MXPA00011018A - PYRROLO[1,2-b]PYRIDAZINE DERIVATIVES HAVING sPLA2 - Google Patents

Abstract

Compounds having sPLA2 inhibitory effect represented by general formula (I), prodrugs thereof, pharmaceutically acceptable salts thereof or solvates of the same, and sPLA2 inhibitors containing the same as the active ingredient, wherein R1 represents -(L1)-R6 (wherein L1 represents a divalent linking group having 1 to 18 atoms, etc.;and R6 represents a carbon ring having one or more non-interfering substituents, etc.);R2 represents C1-3 alkyl, etc.;R3 represents -(L2)-(acidic group);R4 and R5 represent each hydrogen, a non-interfering substituent, a carbon ring, etc.;Xs independently represent each oxygen or sulfur;and RA represents -C(=X)-C(=X)-NH2, etc.

Description

INHIBITOR OF PIRRÓLO sPLA2 [1, 2-B] PYRIDAZINE Field of the Invention The present invention relates to a pyrrolo [1,2-b] pyridazine derivative effective for the inhibition of the release of the fatty acid mediated by sPLA2.

Antecedents of the Invention The sPLA2 (secreted phospholipase A2) is an enzyme that hydrolyzes the phospholipids of the membrane and is considered to be the enzyme that determines the relationship that governs the so-called arachidonate cascade where the arachidonic acid, the hydrolysis product, is the material of departure.' On the other hand, the lysophospholipids that are produced by these by-products in the hydrolysis of the phospholipids are known as important mediators in cardiovascular diseases. Consequently, in order to normalize the excessive functions of the arachidonate cascade and the lysophospholipids, it is important to develop Ref: 124574 compounds that inhibit the release of fatty acids mediated by sPLA2 (for example, arachidonic acid), especially compounds that inhibit the activity or production of sPLA2. Such compounds are useful for the general treatment of symptoms, which are induced and / or sustained by an excess of sPLA2 formation, such as septic shock, respiratory distress syndrome in adults, inflammation of the pancreas, injury, bronchial asthma, allergic rhinitis, chronic rheumatism, arterial sclerosis, cerebral apoplexy, cerebral infarction, inflammatory colitis, psoriasis, heart failure, cardiac infarction, and others. The participation of the sPLA2 is considered to be extremely broad and, in addition, its action is powerful.

Examples of inhibitors of sPLA2 are known, indole derivatives in EP 620214 (JP open to the public No. 010838/95), EP-620215 (JP open to the public No. 025850/95, EP-675110 (JP open No. 285933/95), WO 96/03376, and WO 99/00360, Indene derivatives in WO 96/03120, Indolizine derivatives in WO 96/03383, Naphthalene derivatives in WO 97/21664 and WO 97/21716, tricyclic derivatives in WO 98/18464, pyrazole derivatives in WO 98/24437, phenylacetamide derivatives in WO 98/24756, phenyl glyoxamide derivatives in WO 98/24794, pyrrole derivatives in WO 98/25609.

Description of the invention The present invention provides derivatives of pyrrolo [1,2-b] pyridazine having sPLA2 inhibitory activity and which are useful for the treatment of septic shock, respiratory burnout syndrome in adults, inflammation of the pancreas, injury, bronchial asthma, rhinitis allergic, chronic rheumatism, arterial sclerosis, cerebral hemorrhage, inflammatory colitis, psoriasis, heart failure, and cardiac infarction.

The present invention relates to i [a compound represented by the formula (I): wherein R1 is a group selected from (a) C6 alkyl to C20, C6 alkenyl to C20 alkynyl C6 to C20, carbocyclic groups, and heterocyclic groups, (b) the groups represented by (a) each independently substituted with the minus a selected group of substituents without interference, and (c) - (L1) -R6 wherein L1 is a divalent linking group from 1 to 18 atoms, selected from hydrogen atoms, nitrogen atoms, carbon atoms, carbon atoms, oxygen, and sulfur atoms, and R6 is a group selected from groups (a) and (b); R is hydrogen atom or a group containing from 1 to 4 atoms without hydrogen; R3 is - (L2) - (acid group) wherein L2 is an acid linkage having an acid linkage length of 1 to 5; R4 and R5 are independently selected from a hydrogen atom, substituent (s) without interference, carbocyclic groups, carbocyclic groups substituted with a substituent (s) without interference, heterocyclic groups, and heterocyclic groups substituted by a substituent (s) without interference; Y RA is a group represented by the formula wherein L7 is a divalent linking group selected from a bond or a divalent group selected from -CH2-, -0-, -S-NH-, or -CO-, R27 and R28 are independently hydrogen, Cl to C3 alkyl or halogen; X and Y are independently an oxygen atom or a sulfur atom; and Z is -NH2-, NHNH2; the prodrugs thereof, or their pharmaceutically acceptable salts; or its solvates.

In more detail, the present invention relates to ii) a compound represented by formula II wherein R7 is - (CH2) m -R12 where m is an integer from 1 to 6, and R12 is (d) a group represented by the formula: wherein a, c, e, n, q, and t are independently an integer from 0 to 2, R13 and R14 are independently selected from halogen, C1 to CIO alkyl, C1 to CIO alkyloxy, C1 to CIO alkylthio, aryl, heteroaryl, and haloalkyl Cl up to CIO, a is a hydrogen atom or a sulfur atom, L5 is - (CH2) v-, C = C-, -C = C-, -O-, u -S-, v is an integer from 0 up to 2, ß is -CH2- or - (CH2) 2-,? is an oxygen atom or a sulfur atom, b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, and w are independently an integer from 0 to 5, g is an integer 0 to 2 , r is an integer from 0 to 7, and u is an integer from 0 to 4, or is (e) a member of (d) substituted with at least one substituent selected from the group consisting of Cl to C6 alkyl, alkyloxy Cl up to C6, haloalkyloxy Cl up to C6, haloalkyl Cl up to C6, aryl, and a halogen; R is C1 to C3 alkyl, C2 to C3 alkenyl, C3 to C4 cycloalkyl, C3 to C4 cycloalkenyl, Cl to C2 haloalkyl, Cl to C3 alkyloxy or Cl to C3 alkylthio; R 'is - (L) -R, 15 where L is represented by the formula wherein M is -CH2-, -O-, -N (R24) -, or -S-, R16 and R17 are independently hydrogen atom, Cl alkyl up to CIO, aryl, aralkyl, alkyloxy, haloalkyl, carboxy, or a halogen, and R24 is a hydrogen atom or alkyl Cl up to C6, and R15 is represented by the formula: wherein R18 is a hydrogen atom, a metal, or Cl alkyl up to CIO, R19 is independently a hydrogen atom, or Cl alkyl up to CIO, and t is an integer from 1 to 8; R10 and R11 are independently hydrogen atom or an interference-free substituent selected from C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C7 to C12 aralkyl, C7 to C12 alkaryl, C3 to C8 cycloalkenyl C3 to C8 cycloalkyl phenyl, tolyl, xylyl, biphenylyl, C1 to C8 alkyloxy, C2 to C8 alkynyloxy, C2 to C8 alkynyloxy, C2 to C12 alkyloxylalkyl, C2 to C12 alkyloxykyloxy, C2 to C12 alkylcarbonyl, C2 to C12 alkylcarbonylamino, C2 to C12 alkynylamino, alkylaminoaminocarbonyl C2 to C12, alkylamino Cl to C12, alkylthio Cl to C6, alkylthiocarbonyl C2 to C12, alkylsulfinyl Cl to C8, alkylsulfonyl Cl to C8, haloalkyloxy to C2 to C8, haloalkylsul fonyl Cl to C8, haloalkyl C2 to C8, hydroxyalkyl Cl to C8, -C (O) O (Cl to C8 alkyl), - (CH2) 2-0- (Cl to C8 alkyl), benzyloxy, aryloxy, Cl to C8 aryloxy, arylthio, Cl to C8 alkyl, C alkyl l up to C8, cyano Cl up to C8, - (CONHS02R25), -CHO, amino, amidino, halogen, carbamyl, carboxyl, carbalkoxy, (CH2) -C02H, cyano, cyanoguanidinyl, guanidino, hydrazido, hydrazino, hydrazide, hydroxy, hydroxy ino, iodo, nitro, phosphono, -S03H, thioacetal, thiocarbonyl, or carbonyl, R25 is Cl to C6 alkyl or aryl, z is an integer from 1 to 8; and RB is a group represented by the formula: wherein Z is the same defined above; the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates.

When the above b, d, f, p, r, u, and / or w are 2 or more, a plural number of R13 or R14 may be different from one or the other. When R13 is a substituent on the naphthyl group, the substituent can be substituted at any arbitrary position on the naphthyl group. iii) A compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in i) or ii) above, wherein said R1 and R7 are independently represented by the formula: where R13, R14, b, d, f, g, p, r, u, w, a, ß, y? are the same as defined above, L6 is a bond -CH2-, -C = C-, C = C-, -O-, or -S-.

When the above b, d, f, p, r, u, and / or w are 2 or more, a plural number of R13 or R14 may be different from each other. When R13 is a substituent on the naphthyl group, the substituent can be substituted at any arbitrary position on the naphthyl group. iv) A compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in any of i) to iii), wherein R2 and R8 are Cl to C3 alkyl or C3 to C4 cycloalkyl. v) A compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in any of i) to iv), wherein L2 and L3 are -0-CH2-. vi) A compound represented, by the formula (III): where R is a group represented by the formula: wherein L is a bond, -CH2-, -C = C-, -C = C-, -0- or -S-; R13 and R14 are independently selected from halogen, Cl to CIO alkyl, Cl to CIO alkyloxy, Cl to CIO alkylthio, aryl, heteroaryl, and Cl to CIO haloalkyl; b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, and w are independently an integer from 0 to 5, g is an integer from 0 to 2, r is an integer from 0 to 7, u is an integer from 0 to 4; a is an oxygen atom or a sulfur atom; β is -CH 2 - or - (CH 2) 2-; Y ? it is an oxygen atom or a sulfur atom; R 21 is Cl to C3 alkyl or C3 to C4 cycloalkyl L4 is -0-CH2-, -S-CH2-, -N (R24) -CH2-, -CH2-CH2-, -0-CH (CH3) -, or -O-CH ((CH2) 2Ph) - wherein R24 is a hydrogen atom or Cl alkyl up to C6 and Ph is phenyl; R, 2"2 is -COOH, -S03H, or P (0) (0H) 2; R23 is a hydrogen atom, C1 to C6 alkyl, C7 to C12 aralkyl, Cl to C6 alkyloxy, Cl to C6 alkyloxy, Cl to C6 hydroxyalkyl, C2 to C6 haloalkyloxy, halogen, carboxy, C1 to C6 alkyloxycarbonyl, aryloxy, C1 alkyl to C8 aryloxy, arylthio, C 1 to C 8 arylthio, C 1 to C 8 cyano, a carbocyclic group, or a heterocyclic group; Y R is a group represented by the formula: wherein Z is -NH2 or -NHNH2; the prodrugs thereof, or pharmaceutically acceptable salts, or their solvates.

When the above b, d, f, p, r, u, and / or w are 2 or more, a plural number of R13 or R14 may be different from one or the other. When R13 is a substituent on the naphthyl group, the substituent may be substituted at some absolute position on the naphthyl group. vii) A compound represented by the formula (IV): where R, 20 is a group represented by the formula: wherein L is a bond, -CH2-, -C = C-, -C = C-, -0- or -S-; R13 and R14 are independently selected from halogen, Cl to CIO alkyl, Cl to CIO alkyloxy, Cl to CIO alkylthio, aryl, heteroaryl, and Cl to CIO haloalkyl; b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, and w are independently an integer from 0 to 5, g is an integer from 0 to 2, r is an integer from 0 to 7, u is an integer from 0 to 4; a is an oxygen atom or a sulfur atom; β is -CH 2 - or ~ (CH 2) 2-; Y ? it is an oxygen atom or a sulfur atom; R21 is Cl to C3 alkyl or C3 to C4 cycloalkyl; R23 is a hydrogen atom, C1 to C6 alkyl, C7 to C12 aralkyl, Cl to C6 alkyloxy, Cl to C6 alkyloxy, Cl to C6 hydroxyalkyl, C2 to C6 haloalkyloxy, halogen, carboxy, C1 to C6 alkyloxycarbonyl, aryloxy, C1 alkyl to C8 aryloxy, arylthio, C1 to C8 alkyl, arylthio, C1 to C8 cyano, a carbocyclic group, or a heterocyclic group; RB is a group represented by the formula wherein Z is -NH2 or -NHNH2; and k is an integer from 1 to 3; the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates. viii) A compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in vi), wherein L4 is -0-CH2-. ix) A compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in any of one of i) to viii), wherein R? and RB are -COCONH2-. x) A compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in any of one of i) to viii), wherein Rfi and RB are -CH2CONH2-. xi) A compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in any of one of i) to viii), wherein R and RB are CH2CONHNH2-. xii) A pro-drug as described in one of i) to viii) which are a type of ester. xiii) A pyrrolo [1, 2-b] pi r ida zine compound selected from the group consisting of: (Methyl 5-aminooxalyl-7-benzyl-6-ethylpyrrolo [1,2-b] pyridazine-4-yloxy) acetate, acid (5-aminooxali-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) acet ato (Methyl 5-aminooxali-7-benzyl-6-yl-2-methyl-ylpyrrolo [1,2-b] pyridazine-4-yloxy) acetate, acid (5-aminooxalyl-7-benzyl-6-ethyl-2- et ilpyrolo [1,2-b] pyridazine-4-yloxy) acetic acid, (Methyl 5-aminooxali-7-benzyl-2, 6-dimethyl-pyrrolo [1,2-b] pyridazine-4-yloxy) acetate, (5-aminooxali-7-benzyl, 1-2, 6-dimethylpyrrolo [1, 2-b] pyridazine-4-yloxy) ethyl acetate 2- (morpholine-4-yl) ethyl (5-aminooxalyl-7-benzyl-2, 6- "dimethyl-pyrrolo [1,2-b] pyridazine - -i-loxy) acetate, acid (5-aminooxal.ii-7-benzyl-2,6-dimethyl-pyrrolo [1,2-b] pyridazine-4-yloxy) acetic acid, (Sodium 5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo [1,2-b] pyridazine-4-yloxy) acetate, (5-aminooxali-7-benzyl-6-methyl-methyl-methyl-1-2-phenylpyrrolo [1,2-bjpyridazine-yloxy) acetate, acid (5-aminooxali-7-benzyl-6-methyl-2-phenylpyrrolo [1,2-b] pyridazine-4-yloxy) acetic acid, (Methyl 5-aminooxalyl-7-benzyl-6-ethyl-1-2-phenylpyrrolo [1,2-b] pyridazine-4-yloxy) acetate, (5-aminohexalyl-7-benzyl-6-ethyl-2-phenylpyrrolo [1,2-b] pyridazine-4-yloxy] acetic acid, [5-aminooxalyl-6-ethyl-7- (2-fluorobenzyl) -2 methyl-phenylpyrrolo [1,2-b] pyridazin-4-yloxy] acetate, [5-aminooxalyl-6-et-il-7- (2-fluorobenzyl) -2-phenylpyrrolofl, 2-b] pyridazine-4-yloxy] acetic acid, [5-aminooxalyl-7-benzyl-6-ethyl-2- (4-fluoro-phenyl) -pyrrolo [1,2-b] pyridazine-4-yloxy) -acetic acid methyl ester, [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] acet ato, acid (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo [1,2-b] pyridzin-4-yloxy] acetic acid, [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'-metho ifenyl) pyrrolo [1,2-b] pyridazine-4-yloxy] acetic acid, [5-aminooxalyl-6-ethyl-2-met i 1-7- (2-phenylbenzylpyrrolo [1,2- b] pyridazine-4-yloxy] methyl acetate, [5-aminooxalyl-6-ethyl-2-met-il-7- (2-phenylbenzyl) pyrrolo [1,2-b] pyridazine-4-yloxy] acetic acid, [5-aminooxalyl-6-ethyl-2-methyl-7- (3-phenoxybenzyl) pyrrolo [1,2-b] pyridazin-4-yloxy] methyl acetate, [5-aminooxalyl-6-ethyl-2-methyl-7- (3-phenoxybenzyl) pyrrolo [1,2-b] pyridazine-4-yloxy] acetic acid, (5-amino-oxalyl-7-benzyl-6-methyl- Methyl 2-propylpyrrolo [1,2- b] pyridazin-4-yloxy) acetate, acid (5-aminooxalyl-7-benzyl-6-met il-2-propylpyrrolo [1,2-b] pyridazine-4-yloxy) acetic acid, (5-amino-oxalyl-2, 7-dibenzyl-6-methylpyrrolo [1,2-b] pyridazin-4-yloxy) methyl acetate, acid (5-aminooxalyl-2,7-dibenzyl-6-met-ilpyrrolo [1,2-b] pyridazine-4-yloxy) acetic acid, [5-aminooxalyl-2,6-dimethyl-7- [2- (4-fluorophenyl) encyl] pyrrolo [1,2-b] iridazin-4-yloxy] acetate, and [5-Aminooxalyl-2,6-dimethyl-7- [2- (4-fluorophenyl) benzyl] pyrrolo [1,2-b] pyridazine-4-yloxy] acetic acid, and the prodrugs thereof, or their pharmaceutically acceptable salts; mother acids; or its solvates, xiv) 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, (5-amino-oxalyl-7-benzyl-2, 6-dimethylpyrrolo [1,2-b] pyridazine-4-yloxy) ethyl acetate, 2- (Morpholine-4-yl) ethyl (5-aminooxalyl-7-benzyl-2,6-dimethyl-pyrrolo [1,2-b] pyridazine-4-yloxy) -acetate, (5-aminooxali 1-7-benzyl 1-2, 6-dimethylpyrrolo [1,2-b] pyridazin-4-yloxy) sodium acetate, acid (5-aminooxalyl-7-benzyl-2,6-dimethyl-ilpyrrolo [1,2-b] pyridazine -4 -i-loxi) acetic acid, (Methyl 5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo [1,2- b] pyridazine-] i) oxy) acetate, (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo [1,2-b] pyridazine-4-yloxy) ethyl acetate, 2- (morpholine-yl) ethyl (5-aminooxalyl-7-benzyl) -6-methyl-2-phenylpyrrolo [1,2-b] pyridazine-4-yloxy) acetate, (5-amino-oxalyl-7-benzyl-6-methyl-2-phenyl-pyrrolo [1,2-b] pyridazine-4-yloxy) -acetate sodium, acid (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo [1,2-b] pyridazine-4-yloxy) acetic acid, (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo [1,2-b] pyridazine-4-yloxy) methyl acetate, (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo [1,2-b] pyridazine-4-yloxy) ethyl acetate, -aminooxalyl-7-benzyl-6-ethyl-2-pheno-imetylpyrrolo [1, 2-b] pyridazine-4-yloxy) 2- (morpholino-4-yl) ethyl acetate, (5-aminooxalyl-7-) sodium benzyl-6-ethyl-2-phenoxymethylpyrrolo [1,2-b] pyridazine-4-yloxy) acetate, acid { 5-aminooxalyl-7-benzyl-6-yl-2-phenoxymethylpyrrolo [1,2-b] pyridazine-4-y1oxy) acetic acid, [5-aminooxalyl-6-yl-2-methyl-7- (2-phenylbenzyl) pyrrolo [1,2-b] pyridazin-4-yloxy] methyl acetate, [5-aminooxalyl-6-ethyl-2-methyl-7- (2-phenylbenzyl) pyrrolo [1,2- b] pyridazine-4-yloxy] ethyl acetate, (Morpholino-yl) ethyl 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] pyridazin-4-yloxy] sodium acetate, (5-aminooxalyl-6-et i 1- 2-met il-7 - (2-phenyl-benzyl) pyrrolo [1,2-b] pyridazine-4-yloxy] acetic acid, (Methyl 5-amino-oxalyl-7-benzyl-6-methyl-1, 2-propylpyrrolo [1,2- b] pyridazine-4-yloxy) acetate, (5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo [1,2-b] pyridazine-4-yloxy) ethyl acetate, (Morpholino-4-yl) ethyl 5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo [1, 2-b] pyridazine-4-yloxy) acetate, Sodium 5-aminohexalyl-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, and the prodrugs thereof, or their pharmaceutically acceptable salts; its mother acids; or its solvates. xv) A pharmaceutical composition containing as an active ingredient a compound as described in one of i) to xiv). xvi) A pharmaceutical composition as described in xv), in which it is for the inhibition of sPLA2. xvii) A pharmaceutical composition as described is xv), which is for the treatment or prevention of inflammatory diseases. xviii) A method of inhibiting the release of the fatty acid mediated by sPLA2 which comprises contacting sPLA2 with a therapeutically effective amount of a zirconium [1,2-b] piid compound as described in i) • ' xix) A method of treating a mammal, including a human, to alleviate the pathological effects of inflammatory diseases; wherein the method comprises administering to said mammal a pyrrolo [l, 2-b] pyridazine compound as described in i). . xx) A compound as described in i) or a pharmaceutical formulation containing an effective amount of a pyrrolo [1,2-b] pyridazine compound as described in i) for use in the treatment of inflammatory diseases. xxi) A compound as described in i) or a pharmaceutical formulation containing an effective amount of a pyrrolo [1,2-b] pyridazine compound as described in i) for use as an inhibitor to inhibit the release of an acid fat mediated by sPLA2. xxii) An sPLA2 inhibitor of pyrrolo [1,2-b] pyridazine substantially as described above with reference to any of the examples. xxiii) A compound represented by the formula (XII): wherein R7 is - (CH2) m -R12 wherein m is an integer from 1 to 6, and R12 is (d) a group represented by the formula: wherein a, c, e, n, q, and t are independently an integer from 0 to 2, R13 and R14 are independently selected from a halogen, Cl to CIO alkyl, Cl to CIO alkyloxy, Cl to Cio alkylthio, aryl, heteroaryl and haloalkyl Cl up to CIO, a is an oxygen atom or a sulfur atom, L5 is - (CH2) v-, -C = C-, -C = C-, -O-, or -S-, v is an integer from 0 to 2, ß is -CH2- or ~ (CH2) 2-,? is an oxygen atom or a sulfur atom, b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, and w are independently an integer from 0 to 5, g is an integer from 0 to 2, r is an integer from 0 to 7, and u is an integer from 0 to 4, or is (e) a member of (d) substituted with at least one substituent selected from the group consisting of Cl to C6 alkyl, C1 to C alkyloxy to C6, haloalkyloxy Cl to C6, haloalkyl Cl to C6, aryl, and a halogen; Y R is C1 to C3 alkyl, C2 to C3 alkenyl, C3 to C4 cycloalkyl, C3 to C4 cycloalkenyl, Cl to C2 haloalkyl, Cl to C3 alkyloxy, Cl to C3 alkyl.

In the present specification, the term "alkyl" employed alone or in combination with other terms means a straight or branched chain monovalent hydrocarbon group, having a specific number of carbon atoms. An example of the alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n decanyl, n-undecanyl, n-dodecanyl, n-tridecanyl, n-tetradecanyl, n-pentadecanyl, n-hexadecanyl, n-heptadecanyl, n-octadecanyl, n-nonadecanyl, n-eicosanil and the like.

The term "alkenyl" employed alone or in combination with other terms in the present specification means a straight or branched chain monovalent hydrocarbon group having a specific number of carbon atoms and at least one double bond. An example of the alkenyl includes vinyl, allyl, propenyl, crotonyl, isopentenyl, a variety of butenyl isomers and the like.

The term "alkynyl" used in the present specification means a straight or branched chain monovalent hydrocarbon group having a specific number of carbon atoms and at least one triple bond. The alkynyl may contain (a) double bond (s). An example of alkynyl includes ethynyl, propynyl, 6-heptynyl, 7-octynyl, 8-nonynyl and the like.

The term "carbocyclic group" used in the present specification means a group derived from ring-forming atoms whose substituted or unsubstituted saturated or unsaturated organic nuclei of 5 to 14 members, preferably 5 to 10 members, (different from hydrogen atoms) are only carbon atoms. A group containing two to three of the carbocyclic group is also included in the group indicated above. An example of typical carbocyclic groups include (f) cycloalkyl (such as, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl); cycloalkenyl (such as cyclobutylenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexyl) phenyl, spiro [5, 5] undecanyl, naphthyl, norbornyl, bicycloheptadienyl, tolyl, xylyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, fernylcyclohexenyl , acenaphthyl, antoryl, biphenylyl, bibenzylyl, and a phenylalkylphenyl derivative represented by the formula: where x is an integer from 1 to 8 The term "spiro [5, 5] undecanyl" refers to the group represented by the formula: Phenyl, cyclohexyl, or the like are preferred as carbocyclic groups in R 4 and R 5.

The term "heterocyclic group" used in the present specification means a group derived from monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic nuclei having from 5 to 14 rings of atoms and containing from 1 to 3 heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom. An example of. heterocyclic group includes pyridyl, pyrrolyl, pyrrolidinyl, piperidinyl, furyl, benzofuryl, thienyl, benzothienyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, nore anilo, azaindolyl, benzofuranyl, dibenzothiophenyl, indazolyl, imidazo [1, 2-a] pyridinyl, benzotriazolyl, anthranilyl, 1, 2-benzisoxazolyl, benzothiazolyl, purinyl, puridinilo, dipyridinyl , phenylpyridinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolyl, phthalazinyl, zolinyl quinazine, quinoxalinyl, morpholino, thiomorpholino, opiperazinilo ho, tetrahydrofuranyl, tetrahydropyranyl, oxacanilo, 1, 3-dioxolaní as, 1, 3-dioxanyl, 1, 4 -dioxanilo, 1, 4 ioxanilo -t, azetidinyl, hexametilenoiminio, ilenoiminio, piperazinyl and the like heptamet.

Furyl, thienyl or the like are preferred as a heterocyclic group in R 4 and R 5.

The preferred carbocyclic and heterocyclic groups in R1 are (g) a group represented by the formula: wherein R, 13 and R, 14 are independently selected from halogen, Cl alkyl up to CIO, alkyl.oxi C! up to CIO, Cl-Cl up to CIO, aryl, heteroaryl, and haloalkyl Cl up to CIO, a is an oxygen atom or an sulfur, L5 is - (CH2) v-, -C = C-, -C = C-, -O-, or -S-, v is an integer from 0 to 2, ß is -CH2- or (CH2) 2-,? is an oxygen atom or a sulfur atom, b is an integer from 0 to 3, d is an integer "from 0 to 4, f, p, and w are an integer from 0 to 5, r is an integer from 0 to 7, yu is an integer from 0 to 4. When the previous b, d, f, p, r, u, and / ow are 2 or more, a plural number of R13 or R14 may be different from each other. is a substituent on the naphthyl group, the substituent can be substituted at any arbitrary position on the naphthyl group, A more preferable example includes (h) a group represented by the formula: where R13, R14, a, ß, and? they are the same as defined above, L6 is -CH2-, -C = C-, C = C-, -O-, or -S-, and y is 0 or 1. When R 13 is a substituent on the naphthyl group , the substituent can be substituted at any arbitrary position in the naphthyl group.

The "pyrrolo [1, 2-b] pyridazine core" is represented by the following structural formula together with its numerical ring position for substituent placement: The term "substituent without interference" in the present specification means an appropriate group for the substitution at position 2, 3 • and 7 in the nucleus of pyrrolo [1,2-b] pyridazine represented by the formula (I) as well as a group appropriate for the substitution of the previously described "carbocyclic group" and "heterocyclic group". An example of the substituent without interference includes alkyl Cl to C8 alkyl, C2 to C8 alkynyl C2 to C8, C7 to C12 (such as benzyl, and phenethyl), alkaryl C7 to C12 alkenyloxy, C2 to C8 alkynyloxy, C2 to C8, C3 to C8 cycloalkyl, C3 to C8, phenyl, tolyl, xylyl, biphenylyl, alkyloxy Cl to C8, alkyloxyalkyl C2 to C12 (such as meth iloximet yl, et i loximet yl, meth iloxiet yl, and etiloxietilo), alkyloxyalkyloxy C2 to C12 (such as meth iloximet yloxy and meth iloxiet yloxy) alquicarbonilo C2 to C12 (such as methylcarbonyl and ethylcarbonyl) alkylamino, C2 to C12 (such as methylcarbonylamino and ethylcarbonylamino), alquiloxiamino C2 to C12 (such as metiloxiamino and atiloxiamino), alquiloxiaminocarbonilo C2 to C12 (such as methyloxyaminocarbonyl and ethoxyaminocarbonyl), alkylamino Cl to C12 (such as methylamino, ethylamino, dimethylamino, and ethylmethylamino), alkylthio Cl to C6, alkylthiocarbonyl C2 to C12 (such as methylthiocarbonyl and ethylthiocarbonyl), alkylsulfinyl Cl to C8 (such as methylsulfinyl and ethylsulfinyl), alkylsulfonyl Cl up to C8 (such as methylsulfonyl and ethylsulfonyl), haloalkyloxy C2 to C8 (such as 2-chloroethyloxy and 2-bromoethyloxy), haloalkylsulfonyl Cl up to C8 (such as chloromethylsulfonyl and bromomethylsulfonyl), haloalkyl C2 to C8, hydroxyalkyl (such as hydroxymethyl and hydroxyethyl), -C (0) 0 (Cl to C8 alkyl) (such as methyloxycarbonyl and ethoxycarbonyl, (CH2) z-0- (Cl to C8 alkyl), benzyloxy, aryloxy (such as phenyloxy), arylthio (such as phenylthio), - (C0NHS02R25), -CHO, amino, amidino, halogen, carbamyl, carboxyl, carbalkyloxy, - (CH2) z-C00H (such as carboxymethyl, carboxyethyl, and carboxypropyl), cyano, cyanoguanidino, guanidino, hydrazido, hydrazino, hydrazide, hydroxy, hydroxyamino, nitro, phosphono, -S03H, thioacetalo, thiocarbonyl, carbonyl, carbocyclic groups , heterocyclic groups and the like wherein z is an integer from 1 to 8 and R25 is Cl to C6 alkyl or aryl. These groups can be substituted by at least one substituent selected from the group consisting of Cl to C6 alkyl, Cl to C6 alkyloxy, C2 to C6 haloalkyloxy, Cl to C2 haloalkyl, and halogens.

Preferred halogens are Cl-alkyl up to C6, C1 to C6 alkyloxy, Cl to C6 alkylthio, and Cl to C6 haloalkyl as the "substituent without interference" in R1. More preferably, they are halogens, C1 to C3 alkyl, C1 to C3 alkyloxy, Cl to C3 alkyl, and Cl to C3 haloalkyl.

Preferred are (i) Cl to C6 alkyl, aralkyl, Cl to C6 alkyloxy, Cl to C6 alkylthio, Cl to C6 hydroxyalkyl, C2 to C6 haloalkyloxy, halogens, carboxy, Cl to C6 alkyloxycarbonyl, aryloxy, arylthio, carbocyclic groups, and heterocyclic groups as the "substituents without interference" in R4, R5, R10, and R11. More preferably they are (j) Cl to C6 alkyl, aralkyl, carboxy, Cl to C6 hydroxyalkyl, phenyl, and Cl to C6 alkyloxycarbonyl.

The term "halogen" in the present specification means fluorine, chlorine, bromine, and iodine.

The term "cycloalkyl" in the present specification means a monovalent cyclic hydrocarbon group having a specific number of carbon atoms. An example of the cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The term "cycloalkenyl" in the present specification means a monovalent cyclic hydrocarbon group having a specific number of carbon atoms and at least one double bond (s). An example of the cycloalkenyl includes 1-cyclopropenyl, 2-cyclopropenyl, 1-cyclobutenyl, 2-cyclobutenyl and the like.

In the present specification, an example of "alkyloxy" includes methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, n-pentyloxy and the like.

In the present specification, an example of "alkylthio" includes methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, n-pentylthio, and the like.

The term "acid group" in the present specification means an organic group functioning as a proton donor capable of binding hydrogen when bound to the core of pyrrolo [1,2-b] pyridazine through an appropriate linking atom (from hereinafter referred to as "binding acid"). An example of the acid group includes (k) a group represented by the formula: wherein R18 is a hydrogen atom, a metal, or Cl alkyl up to CIO and each R19 is independently a hydrogen atom or Cl alkyl up to CIO. Preferably it is (l) -COOH, -S03H, or P (O) (OH) 2- More preferably it is (m) -COOH.

The term "binding acid" in the present specification means a divalent linking group represented by a symbol - (L2) -, and functions to join the core of position 4 of the pyrrolo [1,2-b] pyridazine to a " Acid group "in a general relationship. An example of this includes (n) a group represented by the formula: wherein M is -CH 2 -, -O-, -N (R 24) -, or -S-, and R 16 and R 17 are, independently, hydrogen atom, Cl alkyl up to CIO, aralkyl, carboxy, or halogen. Preferred are (o) -0-CH2-, -S-CH2-, - (R24) -CH2-, -CH2-CH2-, -0-CH (CH3) -, or -0-CH ((CH2) 2Ph) - wherein R24 is a hydrogen atom or Cl alkyl up to C6 and Ph is phenyl. More preferable is (p) -0-CH2- or -S-CH2-.

In the present specification, the term "acid link length" means the number of atoms (except for hydrogen atoms) in the short chain of a linking group - (L) - which connects position 4 in the pyrrolo nucleus [1, 2-b] pyridazine with the "acid group". The presence of a carbocyclic ring in - (L2) - has the number of atoms approximately equivalent to the calculated diameter of the carrizocylic ring. In this way, a benzene and cyclohexane ring in the acid bond has two atoms in the calculation of the length of - (L2) -. The preferred length is from 2 to 3.

The symbol k in the formula (iv) is preferably 1.

The term "haloalkyl" in the present specification means the above-described "alkyl" substituted with the "halogen" described above in an arbitrary position (s). An example of haloalkyl includes chloromethyl, trifluoromethyl, 2-chloromethyl, 2-bromomethyl and the like.

The term "hydroxyalkyl" in the present specification means the above-mentioned "alkyl" substituted with hydroxy in an arbitrary position (s). An example of the hydroxyalkyl includes hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and the like. In this case, hydroxymethyl is preferred.

In the present specification, the term "haloalkyl" in "haloalkyloxy" is the same as defined above. An example of this includes 2-chloroethyloxy, 2,2,2-trifluoroethyloxy, 2-chloroethyloxy and the like.

The term "aryl" in the present specification means a monocyclic or condensed cyclic aromatic hydrocarbon. An example of the aryl includes phenyl, 1-naphthyl, 2-naphthyl, anthryl and the like. Particularly, phenyl and 1-naphthyl are preferred. Such "aryl" is optionally substituted with Cl to C6 alkyl, hydroxy, Cl to C3 alkyloxy, halogen, nitro, substituted or unsubstituted amino, cyano, Cl to C3 haloalkyl, and the like in one or more positions.

The term "aralkyl" in the present specification means a group wherein the above-mentioned "alkyl" is substituted with the "aryl" mentioned above. Such an aryl can have a bond in any appropriate position. An example of this includes benzyl, phenethyl, phenylpropyl (such as 3-phenylpropyl), naphthylmethyl (such as 1-naphthylmethyl) and the like.

The term "group containing 1 to 4 non-hydrogen atoms" refers to relatively small groups that form substituents at the 6-position of the pyrrolo [1,2-b] pyridazine core, said groups may contain only non-hydrogen atoms , or non-hydrogen atoms plus hydrogen atoms as required to satisfy the unsubstituted value of non-hydrogen atoms, for example; (ii) absent groups of hydrogen containing not more than 4 non-hydrogen atoms such as -CF3, -Cl, -Br, -N02, -CN, -S03; and (iii) groups having hydrogen atoms containing less than 4 non-hydrogen atoms such as -CH3, -C2H5-, -CH = CH2, CH (CH3) 2, and cyclopropyl.

An example of "alkyloxycarbonyl" in the present specification includes methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, and the like.

The term "amino substituted" in the present specification includes amino substituted with C 1 to C 6 alkyl, aralkyl, C 1 to C 6 alkylcarbonyl, C 1 to C 6 alkyloxycarbonyl, and the like in one or two positions.

Preferred embodiments of R7 of formula (XXII) are C5 to C8 cycloalkylmethyl and phenylmethyl which is optionally substituted with halogen, Cl to C6 alkyl, aryl, alkyloxy, or aryloxy.

Preferably it is C1 to C6 alkyl as the R8 of the formula (XXII).

A group of preferred substituents such as R1 to R5 and the RA of the compound represented by formula (I) are observed in points (A) to (W). The points (f) to (m) are the same group as described above.

Like R1, (A): - (La) -R6, (B): - (CH2) 1-2- (f), (C): - (CH2)? - 2- (g), and (D) ): - (CH2) 1-2- () are preferred.

As the R2, (E): hydrogen atom, halogen, Cl to C3 alkyl, C3 to C4 cycloalkyl, or Cl to C3 alkyloxy; and (F): Cl to C3 alkyl or C3 to C4 cycloalkyl are preferred.

As the RA, (G): -C (= 0) -C (= 0) -NH2, -CH2C (= 0) -NH2, or -CH2C (= 0) -NHNH2; and (H): -C (= 0) -C (= 0) -NH2 are preferred.

Like R3, (I): - (n) - (k), (J): - (n) - (l), (K): - (n) - (m), (L): - (or ) - (k), (M): - (o) - (l), (N): - (o) - (m), (0): - (p) - (k), (P): - (p) - (l), and (Q): - (p) - (m) are preferred.

As the R4, (R): hydrogen atom or substituent that does not interfere, (S): hydrogen atoms u (i), and (T): hydrogen atom or (j) are preferred.

As the R5, (U): hydrogen atom or (i), (V): hydrogen atoms or (j), and (W): hydrogen atoms are preferred.

A preferred group of compounds represented by the formula (I) is shown below.

(R1, R2, RA, R4 R5) (A, E, G, R, U), (A, E, G, R, W) (A, E, G, S, U) (A, E, G) , S, W) (A, E, G, T, U) (A, E, G, T, W) (A, E, H, R, U) (A, E, H, R, W) ( A, E, H, S, U) (A, E, H, S, W) (A, E, H, T, U) (A, E, H, T, W) (A, F, G, R, U) (A, F, G, R, W) (A, F, G, S, U) (A, F, G, S, W) (A, F, G, T, U) (A , F, G, T, W) (A, F, H, R, U) (A, F, H, R, W) (A, F, H, S, U) (A, F, H, S , W) (A, F, H, T, U) (A, F, H, T, W) (B, E, G, R, U) (B, E, G, R, W) (B, E, G, S, U) (B, E, G, S, W) (B, E, G, T, U) (B, E, G, T, W) (B, E, H, R, U) (B, E, H, R, W) (B, E, H, S, U) (B, E, H, S, W) (B, E, H, T, U) (B, F) , G, R, U (B, F, G, R rV), (B, F, G, S, U (B, F, G, S, V), "(B, F, G, T, Ü (B, F, G, t -V), (B, F, H, R, U (B, F, H, R rV), (B, F, H, S, U (B, F, H, sr V), (B, F, H, T, U (B, F, H, t V), (C, _ E, G, R, U (C, E, G, R, V), (C , E, G, S, U (C, E, G, s, V), (C, E, G, T, U (C, E, G, t, V), (C, E, H, R , U (C, E, H, R, V), (C, E, H, S, U (C, E, H, s, V), (C, E, H, T, U (C, E , H, t, V), (C, F, G, R, U (C, F, G,, V), (C, F, G, S, U (C, F, G, s, V) , (C, F, G, T, U (C, F, G, t, V), (C, F, H, R, U (C, F, H, R, V) ', (C, F , H, S, U (C, F, HS, V), (C, F, H, T, U (C, F, H r, V), (D, E, G, R, U (D, E, G, R, V), (D, E , G, S, U (D, E, G, s, V), (D, E, G, T, U (D, E, G r, V), (D, E, H, R, U ( D, E, HRV), (D, E, H, S, U (D, E, H, s, V), (D, E, H, T, U (D, E, H r, V), (D, F, G, R, U (D, F, G, R, V), (D, F, G, R, W), (D, F, G, S, U), (D, F , G, S, V), (D, F, G, S, W), (D, F, G, T, U), (D, F, G, T, V), (D, F, G , T, W), (D, F, H, R, U), (D, F, H, R, V), (D, F, H, R, W), (D, F, H, S , U), (D, F, H, S, V), (D, F, H, S, W), D, F, H, T, U), (D, F, H, T, V) , and (D, F, H, T, W).

Preferred embodiments of this invention are compounds wherein R3 is any of (I) through (Q) and (R1, R2, RA, R4, R5) is any of the above combinations.

The term "Inflammatory Diseases" refers to diseases such as inflammatory bowel disease, sepsis, septic shock, adult respiratory distress syndrome, inflammation of the pancreas, shock induced by trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, chronic rheumatism, arterial sclerosis, cerebral hemorrhage, cerebral infarction, cardiac failure, cardiac infarction, psoriasis, cystic fibrosis, attack, acute bronchitis, acute bronchiolitis, chronic bronchitis, osteoarthritis, gout, spondilartopatris, ankylosing spondylitis, Reiter's syndrome, psoriatic arthropathy, enteropathy spondylitis Juvenile arthropathy or juvenile ankylosing spondylitis, reactive arthropathy, infectious or post-infectious arthritis, gonococcal arthritis, tuberculous arthritis, viral arthritis, fungal arthritis, syphilitic arthritis, Lyme disease, arthritis associated with "vasculitic syndromes", polyarteritis nodosa, vasculitis hypersensible, Luegenec granulomatosis, polymialgina rheumatica, cell arteritis <, Like the art-cula = Lcres rt ropatris deposition of calcium crystals, pseudo gout, non-articular rheumatism, bursitis, tenosinomit is, epicondilit is (tennis elbow), carpal tunnel injury syndrome repetitive use (typing) , forms of miscellaneous arthritis, neuropathic joints (puddle and joint), hemarthrosis (hemartrosica), Henoch-Schonlein purpura, osteoartropat ia hypertrophic uíticéntrica reticulohistiocytosis, arthritis associated with certain diseases, surcoilosis, hemochromatosis, falcifsrme cell disease and other disease hemoglobinopatrísa, hyperlipoproteinemia, hypogammaglobulinemia, hiperparatiroisdismo, acromegaly, familial Mediterranean fever, Behat's disease, systemic erythrematosis lupus, or relapsed polychondritis and related diseases comprising administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula I in a sufficient amount e to inhibit the release of fatty acid mediated by sPLA2 and thereby inhibit or prevent the cascade of arachidonic acid and its perjury products.

The terms "mammal" and "mammals" include the human.

The term "solvate" includes, for example, solvates with organic solvents, hydrates, and the like.

Best Way to Carry Out the Invention The compounds of the invention represented by the formula (I) can be synthesized according to the following method A. The compound (XV) in the method A can also be synthesized according to the following method B.

(Method A) (XVII) wherein R1, R2, R4, R5, X, and Y are as defined above; R26 is an acid group.

(Step 1) To a solution of the compound (VI) that is commercially available or is synthesized in accordance with a well-known method in a solvent such as tetrahydrofuran, diethyl ether, and ethylene. glycol dimethyl ether, a base such as lithium diisopropyl amide and n-butyllithium is added at -78 ° C to -20 ° C, preferably -78 ° C to -60 ° C. To the reaction mixture is added alkenyl halide such as allyl bromide and allyl chloride at the same temperature and the resulting mixture is stirred for 1 to 24 hours, preferably 1 to 8 hours. After the reaction mixture has been subjected to a usual work, the compound (VII) can be obtained (see J. Chem. Soc. Parkin, Trans. 1, 1987, 1986).

(Step 2) To a solution of the compound (VII) in a solvent such as tetrahydrofuran, diethyl ether, and ethylene glycol dimethyl ether, Grignard reagent (RxMgHal: Hal is a halogen) is added at -20 ° C to 0 ° C, preferably - 15 ° C to -10 ° C and the resulting mixture is stirred for 1 to 15 hours, preferably 1 to 8 hours at -20 ° C to 30 ° C, preferably 0 ° C to 25 ° C. after the reaction mixture is subjected to a usual work, the compound (VIII) can be obtained (see Synthesis, 996, 1988).

(Step 3 The present step includes oxidation by ozone of the double bond. A solution of the compound (VIII) in a solvent such as dichloromethane, ethyl acetate, and methanol was treated with ozone "at -78 ° C to 0 ° C, preferably -78 ° C to -60 ° C. Ozone, the mixture was treated with a reducing agent such as dimethyl sulfide, triphenylphosphine, triethoxyphosphine, and zinc-acetic acid or hydrogen to give the aldehyde derivative (IX).

(Step 4) To a solution of the compound (IX) in a solvent such a combooxane, tetrahydrofuran, and diethyl ether, was added the compound (X) and an acid such as hydrochloric acid, sulfuric acid, and acetic acid. The resulting mixture was stirred for 0.5 to 3 hours at 50 ° C to 100 ° C to give the pyrrolo derivative (XI) which is protected by phthalimide at the N-position (Chem. Ver., 102, 3268, 1969).

(Step 5) The present step is the only one to deprotect the phthalamide group of the compound (XI). This step can be carried out in accordance with a usual deprotection method as described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley &Sons). For example, to a solution of the compound (XI) in an alcohol solvent such as ethanol, hydrazine is added and the resulting mixture is stirred for 0.5 to 3 hours at 50 ° C to 100 ° C to give the amino derivative ( XII).

(Step 6) This step is the only one to rent the amino group. The compound (XII) and the compound (XIII) are reacted for 10 to 60 minutes at 100 ° C to 150 ° C to give the compound (XIV) (see J. Heterocyclic Chem., 31, 409, 1994).

(Step 7) The present step is the only one to build the pyrrolo [1, 2-b] pyridazine ring. The compound (XIV) is dissolved in a solvent such as Dowtherm-A and SAS-296 and the mixture is stirred for 1 to 8 hours at 150 ° C to 250 ° C to give the pyrrolo derivative [1,2-b] pyridazine ( XV) (see J. Heterocyclic Chem., 31, 409, 1994). The hydroxy group in position 4 is converted to halogen by the usual method, then the halogen can be converted into a thiol group or the like.

(Step 8) To a solution of the compound (XV) in a solution such as tetrahydrofuran and dimethylformamide was added a base such as potassium carbonate and sodium hydride and R26-Hal (Hal is halogen) and the resulting mixture was stirred for 1 to 15 minutes. hours at 0 ° C to 100 ° C, preferably 20 to 40 ° C to give the compound (XVI).

(Step 9) The present step is the only one for introducing a substituent at the 5-position. The compound (XVI) is dissolved in a solvent such as 1,2-dichloroethane, tetrahydrofuran, and Hal-C (= X) -C (= X) - Hal (for example, oxalyl chloride) and a base such as N-methylmorpholine, triethylamine is added to the solution, and the mixture is stirred for 1 to 10 hours, preferably 3 to 6 hours at 30 ° C to 70 ° C, preferably 40 ° C to 60 ° C. The reaction mixture is poured into cold aqueous ammonia, and the resulting mixture is stirred for 5 to 30 minutes, preferably 10 to 20 minutes. After the reaction mixture is subjected to ordinary work, the compound (XVII) can be obtained.

(Method B; wherein R1, R2, R4, and R5 are as defined above, R27 is Cl to C3 alkyl, R28 is lower alkyl or R28 to the adjacent oxygen can form a 1,3-dioxolane ring, and R29 is a phthalimido or NHC02Et .

(Step 1) To a solution of the compound (XVIII) in a solvent such as dimethylformamide, a halogenated alkyl derivative such as ethylene acetal bromoacetaldehyde and a base such as potassium carbonate, potassium t-butoxide, and sodium hydride are added and the resulting mixture is added. stir for 3 to 80 hours, preferably 5 to 7 hours at room temperature to 180 ° C, preferably 20 to 150 ° C to give the compound (XIX).

(Step 2) To a solution of the compound (XIX) in a solvent such as dimethisulfoxide, a reagent such as potassium acetate and sodium acetate was added and the resulting mixture is stirred for 1 to 20 hours, preferably 3 to 15 hours at 20 hours. ° C to 200 ° C, preferably from 100 ° C to 180 ° C to give the compound (XX).

(Step 3) To a solution of Grignard reagent (R1MgHal, Hal is halogen) or R1Li in a solvent such as ether, tetrahydrofuran, and dimethoxyethane, and a solution of compound (XX) in ether, tetrahydrofuran, and dimethoxyethane, and the resulting mixture were added. it was stirred for 1 to 48 hours, preferably 2 to 24 hours at 0 ° C to 70 ° C, preferably 20 to 60 ° C to give the compound (XXI) '.

(Step 4) To a solution of the compound (XXI) in a solvent such as ethanol, methanol, dioxane, and tetrahydrofuran, was added N-aminophthalimide (compound (X)) or ethyl carbazate (compound (XXII)) and an acid such as trifluoroacetic acid, hydrochloric acid, and sulfuric acid and the resulting mixture was stirred for 5 minutes to 2 hours, preferably 10 minutes to 1 hour at 20 ° C to 120 ° C, preferably 50 to 100. ° C to give the compound (XXIII).

(Step 5) The present step can be carried out in accordance with the same procedure as that of method A - step 5.

(Step 6) To a solution of the compound (XII ') in a solvent such as chloroform, dichloroethane, tetrahydrofuran, and toluene, β-ketoester was added such as acetoacetic acid methyl ester and an acid catalyst such as p-toluenesulfonic acid, methanesulfonic acid, acid hydrochloric, trifluoroacetic acid and the resulting mixture was stirred for 1 to 20 hours, preferably 3 to 15 hours to give the compound (XV). The water generated in situ is dehydrated by a Dean-Stark apparatus with a 4A molecular sieve or similar.

(Method C) wherein R1, R2, R4, R26, X, and Y are as defined above, Hal is halogen, R30 is -OR, 31 -SR 31 -NHR 31 N (R) 2, -CN, -N3 or the like, wherein R 31 is independently alkyl, aryl, or the like.

(Step 1) The compound (XVI ') is obtained in a manner similar to that described in method A - step 8.

(Step 2) The compound (XVI ') is dissolved in a solvent such as dimethylformamide, acetonityl, acetone, dimethisulfoxide, methanol, ethanol, isopropanol and the solution is added to a base such as a dehydrohalogenating agent such as potassium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium acetate, sodium hydroxide, potassium hydroxide, potassium t-butoxide. A reagent such as R310H, R31SH, R31NH2, (R31) 2NH and the resulting mixture is stirred for 1 to 48 hours, preferably 1 to 24 hours at -20 ° C to 100 ° C, preferably 0 ° C to 80 ° C to give the compound ( XXIV).

(Step 3) Compound EJ (XVII ') is obtained in a manner similar to that described in method A - step 9.

(Method D) wherein R1, R4, R26, R30, X, Y, and Hal are as defined above.

(Step 1) The compound (XXV) is obtained in a manner similar to that described in method A - step 9.

(Step 2) The compound (XVII ') is obtained in a manner similar to that described in method C-step 2.

Where a compound of the present invention has an acidic or basic functional group, a variety can be formed each having high solubility in water and more physiologically appropriate properties than those of the parent compound. An example of typical pharmaceutically acceptable salts includes salts with alkali metal and alkaline earth metal such as lithium, sodium, potassium, magnesium, aluminum and the like, but it will be noted that such pharmaceutically acceptable salts are not limited thereto. A salt is easily made from a free acid either by treating with an acid in a solution with a base, or by allowing an acid to be in contact with an ion exchange resin. The addition salts of the compounds according to the present invention with relatively non-toxic organic bases and inorganic bases, for example, amine cation, ammonia, and quaternary ammonia derived from nitrogenous bases having a sufficient base to form a salt of the compounds of the present invention are included in the definition "pharmaceutically acceptable salts" (for example, SM Berge et al., "Pharmaceutical Salts", J. Phar. Sci., 66, 1-19 (1977)). Additionally, the basic groups of a compound according to the present invention are reacted with an appropriate organic or inorganic acid to form salts such as acetates, benzenesulfonates, benzoates, bicarbonates, bisulfates, bitartarate, borates, bromides, campyrates, carbonates, chlorides, clubranatos, citratos, edetatos, ediciratos, estratos, ethylates, fluoruros, fumaratos, gluseptatos, gluconatos, glutamatos, glycolialsaniratos, heiresorci atos, hidroxinaftoatos, iodides, isotionates, lactatos, lactobionaatos, lauratos, malatos, malseatos, manderatos, mesilate, methyl bromides, methynnit ratos, metisulfates, mucatos, napcylates, nitrates, oleates, oxyrates, palmitates, pantotenates, phosphates, polygalacturonates, salicylates, stearates, subacetates, sucinates, tanatos, tartrates, tosylates, trifluoroacetates, trifluoromethanesulfonates, valerate and the like. In case of forming a hydrate, the compound in question can be coordinated with a number of appropriate water molecules.

In the case where a compound of the present invention has one or more chiral centers, it can exist as an optical active member. Similarly, in the case where a compound contains alkenyl or alkenylene, there is a possibility of cis- and trans isomers. Mixtures of R- and S- isomers as well as cis- and trans- isomers, and mixtures of R- and S- isomers containing racemic mixtures are included within the scope of the present invention. The asymmetric carbon atom may also exist in a substituent such as an alkyl group. All these isomers are included in the present invention together with these mixtures. In the case where a specific stereoisomer is desired, whether it is made by applying it in a manner that is well known to those skilled in the art where a starting material having an asymmetric center that has been previously separated is subjected to a stereospecific reaction to the starting material, or is made by preparing a mixture of stereoisomers, and subsequently separating the mixture in accordance with a well-known manner.

The pro-drug is a derivative of the compound that has a group that can be broken down chemically or metabolically, and such a pro-drug is a compound according to the present invention that becomes pharmaceutically active by means of solvolysis or by placing the compound in vivo under a physiological condition. Although a derivative of the compounds according to the present invention exhibit activity in both forms of acid derivative or basic derivative, the acid derivative is more advantageous in solubility, tissue affinity, and release control in a mammalian organism (Bungard, H., Design of Prodrugs, pages 7-9, 21-24, Elsevier, Amsterdam, 1985). The ester pro-drugs are well known (see, Silverman, Richard B, The Organic Chemistry of Drug Design and Drug Action, Chapter 8, New York, NY Academic Press, ISBN 0-12-643730-0) and are a form of preferred drug for the compounds of this invention and also for the pro-drugs used in the method of treating Inflammatory Diseases as taught herein. For example, pro-drugs that each contain an acid derivative such as an ester that is prepared by reacting an acid-based compound with an appropriate alcohol, or an amide that is prepared by reacting an acid-based compound with an amine appropriate are well known to those skilled in the art. The simple aliphatic or aromatic esters derived from acid groups contained in the compounds according to the present invention are the preferred prodrugs. Particularly preferred esters as pro-drugs are methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, tert-butyl ester, morpholino ester, and sodium ester. N, -diet ilglicolamido.

The methyl ester pro-drugs can be prepared by reacting the sodium salt of the compound of Formula (I) (in a solvent such as dimethylformamide) with methane iodine (available from Aldrich Chemical Co., Milwaukee, Wisconsin USA; Article No. 28,956 -6).

Ethyl ester pro-drugs can be prepared by reacting the sodium salt of a compound of Formula (I) (in a solvent such as dimethylformamide) with iodoethane (available from Aldrich Chemical Co., Milwaukee, Wisconsin, USA; 1-778-0).

The N, N-diethylglycolamido ester prodrugs can be prepared by reacting the sodium salt of a compound of Formula (I) (in a medium such as dimethylformamide) with 2-chloro-N, N-diethylacetamide ((available from Aldrich Chemical Co., Milwaukee, Wisconsin USA; Article No. 25, 099-6).

The morpholinylethyl ester prodrugs can be prepared by reacting the sodium salt of a compound of Formula (I) (in a medium such as dimethylformamide) with 4- (2-chloroethyl) -orpholine hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wisconsin USA; Article No. C4, 220-3).

The pro-drugs of the double ester type such as ester (acyloxy) alkyl or ester ((alkyloxycarbonyl) oxy) alkyl can optionally be made.

The term "inhibit" means that the release of the fatty acid initiated by sPLA2 is significantly reduced by the compounds of the present invention from the point of view of the prevention and treatment of diseases. The term "pharmaceutically acceptable" means that the carriers, diluents, or additives are compatible with other ingredients in a formulation and are not detrimental to the receptors.

The compounds of the present invention exhibit inhibitory activity of sPLA2 as for the description of the experimental examples described hereinafter. Accordingly, when a curatively effective amount of the compounds represented by the formulas (I), (II), (III), and (IV), the pro-drugs derived therefrom, or their pharmaceutically acceptable salts, or their solvates , they are administered to any of the mammals (including humans) they work effectively as a healing medicine for diseases of septic shock, respiratory distress syndrome in adults, inflammation of the pancreas, injury, bronchial asthma, allergic rhinitis, chronic rheumatism, arterial sclerosis , cerebral hemorrhage, inflammatory colitis, heart failure, and cardiac infarction.

The compounds of the present invention can be administered to a patient through a variety of routes including oral, aerosol, rectal, percutaneous, subcutaneous, intravenous, intramuscular, and nasal routes. A formulation according to the present invention can be made by combining (for example, mixing) a curatively effective amount of a compound of the present invention with a pharmaceutically acceptable carrier or diluent. The formulation of the present invention can be made with the use of readily available and well-known ingredients according to a known method.

In the case of making a composition according to the present invention, either the active ingredients are mixed with a carrier, or these are diluted with a carrier, or these are stored in a carrier in the form of a capsule, sachet, paper, or another container. In case a carrier serves as a diluent, the carrier is a solid, semi-solid, or liquid material that functions as a medium. Accordingly, a formulation according to the present invention can be produced in the form of a tablet, pill, medicinal powder, intra-oral medicine, elixir agent, suspending agent, emulsifier, solvent agent, syrup agent, aerosol agent ( solid in liquid medium), and ointment. Such a formulation may contain up to 10% of an active compound. It is preferred to prepare a compound according to the present invention before administration.

Any suitable carrier that is well known to those skilled in the art can be used in the formulation. In such a formulation, a carrier is in the form of solid, liquid, or a mixture of solid and liquid. For example, a compound of the present invention is dissolved in 4% dextrose / 0.5% aqueous sodium citrate solution to be a concentration of 2 mg / ml for intravenous injection. The solid formulation includes powders, tablets and capsules. The solid carrier consists of one or more materials to also serve as a fragment, lubricant, solvent agent, suspension, binder, tablet disintegrator, capsule. A tablet for oral administration contains an appropriate excipient such as calcium carbonate, sodium carbonate, lactose, calcium phosphate and the like together with a disintegrator such as corn starch, alginic acid and the like and / or a binder such as gelatin, acacia and the like, and a lubricant such as magnesium stearate, stearic acid, talc and the like.

In a medicinal powder, a carrier is a finely powdered solid that is mixed with finely powdered active ingredients. In one tablet, the active ingredients are mixed with a carrier having the required mixing powder in an appropriate ratio, and solidified into a desired shape and size. The medicinal powder and the tablet contain about 1 to about 99% by weight of the active ingredients which are novel compounds according to the present invention. An example of suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose, low melting wax, and cocoa butter.

An axenic liquid formulation contains suspending agent, emulsifier, syrup agent, and elixir agent. The active ingredients can be dissolved or suspended in a pharmaceutically acceptable carrier such as sterilized water, sterilized organic solvent, or mixtures thereof and the like. The active ingredients can often be dissolved in an appropriate organic solvent such as an aqueous propylene glycol solution. When the finely powdered active ingredients are dispersed in aqueous starch, sodium carboxymethylcellulose solution, or appropriate oil, the other compositions can be prepared.

A lyophilized preparation can be prepared by dissolving active ingredients in a solution such as water, if necessary, with a solubilizer such as citric acid, edetic acid, polyphosphoric acid and its salts and a stabilizer such as mannitol, xylitol, sorbitol, glucose, fructose, lactose and maltose and lyophilize.

The method of the invention for inhibiting the release of fatty acid mediated by sPLA2 comprises contacting the mammalian sPLA2 with a therapeutically effective amount of sPLA2 inhibitors of pyrrolo [1,2-b] pyridazine (and formulations containing such inhibitors) as taught at the top.

Preferably, the compounds of the invention (by Formula (I) or (II) or (IV) or pharmaceutical formulations containing these compounds) are in unit dosage form for administration to a mammal. The unit dosage form can be a capsule or a tablet itself, or the appropriate number of any of these. The amount of active ingredient in a unit dose of the composition may vary or adjust from about 0.1 to about 1000 milligrams or more in accordance with the particular treatment involved. It can be appreciated that it may be necessary to develop routine variations to the dose depending on the age and condition of the patient. The dose also depends on the route of administration.

The improved method of treating sepsis using the sPLA2 inhibitors of pyrrolo [1, 2b] pyridazine (and the formulation containing such inhibitors) can be practiced as follows: Inhibitors of this invention are given by injection, either subcutaneously or in muscle tissue or by injection into a vein. Intravenous injection is the preferred mode of delivery to the mammal being treated and offers the advantage of rapid effect and rapid access to the circulatory system, particularly in emergency situations.

It can be appreciated that it may be necessary to develop routine variations to the dose depending on the age and condition of the patient. The specific dose of a compound administered according to this invention to obtain therapeutic or prophylactic effects is, of course, determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration and the condition treat. Typical daily doses contain a dose level of the non-toxic compound (I) from about 0.01 mg / kg to about 50 mg / kg of body weight of an active ingredient of this invention.

This invention is a method of treating or preventing an inflammatory disease, (eg, sepsis, rheumatoid arthritis, osteort ritis, asthma) by administering to a mammal in need thereof a therapeutically effective amount of inhibitor. The administration to a septic patient can be either continuous or intermittent.

The decision to make therapy for sepsis is based on the appearance of the clinical manifestations of sepsis or laboratory tests that show the onset of the sepsis cascade (including of renal complications or abnormalities in coagulation or organ failure). multiple). Typical clinical manifestations are fever, chills, tachycardia, tachypnea, altered mental status, hypothermia, hyperthermia, rapid or repressed breathing or heartbeat, increase or decrease in white blood cell count, and hypotension. These and other symptoms are well known in the art as they are placed on. standard references such as, Harrison's Principies of Infernal Medicine (ISBN 0-07-032370-4) 1994, pages 511-515.

The decision to determine the length of therapy can be supported by standard clinical laboratory results from commercially available assays or instrumentation that supports the eradication of the symptoms that define sepsis. The method of the invention can be practiced by continuously or intermittently administering a therapeutically effective dose of the inhibitor. The administration can be conducted for up to a total of about 60 days with a preferred course of therapy remaining for up to 10 days.

The decision to terminate therapy by the method of the invention can be supported by standard clinical laboratory results from commercially available assays or the instrumentation or disappearance of clinical symptoms characteristic of sepsis. Therapy can be restarted by the return of sepsis. Pediatric forms of sepsis are also successfully treated by the methods, compounds, and formulations of this invention.

When the compound of the present invention is a crystallized, it can show various crystal shapes and crystal habitats.

The present invention is described in more detail in conjunction with the examples and test examples hereafter, but it is noted that the present invention is not limited thereto.

In the examples, the following abbreviations are used: Me: methyl Et: ethyl Pr propyl Ph: phenyl NPhth: phthaloylimide (d) melting point: DBU decomposition temperature: l, 8-diazabicyclo [5.4.0] -7- undeceno And emplos Example 1 Example 1 - Step 1 Compound (1) (18.2g, 0.160 mol) and 90% acetaldehyde (9.43g, 0.190 mol) were dissolved in 20 ml of acetic acid and to the mixture where 10% of a Pd-C catalyst (300 mg) was added. ) and acetic acid solution (10 ml) of piperidine (0.63 ml, 6.37 mmol). The resulting mixture was stirred for 3 hours at room temperature under hydrogen at an atmosphere of 1 to 2. The reaction mixture was filtered to remove the catalyst, diluted with toluene, and washed with water. The mixture was distilled under reduced pressure to give compound (2) (20.00g, 88%, boiling point 92 to 94 ° C (13 mmHg)) as a colorless liquid (see OS, III, 385, 1955. J Am. Chem. Soc., 66, 886 (1944)).

Example 1, - Step 2 To a solution of component (2) (19.2 g, 0.140 mol) in acetone (200 ml) was added allyl bromide (60.2 ml, 0.700 mol) and potassium carbonate. (36.0 g, 0.260 mol) and the resulting mixture was heated under reflux temperature for 5 hours.

The reaction mixture was filtered and the filtrate was distilled under reduced pressure to give compound (3) (22.0 g, 89%, boiling point 107 to 109 ° C (14 mm Hg)) as a colorless liquid (see Compt. Rend. ., 253. 1808 (1961)).

Example 1 - Step 3 Compound (3) (16.8 g, 92.5 mmol) and potassium acetate (10. Og, 102 mmol) were dissolved in 85 ml of dimethyl sulfoxide and the resulting mixture was stirred for 5 hours at 150 ° C. Water was added to the reaction mixture, the mixture was extracted with ether, and the organic layer was washed with water, dried over magnesium sulfate, and distilled in atmospheric to give compound (4) (8.00 g, 79 %, boiling point 168 to 172 ° C) (see Compt. Rend., 253, 1808 (1961) and Indian J. Chem., 25, 1249 (1986)).

Also, the compound (4) can be synthesized according to the method described in J. Chem. Soc. Perkin Trans. 1, 1837, 1986.

Example 1 - Step 4 To a solution of magnesium (3.03 g, 0.125 mol) and 1,2-dibromoethane (0.49 ml, 5.67 mmol) in 70 ml of ether was added a solution of benzyl bromide (21.3 g, 0.125 mmol) in 30 ml of ether under ice cooling. The mixture was allowed to warm to room temperature and was stirred until the magnesium dissolved. A solution of compound (4) (12.4 g, 0.113 mol) in 30 ml of ether was added dropwise to the resulting mixture and the reaction mixture was heated under reflux temperature for 2 hours. Water was added to the reaction mixture under ice-cooling and the mixture was acidified with 50 ml of 2.5 N sulfuric acid. The reaction mixture was stirred for 100 minutes in a water bath (90 ° C) while stirring. ether. The reaction mixture was extracted with ether and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on silica gel using ethyl acetate-hexane (1:20) and appropriate fractions were distilled under reduced pressure to give compound (5) (17.6 g, 77%, boiling point 90 to 91 ° C (0.4 mmHg)) as a colorless liquid (see Synthesis, 996 , 1988).

A-NHR (CDC13): 0.81 (3H, t, J = 7.4 Hz), 1.41-1.78 (2H, m), 2.09-2.41 (2H, m), 2.56-2.70 (1H, m), 3.71 (2H, s), 4.96-5.06 (2H, m), 5.56-5.77 (lH, m), 7.15-7.37 (5H, m).

Example 1 - Step 5 Compound (5) (13.4 g, 66.1 mmol) was dissolved in 150 ml of dichloromethane, ozone gas was introduced to the mixture at -78 ° C until the starting material was dispersed, and the excess amount of gas from Ozone was replaced by argon gas. To the resulting mixture was added a solution of triphenylphosphine (17.7 g, 67.4 mmol) in 50 mL of dichloromethane and the mixture was stirred for 30 minutes at room temperature. After the solvent was removed, the precipitated crystals were filtered by washing with a solvent mixture of ethyl acetate and hexane and the filtrate was concentrated in vacuo. The resulting residue was subjected to silica gel column chromatography and using ethyl acetate and hexane (1.4) as an eluent to give compound (6) (11.2 g, 83%) as a colorless liquid. 1H-NHR (CDC13): 0.87 (3H, t, J = 7.5Hz), 1.41-1.75 (2H, m), 2.50 (1H, dd, J = 18.3, 3.9Hz), 2.96 (1H, dd, J = 18.3, 9.6Hz), 3.06-3.15 (1H, m), 3.84 (1H, d, J = 16.2Hz), 3.91 (1H, d, J = 16.2Hz), 7.20-7.36 (5H, m), 9.70 (1H, s).

Example 1 - Step 6 Compound (6) (11.2 g, 54.6 mmol) and N-aminophthalimide (8.85 g, 54.6 mmol) was suspended in 250 mL of dioxane, 5 N hydrochloric acid (6 mL, 30.0 mmol) was added to the suspension, and the mixture was added to the suspension. stirred for 30 minutes at 100 ° C. Half of the reaction mixture was concentrated, diluted with ether, washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was subjected to silica gel column chromatography and the fractions were eluted with chloroform / hexane = 2: 1 were collected and recrystallized from hexane to give compound (7) (14.8 g, 82%, melting point 153 to 154 ° C) as colorless crystals (see Chem. Ver., 102, 3268 (1969)).

Elemental Analysis C2? H? SN202 Calculated: C, 76.34; H, 5.49; N, 8.48. Found: C, 76.11; H, 5.47; N, 8.69.

A-NHR (CDC13): 1.22 (3H, t, J = 7.5 Hz), 2.52 (2H, q, J = 7.5 Hz), 3.81 (2H, s), 6.24 (1H, d, J = 3.3 Hz), 6.60 (1H, d, J = 3.3 Hz), 6.91-7.03 (5H, m), 7.74-7.83 (4H, m).

Example 1 Step 7 Compound (7) (14.9 g, 45.2 mmol) was suspended in 300 ml of ethanol, hydrazine monohydrate (5.5 ml, 113 mmol) was added to the suspension, and the mixture was stirred for 30 minutes at 100 ° C. The precipitated crystals were filtered completely and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel using chloroform to give compound (XII-1) (9.00g, 99%) as a colorless oil. 1H-NHR (CDC13): 1.16 (3H, t, J = 7.5Hz), 2.46 (2H, q, J = 7.5 Hz), 3 9 (2H, s), 4.23 (1H, br s), 5.94 (1H , d, J = 2.7Hz), 6.64 (1H, d, J = 2.7Hz), 7.07 (5H, m).

Example 1 - Step 8 The diethyl ethoxymethylenemalonate (7.57g, 35.0 mmol) was added to the compound (XII-1) (6.38 g, 31.9 mmol) and the mixture was heated for 40 minutes at 125 ° C by removing ethanol generated in situ. To the reaction mixture was added hexane and the precipitated crystals were filtered to give compound (8) (7.67 g, 65%, melting point 60 to 61 ° C) as colorless crystals. The filtrate was purified by chromatography on silica gel (elution with ethyl acetate / hexane = 1/6) to give compound (8) (3.54 g, 30%) as colorless crystals (see J. Heterocyclic Chem., 31, 409, 1994).

Elemental Analysis C2? H26N204, Calculated: C, 68.09; H, 7.07; N, 7.56 Found: C, 67.69; H, 7.06; N, 7.68 1H-NHR (CDC13): 1.20 (3H, t, J = 7.2Hz), 1.21 (3H, t, J = 7.2Hz), 1.33 (t, J = 6.9Hz), 2.51 (2H, q, J = 6.9Hz), 3.88 (2H, s), 4.08 (2H, q, J = 7.2Hz), 4.24 (2H, q, J = 7.2Hz), 6.07 (1H, d, J = 3.3Hz), 6.66 (1H, d, J = 3.3Hz), 7.00-7.28 (5H, m), 7.67 (1H, d, J = 11.1Hz), 10.32 (1H, d, J = 11.1Hz).

Example 1 - Step 9 Compound (8) (11.9 g, 32.1 mmol) was dissolved in SAS-296 (phenylxylylethane) and the mixture was heated for 5 hours at 200 up. 210 ° C under an argon atmosphere. The reaction mixture was chromatographed on silica gel using toluene / hexane (= 1/2) to give compound (9) (6.85 g, 66%) as yellow crystals. The crystals were recrystallized from hexane (melting point 75 to 76 ° C).

Elemental Analysis C? 6H? 6N20, Calculated: C, 70.35; H, 6.21; N, 8.64. Found: C, 70.22; H, 6.28; N, 8.88. 1H-NHR (CDC13): 1.24 (3H, t, J = 7.5 Hz), 2.66 (2H, q, J = 7.5Hz), 4.37 (2H, s), 6.88 (1H, s), 7.12-7.25 (5H, m), 8.28 (1H, s), 12.18 (1H, s).

Example 1 - Step 10 Compound (9) (3.02 g, 9.30 mmol) was dissolved in 10 ml of dimethyl sulfoxide. Sodium chloride (598 mg, 10.2 mmol) and water (519 mg, 28.8 mmol) were added to the solution and the mixture was stirred for 4 hours at 150 ° C. The solvent was removed and the residue was purified by chromatography on silica gel (elution with ethyl acetate / hexane = 1/4) to give compound (10) (1.32 g, 63%) as colorless crystals. These crystals were recrystallized from ether and hexane (boiling point 113 to 114 ° C).

Elemental Analysis C? 6H? 6N20, Calculated: C, 76.16; H, 6.39; N, 11.10. Found: C, 75.93; H, 6.45; N, 11.27.

A-NHRÍCDCla): 1.24 (3H, t, J = 7.5 Hz), 2.68 (2H, q, J = 7.5Hz), 4.39 (2H, s), 5.85 (1H, d, J = 5.4Hz), 6.53 ( 1H, s), 7.12-7.25 (5H, m), 7.80 (1H, d, J = 5.4Hz).

Example 1 - Step 11 Compound (10) (1.03 g, 4.10 mmol) was dissolved in 8 ml of tetrahydrofuran. Potassium carbonate (680 mg, 4.92 mmol) and a solution of methyl bromoacetate (753 mg, 4.92 mmol) in 2 ml of tetrahydrofuran were added to the solution and the mixture was heated for 3 hours at 50 ° C. The reaction mixture was diluted with chloroform and filtered. The filtrate was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was subjected to silica gel column chromatography (eluting with toluene / ethyl acetate = 1: 50) to give compound (11) (850 mg, 64%) as colorless crystals. These crystals were recrystallized from ether and methanol (melting point 94 to 95 ° C).

Elemental Analysis C? 9H2oN203, Calculated: C, 70.35; H, 6.21; N, 8.64. Found: C, 70.32; H, 6.29; N, 8.88. 1H-NHR (CDC13): 1.24 (3H, t, J = 7.5Hz), 2.69 (2H, q, J = 7.5 Hz), 3.82 (3H, s), 4.38 (2H, s), 4.78 (2H, s ), 5.72 (1H, d, J = 5.4Hz), 6.63 (1H, s), 7.10-7.25 (5H, m) 7.84 (1H, d, J = 5.4Hz).

Example 1 - Step 12 To a solution of oxalyl chloride (752 mg, 5.92 mmol) in 7 ml of dichloromethane was added a solution of compound (11) (384 mg, 1.18 mmol) in 3 ml of dichloromethane and N-methylmorpholine (240 mg, 2.37 mmol) at -15 ° C and the mixture was stirred for 2 hours at Q ° C. After the mixture was added to aqueous ammonia cooled with ice, stirring for 10 minutes at room temperature, the mixture was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was recrystallized from methanol to give compound (1-1) (416 mg, 89%, melting point 210 to 212 ° C) as pale yellow crystals.

Elemental Analysis C2? H2? N3? 5, Calculated: C, 63.79; H, 5.35; N, 10.63 Found: C, 63.59; H, 5.39; N, 10.91 A-NHRÍCDCla): 1.16 (3H, t, J = 7.5Hz), 2.86 (2H, q, J = 7.5Hz), 3.80 (3H, s), 4.37 (2H, s), 4.76 (2H, s), 5.56 (1H, br.s), 6.06 (1H, d, J = 5.4Hz), 6.70 (1H, br.S), 7.13-7.25 (5H, m), 8.02 (1H, d, J = 5.4Hz).

Example 1 - Step 13 The compound (1-1) (248 mg, 0.627 mmol) was suspended in 3 ml of methanol, 1 ml of 1N sodium hydroxide was added to the suspension at room temperature, and the mixture was stirred for 1 hour. The mixture was acidified with IN hydrochloric acid. under cooling on ice and the precipitated crystals I were filtered to give the compound (1-2) (162 mg, 86%, decomposition point 252 to 255 ° C) as I pale yellow crystals.

Elemental Analysis C2oH19N3? 5, Calculated: C, 62.99; H, 5.02; N, 11.02. Found: C, 62.80; H, 5.06; N, 11.21.

A-NHR (CDC13): 1.04 (3H, t, J = 7.2Hz), 2.79 (2H, q, J = 7.2Hz) 4.35 (2H, s) 4.88 (2H, s), 6.48 (lH, d, J = 5.4Hz), 7.12-7.29 (5H, m), 7.40 (lH, br s), 8.23 (1H, d, J = 5.4Hz), 13.29 (1H, br s).

The compound (1-2) (51.4 mg, 0.134 mmol) was suspended in 2 ml of H20 and 0.1 N sodium hydroxide (1.34 ml, 0.134 mmol) was added to the mixture under cooling on ice. The mixture was filtered and lyophilized to give compound (1-3) (50.1 mg, decomposition point 280 ° C) as a yellow powder.

Example 2 (Step 1) A mixture of compound (XII-1) (601 mg, 3 mmol), methyl acetoacetate (348 mg, 3 mmol), p-toluenesulfonic acid monohydrate (29 mg, 0.15 mmol) and 20 ml of chloroform, was heated under Reflux temperature for 15 hours with an oil bath. The water generated was dehydrated by a Dean-Stark apparatus with a 4A molecular sieve. Water and 25 mg of sodium bicarbonate were added to the reaction mixture. The mixture was extracted with chloroform, dried over magnesium sulfate, and subjected to silica gel column chromatography (16g of silica gel, eluting with 2.5% chloroform-acetonitrile) to give the compound (12) (800 mg, 100%) as a brown oil.

- -NHRÍCDCls): 1.21 (3H, t, J = 7.4Hz), 2.65 (2H, q, J = 7.4Hz), 4.36 (2H, s), 5.79 (1H, s), 6.43 (1H, s), 7.20 (5H, m).

A mixture of compound (12) (799 mg, 3 mmol), methyl bromoacetate (0.37 ml, 3.9 mmol), potassium carbonate (539 mg, 3.9 mmol), and 10 ml of dimethylformamide were stirred for 1 hour at room temperature. Water was added to the reaction mixture. The mixture was extracted with toluene, washed with water, dried over magnesium sulfate, subjected to silica gel column chromatography (20 g of silica gel, eluting with toluene) to give 797 mg of the eluate. The eluate was recrystallized from acetene and isopropyl ester to give compound (13) (739 mg, 72.5%, boiling point 120 to 121 ° C) as white crystals.

A-NMR (CDC13): 1.22 (3H, t, J = 7.4 Hz), 2.38 (3H, s), 2.65 (2H, q, J = 7.4Hz), 3.83 (3H, s), 4.35 (2H, s) ), 4.77 (2H, s), 5.60 (1H, s), 6.54 (1H, s), (7.20 (5H, s).

(Step 3) Compound (13) (676 mg, 2 mmol) and N-methylmorpholino (0.44 ml, 4 mmol) was dissolved in 10 ml of dichloromethane. The mixture was added to a solution of oxalyl chloride (0.87 ml, 10 mmol) in 17 ml of dichloromethane, cooled to -10 ° C in a methanol-ice bath, and the resulting mixture was stirred for 30 minutes at room temperature. same temperature. The reaction mixture was added to 10 ml of concentrated aqueous ammonia and the insoluble material was completely filtered. The filtrate was extracted with chloroform, washed with water, dried over magnesium sulfate, and subjected to silica gel column chromatography (30 g of silica gel, eluting with 50% acetonitrile-chloroform). The eluate was recrystallized from acetone and ethyl acetate to give the compound (1-4) (774 mg, 94.5%, boiling point 225 to 226 ° C) as pale yellow crystals.

A-NMR (d6-DMSO): 1.02 (3H, t, J = 7.2Hz), 2.41 (3H, s), 2.76 (2H, q, J = 7.2Hz), 3.72 (2H, s), 4.32 (2H , s), 4.95 (2H, s), 6.50 (1H, s), 7.15-7.30 (5H, m), 7.36 (1H, br.s), 7.75 (1H, br.s).

Step 4) The compound (1-5) was synthesized in a manner similar to that described in Example 1 Step 13. 1 H-NMR (d 6 -DMSO): 1.02 (3H, t, J = 7.5Hz), 2.40 (2H, s), 2.76 (2H, q, J = 7.5Hz), 4.32 (2H, s), 4. 84 (2H, s), 6.44 (1H, s), 7.16-7.28 (5H, m), 7.36 (1H, br.s), 7.75 (1H, br.s).

Example 3 NC (14) (15) (xp-2) (Step 1) A mixture of compound (14) (25.8 g, 0.203 mol), bromoacetaldehyde diethylacetal (48.0 g, 0.244 mol), potassium carbonate (33.7 g, 0.244 mol), and 130 ml of dimethylformamide was heated for 24 hours at 110 ° C. under nitrogen. The dimethylformamide was removed under reduced pressure and water was added to the residue. The mixture was extracted with toluene, washed with water, dried over magnesium sulfate, and the toluene was removed under reduced pressure. The residue was distilled under reduced pressure to give compound (15) (39.55 g, 80.1%, boiling point 99 to 102 ° C (1 mmHg)) as a colorless liquid.

A-NMR (CDC13): 1.38 (3H, t, J = 7.0Hz), 1.21 (3H, t, J = 7.0Hz), 1.62 (3H, s), 2.01 (1H, m, J = 14.2 Hz, J = 4.2Hz), 2.40 (1H, m, J = 14.2 Hz, J = 7.4Hz) 3.49-3.75 (4H, m) 4.24 (1H, J = 7. .0Hz), 4.25 (1H, q, J = 7.0Hz), 4.75 (1H, m, J = 7.4Hz, J = .2Hz).

(Step 2) A mixture of compound (15) (43.6 g, 0.179 mol), potassium acetate (19.3 g, 0.197 mol), and 87 ml of dimethyl sulfoxide was heated for 14 hours in an oil bath (160 ° C) under nitrogen. Then, the mixture was cooled, water was added to the mixture, and the mixture was extracted with ether. The organic layer was washed with water, dried over sulfate and magnesium, and concentrated in vacuo. The residue was distilled under reduced pressure to give compound (16) (29.48 g, 96.0%, boiling point 110-113 ° C (23 mmHg)) as a colorless liquid.

A-NMR (CDC13): 1.22 (3H, t, J = Hz), 1.23 (3H, t, J = 7Hz), 1.35 (3H, d, J = 7.6Hz), 1.73-2.00 (2H, m), 2.79 (1H, m), 3.47-3.80 (4H, m), 4.67 (1H, m).

(Step 3) To a Grignard reagent which was prepared by magnesium (1.53 g, 0.063 mol), 71 ml of ether, 1,2-dibromoethane (0.26 ml, 0.003 mol), and benzyl bromide (7.14 ml, 0.060 mol) was added a Solution of the compound (16) (7.06 g, 0.05 mol) in m of ether and the resulting mixture was stirred for 4 hours at room temperature and heated for 5 hours under reflux temperature in an oil bath (60 ° C). To the reaction mixture was added aqueous ammonium chloride (5.35 g, 0.1 mol, 50 ml) under ice cooling and 63 ml of 2N sulfuric acid and the mixture was stirred for 30 minutes. The reaction mixture was neutralized by adding sodium bicarbonate (3.36 g, 0.040 mol) and extracted with ether. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in toluene and purified by chromatography on silica gel (90 g, eluting with 10% ethyl acetate-toluene) to give compound (17) (9.13 g, 78%).

XH-NMR (CDC13): 1.11 (3H, d, J = 7Hz), 1.58-2.24 (2H, m), 2.90 (1H, m), 3.77 (2H, s), 3.78-3.90 (4H, m), 4.87 (1H, T, J = 4.8Hz) ,. 7.14-7.37 (5H, m).

(Step 4) Compound (17) (35.9 g, 0.129 mol) and N-aminophthalimide (20.9 g, 0.129 mol) was suspended in 95% ethanol (250 ml). To the suspension was added INN hydrochloric acid (13 ml, 0.013 mol) and the resulting mixture was heated for 30 minutes under reflux in an oil bath. After cooling, the precipitated crystals were filtered to give compound (18) (35.96 g, 84.4%, boiling point 151 to 152 ° C) as pale yellow crystals.

XH-NMR (CDCI3): 1.22 (3H, t, J = 7.4Hz), 2.52 (2H, q, J = 7.8Hz), 3.81 (2H, s), 6.24 (1H, d, J = 3Hz), 6.60 (1H, d, J = 3Hz), 6.92-7.03 (5H, m), 7.79 (4H, m).

(Step 4' ) To the solution of compound (17) (1.69 g, 8.6 mmol) and ethyl carbazate (0.90 g, 8.6 mmol) in 20 ml of dioxane, 5N hydrochloric acid (0.86 ml, 4.3 mmol) was added and the resulting mixture was heated for 30 minutes in an oil bath (100 ° C). The dioxane was removed under reduced pressure, and water was added to the residue. The mixture was made alkaline with aqueous sodium bicarbonate, extracted with toluene, dried over magnesium sulfate, subjected to silica gel column chromatography (50 g of silica gel, eluting with toluene) to give the compound ( 19) (0.734 g, 33.1%) as a colorless oil. 1 H-NMR (CDCl 3): 1.21 (3H, br.t), 2.08 (3H, s), 3.84. (2H, s), 4.10 (2H, br), 5.98 (1H, d, J = 3 Hz), 6. 55 (1H, d, J = 3 Hz), 6.79 (1H, br), 7.07-7.30 (5H, m).

(Step 5) Using the compound (18) or the compound (19) as the starting material, the compound (XII-2) was synthesized in a manner similar to that described in Example 1-Step 7.

The compound (XII-3) or the compound (XII-10) were synthesized by carrying out the same reactions as described above. The physical data of each compound are shown in Table 1.

H2 Example 4 (21) (22) (? -6) (Step 1) A mixture of compound (XII-1) (11.06 g, 54.5 mmol), ethyl 4-chloroacetoacetate (8.97 g, 54.5 mmol), p-toluenesulfonic acid monohydrate (518 mg, 2.73 mmol), and 180 mL of chloroform, it was heated for 4 hours under reflux temperature. The water generated in situ is dehydrated by a Dean-Stark apparatus with a 4A molecular sieve. To the reaction mixture was added water and sodium bicarbonate (250 mg) and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give compound (10) (15.17 g, 92.5%) as a brown oil.

A-NMR (CDC13): 1.23 (3H, t, J = Hz), 2.68 (2H, q, J = 7.5Hz), 4.36 (2H, s), 4.53 (2H, s), 6.08 (1H, s) , 6.51 (1H, s), 7.14-7.24 (5H, m).

A mixture of compound (20) (1.49 g, 4.95 mmol), methyl bromoacetate (0.61 ml, 6.44 mmol), potassium carbonate (684 mg 4.95 mmol) and 15 ml of dimethylformamide was stirred for 1 hour at room temperature. Water was added to the reaction mixture and the mixture was extracted with toluene. The organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was subjected to silica gel column chromatography (28 g), fractions eluted with toluene were collected, and concentrated in vacuo. The residue (1.40 g) was recrystallized from ether and petroleum ether to give compound (21) (1.19 g, 64.4%), boiling point 73-73.5 ° C) as white crystals.

A-NMR (CDC13): 1.23 (3H, t, J = 7.5 Hz), 2.67 (2H, q, J = 7.5Hz), 3.84 (3H, s), 4.35 (2H, s), 4.55 (2H, s) ), 4.82 (2H, s), 5.89 (1H, s), 6.62 (1H, s), 7.12-7.24 (5H, m).

(Step 3) A mixture of compound (21) (373 mg, 1 mmol), phenol (113 mg, 1.2 mmol), potassium carbonate (166 mg, 1.2 mmol) and 10 mL of acetone was heated for 22 hours under reflux temperature in an oil bath. The acetone was removed, the residue was treated with toluene, the insoluble material was completely filtered, and the solvent was removed. The residue was subjected to silica gel column chromatography (13 g), fractions eluted with 5% ethyl acetate-toluene were collected, and concentrated in vacuo to give compound (22) (350 mg, 81.4% ) as a colorless oil.

A-NMR (CDC13): 1.24 (3H, t, J = 7.5Hz), 2.69 (2H, q, J = 7.5Hz), 3.75 (3H, s), 4.37 (2H, s), 4.77 (2H, s ), 5.06 (2H, s), 5.96 (1H, s), 6.60 (1H, s), 6.93-7.25 (10H, m).

(Step 4) Compound (22) (350 mg, 0.813 mmol) and N-methylmorpholine (0.18 ml, 1.63 mmol) were dissolved in 5 ml of dichloromethane. To the mixture was added a solution of oxalyl chloride (0.21 ml, 2.44 mmol) in 3 ml of dichloromethane which was cooled under ice cooling and the resulting mixture was stirred for 2 hours at the same temperature. The reaction mixture was poured into 2 ml of concentrated aqueous ammonia under ice-cooling, the insoluble material was filtered off completely, and the filtrate was extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and a vacuum concentrated. The residue was subjected to silica gel column chromatography (12 g), the fractions eluted with 50% acetonitrile-chloroform were collected, and concentrated in vacuo. The residue was recrystallized from acetone and ethyl acetate to give compound (1-6) (375 mg, 91.9%, boiling point 185-186 ° C) as pale yellow crystals.

XH-NMR (d6-DMS0): 1.04 (3H, t, J = 7.2Hz), 2.79 (2H, q, J = 7.2Hz), 3.67 (2H, s), 4.33 (2H, s), 4.99 (2H) , s), 5.15 (2H, s), 6.68 (1H, s), 6.93-7.29 (10H, m), 7.40 (1H, br.s), 7.79 (1H, br.s).

Example 5 (21) (23) (1-7) (Step 1) Compound (21) (5.0 g, 13.4 mmol) and N, N-diisspropyl-N-ethylamine (3.5 ml, 20.1 mmol) was dissolved in 25 ml of dichloromethane. This solution was added to a solution of oxalyl chloride (3.5 ml, 40.2 mmol) in 35 ml of dichloromethane which was cooled in an ice bath and methanol (-10 ° C) and the mixture was stirred for 2 hours at the same temperature. The reaction mixture was poured into a mixed solution of concentrated aqueous ammonia (10.7 ml) and chloroform (40 ml) under cooling with ice. The insoluble material was removed by filtration and the filtrate was extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was subjected to silica gel column chromatography (42 g), the fractions eluted with 50% acetonitrile and chloroform were collected, and concentrated in vacuo. The residue was recrystallized from tetrahydrofuran-ethyl acetate to give compound (23) (5.36 g, 90.0%, boiling point 191-194 ° C) as pale yellow crystals.

A-NMR (d6-DMSO): 1.03 (3h, T, j = 7.5Hz), 2.78 (2H, q, J = 7.5Hz), 3.72 (2H, s), 4.34 (2H, s), 4.76 (2H , s), 5.00 (2H, s), 6.71 (1H, s), 7.16-7.28 (5H, m), 7.42 (1H, br.s), 7.82 (1H, br.s).

(Step 2) A mixture of compound (23) (500 mg, 1.13 mmol), 4-fluorophenol (152 mg, 1.35 mmol), potassium carbonate (187 mg, 1.35 mmol), potassium iodide (38 mg, 0.226 mmol), and ml of acetone, heated for 7 hours under reflux temperature in an oil bath. The acetone was removed, the residue was treated with toluene, the insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was subjected to silica gel column chromatography (9.4 g), fractions eluted with 5% ethyl acetate-toluene were collected, and concentrated in vacuo. The residue was recrystallized from tetrahydrofuran and ethyl acetate to give compound (1-7) (419 mg, 71.6%, boiling point 178-179 ° C) as white crystals.

A-NMR (CDCI3): 1-04 (3H, t, J = 7.5Hz), 2.79 (2H, q, J = 7.5Hz), 3.68 (3H, s), 4.33 (2H, s), 5.00 (2H, s), 5.13 (2H, s), 6.68 (1H, s), 7.00-7.24 (9H, m), 7.40 (1H, br.s), 7.80 (1H, br.s) Example 6 - Example 86 The compounds (1-8) to (1-84) represented by the following formula were synthesized by the same reactions described in the previous Examples. The physical data is shown in Tables 2 through 11.

With the proviso that A in the Tables means a group represented by the following formula: Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 The compounds shown in Tables 12 to 17 can be synthesized according to the same method described in the previous Examples. The abbreviations used in Tables 12 through 17: AA, AB, AC, AD, AE, AF, AG, AH, AI, AJ, AK, AL, AM, AN, AO, AP, AQ, AR, AS, AT, AU, AV, AW, AX, AY, AZ, BA, BB, BC, BD, BE, BF, BG, BH, and Bl show the substituents described as follows.

Table 12 Table 13 Table 14 Table 15 Table 16 H2 Table 17 H2 Test Example: Inhibition Test of Secreted Human Phospholipase A2.

Analytical experiment In order to identify and evaluate an inhibitor of recombinant human secreted phospholipase A2, the following chromogenic assay is used. This test was applied for a high purification volume where 96-well microplates are used. A general explanation of such an assay is described in "Analysis of Human Synovial Fluid Phospholipase A2 on Short Chain Phosphat idylcholine-Mixed Micells: Development of a Spectrophotometric Assay Suitable for a Micortiterplate Reader" (Analytical Biochemistry, 204, pages 190-197, 1992 by Laure J. Reynolds, Lori L. Hughes and Edward A. Dennis, the description of which is incorporated herein by reference.

Reagents: Reaction Shock Absorber CaCl2.6H20 (2.19 g / L; KCl (7.455 g / L; Bovine Albumin Serum (free of fatty acid) (1 g / L) (Sigma A-7030) Tris-HCl (3.94 g / L) pH 7.5 (adjusted with NaOH) Enzyme Buffer Solution 0.05 M-AcONa 0.2 M-NaCl pH 4.5 (adjusted with acetic acid; Enzyme solution 1 mg of sPLA2 is dissolved in 1 ml of enzyme buffer. Subsequently, the solution is maintained at 4 ° C. In the assay, 5 μl of the solution is diluted with 1995 μl of the reaction buffer to be used.

DTNB 198 g of 5, 5'-dithiobis-2-benzoic acid (manufactured by Wako Pure Chemicals) is dissolved in 100 ml of H20. pH 7.5 (adjusted with NaOH) Substrate Solution 100 mg of racemic 1, 2-bis (heptanoylthio) -1,2-dideoxy-sn-glycero-3-phospholylcholine was dissolved in 1 ml of chloroform.

Triton-X 100 624.9 mg Triton-X 100 was dissolved in the reaction buffer.

Reaction enzyme: for 1 microtitre plate. 1) 0.106 ml of the substrate solution was placed in a centrifuge tube, and flushed with nitrogen gas to remove the solvent. 0.51 ml of Triton-X 100 was added thereto, the mixture was stirred, then sonified in a sonification-type bath to dissolve. To the resulting product was added 17.8 ml of the reaction buffer and 0.46 ml of DTNB, and 0.18 ml of each mixture was added to the 96 microtiter trays. 2) 10 μl of a test compound (or blank solvent) was added in accordance with the alignment of the trays that were previously placed. 3) Incubation was carried out at 40 ° C for 15 minutes 4) 20 μl of an enzyme solution (sPLA2) that was previously diluted (50 ng / well) was added to the starting reaction (40 ° C, 30 minutes).

) Changes in absorbance for 30 minutes were measured by a plate reader, and the inhibitory activity was calculated (OD: 405 nm). 6) The IC5o was determined by a concentration plotted in a log with respect to the inhibition values within the inhibition range of 10% to 90%.

The results of the inhibition test of human secreted phospholipase A2 are shown in the following Table 18.

Table 18 Formulation Example It will be noted that the following Formulation Examples 1 through 8 are merely illustrative, but are not intended to limit the scope of the invention. The term "active ingredient" means the compounds represented by the formula (I), the prodrugs thereof, their pharmaceutically acceptable salts, or their solvates.

Formulation Example 1 Hard gelatin capsules were prepared using the following ingredients: Dosage (mg / capsule) Active ingredient 250 Starch, dry 200 Magnesium stearate 10 Total 460 mg Formulation Example 2 A tablet was prepared using the following ingredients Dose (mg / tablet) Active ingredient 250 Cellulose, microcris such 400 Silicon dioxide, gas 10 Stearic acid 5 Total 665 mg The components were mixed and compressed to form tablets each weighing 665 mg.

Formulation Example 3 An aerosol solution was prepared containing the following components: Weight Active ingredient 0.25 Ethanol 25.75 Propellant 22 (chlorodifluoromethane) 74 Total 100.00 The active compound was mixed with ethanol and the mixture was added to a portion of the propellant 22, cooled to -30 ° C and transferred to a filling device. The required amount was then fed to a stainless steel vessel and diluted with the rest of the propellant. The units of value were then adapted to the container.

Formulation Example 4 Tablets were prepared as follows, each containing 60 mg of active ingredient. Active ingredient 60 mg Starch 45 mg Cellulose microcrystals 35 mg Polyvinyl pyrrolidone (as 4 mg a 10% solution in water) Carboxymethyl starch 4.5 mg sodium Magnesium stearate 0.5 mg Talc 1 mg Total 150 mg The active ingredient, starch, and the cellulose was passed through a No. 45 US mesh screen, and mixed thoroughly. The aqueous solution containing polyvinylpyrrolidone was mixed with the resulting powder, and the mixture was then passed through a No. 14 U.S. mesh screen. The granules thus produced were dried at 50 ° C and passed through a No. 18 mesh U.S. Sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 US mesh screen, were then added to the granules which, after mixing, were compressed into a tablet machine to produce tablets. , each weighing 150 mg.

Formulation Example 5 Capsules were made, each containing 80 mg of the active ingredient, as follows: Active ingredient 80 mg Starch 59 mg Cellulose microcrystals' 59 mg Magnesium stearate 2 mg Total 200 mg The active ingredient, cellulose, starch, and magnesium stearate are mixed, passed through a mesh sieve No. 45 US, filled into hard gelatin capsules in amounts of 200 mg.

Formulation Example 6 Suppositories were prepared, each containing 225 mg of the active ingredient, as follows: Active ingredient 225 mg Fatty acid glycerides 2000 mg saturated Total 2225 mg The active ingredient was passed through a No. 60 U.S. mesh screen. and was suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture was then emptied into a suppository mold of 2 g nominal capacity and allowed to cool.

Formulation Example 7 Suspensions were prepared, each containing 50 mg of the active ingredient per 5 ml of dose, as follows: Active ingredient 50 mg Sodium caproxymethyl cellulose 5 0 mg Syrup 1. 2 5 ml Benzoic acid solution 0. 10 ml Sabori zante c. s • Color c. s Purified water for the total 5 ml The active ingredient was passed through a No. 45 U.S. mesh screen, and mixed with the sodium carboxymethyl cellulose and the syrup to form a smooth paste. The benzoic acid, flavoring and coloring solution was diluted with a portion of the water and added, with stirring. Sufficient water was then added to produce the required volume.

Formulation Example An intravenous formulation can be prepared as follows: Active Ingredient 100 mg Isotonic saline 1000 mg The solution of the above ingredients is generally administered intravenously to a subject in a range of 1 ml per minute.

Formulation Example 9 The composition of the lyophilized preparations (in 1 small vial) were made as follows: Active ingredient 127 mg Trisodium citrate dihydrate 50 mg Mannitol 180 mg The above materials were dissolved in water for an injection such that the concentration of the active ingredient is 10 mg / g. The primary freezing step is given for 3 hours at -40 ° C, the heat treatment step for 10 hours at -10 ° C, and the re-freezing step for 3 hours at -40 ° C. Then, the primary drying step is executed for 60 hours at 0 ° C, 10 Pa and the secondary drying step for 5 hours at 60 ° C, 4 Pa. In this way, the lyophilized preparation is obtained.

Industrial Application The compounds according to the present invention have inhibitory activity of sPLA2 in such a way that the compounds of the invention inhibit the release of the fatty acid mediated by sPLA2 (such as arachidonic acid), therefore it is effective for the treatment of septic shock. and similar.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (23)

Claims

1. A compound represented by the formula (I): characterized in that R1 is a group selected from (a) C6 to C20 alkyl, C6 to C20 alkenyl, C6 to C20 alkynyl, carboxylic groups, and heterocyclic groups, (b) the groups represented by (a) each independently substituted with at least one a selected group of substituents without interference, and (c) - (L1) -R6 wherein L1 is a divalent linking group from 1 to 18 atoms, selected from hydrogen atoms, nitrogen atoms, carbon atoms, oxygen atoms , and sulfur atoms, and R6 is a group selected from groups (a) and (b); R2 is a hydrogen atom or a group containing from 1 to 4 atoms without hydrogen; R is - (L) - (acid group) wherein L "is an acid bond having an acid linkage length of 1 to 5; R4 and R5 are independently selected from a hydrogen atom, substituent (s) without interference, carbocyclic groups, carbocyclic groups substituted with a substiuent (s) without interference, heterocyclic groups, and heterocyclic groups substituted by a substituent (s) without interference; Y RA is a group represented by the formula wherein L7 is a divalent linking group selected from a bond or a divalent group selected from -CH2-, -O-, -S- -NH-, or -CO-, R27 and R28 are independently hydrogen, Cl to C3 alkyl or halogen; X and Y are independently an oxygen atom or a sulfur atom; and Z is -NH2-, NHNH2; the prodrugs thereof, or their pharmaceutically acceptable salts; or its solvates.

A compound represented by the formula (I JJ characterized in that R7 is - (CH2) m -R12 wherein 'm is an integer from 1 to 6, and R12 is (d) a group represented by the formula: wherein a, c, e, n, q, and t are independently an integer from 0 to 2, R13 and R14 are independently selected from halogen, C1 to CIO alkyl, C1 to CIO alkyloxy, C1 to CIO alkylthio, aryl, heteroaryl, and haloalkyl Cl up to CIO, a is a hydrogen atom or a sulfur atom, L5 is - (CH2) v-, C = C-, -C = C-, -O-, u -S-, v is an integer from 0 to 2, ß is -CH2- or - (CH2) 2-,? is an oxygen atom or a sulfur atom, b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, and w are independently an integer from 0 to 5, g is an integer 0 to 2 , r is an integer from 0 to 7, and u is an integer from 0 to 4, or is (e) a member of (d) substituted with at least one substituent selected from the group consisting of Cl to C6 alkyl, alkyloxy Cl up to C6, haloalkyloxy Cl up to C6, haloalkyl Cl up to C6, aryl, and a halogen; R is C1 to C3 alkyl, C2 to C3 alkenyl, C3 to C4 cycloalkyl, C3 to C4 cycloalkenyl, Cl to C2 haloalkyl, Cl to C3 alkyloxy or Cl to C3 alkylthio; Rb is (L3) -R15 where L is represented by the formula: wherein M is -CH2-, -O-, -N (R24) -, or -S-, R16 and R17 are independently hydrogen atom, Cl alkyl up to CIO, aryl, aralkyl, alkyloxy, haloalkyl, carboxy, or a halogen, and R24 is a hydrogen atom or alkyl Cl up to C6, and R15 is represented by the formula: wherein R18 is a hydrogen atom, a metal, or Cl alkyl up to CIO, R19 is independently a hydrogen atom, or Cl alkyl up to CIO, and t is an integer from 1 to 8; R10 and R11 are independently hydrogen atom or an interference-free substituent selected from C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C7 to C12 aralkyl, C7 to C12 alkaryl, C3 to C8 cycloalkenyl C3 to C8 cycloalkyl , phenyl, tolyl, xylyl, biphenylyl, C1 to C8 alkyloxy, C2 to C8 alkynyloxy, C2 to C8 alkynyloxy, C2 alkyloxyalkyl to 012, C2 to C12 alkyloxyalkyloxy, C2 to C12 alkylcarbonyl, alkylcarbonylamino 02 to 012, alkykylamino C2 to C12, C2 to C12 alkylaminocarbonyl, Cl up to C12 alkylamino, Cl to C6 alkylthio, C2 to C12 alkylthiocarbonyl, Cl to C8 alkylsulfinyl, Cl to C8 alkylsulfonyl, C2 to C8 haloalkyloxy to haloalkylsulfonyl Cl to 08, halo to 02 to 08, hydroxyalkyl Cl to 08 , -C (0) 0 (Cl alkyl up to 08), - (CH 2) 2-0- (Cl up to C 8 alkyl), benzyloxy, aryloxy, Cl up to C 8 aryloxy, arylthio, Cl up to C 8 arylthio, Cl up to C8, cyano Cl to C8, - (CONHS02R25), -CHO, amino, amidino, halogen, carbamyl, carboxyl, carbalkoxy, (CH2) 2-C02H, cyano, cyanoguanidinyl, guanidino, hydrazido, hydrazino, hydrazide, hydroxy, hydroxyamino, iodine, nitro, phosphono, -S03H, thioacetal, thiocarbonyl, or carbonyl, R25 is alkyl Cl up to 06 or aryl, z is an integer from 1 to 8; and RB is a group represented by the formula: wherein Z is the same defined above; the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates.

3. The compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as claimed in claims 1 or 2, characterized in that the R1 and R7 are represented by the formula: J "- (R"), where R13, R14, b, d, f, g, p, r, u, w, a, ß, y? are the same as defined above, L6 is a union -CH2-, -C = C-, C = C -, -0-, or -S-

4. The compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as claimed in claims 1 to 3, characterized in that R2 and R8 are C1 to C3 alkyl or 03 to C4 cycloalkyl.

5. The compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as claimed in claims 1 to 4, characterized in that L2 and L3 are -0-CH2-.

6. A compound, represented by the formula (III): characterized in that R, 20 is a group represented by the formula: wherein L is a bond, -CH2-, -C = C-, -C = C-, -0- or -S-; R13 and R14 are independently selected from halogen, Cl-alkyl up to. CIO, ClO alkyloxy up to CIO, Cloth alkylthio up to CIO, aryl, heteroaryl, and haloalkyl Cl up to CIO; b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, and w are independently an integer from 0 to 5, g is an integer from 0 to 2, r is an integer from 0 to 7, u is an integer from 0 to 4; a is an oxygen atom or a sulfur atom; β is -CH 2 - or - (CH 2) 2-; Y ? it is an oxygen atom or a sulfur atom; R, 2'1 is alkyl Cl up to 03 cycloalkyl 03 to 04 L4 is -0-CH-, -S-CH2-, -N (R24) -CH2-, -CH2-CH2-, -0-CH (CH3) -, or -O-CH ((CH2) 2Ph) - wherein R24 is a hydrogen atom or Cl alkyl up to C6 and Ph is phenyl; R22 is -COOH, -S03H, or P (0) (0H) 2; R23 is a hydrogen atom, C1 to C6 alkyl, C7 to C12 aralkyl, Cl to C6 alkyloxy, Cl to C6 alkyloxy, Cl to C6 hydroxyalkyl, C2 to 06 haloalkyloxy, halogen, carboxy, Cl to C6 alkyloxycarbonyl, aryloxy, Cl alkyl to 08 aryloxy, arylthio, Cl to C 8 alkyl, C 1 to C 8 cyano, a carbocyclic group, or a heterocyclic group; Y R is a group represented by the formula wherein Z is -NH2 or -NHNH2; the prodrugs thereof, or pharmaceutically acceptable salts, or their solvates.

7. A compound represented by the formula (IV) characterized in that R, 2 0 is a group represented by the formula: wherein L6 is a bond, -CH2-, -C = C-, -C = C-, -0- or -S-; R13 and R14 are independently selected from halogen, Cl to CIO alkyl, Cl to CIO alkyloxy, Cl to CIO alkylthio, aryl, heteroaryl, and Cl to CIO haloalkyl; b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, and w are independently an integer from 0 to 5, g is an integer from 0 to 2, r is an integer from 0 to 7, u is an integer from 0 to 4; a is an oxygen atom or a sulfur atom; ß is -CH2-o - (CH2) 2 - / * y? it is an oxygen atom or a sulfur atom; R, 2"1 is C1 to C3 alkyl or cycloalkyl to 03 to 04 R23 is a hydrogen atom, C1 to C6 alkyl, 07 to C12 aralkyl, Cl to C6 alkyloxy, Cl to C6 alkyloxy, Cl to C6 hydroxyalkyl, C2 to C6 haloalkyloxy, halogen, carboxy, C1 to C6 alkyloxycarbonyl, aryloxy, C1 alkyl to C8 aryloxy, arylthio, C1 to C8 alkyl, arylthio, C1 to C8 cyano, a carbocyclic group, or a heterocyclic group; RB is a group represented by the formula wherein Z is -NH2 or -NHNH2; and k is an integer from 1 to 3; the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates.

8. The compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as claimed in claim 6, characterized in that L 4 is -0-CH 2 -.

9. The compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as claimed in any of claims 1 to 8, characterized in that the Rñ and RB are -COCONH2.

10. The compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as claimed in any of claims 1 to 8, characterized in that the Rft and RB are -CH2CONH2.

11. The compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as claimed in any of claims 1 to 8, characterized in that the RA and RB are -CH2CONHNH2.

12. The pro-drugs as claimed in any of claims 1 to 8, characterized in that they are in the form of a # ester.

13. A pyrrolo [1,2-b] pyridazine compound, characterized in that it is selected from the group consisting of: (5-aminooxalyl-7-benzyl-6-ethylpyrrolo [1,2-b] pyridazine-4-yl0? I) methyl acetoate, (5-amino-oxalyl-7-benzyl-6-yl-pyrrolo [1,2- b] pyridazine-4-yloxy) -acetic acid, (Sodium 5-aminooxalyl-7-benzyl-6-ethylpyrrolo [1, 2-b] pyridazine-4-yloxy) acetate, (5-aminooxal-0-7-benzyl-6-methyl-2-methyl-ilpyrrolo [1,2 b] pyridazine-4-yloxy) methyl acetate, (5-aminooxali-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, (5-amino-oxalyl-7-benzyl 1-2, 6-dimethylpyrrolo [1,2-b] pyridazine-4-yloxy) ethyl acetate 2- (morphsin-4-yl) ethyl (5-aminooxali-7-benzyl-2,6-dimethyl-pyrrolo [1,2-b] pyridazine-4-yloxy) -acetate, acid (5-aminooxali? _7-benzyl-2,6-dimethyl-ilpyrrolo [1,2-b] pyridazine-4-yloxy) acetic acid, (5-amino-oxalyl-7-benzyl 1-2, 6-dimethylpyrrolo [1,2- b] pyridazine-4-yloxy) sodium acetate, (Methyl 5-aminooxalál-7-bencil-6-met i 1-2- phenylpyrrolo [1,2-b] pyridazine-4-yloxy) acet ato, acid (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo [1,2-b] pyridazine-4-yloxy) acetic acid, (5-aminooxali-7-benzyl-β-ethyl-2-phenylpyrrolo [1 , 2-b] pyridazine-4-yloxy) methyl acetate, acid (5-aminooxalyl-7-benzyl-6-ethyl-1-2-phenylpyrrolo [1,2-b] pyridazine-4-yloxy] acetic acid, [5-aminooxalyl-6-ethyl-7- (2-fluorobenzyl) -2-phenylpyrrolo [1,2-b] pyridazin-4-yloxy] methyl acetate, [5-aminooxalyl-6-ethyl-7- (2-fluorobenzyl) -2-phenylpyrrolo [1, 2-b] pyridazine-4-yloxy] acetic acid, [5-aminooxalyl-7-benzyl-6-ethyl-2- (4-fluorophenyl) pyrrolo [1,2-b] pyridazin-4-yloxy) methyl 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-yl-2-) phenoxymethylpyrrolo [1,2-b] pyridzin-4-yloxy] acetic acid, [5-aminooxalyl-7-benzyl-6-et-il-2- (4-methoxyphenyl) pyrrolo [1,2-b] pyridazine-4-yloxy] acetate, [5-aminooxalyl-7-benzyl-6-et i 1-2- (4-methoxyphenyl) pyrrolo [1,2-b] pyridazine-4-yloxy] acetic acid, [5-aminooxalyl-6-ethyl-2-met i 1-7 - (2-phenylbenzyl) pyrrolo [1,2- b] pyridazin-4-yloxy] methyl acetate, [5-aminooxalyl-6-ethyl-2-methyl-7- (2-phenylbenzyl) pyrrolo [1, 2-b] pyridazine-4-yloxy] acetic acid, [5-aminooxalyl-6-yl-2-met i 1-7- (3-phenoxybenzyl) pyrrolo [1,2-b] pyridazine-4-yloxy] methyl 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, acid (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, acid (5-aminooxalyl-2,7-dibenzyl-6-methylpyrrolo [1,2-b] pyridazine-4-yloxy) acetic acid, [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, and the prodrugs thereof, or their salts pharmaceutically acceptable; its mother acids; or its solvates.

14. A pyrrolo [1,2-b] pyridazine compound characterized in that it is selected from the group consisting of: (Methyl 5-aminooxalyl-7-benzyl-2, 6-dimethylpyrrolo [1,2-b] pyridazine-yloxy) acetate, (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo [1,2- b] pyridazine-yloxy) ethyl acetate, 2- (morpholine-4-yl) ethyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo [1,2-b] pyridazine-4-i loxy) acetate, (Sodium 5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo [1, 2-b] pyridazine-4-yloxy) acetate, acid (5-aminooxalyl-7-benzyl-2,6-dimethyl-ilpyrrolo [1,2-b] pyridazine-4-yloxy) -acetic acid (5-amino-oxalyl-7-benzyl-6-methyl-2-phenylpyrrolo [1] , 2-b] pyridazin-4-yloxy) methyl acetate, (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo [1, 2-b] pyridazin-4-yloxy) ethyl acetate, 2- (morpholine-4-yl) ethyl (5-aminooxal) 1- 7 -benzyl 1-6-met il-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-amino-oxalyl-7-benzyl-6-meth i 1-2-phenylpyrrolo [1,2-b] pyridazine-4-yloxy) acetic acid, (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo [1,2-b] pyridazin-4-yloxy) methyl acetate, (5-Aminooxa-lyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo [1,2-b] pyridazine-4-yloxy) ethyl acetate, 5-aminooxalyl-7-benzyl-6-ethyl 1-2 - 2- (morpholino-4-yl) ethyl phenoxymethylpyrrolo [1, 2-b] pyridazine-4-yloxy) acetate, (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo [1,2-b] pyridazin-4-yloxy) sodium acetate, acid (5-aminooxalyl-7-benzyl-6-yl-2-phenoxymethylpyrrolo [1,2-b] pyridazine-4-yloxy) acetic acid, [5-aminooxalyl-6-ethyl-2-methyl-7 - (2-phenylbenzyl) pyrrolo [1,2-b] pyridazin-4-yloxy] methyl acetate, [5-amino-oxal-6-ethyl-2-methyl-7- (2-phenylbenzyl) pyrrolo [1, 2-b] pyridazine- 'yloxy] ethyl acetate, 5-aminooxalyl-6-ethyl-2-met-il-7- (2-phenylbenzyl) pyrrolo [1, 2-b] pyridazine-4-yloxy) 2- (morpholino-4-yl) ethyl acetate, [5- Aminolaryl-6-ethyl-2-methyl-7- (2-phenylbenzyl) pyrrolo [1,2-b] pyridazine-4-yloxy] sodium acetate, acid (5-aminooxalyl-6-yl-2-met-il-7- (2-phenylbenzyl) pyrrolo [1,2-b] pyridazin-4-yloxy] acetic acid, (5-amino-oxalyl-7-benzyl-6-methyl-2-propy-methyl] -pyrrolo [1,2-b] pyridazine-4-yloxy) acetate, (5-aminooxalyl-7-benzyl-6-methyl-2-propyl-1-pyrrolo [1,2-b] pyridazine-4-yloxy) ethyl acetate, 5-aminooxalyl-7-benzyl-6-methyl-2-pro-ilpyrrolo [1,2-b] pyridazine-4-yloxy) acetate 2- (morpholino-4-yl) ethyl, (5-aminooxali-1-7-benzyl-6-methyl-2-propylpyrrolo [1,2-b] pyridazine-4-yloxy) sodium acetate, and (5-aminooxalyl-7-benzyl-6-metyl) 2-propylpyrrolo [1,2-b] pyridazine-4-yloxy) acetic acid, and the prodrugs thereof, or their pharmaceutically acceptable salts; its mother acids; or its solvates.

15. A pharmaceutical composition, characterized in that it contains a compound as claimed in any of claims 1 to 14 as an active ingredient.

16. The pharmaceutical composition as claimed in claim 15, characterized in that the composition is for inhibiting sPLA2.

17. The pharmaceutical composition as claimed in claim 15, characterized in that the composition is for the treatment or prevention of Inflammatory Diseases.

18. A method for inhibiting the release of fatty acid mediated by sPLA2, characterized in that they comprise contacting the sPLA2 with a therapeutically effective amount of a pyrrolo [1,2-b] pyridazine compound as claimed in claim 1.

19. A method for the treatment of a mammal, including the human, to alleviate the pathological effects of Inflammatory Diseases; characterized in that the method comprises administering to the mammal a pyrrolo [1,2-b] pyridazine compound as claimed in claim 1, in a pharmaceutically effective amount.

20. The compound of claim 1, or a pharmaceutical formulation containing an effective amount of a pyrrolo [1,2-b] pyridazine compound of claim 1, characterized in that it is for use in the treatment of Inflammatory Diseases.

21. The compound of claim 1, or a pharmaceutical formulation containing an effective amount of a pyrrolo [1,2-b] pyridazine compound of claim 1, characterized in that it is to be used as an inhibitor to inhibit the release of fatty acid mediated by the sPLA2.

22. An sPLA2 inhibitor of pyrrolo [1,2-b] pyridazine substantially as described above with reference to any of the examples.

23. A compound represented by the formula (XII) wherein R7 is - (CH2) m -R12 wherein m is an integer from 1 to 6, and R12 is (d) a group represented by the formula: wherein a, c, e, n, q, and t are independently an integer from 0 to 2, R13 and R14 are independently selected from a halogen, Cl to CIO alkyl, Cl to CIO alkyloxy, Cl to Cio alkylthio, aryl, heteroaryl and haloalkyl 01 to CIO, a is an oxygen atom or a sulfur atom, L5 is - (CH2) v-, -C = C-, -C = C-, -0-, or -S-, v is an integer from 0 to 2, ß is -CH2- or ~ (CH2) 2-,? is an oxygen atom or a sulfur atom, b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, and w are independently an integer from 0 to 5, g is an integer from 0 to 2, r is an integer from 0 to 7, and u is an integer from 0 to 4, or is (e) a member of (d) substituted with at least one substituent selected from the group consisting of C1 to 06 alkyl, C1 alkyloxy to 06, haloalkyloxy Cl to C6, haloalkyl Cl to C6, aryl, and a halogen; Y R is alkyl Cl up to C3, alkenyl 02 up to C3, cycloalkyl 03 up to C4, cycloalkenyl C3 up to C4, haloalkyl Cl up to C2, alkyloxy Cl up to 03, alkyl up to 03. Summary of the Invention The present invention provides a compound having inhibitory activity of sPLA2. The compound is 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 substituent without interference or the like; R2 is Cl to C3 alkyl or the like; R3 is - (L2) - (acid group); R4 and R5 are hydrogen atoms, substituents without interference, carbocyclic groups or the like; X is, independently, an oxygen atom of a sulfur atom; and R n is -C (= X) -C (= X) -NH 2 or similar; the prodrugs thereof, their pharmaceutically acceptable salts, or their solvates, and a composition for inhibiting the sPLA2 which contains it as active ingredients.