US 6,472,389 B1Granted

Pyrrolo[1,2-b] pyridazine derivatives having sPLA2 inhibitory effect

AssigneeShionogi & Co., Ltd.

InventorsMitsuaki Ohtani, Masahiro Fuji, Yoshikazu Fukui, Makoto Adachi

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Abstract

The present invention provides a compound having sPLA2 inhibiting activity. The compound represented by the formula (I): wherein R1 is —(L1)—R6 wherein L1 is a divalent linking group of 1 to 18 atoms or the like, and R6 is a carbocyclic ring substituted by at least one non-interfering substituent or the like; R2 is C1 to C3 alkyl or the like; R3 is —(L2)-(acidic group); R4 and R5 are hydrogen atoms, non-interfering substituents, carbocyclic groups or the like; X is independently oxygen atom of sulfur atom; and RA is —C(═X)—C(═X)—NH2 or the like; the prodrugs thereof, their pharmaceutically acceptable salts, or their solvates, and a composition for inhibiting sPLA2 containing them as effective ingredients.

Claims7

Dependent claims

A compound represented by the formula (I):

wherein R1 is methyl or a group represented by the formula:
wherein L6 is a bond or —O—;
R13 and R14 are independently selected from the group consisting of halogen, C1 to C10 alkyl, C1 to C10 alkoxy, C1 to C10 alkylthio, aryl, thienyl, benzothienyl, thiazolyl, benzothiazolyl, oxazolyl, benzoxazolyl, and C1 to C10 haloalkyl;
p and w aye independently an integer from 0 to 5, u is an integer from 0 to 4;
R2 is C1 to C4 alkyl;
R3 is —O—(CH2)k—COOH, wherein k is an integer from 1 to 3;
R4 is a hydrogen atom;
R5 is selected from the group consisting of hydrogen atom, C1 to C6 alkyl, C7 to C12 aralkyl, C1 to C6 alkyloxy, C1 to C6 alkylthio, C1 to C6 hydroxyalkyl, C2 to C6 haloalkyloxy, halogen, carboxy, C1 to C6 alkyloxycarbonyl, axyloxy, aryloxy C1 to C8 alkyl, arylthio, arylthio C1 to C8 alkyl, cyano C1 to C8 alkyl, phenyl, cyclohexyl, 4-fluorophenyloxymethyl, trifluoromethyl, cbloromethyl, pyrrolidin-1-ylmethyl, morpholinomethyl, 4methylpiperazin-1-ylmethyl, 4-fluorophenyl, 4-methyloxyphenyl, cyclopentyl, benzodioxol-5-yl, methylthiomethyl, methyloxymethyl, 4-methyloxyphenyloxymethyl, 3,4-dimethyloxyphenyloxymethyl, 4-methylphenyloxymethyl, and 2,5-dioxopyrrolidin-1-ylmethyl;
and
RA is a group represented by the formula:
wherein Z is —NH2 or —NHNH2, or a pharmaceutically acceptable salt, hydrate or ester thereof.

8 more elements

A pyrrolo[1,2-b]pyridazine compound selected from the group consisting of:

Methyl (5-aminooxalyl-7-benzyl-6-ethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
(5-aminooxalyl-7-benzyl-6-ethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,
Sodium (5-aminooxalyl-7-benzyl-6-ethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
Methyl (5-aminooxalyl-7-benzyl-6-ethyl-2-methylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
(5-aminooxalyl-7-benzyl-6-ethyl-2-methylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,
Methyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
Ethyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
2-(Morpholine-4-yl)ethyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
(5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,
Sodium (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
Methyl (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
(5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,
Methyl [5-aminooxalyl-7-benzyl-6-ethyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy]acetate,
[5-aminooxalyl-6-ehtyl-7-(2-flourobenzyl)-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid
Methyl [5-aminooxalyl-7-benxyl-6-ethyl-2-(4-fluorobenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate,
[5-aminooxalyl-6-ethyl-7-(2-fluorobenzyl)-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid,
Methyl [5-aminooxalyl-7-benzyl-6-ethyl-2-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate,
[5-aminooxalyl-7-benzyl-6-ethyl-2-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid,
Methyl (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
(5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,
Methyl [5-aminooxalyl-7-benzyl-6-ethyl-2-(4-methoxyphenyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate,
[5-aminooxalyl-7-benzyl-6-ethyl-2-(4-methoxyphenyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid,
Methyl [5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate,
[5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid,
Methyl [5-aminooxalyl-6-ethyl-2-methyl-7-(3-phenoxybenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate,
[5-aminooxalyl-6-ethyl-2-methyl-7-(3-phenoxybenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid,
Methyl (5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
(5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,
Methyl (5 -aminooxalyl-2,7-dibenzyl-6-methylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
(5-aminooxalyl-2,7-dibenzyl-6-methylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,
Methyl[5-aminooxalyl-2,6-dimethyl-7-[2-(4-fluorophenyl)benzyl]pyrrolo[1,2-b]pyridazine-4-yloxy]acetate, and
[5-aminooxalyl-2,6-dimethyl-7-[2-(4-fluorophenyl)benzyl]pyrrolo[1,2-b]pyridazine-4-yloxy]acetic acid;
or a pharmaceutically acceptable salt, hydrate or ester thereof.

30 more elements

A pyrrolo[1,2-b]pyridazine compound selected from the group consisting of

Methyl(5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
Ethyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
2-(Morpholine-4-yl)ethyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
Sodium (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
(5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,
Methyl (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
Ethyl (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
2-(Morpholine-4-yl)ethyl (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
Sodium (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
(5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,
Methyl (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
Ethyl (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
2-(Morpholine-4-yl)ethyl 5 -aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
Sodium (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
(5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,
Methyl [5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate,
Ethyl [5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate,
2-(Morpholine-4-yl)ethyl 5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
Sodium [5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy]acetate,
(5-aminooxalyl-6-ethyl-2-methyl-7-(2-phenylbenzyl)pyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid,
Methyl (5 -aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
Ethyl (5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
2-(Morpholine-4-yl)ethyl 5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate,
Sodium (5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo[1,2-b]pyridazine-4-yloxy)acetate, and
(5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo[1,2-b]pyridazine-4-yloxy)acetic acid, or a pharmaceutically acceptable salt, hydrate or ester thereof.

22 more elements

Dependencies are inferred from the claim text.