CZ20003952A3 - Pyrrolo[1,2-b]pyridazine compound, pharmaceutical preparations and processes of fatty acid release - Google Patents

Abstract

Compounds with an inhibitory effect on sPLA2, represented by the general formula I, their prodrugs, pharmaceutically acceptable salts and solvates thereof, and inhibitors, containing the same active ingredients, wherein R 1 represents a group - (L ') - R 6 (where L 1 represents a divalent linking group s 1 to 18 atoms, etc., and R 6 represents a carbon ring by one or more non-interfering substituents, etc.), R 2 represents C 1-3 alkyl, etc., R 3 represents - (L 2) - (acidic group, R 4 and R 5 each represents hydrogen, non-interfering substituent, and carbon a ring, etc., X 5 are each independently oxygen or sulfur, and R a represents -C (= X) -C (= X) -NH 2, etc.

Description

Pyrrolo [1,2-b] pyridazine compound, pharmaceutical compositions and methods for inhibiting fatty acid release

Technical field

The present invention relates to pyrrolo [1,2-b] pyridazine derivatives having sPLA ₂ mediated fatty acid release inhibitory activity.

BACKGROUND OF THE INVENTION sPLA ₂ (secretory phospholipase A ₂ ) is an enzyme that hydrolyzes a phospholipid membrane and is considered to be a rate-determining enzyme that controls the so-called arachidonic cascade, where arachidonic acid, the hydrolysis product, is a starting material. In addition, lysophospholipids, which are a byproduct in the hydrolysis of phospholipids, are known to be important mediators in cardiovascular diseases. In order to normalize excessive activity of the arachidone cascade and lysophospholipids, it is very important to develop compounds that inhibit the release of fatty acids by sPLA ₂ (e.g., arachidonic acid), namely, compounds that inhibit the activity or formation of sPLA ₂ . Such compounds are generally useful for treating the manifestations induced and / or persisted by excessive sPLA ₂ formation, such as septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, chronic rheumatism, arteriosclerosis, stroke, stroke , colon inflammation, psoriasis, heart disease, heart attack, etc. sPLA ₂ is believed to be extremely broad and, in addition, its potency is potent.

Examples of sPLA ₂ inhibitors are known, such as indole derivatives in EP-620214 (JP-010838/95), EP-620215 (JP-025850/95), EP-675110 (JP-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; phenylglyoxamide derivatives in WO 98/24794; pyrrole derivatives in WO 98/25609.

SUMMARY OF THE INVENTION

The present invention provides pyrrolo [1,2-b] pyridazine derivatives having sPLA ₂ inhibitory activity and useful for the treatment of septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, chronic rheumatism, arteriosclerosis, stroke, cerebral infarction, colon inflammation, psoriasis, heart defect, heart attack.

The present invention relates to i) compounds represented by the general formula I:

wherein R ¹ is a group selected from a) C 6 to C 20 alkyls, C 6 to C 20 alkenyls, C 6 to C 20 alkynyls, carbocyclic and heterocyclic groups, b) groups represented by a) each independently substituted with at least one group selected from non-interfering substituents; and c) - (R) - R ⁶ , wherein L ¹ is a divalent linking group of 1 to 18 atoms selected from hydrogen, nitrogen, carbon, oxygen and sulfur atoms, and R ⁶ is a group selected from groups a) and b);

R ² is a hydrogen atom or a group containing 1 to 4 non-hydrogen atoms;

R ³ is - (L ^a) - (acidic group) wherein L ² is an acid linker group having a length of 1 to 5;

R ⁴ and R ⁵ are independently selected from hydrogen, non-interfering substituents, heterocyclic groups, and heterocyclic groups substituted with non-interfering substituents; and

R ^A is a group represented by the general formula:

Y or

Y

wherein L 'is a divalent linking group selected from a single bond or a divalent group such as -CH ₂ -, -O-, -S-, -NH-, or -CO-, R ²⁷ and R ²⁸ are independently hydrogen, C1 to C3 alkyl or halogen; X and Y are independently oxygen or sulfur; and Z is -NH ₂ or -NHNH ₂ ; prodrugs thereof; or a pharmaceutically acceptable salt thereof; or solvates thereof.

In particular, the present invention relates to (ii) a compound represented by the general formula:

where R ⁷ is - (CH ₂ ) m R ¹² , where m is an integer from 1 to 6, and R ¹² is d) a group represented by the general formula:

(R ¹³ ) g (R ¹⁴ ) w

<ch ₂ ), 4a - (CH ₂ ) cr "3- (R ' ³ ) <i β or ^{íCH 2) e} OC ^{3 - (R 3)} where a, c, e, n, q and t are independently integers from 0 to 2, R ¹³ and R ¹⁴ are independently selected from halogen, C1 to C10 alkyl, C1 to C10 alkoxy, C1 to C10 alkylthio, aryl, heteroaryl and C1 to C10 haloalkyl, and is an oxygen atom or a sulfur atom, L ⁵ is - (CH ₂ ) v -, -C = C-, -CO, -O-, or -S-, v is an integer from 0 to 2, β is -CH ₂ - or- (CH ₂ ) ₂ -, γ is an oxygen atom or a sieve atom, b is an integer from 0 to 3, d is an integer from 0 to 4, f, p and w are independently integers 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 e) member d) is substituted with at least one substituent

selected from the group consisting of C1-C6 alkyl, C1-C6 alkyloxy, C1-C6 haloalkyloxy, C1-C6 haloalkyl, aryl and halogen;

R ⁸ is C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 3 -C 4 cycloalkyl, C 3 -C 4 cycloalkenyl, C 1 -C 2 haloalkyl, C 1 -C 3 alkyloxy or C 1 -C 3 alkylthio;

R ⁹ is (L ³ ) -R ¹³ where L ³ is represented by the general formula:

R

-M-C i

R

16 17

wherein M is -CH ₂ -, -O-, -N (R ^M ) -, or -S-, R ¹⁶ and R ¹⁷ are independently hydrogen, C 1 to C 10 alkyl, aryl, aralkyl, alkyloxy, haloalkyl, carboxy, or halogen, and R ²⁴ is a hydrogen atom or C 1 -C 6 alkyl, and R ¹⁵ is represented by the general formula:

wherein R ¹⁸ is a hydrogen atom, a metal or C 1 to C 10 alkyl, R ¹⁹ is independently a hydrogen atom, or a C 1 to C 10 alkyl, and is an integer from 1 to 8;

R ¹⁰ and R ⁿ are independently hydrogen or a noninterfering substituent such as Cl to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C7 to C12 aralkyl, C7-C12 alkaryl, C3 to C8 cycloalkyl, C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl, phenyl, tolyl, xylyl, diphenylyl, C1 to C8 alkyloxy, C2 to C8 alkenyloxy, C2 to C8 alkynyloxy, C2 to C12 alkyloxyalkyl, β ·

C 2 -C 12 alkyloxyalkyloxy, C 2 -C 12 alkylcarbonyl, C 2 -C 12 alkylcarbonylamino, C 2 -C 12 alkyloxyamino, C 2 -C 02 alkyloxyaminocarbonyl, C 1 -C 12 alkylamino, C 1 -C 6 alkylthio, C 2 -C 12 alkylthiocarbonyl, C 1 -C 8 alkylsulfinyl, C 1 -C 8 alkylsulfonyl, C 2 to C 8 haloalkyloxy, C 1 to C 8 haloalkylsulfonyl, C 2 to C 8 haloalkyl, C 1 to C 8 hydroxyalkyl, -C (O) O (C 1 to C 8 alkyl), - (CH 2) ₂ -O- (C 2 to C 8 alkyl), benzyloxy, aryloxy, aryloxy, Cl to C8 alkyl, arylthio, arylthio ažC8 Cl alkyl, cyano, Cl to C8 alkyl, (CONHSO 2 R ^25), -CHO, amino, amidino, halo, carbamyl, carboxyl, carbalkoxy, _(CH2) -CC> 2H, cyano, cyanoguanidinyl, guanidino, hydrazido, hydrazino, hydrazide, hydroxyl, hydroxyamino, iodo, nitro, phosphono, -SO ₃ H, thioacetal, thiocarbonyl, or carbonyl, R ²⁵ is C 1 -C 6 alkyl or aryl, z is an integer from 1 to 8; and R ^B is a group represented by the general formula:

Η ^η · -'- r θ or θ wherein Z is as defined above; prodrugs thereof, or pharmaceutically acceptable salts thereof, solvates thereof.

When the above b, d, f, p, r, u, and / or w are 2 or more, the plural forms R ⁿ or R ¹⁴ may differ from each other. When R ¹³ is a substituent on the naphthyl group, the substituent can be replaced at any position of the naphthyl group.

(iii) The compound, prodrugs thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, as described in (i) or (ii) above, wherein said R ^x and R ⁷ are independently represented by the general formula:

where R ¹³ , R ¹⁴ , b, d, ζg, p, r, u, w, α, β and γ are as defined above, L ⁶ is a bond, -CH ₂ -, -C = C-, -C = C-, -O-, or -S-.

When the above b, d, f, p, r, u, and / or w are 2 or more, R ¹³ or R ¹⁴ may differ from each other. When R ¹³ is a substituent on the naphthyl group, this substituent can be replaced at any position of the naphthyl group.

iv) The compound, prodrugs thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, as described in any one of i) to iii), wherein R ² and R ⁸ are C 1 -C 3 alkyl or C 3 -C 4 cycloalkyl.

v) The compound, prodrugs thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, as described in any one of i) to iv), wherein L ² and L ³ are -O-CH ₂ -.

(vi) Compound represented by the general formula ΙΠ:

where R ²⁰ is a group represented by the general formula:

wherein L ⁶ is a bond, -CH ₂ -, -C =C-, -C ^C-, -O- or -S-; R ¹³ and R ¹⁴ are independently selected from functional groups such as halogen, C 1 to C 10 alkyl, C 1 to C 10 alkyloxy, C 1 to C 10 alkylthio, aryl, heteroaryl, and C 1 to C 10 baloalkyl; b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, aw are independently integers 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 an atom atom; β -CH ₂ - or - (CH ₂ ) ₁ - and γ an oxygen atom or an atom atom;

R ²¹ is C 1 -C 3 alkyl or C 3 -C 4 cycloalkyl;

L ⁴ is -O-CH 2 -, -S-CH ₂ - -MER ²⁴ ) -®-, -CH 2 -CH ₂ -, -OCH (CH ₃ ) -, or -O-CH ((CH ₂ ) ₂ Ph) wherein R ²⁴ is a hydrogen atom or C 1 -C 6 alkyl and Ph is phenyl;

R ²² is -COOH, -SO 5 H, or Ρ (θχθΗ) ₂ ;

R ²³ is hydrogen, C 1 -C 6 alkyl, C 7 -C 02 aralkyl, C 1 -C 6 alkyloxy, C 1 -C 6 alkylthio, C 1 -C 6 hydroxyalkyl, C 2 -C 6 haloalkyloxy, halogen, carboxy, C 1 -C 6 alkyloxycarbonyl, aryloxy, aryloxy C 1 -C 6 C8 alkyl, arylthio, arylthio C1 to C8 alkyl, cyano C1 to C8 alkyl, carbocyclic group, or heterocyclic group; and R ^B is a group represented by the general formula:

Ar ^{NH 2} '

O or O wherein Z is -NH ₂ or -NHNH ₂ ; prodrugs thereof, or pharmaceutically acceptable salts thereof, or solvates thereof.

When the above b, d, f, p, r, u, and / or w are 2 or more, the plural R ¹³ or R ¹⁴ may differ from each other. When R ¹³ is a substituent on the naphthyl group, the substituent can be replaced at any position of the naphthyl group.

(vii) Compound represented by the general formula (IV):

where R ²⁰ is a group represented by the general formula:

(IV)

wherein L ⁶ is a bond, -CH 2 -, -C =C-, -CO, -O-, or -S-; ^Rn and ^R14 are independently selected from functional groups such as 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, aw are independently integers 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 -CH ₂ - or - (CH ₂ ) ₂ - and γ oxygen atom or atom;

R ²¹ is C 1 -C 3 alkyl or C 3 -C 4 cycloalkyl;

R ²³ is hydrogen, C 1 -C 6 alkyl, C 7 -C 12 aralkyl, C 1 -C 6 alkyloxy, C 1 -C 6 alkylthio, C 1 -C 6 hydroxyalkyl, C 2 -C 6 haloalkyloxy, halogen, carboxy, C 1 -C 6 alkyloxycarbonyl, aryloxy, aryloxy C 1 -C 6 C8 alkyl, arylthio, arylthio C1 to C8 alkyl, cyano C1 to C8 alkyl, carbocyclic, or heterocyclic; and R ^b is a group represented by the formulas:

Ar ^{, n} O or O wherein Z is -NH ₂ or -NHNH ₂ ; when the integer is from 1 to 3; prodrugs thereof, or pharmaceutically acceptable salts thereof, or solvates thereof.

• · · ·

viii) The compound, prodrugs, or pharmaceutically acceptable salts thereof, or solvates thereof, as described in vi), wherein L ⁴ is -O-CH ₂ -.

ix) The compound, prodrugs, or pharmaceutically acceptable salts thereof, or solvates thereof, as described in any one of i) to viii), wherein R ^A and R ^B are - COCONH 2 -.

x) The compound, prodrugs thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, as described in any one of i) to viii), wherein R ^A and R ^B are -CH ₂ CONH ₂ -.

xi) The compound, prodrugs, or pharmaceutically acceptable salts or solvates thereof, as described in any one of i) to viii), wherein R ^A and R ^B are -CH ₂ CONHNH ₂ -.

xii) A prodrug as described in any one of i) to viii) which is an ester type.

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

methyl (5-aminooxalyl-7-benzyl-6-ethylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, (5-ammooxalyl-7-benzyl-6-ethylpynolo [1,2-b] pyridazine-4) -yloxy) acetic acid, (5-aminooxalyl-7-benzyl-6-ethylpyrrolo [1,2-b] pyridazin-4-yloxy) sodium acetate, methyl (5-aminooxalyl-7-benzyl-6-methylpyrrolo [1, 2-b] pyridazin-4-yloxy) acetate, (5-aminooxalyl-7-benzyl-6-ethylpynolo [1,2- b] pyridazin-4-yloxy) acetic acid, methyl (5-aminooxalyl-7-benzyl-). 2,6-dimethylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, ethyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, 2- (morpholin-4-yl) ethyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, (5-aminooxalyl-7-benzyl-2), 6-dimethylpyrrolo [1,2-b] pyridazin-4-yloxy) acetic acid, (5-aminooxalyl-7-benzyl-2,6-dimethylpynolo [1,2-b] pyridazin-4-yloxy) acetic acid, methyl (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo [1, 2-b] pyridazin-4-yloxy) acetic acid µ, methyl (5-aminooxalyl-7-benzyl-6-ethyl-2-phenylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, (5-aminooxalyl-7-benzyl-6-ethyl-2-phenylpyrrolo [1,2-b] pyridazin-4-yloxy) acetic acid, methyl (5-aminooxalyl-6-ethyl-7- (2-fluorobenzyl) -2-phenylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, [5-aminooxalyl-6-ethyl-7- (2-fluorobenzyl) -2-phenylpyrrolo [1,2-b] pyridazin-4-yloxy) acetic acid;

• ·

methyl [5-aminooxalyl-7-benzyl-6-ethyl-2- (4-fluorophenyl) p) trolo [1,2-b] pyridazin-4-yloxy) acetate, [5-aminooxalyl-7-benzyl-6- ethyl 2- (4-fluorophenyl) pyrrolo [1,2-b] pyridazin-4-yloxy) acetic acid, methyl [5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo [1,2-b] pyridazin-4-yloxy) acetic acid, methyl [5-aminooxalyl-7-benzyl- 6-ethyl-2- (4-methoxyphenyl) pyrrolo [1,2-b] pyridazin-4-yloxy) acetate, [5-aminooxalyl-7-benzyl-6-ethyl-2- (methoxyphenyl) pyrrolo [1,2] -b] pyridazin-4-yloxy) acetic acid, methyl [5-aminooxalyl-6-ethyl-2-methyl-7- (2-phenylbenzyl) pyrido [1,2-b] pyridazin-4-yloxy) acetate, [ 5-aminooxalyl-6-ethyl-2-methyl-7- (2-phenylbenzyl) pyrrolo [1,2-b] pyridazin-4-yloxy) acetic acid, methyl [5-aminooxalyl-6-ethyl-2-methyl- 7- (3-phenoxybenzyl) pyrrolo [1,2-b] pyridazin-4-yloxy) acetate, [5-aminooxalyl-6-ethyl-2-methyl-7- (3-phenoxybenzyl) pyrido [1,2-b] pyridazine-4-oxy) acetic acid, methyl (5-aminooxalyl-7-benzyl) 6-methyl-2-propylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, (5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo [1,2-b] pyridazine-4- yloxy) acetic acid, methyl (5-aminooxalyl-2,7-dibenzyl-6-methylpyrido [1,2-b] pyridazin-4-yloxy) acetate, (5-aminooxalyl-2,7-dibenzyl-6-methylpyirolo [ 1,2-b] pyridazin-4-yloxy) acetic acid, methyl [5-aminooxalyl-2,6-dimethyl-7- [2- (4-fluorophenyl) benzyl] pyrrolo [1,2-b] pyridazin-4 -yloxy] acetate, and [5-aminooxalyl-2,6-dimethyl-7- [2- (4-fluorophenyl) benzyl] pyrrolo [1,2-b] pyridazin-4-yloxy) acetic acid, and prodrugs thereof or a pharmaceutically acceptable salt thereof; their parent acids; or solvates thereof.

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] pyridazin-4-yloxy) acetate, ethyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo [1,2-] b] pyridazin-4-yloxy) acetate, · · · · · · · · · · · · · · ·

2- (morpholin-4-yl) ethyl (5-aminooxalyl-7-benzyl-2,6-dimethylpynolo [1,2-b] pyridazin-4-yloxy) acetate, (5-aminooxalyl-7-benzyl-2), Sodium 6-dimethylpynlo [1,2-b] pyridazin-4-yloxy) acetic acid, (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo [1,2-b] pyridazin-4-yloxy) acetic acid, methyl (5-Anunooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, ethyl (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpynolo [1]) 2-b] pyridazin-4-yloxy) acetate, 2- (morpholin-4-yl) ethyl (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpynolo [1,2- b] pyridazin-4-one) yloxy) acetate, (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo [1,2-b] pyridazin-4-yloxy) sodium acetate, (5-aminooxalyl-7-benzyl-6-methyl-2) -phenylpyrrolo [1,2-b] pyridazin-4-yloxy) acetic acid, methyl (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate ethyl (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate,

2- (morpholin-4-yl) ethyl (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, (5-aminooxalyl-7-benzyl-) Sodium 6-ethyl-2-phenoxymethylpyrrolo [1,2-b] pyridazin-4-yloxy), (5-anunooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrido [1,2-b] pyridazine-4-) yloxy) acetic acid, methyl (5-aminooxalyl-6-ethyl-2-methyl-7- (2-phenylbenzyl) pyrido [1,2-b] pyridazin-4-yloxy) acetate, ethyl (5-aminooxalyl-6- ethyl 2-methyl-7- (2-phenylbenzyl) pyrrolo [1,2-b] pyridazin-4-yloxy) acetate,

2-morpholin-4-yl) ethyl (5-aminooxalyl-6-ethyl-2-methyl-7- (2-phenylbenzyl) pyrrolo [1,2-b] pyridazin-4-yloxy) acetate, (5-aminooxalyl- 6-ethyl-2-methyl-7- (2-phenylbenzyl) pyrrolo [1,2-b] pyridazin-4-yloxy) sodium acetate, (5-aminooxalyl-6-ethyl-2-methyl-7- (2- phenylbenzyl) pyrrolo [1,2-b] pyridazin-4-yloxy) acetic acid, methyl (5-ammooxalyl-7-benzyl-6-methyl-2-propylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate , ethyl (5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate;

• φ

2-Morpholin-4-yl) ethyl 5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, (5-aminooxalyl-7-benzyl-6- sodium 2-propylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, and (5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo [1,2-b] pyridazin-4-yloxy) acetic acid, and prodrugs thereof, or a pharmaceutically acceptable salt thereof; their parent acids; or solvates thereof.

xv) Pharmaceutical compositions containing as active ingredient the compounds described in any one of i) to xiv).

xvi) The pharmaceutical composition described in xv) that inhibits sPLA ₂ .

xvii) A pharmaceutical composition as described in xv), for the treatment or prevention of inflammatory diseases.

xviii) A method of inhibiting sPLA ₂ mediated fatty acid release comprising reacting sPLA ₂ with a therapeutically effective amount of the pyrrolo [1,2-b] pyridazine compound described in vi).

xix) A method of treating a mammal, including a human, to alleviate the pathological effects of inflammatory diseases; this method is based on the administration of the pyrrolo [1,2-b] pyridazine compound described in i).

xx) The compound described in i) or a pharmaceutical composition comprising an effective amount of the pyrrolo [1,2-b] pyridazine compound described in i) for the treatment of inflammatory diseases.

xxi) The compound described in vi) or a pharmaceutical composition comprising an effective amount of a pyrrolo [1,2-b] pyridazine compound for use as a sPLA ₂ mediated fatty acid release inhibitor.

xxii) Pyrrolo [1,2-b] pyridazine, a sPLA ₂ inhibitor essentially as described above with reference to the examples below.

(xxiii) Compound represented by the general formula ΧΠ:

NH ₂

and

wherein R ⁷ is - (CH ₂ ) m R ¹² , wherein m is an integer from 1 to 6, and R ¹² is d) a group represented by

wherein a, c, e, n, q, t and t are independently an integer from 0 to 2, R ¹³ and R ¹⁴ are independently selected from functional groups such as halogen, C 1 to C 10 alkyl, C 1 to C 10 alkyloxy, C 1 to C 10 alkylthio , aryl, heteroaryl, and C1 to C10 haloalkyl; and is an oxygen or sulfur atom,

L ⁵ is - (CH ₂ ) v -, -CC-, -C = C-, -O-, or -S-, v is an integer from 0 to 2, β is -CH ₂ - or (CH ₂ ) ₂ -, y is an oxygen or sulfur atom, b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, aw are independently integers 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 e) member d) is substituted with at least one substituent selected from the group consisting of C1 to C6 alkyl, C1 to C6 alkyloxy, C1 to C6 haloalkyloxy C1 to C6 haloalkyl, aryl and halogen; and

R ⁸ is C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 3 -C 4 cycloalkyl, C 3 -C 4 cycloalkenyl, C 1 -C 2 haloalkyl, C 1 -C 3 alkyloxy, or C 1 -C 3 alkylthio.

In the present specification, the term alkyl alone or in combination with other terms means a straight or branched chain monovalent hydrocarbon group with a certain number of carbon atoms. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decanyl, n-undecanyl , n-dodecanyl, n-tridecanyl, n-tetradecanyl, npentadecanyl, n-hexadecanyl, n-heptadecanyl, n-octadecanyl, n-nonadecanyl, n-eicosanyl and the like.

The term alkenyl, as used herein alone or in combination with other terms, means a straight or branched chain monovalent hydrocarbon.

9 9

9 9

a group having a certain number of carbon atoms and at least one double bond. Examples of alkenyl are vinyl, allyl, propenyl, crotonyl, isopentenyl and various butenyl isomers, and the like. The term alkynyl, as used herein alone or in combination with other terms, means a straight or branched chain monovalent hydrocarbon group having a certain number of carbon atoms and at least one triple bond. Examples of alkynyl are ethynyl, propynyl, 6-heptinyl, 7-octinyl, 8-noninyl and the like.

The term carbocyclic group, as used herein, means a group derived from a saturated or unsaturated, substituted or unsubstituted 5 to 14 membered, preferably 5 to 10 membered, more preferably 5 to 7 membered, organic ring having ring-forming atoms (other than hydrogen atoms) are exclusively carbon atoms. A group containing two or three carbocyclic groups is also included in the above group. Examples of typical carbocyclic groups include f) cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl); cycloalkenyl (such as cyclobutylenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl); phenyl, spiro [5,5] undecanyl, naphthyl, norbomyl, bicycloheptadienyl, tolyl, xylyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenylcyclohexenyl, acenaphthyl, anhoryl, diphenylyl, dibenzylyl, and phenylalkylphenyl derivative:

where x is an integer from 1 to 8.

The term spiro [5,5] undecanyl refers to the group represented by the formula:

oo

Phenyl, cyclohexyl, etc. is more preferred as a carbocyclic group in R ^{4 and} R ⁵ .

The term heterocyclic group, as used herein, means a group derived from a monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic ring having from 5 to 14 atoms in the book and containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom , oxygen and sulfur. Examples of heterocyclic groups include pyridyl, pyrrolyl, pyrrolidinyl, piperidinyl, thiyl, benzofiiryl, thienyl, benzothienyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuransL, dibenzofuranyl, dibenzothiophenyl, indazolyl, imidazo [1,2-b] pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl, benzoxazolyl, benzoxolyl, benzoxazolyl, benzoxazolyl, benzoxazolyl, benzoxazolyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazil, 1,3,5-triazyl, quinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, morpholino, thiomoifolino, homopiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, oxakanyl, 1,3dioxolanyl, 1,3-dioxanynyl, 1,3-dioxanynyl, 1,3-dioxanynyl, 1,3-dioxanynyl 4-dioxanyl, 1,4-thioxanyl, azetidinyl, hexamethylenimine, heptamethylenimine, piperazinyl and the like.

Furyl, thienyl and the like is more preferred as the heterocyclic group in R ⁴ and R ⁵ .

Preferred carbocyclic groups in R ¹ are g) groups represented by the general formula

- (R ¹³ ) _f

R ¹³ and R ¹⁴ are independently selected from functional groups such as halogen, C 1 to C 10 alkyl, C 1 to C 10 alkyloxy, C 1 to C 10 alkylthio, aryl, heteroalyl, and C 1 to C 10 haloalkyl; a is an oxygen or sulfur atom, L ⁵ is - (CH ₂ ) v -, -C ,C-, -C ^C-, -O-, or -S-, v is an integer from 0 to 2, β is -CH ₂ - or (CH ₂ ) ₂ -, 7 is an oxygen or sulfur atom, b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, aw are independently integers from 0 to 5, r is an integer from 0 to 7 and u is an integer from 0 to 4. If the aforementioned b, d, f, p, r, u, and / or w are 2 or more, then the plural R ¹³ or R ¹⁴ may be different When R ¹³ is a substituent on the naphthyl group, the substituent may be substituted in any one. position of the naphthyl group. A more preferred example includes h) groups represented by the general formula:

··

where R ¹³ , R ¹⁴ , α, β, γ are as defined above, L ⁶ is -CH ₂ -, -C = C-, -CsC-, -O- or -S-, y is 0 or 1. When R is ¹³ is a substituent on the naphthyl group, the substituent may be substituted at any position of the naphthyl group.

The core of pynOlo [1,2-b] pyridazine is represented by the following structural formula with numbered positions on the ring for substituents.

The term non-interfering substituent in the present specification means a group suitable for substitution at the 2, 3 and 7 position on the pyirolo [1,2-b] pyridazine nucleus represented by formula (I) as well as a group suitable for substitution by the above-described carboxyl and heterocyclic group . Examples of non-interfering substituents are C 1 to C 8 alkyl, C 2 to C 8 alkenyl, C 2 to C 8 alkynyl, C 7 to 02 aralkyl (such as benzyl and phenethyl), C 7 to C 2 alkaryl, C 2 to C 8 alkenyloxy, C 2 to C 8 alkynyloxy, C 3 to C8 cycloalkyl, C3 to C8 cycloalkynyl, phenyl, tolyl, xylyl, biphenylyl, 0 to C8 alkyloxy, C2 to 02 alkyloxyalkyl (such as methyloxymethyl, ethyloxymethyl, methyloxyethyl and ethyloxyethyl), C2 to 02 alkyloxyalkyloxy (methyloxymethyloxy and methyloxyethyloxy), C2 to 02 alkylcarbonyl (such as methylcarbonyl) and ethylcarbonyl), C2 to 02 alkylcarbonylamino (such as methylcarbonylamino and ethylcarbonylamino), C2 to 02 alkyloxyamino (such as methyloxyamino and ethyloxyamino), C2 to 02 alkyloxyaminocarbonyl »

· * * · · · · · · · · · ·

W 9

4 ·

(Such as methyloxyaminocarbonyl and ethyloxyaminocarbonyl), C1 to C12 alkylamino (such as methylamino, ethylamino, dimethylamino, and ethylmethylamino). C1 to C6 alkylthio, C2 to 02 alkylthiocarbonyl (such as methylthiocarbonyl and ethylthiocarbonyl), C1 to C8 alkylsulfinyl (such as methylsulfinyl and ethylsulfinyl), C1 to C8 alkylsulfonyl (such as methylsulfonyl and etbylsulfonyl), C2 to C8 haloalkyloxy (such as 2-chloroetbyloxy) bromoethyloxy), C1 to C8 haloalkylsulfonyl (such as chloromethylsulfonyl and bromometbylsulfonyl), C2 to C8 haloalkyl, C1 to C8 hydroxyalkyl (such as hydroxymethyl and hydroxyethyl), -C (O) O (C1 to C8 alkyl) (such as methyloxycarbonyl and ethyloxycarbonyl, - ( _CH2) taken into (C1 to C8 alkyl, benzyloxy, aryloxy (such as phenyloxy), aiylthio (such as phenylthio), ~ (CONHSO ₂ R ^25), -CHO, amino, amidino, halo, carbamyl, carboxyl, karbalkyloxy - ( CH ₂ ) z-COOH (such as carboxymethyl, carboxyetbyl and carboxypropyl), cyano, cyanoguanidino, guanidino, hydrazido, hydrazino, hydrazide, hydroxy hydroxyamino, nitro, phosphono, -SO ₃ H, thioacetal, thiocarbonyl, carbonyl, carbocyclic groups, heterocyclic groups and the like, wherein z is an integer from 1 to 8 and R is ²⁵ is C1 to C6 alkyl or aryl. These groups may be substituted with at least one substituent selected from the group consisting of C1 to C6 alkyl, C1 to C6 alkyloxy, C2 to C6 haloalkyloxy, C1 to C6 haloalkyl and halogens. Preferred halogens are Cl to C6 alkyl, Cl to C6 alkoxy, Cl to C6 alkylthio, and Cl to C6 haloalkyl as a non-interfering substituent R in ^{the first} More preferred are halogens, C1 to C3 alkyl, C1 to C3 alkyloxy, C1 to C3 alkylthio and C1 to C3 haloalkyl.

Preferred are i) C1 to C6 alkyl, aralkyl, C1 to C6 alkyloxy, C1 to C6 alkylthio, C1 to C6 hydroxyalkyl, C2 to C6 haloalkyloxy, halogens, carboxy, C1 to C6 alkyloxycarbonyl, aryloxy, arylthio, carbocyclic groups and heterocyclic groups such as non-interfering substituents R ^4, R ^5, R ¹⁰ and R ^n. More preferred are j) C1 to C6 alkyl, aralkyl, carboxy, C1 to C6 hydroxyalkyl, phenyl and C1 to C6 alkyloxycarbonyl.

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

The term cycloalkyl in the present specification means a monovalent hydrocarbon group having a certain number of carbon atoms. Exemplary cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The term cycloalkenyl in the present description means a monovalent cyclic hydrocarbon group having a certain number of carbon atoms and at least one double bond. Examples of cycloalkenyl are 1-cyclopropenyl, 2-cyclopropenyl, 1-cyclobutenyl, 2-cyclobutenyl and the like.

In the present disclosure, an example for alkoxy includes methyloxy, ethyloxy, npropyloxy, isopropyloxy, n-butyloxy, n-pentyloxy, n-hexyloxy and the like.

In the present description, an example for alkylthio includes methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, n-pentylthio, n-hexylthio and the like.

The term acidic group in the present description means an organic group acting as a proton donor capable of binding hydrogen when attached to the core of pyrrolo [1,2-b] pyridazine via a suitable bonding atom. An example of an acidic group are k) groups represented by the formulas:

wherein R ¹⁸ is a hydrogen atom, a metal or C 1 to C 10 alkyl. Preferred are 1) -COOH, -SO 3 H, P (OXOH) ₂ .

More preferred is m) -COOH.

The term acid linking group in the present specification means a divalent linking group represented by the symbol - (L ² ) - which forms a bond between the 4-position of the pyrrolo [1,2-b] pyridazine core and the acidic group in the general relationship. An example is the group n) represented by the general formula:

R

M-C-1 R

16 17

Where Μ is -CH ₂ -, -Ο-, -N (R ²⁴ ) -, or -S -, and R ¹⁶ and R ¹ are independently hydrogen, C 1 to C 10 alkyl, aryl, aralkyl, carboxy or halogens. Preferred are o) -O-CH 2 -, S-CH 2 -, -N (R ²⁴ ) -CH ₂ -, -CH ₂ -CH ₂ -, -O-CH (CH ₃ ) - or -O-CH ((CH ₂ ) ₂ Ph) -, wherein R ²⁴ is a hydrogen atom or C 1 -C 6 alkyl and Ph is phenyl. More preferred is p) -O-CH ₂ - or -S-CH ₂ -.

In the present specification, the term acid linker length refers to the number of atoms (excluding hydrogen atoms) in the shortest chain of the linking group - (L ² ) - that connects the 4th position of the pyrrolo [1,2-b] pyridazine core to the acid group. The presence of the carbocyclic ring in - (L ² ) - is calculated as the number of atoms approximately equivalent to the calculated diameter of the carbocyclic ring. Thus, the benzene and cyclohexane ring in the acid linker is calculated as two atoms in the length (- L ² ) calculation. The preferred length is 2 to 3. The symbol k in formula IV) is preferably 1.

The term haloalkyl in the present specification means the above-described alkyl, substituted with the above-described halogen at any position (s). Examples of haloalkyl are chloromethyl, trifluoromethyl, 2-chloromethyl, 2-bromomethyl and the like.

The term hydroxyalkyl in the present specification means the aforementioned alkyl substituted with a hydroxyl group at any position (s). Examples of hydroxyalkyl are 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 described above. Examples thereof include 2-chloroethyloxy, 2,2,2-trifluoroethyloxy, 2-chloroethyloxy and the like.

The term aryl in the present specification means a monocyclic or fused cyclic aromatic hydrocarbon. Examples are phenyl, 1-naphthyl, 2-naphthyl, anthryl and the like. Phenyl and 1-naphthyl are particularly preferred. Such aryl is optionally substituted with C1 to C6 alkyl, hydroxy, C1 to C3 alkoxy, halogen, nitro, substituted or unsubstituted amino, cyano, C1 to C3 haloalkyl and the like, in one or more positions. The term aralkyl in the present description means a group in which the aforementioned alkyl is substituted with the aforementioned aryl. The aryl may be attached to the alkyl at all substitutable positions. Examples of aralkyl are benzyl, phenethyl, phenylpropyl (such as 3-phenylpropyl), naphlylmethyl (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 non-hydrogen atoms alone, or non-hydrogen atoms plus hydrogen atoms necessary, e.g. to saturate the unsubstituted valence of non-hydrogen atoms;

without hydrogen containing no more than 4 non-hydrogen atoms, such as -CF 3, -Cl, -Br, -NO ₂ ,

-CN, -SO ₃ ; and iii) groups with hydrogen atoms containing less than 4 non-hydrogen atoms, such as -CH ₃ , -C ₂ H ₅ , -CH = CH ₂ , -CH (CH ₃ ) _2, and cyclopropyl.

Examples of alkoxycarbonyl in the present disclosure include methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl and the like.

The term substituted amino in the present specification includes an amino group substituted with C1 to C6 alkyl, aralkyl, C1 to C6 alkylcarbonyl, C1 to C6 alkyloxycarbonyl and the like, in one or two positions.

Preferred R ⁷ in formula ΧΧΠ are C 5 to C 8 cycloalkylmethyl and phenylmethyl, which are optionally substituted with halogen, C 1 -C 6 alkyl, aryl, alkyloxy or aryloxy.

Preferred Cl-C6 alkyl group as R ⁸ in formula ΧΧΠ.

A group of preferred substituents R ¹ to R ³ and R ^{A of the} compound represented by the formula (I) will be indicated in letters A) to W). Under (f) to (m), the groups are identical to those described above.

As R ¹ , (A): - (R) - R ⁶ , (Β): <Η ₂ ) _μ2 - (ί), (C): - (CH ₂ ) i. ₂ - (g), and (D): - (CH ₂ ) ,. _2- (h) are preferred.

Such as R ² , (E): hydrogen atom, halogen, C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl or C 1 -C 3 alkyloxy; and (F); C1 to C3 alkyl or C3 to C4 cycloalkyl are preferred.

As R ^a , (G): -C (= O) -C (= O) -NH ₂ , -CH ₂ C (= O) -NH _2, or -CH ₂ C (= O) -NHNH ₂ ; and (H): -C (= O) -C (= O) -NH ₂ are preferred.

As R ³ , (I): - (n) - (k), (J): - (n) - (1), (K): - (n) - (m), (L); - (o) - (k), (M): - (o) - (l), (N): - (o) - (m), (O): - (p) - (k), (P ): - (p) -O) and (Q); - (p) - (m) are preferred.

As R ⁴ , (R): a hydrogen atom or a non-interfering substituent, (S): a hydrogen atom or i), and (T): a hydrogen atom or j) are preferred.

As R ⁵ , (U): a hydrogen atom or i), (V): a hydrogen atom or j) and (W): a hydrogen atom are preferred.

The following is a preferred group of compounds represented by formula (I):

(A, E, G, R, W), (A, E, G, R, W), (A, E, G, R, W), (A, E, G, S) , A, E, G, T, U, A, E, G, T, V, A, E, G, T, W, A, E , H, R, U, A, E, H, R, V, A, E, H, R, W, A, E, H, S, U, A, E, H (A, E, H, S, W), (A, E, H, T), (A, E, H, T), (A, E, H, T) , (W), (A, F, G, R, W), (A, F, G, R, W), (A, F, G, R, W), (A, F, G, R, W) ), (A, F, G, S, W), (A, F, G, S, W), (A, F, G, T, V), (A, F, G, T, W), (A, F, H, R, U), (A, F, H, R, V), (A, F, H, W), (A, F, H, S) , (A, F, H, S, W), (A, F, H, S, W), (A, F, H, T) ), (A, F, H, T, W), (B, E, G, R, U), (B, E, G, R, W), (B, E, G, S, W), (B, E, G, S, W), (B, E, G, S, W), (B) (E, G, T, W), (B, E, G, T, W), (B, E, H, R, U) , H, R, W), (B, E, H, S), (B, E, H, S), (JE, Ε, Η, Τ , ϋ), (B, E, H, T, W), (B, E, H, T, W), (B, F, G, R, V) ), (B, F, G, S, W), (B, F, G, S, V), (B, F, G, S, W), (B, F, G, T), (B, F, G, T), (B, F, G, T), (B, F, G, T) (F, H, R, V), (B, F, H, R, W), (B, F, H, S), (B, F, H, S), (B, F, H) , (S, W), (B, F, H, T), (C, F, H, T), (C, F, H, T), (CJE, G, R, U) ), (C, E, G, R, W), (C, E, G, R, W), (C, E, G, S, U), (C, E, G, S, V) <

(C, E, G, S), (C, E, G, T), (C, E, G, T), (C, E, G, T) , C, E, H, R, V, C, E, H, R, W, C, E, H, S, U, C, E , H, S, V, (C, E, H, S, W), (C, E, H, T), (C, E, H, T, V), (C, E, H) , T, W), (C, F, G, R, U), (C, F, G, R, W), (C, F, G, R, W), (C, F, G, S, U) ), (C, F, G, S, W), (C, F, G, S, W), (C, F, G, T, V), (C, F, H, R, W), (C, F, H, R, U), (C, F, H, R, W), (C, F, H, R, W) (H, S, U), (C, F, H, S, V), (C, F, H, T, V), (C, F, H, T, V), ( (D, E, G, R, U), (D, E, G, R, W), (D, E, G, R, W), (D, E, G, R, W) (D, E, G, S), (D, E, G, S), (D, E, G, S), (D, E, G, S, W) G, T, W, (D, E, H, W,), (D, E, H, R, U), (D, E, H, R, V), (D, E, H, R, W), (D, E, H, S, W), (D, E, H, S, W), (D, E, H, S, W), (D, E, H, T, U), (D, E, H, T), (D, E, H, T), (D, F, G, R), (DJF, ^ V), (D, F) , (G, R, W), (D, F, G, S), (D, F, G, S), (D, F, G, S), (D, F, G) , (D, F, G, T, V), (D, F, G, T), (D, F, G, T), (DJ, H, R, V) ), (DJXR, W), (D, F, H, S), (D, F, H, S), (DJASM (D, F, H, T), (D, F) , H, T, V), and (D, F, H, T, W).

Preferred in this invention are compounds wherein R ³ is any one of options I) through Q) and (R 1, R ² , R ^a , R ⁴ , R ⁵ ) is any of the above combinations.

* 4 • ·

The term inflammatory diseases refers to diseases such as colon inflammation, sepsis, septic shock, adult respiratory distress syndrome, pancreatitis, trauma shock, bronchial asthma, allergic rhinitis, rheumatoid arthritis, chronic rheumatism, arterial obstruction, cerebral hemorrhage, cerebral infarction, cerebral infarction heart, heart attack, psoriasis, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, gout, spondylartropathy, ankylosing spondylitis, Reiter's syndrome, psoriatic arthropathy, anapatotic spondylitis, enterapatric spondylitis arthropathy, infectious or post-infectious arthritis, gonococcal arthritis, tuberculous arthritis, viral arthritis, fungal arthritis, syphilitic arthritis, Lyme disease, arthritis associated with vascular syndromes, nodular polyarteritis, hypersensitive vasculitis a, Luegenec's granulomatosis, polymyalgia rheumatica, joint cell arteritis (joint cell arteritis), lime crystals, pseudoderma, extracorporeal rheumatism, bursitis (inflammation of the sac), inflammation of the tendon sheath (tenosynomitis), epicondylitis (tennis), carotid epithelialitis (tennis) recurrent injuries (typed), various forms of arthritis, neuropathic joint disease (charco and joint), haemarthrosis (haemarthrosis), HenochScholein purpura, hypertrophic osteoarthropathy, multicentric reticulohistiocytosis, arthritis associated with ectopic diseases, haemolytosis (surcoosis) sickle cell disease) and other hemoglobinopathies, hyperlipoproteinaemia, hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Behat's disease, systemic lupus erythrematosis or recurrent polychondritis and related diseases that are required to treat mammals Duji administering a therapeutically effective amount of a compound of formula I at dosages sufficient to inhibit the release of fatty acids induced by sPLA _2> and thereby inhibit or prevent the arachidonic acid cascade and its deleterious products.

The terms mammal and mammalian include human.

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

The best way to practice the invention

The components of the invention represented by the formula I can be synthesized by the following method A.

Compound XV in Method A can be synthesized according to the following Method B (Method A)

Stage 1 ^R \ x ^CN Stage 2 _R 2

R ² CH ₂ CN (VI)

Stage 3 (VII)

R ¹ (m)

R‘- 'N'

AND

N

Grade 4 yO

X (IX) (X)

O (XI)

R ²

Stage 5

Stage 6

R ^2, -B

R ^R N EtO R * (R) nh ₂ > = <(XHI) (XIV) _R 5 COOEt

N COOEt HN

Grade 7 ^r4 ·

(XV)

(XVH) wherein R ¹ , R ² , R ⁴ , X and Y are as defined above; R ²⁶ is an acidic group.

(Stage 1)

To a solution of compound VI which is commercially available or synthesized by well-known solution methods such as tetrahydrofuran, diethyl ether and ethylene glycol dimethyl ether is added a base such as lithium diisopropylamide and n-butyllithium at -78 ° C to -78 ° C to -78 ° C. • · · · · · · · · · · · · · · · · · · · · · · ·

-20 ° C, preferably at -78 ° C to -60 ° C. An alkenyl halide such as allyl bromide and allyl chloride is further added to the reaction mixture at the same temperature, and the resulting mixture is stirred for 1 to 24, preferably 1 to 8 hours. After the reaction mixture is prepared in a conventional manner, VH can be obtained (see J. Chem. Soc. Parkin. Trans. 1, 1987, 1986).

(Stage 2)

To a solution of the compound VH in a solvent such as tetrahydrofuran, diethyl ether and ethylene glycol dimethyl ether is added Grignard reagent (IRMgHal: Hal is halogen) 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 prepared in a conventional manner, compound Vin can be obtained (see Synthesis, 996, 1988). (Stage 3)

This step involves the oxidation of the double bond by ozone. A solution of Compound Vin in a solvent such as dichloromethane, ethyl acetate and methanol is reacted with ozone at -78 ° C to 0 ° C, preferably -78 ° C to -60 ° C. Without isolation of the ozonide, the mixture is contacted with a reducing agent such as dimethylsulfide, triphenylphosphine, triethoxyphosphine, and zinc acetic acid or hydrogen to give the aldehyde IX derivative.

(Stage 4)

To a solution of compound IX in a solvent such as dioxane, tetrahydrofuran and diethyl ether is added compound X and an acid such as hydrochloric acid, sulfuric acid and acetic acid. The resulting mixture is stirred for 0.5 to 3 h at 50 ° C to 100 ° C to give the pyrrole derivative Χζ which is protected with phthalimide in the N-position. (Chem.Ber., 102, 3268, 1969).

(Stage 5)

At this stage, the phthalimide protecting group of compound XI is removed. This step can be carried out by conventional methods to remove the temple groups as described in Protective Groups in Organic Synthesis by Theodora W. Green (John Wiley & Sons). For example, hydrazine is added to a solution of compound XI in an alcoholic solvent such as ethanol, and the resulting mixture is stirred for 0.5 to 3 hours at 50 ° C to 100 ° C to give the amine derivative XII.

(Stage 6)

In this step, the amino group is alkylated. Compound XII and compound XIII are reacted together for 10 to 60 min. at 100 ° C to 150 ° C to give compound XIV (see J. Heterocyclic Chem., 31, 409, 1994).

(Stage 7)

At this stage, a pyrrolo [1,2-b] pyridazine ring is formed. 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 pynolo [1,2-b] pyridazine XV derivative (see J Heterocyclic Chem., 31, 409, 1994). The 4-hydroxy group is converted to a halogen by a conventional method, then the halogen is converted to a thiol group or the like.

(Grade 8)

To a solution of compound XV in a solution such as tetrahydrofuran and dimethylformamide is added a base such as potassium carbonate, sodium hydride and R ²⁶ -Hal (Hal is halogen) and the resulting mixture is stirred for 1-15 h at 0 ° C to 100 ° C. , preferably at 20 to 40 ° C, to obtain compound XVI.

(Stage 9)

This step introduces the substituent at the 5-position. Compound XVI is dissolved in a solvent such as 1,2-dichloroethane, tetrahydrofuran and Hal-C (= X) -C (= X) -Hal (e.g. oxalyl chloride) and the solution is added a base such as N-methylmorpholine, triethylamine, and the mixture is stirred for 5 to 30 minutes, preferably 10 to 20 minutes. Once the mixture is completed in the usual manner, compound XVK (Method B) is obtained.

R ²

NC ^ COOR ²⁷

Stage 1

NC

R ² OR ²⁸ —ch ₂ ch ^of COOR ²⁷ OR ²⁸ (XIX)

(XVIH)

(XV) wherein R ¹ , R ² , R ⁴ and R ⁵ are as defined above, R ²⁷ is C 1 -C 3 alkyl, R ²⁸ is lower alkyl or _R 28 is adjacent oxygen may form a 1,3-dioxolane ring and R ²⁹ is phthalimido or -NHCO 2 Et.

(Stage 1)

To a solution of compound XVIII in a solvent such as dimethylformaldehyde is added a halogenated alkyl derivative such as bromoacetaldehyde, ethylene acetal and a base such as potassium carbonate, potassium tert-butoxide and sodium hydride and the resulting mixture is stirred for 3 to 80 h, preferably 5 to 7 h at room temperature to 180 ° C, preferably 20 to 150 ° C, to obtain compound XIX. (Stage 2)

To a solution of compound XIX in a solvent solution such as dimethysulfoxide is added a reactant such as potassium acetate and the resulting mixture is stirred for 1 to 20 hours, preferably 3 to 15 hours at 20 ° C to 200 ° C, preferably at 100 ° C to 180 ° C to obtain compound XX.

(Stage 3)

To a solution of the Grignard reagent (R 1 g Hal, Hal is halogen) or R 1 Li in a solvent such as ether, tetrahydrofuran and dimethoxyethane is added a solution of compound XX in ether, tetrahydrofuran and dimethoxyethane, and the resulting mixture is stirred for 1 to 48 h. preferably 2 to 24 h at 0 ° C to 70 ° C, preferably 20 to 60 ° C to obtain compound XXI.

(Stage 4)

To a solution of compound XXI in a solvent such as ethanol, methanol, dioxane and tetrahydrofuran was added N-aminophthalimide (compound X) or ethylcarbazate (compound XXII) and an acid such as trifluoroacetic, hydrochloric and sulfuric and the resulting mixture was stirred for 5 min. to 2 h, preferably 10 min. up to 1 hour at 20 ° C to 120 ° C, preferably 50 to 100 ° C, to obtain ΧΧΠΙ.

(Stage 5)

This step can be carried out in the same manner as the same step 5 for Method A. (Step 6)

To a solution of compound XH 'in a solvent such as chloroform, dichloroethane, tetrahydrofuran and toluene is added a β-ketoester such as methyl acetoacetic acid, and an acid catalyst such as p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, trifluoroacetic acid, and the resulting mixture The mixture is stirred for 1 to 20 hours, preferably for 3 to 15 hours, to give compound XV. The formed water in situ is removed with a Dean-Stark 4A molecular sieve or the like.

4 Method 4 (Method C)

Step 2 wherein R ¹ , R ² , R ⁴ , X and Y are as defined above, Hal is halogen, R ³⁰ is -OR ³¹ , -SR ³¹ , -NHR ³¹ -N (R ³¹ ) ₂ , -CN, -N ₃ or the like, wherein R ³¹ is independently alkyl, aryl, or the like.

(Stage 1)

Compound XVI 'was obtained in a similar manner as described for Method A - Step 8. (Step 2)

Compound XVI 'is dissolved in a solvent such as dimethylformaldehyde, acetonitrile, acetone, dimethylsulfoxide, methanol, ethanol, isopropanol and to this solution is added a base such as a dehydrohalogenating agent such as potassium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, sodium hydroxide , potassium hydroxide, sodium hydride, potassium tert-butoxide. Then a reagent such as R ³¹ OH, R ³¹ SH, R ³¹ NH 2, (R ³¹ ) 2NH is added to the mixture, and the resulting mixture is stirred for 1 to 48 h, preferably 1 to 24 h at -20 ° C to 100 ° C. preferably at 0 ° C to 80 ° C to obtain compound XXIV.

(Stage 3)

Compound XVII 'was obtained in a similar manner as described for Method A-Step 9.

··

(Method D)

wherein R ¹ , R ² , R ⁴ , R ²⁶ , R ³⁰ , X, Y and Hal are as described above.

(Stage 1)

Compound XXV was prepared in a similar manner to that described for Method A-Step

9.

(Stage 2)

Compound XVII 'is obtained in a similar manner to that described for Method C - Step 2. Where the compound of the invention has an acidic or basic functional group, each of their different salts has higher water solubility and more physiologically acceptable properties than as the original compound can provide. Examples of typical pharmaceutically acceptable salts are lithium, sodium, potassium, magnesium, aluminum and the like, but it is to be understood that the list of such pharmaceutically acceptable salts is not limited thereto. The salt can be easily made from the free acid either by reacting the acid in solution with a base or by reacting the acid with an ion exchange resin. Other salts of the compounds of the invention with relatively non-toxic inorganic bases and organic bases, eg, amine cation, ammonium, quaternary ammonium, derived from nitrogen bases, having a basicity sufficient to form a salt of the compounds of the invention are included in the definition of a pharmaceutically acceptable salt. (SMBeige et al., Pharmaceutical Salts, J. Pharm. Sci., 66,119, (1977)) In addition, the basic groups of the compound of the invention can be reacted with suitable organic or inorganic acids to form salts such as acetates , benzenesulfonates, benzoates, hydrogencarbonates, hydrogensulfates, bitartarates, borates, bromides, camcyrates, carbonates, chlorides, clubranates, citrates, edetates, edratates, estratates, ethylates, fluorides, fumarates, gluseptates, gluconates, glutamates, glycolialstoates, hexyl resorphorates, hexyl resorates, hexyl resorates , isothionates, lactates, lactobionates, laurates, malate, malseates, mandelates, mesylates, methylbromides, methylbynitrates, methylsulphates, mucats, napcylates, nitrates, oleate, oxalates, palmitates, pantothenates, phosphates, polygalacturonates, stannates, silicilate, silicilate, silicilate, , tartrates, tosylates, trifluoroacetates, trifluoromethanesulfonates, valerates and the like (Compounds, quoted herein in quotation marks) s are not placed in the valid Czech chemical nomenclature org. compounds)

In the case of hydrate formation, the compound in question can be coordinated with an appropriate number of water molecules.

In the case where the compound of the invention has one or more chiral centers, it may exist as an optionally active member. Similarly, in the case where the 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 this invention. Asymmetric carbon may also exist for a substituent such as an alkyl group. All such isomers are included in the invention, together with mixtures thereof. Where a specific stereoisomer is desired, it is prepared either by applying a method well known in the art, wherein the starting material with an asymmetric center which has been previously isolated is subjected to a stereospecific reaction, or obtained from a mixture of stereoisomers and then isolated in a known manner . A prodrug is a derivative of a compound with a moiety that can be degraded chemically or metabolically, and such a prodrug is a compound of the invention that becomes pharmaceutically active by solvolysis or by placing the compound in vivo under physiological conditions. Although the derivative of the compounds of the invention exhibits activity in both acidic and basic forms, the acidic derivative is more preferred for its solubility, tissue affinity, and controlled release in mammalian organisms (Bungard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam, 1985). Ester prodrugs are well known (see Silverman, Richard B, The Organic Chemistry of Drug Action, Chapter 8, New York, NY Academic Press, ISBN 0-12-643730-0) and is a form preferred for compounds of the invention, and also suitable for prodrugs used in the treatment of inflammatory diseases as mentioned herein. For example, prodrugs containing acid derivatives such as an ester prepared by reacting a base acid with a suitable alcohol, or an amide prepared by reacting a base acid with a suitable amine are well known in the art. Simple aliphatic or aromatic esters derived from the acid groups contained in the compounds of the invention are preferred prodrugs. Particularly preferred esters such as prodrugs are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, morpholino-ethyl and N, N-diethylglycolamidoesters.

Methyl ester prodrugs can be prepared by reacting the sodium salt of a compound of Formula I (in solution, such as dimethylphonamide) with iodoethane (available from Aldrich Chemical Co., Milwaukee, Wisconsin USA; Item No. I-778-0).

The Ν, Ν-diethylglycolamidoester prodrugs can be prepared by reacting the sodium salt of a compound of formula I (in dimethylformamide) with 4- (2-chloroethyl) morpholine hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wisconsin USA; Item No.C4,220- 3).

Optionally, double ester prodrugs such as (acyloxy) alkyl ester or ((alkyloxycarbonyl) oxy) alkyl ester may be prepared.

The term inhibit means that with the compounds of the invention, it significantly suppresses sPLA _2- induced fatty acid release in terms of disease prevention and treatment. The term pharmaceutically acceptable means that the carriers, diluents or additives are compatible with the other ingredients in the prescription and are not harmful to the recipient.

The compounds of the invention exhibit SPLA2 inhibitory activity as described in the experimental section below.

And when therapeutically effective amounts of the compounds represented by formulas I, Π, IH, and IV, prodrugs thereof, pharmaceutically acceptable salts thereof, or solvates thereof, are administered to mammals (including humans), they will act as effective therapeutics for the treatment of diseases such as septic shock, adult respiratory distress syndrome, pancreatitis, hronchial asthma injuries, allergic rhinitis, chronic rheumatism, arteriosclerosis, cerebral haemorrhage, cerebral infarction, inflammatory colitis, scabies, heart failure, heart attack.

The compounds of the invention can be administered to patients by various routes, such as orally, in the form of an aerosol, rectally, cutaneously, subcutaneously, intravenously, into muscle and through the nose. The compositions of the invention can be prepared by combining (eg, mixing) a therapeutically effective amount of the compounds of the invention with a pharmaceutically acceptable carrier or diluent. The formulations of the invention can be prepared using well known or readily available ingredients using known methods.

In the manufacture of the compositions of the invention, the components are either mixed with the carrier, or diluted with the carrier, or incorporated into the carrier in the form of capsules, sachets, paper or other containers. When the carrier acts as a diluent, is a solid, semi-solid, or liquid substance, it behaves as an environment. The formulations of the present invention can be made in the form of tablets, pills, powders, oral drugs, elixirs, suspensions, emulsions, solvents, syrups, aerosols (solids in liquid media) and ointments. Such preparations may contain up to 10% of the active ingredient. It is preferred that a compound of the invention is prepared prior to administration of the formulation.

Any carrier well known in the art may be used to prepare the preparations. In such formulations, the carrier may be a solid, liquid, or a mixture of a solid and a liquid. For example, the compound of the invention is dissolved in an aqueous solution of 4% dextrose 0.5% sodium citrate so that the concentration for intravenous injection is 2 mg / ml. Solid form preparations include powder, tablets and capsules. A solid carrier consists of one or more substances serving as a fragrance, a lubricant, a solvent, a suspending agent, a binder, a tablet disintegrator, a capsule. Tablets for oral administration include a suitable excipient such as calcium carbonate, sodium carbonate, lactose, calcium phosphate and the like, together with a disintegrant such as starch grain, 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 powder formulations, the carrier is finely divided into powder, which is then mixed with the powdered active ingredients. In tablets, the active ingredients are mixed in suitable proportions with the carrier having the desired binding properties and then compressed to the desired shape and size. Powder medicaments and tablets contain about 1 to 99 wt. active ingredients exhibiting novelty according to the invention. Examples of suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth juice, methylcellulose, carboxymethylcellulose sodium, low wax and cocoa butter.

Axenic liquid preparations include a suspending agent, an emulsifier, a syrup, and an elixir. The active ingredients may be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, a sterile organic solvent, mixtures thereof, and the like. Active ingredients may often be dissolved in a suitable organic solvent, such as an aqueous solution of propylene glycol. If finely powdered active ingredients are dispersed in aqueous starch, sodium carboxymethylcellulose or a suitable oil, other compositions may be prepared. The lyophilized formulation can be prepared by dissolving the active ingredients, e.g., in water, if desired, with a solubilizer such as citric, edetic, polyphosphoric and their salts and a stabilizer such as mannitol, xylitol, sorbitol, glucose, fructose, lactose and maltose, followed by lyophilization.

The method of the invention, ie, inhibiting sPLA _2- induced fatty acid release, comprises contacting mammalian sPLA ₂ with a therapeutically effective amount of sPLA ₂ inhibitors.

based on pyrrolo [1,2-b] pyridazine (and assembly of such inhibitory preparations) as mentioned above.

Preferred compounds of the invention (Formulas I, Π, ΠΙ, IV or pharmaceutical preparations containing these compounds) are in unit dosage form when administered to a mammal. The unit dosage form may be a capsule or tablet, or an appropriate number thereof. The amount of active ingredient in a unit dose of the composition may be varied or adjusted to be about 0.1 to 1000 milligrams or more, depending on the particular therapeutic purpose. This may also be due to the need for dosage according to the age and condition of the patient. The dosage is also dependent on the mode of administration of the drugs.

An improved method of treating sepsis using sPLA ₂ inhibitors based on pyirolo [1,2-b] pyridazine (and preparations containing such inhibitors) can be performed as follows:

The inhibitors of the invention may be administered by injection subcutaneously or into muscle tissue or intravenously. The intravenous route of administration to the mammal being treated is more advantageous and offers the advantage of rapid action and rapid penetration into the circulatory system, particularly in emergencies.

It should be appreciated that when administering drugs, it may become necessary to make routine changes in dosage, depending on the age and condition of the patient. The specific dose of the compound to be administered, of the invention, to achieve a therapeutic and prophylactic effect will, of course, be determined by the particular circumstances of the case, including, for example, the type of compound to be administered, the mode of administration and the condition being treated. Typical daily doses will contain nontoxic Compound I in an amount of about 0.01 mg / kg to 50 mg / kg body weight, of the active ingredient of the invention.

The present invention is a method of treating or preventing inflammatory diseases (ie, sepsis, rheumatoid arthritis, osteoarthritis, asthma), based on administering to a mammal in need thereof a therapeutically effective amount of an inhibitor. Administration to septic patients may be either regular or occasional.

The decision to start sepsis treatment is dependent on the clinical manifestations of sepsis, or laboratory test results that indicate an onset septic cascade (including renal complications or clotting abnormalities, or multiple organ failure). Typical clinical manifestations are: fever, shivering, tachycardia, rapid breathing, mental state changes, hypothermia, hyperthermia, breathing faster or slower or heart rhythm, increased or decreased white blood cell count and low blood pressure. These and other symptoms are well known in the art and are referred to in standard references, such as Harrison 'Principles of Intemal Medicine (ISBN 0-07-032370-4) 1994, pp.511-515.

• this ··················

The decision to determine the duration of treatment may be based on the results of standard clinical laboratory tests from commercially available assays and instrumentation to support the removal of symptoms defining sepsis. The method of the invention may be practiced either by periodically or occasionally administering therapeutically effective doses of the inhibitor. Administration can be for up to 60 days, with a more advantageous course of treatment lasting up to 10 days. The decision to discontinue the treatment according to the invention may be based on the results of standard clinical tests from commercially available assays and instrumentation, or by the disappearance of clinical signs characteristic of sepsis. Treatment may be resumed upon return of sepsis. Pediatric forms of sepsis are also successfully treated with the methods, compounds and preparations of the invention.

When the compounds of the invention are in crystalline form, they may exist in different crystalline forms and may have a different appearance.

The present invention will now be described and explained in more detail by way of examples and tests, but it is to be understood that the invention is not limited thereto.

The following abbreviations are used in the examples.

Me; methyl

Et: ethyl

Pr: propyl

Ph: phenyl

Nphth: phthaloylimide (d) at melting point: decomposition temperature

DBU: 1,8-diazabicyclo [5.4.0] -7-undecene

DETAILED DESCRIPTION OF THE INVENTION

He did

COOEt ^Stu P ^{eft 1}

-►

CN (i)

COOEt Stage 2 / '(*' CN (2) ^^ COOEt

Stage 3

-►

NaO ₂ CO COCONH

Stage 14

Ph 'd 3) «0 ·· ··

9 9 9 9 · 9 · 9 9

9 9 9 9 9

99 99 999 99

Example 1 - Stage 1

Compound 1 (18.2 g, 0.160 mol) and 90% acetaldehyde (9.43 g, 0.190 mol) were dissolved in 20 mL acetic acid and 10% Pd-C catalyst (300 mg) and piperidine solution ( 0.63 mL, 6.37 mol) in acetic acid (10 mL). The resulting mixture was stirred for 3 h at room temperature under hydrogen at 50 psi. Next, the reaction mixture was filtered to remove the catalyst, diluted with toluene and washed with water. It was then distilled under reduced pressure to give compound 2 (20.00 g, 88%, bp 92-94 ° C, (13 mm lig)) as a colorless liquid (see OS, ΙΠ, 385, 1955. J. Am. Soc., 66, 886 (1944). Example 1 - Stage 2

To a solution of compound 2 (19.2, 0.14 mol) in acetone (200 mg) was added allyl bromide (60.2 mL, 0.700 mol) and potassium carbonate (36.0 g, 0.260 mol) and the resulting mixture was stirred under The reaction mixture was then filtered and the filtrate distilled under reduced pressure to give compound 3 (22.0 g, 89%, bp 107-109 ° 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 (10.0 g, 102 mmol) were dissolved in 85 mL of dimethylsulfoxide and the resulting mixture was stirred at 150 ° C for 5 h. 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 at atmospheric pressure. This gave compound 4 (8.00 g, 79%, bp 168-172 ° C) (see Compt. Rend., 253, 1808 (1961) and Indian J. Chem., 25,1249 (1986))

Compound 4 can also be synthesized by 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 ether was added a solution of benzyl bromide (21.3 g, 0.125 mmol) in 30 mL ether with ice cooling. The mixture was warmed to room temperature and 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 for 2 h. Water was then added to the reaction mixture under ice-cooling, acidified with 50 mL 2.5 N sulfuric acid. The resulting mixture was stirred for 100 min. in a water bath (90 ° C) to remove the ether. The reaction mixture was further extracted with ether and the organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed

9 «44 494 444

49,444 9,449 9 9

9950 4 4 4 44 9

99-499444444 analyzed on silica gel with ethyl acetate-hexane (1:20) and the appropriate fractions distilled under reduced pressure. Compound 5 (17.6 g, 77%, bp 90-91 ° C (0.4 mm Hg)) was obtained as a colorless liquid (see Synthesis, 996.1988).

1 H-NHR (CDCl ₃ ): 0.81 (3H, t,> 7.4 Hz), 1.41-1.78 (2H, m), 2.09-2.41 (2H, m), 2.562.70 (1H, m), 3.71 (2H, s), 4.96-5.06 (2H, m), 5.56-5.77 (1H, m), 7.15-7, 37 (5 H, m).

Example 1 - Step 5

Compound 5 (13.4 g, 66.1 mmol) was dissolved in 150 mL of dichloromethane, ozone was introduced into the solution at -78 ° C until the starting material disappeared, and the excess ozone was then replaced with argon. 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 min at room temperature. When the solvent was removed, the precipitated kiystals were filtered off, washed with a solvent mixture of ethyl acetate and hexane, and the filtrate concentrated in vacuo. The resulting residue was subjected to silica gel column chromatography, with ethyl acetate-hexane (1: 4) as eluent to give compound 6 (11.2 g, 83%) as a colorless liquid.

1 H-NMR (CDCl ₃ ): 0.87 (3H, t,> 7.5 Hz), 1.41-1.75 (2H, m), 2.50 (1H, dd,> 18.3, 3) 9 Hz), 2.96 (1H, dd, > 18.3, 9.6 Hz), 3.06-3.15 (1H, m), 3.84 (1H, d, > 16.2 Hz) 1.91 (1H, d,> 16.2 Hz), 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) were suspended in 250 mL dioxane, 5N hydrochloric acid (6 mL, 30.0 mmol) was added. ) and the mixture was stirred for 30 min. 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 purified by silica gel column chromatography and the fractions eluted with chloroform / hexane = 2: 1 were collected and recrystallized from hexane to give compound 7 (14.8 g, 82%, mp 153-154 ° C, as colorless crystals (see Chem. Ber., 102, 3268 (1969)).

Elemental analysis: C 21 H 18 N 2 O 2

Calcd: C, 76.34; H, 5.49; N, 8.48.

Found: C, 76.11; H, 5.47; N, 8.69. @ 1 H-NHR (CDCl3): 1.22 (3H, t, J = 7.5Hz), 2.52 (2H, q, J = 7.5Hz), 3.81 (2H) , s), 6.24 (1H, d, J = 3.3Hz), 6.60 (1H, d, J = 3.3Hz), 6.91-7.03 (5H, m), 7 74-7.83 (4 H, 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 and the mixture was stirred for 30 min. at 100 ° C.

The precipitated crystals were filtered off and the filtrate concentrated in vacuo. The residue was chromatographed on silica gel using chloroform to afford sloučeninaΠ-1 (9.00 g, 99%) as a colorless oil.

Ή-NHR (CDCl 3): 1.16 (3H, t, J = 7.5 Hz), 2.46 (2H, q, J = 7.5 Hz), 3.99 (2H, s), 4, 23 (1H, br s) 5.94 (1H, d, J = 2.7Hz), 7.07-7.30 (5H, m).

Example 1 - Step 8

To ΧΠ-1 (6.38 g, 31.9 mmol) was added diethylethoxymethylene malonate (7.57 g, 35.0 mmol) and the mixture was heated for 40 min. at 125 ° C with removal of the ethanol formed in situ. Hexane was added to the reaction mixture and the precipitated crystals were filtered off to give compound 8 (7.67 g, 65%, mp 60-61 ° C) as colorless crystals. The filtrate was purified by silica gel chromatography (eluting 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: C21H26N2O4,

Calcd: C, 68.09; H, 7.07; N, 7.56.

Found: C, 67.69; H, 7.06; N, 7.68.

Ή-NHR (CDCl 3): 1.20 (3H, t, J = 7.2 Hz), 1.21 (3H, t, J = 7.2 Hz), 1.33 (t, J = 6.9 Hz) ;

2.51 (2H, q, J = 6.9Hz), 3.88 (2H, s), 4.08 (2H, q, J = 7.2Hz), 4.24 (2H, q, J) = 7.2 Hz), 6.07 (1H, d, J = 3.3 Hz), 6.66 (1H, d, J = 3.3 Hz), 7.00-7.28 (5H, m 7.67 (1H, d, J = 11.1 Hz), 10.32 (1H, d, J = 11.1 Hz).

Example 1 - Step 9

Compound 8 (11.9 g, 32.1 mmol) was dissolved in SAS-296 (phenylxylylethane) and the mixture was heated at 200-210 ° C under argon for 5 h. The reaction mixture was then purified by silica gel chromatography using toluene / hexane (= 1/2) to give compound 9 (6.85 g, 66%) as yellow crystals. The crystals were further recrystallized from hexane (m.p. 75-76 ° C).

Elemental analysis: C19H20N2O3,

Calcd. C, 70.35; H, 6.21; N, 8.64

Found: C, 70.22; H, 6.28; N, 8.88

Ή-NHR (CDCB): 1.24 (3H, t, J = 7.5Hz), 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 dimethylsulfoxide. Sodium chloride (598 mg, 10.2 mmol) and water (519 mg, 28.8 mmol) were added to the solution, and the mixture was stirred at 150 ° C for 4 h. The solvent was removed and the residue purified by silica gel chromatography (eluting with ethyl acetate / hexane = 1/4) to give compound 10 (1.32 g, 63%) as colorless crystals. These kiystals were recrystallized from ether and hexane (m.p. 113-114 ° C).

Elemental analysis: C ₁₆ H ₁₆ N ₂ O,

Calcd: C, 76.16; H, 6.39; N, 11.10.

Found: C, 75.93; H, 6.45; N, 11.27.

1 H-NHR (CDCB): 1.24 (3H, t, J = 7.5Hz), 2.68 (2H, q, J = 7.5Hz), 4.39 (2H, s), 5 , 85 (1H, d, J = 5.4 Hz), 6.53 (1H, s), 7.12-7.25 (5H, m), 7.80 (1H, d, J = 5.4 Hz).

Example 1 - Step 11

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

Elemental analysis: C49H20N2O3,

Calcd. C, 70.35; H, 6.21; N, 8.64.

Found: C, 70.32; H, 6.29; N, 8.88.

1 H-NMR (CDCl 3): 1.24 (3H, t, J = 7.5 Hz), 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 = 5.4 Hz), 6.63 (1H, s), 7.10-7.25 (5H m) 7.84 (1H d, J = 5.4 Hz).

Example 1 - Step 12

To a solution of oxalyl chloride (752 mg, 592 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 at 0 ° C for 2 h. After the mixture was added to ice-cooled aqueous ammonia and stirred for 10 min. at room temperature, was extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate and / concentrated in vacuo. The residue was recrystallized from methanol to give compound (1-1) (416 mg, 89%, mp 210-212 ° C) as pale yellow crystals.

Elemental analysis: C21H21N3O5,

Calcd: C, 63.79; Η, 5.35; N, 10.63.

Found: C, 63.59; H, 5.39; N, 10.91-NHR (CDC1 _3): 1.16 (3H, t, J = 7.5 Hz), 2.86 (2H, q, J = 7.5 Hz), 3.80 (3H , s), 4.37 (2H, s), 4.76 (2H, s), 5.56 (1H, br. s), 6.06 (IH, d, j = 5.4 Hz), 6 70 (1H, br. S) 7.13-7.25 (5H, m), 8.02 (1H, d, J = 5.4 Hz).

Example 1 - Step 13

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

Elemental analysis: C20H19N3OJ,

Calcd: C, 62.99; H, 5.02; N, 11.02.

Found: C, 62.80; H, 5.06; N, 11.21.

Ή-NHR (DMSO): 1.04 (3H, t, J = 7.5Hz), 2.79 (2H, q, J = 7.2Hz), 4.35 (2H, s), 4, 88 (2H, s), 6.48 (1H, d, J = 5.4 Hz), 7.12-7.29 (5H, m) 7.40 (1H, br. S), 7.79 (1H, m); 1H, br. S) 8.23 (1H, d, J = 5.4 Hz), 13.29 (1H, br. S).

Example 1 - Step 14

Compound 1-2 (51.4 mg, 0.134 mmol) was suspended in 2 mL H ₂ O and 0.1 N sodium hydroxide (1.34 mL, 0.134 mmol) was added under ice-cooling. Then the mixture was filtered and lyophilized to give compound 1-3 (50.1 mg, decomposition temperature 280 ° C) as a yellow powder.

Example 2

COCONH,

Stage 4

HO ₂ CO

Ph '(1-5) (1-5) • · · · s · s · s · s · · · ·

Stage 1

A mixture of ΧΠ-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 for 15 h in an oil bath. The water formed was dehydrated on a Dean-Stark 4A molecular sieve. Water and 25 mg sodium bicarbonate were added to the reaction mixture. The mixture was extracted with chloroform, dried over magnesium sulfate and purified by silica gel column chromatography (16 g silica gel, eluting with 2.5% acetonitrile-chloroform) to give 12 (800 mg, 100%) as a brown oil.

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

Stage 2

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 was stirred for 1 h at room temperature and the reaction water was then added to the mixture. The mixture was further extracted with toluene, washed with water, dried over magnesium sulfate, purified by silica gel column chromatography (20 g silica gel, eluting with toluene) to give 797 mg of eluate. The eluate was recrystallized from acetone and isopropyl ether to give compound 13 (739 mg, 72.5%, mp 120-121 ° C) as white crystals.

Ή-NHR (CDCl 3): 1.22 (3H, t, J = 7.4 Hz), 2.38 (3H, s), 2.65 (2H, q, J = 7.4 Hz), 3, 83 (3H, s), 4.35 (2H, s), 4.77 (2H, s), 5.60 (1H, s), 6.54 (1H, s), 7.20 (1H, s) ).

Stage 3

Compound 13 (676 mg, 2 mmol) and N-methylmorpholine (0.44 mL, 4 mmol) were dissolved in 10 mL of dichloromethane. This 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 dry ice-methanol bath, and the resulting mixture was stirred for 30 min. at the same temperature. The reaction mixture was added to 10 mL conc. aqueous ammonia and insoluble matter was filtered off. The filtrate was extracted with chloroform, washed with water, dried over magnesium sulfate and purified by silica gel column chromatography (30 g silica gel, eluting with 50% acetonitrile-chloroform). The eluate was recrystallized from acetone and ethyl acetate to give compound 1-4 (774 mg, 94.5%, mp 225-226 ° C) as pale yellow crystals.

1 H-NMR (d 6 -DMSO): 1.02 (3H, t, J = 7.2 Hz), 2.41 (3H, s), 2.76 (2H, q, J = 7.2) Hz), 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).

Stage 4

Compound 1-5 was synthesized in the same manner as described in Example 1, step 13.

Ή-NHR (d 6 -DMSO): 1.02 (3H, t, J = 7.5 Hz), 2.40 (2H, s), 2.76 (2H, q, J = 7.5 Hz), 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

Me

NC ^ COOEt (15)

Grade 1 Me OEt Grade 2 ^Me

-►NC- | -CH ₂ CH -►

COOEt OEt (14)

NC> —OEt

EtO (15)

Me

NH ₂ (ΧΠ-1)

Stage 1

A mixture of compound 14 (25.8 g, 0.203 mol), bromoacetaldehyde diethyl acetal (48.0 g, 0.244 mol), potassium carbonate (33.7 g, 0.244 mol) and 130 mL of dimethylformamide was heated at 110 ° C for 24 h. nitrogen. 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%, bp 99-102 ° C (1 mmHg)) as a colorless liquid.

Ή-NHR (CDCl 3): 1.38 (3H, t, J = 7.0 Hz), 1.21 (3H, t, J = 7.0 Hz), 1.62 (3H, s), 2, 01 (1H, m, J = 14.2 Hz, J = 4.2 Hz), 2.40 (1H, m, J = 14.2 Hz, J = 7.4 Hz), 3.49-3, 75 (4 H, m),

4.24 (1H, q, J = 7.0Hz), 4.25 (1H, q, J = 7.0Hz), 4.75 (1H, m, J = 7.4Hz, J = 4Hz) , 2 Hz).

Stage 2

Stage 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 in an oil bath (160 ° C) under nitrogen for 14 h. After cooling the mixture, water was added and the mixture was extracted with ether. The organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was distilled under reduced pressure to give compound 16 (29.48 g, 96.0%, 110-113 ° C (3 kPa)) as a colorless liquid.

Ή-NHR (CDCl ₃ ): 1.22 (3H, t, J = 7Hz), 1.23 (3H, t, J7Hz), 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).

Stage 3

To the Grignard reagent prepared from magnesium (1.53 g, 0.063 mol), 71 mL of ether,

Of 1,2-dibromoethane (0.26 mL, 0.003 mol) and benzyl bromide (7.14 mL, 0.060 mol), a solution of compound 16 (7.06 g, 0.05 mol) in 35 mL of ether was added and the resulting mixture was The mixture was stirred at room temperature for 4 h and heated at reflux in an oil bath (60 ° C) for 5 h. Aqueous ammonium chloride (5.35 g, 0.1 mol, 50 mL) was added to the reaction mixture with ice-cooling and 63 mL of 2N sulfuric acid, and the mixture was stirred for 30 min. Then the reaction mixture was neutralized by the addition of 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 silica gel chromatography (90 g, eluting with 10% ethyl acetate-toluene) to give compound 17 (9.13 g, 78%).

Ή-NHR (CDCl 3): 1.11 (3H, d, J = 7 Hz), 1.58-2.24 (2H, m), 2.90 (1H, m), 3.77 (2H, s) 1.78-3.90 (4H, m), 4.87 (1H, t, J = 4.8 Hz), 7.14-7.37 (5H, m).

Stage 4

Compound 17 (35.9 g, 0.129 mol) and N-aminophthalimide (20.9 g, 0.129 mol) were suspended in 95% ethanol (250 mL). 1 N-hydrochloric acid (13 mL, 0.013 mol) was added to the suspension and the resulting mixture was heated for 30 min. under reflux in an oil bath. After cooling, the precipitated crystals were filtered off to give compound 18 (35.96 g,

84.4%, m.p. 151-152 ° C), as pale yellow crystals.

Ή-NHR (CDCl 3): 1.22 (3H, t, J = 7.4 Hz), 2.52 (2H, q, J = 7.8 Hz), 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).

Stage 4 '

To a solution of compound 17 (1.69 g, 8.6 mmol) and ethyl carbazate (0.90 g, 8.6 mmol) in 20 mL dioxane was added 5N-hydrochloric acid (0.86 mL, 4.3 mmol) and the resulting mixture was heated for 30 min. in an oil bath (100 ° C). The dioxane was removed under reduced pressure and ke

water was added to the residue. The mixture was further basified with aqueous sodium bicarbonate, extracted with toluene, dried over magnesium sulfate and purified by silica gel column chromatography (50 g silica gel, eluting with toluene) to give compound 19 (0.734 g, 33.1%) as a colorless oil.

1 H-NHR (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).

Stage 5

Using compound 18 or compound 19 as a starting material, ΧΠ-2 was synthesized in a similar manner as described in Example 1 - step 7. Compounds ΧΠ-3 to ΧΠ-10 were synthesized by the same sequence of reactions as described above. The physical data of each compound is shown in Table 1.

• ·

Table 1

R ²

t

NH ₂

Compound no. Ri R2 Ή-NMR (CDCl 3) XII-2 σ ^0Η2 Me 2.08 (3H, s), 3.98 (2H, s), 5.88 (1H, s), 6.62 (IH, br. S), 7.09-7.30 (5H, m) XII-3 _{F is} ^CH2 Et 1.15 (3H, t, J = 7.5Hz), 2.45 (2H, q, J = 7.5Hz), 3.96 (2H, s), 5.94 (IH, s), 6.64 (IH, br. S), 6.91-7.07 (3H, m) XII-4 αΓ Et 1.13 (3H, t, J = 7.5Hz), 2.43 (2H, q, J = 7.5Hz), 4.00 (2H, s), 5.94 (IH, s), 6.67 (IH, brs), 6.83-7.23 (3H, m) XII-5 Et 1.09 (3H, t, J = 7.2Hz), 2.34 (2H, q, J = 7.2Hz), 3.89 (2H, s), 5.88 (1 H, s), 6.57 (1 H, br.s), 6.93 (1 H, m), 7.23-7.46 (9 H, m) XII-6 g ^CH2 O Et 1.13 (3H, t, J = 7.8Hz), 2.43 (2H, q, J = 7.8Hz), 3.97 (2H, s), 5.92 (1H, s), 6.63 (1H, br.s), 6.81- 7.36 (10H, m) XH-7 Me Me 2.09 (3H, s), 3.98 (2H, s), 5.88 (1 H, s), 6.61 (1 H, br.s), 7.08-7.31 (5 H, m) XII-8 QzCH ₂ Me 1.96 (3H, s), 3.86 (2H, s), 5.83 (1 H, s), 6.91 (1 H, br.s), 7.07-7.34 (8 H, s) XII-9 0 ^ Me 2.10 (3H, s), 4.03 (2H, s), 5.90 (1H, s), 6.75 (1H, br.s), 7.15-7.57 (9H, m) ΧΠ-10 Pj.ch ₂ kXp Et 1.08 (3H, t, J = 7.5Hz), 2.32 (2H, q, J = 7.5Hz), 3.86 (2H, s), 5.90 (1H, s), 6.6O (1H, br.s), 7.34 (8H, m)

Stage 1

A mixture of ΧΠ-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 was heated under reflux for 4 h. The formed water in situ was removed in a Dean-Stark 4A molecular sieve. Water and sodium bicarbonate (250 mg) were added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give compound 20 (15.17 g, 92.5%) as a brown oil.

Ή-NHR (CDCl 3): 1.23 (3H, t, J = 7.5 Hz), 2.68 (2H, q, J = 7.5 Hz), 4.36 (2H, s), 4, 53 (2H, s), 6.08 (1H, s), 6.51 (1H, s), 7.14-7.24 (5H, m).

Stage 2

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 h at room temperature. Water was added to the reaction mixture, followed by extraction with toluene. The organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (28 g), the 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 (1.91 g, 64.4%, mp 73-73.5 ° C) as white crystals.

-N -NHR (CDCl ₃ ): 1.23 (3H, t, J = 7.5Hz), 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).

Stage 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 in an oil bath for 22 h under reflux. The acetone was removed, the residue was treated with toluene, the insoluble material was filtered off and the solvent was removed. The residue was purified by silica gel column chromatography (13 g), fraction eluting with 5% ethyl acetate-toluene and concentrated in vacuo. This gave compound 22 (350 mg, 81.4%) as a colorless oil.

1 H-NHR (CDCl ₃ ): 1.24 (3H, t, J = 7.5 Hz), 2.69 (2H, q, J = 7.5 Hz), 3.75 (3H, s), 4.37 (2H, s), 4.77 (2H, s), 5.06 (2H, s), 5.96 (1H, s), 6.60 (IH, s), 6.93-7 25 (10H, m).

Stage 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, 244 mmol) in 3 mL of dichloromethane, cooled with ice, and the resulting mixture was stirred at the same temperature for 2 h. The reaction mixture was poured into 2 mL conc. aqueous ammonia under continuous ice cooling. The insoluble material was filtered off 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 purified by silica gel column chromatography (12 g), the fractions eluted with 50% acetonitrile-chloroform were collected and concentrated in vacuo. The residue (1.40 g) was recrystallized from acetone and ethyl acetate to give compound 1-6 (375 mg, 91.9%, mp 185-186 ° C) as pale yellow crystals.

1 H-NHR (d 6 -DMSO): 1.04 (3H, t, J = 7.2 Hz), 2.79 (2H, q, J = 7.2 Hz), 3.67 (2H, s) 4.33 (2H, s), 4.99 (2H, s) 6.68 (1H, s), 6.93-7.29 (10H, m), 7.40 (1H, br.s), 7.79 (1H, br.s). Example 5

(1-7)

Al

Stage 1

Compound 21 (5.0 g, 13.4 mmol) and N, N-diisopropyl-N-ethylamine (3.5 mL, 20.1 mmol) were 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 a dry ice bath of methanol (-10 ° C), and the mixture was stirred at the same temperature for 2 h. This reaction mixture is then poured into a stirred solution of conc. aqueous ammonia (10.7 mL) and chloroform (40 mL) with ice cooling. The insoluble material was filtered off 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 purified by silica gel column chromatography (42 g), fractions eluted with 50% acetonitrile-chloroform were collected and concentrated in vacuo. The residue was recrystallized from tetrahydrofuran-ethyl acetate to give compound 23 (5.36 g, 90.0%, mp 191-194 ° C) as pale yellow crystals. ¹ H-NHR (d 6 -DMSO): 1.03 (3H, t, J = 7.5 Hz), 2.78 (2H, q, J = 7.5 Hz), 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).

Stage 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 20 mL of acetone was heated under reflux in an oil bath for 7 h. 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 purified by 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%, mp 178-179 ° C) as white crystals.

1 H-NHR (CDCl ₃ ): 1.04 (3H, t, J = 7.5 Hz), 2.79 (2H, q, J = 7.5 Hz), 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 to Example 86

Compounds 1-8 to 1-84, represented by the following formula, were synthesized by the same reactions described in the above examples. Physical data are shown in Tables 2 to 11.

Provided that the formula:

A in the tables indicates a group represented by the following oQn-CH2CH2 9 9

Table 2

Compound no. R ¹ R2 R5 RM tt (° C) 1 H-NMR (d 6 -DMSO) 1-8 and ^CH2 Et Et Me 183- 185 1.16 (3H, t, J = 7.5Hz), 1.26 (3H, t, J = 7.5Hz), 2.73 (2H, q, J = 7.5Hz), 2.85 (2H, q, J = 7.5Hz), 3.80 ( 3H, s), 4.33 (2H, s), 4.74 (2H, s), 5.54 (1 H, br), 5.94 (1 H, s), 6.67 (1 H, br), 7.14-7.28 (5 H, m) 1-9 o ^CHí Et n-Pr Me 204- 206 0.93 (3H, t, J = 7.2Hz), 1.16 (3H, t, J = 7.5Hz), 1.70 (2H, m, J = 7.2Hz), 2.66 (2H, t, J = 7.2Hz), 2.85 ( 2H, q, J = 7.5Hz), 3.79 (3H, s), 4.33 (2H, s), 4.74 (2H, s), 5.56 (1H, br), 5.93 (1H, s), 6.68 (1H, br) 7.12-7.27 (5H, m) 1-10 σ ^0Η2 Et i-Pr Me 174- 175 1.17 (3H, t, J = 7.2Hz), 1.25 (6H, d, J = 7.2Hz), 2.87 (2H, q, J = 7.2Hz), 2.96 (1H, m, J = 7.2Hz), 3.80 ( 3H, s), 4.32 (2H, s), 4.75 (2H, s), 5.53 (1 H, br.s), 5.96 (1 H, s), 6.67 (1 H, br.s), 7.137.30 (5 H, s) (m) 1-11 Cr ^CH2 Et Ph Me 236- 239 1.09 (3H, t, J = 7.4 Hz), 2.84 (2H, q, J = 7.4Hz), 3.72 (3H, s), 4.42 (2H, s), 5.14 (2H, s), 7.10-8.05 (10H, m), 7.42 (1 H, br.s), 7.82 (1 H, br.s) 1-12 _f X 7 ^{CH 2} Et Me Me 252- 254 1.02 (3H, t, J = 7.2Hz), 2.41 (3H, s), 2.76 (2H, q, J = 7.2Hz), 3.72 (3H, s), 4.30 (2H, s), 4.95 (2H, s) 6.50 (1H, s), 7.07 (2H, t, J = 8.7Hz), 7.23 (2H, m), 7.35 (1H, br.s), 7.74 (1H, br.s), 8.008.04 ( 2H, m) 1-13 _f jCT ² Et Ph Me 253- 255 1.09 (3H, t, J = 7.5Hz), 2.84 (2H, q, J = 7.5Hz), 3.72 (3H, s), 4.41 (2H, s), 5.14 (2H, s), 7.09 (1H, t) J = 9.0 Hz, 7.10 (1H, s), 7.30 (2H, dd, J = 9.0, 5.7 Hz), 7.41 (1H, br.s), 7.50-7.58 (3H, m), 7.81 (1H, br.s), 8.00-8.04 (2 H, m)

Table 3 • · · 4 • ··

Compound vz CIS. R ¹ R2 R5 RM m.p. (° C) 1 H-NMR (d 6 -DMSO) 1-14 Et 1 CFa Me 200- 202 1.18 (3H, t, J = 7.5Hz), 2.88 (2H, q, J = 7.5Hz), 3.82 (3H, s), 4.32 (2H, s), 4.81 (2H, s >, 5.58 (1H, br) .s.) 6.29 (1H, s), 6.77 (1H, br.s), 6.93 (2H, t, J = 8.7Hz), 7.23 (2H, dd, J = 8.7, 5.4Hz) (by CDCl3) 1-15 σΓ Et Ph Me 244- 246 1.09 (3H, t, J = 7.5Hz), 2.83 (2H, q, J = 7.5Hz), 3.72 (3H, s), 4.43 (2H, s), 5.14 (2H, s), 7.03-7.28 (5H) m / z, 7.42 (1H, br.s), 7.497.56 (3H, m), 7.81 (1H, br.s), 7.97-8.01 (2H, m) 1-16 and ^CH2 Me Me H 271- 272 (d) 2.33 (3H, s); 2.41 (3H, s); 4.31 (2H, s); 4.84 (2H, s); 6.45 (1H, s); 7.12-7.30 (5H, m, 7.39 (1H, br. ), 7.75 (1 H, br.s) 1-17 and ^CH2 Me Ph H 253- 254 (d) 2.42 (3H, s), 4.41 (2H, s), 5.05 (2H, s), 7.05 (1H, s), 7.16-8.07 (10H, m), 7.44 (1H, s), 7.81 (1H, s) 1-18 σ ^0Η2 Et Et H 223- 225 (d) 1.04 (3H, t, J = 7.2Hz), 1.21 (3H, t, J = 7.2Hz), 2.70 (2H, q, J = 7.5Hz), 2.79 (2H, q, J = 7.5Hz), 4.31 ( 2H, s), 4.84 (2H, s), 6.45 (1H, s), 7.15-7.28 (5H, m), 7.36 (1H, br s), 7.75 (1H, br.s) 1-19 _σ οκ ₂ Et n-Pr H 231- 233 (d) 0.87 (3H, t, J = 7.2Hz), 1.04 (3H, t, J = 7.2Hz), 1.67 (2H, m, J = 7.5Hz), 2.65 (2H, q, J = 7.2Hz), 2.79 ( 2H, q, J = 7.5Hz, 4.31 (2H, s), 4.86 (2H, s), 6.46 (1H, s), 7.13-7.25 (5H, m), 7.36 (1H, s), 7.75 (1H) , s) 1-20 and ^CH2 Et i-Pr H 234- 236 (d) 1.06 (3H, t, J = 7.2Hz), 1.23 (6H, d, J = 6.6Hz), 2.81 (2H, q, J = 7.5Hz), 2.98 (1H, m, J = 6.6Hz), 4.30 ( 2H, s), 4.87 (2H, s), 6.48 (1H, s), 7.14-7.28 (5H, m), 7.36 (1H, br.s), 7.75 (1H, br.s) 1-21 and ^CH2 Et Ph H 244- 246 (d) 1.09 (3H, t, J = 7.2Hz), 2.85 (2H, q, J = 7.2Hz), 4.42 (2H, s), 5.04 (2H, s), 7.04 (1H, s), 7.14-8.03 (10H) m, 7.43 (1H, br.s), 7.81 (1H, br.s)

Table 4

Compound no. Ri R2 R5 RM m.p. ('C) 1 H-NMR (d 6 -DMSO) 1-22 _F xx ^CH2 Et Me H 238- 240 1.03 (3H, t, J = 7.5Hz), 2.40 (3H, s), 2.76 (2H, q, J = 7.5Hz), 4.30 (2H, s), 4.84 (2H, s). 6.45 (1H, s), 7.07 (2 H, t, J = 8.7 Hz), 7.23 (2 H, dd, J = 8.7, 5.7 Hz), 7.37 (1H, br. S), 7.75 (IH, br. S), 13.26 (IH, br. S) 1-23 _f xx ^CH! Et Ph H 250- 252 1.09 (3H, t, J = 7.5Hz), 2.84 (2H, q, J = 7.5Hz), 4.41 (2H, s), 5.04 (2H, s), 7.04 (1H, s), 7.09 (2H, t) J = 8.7 Hz), 7.31 (2H, dd, J = 8.7, 5.7 Hz), 7.43 (IH, br.s), 7.507.58 (3H, m), 7.81 (IH, br.s), 8.00- 8.04 (2H, m), 13.26 (1 H, br.s) 1-24 _f xx ^CH2 Et CFs H 248- 250 1.06 (3H, t, J = 7.5Hz), 2.83 (2H, q, J = 7.5Hz), 4.35 (2H, s), 5.04 (2H, s), 6.97 (1H, s), 7.09 (2H, t) J = 8.7 Hz), 7.26 (2H, dd, J = 8.7, 5.7 Hz), 7.53 (IH, br.s), 7.90 (IH, br.s), 13.40 (IH, br.s) 1-25 cC Et Ph H 252- 254 1.09 (3H, t, J = 7.5Hz), 2.83 (2H, q, J = 7.5Hz), 4.43 (2H, s), 5.04 (2H, s), 7.03-7.28 (5H, m), 7.44 (IH) 7.48-7.57 (3H, m), 7.82 (IH, br.s), 7.96-8.01 (2H, m), 13.26 (1H, br.s) 1-26 and ^CH2 Me Me Me ' 163- 165 2.33 (3H, s), 2.31 (3H, s), 3.71 (3H, s), 4.31 (2H, s), 3.95 (2H, s), 6.49 (1H, s), 7.13-7.30 (5H, m) 7.37 (IH, br.s), 7.77 (IH, br.s) 1-27 cr ^CH2 Et -CHaSPh Me 189- 192 0.99 (3H, t, J = 7.2Hz), 2.75 (2H, q, J = 7.2Hz), 3.70 (3H, s), 4.25 (2H, s), 4.29 (2H, s), 4.93 (2H, s) 6.62 (1H, s), 7.14-7.38 (11H, m), 7.77 (1 H, br.s) 1-28 and ^CH2 Et -CH 2 Cl Bn 172- 173 1.14 (3H, t, J = 7.5Hz); 2.84 (2H, q, J = 7.5 Hz), 2.34 (2 H, s), 4.50 (2 H, s), 4.80 (2 H, s), 5.24 (2 H, s), 5.41 (1 H, s), 6.17 (1 H, s) 6.58 (1H, br.), 7.22 (5H, m), 7.36 (5H, s).

Table 5

99

9 9

9 • 9

99 99 999 99

Compound v r CIS. Ri R2 R5 RM m.p. (° C) 1 H-NMR (d 6 -DMSO) 1-29 and ^CH2 Et QN-CH2 Bn 185- 186 1.16 (3H, t, J = 7.2Hz), 1.76 (4H, br.s), 2.48 (4H, br.s), 2.85 (2H, q, J = 7.2Hz), 3.63 (2H, s), 4.34 (2H, s), 4.81 (2H, s), 5.22 (2H, s), 5.36 (1H, br.s), 6.33 (1H, s), 6.54 (1H, br.s), 7.22 (5H, m) 7.36 (5H, s) 1-30 and ^CH2 Et r ~ \ Bn 183- 184 1.17 (3H, t, J = 7.4Hz), 2.37 (4H, m), 2.86 (2H, q, J = 7.4Hz), 3.47 (2H, s), 3.63 (4H, m), 4.32 (2H, s) ), 4.80 (2H, s), 5.22 (2H, s), 5.40 (1H, br.s), 6.27 (1H, s), 6.56 (1H, br.s), 7.12-7.22 (5H, m), 7.34 (5H, s) 1-31 and ^{CH 2} Et Mef £ 2 \ cH ₂ Bn 202- 203 1.17 (3H, t, J = 7.2Hz), 2.29 (3H, s), 2.43 (8H, brs), 2.86 (2H, q, J = 7.2Hz), 3.48 (2H, s), 4.32 ( 2H, s), 4.79 (2H, s), 5.22 (2H, s), 5.39 (1H, br.s), 6.28 (1H, s), 6.55 (1H, br.s), 7.16-7.24 (5H, m) 7.35 (5H, s) 1-32 Et J Me 274- 276 (d) 1.09 (3H, t, J = 7.2Hz), 2.84 (2H, q, J = 7.2Hz), 2.72 (3H, s), 4.40 (2H, s), 5.13 (2H, s), 7.06-7.42 (8H) , m), 7.81 (1H, br. s), 8.078.12 (2H, m). 1-33 and ^CH2 Et Me 249- 253 (d) 1.08 (3H, t, J = 7.2Hz), 2.84 (2H, q, J = 7.2Hz), 3.72 (3H, s), 4.42 (2H, s), 5.13 (2H, s), 7.10-7.41 (9H) , m), 7.80 (1H, br. s), 8.068.11 (2H, m) 1-34 and ^CH2 Et Me 215- 217 (d) 1.09 (3H, t, J = 7.5Hz), 2.84 (2H, q, J = 7.5Hz), 2.72 (3H, s), 3.83 (3H, s), 4.40 (2H, s), 5.13 (2H, s) 7.04-7.28 (8H, m), 7.40 (1H, br.s), 7.79 (1H, br.s), 7.99 (2H, d, J = 8.7Hz) 1-35 Et Me Me 187- 189 0.89 (3H, t, J = 7.2Hz), 2.34 (3H, s), 2.55 (2H, q, J = 7.2Hz), 3.72 (3H, s), 4.25 (2H, s), 4.93 (2H, s) ), 6.45 (1H, s), 6.85-7.48 (10H, m), 7.72 (1H, br. S) 1-36 cf ^H: ° c Et Me Me 201- 202 1.01 (3H, t, J = 7.4Hz), 2.34 (3H, s), 2.76 (2H, J = 7.4Hz), 3.72 (3H, s), 4.28 (2H, s), 4.94 (2H, s), 6.48 (1H, s), 6.79-7.41 (10H, m), 7.74 (1H, br.s);

Table 6 9 9 99

9 99 9 9 9 9 9 9 · · 9 9 9 9 · ·· 9 9

9 9 9 9 9 9 9 9 9 ·· ·· ·· ··· ·· ···

Compound v r CIS. Ri R2 R5 RM m.p. (° C) 1 H-NMR (d 6 -DMSO) 1-37 and ^CH2 Et σ ' Me 207- 209 (d) 1.04 (3H, t, J = 7.5Hz), 1.20-1.90 (10H, m), 2.59-2.70 (1H, m), 2.79 (2H, q, J = 7.5Hz), 3.71 (3H, s), 4.30s (2H, s), 4.97 (2H, s), 6.54 (IH, s), 7.12-7.26 (5H, m), 7.34 (IH, br.s), 7.74 (IH, br.s) 1-38 and ^CH2 Et O- Me 160- 162 (d) 1.06 (3H, t, J = 7.5Hz), 1.56-2.01 (8H, m), 2.80 (2H, q, J = 7.5Hz), 3.08-3.18 (IH, m), 3.71 (3H, s), 4.29s (2H, s), 4.98 (2H, s), 6.49 (IH, s), 7.13-7.27 (5H, m), 7.35 (IH, s), 7.74 (IH, s) 1-39 and ^CH2 Et ςσ Me 245- 247 (d) 1.09 (3H, t, J = 7.5Hz), 2.84 (2H, q, J = 7.5Hz), 3.72 (3H, s), 4.40 (2H, s), 5.12 (2H, s), 6.11 (2H, s, 7.04 (IH, s), 7.07 (IH, d), 7.13-7.28 (5H, m), 7.41 (IH, br. s), 7.56-7.61 (2H, m), 7.80 (IH, br. with) 1-40 and ^CH2 Me Et Me 194- 196 1.23 (3H, t, J = 7.4Hz), 2.35 (3H, s), 2.72 (2H, q, J = 7.4Hz), 3.71 (3H, s), 4.30 (2H, s), 4.96 (2H, s) ), 6.51 (1H, s), 7.20-7.25 (5H, m), 7.36 (1H, brs), 7.74 (1H,> rs) 1-41 and ^CH2 Me n-Pr Me 210- 211 0.89 (3H, t, J = 7.4Hz), 1.69 (2H, m, J = 7.4Hz), 2.35 (3H, s), 2.67 (2H, t, J = 7.4Hz), 3.71 (3H, s), 4.30 (2H, s), 4.96 (2H, s), 6.51 (IH, s), 7.12-7.23 (5H, m), 7.36 (IH, s), 7.75 (IH, s) 1-42 and ^CH2 Me and ^CH2 Me 204- 206 2.37 (3H, s), 3.65 (3H, s), 4.02 (2H, s), 4.28 (2H, s), 4.92 (2H, s), 6.52 (1H, s), 7.21 (5H, m), 7.26 (5H, m), 7.35 (1H, br. S), 7.74 (1H, br. S) 1-43 and ^CH2 Me MeSCHa- Me 210- 211 1.80 (3H, s), 2.36 (3H, s), 3.70 (5H, s), 4.30 (2H, s), 4.96 (2H, s), 6.58 (1H, s), 7.10-7.26 (5H, m) 7.37 (IH, br.s), 7.77 (IH, br) 1-44 and ^CH2 Me MeOCHa- Me 228- 229 (d) 2.35 (3H, s); 3.29 (3H, s); 3.71 (3H, s), 4.32 (2H, 8), 4.46 (2H, s), 5.00 (2H, s), 6.55 (1H, s), 7.13. -7.30 (5H, m), 7.39 (IH, br.), 7.77 (IH, br.)

Table 7 ·· ·· • 0,000

Compound CIS. Ri R2 R5 RM m.p. (° C) 1 H-NMR (d 6 -DMSO) 1-45 and ^CH2 Me Ph Me 251- 252 2.42 (3H, s), 3.71 (3H, s), 4.41 (2H, s), 5.14 (2H, s), 3.15 (1H, s), 7.16-8.06 (10H, m), 7.46 (1H, br) .s), 7.81 (lH, br.s) 1-46 and ^CH2 Et OCH, Φ About me Me 167- 168 1.04 (3H, t, J = 7.5Hz), 2.79 (2H, q, J = 7.5Hz), 3.68 (3H, s), 4.33 (2H, s), 4.99 (2H, s), 5.08 (2H, s) 6.66 (1H, s), 6.80 (2H, d, J = 9Hz), 6.92 (2H, d, J = 9Hz), 7.177.28 (5H, m), 7.40 (1H, s), 7.79 (1H, br.s) 1-47 and ^CH2 Et OCH. About me Me 176- 179 1.03 (3H, t, J = 7.4Hz), 2.79 (2H, q, J = 7.4Hz), 3.67 (3H, s), 3.68 (3H, s), 3.71 (3H, s), 4.34 (2H, s) ), 5.00 (2H, s), 5.09 (2H, s), 6.45-7.28 (8H, m), 7.41 (1H, br.s), 7.80 (1H, br.s) 1-48 o ^CH2 Et och ₂ Φ Me Me 191- 192 1.04 (3H, t, J = 7.2Hz), 2.21 (3H, s), 2.79 (2H, q, J = 7.2Hz), 3.67 (3H, s), 4.33 (2H, s), 4.99 (2H, s) 6.67 (2H, d, J = 9Hz), 7.11 (2H, d, J = 9Hz), 7.16-7.28 (5H, m), 7.39 (1H, br.s), 7.79 (1H, br.s) 1-49 and ^CH2 Et ch ₂ Me 188- 189 1.04 (3H, t, J = 7.0Hz), 2.60 (4H, s), 2.78 (2H, J = 7.0Hz), 3.73 (3H, s), 4.22 (2H, s), 4.66 (2H, s) 4.97 (2H, s), 6.54 (1H, s), 7.20-7.28 (5H, m), 7.40 (1H, > rs), 7.79 (1H, br.s) 1-50 and ^CH2 Et N ₃ CH ₂ - Bn 178- 179 1.03 (3H, t, J = 7.4Hz), 2.79 (2H, q, J = 7.4Hz), 4.35 (2H, s), 4.49 (2H, s), 5.07 (2H, s), 5.21 (2H, s) 6.63 (1H, s), 7.12-7.36 (10H, m), 7.41 (1H, br.s), 7.81 (1H, jr.s) 1-51 Me. Me and ^CH2 Me 199- 201 2.29 (3H, s), 2.43 (3H, s), 3.63 (3H, s), 4.04 (2H, s), 4.92 (2H, s), 6.46 (1H, s), 7.21-7.32 (6H, m) 7.71 (1H, br.s) 1-52 0 ^ Me Me Me 194- 196 2.18 (3H, s), 2.37 (3H, s), 3.79 (3H, s), 4.24 (2H, s), 4.74 (2H, s), 5.91 (1H, s), 5.94 (1H, br.s) 8.71 (1H, br.s), 6.98-7.38 (8H, si; -

Table 8 ·· ··

· * • · · > ·· ·· • 9 • · 9 99 • 99 9 9 9 9 99 ·· ·· 999 99 99

Compound Cis. R ¹ R2 R5 RM m.p. (° C) 1 H-NMR (d 6 -DMSO) 1-53 P ' Me Me Me 234- 236 2.44 (3H, s), 2.46 (3H, s), 3.80 (3H, s), 4.37 (2H, s), 4.75 (2H, s), 5.45 (1H, br s), 5.96 (1H, s) 6.67 (1H, br. S), 7.29-7.56 (9H, m) 1-54 Et Me Me 190- 192 0.96 (3H, t, J = 7.2Hz), 2.37 (3H, s), 2.60 (2H, q, J = 7.2Hz), 3.81 (3H, s), 4.25 (2H, s), 4.73 (2H, s) 5.43 (1H, br.s), 5.90 (1H, s), 6.60 (1H, br.s), 6.95-7.37 (8H, m) 1-55 and ^CH2 Me Me Et 197- 199 1.21 (3H, t, J = 7.2Hz), 2.32 (3H, s), 2.41 (2H, s), 4.18 (2H, q, J = 7.2Hz), 4.31 (2H, s), 4.93 (2H, s) 6.47 (1H, s), 7.16-7.28 (5H, m), 7.35 (1H, br.s), 7.72 (1H, br.s) 1-56 σ ^0Η2 Me Me AND 160- 161 2.41 (3H, s), 2.50 (4H, s), 2.71 (4H, m), 2.50 (4H, s), 2.50 (4H, s), 4.33 (4H, s), 4.75 (2H, s, s), 5.94 (1H, br), 5.98 (1H, s), 6.94 (1H, br), 7.15-7.24 (5H, m) 1-57 OP Et och ₂ ó H 218 -220 (d) 1.04 (3H, t, J = 7.5Hz), 2.80 (2H, q, J = 7.5Hz), 4.34 (2H, s), 4.88 (2H, s), 5.14 (2H, s), 6.66 (1H, s) ), 6.93-7.30 (10H, m), 7.41 (1H, tR), 7.80 (1H, br.s) 1-58 and ^CH2 Et sch ₂ ó H 226- 228 (d) 0.99 (3H, t, J = 7.2Hz), 2.74 (2H, q, J = 7.2Hz), 4.25 (2H, s), 4.28 (2H, s), 4.83 (2H, s), 6.60 (1H, s) 7.14-7.39 (11H, m), 7.78 (1H, broad s), 13.33 (1H, br) 1-59 cr ^CH \ Et ch ₂ «ó H 228- 231 (d) 1.05 (3H, t, J = 7.4Hz), 1.77 (4H, br.s), 2.80 (2H, q, J = 7.4Hz), 2.86 (4H, br.s), 4.09 (2H, s), 4.34 (2H, s), 4.66 (2H, s), 6.65 (1H, s), 7.16-7.28 (5H, m) 1-60 σ ^0Η2 Et CH, 0 H 167- 168 1.06 (3H, t, J = 7.2Hz), 2.35 (4H, m), 2.80 (2H, q, J = 7.2Hz), 3.53 (4H, m), 4.31 (2H, s), 4.87 (2H, s) ), 6.50 (1H, s), 7.12-7.24 (5H, m), 7.39 (1H, br.s), 7.78 (1H, bfP-

Table 9

Compound In f CIS. Ri R2 R5 RM m.p. (° C) 1 H-NMR (d 6 -DMSO) 1-61 Cr ^CH2 Et ch ₂ 0 N lile H 249- 250 (d) 1.05 (3H, t, J = 7.2Hz), 2.32 (3H, s), 2.44 (4H, br.s), 2.55 (4H, br.s), 2.79 (2H, q, J = 7.2Hz), 3.52 (2H, s), 4.31 (2H, s), 4.67 (2H, s), 6.39 (1 H, s), 7.10-7.25 (5 H, nx), 7.37 (1 H, br s), 7.79 (1 H, s), br.s) 1-62 and ^CH2 Et Φ F H 245- 248 (d) 1.09 (3H, t, J = 7.5Hz), 2.84 (2H, q, J = 7.5Hz), 4.40 (2H, s), 5.04 (2H, s), 7.05-7.43 (8H, m), 7.82 (1H) , br.s), 8.06-8.12 (2 H, m) 1-63 and ^CH2 Et Φ F H 250- 253 (d) 1.09 (3H, t, J = 7.5Hz), 2.84 (2H, q, J = 7.5Hz), 4.41 (2H, s), 5.04 (2H, s), 7.05 (1H, s), 7.13-7.43 (8H) , m), 7.82 (1 H, br s), 8.058.11 (2 H, m) 1-64 and ^CH2 Et Φ About me H 248- 250 (d) 1.09 (3H, t, J = 7.5Hz), 2.84 (2H, q, J = 7.5Hz), 3.82 (3H, s), 4.40 (2H, s), 4.99 (2H, s), 6.96 (1H, s) 7.06 (2H, d, J = 8.7Hz), 7.14-7.27 (5H, m), 7.41 (1H, br.s), 7.80 (1H, br.s), 7.96 (2H, d, J = 8.7) Hz) 1-65 Et Me H 218- 219 (d) 0.90 (3H, t, J = 7.2Hz), 2.33 (3H, s), 2.55 (2H, q, J = 7.2Hz), 4.24 (2H, s), 4.83 (2H, s), 6.39 (1H, s) 6.85-7.47 (9H, m), 7.73 (1 H, br.s) 1-66 O ° O Et Me H 188- 190 1.02 (3H, t, J = 7.0Hz), 2.34 (2H, s), 2.76 (2H, q, J = 7.0Hz), 4.28 (2H, s), 4.84 (2H, s), 6.44 (1H, s) 6.80-7.41 (10H, m), 7.75 (1 H, m-xs) 1-67 σ ^0Η2 Et σ H 272- 275 (d) 1.04 (3H, t, J = 7.5Hz), 1.20-1.90 (10H, m), 2.50-2.70 (1H, m), 2.79 (2H, q, J = 7.5Hz), 4.30 (2H, s), 4.86 (2H, s), 6.48 (1 H, s), 7.12-7.26 (5H, m), 7.36 (1 H, br.s), 7.75 (1 H, br.s), 13.24 (1 H, xr.s) 1-68 and ^CH2 Et O- H 250- 252 (d) 1.06 (3H, t, J = 7.2Hz), 1.55-2.01 (8H, m), 2.80 (2H, q, J = 7.2Hz), 3.06-3.18 (1H, m), 4.29 (2H, s), 4.87 (2H, s), 6.44 (1H, s), 7.127.27 (5H, m), 7.37 (1H, br.s), 7.75 (1H, br.s), 13; 30 (1H, br.s)

Table 10 φ · · · · · · · • • φ φ · · β

Compound CIS. Ri R2 R5 RM m.p. (° C) 1 H-NMR (d 6 -DMSO) 1-69 and ^CH2 Et ςσ H 240- 243 (d) 1.09 (3H, t, J = 7.5Hz); 2.84 (2H q, J = 7.5Hz, 4.40 (2H, s), 5.01 (2H, s), 6.11 (2H, s), 6.98 (1H, s), 7.06 (1H, d, J = 8.1Hz), 7.137. 30 (5H, m), 7.42 (1H, br.s), 7.55-7.59 (2H, m), 7.81 (IH, br.s), 13.25 (IH, br.s) 1-70 and ^CH2 Me Et H 200- 201 1.22 (3H, t, J = 7.6Hz), 2.35 (2H, s), 2.71 (2H, q, J = 7.6Hz), 4.30 (2H, s), 4.86 (2H, s), 6.46 (1H, s) 7.23 (5H, m), 7.38 (IH, br.), 7.74 (IH, br.) 1-71 σ ^0Η2 Me n-Pr H 204- 205 0.88 (3H, t, J = 7.0Hz), 1.68 (2H, m), 2.35 (3H, s), 2.66 (2H, t, J = 7.0Hz), 4.30 (2H, s), 4.85 (2H, s) ), 6.46 (1H, s), 7.22 (5H, m), 7.34 (IH, br.s), 7.74 (IH, br.s) 1-72 σ ^0Η2 Me and ^CH2 H 245- 247 (d) 2.37 (3H, s), 4.01 (2H, s), 4.28 (2H, s), 4.82 (2H, s), 6.52 (1H, s), 7.20 (5H, m), 7.25 (5H, m), 7.37 (IH, br.), 7.74 (IH, br.) 1-73 and ^CH2 Me MeSCH ₂ - H 228- 229 (d) 1.89 (3H, s); 2.36 (3H, s); 3.71 (2H, s); 4.30 (2H, s); 4.85 (2H, s); 6.54 (1H, s); 7.22 (5H, m); (IH, br.), 7.78 (IH, br.) 1-74 and ^CH2 Me MeOCH ₂ - H 197- 198 2.35 (3H, s), 3.29 (3H, s), 4.32 (2H, s), 4.44 (2H, s), 4.89 (2H, s), 6.49 (1H, s), 7.22 (5H, m), 7.41 (IH, br.), 7.78 (IH, br.), 13.28 (IH, br.) 1-75 and ^CH2 Et och ₂ F H 215- 216 1.04 (3H, t, J = 7.2Hz), 2.79 (2H, q, J = 7.2Hz), 4.32 (2H, s), 4.89 (2H, s), 5.13 (2H, s), 6.65 (1H, s) 6.97-7.25 (9H, m), 7.41 (IH, br.), 7.79 (IH, br.), 13.30 (IH, br.) 1-76 and ^CH2 Et och ₂ Φ OMe H 218- 219 1.04 (3H, t, 7.4Hz), 2.79 (2H, q, J = 7.4Hz), 3.68 (3H, s), 4.33 (2H, s), 4.88 (2H, s), 5.07 (2H, s), 6.63 (1H, s), 6.79 (2H, d, J = 9.2Hz), 6.93 (2H, d, J = 9: 2Hz), 7.15-7.23 (5H, m), 7.40 (1H, brs) 7.79 (1H, br.s), 13.2 (1H, br)

Table 11

Compound no. R ¹ R2 R6 RM m.p. (° C) 1 H-NMR (d 6 -DMSO) 1-77 and ^CH2 Et 0CH2 · About me H 204- 206 1.03 (3H, t, J = 7.4Hz), 2.78 (2H, q, J = 7.4Hz), 3.67 (3H, s), 3.71 (3H, s), 4.33 (2H, s), 4.88 (2H, s) 6.07 (2H, s), 6.49 (IH, d of d, J = 8.8Hz, J = 2.8Hz), 6.64 (IH, s), 6.67 (IH, d, J = 2.8Hz), 6.77 (IH) δ d, J = 8.8 Hz), 7.20 (5H, m), 7.40 (1 H, br.s), 7.80 (1 H, br.s) 1-78 and ^CH2 Et och ₂ Φ Me H 219- 221 1.04 (3H, t, J = 7.0Hz), 2.21 (3H, s), 2.79 (2H, q, J = 7.0Hz), 4.33 (2H, s), 4.87 (2H, s), 5.10 (2H, s) 6.63 (1H, s), 6.88 (2H, d, J = 8.8Hz), 7.04 (2H, d, J = 8.8Hz), 7.21 (5H, m), 7.41 (IH, brs), 7.79 (IH, br) 13.3 (IH, br) 1-79 and ^CH2 Et ch ₂ ° t ° H 210- 212 (d) 1.03 (3H, m), 2.39-2.46 (4H, m), 2.77 (2 H, q, J = 7.0 Hz), 4.30 (2 H, s), 4.33 (2 H, s), 4.81 (2 H, s), 6.38 (IH, s), 7.23 (5H, m), 7.38 (IH, br.), 7.76 (IH, br.) 1-80 and ^CH2 Et N ₃ CH ₂ - H 199- 200 (d) 1.03 (3H, t, J = 7.4Hz), 2.79 (2H, q, J = 7.4Hz), 4.35 (2H, s), 4.51 (2H, s), 4.87 (2H, s), 6.59 (1H, s) 7.23 (5H, m), 7.42 (IH, br.), 7.80 (IH, br.), 13.3 (IH, br.) 1-81 Me Me and ^CH2 H 232- 233 (d) 2.30 (3H, s), 2.42 (3H, s), 4.04 (2H, s), 4.81 (2H, s), 6.47 (IH, s), 7.20-7.32 (6H, m), 7.71 (IH, br. s), 13.27 (lH, br.s), 1-82 Me Me H 242- 244 (d) 2.15 (3H, s); 2.30 (3H, s); 4.22 (2H, s); 4.65 (2H, s); 6.29 (1H, s); 6.86-6.89 (IH, m); 7.18-7.52 (8H, m), 7.81 (lH, br.s), 1-83 Me Me H 271- 276 (d) 2.36 (3H, s); 2.41 (3H, s); 4.35 (2H, s); 4.79 (2H, s); 6.42 (1H, s); 7.27-7.61 (10H, m); with) 1-84 Et Me H 214- 216 (d) 0.88 (3H, t, J = 7.2Hz), 2.31 (3H, s), 2.54 (2H, q, J = 7.2Hz), 4.23 (2H, 8), 4.75 (2H, s), 6.35 (1H, s) 6.87-7.42 (9 H, m); 7.76 (IH, Jr.)

9 4

9 · 9 9 9

The compounds shown in Tables 12-17 below can be synthesized by the same methods described in the above examples. Abbreviations used in Tables 12 to 17: AA, AB, AC, AD, AE, AF, AG, AH AI, AJ, AK, AL, AM, ΑΝ, AO, AP, AQ, AR, AS, AT, AU, AV , AW, ΧΧ, AY, AZ, BA, BB, BC, BD, BE, BF, BG, BH and BI mean the following substituents:

AA AM ^0 ^ Ό- ^Μβ AY cý ~ dsO AB <O ~ ^Me AN ^< C5 ^{> oMe} AZ di3 AC Cý ~ O ” ^0Me AO ó — o BA dťuo AD d ^ ~ d ^ ^CF3 AP BB to AE d ^ -O AQ BC d- $ o AF AR d ^- - O ^f BD AG AS BE ΌΟ AH LJ-Me AT BF to AI About me AU θ-OMe BG AJ AV BH ζΧθ AK w AW d- * BI AL AX d · ^

Table 12

R ³⁸

Compound Cis. R ³⁷ R ³⁸ R39 Compound CÍs. R ³⁷ R38 R39 Compound no. R ³⁷ R38 R ³⁹ II-1 Me AA Me 11-36 Et AA Me 11-71 Ph AA Me II-2 Me AB Me 11-37 Et AB Me 11-72 Ph AB Me II-3 Me AC Me 11-38 Et AC Me 11-73 Ph AC Me II-4 Me AD Me 11-39 Et AD Me 11-74 Ph AD Me II-5 Me AE Me 11-40 Et AE Me 11-75 Ph AE Me II-6 Me AF Me 11-41 Et AF Me 11-76 Ph AF Me II-7 Me AG Me 11-42 Et AG Me 11-77 Ph AG Me II-8 Me AH Me 11-43 Et AH Me Π-78 Ph AH Me II-9 Me AI Me Π-44 Et AI Me 11-79 Ph AI Me 11-10 Me AJ Me 11-45 Et AJ Me 11-80 Ph AJ Me 11-11 Me AK Me 11-46 Et AK Me 11-81 Ph AK Me II-12 Me AL Me 11-47 Et AL Me 11-82 Ph AL Me 11-13 Me AM Me 11-48 Et AM Me 11-83 Ph AM Me II-14 Me AN Me 11-49 Et AN Me 11-84 Ph AN Me 11-15 Me AO Me 11-50 Et AO Me 11-85 Ph AO Me 11-16 Me AP Me 11-51 Et AP Me 11-86 Ph AP Me 11-17 Me AQ Me 11-52 Et AQ Me 11-87 Ph AQ Me 11-18 Me AR Me 11-53 Et AR Me 11-88 Ph AR Me 11-19 Me AS Me 11-54 Et AS Me 11-89 Ph AS Me 11-20 Me AT Me 11-55 Et AT Me 11-90 Ph AT Me 11-21 Me AU Me 11-56 Et AU Me 11-91 Ph AU Me 11-22 Me AV Me 11-57 Et AV Me 11-92 Ph AV Me 11-23 Me AW Me 11-58 Et AW Me 11-93 Ph AW Me 11-24 Me AX Me 11-59 Et AX Me 11-94 Ph AX Me 11-25 Me AY Me 11-60 Et AY Me 11-95 Ph AY Me 11-26 Me AZ Me 11-61 Et AZ Me 11-96 Ph AZ Me 11-27 Me BA Me 11-62 Et BA Me 11-97Ί Ph BA Me 11-28 Me BB Me 11-63 Et BB Me 11-98 Ph BB Me 11-29 Me BC Me 11-64 Et BC Me 11-99 Ph BC Me 11-30 Me BD Me 11-65 Et BD Me 11-100 Ph BD Me 11-31 Me BE Me 11-66 Et BE Me 11-101 Ph BE Me 11-32 Me BF Me 11-67 Et BF Me 11-102 Ph BF Me 11-33 Me BG Me 11-68 Et BG Me 11-103 Ph BG Me 11-34 Me BH Me 11-69 Et BH Me 11-104 Ph BH Me 11-35 Me BI Me 11-70 Et BI Me 11-105 Ph BI Me

Table 13 »to» »

HO 2 O 2 O ^Qv

Compound Ha. R ³⁷ R38 R39 Compound čfs. R ³⁷ R ³³ R ³⁹ Compound; no. R37 R38 R ³⁹ 11-106 Me AA Et 11-141 Et BA Et II-176 Ph BA Et 11-107 Me AB Et 11-142 Et BB Et 11-177 Ph BB Et 11-108 Me AC Et 11-143 Et BC Et 11-178 Ph BC Et 11-109 Me AD Et 11-144 Et BD Et 11-179 Ph BD Et 11-110 Me AE Et 11-145 Et BE Et 11-180 Ph BE Et 11-111 Me AF Et 11-146 Et BF Et 11-181 Ph BF Et 11-112 Me AG Et 11-147 Et BG Et 11-182 Ph BG Et 11-113 Me AH Et 11-148 Et BH Et 11-183 Ph BH Et 11-114 Me AI Et 11-149 Et BI Et 11-184 Ph BI Et 11-115 Me AJ Et 11-150 Et BJ Et 11-185 Ph BJ Et 11-116 Me AK Et 11-151 Et BK Et 11-186 Ph BK Et 11-117 Me AT, Et 11-152 Et BL Et 11-187 Ph BL Et 11-118 Me AM Et 11-153 Et BM Et 11-188 Ph BM Et 11-119 Me AN Et 11-154 Et BN Et 11-189 Ph BN Et 11-120 Me AO Et 11-155 Et BO Et 11-190 Ph BO Et 11-121 Me' AP Et 11-156 Et BP Et 11-191 Ph BP Et 11-122 Me AQ Et 11-157 Et BQ Et 11-192 Ph BQ Et 11-123 Me AR Et II-158 Et BR Et 11-193 Ph BR Et II-124 Me AR Et 11-159 Et BS Et 11-194 Ph BS Et 11-125 Me AT Et 11-160 Et BT Et 11-195 Ph BT Et II-126 Me AU Et 11-161 Et BU Et 11-196 Ph BU Et 11-127 Me AV Et 11-162 Et BV Et 11-197 Ph BV Et 11-128 Me AW Et 11-163 Et BW Et 11-198 Ph BW Et 11-129 Me AX Et 11-164 Et BX Et 11-199 Ph BX Et 11-130 Me AY Et 11-165 Et BY Et 11-200 Ph BY Et 11-131 Me AZ Et 11-166 Et BZ Et 11-201 Ph BZ Et II-132 Me BA Et 11-167 Et CA Et 11-202 Ph CA Et 11-133 Me BB Et 11-168 Et CB Et 11-203 Ph CB Et 11-134 Me BC Et 11-169 Et CC Et 11-204 Ph CC Et II-135 Me BD Et 11-170 Et CD Et 11-205 Ph CD Et 11-136 Me BE Et 11-171 Et CE Et 11-206 Ph CE Et 11-137 Me BF Et 11-172 Et CF Et 11-207 Ph CF Et 11-138 Me BG Et Π-173 Et CG Et II-208 Ph CG Et 11-139 Me BH Et 11-174 Et CH Et 11-209 Ph CH Et 11-140 Me BI Et 11-175 Et Cl Et 11-210 Ph Cl Et

*

Table 14

R ³⁸

Compound Nr. R ³⁷ R ³³ R ³⁹ Compound no. R ³⁷ R ³⁸ R ³⁹ Compound > R ³⁷ R38 R ³⁹ 11-211 Me AA Me 11-246 Et AA Me 11-281 Ph AA Me 11-212 Me AB Me 11-247 Et AB Me 11-282 Ph AB Me 11-213 Me AC Me 11-248 Et AC Me 11-283 Ph AC Me 11-214 Me AD Me 11-249 Et AD Me 11-284 Ph AD Me 11-215 Me AR Me 11-250 Et AE Me 11-285 Ph AE Me 11-216 Me AF Me 11-251 Et AF Me 11-286 Ph AF Me II-217 Me AG Me 11-252 Et AG Me 11-287 Ph AG Me 11-218 Me AH Me 11-253 Et AH Me 11-288 Ph AH Me 11-219 Me AI Me 11-254 Et AI Me 11-289 Ph AI Me 11-220 Me AJ Me 11-255 Et AJ Me 11-290 Ph AJ Me 11-221 Me AK Me 11-256 Et AK Me 11-291 Ph AK Me 11-222 Me AT, Me 11-257 Et AL Me 11-292 Ph AL Me 11-223 Me AM Me 11-258 Et AM Me 11-293 Ph AM Me 11-224 Me AN Me 11-259 Et AN Me 11-294 Ph AN Me 11-225 Me AO Me 11-260 Et AO Me II-295 Ph AO Me 11-226 Me AP Me 11-261 Et AP Me 11-296 Ph AP Me 11-227 Me Aq Me 11-262 Et AQ Me 11-297 Ph AQ Me 11-228 Me AR Me 11-263 Et AR Me 11-298 Ph AR Me 11-229 Me AS Me 11-264 Et AS Me 11-299 Ph AS Me 11-230 Me AT Me 11-265 Et AT Me 11-300 Ph AT Me 11-231 Me AU Me 11-266 Et AU Me 11-301 Ph AU Me 11-232 Me AV Me 11-267 Et AV Me 11-302 Ph AV Me 11-233 Me AW Me 11-268 Et AW Me 11-303 Ph AW Me 11-234 Me AX Me 11-269 Et AX Me 11-304 Ph AX Me 11-235 Me AY Me 11-270 Et AY Me 11-305 Ph AY Me 11-236 Me A Z Me 11-271 Et AZ Me 11-306 Ph AZ Me 11-237 Me BA Me 11-272 Et BA Me 11-307 Ph BA Me II-238 Me BB Me 11-273 Et BB Me 11-308 Ph BB Me 11-239 Me BC Me 11-274 Et BC Me 11-309 Ph BC Me 11-240 Me BD Me 11-275 Et BD Me 11-310 Ph BD Me 11-241 Me BE Me 11-276 Et BE Me 11-311 Ph BE Me 11-242 Me BF Me 11-277 Et BF Me 11-312 Ph BF Me 11-243 Me BG Me 11-278 Et BG Me 11-313 Ph BG Me 11-244 Me BH Me 11-279 Et BH Me 11-314 Ph BH Me 11-245 Me BI Me 11-280 Et BI Me 11-315 Ph BI Me

Table 15 9 9 11 9 9 1 9 9 1

19 11 111 9 9 9 nh ₂ ho ₂ c ^ o

1Γ o rr \ n38 _R 38

Compound Nr. R ³⁷ R ³⁸ R39 Compound Art. R ³⁷ R ³⁸ R ³⁹ Compound Nr. R ³⁷ R ³⁸ R ³⁹ 11-316 Me AA Et 11-351 Et AA Et 11-386 Ph AA Et 11-317 Me AB Et 11-352 Et AB Et 11-387 Ph AB Et 11-318 Me AC Et 11-353 Et AC Et 11-388 Ph AC Et 11-319 Me AD Et 11-354 Et AD Et 11-389 Ph AD Et 11-320 Me AE Et 11-355 Et AE Et 11-390 Ph AE Et 11-321 Me AF Et 11-356 Et AF Et 11-391 Ph AF Et 11-322 Me AG Et 11-357 Et AG Et 11-392 Ph AG Et 11-323 Me AH Et 11-358 Et AH Et 11-393 Ph AH Et 11-324 Me AI Et 11-359 Et AI Et 11-394 Ph AI Et 11-325 Me AJ Et 11-360 Et AJ Et 11-395 Ph AJ Et 11-326 Me AK Et 11-361 Et AK Et 11-396 Ph AK Et 11-327 Me AL Et 11-362 Et AL Et 11-397 Ph AL Et 11-328 Me AM Et 11-363 Et AM Et 11-398 Ph AM Et 11-329 Me AN Et 11-364 Et AN Et 11-399 Ph AN Et 11-330 Me AO Et 11-365 Et AO Et 11-400 Ph AO Et 11-331 Me ' AP Et 11-366 Et AP Et 11-401 Ph AP Et 11-332 Me AQ Et 11-367 Et AQ Et 11-402 Ph AQ Et 11-333 Me AR Et 11-368 Et AR Et 11-403 Ph AR Et 11-334 Me AS Et 11-369 Et AS Et 11-404 Ph AS Et 11-335 Me AT Et 11-370 Et AT Et 11-405 Ph AT Et 11-336 Me AU Et 11-371 Et AU Et 11-406 Ph AU Et 11-337 Me AV Et 11-372 Et AV Et 11-407 Ph AV Et 11-338 Me AW Et 11-373 Et AW Et 11-408 Ph AW Et 11-339 Me AX Et 11-374 Et AX Et 11-409 Ph AX Et 11-340 Me AY Et 11-375 Et AY Et 11-410 Ph AY Et 11-341 Me AZ Et 11-376 Et AZ Et 11-411 Ph AZ Et II - 342 Me BA Et Π-377 Et BA Et 11-412 Ph BA Et 11-343 Me BB Et 11-378 Et BB Et 11-413 Ph BB Et 11-344 Me BC Et 11-379 Et BC Et 11-414 Ph BC Et 11-345 Me BD Et 11-380 Et BD Et 11-415 Ph BD Et 11-346 Me BE Et 11-381 Et BE Et 11-416 Ph BE Et 11-347 Me BF Et 11-382 Et BF Et 11-417 Ph BF Et 11-348 Me BG Et 11-383 Et BG Et 11-418 Ph BG Et 11-349 Me BH Et 11-384 Et BH Et 11-419 Ph BH Et 11-350 Me BI Et 11-385 Et BI Et 11-420 Ph BI Et

Table 16

4 44 44 <44 44 4 nhnh ₂

_r 38

Compound Cis. R37 R38 R39 Compound Nr. R37 R38 R ³⁹ Compound no. R37 R38 R39 11-421 Me AA Me 11-456 Et AA Me 11-491 Ph AA Me 11-422 Me AB Me II-457 Et AB Me 11-492 Ph AB Me 11-423 Me AC Me 11-458 Et AC Me 11-493 Ph AC Me 11-424 Me AD Me 11-459 Et AD Me 11-494 Ph AD Me 11-425 Me AE Me 11-460 Et AE Me 11-495 Ph AE Me 11-426 Me AF Me 11-461 Et AF Me 11-496 Ph AF Me 11-427 Me AG Me Π-462 Et AG Me 11-497 Ph AG Me 11-428 Me AH Me 11-463 Et AH Me 11-498 Ph AH Me 11-429 Me AI Me 11-464 Et AI Me 11-499 Ph AI Me 11-430 Me AJ Me 11-465 Et AJ Me 11-500 Ph AJ Me 11-431 Me AK Me 11-466 Et AK Me 11-501 Ph AK Me 11-432 Me AT, Me 11-467 Et AL Me 11-502 Ph AL Me 11-433 Me AM Me II-468 Et AM Me 11-503 Ph AM Me 11-434 Me AN Me 11-469 Et AN Me 11-504 Ph AN Me 11-435 Me AO Me 11-470 Et AO Me 11-505 Ph AO Me 11-436 Me AP Me 11-471 Et AP Me 11-506 Ph AP Me 11-437 Me AQ Me 11-472 Et AQ Me 11-507 Ph AQ Me 11-438 Me AR Me 11-473 Et AR Me 11-508 Ph AR Me 11-439 Me AS Me 11-474 Et AS Me 11-509 Ph AS Me 11-440 Me AT Me 11-475 Et AT Me 11-510 Ph AT Me 11-441 Me AU Me 11-476 Et AU Me 11-511 Ph AU Me 11-442 Me AV Me 11-477 Et AV Me 11-512 Ph AV Me 11-443 Me AW Me 11-478 Et AW Me 11-513 Ph AW Me 11-444 Me AX Me 11-479 Et AX Me 11-514 Ph AX Me 11-445 Me AY Me 11-480 Et AY Me 11-515 Ph AY Me 11-446 Me A7, Me 11-481 Et AZ Me 11-516 Ph AZ Me 11-447 Me BA Me II-482 Et BA Me 11-517 Ph BA Me 11-448 Me BB Me 11-483 Et BB Me 11-518 Ph BB Me 11-449 Me BC Me 11-484 Et BC Me 11-519 Ph BC Me 11-450 Me BD Me 11-485 Et BD Me II-520 Ph BD Me 11-451 Me BE Me 11-486 Et BE Me 11-521 Ph BE Me 11-452 Me BF Me 11-487 Et BF Me 11-522 Ph BF Me 11-453 Me BG Me 11-488 Et BG Me 11-523 Ph BG Me 11-454 Me BH Me 11-489 Et BH Me 11-524 Ph BH Me 11-455 Me BI Me 11-490 Et BI Me 11-525 Ph BI Me

and

Table 17 nhnh ₂

_r 38 fe · · fe ·· · fefe fefefe · · · · ··· • fefefe fefe fefe · fefe fefe · fe fefe · · fefe · fefe · fefe fefe fefe ·

Compound Nr. R ³⁷ R ³⁸ R ³⁹ Compound Nr. R ³⁷ R ³⁸ R39 Compound Nr. R ³⁷ R ³⁸ R ³⁹ 11-526 Me AA Et 11-561 Et AA Et 11-596 Ph AA Et 11-527 Me AB Et 11-562 Et AB Et 11-597 Ph AB Et 11-528 Me AC Et 11-563 Et AC Et 11-598 Ph AC Et 11-529 Me AD Et 11-564 Et AD Et 11-599 Ph AD Et II-53O Me AE Et 11-565 Et AE Et 11-600 Ph AE Et 11-531 Me AF Et 11-566 Et AF Et 11-601 Ph AF Et 11-532 Me AG Et 11-567 Et AG Et 11-602 Ph AG Et 11-533 Me AH Et 11-568 Et AH Et 11-603 Ph AH Et 11-534 Me AI Et 11-569 Et AI Et 11-604 Ph AI Et 11-535 Me AJ Et 11-570 Et AJ Et 11-605 Ph AJ Et 11-536 Me AK Et 11-571 Et AK Et 11-606 Ph AK Et 11-537 Me AL Et 11-572 Et AL Et 11-607 Ph AL Et 11-538 Me AM Et 11-573 Et AM Et 11-608 Ph AM Et II - 539 Me AN Et 11-574 Et AN Et 11-609 Pb AN Et 11-540 Me AO Et 11-575 Et AO Et 11-610 Ph AO Et 11-541 Me AP Et 11-576 Et AP Et 11-611 Ph AP Et 11-542 Me AQ Et 11-577 Et AQ Et 11-612 Ph AQ Et 11-543 Me AR Et 11-578 Et AR Et 11-613 Ph AR Et 11-544 Me AS Et 11-579 Et AS Et 11-614 Ph AS Et 11-545 Me AT Et 11-580 Et AT Et 11-615 Ph AT Et 11-546 Me AU Et 11-581 Et AU Et 11-616 Ph AU Et 11-547 Me AV Et 11-582 Et AV Et 11-617 Ph AV Et 11-548 Me AW Et 11-583 Et AW Et 11-618 Ph AW Et 11-549 Me AX Et 11-584 Et AX Et 11-619 Ph AX Et 11-550 Me AY Et 11-585 Et AY Et 11-620 Ph AY Et 11-551 Me AZ Et 11-586 Et AZ Et 11-621 Ph AZ Et 11-552 Me BA Et 11-587 Et BA Et 11-622 Ph BA Et 11-553 Me BB Et 11-588 Et BB Et 11-623 Ph BB Et 11-554 Me BC Et 11-589 Et BC Et 11-624 Ph BC Et 11-555 Me BD Et 11-590 Et BD Et 11-625 Ph BD Et 11-556 Me BE Et 11-591 Et BE Et 11-626 Ph BE Et 11-557 Me BF Et 11-592 Et BF Et 11-627 Ph BF Et 11-558 Me BG Et 11-593 Et BG Et 11-628 Ph BG Et 11-559 Me BH Et 11-594 Et BH Et 11-629 Ph BH Et 11-560 Me BI Et Π-595 • Et BI Et 11-630 Ph BI Et

Example of tests performed: Human secretory phospholipase A ₂ inhibition assay

Analytical test

In order to identify and evaluate the recombinant human secretory phospholipase A ₂ inhibitor, the following chromogenic assays were performed. Large amounts of different samples were tested using a 96-well microtiter plate. A general explanation of such assays is given in Analysis of Human Synovial Fluid Phospholipase A ₂ on Short Chain Phosphatidylcholine-Mixed Micelles: Development of a Spectrophotometric Assay Suitable for a Micortiterplate Reader (Anylytical Biochemistry, 204, 190-197, 1992, by Laure). J. Reynolds, Lori L. Hughes and Edward A. Dennis: data from this material are incorporated herein by reference.

Reagents:

Reaction buffer

CaCl ₂ .6H ₂ O (2.19 g / l)

KCl (7.455 g / l)

Bovine Serum Albumin (Fatty Acid Free) (1 g / L) (Sigma A-7030)

Tris-HCl (3.94 g / l) pH 7.5 (NaOH set)

Enzyme buffer

0.05 M-AcONa

0.2 M-NaCl pH 4.5 (adjusted with acetic acid)

The enzyme solution of mg sPLA ₂ was dissolved in 1 ml of enzyme buffer and maintained at 4 ° C. During the test, 5 μΐ of the solution of 1995 μΐ of reaction buffer was diluted.

DTNB

198 mg of 5,5'-dithiobis-2-benzoic acid (manufactured by Wako Pure Chemicals) was dissolved in 100 ml H ₂ O.

pH 7.5 (NaOH set)

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 of Triton-X 100 was dissolved in the reaction buffer.

Enzymatic reaction: for 1 microtiter plate

1) 0.106 ml of the substrate solution was placed in a centrifuge tube and the solvent was removed with a stream of nitrogen. 0.54 ml of Triton-X 100 was added and the mixture was stirred to dissolve the mixture and then sonicated in a sonication bath. 17.8 ml of reaction buffer and 0.46 ml of DNTB were added to the resulting product, 0.18 ml of this mixture was metered into the wells of the microtiter plate.

2) 10 μί of test compound (or blank solution) was added to the pre-set plates.

3) Incubation lasted 15 min. at 40 ° C.

4) To start the reaction (40 ° C, 30 min), 20 μί of pre-diluted enzyme solution (sPLA ₂ ) (50 ng / well) was dosed.

5) Absorbance changes were measured for 30 min with a sensor, and inhibition activity (OD: 405 nm) was calculated from the data obtained.

6) IC ₅₀ was determined by plotting log concentration, relative to inhibitory values, in the range of 10% to 90% inhibition.

The results of inhibition of human secretory phospholipase A _{2 are} shown in Table 18 below.

and

Table 18

Compound IC 50 Compound ICeo Compound IC 50 no. (μΜ) no. (μΜ) no. (μΜ) 1-1 0.248 1-29 1.517 1-57 0.007 1-2 0.009 1-30 4.521 1-58 0.009 1-3 0.013 1-31 15.630 1-59 1.078 1-4 0.150 1-32 0.239 1-60 0.365 1-5 0.011 1-33 0.072 1-61 2.610 1-6 0.238 1-34 0.058 1-62 0.012 1-7 0.223 1-35 0.111 1-63 0.006 1-8 0.184 1-36 0.102 1-64 0.007 1-9 0.165 1-37 0.212 1-65 0.007 1-10 0.296 1-38 0.227 1-66 0.006 1-11 0.067 1-39 0.079 1-67 0.016 1-12 0.745 1-40 0.099 1-68 0.025 1-13 0.238 1-41 0.064 1-69 0.008 1-14 0.883 1-42 0.026 1-70 0.009 1-15 0.097 1-43 0.154 1-71 0.008 1-16 0.012 1-44 0.315 1-72 0.009 . 1-17 0.007 1-45 0.030 1-73 0.019 1-18 0.010 1-46 0.268 1-74 0.015 1-19 0.010 1-47 0.618 1-75 0.009 1-20 0.019 1-48 0.211 1-76 0.006 1-21 0.006 1-49 7.811 1-77 0.010 1-22 0.022 1-50 0.526 1-78 0.005 1-23 0.007 1-51 25.589 1-79 0.464 1-24 0.021 1-52 0.093 1-80 0.013 1-25 0.006 1-53 3.741 1-81 8.186 1-26 0.177 1-54 0.148 1-82 0.093 1-27 0.126 1-55 0.056 1-83 0.083 1-28 1-56 0.052 1-84 0.008

Examples of preparation regulations

It should be noted that the following examples of formulations 1 to 8 are merely illustrative and do not limit the scope of the invention. The term "active ingredient" refers to compounds represented by formula I, prodrugs thereof, pharmaceutically acceptable salts thereof, or solvates thereof.

Example of Regulation 1

Hard gelatin capsules were prepared using the following ingredients:

Dose (mg / capsule)

Active ingredient 250 Starch, dried 200 Magnesium stearate 10 Total 460 mg Example of Regulation Tablets were prepared using the following ingredients: Dose (mg / capsule) Active ingredient 250 Microcrystalline cellulose 400 Silica, drift 10 Stearic acid 5 Total 665 mg The ingredients were mixed and compressed into tablets, each weighing Example of Regulation An aerosol solution was prepared using the following components: Mass Active ingredient 0.25 Ethanol 25.75 Propelent 22 (chlorodifluoromethane) 74.00

Total

100.00 • 9

9 9 9 9 9 9 9 9 9 9

9 9 9 9 9

99 99 999 99

The active ingredient was mixed with ethanol and added to a portion of propellant 22 cooled to -30 ° C and transferred to a filling machine. The required amount was filled into a stainless steel container and diluted with the remainder of the propellant. A valve was then attached to the container.

Example of regulation 4

Tablets, each containing 60 mg of active ingredient, were prepared as follows:

Active ingredient 60 mg

Starch 45 mg

Microcrystalline cellulose 35 mg

Polyvinylpyrrolidone (as a 10% aqueous solution) 4 mg

Carboxymethyl starch sodium 4.5 mg

Magnesium stearate 0.5 mg

Talc 1 mg

Total 150 mg

The active ingredient, starch, cellulose has been screened in U.S. Pat. sieve no. 45 and mixed thoroughly. The aqueous solution containing polyvinylpyrrolidone was mixed with the resulting powder, and the mixture was then sieved through U.S. Pat. sieve no. 14. The granules so prepared were dried at 50 ° C and passed through U.S. Pat. sieve nr.18. Sodium starch sodium, magnesium stearate and talc, previously sieved on U.S. Pat. sieve no. 60, were then added to the granules which, after mixing, were compressed in a tabletting machine to give tablets each weighing 150 mg.

Example of Regulation

Capsules, each containing 80 mg of active ingredient, were prepared as follows:

Active ingredient 80 mg

Starch 59 mg

Microcrystalline cellulose 59 mg

Magnesium stearate 2 mg

Total 200 mg

The active ingredient, cellulose, starch and magnesium stearate were mixed, sieved through U.S. Pat. sieve no. 45 and filled into hard gelatin capsules, each at 200 mg.

Example of regulation 6

Suppositories, each containing 225 mg of active ingredient, were prepared as follows:

Active Ingredients 225 mg

Saturated fatty acid glycerides 2000 mg

Total 2225 mg

The active ingredient was sieved through U.S. Pat. 60 and suspended in saturated fatty acid glycerides previously melted at the minimum temperature required. This mixture was then poured into a suppository formed to a nominal 2 g capacity and allowed to cool slowly.

Example of Regulation 7

A suspension, each containing 50 mg of active ingredient per 5 ml dose, was prepared as follows:

Active ingredient 50 mg Carboxymethylcellulose sodium 50 mg Syrup 1.25 ml Benzoic acid solution 0,10 ml Scent q.v. Color q.v. Purified water to total 5 ml

The active ingredient was sieved through U.S. Pat. sieve no. 45 and mixed with carboxymethylcellulose sodium and syrup to form a smooth paste. The benzoic acid solution, fragrance and color were diluted with a portion of water and added to the paste with stirring. Finally, enough water was added to reach the desired volume.

Example of Regulation 8

The prescription for intravenous administration was prepared as follows:

Active ingredient 100 mg

Isotonic saline solution 1000 ml

Solutions with the above ingredients are generally administered intravenously at a rate of 1 ml per minute.

·· • · ·

Example of regulation 9

A lyophilized preparation mixture (in 1 ampoule) was prepared as follows:

Active Ingredient 127 mg

Trisodium citrate 36 mg

Mannitol 180 mg

The above substances were dissolved in water for injection so that the concentration of the active ingredient was 10 mg / g. The primary freezing stage lasted 3 hours at -40 ° C, the heating stage 10 hours at-10 ° C, and the repeated freezing stage lasted 3 hours at -40 ° C. This was followed by a primary drying stage of 60 h at 0 ° C, 4 Pa. This procedure resulted in a lyophilized preparation.

Industrial applicability

Compounds of the invention having sPLA ₂ inhibitory activity manifested by inhibition of sPLA ₂ induced fatty acid (such as arachidonic acid) release. These compounds are effective in the treatment of septic shock and the like.

Claims (22)

PATENT CLAIMS 1. A compound represented by the general formula I ^{R 2} 0) wherein R ¹ is a group selected from a) a C6 -C20 alkyl, C6 -C20 alkenyl, C6 -C20 alkynyl, carbocyclic and heterocyclic groups, b) the groups represented under a) each independently substituted with at least one group selected from non-interfering substituents, and c) a - (R) - R ⁶ group wherein L ¹ is a divalent linking group of 1 to 18 atoms selected from hydrogen, nitrogen, carbon, oxygen and sulfur atoms, and R ⁶ is a group selected from groups a) and b), R ² is a hydrogen atom or a group containing 1 to 4 non-hydrogen atoms, R ³ is - (L ² ) - (acidic group) wherein L ² is an acidic linking group having a length of 1 to 5, R ⁴ and R ⁵ are independently selected from hydrogen, non-interfering substituents, heterocyclic groups, and heterocyclic groups substituted with non-interfering substituents, and R ^A is a group represented by the general formula: wherein L ⁷ is a divalent linking group, obtained from a single bond or a divalent group such as - CH ₂ -, -O-, -S-, -NH-, or -CO-, R ²⁷ and R ²⁸ are independently a hydrogen atom, C1 to C3 alkyl or halogen; X and Y are independently an oxygen atom or an atom 9 9 9 9 9 9 Or a sulfur atom; and Z is -NH ₂ or -NHNH _2> prodrugs thereof, pharmaceutically acceptable salts thereof, or solvates thereof. 2. Compound represented by the general formula Π: where R ⁷ is - (CH ₂ ) m R ¹² , where m is an integer from 1 to 6, and R ¹² is d) a group represented by the general formula: wherein a, c, e, n, q and t are independently integers from 0 to 2, R ¹³ and R ¹⁴ are independently selected from halogen, C 1 to C 10 alkyl, C 1 to C 10 alkoxy, C 1 to C 10 alkylthio, aryl, heteroaryl and Cl to ClO haloalkyl, and is an oxygen atom or a sulfur atom, L ⁵ is - (CH ₂₎ v-, -C = C-, -C≡C-, -O-, or -S-, v is an integer from 0 to 2, β is -CH ₂ - or- (CH ₂ ) ₂ -, γ is an oxygen or sulfur atom, b is an integer from 0 to 3, d is an integer from 0 to 4, f, p and w are independently integers 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 e) member d) is substituted with at least one substituent selected from the group consisting of Cl C1 to C6 alkyl, C1 to C6 alkyloxy, C1 to C6 haloalkyloxy, C1 to C6 haloalkyl, aryl and halogen, R ⁸ is C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 3 -C 4 cycloalkyl, C 3 -C 4 cycloalkenyl, C 1 -C 2 haloalkyl, C 1 -C 3 alkyloxy or C 1 -C 3 alkylthio; R ⁹ is (L ³ ) -R ¹⁵ where L ³ is represented by the general formula: R ¹⁶ M-C-1 Wherein M is -CH 2 -, -O-, -N (R ²⁴ ) -, or -S-, R ¹⁶ and R ¹⁷ are independently hydrogen, C 1 to C 10 alkyl, aryl, aralkyl, alkyloxy, haloalkyl , carboxy, or halogen, and R ²⁴ is a hydrogen atom or C 1 -C 6 alkyl, and R ¹⁵ is represented by the general formula: wherein R ¹⁸ is a hydrogen atom, a metal or C 1 to C 10 alkyl, R ¹⁹ is independently a hydrogen atom, or a C 1 to C 10 alkyl, and is an integer from 1 to 8, R ¹⁰ and R ¹¹ are independently a hydrogen atom, or a non-interfering substituent, such as Cl 1 to Cl 2 C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C7 to 02 aralkyl, C7 to 02 alkaryl, C3 to C8 cycloalkyl, C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl, phenyl, tolyl, xylyl, diphenylyl, C1 to C8 alkyloxy , C2 to C8 alkenyloxy, C2 to C8 alkynyloxy, C2 to 02 alkyloxyalkyl, C2 to 02 alkyloxyalkyloxy, C2 to 02 alkylcarbonyl, C2 to 02 alkylcarbonylamino, C2 to 02 alkyloxyamino, C2 to 02 alkyloxyaminocarbonyl, C1 to 02 alkylamino, C1 to C6 alkylthio , C 2 -C 02 alkylthiocarbonyl, C 1 -C 8 alkylsulfinyl, C 1 -C 8 alkylsulfonyl, C 2 -C 8 haloalkyloxy, C 1 -C 8 haloalkylsulfonyl, C 2 -C 8 haloalkyl, C 1 -C 8 hydroxyalkyl, -C (O) O (C 1 -C 8 alkyl), - ( CH ₂ ) _Z -O- (C 2 -C 8 alkyl), benzyloxy, aiyloxy, aryloxy C 1 -C 8 alkyl, aaa aaa aa aa aa aa a Arylthio, arylthio C1 to C8 alkyl, cyano C1 to C8 alkyl, - (CONHSO ₂ R ²⁵ ), -CHO, amino, amidino, halogen, carbamyl, carboxyl, carbaloxy, - (CH ₂ ) _Z- CO ₂ H, cyano, cyano oguanidinyl, guanidino, hydrazido, hydrazino, hydrazide, hydroxyl, hydroxyamino, iodo, nitro, phosphono, -SO ₃ H, thioacetal, thiocarbonyl, or carbonyl, R ²⁵ is C 1 -C 6 alkyl or aryl, z is an integer from 1 to 8 , and R ^B is a group represented by the general formula: Or Z wherein Z is as defined above, prodrugs thereof, pharmaceutically acceptable salts thereof, or solvates thereof. The compound, prodrugs thereof, pharmaceutically acceptable salts thereof, or solvates thereof according to claim 1 or 2, wherein said R ¹ and R ⁷ are represented by the general formula: where R ¹³ , R ¹⁴ , b, d, f, g, p, r, u, w, α, β and γ are as defined above, L ⁶ is a bond, -CH ₂ -, -C = C- , -C =C-, -O- or -S-. The compound, prodrugs thereof, pharmaceutically acceptable salts thereof, or solvates thereof, according to any one of claims 1 to 3, wherein R ² and R ⁸ are C 1 -C 3 alkyl or C 3 -C 4 cycloalkyl. The compound, prodrugs prepared therefrom, or pharmaceutically acceptable salts thereof, or solvates thereof, according to any one of claims 1 to 4, wherein L ² and L ³ are -O-CH ₂ -. 6. Compound represented by the general formula ΠΙ: where R ²⁰ is a group represented by the general formula: wherein L ⁶ is a bond, -CH 2 -, -C =C-, -OC-, -O-, or -S-; R ¹³ and R ¹⁴ are independently selected from functional groups such as halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, aryl, heteroaryl, and C1 to C10 haloalkyl, b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, aw are independently integers 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, and is oxygen atom or sulfur atom, β -CH2- or - (CH ₂ ) f and γ oxygen atom or sulfur atom R ²¹ is C 1 -C 3 alkyl or C 3 -C 4 cycloalkyl, R ²³ is hydrogen, C 1 -C 6 alkyl, C 7 -C 02 aralkyl, C 1 -C 6 alkyloxy, C 1 -C 6 alkylthio, C 1 -C 6 hydroxyalkyl, C 2 -C 6 haloalkyloxy, halogen, carboxy, C 1 -C 6 alkyloxycarbonyl, aryloxy, aryloxy C1-C8 alkyl, arylthio, arylthio C1-C8 alkyl, cyano C1-C8 alkyl, carbocyclic, or heterocyclic, and R ^B is a group represented by the general formula: In ¹ o- ¹ O or O wherein Z is -NH ₂ or -NHNH ₂ and k is an integer from 1 to 3, prodrugs thereof, or pharmaceutically acceptable salts thereof, or solvates thereof. 7. Compound represented by the general formula IV: where R ²⁰ is a group represented by the general formula: wherein L ⁶ is a bond, -CH ₂ -, -C =C-, -CO, -O-, or -S-; R ¹³ and R ¹⁴ are independently selected from functional groups such as halogen, C 1 to C 10 alkyl, C 1 to C 10 alkyloxy, C 1 to C 10 alkylthio, aryl, heteroaryl, and C 1 to C 10 haloalkyl; b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, w are independently integers from 0 to 5, g is an integer from 0 to 2, r is an integer from 0 to 7, is an integer from 0 to 4, and is an oxygen or sulfur atom, β -dl ₂ - or - (CH ₂ ) 27a γ an oxygen or sulfur atom, R ²¹ is C 1 -C 3 alkyl or C 3 -C 4 cycloalkyl, R ²³ is hydrogen, C 1 -C 6 alkyl, C 7 -C 02 aralkyl, C 1 -C 6 alkyloxy, C 1 -C 6 alkylthio, C 1 -C 6 hydroxyalkyl, C 2 -C 6 haloalkyloxy, halogen, carboxy, C 1 -C 6 alkyloxycarbonyl, aryloxy, aryloxy C 1 -C 6 C8 alkyl, arylthio, arylthio C1 to C8 alkyl, cyano C1 to C8 alkyl, carbocyclic group, or heterocyclic group; and R ^b is a group represented by the general formula: ArO or O wherein Z is -NH ₂ or -NHNH ₂ when an integer is from 1 to 3, prodrugs thereof, pharmaceutically acceptable salts thereof, or solvates thereof. A compound, prodrugs thereof, pharmaceutically acceptable salts thereof, or solvates thereof, according to claim 6, wherein L ⁴ is -O-CH ₂ -. A compound, prodrugs thereof, pharmaceutically acceptable salts thereof, or solvates thereof, according to any one of claims 1 to 8, wherein R ^A and R ^B are -COCONH ₂ -. A compound, prodrugs thereof, pharmaceutically acceptable salts thereof, or solvates thereof, according to any one of claims 1 to 8, wherein R ^A and R ^B are CH ₂ CONH ₂ -. A compound, prodrugs thereof, pharmaceutically acceptable salts thereof, or solvates thereof, according to any one of claims 1 to 8, wherein R ^A and R ^B are CH ₂ CONHNH _{2 A} prodrug according to any one of the claims, which is in the form of an ester. The compound pyrrolo [1,2-b] pyridazine, selected from the group consisting of: methyl (5-aminooxalyl-7-benzyl-6-ethylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, (5-aminooxalyl) -7-benzyl-6-ethylpyrrolo [1,2-b] pyridazin-4-yloxy) acetic acid, (5-aminooxalyl-7-benzyl-6-ethylpyrrolo [1,2-b] pyridazin-4-yloxy) sodium acetate, methyl (5-aminooxalyl-7-benzyl-6-methylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, (5-aminooxalyl-7-benzyl-6-ethylpyrrolo [1,2-b] pyridazin-4-yloxy) acetic acid, methyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, ethyl (5-aminooxalyl-7-benzyl-) 2,6-Dimethyl-pyrrolo [1,2-b] pyridazin-4-yloxy) acetate, 2- (morpholin-4-yl) ethyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, * ^WW -AA (5-Amino-oxalyl-7-benzyl-2,6-dimethyl-pyrrolo [1,2-b] -pyridine) pyridazin-4-yloxy) acetic acid, (5-ammooxalyl-7-benzyl-2,6-dimethylpyrrolo [1,2-b] pyridazin-4-yloxy) sodium acetate, methyl (5-aminooxalyl-7-benzyl- 6-Methyl-2-phenylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo [1,2-b] pyridazin-4-yloxy) ) acetic acid, methyl (5-aminooxalyl-7-benzyl-6-ethyl-2-phenylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, (5-aminooxalyl-7-benzyl-6-ethyl-2) -phenylpyrrolo [1,2-b] pyridazin-4-yloxy) acetic acid, methyl (5-aminooxalyl-6-ethyl-7- (2-fluorobenzyl) -2-phenylpyrrolo [1,2-b] pyridazine-4- yloxy) acetate, [5-Aminooxalyl-6-ethyl-7- (2-fluorobenzyl) -2-phenylpyirolo [1,2-b] pyridazin-4-yloxy) acetic acid, methyl [5-ammooxalyl-7-benzyl- 6-ethyl-2- (4-fluorophenyl) pyrrolo [1,2-b] pyridazine- 4-yloxy) acetate, [5-aminooxalyl-7-benzyl-6-ethyl-2- (4-fluorophenyl) pyrrolo [1,2-b] pyridazin-4-yloxy) acetic acid, methyl [5-aminooxalyl-7 -benzyl-6-ethyl-2-phenoxymethylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo [1,2-b] pyridazine) 4-yloxy) acetic acid, methyl [5-aminooxalyl-7-benzyl-6-ethyl-2- (4-methoxyphenyl) pyrrolo [1,2-b] pyridazin-4-yloxy) acetate, [5-anunooxalyl-7 -benzyl-6-ethyl-2- (methoxyphenyl) pyrido [1,2-b] pyridazin-4-yloxy) acetic acid, methyl [5-aminooxalyl-6-ethyl-2-methyl-7- (2-phenylbenzyl)] pyrrolo [1,2-b] pyridazin-4-yloxy) acetate, [5-aminooxalyl-6-ethyl-2-methyl-7- (2-phenylbenzyl) pyrrolo [1,2-b] pyridazin-4-yloxy) acetic acid, methyl [5-aminooxalyl-6-ethyl-2-methyl-7- (3-phenoxybenzyl) pyrrolo [1,2-b] pyridazin-4-yloxy) acetate, • [5-aminooxalyl-6-ethyl] -2-methyl-7- (3-phenoxybenzyl) pyrrolo [1,2-b] pyridazin-4-loxy) acetic acid, methyl (5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo [1,2] (b) pyridazin-4-yloxy) acetate, (5-amino oxalyl-7-benzyl-6-methyl-2-propylpynolo [1,2-b] pyridazin-4-yloxy) acetic acid, methyl (5-aminooxalyl-2,7-dibenzyl-6-methylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, (5-aminooxalyl-2,7-dibenzyl-6-methylpynolo [1,2-b] pyridazin-4-yloxy) acetic acid, methyl [5-aminooxalyl-2,6-dimethyl -7- [2- (4-fluorophenyl) benzyl] pyrrolo [1,2-b] pyridazin-4-yloxy) acetate and [5-aminooxalyl-2,6-dimethyl-7- [2 '(4-fluorophenyl)] benzyl] pyrrolo [1,2-b] pyridazin-4-yloxy] acetic acid, and prodrugs thereof, pharmaceutically acceptable salts thereof, their parent acids, or solvates thereof. A pyrrolo [1,2-b] pyridazine compound selected from the group consisting of: methyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, ethyl (5-aminooxalyl-7-benzyl-2,6-dimethylpynolo [1,2-] (b) pyridazin-4-yloxy) acetate, 2- (morpholin-4-yl) ethyl (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, (5-aminooxalyl-7-benzyl-2), Sodium 6-dimethylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, (5-aminooxalyl-7-benzyl-2,6-dimethylpyrrolo [1,2-b] pyridazin-4-yloxy) acetic acid, methyl (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, ethyl (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo [1] 2-b] pyridazin-4-yloxy) acetate 2- (Morpholin-4-yl) ethyl (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, (5-aminooxalyl-7-benzyl- Sodium 6-methyl-2-phenylpyrrolo [1,2-b] pyridazin-4-yloxy), (5-aminooxalyl-7-benzyl-6-methyl-2-phenylpyrrolo [1,2-b] pyridazin-4-) yloxy) acetic acid, ·· 00 »0 0 ·· 00 0 0 • 0 0 0 0 methyl (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, ethyl (5-aminooxaly 1-7 -benzyl) -6-ethyl-2-phenoxymethylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, 2- (morpholin-4-yl) ethyl (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, (5-aminooxalyl-7-benzyl- Sodium 6-ethyl-2-phenoxymethylpyrrolo [1,2-b] pyridazin-4-yloxy), (5-aminooxalyl-7-benzyl-6-ethyl-2-phenoxymethylpyrrolo [1,2-b] pyridazine-4-) yloxy) acetic acid, methyl (5-aminooxalyl-6-ethyl-2-methyl-7- (2-phenylbenzyl) pyrrolo [1,2-b] pyridazin-4-yloxy) acetate, ethyl (5-aminooxalyl-6- ethyl 2-methyl-7- (2-phenylbenzyl) pyrrolo [1,2-b] pyridazin-4-yloxy) acetate, 2-morpholin-4-yl) ethyl (5-aminooxalyl-6-ethyl-2-methyl-7- (2-phenylbenzyl) pyrrolo [1,2-b] pyridazin-4-yloxy) acetate, (5-aminooxalyl- 6-ethyl-2-methyl-7- (2-phenylbenzyl) pyrrolo [1,2-b] pyridazin-4-yloxy) sodium acetate, (5-aminooxalyl-6-ethyl-2-methyl-7- (2- phenylbenzyl) pyrrolo [1,2-b] pyridazin-4-yloxy) acetic acid, methyl (5-ammooxalyl-7-benzyl-6-methyl-2-propylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate ethyl (5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo [1,2-b] pyridazin-4-yloxy) acetate, 2-Morpholin-4-yl) ethyl 5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo [1,2-b] pyridain-4-yloxy) acetate, (5-aminooxalyl-7-benzyl-6-methyl) Sodium 2-propylpynlo [1,2-b] pyridazin-4-yloxy), and (5-aminooxalyl-7-benzyl-6-methyl-2-propylpyrrolo [1,2-b] pyridazin-4-yloxy) acetic acid, and prodrugs thereof, their pharmaceutically acceptable salts, their parent acids or solvates thereof. Pharmaceutical compositions comprising a compound according to any one of claims 1 to 14. as an active ingredient. 16. A pharmaceutical composition according to claim 15, characterized in that said component inhibits sPLA _second 17. The pharmaceutical composition of claim 15, wherein said composition is for treating or preventing inflammatory diseases. A method of inhibiting sPLA ₂ mediated fatty acid release, comprising reacting sPLA ₂ with a therapeutically effective amount of a pyrrolo [1,2-b] pyridazine compound according to claim 1. A method of treating a mammal, including a human, to alleviate the pathological effects of inflammatory diseases, comprising administering the compound pyrrolo [1,2-b] pyridazine, according to claim 1, in a pharmaceutically effective amount. A compound according to claim 1, or a pharmaceutical composition comprising an effective amount of a pyrrolo [1,2-b] pyridazine compound according to claim 1, for the treatment of inflammatory diseases. A compound according to claim 1 or a pharmaceutical composition comprising an effective amount of a pyrrolo [1,2-b] pyridazine compound, for use as a sPLA ₂ mediated fatty acid release inhibitor. 22. Pyrrolo [1,2-b] pyridazine, an sPLA ₂ inhibitor as described above substantially with reference to any of the examples. 23. Compound represented by the general formula (XII): R ⁸ i NH ₂ wherein R ⁷ is - (CH ₂ ) m R ¹² , wherein m is an integer from 1 to 6, and R ¹² is d) a group represented by the general formula: · «·· ·· 84 where a, c, e, η, q, and t are independently integer The number from 0 to 2, R ¹³ and R ¹⁴ are independently selected from functional groups such as halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, aryl, heteroaryl, and C1 to C10 haloalkyl, and is an oxygen atom or atom atom, L ⁵ is - (CH ₂ ) v -, -C =C-, -C =C-. -O-, or -S-, v is an integer from 0 to 2, β is -CH ₂ - or .. (CH ₂ ) ₂ -, y is an oxygen or sulfur atom, b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, aw are independently integers 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) member d) substituted with at least one substituent selected from the group consisting of C1 to C6 alkyl, C1 to C6 alkyloxy, C1 to C6 haloalkyloxy, C1 to C6 haloalkyl, aryl and halogen, and R ⁸ is C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 3 -C 4 cycloalkyl, C 3 -C 4 cycloalkenyl, C 1 -C 2 haloalkyl, C 1 -C 3 alkyloxy, or C 1 -C 3 alkylthio.