where in the compound of formula (I)

R 2 is —(CH2)n-R 7 , wherein n is an integer which may range from 2 to 5, and R 7 is a carboxy or an esterified carboxy, and

17. The process of claim 15 , wherein the compound of formula (I) is