CZ20002039A3 - Novel pyridazinone compounds, process of their preparation and pharmaceutical preparation containing thereof - Google Patents

Abstract

Pyrrol, thienyl, furano-apyrazole [3,4-d] pyridazinones of the formula (I), a method for their preparation, pharmaceutical compositions therefor comprising, a method of preparing pharmaceutical compositions and a method of treatment that includes their use.

Description

Technical field

The present invention relates to certain pyrrole-, thienyl-, furano- and pyrazolo- [3,4-d] pyridazinones, to a process for their preparation, to pharmaceutical compositions containing them and to a process for the preparation of pharmaceutical compositions and to a method of treatment which includes its uses .

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula I

D-R (I) wherein B is CH or N (N), S (S) or O (O); D is carbon (C) or nitrogen (N); E is CR ³ or N (N); if D is carbon then B is sulfur or oxygen and E is CR ³ , and if D is nitrogen then either B is CH and E is CH or N, or B is nitrogen and E is CR ³ ;

R ¹ is a group NR'R where R 'is a hydrogen atom or an alkyl group having 4 to 6 carbon atoms, R is an alkyl group having 4 to 6 carbon atoms, or R' and R together with the nitrogen atom to which they are attached form three or R is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkyloxyalkyl group having 1 to 3 carbon atoms in each alkyl moiety having a C 1-6 alkyloxyalkyl group; .

carbon atoms, phenyl atoms of from 1 to 7 atoms and are bonded to ac5 and unlixu and in the alkoxy o-alkenyl group containing from 3 to 6 and the cycloalkyl group containing carbon, cycloalkylmethyl group containing from 3 to carbon, or a carbon-containing cycloalkenyl group, each of which may be optionally one or more halogen atoms;

is a methyl or alkyl group having 2 to c carbon atoms optionally dried with an alkoxy group having 1 to 6 carbon atoms other than in the 1-position;

is hydrogen or XR or X-Ar '; X is -O-, S (O) n, SO _; N (R ') or C (= O) N (R 6; n is 0, 1 or 2;

is optionally substituted alkyl or alkenyl, or when X is SO ₂ N (R 0) or

C (= 0'N ⁽⁼ R), ^R and R ⁵ form together with the nitrogen to which they are attached, an optionally substituted 3

7-membered heterocyclic ring;

xs e ocorioaoe suesticucvana: o ovnav

R 'is hydrogen, alkyl of 1-6 carbon atoms, or is attached to the group _R, j and k mentioned above;

R ₄ is CHR ⁷ Ar ² or, if D is carbon, C (O) Ar ² or CR ⁷ (OH) Ar ² ;

Ar ² is an aryl or heteroaryl group which may be optionally substituted;

• · <

They are acsaphthenyl, indanyl or succinyl, each of which may be optionally substituted with <5.713. ; 5.

is hydrogen or an alkyl group containing 1 a: carbon, or pharmaceutically acceptable atoms thereof;

In the present application, unless otherwise specified, the alkyl, alkenyl or alkyl substituent in the alkoxy, alkoxycarbonyl, (di) alkylamino, acylamino, alkylsulfamido, alkylamidosuccin, or (di) alkyisulfanyl group may be linear or branched. The alkyl substituents in the dzalkylamino group or the dialkylsulfamoyl group may be Q in the radical or different.

R ~ is a group NR'R '', wherein R 'is a group having from 1 to 6 carbon atoms containing from 1 to 4 atoms per cm of something and a size of about 1 to 6 carbon atoms, preferably from 1 to 6 carbon atoms, preferably from 1 to 6 carbon atoms; C 1-4 alkyl, or R 'and R''together with the nitrogen atom to which they are attached form a 3 to 7-membered saturated heterocyclic ring, or R' is an alkyl group of 1 to 6 carbon atoms, preferably (C 3 -C 5) alkyl (e.g., propyl, isopropyl, butyl or up to 5 carbon atoms (e.g., methoxy, ethoxy, propoxy, isopropyloxy, butoxy, pentoxy, or hexoxy), alkyloxyalkyl containing in each of the alkyl, alkoxy groups) C 1 -C 3 (e.g. -CH ₂ -OCH ₃ ), cycloalkyloxyalkyl of 3 to 6 carbon atoms in the cycloalkyl moiety parts of 1 to 3 carbon atoms (e.g. -CH ₂ -O-cyclopropyl, -CH ₂ -O-cyclobutyl or -CH ₂ -O-cyclopentyl), alke C 3-6 carbon atoms (e.g., a propenyl or butenyl group), a phenyl group, a cycloalkyl group containing:

Cycloalkyl, for example, C7 to C7, preferably C3 to C8, cyclobutyl, some cyclic (e.g., cyclopropylmethyl, cyclobutylmethyl or cyclopentyl (ethyl) to cycloalker), or cycloalkylene to 3 to 7, e.g. 5 carbon atoms (for example cyclopropyl, cyclobutenyl or cyclopencenyl), each of which may be optionally substituted with one or more, preferably one to four, for example one or two, halogen atoms (for example fluorine or chlorine). If groups contain a double bond,

U i in Π! cx C C uhlíku carbon of the group R * cannot in the presence of chi

R 6 is a methyl or alkyl group having 2 to 6, preferably 2 to 4, carbon atoms or an alkoxy group having 1 to S, preferably 1 carbon (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy or isobutoxy) other than in 1-position. Thus, when an alkoxy substituent is present, it is attached to a carbon atom other than that directly bonded to the ring nitrogen atom.

R ^J is hydrogen or XR ³ or X-Arh

X jes _SO: N ^(R) skunina buy on - 0 -, S (0)., 'KDI is 0, 1 or 2 or a group or a group C (= O) NRh Preferably, X is -O-, S (O) -, wherein n is 0, 1 or 2, or C (= O) NR 0.

Group P? It is optionally substituted alkyl or alkenyl group, or when X is SO ₂ N ^(R), or C (= O) N (R ^S), may form the R 'and ^R together with the nitrogen atom to which they are attached, optionally substituted 3 to 7-membered heterocyclic ring.

• *

When R ⁵ occříoadě skuoir.a substituted alkyl, the alkyl group preferably contains 2 i (Ί especially 2 to 6, carbon unííku or until the ^j optionally suostizuovana alkenyl groups, the alkenyl group preferably contains 3 carbon Acom. Skuoiuy R 'ne zv, make currency enamin in heaven

CVC3 cyclic: Ecenyl;

r) are substituted with one or more, for example one, two, three or four substituents independently selected from the group consisting of amide, amino, carboxyl, cyano, hydroxyl, alkoxy of 1 to 6 carbon atoms (preferably alkoxy of up to 4) an alkylcarbonyl group containing up to 6 carbon atoms (preferably an aixylhartonyl group and an alkoxycarbonyl group having 1 to 6 carbon atoms in the alkyl portion (preferably an alkoxycarbonyl group) (C 1 -C 4 alkyl), C 3 -C 7 alkyl (preferably C 5 -C 8 alkyl), (di) alkylamino (preferably (di) methylamino or (di) ethylamino) group, acylamino having 2 to 8 carbon atoms (preferably acylamino (C 2 -C 4), alkyl sulfenamido (C 1 -C 6) (preferably C 1 -C 4 alkylsulfonamido), tetrahydrofuranyl, dioxolane, imidazolyl, haloalkylsulfonamide (C 1 -C 6) and tetrazolyl group. Particularly preferred substituent groups are hydroxyl, carboxyl, methoxy, methylthio, methylcarbonyl, cyclopentyl, -NHC (O) CH ₃ , tetrahydrofuran, dioxolanyl, and imidazyclyl;

; h will t nvrova sxccma something oy:

.ova. Fennel or whelkworm, the kuoins may be biased with the externally-prone nerve of the .ixa, to:

g is four, substituents independently selected from the group consisting of carboxy, C 2 -C 6 hydroxyl, preferably C 2 -C 4, acylamino, alkylamido, alkyl, or alkyl; C1 -C6 alkylsulfamoyl, preferably 1 to 4 carbon atoms in the alkyl moiety, preferably 1 to 4 carbon atoms, and (di) alkylsulfamoyl having 1 to S, preferably 1 to 4, carbon atoms. The Ar 'group is preferably a pyridyl group, zeimene 2-pyridyl.

Fb is CFbAr 'or Ary heaven if: cm C (O) Ar or CR _? (OH) Ar ² . Pb is preferably CHP1Ar ', C (O) Ar' or CR (OH) Ar ² .

R ⁷ is C 1 -C 4 alkyl (for example methyl or ethyl) or most preferably hydrogen.

Ar is an aryl sxup and something neteroary is optionally substituted.

skuGina, who:

Examples of suitable aryl and heteroaryl groups are phenyl, naphthyl, pyridyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, thienyl, benzothienyl, furanyl, furanyl. , thiazolyl, benzothiazolyl scidolyl, indolizinyl, py:

A UY-OY group, an imazazolyl group, an imidazolyl group, a benzimicazolyl group, an imicazylpyrene, a censitriazolyl bite, an acylamino group, optionally substituted with one to four, preferably one to four, preferably one to four, more preferably one to four, in particular , substituent ¹ (independently selected from 1 to 4), S atoms, preferably 1 to 2 to 6, and t, t, i, n, i. venom), trifluoromethyl, trifluoromethoxy, amino, cyano, carboxyl, nitro, alkyl of 1 to 6, preferably 1 to 1, carbon atoms, alkoxy of 1 to 6, preferably 1 to 1, carbon atoms, ( di) C 1 -C 5 alkylamino, C 1 -C 5 acylamino, preferably C 2 -C 4 alkylsulfonamido;

CONH- (alkyl) containing from 1 to 6 carbon atoms in the alkyl moiety, preferably from 1 to 4 carbon atoms, and an alkoxycarbonyl group containing from 1 to 6 carbon atoms in the alkoxy moiety, preferably from 1 to 4 atoms in sxuoirx

Ar is preferably phenyl, naphthyl, pyridyl, quinolinyl or imidazopyridyl, which may be optionally substituted with one to three substituents independently selected from the group consisting of halogen atoms, cyano, trifluoromethyl, alkoxy of 1 to 6 carbon atoms (especially methoxy).

Ar ¹ is an acenaphthenyl, indanyl, or fluorenyl group, each of which may be optionally substituted.

Ά dryness a, for example one to four su: y may be the same as for Ar ² .

Excludes the compounds of the invention

- (2-mesyl • ad - o

1-methyl-1H-pyrrolo [3,4-a] pyridine;

2,6-dihydro-2- (2-mechoxyechyl) -4- (2-methylpropyl) -S- (1-naphthyimechyl) -1H-pyrrolo [3,4-d] pyridazin-1-one,

2,6-dihydro-7 - [(3-hydroxypropyl) thio] -2-methyl-4- (2-methyl) -6- (1-naphthylmethyl) -1H-pyrrolo [3,4-d] pyridazine -1-on

4 - {[2,6-dihydro-2-methyl-4- (2-methylpropyl) -methyl] -1-oxo-1H-pyrrolo [3,4-d] pyridazin-3-one, o-dihydro-7 - [ (3-Hydroxypropyl propyl) -δ- (1-naphthylmethyl)

H-pyrrolo [3,4-d] pyridazin-1-one

2,6-dihydro-7 - [(3-hydroxypropyl) sulfonyl] -2-methyl-4- (2-methylpropyl) -6- (1-naphthylmethyl) -1H-pyrrolo [3,4-d] pyridazine- 1-on

2- [1-hydroxy-1- (1-naphthyl) methyl] -5-methyl-7- (2-methylpropyl) thieno [2,3-a] pyridazin-4 (ΞΗ) -one,

5-Methyl-7- (2-methylpropyl) -2- (pyridazine-4 (5H) -cyclohexyl) thieno [2,3-d]

3 - [(3-hydroxypropyl) quio] -5-methyl-7- (2-methylpropyl) -2 (1-naphthylmethyl) thieno [2,3-d] pyridazin-4 (5H) -one,

5-Methyl-7- (2-methylpropyl) -2- (1-naphthylcarbonyl) thieno [2,3-d] pyridazin-4 (5H) -one, • ···· · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

3 - [(3-hydroxyprooyl) sultinyl] -5-methyl-7- (2-methylprop 2- (1-naphthylmethyl) thieno [2,3-d] pyridazin-4 (5H) -one,

- {[4,5-ddrdr;

Hyl-7- (2-methylpropyl) -2- (i-nartyl-phthyl-tyl) -3- (2-pyrrolo [2,3-d] oyride):

rij -on

3-Hydroxyvoroulfonyl] -4-mechyl-7- (2-methylprooyl-2- (1-naphthylmethyl) thieno [2,3-d] oyridene-4 (5H) -one,

2- [1-hydroxy-1-phenylmethyl] -5-methyl-7- (2-methylpropyl) thieno [2,3-d] pyridazin-4 (5H) -one,

-mecnyc - / - 'z-mecnylorooyi, -4 (ΞΗ) -one, [2,3

- [(3-hydroxypropyl) thio] -5-mechyl-7- (2-methylpropyl) -2-phenylmethylchieno [2,3-d] pyridazin-4 (5H) -one,

3 - [(3-hydroxypropyl) sulfonyl] -5-methyl-7- (2-methylpropyl) -2-phenylmethylthieno [2,3-d] pyridazin-4 (5H) -one, δ-dihydroc-2 - methyl-4-2-methylpropyl) - δ-phenylmethyl 1H-pyrrolo [3,4-d] pyridazin-1-one,

2,6-dihydro-2-methyl-4- (2-methylpropyl) -6-phenylmethyl-7- (2-pyridinylthio) -1H-pyrrolo [3,4-d] pyridazin-1-one,

2, o-dihydro-7 - [(3-hydroxypropyl) thio] -2-methyl-4- (2-methylpropyl) -6-phenylmethyl-1H-pyrrolo [3,4-d] pyridazin-i-one, methyl) -1H-pyrrolo [3,4-d] pyridazin-1-one

2,6-dihydro-2-methyl-4- (2-methylpropyl) -6- (3,4,5-trimethoxyphenyl)

2,6-dihydro-2-yl-6- (1-nonylmethyl) -1H-oyrrolo [3,4-d] oyridazin-1-one,

2,6-dihydro-2-methyl-4- (2-methylpropyl) -6H-pyrrolo [3,4-d] pyrrolidine; not from hy 1 - 2, 5 - o; nycr ^ v x -methyllnyx amino r / ridinvi) limit:

'z -meznviorctzy

6- (3,5-difluorophenyl) mechyl-2,6-dihydro-2-methyl-4- (2-methylpropyl) -1H-pyrrolo [3,4-d] pyridazin-1-one,

6- (2-chloro-6-fluorophenyl) methyl-2,6-dihydro-2-methyl-4- (2-methylpropyl) -1H-pyrrolo [3,4-d] pyridazin-1-one,

- (3-chloro-2-fluorophenyl) methyl-2,6-dihydro-2-methyl-4- (2-methylprooyl) -1H-pyrrolo [3,4-d] pyridazin-1-ene,

2,6-dihydro-2-methyl-4- (2-methylpropyl) -6- (2-quinclinylmethyl) -1H-pyrrolo [3,4-d] pyridazin-1-one,

2,5-dihydro-2-methyl-4- (2-methylpropyl) -6- (2-trifluoromethylphenyl) methyl-1H-pyrrolo [3,4-d] pyridazin-1-one;

2,6-dihydro-6- (2-imidazo [1,2- a] pyridinyl) methyl-2-methyl-4- (2-mesylpropyl) -1H-pyrrolo [3,4-d] pyridazin-1-one,

2,6-dihydro-4 '- [3- (1-1H-imidazolyl) propyl] -2-methyl-4- (2-methylpropyl) -1-oxo-6-phenylmethyl-1H-pyrrolo [3,4- d] pyridazin-1-one-5-carboxamide,

2,5-dihydro-5-methyl-7- (2-methylpropyl) -2- (1-naphthylmethyl) 4H-pyrazolo [3,4-d] pyridazin-4-one,

2,6-dihydro-6-methyl-4- (2-methylpropyl) -2- (1-naphthylmethyl) -7H-pyrazolo [3,4-d] pyridazin-7-one; Iihydro-3- [3-hydroxypropyl) thio] -5-methyl-7- (2-Methylpropyl) -2- (1-naphthylmethyl) -4H-pyrazolo (3,4-d] pyridine [1-hydroxy-1-cyl} methyl] -5-meth (2-methyl)

5-Ethyl-7- (2-methylorocyl) -2-

- yl> _y - | [2,3-d] xy-1- (3-cyano-phenyl) -methyl] -5-methyl-7-1,2-methynyl-ethyl, 3-d] -pyrido:

- (3-cyanophenyl) methyl methyl-7- (2-methylpropyl) furo [2,3] pyridazine-4 (bH) cn,

2- (2-Trifluoromethylphenyl) methyl]

7- (2-MeOH-thieno [2,3-d] pyridazin-4 (5H) -one, 2- [1-hydroxy-1-yndin-3-yl) methyl] -5-methyl-7 - ( 2-methylpropyl) thieno [2,3-d] pyridazin-4 (5H) -one,

5-methyl-7- (2-methylpropyl) -2- (3-pyridinylmethyl) thieno [2,3-d] pyridazine-4 (5H) -cn,

2- (2-chloro-6-fluorophenyl) methyl-5-methyl-7- (2-methylpropyl) thieno [2,3-d] pyridazine-4 (5H) -cn,

2 - [(1-hydroxy-1-quinolin-3-yl) methyl] -5-methyl-7- (2-methylpropyl) thieno [2,3-d] pyridin-1-one, 5-methyl-7 hydrochloride - (2-methylpropyl) -2- (3-quinolinylimethyl) thieno [2,3-d] pyridazin-4 (5H) -one,

2- (3-chlorophenyl) methyl-3- (2-hydroxyethoxy) -7- (methoxymethyl) 5-methylthieno [2,3-d] pyridazin-4 (5H) -one,

- [(3-chlorophenyl) methyl] -7-cyclohexyl-3- (2-hydroxyethoxy) 5-methylthieno [2,3-d] pyridazin-4 (5H) -one, β (3-chlorophenyl) methyl] -3 - (2-Hydroxyethoxy) -5-methyl-7-phenylthieno [2,3-d] pyridazin-4 (5H) -one,

-7-cyclopentyl-3- (2-hydroxyethoxy) -4-methylthieno [2,3-d] pyridazin-4 (5H) -one,

7-Ocyiopropylmethyl-3-methoxy-5-methyl-2 - [(3-trifluoromethylphenyl 1-methyl) thienc [2,3-d] pyridazin-4 (5H) -one,

7-Cyclopropyimethyl-3-methyl-3- [2- (methylthio) ethoxy] 2 - [(3-trifluoromethylphenyl) methyl] thio [2,3-d] pyr 4 (5H i - he,

7-cyclopropyimethyl-3- (2-methoxyethoxy) -b-methyl-2 - [(3-trifluoromethylphenyl) methyl] thieno [2,3-d] pyridazin-4 (5H) -one,

3-Cyclopentylmethoxy-7-cyclopropylmethyl-5-methyl-2 - [(3-trifluoromethylphenyl) methyl] thieno [2,3-d] pyridazin-4 (5H) -cn, cyclopropyimethyl-5-methyl-3- (tetrarry) 2 - [(3-Trifluoromethylphenyl) methyl] -4- (5H) -one, irofuran-2-ylmethoxy) pheno [2,3-d] pyridazine-7-cyclopropyimethyl-3- (3-hydroxy-3-methyl-) butoxy} -5-methyl-2 - [(3-trifluoromethylphenyl) methyl] thieno [2,3-d] pyridazine-4- {3- [7-cyclopropyimethyl-4-oxo-2 - [(3-trifluoromethylphenyl)] methyl] -4,5-dihydrothieno [2,3-d] pyridazin-3-yl] oxypropyl acetamide,

7-cyclopropyimethyl-3 - ((1,3) dioxolan-4-ylmethoxy) -5-methyl-2 - [(3-trifluoromethylphenyl) methyl] thieno [2,3-d] pyridazin-4 (5H) -one, and

7-Cyclopropylmethyl-5-methyl-3- (4-oxopentyl) oxy-2 - [(3-trifluoromethylphenyl) methyl] thieno [2,3-d] pyridazin-4 (5H) -one.

13 • · · · · · · · • · · · · · ···· • · · ··········· ·· · · · · · · · · · · · • · · · · · · · ·

The present invention further provides Process for preparing compounds of formula I as defined above which of < ahrnuje: (a) when X is a group S (C) n and n ie 1 or 2, oxidation of

h r i ' and '5 -R ⁴

R ‘ i.I wherein R 1 is SR ⁵ or a group S-Ar ¹ and 3, D, R ¹ , R ² , R ⁵ R ⁵ and Ar * are as defined above, in the yarn appropriate quantity a suitable oxidizing agent (e.g. Example 3-chloroperoxybenzene acid or potassium persulfate commercially available under brand 'OXCNE') and a suitable orcar eice rozocušzědla (naoří-

kíao Gicaiormetanu) per pocmir.ek ccíjomixun ocore znamyon; (b) when X is a group S (O) _n and _n is 0, the reaction of the corresponding compound of formula (I) in which Ξ is CR * and R 1 is a hydrogen atom with a compound of formula III • n 3 nr? or 3 / -r -r o- '

λ - o - o - re V ι 11! where both groups represent above or a defined group R '; a group Ar *, or with both formula (IV), L - S - R ³ (IV) wherein L is a leaving group such as j ie arylsulfinase group and the radical R ³ is as defined above, vp presence of iithiumdiiscpro-

pylamide (LDA) at -78 ° C to misznoszi (20 ° C); or

9 ·

Ί -1 (c) when X is a group of formula V> O-N (R), reacting compound o;

above, with a compound of formula VI

HNEfR ³ (VI) is the groups R ° and R ° as defined above: sodium hydrogen carbonate flow; or laorixiao in \ GCC

Thank you> J_ GUCcu-. * * / CCc

R

R (knows);

3 in which D, R, R ² and R ⁴ as defined above, with compounds of formula (VI

Linear all in the presence of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 1-hydroxybenzotriazole hydrate in the presence of a solvent such as dimethyl formamide; or (e) when D is carbon, E is CR ³ , R ³ is hydrogen and R 8 is CH (OH) Ar ² , reacting a compound of formula VII in propyl or

Ar CHO (IX) and Ar ^{2 are} defined above, at a temperature of from -73 ° C to a temperature of H 2 µm. 1 1 SC

-1 (20 ° C) when D is a carbon atom, Ξ is a hydrogen group, and P 1 is a group CHR Ar ', a reduction of the formula I in which R ⁴ is a group prepared as described in step in the presence of triethylsilane and triphenyl ^; , wherein the atom corresponding to the compound CR ⁷ (OH) Ar ² (for example (e) above), Luoroacetic acid, (g) when D j <

; ora strike skuo:

CR 1, R ^{J is} m and R is C (O) Ar ² , ox of formula I, wherein R ⁴ is in step (e) above, e.g. or the corresponding compounds of the group CH (OH) Ar ² prepared by the presence of manganiscan dearly) if D is a carbon atom, Ξ is a CR 'group, R ₃ is a hydrogen atom, R. is CR ⁷ (OK) Ar ² and R ⁷ alkyl (C 1 -C 4) group, reacting a corresponding compound of formula (I) in which R ⁴ is the C (O) Ar ^{2 group} prepared in step (g) above with an alkylating agent containing C 1 -C 4 alkyl such as Grignard reagent such as

_C -C -aikylmagnesiumhalcgenid in the presence rozpoušzěd), for example tetrahydrofuran; or (i) if C is a carbon atom, ir / function:

and CR ³ , R ₃ is a hydrogen atom is an Ar ³ group, reacting a compound of formula VI: with 1-indanone, 2-indanone, 9-fluorucrenone or i.ercne in the presence of lithium diisopropylamide and, optionally, cerium chloride at t. (20 ° C) followed by rysysian and Zrifluoroacetic acid; or is (nitrogen), wherein R ₃ is CR ³ , R ₃ is a hydrogen atom of 0-0hC, the reaction of a compound of the general formula

N- R (x) wherein R 'is an alkyl group (for example, a C 1 -C 6 alkyl group as a methyl group) and R ‘and R‘ are as defined above, with a compound of formula (XI),

R ² NH-NK, (XI) in each Rh is as defined above, in the presence of a solvent such as ethanol at boiling; or (k) when D is nitrogen, 3 is CH, and Ξ is nitrogen, reacting a compound of formula (XII);

In which R ' ³ containing up to and including children is nevertheless above, in terms of

a1kv1cvá skuoina (for example alkyl sk ' udí na 6 carbon atoms j as methyl ) and R 'a R? j sou with compound v target (XI) defined .cu above deserts like ethanol za boiling;

when D is nitrogen, 3 and R ³ is hydrogen, the reaction is nitrogen, Ξ is a group of compounds in the general formula R

wherein R ^{11 is an} alkyl group (for example, an alkyl group having 1 to 6 carbon atoms such as methyl) and R ¹ and R ^{4 are} as defined above, with a compound of formula (XI) as defined above in the presence of a solvent such as ethanol at boiling;

(m) when X is -O reacting a compound of formula

(XIIIA)

wherein 3, D, R ', 3e and R ⁴ are as defined above, of formula (XII13)

R ^s (XII13) mici sxucm;

ookuo D is an un R ³ -e group -OR ⁵ O, 3 is a sulfur or oxygen atom, and R ⁴ is a CROAr moiety, a reaction of formula XIIIC ec

in which 3 'is a sulfur atom or an oxygen atom and R', as defined above, with a compound of formula XI as defined above in the presence of a solvent such as ethanol at boiling;

and optionally subsequently converting the compound of formula (I) to another compound of formula I and / or forming a pharmaceutically acceptable salt or solvate of the compound of formula I.

The reaction of R 'is a hydrogen atom, an amide at amide temperature in a water / hydrogen sulfide solvent.

A compound of formula V can easily be prepared by formula I in which Ξ is CR ³ and with sulfur dioxide and 1-lithium diisopropyl -73 ° C, followed by reaction with N-chlorosuccinines (for example, in a two-phase system such as acid / dichloromethane).

Compounds of formula VII can be readily prepared by reacting a compound of formula I in which E is CR ³ and R ³ is hydrogen with carbon dioxide in the presence of lithium diisopropylamide.

• · * * * * * *

Compounds of formula (X) may be reacted with sicucene

R '

-Cl

Ol ± 7 wherein R 1 and R ⁹ are as defined above;

CN

N-R ⁴ (XVI) is a suitable and suitable solvent, such as acetonitrile.

Compounds of Formula X wherein R ⁹ is CH-Ar can alter natively ^from ořioravit a compound of formula (XVI)

in which they are of formula XVII,

R ⁹ as defined above, by reaction with a compound

Ar ² CH ₂ L (XVII) ♦ - ♦ »ve ve ve ve ve ve ve ve ve ve ve ve ve wherein L is a leaving group such as a halogen atom and Ar ² is as defined above. The reaction may be carried out in the presence of a base in a suitable solvent, for example sodium hydride / dimethylformamide (NaH / DMF), optionally in the presence of potassium iodide

XVI XVI can be prepared by reacting a compound of formula XVIII

R (XVIII) in which R ¹ and R ^{9 are} as defined above, with tosylmethyl isocyanate. The reaction is preferably carried out in the presence of a base such as sodium hybrid in a solvent mixture such as ether / dimethyl sulfoxide.

The preparation of the compounds of formulas XII and XIII is described by the following reaction scheme, in which R = R = R s R-y THF denotes tetrahydrofuran, DMF denotes dimethylformamide, Hal denotes a halogen atom, and T denotes an intermediate:

Trimethylsilyldiazomethane

N ‘

IL

N

CCjH

L.

SiMe.

THF

R ’

Known in Literature (XIV)

σ ² )

CS ₃ CO ₃ / DMF / R * Hal

O.

R

(XII)

Compounds of Formula XIIIA. can be prepared according to the following scheme:

him

MoCPH =

suifonyloxaziričin

Ar

O

// ° //

Ad

Compounds of formula XIIIC can be prepared according to the following reaction scheme:

FENHNH 3 / EtOH / var

B • * II

I · · · · · · · ·

• 9

Compounds of formula III, IV, VI, VIII, IX, XI, XIII 3, XIV, XV and XVIII are either commercially available, known from the literature, or can be readily prepared by known techniques.

Compounds of the oP o-o-o- ⁵ _; p

A compound of the formula with a hydroxyl-substituted alkyl group, such as - (CH 2 OH), can be converted to compounds of formula I wherein v is an acid-substituted alkyl group such as - (CH 3 -CN) reaction of methanesulfonylchicride (MsCl) triethylamine and dichloromethane and subsequent reaction. The compound of formula (I) may be further converted to other compounds of formula (±), wherein R ⁵ is a tetrazolyl substituted alkyl group by reaction with srimetnylolazide (Me, SnNj in toluene from <

and gave the kenver:

where '' Alk 'ha1coenu:

THERE ARE GOING ON IN THE FOLLOWING REXATION SENSE, ZLIO-CL1 ^ S 5.x.

Ha.

O 22750117

• • • •

It will be appreciated by those skilled in the art that in the present invention it may be desirable to protect certain functional groups, such as hydroxyl or amino groups, with protecting groups. Therefore, the last step of preparing the compounds of Formula I may include removing the fake or several protecting groups.

5. CGSurSncill · ΟΠΓλΓ.Ι Cl Objective of UUZKCfiiCf. SKZOIZ 16 written in "Protective Grups in Organic Chemistry", published

J.W.p. McOmie, Plenum Pres ne a

XUtS: ieza)

The above compounds of formula (I) may be converted into pharmaceutically acceptable salts or solvates, preferably acid addition salts such as hydrochloride, hydrobromide, phosphate, acetate, fumarate, malt, citrate, oxalate, or sodium alkali metal salts. : Ct i.

Some of the compounds of formula (I) are scholarly in stereoisomeric forms. The present invention encompasses all of the ometric and optical isomers of the compounds of formula and levot, including racemates. Tautomers and mixtures thereof are also mole; of the present invention.

The compounds of the present invention are advantageous because they have pharmacological activity in humans and other animals. They are therefore suitable as medicaments for use in the (prophylactic) treatment of autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically affected diseases including rejection of transplanted organs or tissues and acquired immune deficiency syndrome (AIDS).

Examples of these diseases are:

(Airways) reversible obstructive airway problems including asthma such as bronchial, allergic, intrinsic, external and dust asthma, especially chronic asthma (e.g. late asthma and airway hypersensitivity); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, curulez rhinitis, sieca rhinitis and medicamenZosa rhinitis; membrane rhinitis including diphtheria, fibrin and pseudo-membrane rhinitis and quartz rhinitis, seasonal rhinitis including rhinitis nervosa (hay fever) and vascctoric rhinitis; sarcoidosis, farmer's lung and related diseases, fibroid lung and idiopathic interstitial pneumonia;

(2) (bones and ligaments) rheumatoid arthritis, seronegative spondylcarthropathies (including ankylosing spondylitis, pscriatic arthritis and Reiter's disease), Behcetc's Sjogren's syndrome and svstemic sclerosis;

3) (skin) psoriasis, atopic dermatitis, contact dermatitis and other eczema dermatitis, seborrheatic dermatitis, Lichen planus, Pemfigus, oxen Pemfigus, Epidermolysi; bullosa, urticaria, angioderma, vasculitis, erythema, cutaneous eosinophilia, uveitis, Alopecia areata, allergic conjunctivitis and spring conjunctivitis;

(4) (gastrointestinal tract) abdominal diseases, procositis, ecsinopilic gastroenteritis, mastocytosis, Chernivs disease, ulcerative colitis, food allergy with effects outside the intestine such as migraine, rhinitis and eczema;

(5) (other tissue diseases and systemic diseases) multiple sclerosis, atherosclerosis, AIDS, lupus erythematosus, systemic lupus, erythematosus, Hashimoto's thyroiditis, rayascnema gravis, aiacetes type i, syncretes necrosis, ecsincfilia fascitis, hyper IgE syndrome, leprcmatous leprosy, sesar syndrome and idiopathic thromrocytcpenia ououra;

j auuzn:

cnrcnicna napri.o ___________ ________ _______, _t ._____ OLIC, bone marrow, skin and cornea; and chronic disappearance of the host.

The compounds of the present invention are suitable for use as antimicrobial agents, and can therefore be used for the treatment of diseases caused by and by microorganisms.

oro

Accordingly, the present invention provides compounds of Formula I, or pharmaceutically acceptable salts or solvases thereof, as not mentioned above, for use in therapy.

In another aspect, the invention provides for the use of compounds of formula (I), or their stabilization, of salts or solvases as mentioned above in the manufacture of a medicament for use in therapy.

The invention further provides a method of affecting immununosuppression, which comprises administering to a patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof.

The invention further provides a method of treating or reducing the risk of obstructive reversible airway disease in a patient suffering from or at risk of said disease which comprises administering to a patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof.

ja <is given · · ···· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · The above-mentioned theraoeutic oculars:

Of course, there will be a wide variation in the administration and administration of the compound, the mode of treatment administered and the disease indicated.

The compounds of formula I and their pharmaceutically acceptable salts or solvates can be used alone or are generally administered in the form of a pharmaceutical composition wherein the compound of formula I / salt / salts (active ingredient; present in conjunction with ice-thiocyte); wear something:

pharmaceutical) d

0.10 to 99.9% by weight, more preferably from 0.10 to 7% of unchanged active ingredients, more preferably from 30 to 9.90, from 1 to 10% of any of the non-aqueous pharmaceutical ingredients, diluents or carriers. All percentages given

Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in association with pharmaceutically acceptable excipients, diluents or carriers.

The invention further provides a process for preparing a pharmaceutical composition of the present invention which comprises admixing a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined with pharmaceutically acceptable excipients, diluents or carriers.

the pharmaceutical composition according to the topical (for example, the lungs of the present invention and / or the respiratory tract can be administered or administered through the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, for example, orally in the form of tablets, capsules, syrups, powders or granules, not in the form of a liquid or rectally in the form of a sorghum or walnut skin:

DETAILED DESCRIPTION OF THE INVENTION

The present invention is further illustrated by the following wherein, unless otherwise indicated, chromatography is performed on silica gel and the organic solutions are dried with magnesium sulfate; Terms GC, MS, NNM, CDCl. and DMSO refer to gas chromate graphite, mass spectrometry, nuclear magnetic cut, deuterated chlorine, and dimethylsulfoxide.

Example 1

2,6-Dihydro-2-methyl-4- (2-methylpropyl) -6- (1-naphthylmethyl) -1H-pyrrolo [3,4-d] pyridazin-1-one

Q

a) (E) -Methyl-6-methyl-4-oxo-2-heptenoate

To a stirred solution of 4-methyl-2-pentanone (25 mL) in Meohanol (120 mL) was added bromine (10.0 mL) under nitrogen at -2 ° C.

is then further stirred for coloring. It was then added to saturate the salt and then washed with an aqueous then saturated solution to give 31 g of 1-brominated about 10%

The temperature of the mixture was raised to 5 ° C. Mixture

The mixture is stirred for 16 hours, extracted with diethyl ether, sodium bicarbonate solution and sodium chloride four times. Drying and evaporating 4-methyl-2-pentanone as an oil cont

Of the 3-bromoisomer. GC / MS (EI) 178/180 (Mj).

0 g of 1-bromomethyl-2-penzanone in 30 m: drive at 90 ° C to a stirred suspension of (oranylidene) acetate in 300 ml of dry lnyl (diphenylphenyl), the yellow-yellow suspension is cooled and filtered. 15 ml of mesyl bromocyzate and the mixture is stirred at 90 DEG C. for 2 hours, after cooling from the decomposed, precipitated, diphenylphosphonium bromide and tonicly purified on silica, eluting with a mixture of isocyanose xyxamines, unchanged.

7hyiv o 'f czrcmatcc:

xane-dichloromethane (10: 1). 10.2 g of kezoeszer in ocdnadois of taxo oil are obtained.

GC / MS (ΞΙ) 170 (My, li;

Boiling point ^{: 1} H NMR (CDCl 3): δ 0.95, 2.13 (m, 1H), 2.50 (d, 2H), 3.31 (s, 3H), 6.66 (d, 1H) J = 15.9 Hz), 7.06 (d, 1H, u = 15.9 Hz)

b) Methyl 4- (3-methyl-1-hexobutyl) -1H-pyrrel-3-carboxylate

A solution of 10 g of (Ξ) -methyl-6-meshyloxo-2-hepenzenase prepared as described in step a) above and 11.5 g of (p-toluenesulfonyl) methyl isocyanide in a mixture of 30 ml of dry dimethylsulfoxide and 30 ml of diethyl ether with pcd nitrogen To the mixture was added 2.75 g of sodium hydride (60% oil dispersion, 0.063 mol) stirred in 90 ml dry diethyl ether. After an additional hour, saturated ammonium chloride solution was added and the mixture was extracted with ethyl acetate, which was then washed well with water, dried and evaporated to give a honey-like residue. The residue was purified by chromatography on silica gel, eluting with ethyl acetate-isohexane (2: 3) to give 3.3 g of a solid which was recrystallized from ethyl acetate-cyclchexane. This yields the eser indicated in the subheading.

M.p .: 136 ° C

Mass spectrum (+ ve APCI) (M + H) + 210 ^{: 1} H NMR (CDCl 3: δ 0.36 (d, SH), (s, 3H), 7.26 (t, 1H) 7.33, 22 (m, 1H), 2.73 (d, 2H), 3.33 (t, 1H), 3.3 (br, 1H) Methyl 4- (3-methyl-1) -oxobutyl) -1- (1-naphthylmethyl) -1E-pyrrole, 3-carboxylate

To 0.42 g of sodium hydride (60% oily dispersion, de-oiled and stirred in 15 ml of snow) is treated with nitrogen for 20 minutes in portions of mc · 1) of ramed, 2 g

4- (3-methyl-1-oxobutyl) -1H-o-yrrole-3-carboxylate according to the procedure described in step b) above. After 10 minutes, 0.01 g of potassium poison and 1.35 g of (1-naphthyl} methylohlori-dimethyliormamide were added. The mixture was stirred for 4 hours and then

Of 0.5 M hydrochloric acid, and the ethynylation is exothermic.

The organic layer was washed well with water, saturated sodium chloride solution and evaporated to give a honey-like solid which was chromatographed on silica gel, eluting with ethyl acetate-isohexane (1: 3) to give an oil which was recrystallized from cyclohexane. 2.6 g of pyrrole are obtained.

Melting point: 81-82 ° C;

m / s (A? Ci) 350 (M + H)

1 H NMR (CDCl 3): δ 0.34 (d, 6H), 2.2 (m, 1H), 2.76 (d, 2H) , 3.73 (s, 3H) 5 . 5 0 (s, 2H) 7.17 (d, 1H, u = 2.7 Hz) , 7.23 (ά, 1H, J = 2.7Hz), 7, 25 (m, IH) ), 7.46 (dd, 1H), 7.55 (m, 2H) , 7.30

(m, 1H); 7.95 (m, 2H)

d] 2,6-Dihydro-2-methyl-4- (2-methylpropyl) -6- (1-naphthylmethyl) -1H-pyrrolo [3,4-d] pyridazin-1-one

0.35 g of methyl 4- (3-methyl-1-oxobutyl) -1- (1-naphthylmethyl) -1H-pyrrole-3-carboxylate prepared as described in step c) and 0.10 ml of methylhydrazine in 15 ml of ethanol with 16 hours zah31

The mixture was poured

0.15 g of 2,6-dihydro-2-mosses are refluxed with hydrochloric acid and extracted with ethyl acetate, which is then washed with saturated sodium chloride solution and evaporated; recovery of the remainder. This is purified by chromatography; silica gel, eluting with ethyl acetate-ischexane (1: 1) to give; The solid was recrystallized from cyclohexane. 1-4- (2-methylpropyl) -6- (1-naphthylmethyl) -pyrrolo [3,4-d] pyridine is obtained: 110-112 ° C

NMR spectrum (A? C ±) 345 (M + H) +

1 H NMR (CDCl 3): δ 0, , 94 (a, 6H) , 2,1 .1 (m, 1H). , 2, t c (li, z - /, 3.7 _ (s, 3H) 3 (with, 2H), 7.04 (d, 1H, &gt;) J = 2.1 Hz}, 7.22 (c, 1H), 7.52 (d / 1H, J = 2.1 Hz), 7.53 (m, 3H), 7.33 (m, 1H), 7.91 (m, 2 H) 1

Example 2

2,6-Dihydro-2- (2-methoxyethyl) -4- (2-methylpropyl) -6- (1-naphthyl methyl) -1H-pyrrolo [3,4-d] pyridazin-1-one

a) 2,6-Dihydro-4- (2-methylpropyl) -6- (1-naphthylmethyl) -1H-pyrrolo [3,4-d] pyridazin-1-one

0.35 g of methyl 4- (3-methyl-1-oxobutyl) -1- (1-naphthylmethyl) -1H-pyrrole-3-carboxylate prepared as described in the example

1c) above and 0.2 ml of hydrazine hydrate are stirred in 10 ml of ethanol for 2 days. The reaction mixture was poured into water to give a solid which was collected and recrystallized from ethyl acetate-cyclohexane. 0.22 g of the pyrrole in the subtitle is obtained.

183 °

Mass Spectrum (APCI) 332 (M + H) +

HN? 4R (CDCl ₂ ): δ / λ r · r- i, v 5 (d, , 6H) , 2.11 (m, 1H), 2.53 (d, 2H), 5.75 (s, 2H), 7 , 10 (d, 1H, , J - 2 , 1 Hz) ř / t 2 6 (m (1H), 7, 52 (d, X «i; J = 2.1 Hz), / _z 52 ( m, 3H), 7.82 (m, 1H), 7.92 \ * ¹¹ / 2H), 9, 08

(br, 1H)

b) 2,6-Dihydro-2- (2-methoxyethyl) -4- (2-methylpropyl) 6- (1-naphthylmethyl) -1H-pyrrolo [3,4-d] pyridazine-1 - one g of 2,6-dihydro-4- (2-methylpropyl) -6-ylmethyl) -1H pyrrolo [3,4-d] pyridazin-1-one prepared as described in step a) above is added portionwise to 0.020 g The oil-free sodium hydride (60% oil dispersion, 0.5 mm cc) was stirred in dry dimethylformamide. After 0.5 h, 0.04 mL of bromoethyl methyl ether was added and the mixture was stirred for 16 h. It was then poured into 0.5M hydrochloric acid and extracted with ethyl acetate, then washed with saturated sodium chloride solution, to give an oil which was chromatographed on silica gel, eluting with ethyl acetate-isohexane (1: 1). There was obtained 0.027 g of 2,6-dihydro-2- (2-methoxyethyl) -4- (2-methylpropyl) -6- (1-naphthylmethyl) -1H-pyrrolo [3,4-d] pyridazin-1-one.

Melting point: 96-38 ° C

Mass Spectrum (APCI) 390 (M + H) &lt; + &gt;

NMR (CDC1 _3): δ 0.94 (d, 6H) 2.11 (m, 1H) , 2.53 (d, 2H) , 3.35 (with 3H) 3.75 (t, 2H) , 4, 33 (t, 2H) , 5, 72 (s, 2H), 7, 02 (d, 1H , J = 2.1 Hz), 7, 22nd (d, 1H), 7.54 (m, 4H), 7.82 (m (1H), 7, 90 (m. 2H) -

· Β · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Tt ·

Example 3

2,6-Dihydro-7-propyl) -6- (1H-3-hydroxypropylthio) -2-methyl-4- (2-methylmethylmethyl) -1H-pyrrolo [3,4-d] pyridazine-1- cn

To 0.345 g 2,6-dihydro-2-methyl-4- (2-methylpropyl) - (methyl) -1H-pyrrolo [3,4-d] pyridazin-1-one prepared

303 tuo as described in Example 1 above and 0.72 g of S- {3 - [(1,1-dimethylezethyl) dimethylsilyl] oxypropyl] p-toluenethicsulfonate (J. Med. Chem., 1395, 33, 2557) in 10 ml of dry tetrahydrofuran Stir at -73 ° C under nitrogen atmosphere add lithium diisopropylamide in tetrahydrofuran (0.3SM solution, 5.1 mL). The reaction mixture was allowed to warm to room temperature overnight and saturated ammonium chloride solution was added. The mixture was extracted with ethyl acetate, which was then washed with saturated sodium chloride solution, dried and evaporated to give a honey-like residue which was then purified by silica gel chromatography, eluting with ethyl acetate-isohexane (1: 1). 0.25 g of t-butyldimethylsilyl ether was obtained as a solid.

Mass Spectrum (ARCI) 550 (M + H) ’

To a stirred suspension of 0.25 g of this solid in 10 ml of dry acetonitrile was added 0.07 ml of 40% hydrofluoric acid. After 16 hours, aqueous sodium bicarbonate solution was added and the mixture was partially evaporated to leave a residue. This was extracted with ethyl acetate, which was washed with a saturated chloride solution, dried, and capped to obtain a solid, which was chromatographed on silica gel, eluting with ethyl acetate-isohexane (3: 2). Overlaying with diethyl ether-ischexane gives Q, 17 g of 2,6-dihydro-7 - [(3-hydroxypropyl) thio] -2-methyl-4- (2-methylpropyl) -6- (1-naphthylmethyl) -1H -cyrrolo [3,4-d] mota melting point: xox ° C imperosulfur (APCI) 435 (MeH)

1 H-NMR (CDCl 3): δ 0.30 (d, 6H), 1.77 (quint, 2H), 1.33-2.12 (m, 1H), 2.43 (d, 2H), 3.12 (t, 2H), 3.75 (s, 3H), 3.37-4.01 (m, 3K), 5.37 (s, 2H), 5.75 (d, .delta.), 7.05 ( dd, 1H), 7.53-7.51 (m, 2H), 7.35 (d, 1H), 7.39-7,

Example 4, m,

7U1

- / [2,6-Dihydi (2 -me moment · / 7.

-cxo-1H-pyrrolo [3,4-d] pyridazin-7-yl] quinic acid

a] S- {3- [4-Methyl-2,6,6-trioxabicyclo [2.2.2] octan-1-yl] propylene p-toluenethicsulfonate

To 9.4 g of 1- (3-bromopropyl) -4-methyl-2,6,7-trioxabicyclo [2.2.2] octane (Tetrahedron Lett. 1983, 24, 5571) and 5 ml of trielhylamine in ml of dry hexamethylphosphoramide potassium p-toluenethiosulfonate (8.5 g) was added and the mixture was stirred for 3 days. Then add ·· · ·% ·· ·· ···· · · · ···· · · · 9 9 9 9 9 9 9 9 ·

The resulting precipitate was filtered off, dissolved in ethyl acetate, which was then washed with water, dried over sodium sulfate, evaporated and evaporated.

layer with diethyl ether. 3.0 g of the subtitle ester are obtained in the form of a solid.

Mass Spectrum (APCI) 359 (MH +)

1 H-NMR (DMSO-d 6): δ 0.73 (s, 3H), 1.59 (m, 4H), 2.47 (s, 3H), 2.99 (t, 2H), 3.77 (s, 6H), 7.43 (d, 2H), 7.79 (d, 2H)

:) Methyl 4 - {[2,6-dihydro-2-methyl-4- (2-methylpropyl) naphthylmethyl} xo-1H-pyrrolo [3,4-d] pyridazin-7-yl]

-.nio -nuzanoai

To a stirred solution of 0.345 g of 2,6-dihydro-2-methyl-4- (2-methylpropyl) -6- (1-naphthylmethyl) -1H-pyrrolo [3,4-a] pyridazin-1-one prepared as described in Example 1 above and 0.70 g

S - {3- [4-Methyl-2,6,7-trioxabicyclo [2.2.21 octan-1-yl] propyl)] fluorenium. zonatu uvezeno postu;

itosanvm v

At 78 ° C above, 5.1 ml of a solution of lithium diiscopropylamide in tetrahydrofuran (0.39M solution) was added dropwise under a nitrogen atmosphere under nitrogen. After one hour, aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate, which was then washed with saturated sodium chloride solution, dried over sodium sulfate, evaporated, and the resulting honey was immediately dissolved in methanolic hydrogen chloride solution. After 16 hours the solution was evaporated, the residue was dissolved in ethyl acetate and washed with saturated sodium chloride solution, dried and evaporated. A honey-like residue is obtained which is purified by chromatography on silica gel, eluting with ethyl acetate-isohexane (1: 3). 0.24 g of the subtitle ester is obtained in the form of a clear oil.

Mass Spec (APCI) 478 (M + H)

Ή NMR (CDCl 3), protruding peaks: δ 3.10 (t, 2H), 3.62 (s, 3H),

3.75 (s, 3H), 5.95 (s, 2H), 7.02 (s, 1H)

o) 4 - {[2,6-Dihydro-2-methyl-4- (2-methylpropyl) -6- (1-naphthylmethyl) -1-oxo-1 H -pyrrolo [3,4- d] pyridazine- 7-yl] thioylbutane xv

0.24 g of methyl 4-iodo-2,6-dihydro-2-methyl-4- (2-methylpropyl) -6- (1-naphthylmethyl) -1-oxo-1H-pyrrolo [3,4-d] pyridazine- The 7-ylthiobutanate prepared as described in step b) above was stirred with 0.060 g of lithium hydroxide hydrate in tetrahydrofuran-water-methanol (3: 1: 1) for 3 hours. The solution was then evaporated and the residue was partitioned between ethyl acetate and dilute hydrochloric acid. The organic layer was washed with brine, dried and evaporated. The residue is purified by chromatography on silica gel in ethyl acetate / ischexane mixture;

ethyl acetate / cyclohexane mixtures;

0.075 g of 4-K2,6-dihydro-2-methyl-4- (2-methylpropyl) -6- (1-naphthyimethyl) -1-oxo-1H-pyrrolo [3,4-d] pyridazin-7-yl] thic) Butanoic acid.

Melting point: 167 ° C

Mass Spectrum (ARCI) 464 (M + H) ’

1 H NMR (CDCl.): Δ 0, , 90 (d, 6H), 1.86 (m, 2H) 2.05 (m, 1H); 2.49 (m, 2H), 2.70 (t, 2H) 2.84 (t , 2H), 3.77 (s, 3H), 6.0 (3, 2H, 6.80 (d, 1H), 7.10 (s, 1H), 7 40 (t, 1 H), 7.58 (m, 2H) , 7.85-7.94 (m, 3H)

Example 5

2,6-Dihydro-7 - [(3-hydroxypropyl) sulfinyl] -2-methyl-4- (2-methylpropyl) -6- (1-naphthylmethyl) -1H-pyrrolo [3,4-d] pyridazine- 1-one (A) a

• · ·

7-f (3-hydroxypropyl) sulfonyl] -2-methyl-4- (2-methyl-naphthylmethyl) -1H-pyrrolo [3,4-d] pyridazin-1-one (Bj

OH

O, (A)

(B)

... -. 0.34 g of 2,6-Dihydro-7-L (3-hydroxypropyl) thio] -2-methylpropyl) - - - - - - - - - - The 5- (1-naphthylmethyl) -1H-pyrrolo [3,4-d] pyridazin-1-one prepared as described in Example 3 above was dissolved in 7 ml of dichloromethane and 229 mg of 3-chloroperoxybenzoic acid was added. After 4 hours, sodium bicarbonate (aqueous) and sodium metabisulfite (aqueous) were added and the mixture was extracted three times with dichloromethane. Combined organic extracts with solution

sodium chloride, dry from saturated water and evaporate. The residue was first purified by silica gel chromatography, eluting with cate and then with ethyl acetate: ethanol (19: 1 to 9: 1) to give 2 products. The more polar of these was overlaid with ether to give 43 mg of 2,6-dihyaro-7 - [(3-hydroxypropyl) sulfinyl] -2-methyl-4- (2-methylpropyl) -6- (1-naphthylmethyl) -1H-pyrrolo [3,4-d] pyridazin-1-one (A). The less polar product was recrystallized from isohexane-ethyl acetate to give 94 mg of 2,6-dihydro-7 - [(3-hydroxypropyl) sulfonyl] -2-methyl-4- (2-methylpropyl) -6- (1-naphthylmethyl) -1H-pyrrolo [3,4-d] pyridazin-1-one (3).

Compound A:

Melting point: 164-166 ° C

Mass spectrum (+ in APCI) (M + H) * 452 • · · ·

33 • · • · • · • • • · · • · · · · · • · · · • · · · · 1 H NMR (DM.SQ-) δ 0,83 (3H, d) 0.8 0.8 (3 d), 1.47 -1.65 (2H, m), 1,97- -2.10 (1H, m), 2.53 (2H, d i of 3,15- -3, 24 (LH, m), 3,30-3,35 (2H m), 3.39-3.43 (1 H, m) / 3, 60 (3 H, si, 4.56 (1 H, t), 6.30 (1H, d), 6.41 (1H, d) and 6.73 (1H, d), 7.45 (1 H, t), 7.57 -7.65 (2H, m), 7.33 (1 at i * / 3}, 7.91 (1H, di, 7.33-8.02 (1H, m), 8 , 11-3.14 (1 H, m) Compound: ·: Melting point .· 150 - 151 [deg.] C Weight sp ectrum (+ ve APCI) (M; HJ + 463 ¹ H NMR (DMSO-) d,) Q ' δ 0,92 (6H, d), 1.57-1. 6 6 (2H, mi, 2.10-2.15 (LH, m), 2.60 (2H, d), 3.30-3.36 (2 7 V i- / m), 3.65 (3H, s) 3,30-3,35 (2H, m), 4 53 (1H, t), 6.35 (1 H, d) , δ, 36 (2H, s); 7.38 (1H , t) , 7.53-7.68 (2 R, m), 7 86 (1H, d), 8.00 (1H, dd), 3.12 (1H, d ), 3.13 (1H, s)

Example δ

2- [pyridyl-1- (1-naphthalenyl) methyl] -5-methyl-7- (2-methylpropyl) thieno [2,3-d] pyridazin-4 (5H) -one

a) 2- (3-Methyl-1-oxobutyl) thiophene-3-carboxylic acid A lithium diisopropylamide mmol in 30 ml of tetrahydrofuran was added at 0 ° C to a solution of 5 g of thiophene-3-carboxylic acid in 50 ml of tetrahydrofuran. 4.6 ml of isovaleraldehyde is added as a solution in 30 ml of tetrahydrofuran at 0 ° C and the mixture is stirred for 3 hours.

I · · · · ·

• Stir 4 ° C. Then 10 mL of water was added and tetrahydrofuran was removed in vacuo. The residue is extracted with ethyl acetate and the aqueous phase is added to 12.3 g of potassium permanganate and heated at 60 ° C for 1.5 hours. The mixture was filtered, cooled to room temperature and then acidified with dilute hydrochloric acid. The acidic aqueous solution was extracted with ethyl acetate and the organic extract was dried and evaporated.

The zzou szoucemny shown in oconaooisu in zo ozeze.

Mass Spectrum (APCI) (M-R1) 211

1 H-NMR (CDCl 3): δ 1.0 3 (6H,

7.70 (IR, d), 7.97 (1H, d), 37 (1H, in), 2 ', 2H, O',

b) 5-Methyl-7- (2-methylpropyl) thieno [2,3-d] pyridazin-4 (1H, -one)

5.3 g of 2- (3-methyl-1-oxobutyl) thiophene-3-carboxylic acid prepared in neck a) are dissolved in 30 ml of ethanol and 1.5 ml of methylhydrazine is added. The resulting mixture was heated to reflux for 10 hours. It is then evaporated and the residue is dissolved in ethyl acetate. The organic phase is washed twice with dilute hydrochloric acid, twice with saturated sodium bicarbonate solution and once with saturated sodium chloride solution, then dried and evaporated. The residue was purified by chromatography on silica gel, eluting with isohexane: ethyl acetate (2: 1 to 1: 1). 3.55 g of the sub-title compound are obtained in the form of an oil.

Mass spectrum (APCI) ((M. + H) ⁺ ) 223 ^{: 1} H NMR (CDCl 3: δ 1.00 (6H, d), 2.05 (1H, m), 2.75 (2H, d), 3 85 (3H, s), 7.60 (1 H, d), 7.80 (1 H, d)

c) 2- [1-Hydroxy-1- (1-naphthyl) methyl] -5-methyl-7- (2-methylpropyl) thieno [2,3-d] pyridazin-4 (5H) -one;

4) · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

6.75 mmol of lithium diiscopropylamide in 8 ml of tetrahydrofuran and

0.7 ml of 1-naphthalidehyde with 5 ml of tetrahydrofuran

1) th:

to a solution of 1 g of 5-methyl-7- (2-methylpropyridazin-4 (5H) -one prepared in step b) by the amount of propyl [2,3-a] in tetraydrofuran (20 ml) at 0 ° C. After two days, add 10 ml of water, rotate the mixture with hydrochloric acid;

acid and then extracted with ethyl acetate. The organic phase was once oromycled with dilute hydrochloric acid, twice saturated with cniorium solution and the pax was dried and oopart. The residue is purified by chromatography on silica gel, eluting with r / m

i s o h e x e n e / e t h y a c e t t (I: t); followed HP LC se s t mobile . running. OF 0.4 g is obtained compounds mentioned in over' Temperature Melting point: 165-7 Noc: 2 ° C Mass spectrum (APCI) (M + H) ) 379 t4 NMR ( DMSO-d _s). · 5 0.91- (6H, d), 2.12 (1 H, m), 2.57 (2H, 3.64 (3H, s) 77 (IH, d) 6.84 (1 H, d), 7.28 (1Η, 7.48 -53 (2 H, m, 7.57 (1 H, t), 7.79 (1K, (d) , 7.92 ( ⁴

whose

7.96 (1 H, dd), 8.26 (1 H, dd)

Example 7

5-Methyl-7- (2-methylpropyl) -2- (1-naphthylmethyl) thieno [2,3-d] pyridazin-4 (5H) -one

To a solution of 0.3 g of 2- [1-hydroxy-1- (1-naphthyl) methyl] -5-methyl-7- (2-methylpropyl) thieno [2,3-d] pyridazin-4 (5H) -one prepared

4 99 94 99 99

9 9 9 9 4 9 9 9 9

4 · 4 9 4 9 9 9 4 4

9 9 9 9 9

4 4 9 4 9 9

9 94 4 4 4 9 4 9 9 49 ml three fluoroacetic ml triethylsian. The residue was dissolved as described in Example 5 above and 0.3 acids were added in 10 ml of dichloromethane. After 30 minutes, the reaction mixture was evaporated and taken up in ethyl acetate. This solution was washed twice with saturated

flow of bvdocerials' Sodium perchlorate and once with a saturated solution sodium chloride, then it is dried and evaporate. The residue is chromatographed. graphically clean on silica gel, el uce isonexane / ethylacetate mixtures and cuts H PLC, elution with ischexane mixtures: ethyl acetate (2: 1) . Z i s κ a se 0, z: g sl .oucenmy in the name. Melting point: 103 Noc: 2 ° C Mass Spectrum: m (APCI) (M + H) and a 1 + 63 @ 1 H NMR (DMSO-d6): .delta. δ 0.86 (6 Η, d) , 2 04 (1H, m, 2.51 (2H, d)), 3.65 (3 ohms, s), 4.81 (2 H, s), 7 / 47 (1H, s), 7.43-7.53 (3 H, m, 7.60 (1 H, d), 7.89 (1K, C); , 96 (1 H, Cd), 3.15 (1 H, cd)

Example 3

3 - [(3-Hydroxypropyl) thio] -5-methyl-7- (2-methylpropyl) -2- (1-naphthylmethyl) thieno [2,3-d] pyridazin (5H) -one

Prepared from 385 mg of 5-methyl-7- (2-methylpropyl) -2- (1-naphthylmethyl) thieno [2,3-d] pyridazin-4 (5H) -one described in Example 7 above and 600 mg of S - (3 - [(1,1-dimethylethyl) dimethylsilyl] oxypropyl) -p-toluenethiosulphonate (J. Med. Chem., 1995, 38, 2557) »· <.....

, ·. ·· · ·· <

t ·. Using the procedure described in the title.

of Example 3. Gets e from 10 mc szcuc?

Melting point: 123-130 ° C

Mass spectrum (+ ve APCi) (M + H) + 453 ^{: 1} H NMR (DMSO-d 6: δ 0.33 (SH, d), 1.67 (2H, quin), 1.93-2.0?

δ H, d), 3.13 (2H, t), 3.50 (2H

3), 4.53 (1H, t), 4.53 (2H, 5), 7.45-7, (1H, d), 7.95-3.04 (2H, m)

Kv, 3.7 (4H, m),

Example 9

5-Methyl-7- (2-methylpropyl) -2- (1-naphthylcarbonyl) thieno [2,3-d] pyridazin-4 (5H) -one

ff

i o

0.335 g of potassium permanganate and 10 mg of 18-crown-S are added to a solution of 0.40 g of 2- [1-hydroxy-1- (1-naphthyl) methyl] -5-methyl-7- (2-methylpropyl) thieno at room temperature. [2,3-d] pyridazin-4 (5H) -one (Example 7) in 30 mL of dichloromethane. After 1 hour an additional 0.30 g of potassium permanganate was added and stirring was continued for another hour. The mixture is filtered, diluted with 70 ml of dichloromethane, washed twice with water, then with saturated sodium chloride solution, then dried, filtered and evaporated. The residue is purified by chromatography on silica gel, eluting with ethyl acetate: isohexane (1: 2). 0.14 g of the title compound is obtained. This was further purified by normal phase preparative HPLC with an ethyl acetate-isohexane gradient.

• · · · · · · · · · · · ·

4?

_ U -L o-- U CX cání: 121 ° C Weight tni sp ectrum (+ ve APCI) 377 (] M + H) + ^: H MMR (DMSO dý δ 0,93 (SH, d), 2.1 4 - 2.2 6 (LH, m), 2.74 (2H, d), 3, 70 (3H, s), 7 60-7, 65 (2H, m), 7, 70 (1 H, dd, 7.79 (1H , s), 7.93 (1K, dd •), 3, u 7 - 3.11 (2H, m) , 3.25 (1Η, G).

Example 10 [(3-Hydroxy-propyl) -sulfonyl] -5-methyl-thieno [2,3-a] pyrrole

1-7- (2-methylpropyl) azin-4 (5H) -one

OH <

\

Example 3) in 20 ml of dichloromethane is clarified by temperature

To a stirred solution of 0.14 g of 3 - ([3-hydroxypropyl] thic) -5-methyl-7- (2-methylpropyl) -2- (1-naphthylmethyl) thieno [2,3-d] pyridazin4 (5H) -one at room temperature is added 0.055 g of 3-chloroperoxybenzoic acid (30% purity). After 20 hours, the mixture is diluted with 30 mL of dichloromethane, washed with saturated sodium bicarbonate solution, dried, filtered and evaporated. The residue is purified by chromatography on silica gel, eluting with ethyl acetate: isohexane (1: 1 to 2: 1). Followed by preparative normal phase KPLC with an ethyl acetate-isohexane gradient. 0.05 g of the title compound is obtained in the form of a foam.

Melting point: 60-65 ° C ··· · dd

APCI) 469 ((M + H) +)

NMR (DMSO - d 6) d _s ) δ 0.80 (3 H, d), 0.82 (3H, d), 1.81-1.99 (2H m), 2.03 -2.15 (1H, m), 2.44 (2H, d) 3.23-3.39 (2H, (m) 3.53 (2H , kv), 3.67 (3 H, t), 4.65 (1 H, t), 4.8 4 '(1H, (d) 5.30 (1H , d), 7.51-7.56 (3 Η, m), 7.61 (1H, d) 7.92 (1H d), 7,95- -7,99 (1H, m), 3.14-8. .17 (1H, m).

Example 1 (b-mesyl-7- (2-methylcropyl) -2- (1-naphthylmethyl),

oxo-thieno [2,3-d] pyridazin-3-yl] -thio / butanic acid

/ '

(a) 4,4,4-Trimethoxybutyl-4-methylbenzenesulzonzhioate meso-crassme amol salt of p-toluene thiosulfones xvs. my ml hexamethyl:

Trimethyl 4-bromo-butyrate amide (mmol) was stirred at room temperature for 43 hours and then poured into 10: 1 hexane / diethyl ether (500 mL) and shaken vigorously. The mixture was then washed twice with 200 ml of water and saturated sodium chloride solution. The organic phase was dried (MgSO 4) and evaporated. 5.3 g of the title compound are obtained in the form of an oil containing g of the ester indicated in the sub-base of 7% 4,4,4-trimethoxybutyl-4-methylbenzenesulfondithioate.

• · * δ 1.95 (291, η), 2.37 (2Η, Li, 2.44 (3Η, si, 3.02 (2Κ,, 16 (SH, si, 7.33 (2Η, d)) , 7.30 (2', 6'-methyl-4 - {[4,5-dihydro-5-methyl-7-methylmethyl} -4-oxothieno [2,3-d] pyridaz (2-methylpropyl), - 2- (1-naphth-3-yl) thio-buzanoate

X A solution of 0.30 g of 5-methylthyl-thieno [2,3-d] pyridazine-4,4,4-trimethoxybutyl-4-methyl-tetrahydrofuran is added dropwise to a solution of 1.3 mmol of 1-tetrahydrofuran. After 2 hours

7- (2-methylpropyl) -2- (1-naphthyl (5H) -one (Example 7)) and 0, benzenesulfonate in 15 ml at -73 ° C under thiumdiiscopropylamide in 5 ml, allowed to warm to room temperature, The organic extracts were washed with 1M hydrochloric acid, then with sodium bicarbonate solution, then with saturated sodium chloride solution, dried, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with ethyl acetate. : isohexane (1: 4, 1: 2, 1: 1 then 1: 0) to give 0.25 g of the sub-title compound as an oil.

Mass Spectrum (+ ve APCI) 495 ((MeH) +)

1 H-NMR (CDCl 3) δ 0.33 (6H, d), 2.00 (2H, quin), 1.99-2.11 (1H, m), 2.44 (2H, dl, 2.55 (2H) t, 3.20 (2K, t), 3.65 (3H, s), 3. S2 (3H, 3), 4.37 (2H, s), 7.40-7.50 (4H, m), 7.84 (1 H,

d), 7.90 (1H, dd), 7.93 (1H, dd).

c) 4 - [[4,5-Dihydro-5-methyl-7- (2-methylpropyl) -2- (1-naphthylmethyl) -4-oxothieno [2,3-d] pyridazin-3-yl] thio] butanoic acid

A solution of 0.035 g of lithium hydroxide hydrate in 1 ml of water was added to a solution of 0.20 g of methyl 4 - {[4,5 dihydro-5-methyl-7- (2-methylpropyl) -2- (1-naphthylmethyl) at room temperature. ) -4-oxo

thieno [2,3-d] pyridazin-3-yl] thio} butanoate in 6 mL of tetrahydrofuran. After 2 days, 20 ml of 1M hydrochloric acid are added and the mixture is extracted with 20 ml of ethyl acetate. The organic extracts were washed with saturated sodium chloride solution, dried, dried and evaporated. The residue was dissolved in the mixture; (1-2) and the resulting precipitate was collected. Tnc: iscnexane suspended in 20 microns;

etnyiacecatu, ccniaoi íninv in the title.

oooeli. This will make a profit;

Mass Spectrum (+ ve APCx) 431 ((M + H) +)

1 H NMR (DMSO d Δ 0.35 (6H, d), 1.76 (2H, kvin), 1 ₁ QJ. -2.06 (1H, m, 2.33 (2 Η, t), 2.45 (2H, d) 3 11 (2H, i) -S / . 6 5 k Z Γ! , 3), 4.33 (2H, s), 7.45-7.53 (4H, m, 7) . 90 (1 H, d), 7, , 97 -3.01 (2H, m) 12.09 (1 H, brs).

Example 12

5-Methyl-7- (2-methylpropyl) -2- (1-naphthylmethyl) -3- (2-pyridinylthio) thieno [2,3-d] pyridazin-4 (5H) -one

0.60 ml of a solution of butyllithium in hexane (2.5 M) was added to a solution of 0.16 ml of diisopropylamine in ml of tetrahydrofuran at 0 ° C and under nitrogen. After 30 minutes, 4 ml of the resulting solution was added at -73 ° C to a solution of 0.207 g of 5-methyl-7- (2-methylpropyl) -2- (1-naphthylmethyl) thieno [2,3-d] pyridine. ·, U «···· * ·· *

7-methyl-4 (5H) -one (Example 7); and 0.1 ml of tetrofuran. The mixture was quenched with 25 mL saturated

-dipyncylc is extracted with 50 ml of ethyl acetate. The organic extract was washed with a saturated ammonium chloride solution, twice in each case;

Z'rr roztoxu cnionau societo, dry, down.

purified by chromatography on silica gel; 1: 2 ' -Ethyl-e-acetyl / ischexane gradient. The title is obtained in the term of the price.

isonexane (1: 2 and oak 1: 1). NiIt / ischex;

0.077 se

- z_ p

Lcemnv

Mass Spectrum (-ve APG_) 472 ((M + H))

NMR d), (DMSO 3, 59 d ( _s ) δ (3H, 0, S5 s), 4, (6H , 83 (d) , -! , (2H, 1.97 s), -2.03 (1H 7.09 (1 H, , m), d), 2, 7, 5 0 (.2 H dd) , 7.3 5 (1H, td), 4 3-, 7 , 52 (3H, m) Ί CC : OF H, td)

(3H, m), 3.3? -3.40 (1H, m).

7,87-7,

Example 13

- [(3-Hydroxypropyl) -sulfonyl] -5-methyl-7- (2-methyl-propyl) 2-1-naphthyl-methyl) -thieno 12,3-dloyridazine-4 (5H) -quinoline

0.27 g of 3-chloroperoxybenzoic acid (80% purity) is added to a stirred solution of 0.28 g of 3 - {[3-hydroxypropyl] thio} 5-methyl7- (2-methylpropyl) -2- (1-naphthylmethyl) thieno [2,3-d] pyridazin-4 (5H) -one (Example 7) in 10 mL of dichloromethane. After 24 hours, the mixture is diluted with 40 ml of dichloromethane, washed with saturated sodium bicarbonate solution, dried, filtered and evaporated. The residue is purified by chromatography on silica gel, eluting with ethyl acetate: isohexane (1: 1 then 2: 1 then 1: 0), followed by recrystallization from ethyl acetate / ischexane. 0.209 g of the title compound is obtained.

emi mře

Mp 160-163 ° C

Mass spectrum (+ ve Al 2 Cl) 485 ((M + H) +) 1 H NMR (DMSO d6 0.81 (6H, d), 1.37-1.99 (3H, m), 2.45 (2H, d), 3.50 (2H, kv), 3.71 (3H, s), 3.96-4.05 (2H, m), 4.70 (1H, t), 5.23 ( 2H, s), 7.51-7.59 (4H, m), 7.94-9.02 (3H, m).

Example 14

- (1-Hydroxy-1-phenylmethyl) -5-methyl-7- (2-methylpropyl) thiano [2,3-d] ovridazin-4 (5H) -one

A solution of 13.6 mmol · 1 ithium diisopropylamide in 22 mL tetrahydrofuran / hexane (2: 1) was added dropwise at -70 ° C and under nitrogen atmosphere to a solution of 2.00 g 5-methyl-7- ( 2-methylpropyl) thieno [2,3-a] pyridazin-4 (5H) -one (Example 6, step b) in 24 mL of tetrahydrofuran. Then 2 ml of benzaldehyde (2.00 ml) were added and after 15 minutes the mixture was allowed to warm to room temperature. 50 ml of 1N hydrochloric acid are then added and the mixture is extracted with 100 ml of ethyl acetate. The organic extracts were washed twice with 1M hydrochloric acid, twice with saturated solutions.

sccmefc, to saturated sodium chloride solution, dried, filtered and evaporated. The residue is purified by chromatography on silica gel, eluting with ethyl acetate (1: 3 cc:

1: 2 then 1-l), to obtain 2.43 g la + L- - r -X / z from which stí prep isrstivni HerC on normal stage with gradient ) i c h i c rme tan. 0.33 was obtained g of compound mentioned in the title. me oil ii spektr µm (rt APCI) 329 ((M + H) -) : MSO dý δ 0.92 (6H, d); r, £. _ About IQ '/ ¹ C-t - O \ Ί v. - ¹ - t m), 2.60 i.2 Η, S7 (3H, s), S, 11 (1 H, a), 6.71 (1 H, d), 7.23 (1 H, t), (1 H, s), 7.39 (2 H, t), 7.4 9 (2 H, d).

Example 15

5-Methyl-7- (2-methylpropyl) -2-phenylmethylthieno [2,3-d] pyrimidine-4 (5H) -one

1.0 ml of triethylsilane was added to a stirred solution of 1.44 g of 2- [1-hydroxy-1-phenylmethyl) -5-methyl-7- (2-methylpropyl) thieno [2,3-d] pyridazine-4 ( 5H) -one, prepared as described in Example 14, in 2 ml of trifluoroacetic acid and 10 ml of dichloromethane. After 24 hours, 100 mL of saturated sodium bicarbonate solution was added and the mixture was extracted with 100 mL of ethyl acetate. The organic extracts were washed twice with saturated sodium bicarbonate solution, then with saturated sodium chloride solution, then dried, filtered and evaporated. The residue is chromatographed on silica gel, eluting with · ·

Ο ethyl acetate: isohexane (1: 4 to 1: 3; title compounds as solids).

1.1 g are obtained

Melting point: 97 -93 ° c Mass spectra rum (eve APCI) 313 (( M-1H) 1 H NMR (DMSO d ₆ ) δ 0, 100 (6H, d) , 2, 4 - 2.16 (1K 3.67 (3H, s) d / - 1 32 (2H, S); of 7/25 (1H, m,

di r

with)

Example l

- L (3-Hydroxypropylthiol-o-methyl-N- (2-mesylpropyl) -2-methylthieno (2,3-d) pyridazin-4 (5H) -one

-nyi -

1.3 ml of a 2.5 M solution of butyllithium in hexane was added to a solution of 0.45 ml of diisopropylamine in 6 ml of tetrahydrofuran at 0 ° C under nitrogen. After 30 minutes at -73 ° C and under a nitrogen atmosphere, 5 ml of the resulting solution was added to a solution of 0.50 g of 5-methyl-7- (2-methylpropyl) -2-phenylmethylthieno [2,3-d] pyridazine-4. (5H) -one, prepared as described in Example 15, and 0.35 g of S- [3 - ([(1,1-dimethylethyl) dimethylsilyl] oxy) propyl] 4-methylbenzenesulfonothioate, (u. Med. Chem. 1995 , 33, 2557) in 10 mL of tetrahydrofuran. The reaction mixture was allowed to warm to room temperature, quenched by the addition of 25 mL of saturated aqueous ammonium chloride solution, and extracted with 50 mL of ethyl acetate. The organic extracts were washed twice with a saturated aqueous chloride solution

ammonium chloride, twice with saturated sodium bicarbonate solution, then with saturated sodium chloride solution, dried, filtered and evaporated. The residue was dissolved in 20 ml of acetonitrile and added with 50 ml of saturated sodium bicarbonate solution and the mixture was extracted with 50 ml of ethyl acetate. The organic extracts were washed with saturated sodium chloride solution, dried, filtered and evaporated. The residue is chromatographed cis? ethyl acetate: isohexane isocoel, eluting

Zí skc se

0.51 g of the title compound as a solid.

Melting point: 60-65 ° C

Mass spectrum (+ ve APCI) 403 ((M + H) +) ^H NMR (DMSO- d _s) δ 0.88 (6H, d), 1.57 (2H, quin), 2.08 (1H, m 2.53 (2H, d), 3.00 (2H, t), 3.43 (2H, kv), 3.70 (3K, s), 4.44 (2H, s), 4.48 (1H, t), 7.22-7.34 (5H, m).

Example 17

3 - [(3-Hydroxypropyl) sulfenyl] -b-methyl-7- (2-methylpropyl) -2-phenylmethylthieno [2,3-d] pyridazine-4 (5H) -cn

Prepared according to the procedure described in Example 13, from 0.32 g

3 - {[3-hydroxypropyl] thio} -5-methyl-7- (2-methylpropyl) -2-phenylmethylthieno [2,3-dlpyridazin-4 (5H) -one and 0.32 g of 3-chloroperoxybenzoic acid (86) % purity) in 20 mL of dichloromethane. 0.18 g of the title compound is obtained in the form of a foam.

* · Φφφ

Melting point: 105-107 ° C

Mass Spectrum (+ ve ARCI) 435 ((M + H) +)

1 H NMR (DMSO d6 δ 0.89 (6H, d), 1.74-1.33 (2H, m), 1.39-2.10

8.36-7.97 (.7H m), 4.63 (1H, (1H, m), 2.57 (2H, 92 (2H, (5H, m))).

3.44 (2H, kv), 3.71 (3H, s), 4.75 (2H, s), 7.28-7.33

Example 13

2,6-Dihydro-2-ylethyl-4- (2-methylcyclyl) -4-phenylmethyl-1H-pyrrolo [3,4-d] pyridazin-1-one

a) 2, 6-Dihydro-2-methyl-4- (2-methyl-propyl) -1H-pyrrole;

pyridazine-1-cn

0.7 g of methyl 4- (3-methyl-1-oxobutyl) -1H-pyrrol-3-one prepared as described in Example 1 - step b of methylhydrazine in 20 ml of ethanol was heated under reflux for 16 hours. The solution was evaporated and the residue s

Of 4-dimethylate, and 0.6 min. Were triturated between ethyl acetate and dilute hydrochloric acid. The organic phase was dried and evaporated. 0.65 g of 2,6-dihydro-2-methyl-4- (2-methylpropyl) -1H-pyrrolo [3,4-d] pyridazin-1-one is obtained as a red oil (0.65 g).

Mass spectrum (+ ve ARCI) 206 ((MH +)) @ 1 H NMR (CDCl3) .delta. 0.97 (6H, d), 2.08-2.32 (1H, m), 2.62 (2H, m) ,

3.73 (3H, s), 7.24 (1H, t), 7.57 (1H, t), 11.56 (1H, br).

b) 2,6-Dihydro-2-methyl-4- (2-methylpropyl) -6-phenylmethyl-1H-pyrrolo (3,4-d] pyridazine

A solution of 0.55 g of 2,6-dihydro-2-methyl-4- (2-methylpropyl) -1H-pyrrolof3,4-d] pyridazin-1-one in 3 ml of dry dimethylformamide is added dropwise to 0, while stirring. 15 g of sodium hydride (60% dis with 10 ml of dimethylformamide) was added potassium iodide for 20 minutes. The mixture was added with 0.45 ml of benzyl bromide and the crystal was stirred for 11 days. It is purified by chromatography on silica gel (ethyl acetate / isohexane 3: 1) and crystallized from cyclohexane to give 0.3 g of 2,6-dihydro-2-methyl-4- (2-methylpropyl). -6-phenylmethyl-1H-pyrrolo [3,4-d] pyridazin-1-one (0.3 g).

Melting point: 104 ° C

Mass spectrum (+ ve AFCI) 255 ((M + H) +) 1 H NMR (CDCl 3 δ 0-95 (SH, s)), 2.12 (1H, m, 2.55 (2H, d), 3, 72 (3K, s), 5.27 (2H, s), 7.08 (1H, d, J = 2.1 Hz), 7.15 (2H, m, 7.37 (.3H, m, 7) .49 (1H, d (J = 2.1 Hz).

Example 19

2,6-Dihydro-2-methyl-4- (2-methylpropyl) -6-phenylmethyl-7- (2-pyridinylthio) -1H-pyrrolo [3,4-d] pyridazin-1-one

\ // • · · ·

To a stirred solution of 0.1 ml of diisopropylamine in 2 ml of dry tetrahydrofuran was added dropwise at 0 ° C under a nitrogen atmosphere, 32 ml of a solution of butyllithium in hexane (2.5M solution; stirred at 0 ° C for 30 minutes). cool to heartbeat

-78 ° C and a solution of 0.2 g of 2,6-dihydro-2-methyl-4- (2-methylpropyl) -β- (1-phenylmethyl) -1H-pyrrolo [3,4-d] pyridazine- 1-one (prepared as described in Example 18) in 2 ml dry tetrahydrofuran. Stirring is continued for 30 minutes. Then a solution of 0.155 g of 2,2'-dipyridyl disulfide in 2 ml of dry tetrahydrofuran is added. The reaction mixture was allowed to warm to room temperature overnight, then quenched by the addition of saturated ammonium chloride solution. The mixture is extracted into diethyl ether, washed with saturated sodium chloride solution and dried.

to give a yellow oil. This was purified by silica gel eluting with dichloromethane: acetone (4: 1). This is followed by reverse phase HPLC with an acetonitrile: aqueous citrate gradient.

0,0 o g of sulfur in the name, vu.

melting point: 131-132 ° C

Mass Spectrum (+ in APCi) ((M + H) ’)

1 H NMR (CDCl 3 δ 0.97 (d, 6H), 2.05-2.19 (m, 1H), 2.55 (d, 2H),

3.70 (s, 3H), 5.44 (s, 83 (a, 1H), 5.93 (dd, 1H),

7.10-7.12 (m, 2H); 7.25-7.27 (m, 4H); 7.40 (t, 1H; 3.32 (d, 1H).

Example 20

2,6-Dihydro-7 - [(3-hydroxypropyl) thio] -2-methyl-4- (2-methylpropyl) -6-phenylmethyl-1H-pyrrolo [3,4-d] pyridazin-1-one · ··· · · ··········· ** ** '** · ^β ** ··

cu iscprcp τ + ί ·

0.32 ml of butyllithium (2.5M solution in hexane) was added dropwise to a stirred solution of 0.11 ml of dry tetrahydrofuran at 0 ° C under nitrogen. the reaction mixture f

The ethyl acetate was stirred in 2 and then cooled to -73 ° C. 0.2 g of 2,6-dihydro-2-methyl-4- (2-methyl) is added to the solution;

-phenylmethyl-1H-pyrrolo [3,4-d] pyridazin-1-one (prepared as described in the example) in 2 ml of dry tetrahydrofuran and stirring was continued for another 30 minutes. A 0/25 g solution is then added

S- [3 - {[(1,1-dimethylethyl) dimethylsilyl] oxy] propyl] 4-methylbenzenesulfonothioate, (J. Med. Chem. 1995, 33, 2557) in 2 ml dry tetrahydrofuran. The reaction mixture was allowed to warm to room temperature overnight and then quenched by addition of saturated ammonium chloride solution. The mixture was extracted into diethyl ether, washed with saturated sodium chloride solution, dried and evaporated. The residue was purified by silica gel chromatography, eluting with ethyl acetate / isohexane (3: 7) to give a yellow oil (0.24 g), mass spectrum (APCI) 500 (M + H) -.

To a stirred solution of 0.24 g of this oil in 2 mL of methanol was added 0.25 mL of concentrated hydrochloric acid. After 2 hours, the pH of the mixture was made alkaline by addition of saturated sodium bicarbonate solution. The mixture was extracted into ethyl acetate, washed with saturated sodium chloride solution, dried and evaporated. The residue is chromatographed on silica gel with ethyl56

acecate. This is followed by an overlay of isohexane: diethyl ether. This afforded 0.105 g of the title compound.

Melting point: 91-92 ° C

Mass spectrum (* in APCI) ((M + H)) 386

HH NMR (DMSO d _s) δ 0.92 (d, 6H), 1.46 (quint, 2H), 2.04-2.14 (m,

1H), 2.53 (d, 2H), 2.83 (t, 2H), 3.30-3.37 (m, 2H), 3.55 (s, 3H), 4.44 (t, 1H) ), 5.52 (s, 2H), 7.11 (s, 1H), 7.14 (d,

1H), 7.25-7.37 (m, 3H), 7.38 (s, 1H).

Example 21

2,6-Dihydro-2-methyl-4- (2-methylpropyl) -6- (3,4,5-trimethoxyphanyl) methyl-1H-pyrrolo [3,4-d] pyridazin-1-one

A mixture of 0.031 g of 2,6-dihydro-2-methyl-4- (2-methylpropyl) -1H-Oyrrolo [3,4-d] pyridazin-1-one (prepared according to the procedure described in Example 18, step a), 0.038 g 3,4,5-trimethoxybenzyl chloride and 0.090 cesium carbonate in 0.3 ml dimethylformamide were stirred for 15 hours, then dilute hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated. The residue is purified by chromatography on silica gel (dichloromethane / ethanol 9: 1). There was obtained 0.033 g of 2,6-dihydro-2-methyl-4- (2-methylpropyl) -6- [3,4,5-trimethoxyphenyl] methyl-1H-pyrrolo [3,4-d] pyridazin-1-one.

• · · • · · · • · · • · · of; ~ 7 · · · · · • · • · • · • · • · • · • · • · · · • · · TecLet and Melting. 154.5-155 ° C Kmetnestni sp electron (+ ve APCI) 386 ((M-H) +) 1 H NMR (CDCl 3)? Δ 0.96 (6H, d), 2.14 (1H, m, 2.56 (2µ 3.73 (3H, s) 3.81 (6H, S), 3.84 (3K, s), 5.19 (2H, you, 6.37 (2H, s), 7.01 (1H, d, J = 2.1Hz), 7.50 (1H, d, J = i, 8Hz)

Example 22

2,6-Dihydro-2-methyl-6- (1-naphthylmethyl) -4- (1-methyl-1H-pyrrolo [3,4-d] pyridazin-1-one) -

a) Diethyl 1- (1-naphthylmethyl) pyrrole-3,4-dicaroxylate g of potassium carbonate and 4.60 g of 1- (chloromethyl) naphthalene are added to a solution of 5.00 g of diethyl 3,4-pyrrolo dicarboxylate in 50 ml. acetone. The mixture was stirred at room temperature for 4 days, then the ICO of the diluted hydrochloric acid was added with ex:

2 x 100 ml of ether was added. The organic extracts were dried, filtered and evaporated. 7.62 g of the sub-title compound is obtained as a solid.

Ή NMR (CDCl 3) δ 1.31 (6H, t), 4.27 (4H, kv), 5.43 (2H,

7.21-7.28 (3H, m), 7.46 (1H, t), 7.50-7.57 (2H,

7.80-7.93 (3 H, m).

with)

(m)

b) 2,3-Dihydro-2-methyl-6- (1-naphthylmethyl) -1H-pyrrolo [3,4-d] pyridazine-1,4 (6H) -dione • · · ·

0.55 ml of methylhydrazine was added to a solution of 1.00 c of diethyl 1- (1-naphthylmethyl) pyrrole-3,4-dicarbonylate in 10 ml of ethanol. The mixture was heated to 200 ° C in a calibrated tube for 3 days. It is then evaporated and the residue is purified by chromatography on silica gel, eluting with ethyl acetate: methanol (19-1). The resulting solid was suspended in 25 mL of ethyl acetate, heated to boiling and allowed to cool to room temperature. Filtration gave 0.105 g of the title compound.

Mass scektrum H NMR (DMSO- d _s) δ 3.33 (3H, s), 5.83 (2H,

7.50-7.64 (5H, m), 7.94 (1H, d), 7.99

d), 10.94 (1H, s, b).

7.32

d.), 3.19 (1H

c) 4-Chloro-2,6-dihydro-2-methyl-6- (1-naphthylmethyl) -1H-oyrrolo [3,4-d] pyridazin-1-one

Suspension 0,10 g 2,3-dihydro-2-methyl-6- (1-naphthylmethyl) -1H-pyr-

rolo [3,4-d] pyrida zine-1,4 (6H 1 -diene in 1 ml of phosphophorotyl chloride Heats for 30 minutes under reflux to then boil cool down. Then evaporate solvent, add 25 ml of water and the mixture is extracted 2x25 ml ethyl acetate. The organic extracts are dried, filtered and evaporate. 0.095 was obtained g of the compound mentioned

in the subheading.

MS (+ ve APCI) 324/326 ((M + H) +)

d) 2,6-Dihydro-2-methyl-6- (1-naphthylmethyl) -4- (2-propyl) amino-1H-pyrrolo [3,4-d] pyridazin-1-one ml isopropylamine was added to a solution of 0.095 g 4-chloro-2,6-dihydro-2-methyl-6- (1-naphthylmethyl) -1H-pyrrolo [3,4-d] pyridazin-1-one (0.095g) in 4 mL of ethanol. Heat the mixture in a sealed tube at 200 ° C for 3 days and then at 24 ° C for 24 hours.

I · 4 · 9 9

250 ° C. It is then evaporated and the residue is purified by chromatography on silica gel, eluting with ethyl acetate. It was then recrystallized from ethyl acetate / isohexane to give 0.013 g of the title compound.

221-222 ° C

Mass spectrum (ave APCI) 347 ((M + -K) -) ^{: 1} H NMR (DMSO d6 δ 1.12 (6H, d), 3.39 (3H, s), 3.80-3.92 (1H, m, 5.86 (2H, s), 5.98 (1H, d), 7.34 (1H, d), 7 _and 40 (1H, d),

7.44-7.60 (3H, m), 7.72 (1H, d), 7.95-3.01 (2H, m,

8.07-3.10 (1 H, m).

Example 23

2,6-Dihydro-2-methyl-4- (2-methylpropyl) -6- (4-pyridinyl) methyl 1H-pyrrolo [3,4-d] pyridazin-i-one

a) 2,6-Dihydro-2-methyl-4- (2-methylpropyl) -1H-pyrrolo [2,4-d] pyridazin-1-ene

7.3 g of methyl 4- (3-methyl-1-oxobutyl) -1K-pyrrole-3-carboxylate (prepared as described in Example 1, step b) and 6 ml of methylhydrazine were heated under reflux for 13 hours. The solvent was then evaporated and the residue purified by chromatography on silica gel eluting with dichloromethane-ethanol (19: 1). 5.2 g of the sub-title compound are obtained as a sand-colored solid.

• * · ·.-Mot carried rum (eve APCI) ((M-CH) ') 20 ‘

NMR (DMSO d6) 0.91 (d, 6H), 2.05-2.13 (m, 1H), 2.54 (d,

2H), 3.54 (s, 3H), 7.46 (t, 1H), 7.57 (t, 1H), 12,

1H).

'bi

b) 2,6-Dihydro-2-methyl-4- (2-methylpropyl) -6- (4-pyridinyl) methyl-1H-pyrrolo [3,4-d] pyridazin-1-one

A mixture of 0.04 g of 2,6-dihyaro-2-methyl-4- (2-methylpropyl) -1H-pyrrolo [3,4-d] pyridazin-1-one (prepared as described in Example 23, step a.) 0.2 g of cesium carbonate, 0.035 g of 4-chloromethylpyridine hydrochloride and 4.5 ml of dimethylformamide were shaken periodically for 13 hours, then the reaction mixture was evaporated under reduced pressure and the residue was purified by normal phase HPLC, eluting with dichloromethane: ethanol gradient. This afforded 0.024 g of the title compound.

. O. L. CLt, ml: 91-93 = C

Mass spectrum (+ ve APCI) ((M + H) +) 297

1 H NMR (CDCl 3)? δ 0 96 (d , 6H), 2.07-2.20 (m, 1H), 2.56 (d, 2H) 3.73 (s, 3H), 5.30 (s, 2H), 6.93-7.01 (m, 3H) 7.51 (d, 1H), 3.61 (d, 2H). - Next p torch eniny is prepared and cleaned procedure described in the example 23, step b), from 2,6-dihyaro-2 - methyl-4 - ( 2-methyl-

propyl) -1H-pyrrolo [3,4-d] pyridazin-1-one, cesium carbonate and the corresponding benzyl halide.

· Ti ί t t t t t t t ti ti ti ti ti ti

• · ·

Example 31

2,6-Dik propyl) ydro-N- [3- (1-1H-imidazolyl) propyl] -2-methyl-4- (2-methyl-1-oxo-6-phenylmethyl-1H-pyrrolo [3,4] -d] pyridazin-1-one 5-carbamate d

a) 2,6-Dihydro-2-methyl-4- (2-methylpropyl) -6-phenylmethyl-1H-pyrrolo [3,4-d] pyridazine-1-ene-5-carboxylic acid

2.35 ml of butyllithium (2.5M solution in hexane) was added dropwise at 0 ° C under nitrogen to a stirred solution of 0.85 ml of diisopropylamine in 10 ml of dry tetrahydrofuran. The reaction mixture was stirred at 0 ° C for 30 minutes and then cooled to -78 ° C. To this mixture is added a solution of 1.5 g of 2,6-dihydro-2-methyl-4- (2-methylpropyl) -6- (1-phenyimethyl) -1H-pyrrolo [3,4-d] pyridazin-1-one (prepared as described in Example 14, step b) in 10 ml dry telrahydrofuran. Stirring is continued for another 30 minutes. This anion is then added to the excess solid carbon dioxide. The reaction mixture was allowed to warm to room temperature overnight and then quenched by the addition of water. The mixture was extracted into ethyl acetate, washed with saturated brine, dried and evaporated to give a yellow oil. This was chromatographed on silica gel, eluting with ethyl acetate:

Isohexane (3: 7). 0.91 g of the title compound is obtained as a yellow solid (0.91 g).

Melting point: 129-130 ° C

Mass spectrum (+ ve APCI) ((M + H) +) 340'-NMR (CDCl ₃ ) δ 0.96 (d, 6H), 2.04-2.13 (m, 1H), 2.61 (d, 2H), 3.82 (s, 3H), 5.99 (s, 2H), 7.22-7.33 (m, 6H), 16.43 (s, 1H).

b) 2,6-Dihydro-2-methyl-4- (2-methylpropyl) -6-phenylmethyl-1H-pyrrolo [3,4-d: pyridazine-5-carbonyloxy] -3- (1-imidazolyl) propylamide n-1-admixture 0.04 g of 2,6-dihydro-2-methyl-4- (2-methylpropyl) -6-phenylmethyl-1H-pyrrolo [3,4-d] pyridazin-1-one-5-carboxylic acid, 0,5 ml of hydroxybenzotriazole (0.49M solution in dimethylformamide), 0.5 ml of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.47M solution in dimethylformamide), 0.03 g of N- (3-aminopropyl) imidazole and dimethylformamide (3 ml) was shaken periodically for 43 hours, then the solvent was evaporated and the residue was chromatographed on silica gel, eluting with dichloromethane: ethanol (19: 1). 0.01 g of the title compound is obtained.

Mass spectrum (+ ve APCI) ((M + H) +) 447

¹ H NMR (CDC1 ₃ ) δ 0.98 (d, 6H), 2 12-2.20 (m. 3H), 2.62 (d, 2H), 3, 40 (σ, 2H), 3.82 (s, 3H) 4.15 (q, 2H). 6.05 (with, 2H), 7, 10 (d, 2H), 7.20 (s, 1H). 7.30-7.40 (m, 5H) , 8.51 (with, . 1H,

11.81 (t, 1H);

• »• ·

Example 32

2,5-Dihydro-5-methyl-7- (2-methylpropyl) -2- (1-naphthylmethyl) 4H-pyrazolo (3,4-d) pyridazin-4-one

(a) Ethyl 4-hydroxy-6-methyl-2-hepmol c

To 6.0 ml of fresh ethylipropiclate (6.0 ml) in 75 ml of dry tetrahydrofuran was added dropwise over 40 minutes under nitrogen at a temperature below -63 ° C (maintained by external cooling) with stirring, 22.5 ml of n-butyllithium ( 2.5M solution in hexane). After 30 minutes, 6.5 mL of iscalvaldehyde in 15 mL of dry tetrahydrofuran was added over 15 minutes, maintaining the temperature below -69 ° C. After one hour, 10 mL of trimethylsilyl chloride was added and the reaction mixture was allowed to warm to room temperature. Water was then added and the mixture was extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride solution, dried and evaporated. 9.5 g of ethyl 4-hydroxy-6-methyl-2-heptinoate are obtained in the form of an oil.

GC / MS (after BSTMA) EI: 241 (M-15)

b) Ethyl 6-methyl-4-oxo-2-heptinoate

To 9.5 g of ethyl 4-hydroxy-S-methyl-2-heptinoate in 30 ml of acetone in an ice bath (maintaining the temperature at about 10 ° C) was added dropwise Jones reagent (prepared from 4 g of chromium trioxide) with stirring. . After 30 minutes, the reaction mixture was diluted with 300 mL of water and extracted three times with diethyl ether. The organic phase is washed with saturated sodium chloride solution, dried and evaporated. 7.0 g of ethyl 6-methyl-4-oxo-2-heptinoate are obtained in the form of an oil.

GC / MS EI: 167 (M-15)

NHNMR (CDCl ₃ ) δ 0.97 (6H, d), 1.30 (3H, t), 2.20 (1H, m, 2.51 (2H, d), 4.30 (2H, kv).

c) Ethyl 5- (3-methyl-1-oxobutyl) -1H-pyrazole-4-carboxylate and ethyl 4- (3-methyl-1-oxobutyl-1H-pyrazole-5-carboxylate)

To 7.0 g of ethyl o-methyl-4-oxo-2-heptinoate in 20 ml of dry tetrahydrofuran in a cold bath was slowly added 25 ml of dimethylsilyldiazomethane (2.0 M in hexane) under stirring under nitrogen. After 16 hours, the reaction mixture was evaporated to give an oil which was purified by chromatography on silica gel (ethyl acetate: isohexane 1: 2). 2.33 g of ethyl 5- (3-methyl-1-oxobutyl) -1H-pyrazole-4-carboxylases were obtained as the first eluted product.

Melting point: 105-107 ° C

Mass Spectrum (+ ve APCI) 225 ((M + H) +)

NH NMR (CDCl3) δ 0.99 (6H, d), 1.33 (3H, z), 2.25 (1H, m), 3.07 (2H, d), 4.35 (2H, kv), 3.12 (1H, s), 11.5 (1H, b).

The second eluted product was 1.22 g of ethyl 4- (3-methyl-1-oxobutyl) 1H-pyrazole-5-carboxylate (1.22g).

Melting point: 61-62 ° C

Mass spectrum (+ ve APCI) 226 ((M + H) +) ^X ¹H NMR (CDCl₃) δ 0.98 (6H, d), 1.42 (3H, t), 2.23 (1H, m, 2 79 (2H, d), 4.46 (2H, kv), 8.09 (1H, s), 12.55 (1H, br).

•. »· · · · · · · · · · ·

d) Ethyl 3- (3-methyl-1-oxobutyl) -1- (1-naphthylmethyl) -1H-pyrazole-4-carboxylate

In 15 ml SUChé him of domethylformamide under a nitrogen atmosphere spinal cord 24 hours 0.75 9 ^e thyl-5- (3-methyl-1-oxobutyl) -1H-pyrazole- 4-kar- bxylate, , 0.6 9 Of 1-naphthalenemethyl chloride and 1.25 g of union čitan q θ 3 Čd Π1Θ S s e then diluted with hydrochloric acid and extra-

It was extracted with ethyl acetate. The extract was washed with sodium chloride, dried and evaporated. Obtained in the name as a fruity residue.

Mass spectrum A.P + ve 365 (M + 1) saturated rttox of the compound indicated

1 H NMR (CDC1 ₃ ) 5 0.98 (6H, d) O , Λ O (3H - 1 / - / , 2, 21-2 , 37 (LH, m), C r 92 (2 H, (d) , 4.2 i (2K, kv) , 5, , 77 (2H, with) , 7, 39-7 57 (2 Η) (m) , 7.50 (1H , d), 7.61 (1 H, s), 7, 80-7, , 95 (2H, m), 7.95 (I

@ d).

e) 2,5-Dihydro-5-methyl-7- (2-methylpropyl) -2- (1-naphthylmethyl-4H-pyrazolo [3,4-d] pyridazin-4-one)

In 20 ml of ethanol, 1.8 g of ethyl 3- (3-methyl-1-oxobutyl) -1- (1-naphthylmethyl) -1H-pyrazole-4-carboxylate and 0.6 g were heated to reflux for 16 hours. methylhydrazine. The solution was then cooled and evaporated. The residue is purified by chromatography on silica gel (ethyl acetate: isobexane 2: 3). Crystallization from ethyl acetate / cyclohexane gave 0.43 g of 2,5-dihydro-5-methyl-7- (2-methylpropyl) -2- (1-naphthylmethyl) -4H-pyrazo [3,4-d] pyridazine-4- onu.

Melting point 166-167 ° C

Mass Spectrum (+ ve APCI) 347 ((M + H) &lt; + & gt ^; )

NMR (CDCl ₃ ) δ 1.02 (6H, d), 2.33 (1H, m), 2.82 (2H, d), 3.71 (3H, s), 5.97 (2K, s) 7.35-7.50 (4H, m), 7.3δ (1H, s), 7.36 (1H, d), 7.91 (1H, d), 7.93 (1H, d).

Example 33

2,6-Dihydro-6-methyl-4- (2-methylpropyl) -2- (1-naphthylmethyl) 7H-pyrazolo [3,4-d] pyridazin-7-one

a) Ethyl 4- (3-methyl-1-oxobutyl) -1- (1-naphthylmethyl) -1H-pyrazole-3-carboxylate

0.62 g of ethyl 4- (3-methyl-1-oxobutyl) -1H-pyrazole-5-carboxylate (prepared as described in Example 32, step c), 0.53 g, was stirred in 8 ml of dry dimethylformamide for 43 hours. g of 1-naphthylmethyl chloride and 1.1 g of cesium carbonate. The mixture was then diluted with hydrochloric acid and extracted with ethyl acetate, washed with saturated brine, dried and evaporated. 0.15 g of ethyl 4- (3-methyl-1-oxobutyl) -1- (1-naphthylmethyl) -1H-pyrazole-3-carboxylate is obtained in the form of a honey-like residue.

Mass spectrum (+ ve APCI) 365 ((M + H) ⁺ ) ^{: 1} H NMR (CDCl ₃ ) δ 0.87 (6H, d), 1.43 (3H, t), 2.12 (1H, m) 2.66 (2H, d), 4.47 (2H, kv), 5.80 (2H, s), 7.50 (1H, s), 7.4-7.6 (4H, m), 7.8-7.9 (3 H, m)

b) 2,6-Dihydro-6-methyl-4- (2-methylpropyl) -2- (1-naphthylmethyl) -7H-pyrazolo [3,4-d] pyridazin-7-one · · · · ·

A mixture of 0.15 g of ethyl 4- (3-methyl-1-oxobutyl) -1- (1-naphthylmethyl) -1H-pyrazole-3-carboxylate and 0.1 ml of methylhydrazine is heated under reflux for 2 hours in 2 ml of ethanol. reflux condenser. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried and filtered and evaporated. The residue was purified by chromatography on silica gel with dichloromethane: ethanol (19: 1). This afforded 0.03 g of the title compound.

likagelu,

M.p. 163-164 ° C

Mass (+ ve ARCI) ((M + H) +) 347 ^{: 1} H NMR (CDCl ₃ ) δ 0-35 (d, 6H), 1.39-2.03 (m, 1H), 2.44 (d 2H, 3.30 (s, 3H), 6.03 (s, 2H), 7.46-7.55 (m, 5H), 7.90-7.96 (m, 3H).

Example 34

2,5-Dihydro-3 - [(3-hydroxypropyl) thiol-5-methyl-7- (2-methylpropyl) -2-naphthylmethyl) -4H-pyrazolo [3,4-d] pyridazin-4-one

To a solution of 0.17 g of 2,5-dihydro-5-methyl-7- (2-methylpropyl) -2- (1-naphthylmethyl) -4H-pyrazolo [3,4-d] pyridazin-4-one and 0.34 g

S- [3 - {[(1,1-dimethylethyl) dimethylsilyl] oxyjpropyl] 4-methylbenzenesulfonothioate (J. Med. Chem. 1995, 38, 2557) in 7 ml 2 ml of lithium diisopropylamide (0.4 M solution in tetrahydrofuran) were slowly added to 1 dry tetrahydrofuran stirred at -73 ^° C under nitrogen. After 3 hours, saturated sodium bicarbonate solution was added, the mixture was allowed to warm to room temperature and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried and evaporated. 0.4 g of an oil is obtained, which is dissolved in 7 ml of acetonitrile and 0.4 ml of hydrofluoric acid (40% solution) is added. After 16 hours, an excess of saturated sodium bicarbonate solution was added, the mixture was washed with saturated sodium chloride solution, ext and evaporated. The residue is purified by chromatography to (ethyl acetate: isohexane 2: 1). Recrystallized from cyclohexane / ethyl acetylate 0.135 g of 2,5-dihydro-3 - [(3-hydroxypropyl) thio] -5-methyl-7- (2-methylpropyl) -2- (1-naphthylmethyl) -4H-pyrazolo [3,4-d] pyridazin-4-one.

ethyl acetate lacetátem, : ho, extract se vysust cleans on silica gel natural substance, which is .cezát. The team se ooorzi

141-142 ° C

Mass spectrum (+ in APCI) 43 / ((M + H) -)

(CDClý δ 0. 97 (6H, d), 1.76 (2H, quint), 2.30 (1H, m) 76 (2H, d), 3.27 (2H, t ), 3, 43 (1K, t), 3.76 (4H, s) 3 0 (2H, kv), 6.18 (2H, s) , 6.8 Δ (1H, d), 7.3-7.6 (3H, m) 81 (1H, d), 7.90 (1 H, d), 8.27 (1 H, d).

Example 35

2- [1-Hydroxy-1- (1-naphthyl) methyl] -5-methyl-7- (2-methylpropyl) fur [2,3-d] pyridazin-4 (5H) -one

and)

2- (1-Hydroxy-3-methylbutyl) furan-3-carboxylic acid

2.85 g of 3-furanoic acid are dissolved in 50 ml of tetrahydrofuran and cooled to -73 ° C. A solution of 56 mmol of lithium diisopropylamide in 100 ml of tetrahydrofuran was added dropwise. Mix with micna or:

m.p. -73 ° C

solution 3. , 0 ml 3 -me- . Reaction mixture with 1 hour e heats up to the temperature the aqueous phase is acidifies 2M twice extra huje ethyl-

acetate. The organic phases are washed with saturated sodium chloride solution, dried, filtered and evaporated. The residue is purified by chromatography on silica gel, eluting with dichloromethane: ethyl acetate: acetic acid (160: 40: 1). 2.75 g of the sub-title compound are obtained.

Mass Spectrum (-ve APCI) 197 ((M-H) -)

NMR (CDCl 3 δ 0.96 (6H, m, 1.62-1.89 (3H, m, 5.12 (1H, dd)),

6.73 (1H, d); 7.32 (1H, d).

b) Trimethylsilylmethyl-2- (1-hydroxy-3-methylbutyl) furan-3-carboxylate

800 mg of 2- (1-hydroxy-3-methylbutyl) furan-3-carboxylic acid is dissolved in 30 ml of dichloromethane and 2.1 ml of a solution of trimethylsilyldiazomethane (2M solution in hexane) is added. The mixture was stirred for hours, then diluted with dichloromethane and washed twice.

I with hydrochloric acid. The organic phase was washed with saturated sodium chloride solution, dried, filtered and evaporated. The residue is purified by chromatography on silica gel, eluting with diethyl ether: isohexane (1: 1). 435 mg of the sub-title compound are obtained.

Mass spectrum (+ ve APCI) 257 ^((M-Me)): H NMR _(CDCl3) δ 0.12 (9H, s), 0.95 (6H, dd), 1.50 to 1.33 (3H , m,

3.96 (2H, s), 4.37 (1H, d), 5.01 (1H, m), 6.64 (1H, d),

7.26 (1 H, d).

c) Trimethylsilylmethyl -2- (3-methyl-1-hexyl) fluoro-3-carbonyl.

Dissolve 125 μΐ of dimethylsulfoxide in 10 ml and cool to -78 ° C. 30 µl of dichloromethane and oxalyl chloride and methyl 2- (1-hydroxy-3-methylbutyl) furan-3-carboxylate in 10 ml of dichloromethane are added dropwise and the mixture is stirred for 20 minutes, then 0.49 ml of triethylamine is added, stirred 20 minutes, then warmed to room temperature, poured into water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried, filtered and evaporated. 170 mg of the sub-title compound are obtained.

MS (+ ve APCI) 233 ((M + H) &lt; + & gt ^; )

d) 5-Methyl-7- (2-methylpropyl) furo [2,3-d] pyridazin-4 (5H) -one

170 mg of trimethylsilylmethyl 2- (3-methyl-1-oxobutyl) furan-3-carboxylate and 40 μΐ of methylhydrazine are dissolved in 10 ml of xylene. The mixture was heated to reflux for 5 hours. It was then allowed to cool to room temperature, poured into water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, filtered and evaporated. The residue was chromatographed on silica gel, eluting with ischexane: ethyl acetate (3: 2). 49 mg of the title compound are obtained.

Mass spectrum (+ ve APCI) 207 ((M + H) +) ^{: 1} H NMR (CDCl 3) δ 0.98 (6H, d), 2.12-2.26 (1H, d), 2.73 ( 2H, d)

3.84 (3H, s), 7.05 (1H, d), 7.65 (1H, d).

e) 2- [1-Hydroxy-1- (1-naphthyl) methyl] -5-methyl-(- (2-methylpropyl / furo-2,3-d] pyridazin-4 (5H) -one

5 mg of 5-methyl-7- (2-methylpropyl) furo [2,3-d] pyridazin-1 (5H) -one is dissolved in 5 ml of tetrahydrofuran and cooled to room temperature.

-73 ° C. Tetrahydrofuran (1M solution) is added to the solution with 80 μl! 1-Naphthaldehyde

0.56 ml of lithium diisopropylamide in and the mixture was stirred for 30 minutes. then, and the mixture is stirred for 30 minutes. It is then brought to room temperature, poured into water, extracted three times with ethyl acetate, the organic phases are washed with saturated sodium chloride solution, dried, filtered and evaporated. The residue is purified by chromatography on silica gel, eluting with ischexane: ethyl acetate (1: 1). 50 mg of the title compound are obtained.

Melting point 110-112 ° C

Mass spectrum (+ ve APCI) 363 ((M + H) +) 1 H NMR (CDCl 3) δ 0-91 (6H, dd), 2.04-2.18 (1H, m), 2.67 ( 2H, d)

2.81 (1H, d), 3.79 (3H, s), 6.66 (1H, d), 6.73 (1H, s),

7.48-7.53 (3H, m), 7.65 (1H, d), 7.87-7.91 (2H, m), 8.04-8.06 (1H, m).

• ·

Example 36

5-Methyl-7- (2-methylpropyl) -2- (1-naphthylmethyl) furo [2,3-d] pyridazine-4 (5H) -one

63 mg of 2- [1-hydroxy-1- (1-naphthyl) methyl] -5-methyl-7- (2-methylpropylfuro [2,3-d] pyridazin-4 (5H) -one) are dissolved in 3 ml of dichloromethane. 1 ml of trifluoroacetic acid and 1 ml of methylsilane are added and the mixture is stirred for 24 hours, poured into 2M sodium hydroxide solution and extracted twice with ethyl acetate, and the combined organic phases are washed with saturated sodium chloride solution, dried, filtered and evaporated. Purify on silica gel, eluting with isohexane: ethyl acetate (1: 1) to give 52 mg of the title compound.

Mp 73-75 ° C

Mass spectrum (ν / e APCI) 347 ((MiH) ⁺ )

NMR (CDCl 3 δ 0.94 (6H, d), 2.0 3-2.2 2 (1H, m), 2.69 (2H, d),

3.79 (3H, s), 4.56 (2H, s), 6.50 (1H, s), 7.37-7.53 (4H,

m), 7.81-7.99 (3 H, m).

Example 37

- [1-Hydroxy-1- (3-cyanophenyl) methyl] -5-methyl-7- (2-methylpropyl) furo [2,3-d] pyridazin-4- (5H) -one

CN

Following the procedure described in Example 35, step e, prepare from 5-methyl-7- (2-methylpropyl) furo [2,3-dpyridazin-4 (5H) -one (prepared as described in Example 35, step d) and 3). -cyanob enza 1de hydu.

Melting point: 106-103 ° C

MS (+ ve APCI) 333 ((M + H) +) ^{: 1} H NMR (CDCl 3 δ 0.93 (6H, α), 2.04-2.13 (1H, m), 2.67 (2H, d), 3.30 (1H, d), 3.81 (3H, s), 6.00 (1H, d), 6.81 (1H, s), 7.52 (1H, t), 7, 67 (2H, m), 7.81 (1 H, s).

Example 33

2- (3-Cyano phenyl) methyl-5-methyl-7- (2-methylpropyl) furo [2,3-d] pyridazin-4 (5H) -one

CN

M.p .: 76-78 ° C

Using the procedure described in Example 36, 2- (1-hydroxy-1- (3-cyanophenyl) methyl) -5-methyl-7- (2-methylpropyl) furo (2,3-d) pyridazin-4 (5H) -one was prepared.

Weight

[α] + (APCI) 322 ((M + H) +)

^; 1 H NMR (CDCl 3) δ 0.95 (6H, d), 2.13 (1H, m), (3H, s), 4.17 (2H, s), 6.68 (1H, s),

7.53-7.50 (2 H, m)

3.63 (2H, d), 3.82

7.44-7.52 (2 H, m,

Example 39

2- (2-Trifluoromethylphenyl) methyl-5-methyl-7- (2-methylpropyl) thieno [2,3-d] pyridazine-4 (5H) -one

To a solution of 1.00 g of 5-methyl-7- (2-methylpropyl) thieno [2,3-d] pyridazin-4 (5H) -one (prepared as described in Example 6, step b) in 20 ml of tetrahydrofuran was added A solution of lithium diisopropylamide (11.3 mmol) in tetrahydrofuran / hexane (2.-1) (16 ml) was added dropwise at -78 ° C under nitrogen. After 5 minutes, 1.57 g of 2-trifluoromethylbenzaldehyde was added. The mixture was stirred at -78 ° C for 3 hours, then 50 mL of saturated sodium bicarbonate solution was added and the mixture was allowed to warm to room temperature. It is extracted with 50 ml of ethyl acetate, the organic extract is washed twice with saturated sodium bicarbonate solution, then with saturated sodium chloride solution, then it is dried, filtered and evaporated. The residue was dissolved in 5 mL of trifluoroacetic acid and 2 mL of triethylsilane was added. After 24 hours, an additional 5 mL of trifluoroacetic acid and 2 mL of triethylsilane were added. After an additional three days, the mixture was diluted with 50 mL of water and extracted with 50 mL of ethyl acetate.

The organic extract was washed twice with 1M sodium hydroxide solution, then with saturated sodium chloride solution, then dried, filtered and evaporated, and the residue was purified by chromatography on silica gel, eluting with an ethyl acetate / isohexane gradient. Followed by normal phase oreoarative HPLC with a dichloromethane / ethanol gradient and a eohylacezate / isohexane gradient. This afforded 0.055 g of the title compound.

Melting point 112-114 ° C

The spectrum is in APCI; 381 ((M + H) +) ^{: 1} H NMR (CDCl 3) δ 0.97 (6H, d), 2.12-2.24 (1H, m), 2.59 (2H, d), 3.31 ( 3H, s), 4.41 (2H, s), 7.35-7.43 (3H, m), 7.53 (1H, t), 7.70 (1H, d).

Example 40

2 - [(1-hydroxy-1-pyridin-3-yl) methyl] -5-methyl 7- (2-methylpropyl) thieno [2,3-d] pyridazin-4 (5H) -one hydrochloride

Compound (crude product gave 1.00 g of the title product as the free base)

5-methyl-7- (2-methylpropyl) thieno [2,3-d] pyridazin-4 (5H) -one (prepared as described in Example 6, step b) and 0.96 g of 3-pyridinecarboxaldehyde as described in Example 14. This material is purified by chromatography on silica gel, eluting with an ethyl acetate / ethanol gradient. It is then dissolved in 50 ml of ether and 0.5 ml of 4M chlo99 solution is added.

Equilibrium in 1,4-dioxane. The resulting precipitate was collected and dried in vacuo. This gave 0.06 g of the title compound.

Melting point: 154-156 ° C

Mass Spec (+ ve APCI) 330 ((M + H) +)

Ή NMR (DMSO d ₆ ) δ 0, 96 (6H, d), 1, 39 (1 H, s), 2.10-2.24 (1H, m), 2.59 (2H, d), 3, , 80 (3H, with) , 6.16 (1H , s), 7.32 (1H, dd) , 7.43 (1H,  s), 7.81 (if and, dt), 8 . 5 5 (1 H, dd), 8.63

(1H, d).

Example 41

5-Methyl-7- (2-methylpropyl) -2- (3-pyridinylmethyl) thieno [2,3-d] pyridazine; (5H) -one

Following the procedure described in Example 43b, 2 - [(1-hydroxy-1-pyridin-3-yl) methyl] -5-methyl-7- (2-methylpropyl) thieno [2,3-d] pyridazine hydrochloride was prepared from 0.54 g. -4 (5H) -nu (prepared as described in Example 40). The crude product residue is chromatographed on silica gel, eluting with ethyl acetate: methanol: aqueous ammonia (39: 0: 1.94: 5: 1 to 89: 10: 1). This is followed by an overlay with ether. 0.30 g of the title compound is obtained.

Melting point: 118-119 ° C

Mass Spectrum (+ ve APCR) 314 ((M + H) +)

1 H NMR (C DClý δ 0.96 (6K, d), 2, 13-2, 22 (LH, m), 2.59 (2H, a) 3, 81 (3H, s, 4.25 (2H, s), 7.23 ( 1H, dd) 7.43 (1H, s) 7, 57 (1H, d), 8.54-8.57 (2H, m).

Example 42

2- (2-Chloro-6-fluorophenyl) methyl-5-methyl-7- (2-methylpropyl) thieno [2,3-d] pyridazine-4 (5H) -one

Following the procedure described in Example 14, 1.00 g of 5-methyl-7- (2-methylpropyl) thieno (2,3-d) pyridazin-4 (5H) -one (prepared as described in Example 6, Step 5) was prepared. b) and 0.96 g of 2-chloro-6-fluorobenzaldehyde The crude product was purified by preparative HPLC with a dichloromethane / ethanol gradient followed by crystallization from isohexane to give 0.07 g of the title compound.

Melting point 35-36 ° C

Mass spectrum (+ ve APCi) 365/367 ((M + - H) ⁺ ) ³ Η NMR (CDCl 3) δ 0.97 (6H, d), 2.15-2.24 (1H, m), 59 (2H, d);

3.80 (3H, s), 4.39-4.40 (2H, s), 7.01-7.03 (1H, m),

7.19-7.26 (2 H, m), 7.42 (1 H, s).

Example 43

- [(1-Hydroxy-1-quinolin-3-yl) methyl] -5-methyl-7- (2-methylpropyl)

1) thieno [2,3-d] pyridazin-4 (5H) -one.

Β · · · ·· ··

Following the procedure described in Example 14, 1.00 g of 5-methyl-7- (2-methylpropyl) thieno [2,3-d] pyridazin-4 (5H) -one (prepared as described in Example 6, step b) was prepared. and 1.06 g of 3-quinolinecarboxaldehyde. The crude product is purified by chromatography on silica gel, eluting with ethyl acetate: triethylamine (99: 1) and then ethyl acetate / methanol / triethylamine (39: 10: 1). 0.50 g of the title compound is obtained as an oil.

Mass Spectrum (+ ve APP) 380 ((M + H) +).

Example 44

Hydrochloride.

5-Methyl-7- (2-methylpropyl) -2- (3-quinolinylmethyl) thienof [2,3-d] pyridazin-4 (5H) -one

To a solution of 2 - [(1-hydroxy-1-quinolin-3-yl) methyl] -5-methyl-7- (2-methylpropyl) thieno [2,3-d] pyridazin-4 (5H) -one in 8 mL of dichloromethane 0.10 ml of thionyl chloride is added at room temperature. After 3 hours the solution was evaporated and the residue was dissolved in 15 ml of ethyl acetate. 0.50 ml of triethylamine was added and the solution was hydrogenated to 0.035 g of palladium on carbon (5% mixture) for 20 hours. The mixture was stirred for 20 hours. · »· · ·

I ···· · ·· ⁴ »· · ···« · | The mixture is filtered and the catalyst is washed with 50 ml of ethyl acetate. The filtrate was washed with water, then twice with saturated sodium bicarbonate solution and then with saturated sodium chloride solution. The organic phase is dried, filtered and evaporated. The residue is purified by chromatography on silica gel, eluting with ethyl acetate: isohexane: triethylamine (50: 50: 1, 66: 33: 1 then 100: 0: 1). The resulting oil was dissolved in 50 ml of ether and 0.5 ml of a 4M solution of hydrogen chloride in 1,4-dioxane was added. The resulting precipitate was collected and dried in vacuo. This afforded 0.09 g of the title compound.

Melting point> 230 ° C (decomposition)

Mass spectrum (+ ve APCI) 364 ((M + H)) @ 1 H-NMR (DMSO d6): 0.90 (6H, d), 2.06-2.15 (1H, m, 2.53 (2H, d),

3.63 (3H, s), 4.66 (2H, d), 7.60 (1H, s), 7.73 (1H, t), 7.95 (1H, t), 3.14-3 20 (2H, m, 8.74 (1H, s)), 9.13 (1H, s).

Example 45

2- (3-Chlorophenyl) methyl-3- (2-hydroxyethoxy) -7- (methoxymethyl) 5-mesylthieno [2,3-d] pyridazin-4 (5H) -one

Cl

a) Methyl -5 - [(3-chlorophenyl) methyl] -4-hydroxythiophene-3-carboxylate

A mixture of 18.5 g of methyl 4-oxotetrahydrothiophene-3-carboxylate and 48.5 g of 3-chlorobenzaldehyde was heated to 100 ° C for 15 minutes with 4 ml of piperidine. The mixture was cooled to room temperature and the resulting p-toluenesulfonic yellow solid was added and stirred in 300 mL of methanol for 13 hours. and then separate. The yellow solid was suspended in 300 mL of ethanol and 200 mL of acid dichloromethane. The suspension was heated to reflux for 43 hours. The reaction mixture was allowed to cool and then concentrated. The residue is purified by chromatography on silica gel, eluting with 10: 1 isohexane: dichloromethane. 22.32 g of the poonaapis compound are obtained.

Mass spectrum (+ ve APCI) ((M + H) ') 233/5 ^H NMR (DMSO- d _s) δ 3.7 9 (3H, s), 4, 03 (2H, 5), 7.04 (1 H, s), 7.33-7.39 (1 H, m, 7) , 45-7, 57 (2 H, m, 7, 6 5 (1H, s) 10.76 (1 H, s).

b) Methyl 5 - [(3-chlorophenyl) methyl] -4- {2- (1,1-dimethylethyl) dimethylsilyl] oxyethoxy)} thiophene-3-carboxylate

A mixture of 11 g of methyl 5 - [(3-chlorophenyl) methyl] -4-hydroxythicophene-3-carboxylate, 5.45 g of potassium carbonate and 10 g of (2-bromoethoxy) (1,1-dimethylethyl) dimethylsilane is dissolved in 250 ml of acetone. and refluxed for 36 hours. It is then allowed to cool, filtered, concentrated and the residue is purified by chromatography on silica gel, eluting with 10: 1 ethyl acetate: isohexane. 8 g of the sub-title compound are obtained.

Mass spectrum (+ ve APCI) ((M + H) +) 442/4

c) 5 - [(3-Chlorophenyl) methyl] 4- (2-1,1-dimethylethyl) dimethylsilyl] oxyethoxy / thiophene-3-carboxylic acid

In a mixture of 50 ml of 1M lithium hydroxide solution, 50 ml of methanol and

10.2 g of methyl 5 - [(3-chlorophenyl) methyl] -4- {2 - [(1,1-dimethylethyl) dimethylsilyl] oxyethoxide are dissolved in 150 ml of tetrahydrofuran. carboxylate and stirred for 13 hours. The reaction mixture was concentrated and the residue was partitioned between dichloromethane and 2M hydrochloric acid, the organic layer was separated, dried and filtered. 7 g of t-butyl-dimethylsilyl chloride and 3.1 g of imidazole are added to the solution, and the mixture is stirred for 72 hours, the reaction mixture is concentrated and the residue is dissolved in methanol. 5 g of potassium carbonate are added and the mixture is stirred vigorously for 3 minutes. It is then filtered and concentrated. The residue was dissolved in ethyl acetate, washed with 2M hydrochloric acid, dried, filtered and concentrated. The residue is purified by chromatography on silica gel, eluting with 10: 1: 1 isohexane: ethyl acetate: acetic acid. 4.2 g of the sub-title compound are obtained.

Mass spectrum (-ve APCI) ((M-Me)) 427/9

d) 2 - [(3-Chloro-phenyl) methyl] -3- (2-hydroxy-ethoxy) -4- (methoxymethyl) -S-methyl-thieno [2,3-d] pyridazin-4 (5H) -one ml 2 A 1.0 M solution of butyllithium in hexane was diluted with 3 mL of tetrahydrofuran and cooled to -20 ° C. 1 ml of a 1M solution of 5-L (3-chlorophenyl) methyl] -4- (2 - [(1,1-dimethylethyl) dimethylsilyl] oxyethoxy) thiophene-3-carboxylic acid in tetrahydrofuran is slowly added. The solution was stirred for 10 minutes and then 1 mmol of 2, N-dimethoxy-N-methylacetamide in 1 mL of tetrahydrofuran was added. The solution was stirred for 10 minutes and then added to 5 mL of ammonium chloride solution. The reaction mixture was evaporated in air for 18 hours, the residue was dissolved in dichloromethane and washed twice with water. The solvent was evaporated in air and the residue was dissolved in 5 ml of ethanol. To this solution was added 92 mg of methylhydrazine. The resulting solution was heated to reflux for 4 hours. The mixture was allowed to cool and the solvent was evaporated. The residue is purified by chromatography on silica gel, eluting with an isohexane: ethyl acetate gradient. 4 mg of the title compound is obtained.

MS (+ ve APCI) 395/397 (M + H;

NH NMR (DMSO d6) = 3.33 (3H, s), 3.76 (3H, s), 3.80-3.84 (2H,

4.12 (2H, s), 4.13-4.16 (2H, m, 4.43 (2H, s)), 7.07-7.93 (4H, m / z);

The following compounds were prepared as described in the example using the appropriate N, O-dimethylhydroxylamide.

• · · · · · · · · · · · · · · · · · · · · · · · ·

• ·

Example 49

-Cyclopropylmethyl-3-methoxy-5-methyl-2 - [(3-trifluoromethylphenyl / methyl) thieno [2,3-d] pyridazin-4 (5H) -one

a) Butyl 5 - [(3-trifluoromethylphenyl) methyl] -4-hydroxythioph 3-carboxylate

A mixture of 3.2 g of methyl 4-oxotetrahydrothiophene-3-carboxylate and 10.6 g of 3-trifluoromethylbenzaldehyde was heated at 100 ° C for 15 minutes with 170 mcf oiceridine. It is then allowed to cool to room temperature.

and the solid is collected for 18 hours in ~ 50 m methanol. It is separated and suspended in 150 ml of butanol with 10 g of p-toluenesulphonic acid and heated under reflux for 43 hours. The reaction mixture was concentrated and purified by chromatography on silica gel, eluting with 10: 1 isohexane / dichloromethane. 2.5 g of the sub-title compound are obtained.

Mass Spectrum (+ ve APCI) ((M + H) +) 359

b) Butyl 4-methoxy-2 - [(3-trifluoromethylphenyl) methyl] thiophene-3-carboxylate

2.5 g of butyl 5 - [(3-trifluoromethylphenyl) methyl] -4-hydroxythiophene-3-carboxylate are dissolved in 50 ml of acetone. 1 g of potassium carbonate and 0.45 ml of methyl iodide are then added and the mixture is heated under reflux for 18 hours. The mixture was allowed to cool, then concentrated, the residue was dissolved in ethyl acetate, washed with water, dried, filtered and evaporated. The residue is purified by chromatography on silica gel, eluting with 40: 1 isohexane: ethyl acetate. 1.75 g of the title compound are obtained.

1 H NMR (DMSO d6 δ 0.92 (3H, t), (2H, m, 3.72 (3H, s)), 4.13 (21 (4H, m, 8.10 (1H, s)).

34-1.47 (2H, m, 1.61-1.70)

s), 4.21 (2H, d), 7.55-7.62 cm -1; 4-Methoxy-5 - [(3-trifluoromethylphenyl) methyl] thiophene-3-carboxylic acid

1.75 g of bucyl 4-methoxy-2 - [(3-trifluoromethylphenyl) methyl] thiophene-3-carboxylate are dissolved in a mixture of 10 ml of 1M odd hydroxide, 30 ml of tecrahydrofuran and 10 ml of methanol, and the solution is stirred for 18 hours. The reaction mixture was then concentrated and the residue was dissolved in ethyl acetate and washed with 2M hydrochloric acid. The organic layer was dried and concentrated. 1.25 g of compound is obtained

listed in the title in form white solids (1 25 g). Mass spectrum (-ve APCI) ((M-H) ’) 315 ¹ H NMR (DMSO d ₆ ) δ 3.71 (3H, s), 4.16 (2H, s), 7.54-7.61 (4H m), 8.04 (1H, s ), 12, 64 (1 H, s).

d) 2- (2-Cyclopropyl-ethyl) -4-methoxy-5 - [(3-trifluoromethyl) phenyl] methyl] thiophene-3-carboxylic acid

To a solution of 500 mg of 4-methoxy-5 - [(3-trifluoromethylphenyl) methyl] thiophene-3-carboxylic acid in 30 mL of tetrahydrofuran was slowly added at -78 ° C 1.75 mL of a 2M solution of butyllithium in hexane. The resulting red solution was stirred for 20 minutes and then 229 mg of 2-cyclopropyl-N-methoxy-N-methylacetamide in 3 ml of tetrahydrofuran was added. The mixture was stirred at -78 ° C for 20 minutes and then allowed to warm to room temperature. After 5 hours, water was added and the mixture was extracted with ethyl acetate. The organic phase is dried and concentrated. The residue is purified by chromatography on silica gel, eluting with 10: 10: 1 isohexane: ether: acetic acid. 177 mg of the sub-title compound are obtained.

Mass Spectrum (+ ve APCR) ((M + H) +) 399

1 H NMR- (DMSO-) - r-3 '} δ 0.91-1.14 (2H, m, 0.44-0.49 (2H, m)) 0.94-1.14 (1H, m), 2.66 (2H, d), 3.77 (3H, s), 4.26 (2H, s), 7,56-7,66 (3K, m), 7.69 (1 H, s), 13.66 (1 H, bs). e) 7 -Cyclic oil y lmethyl -3-methoxy · -5-methyl-2 - [(3-trifluoromethyl-

phenyl) methyl] thieno [2,3-d] pyridazin-4 (5H) -one

8.65 g of 2- (2-cyclopropylacetyl) -4-methoxy-5 - [(3-trifluoromethylphenyl) methyl] thiophene-3-carboxylic acid are dissolved in 125 ml of ethanol. To this solution was added 2.34 ml of methylhydric acid. The organic mixture was heated to reflux for 18 hours. The mixture was then allowed to cool and concentrated.

between ethyl acetate and 2M hydrochloric layer was separated, dried, filtered and 8 g of the title compound.

Return of the selenium salt. thicken behind

Mass spectrum (+ ve APCI) ((M + H) + 409)

1 H NMR (DMSO d6 δ 0.22 (2H, m), 0.48 (2H, m), 1.00 -1, 10 (1H, m), 2.61 (2H, d), 3.69 ( 3H, s), 3.88 (3H, s), 4.33 (2H, s),

7.55-7.64 (3 H, m), 7.69 (1H, s).

Example 50

-Cyclopropane methyl-5-methyl-3- [2- (methylthio) ethoxy] -2 - [(3-trifluoromethylphenyl) methyl] thieno [2,3-d] pyridazine-4 (5H) - he

a) 7-Cyclopropylmethyl-3-hydroxy-5-methyl-2 - [(3-trifluoromethylphenyl) methyl] thieno [2,3-d] pyridazin-4 (5H) -one

Dissolve 8,3 g of 7-cyclopropylmethyl-3-mechoxy-5-methyl-2 - [(3-trifluoromethylphenyl) methyl] thieno [2,3-d] pyridazin-4 (5H) -one in 250 ml of dichloromethane and cool to 5 ° C. Then, 24 ml of a 1M solution of boron tribromide in dichloromethane is added. The reaction mixture was allowed to warm to room temperature and stirred for 72 hours. Water was then added and the mixture was extracted with ethyl acetate. The extract is dried, filtered and concentrated. The residue is purified by chromatography on silica gel, eluting with 1: 1 isohexane: ether, and then recrystallized from isohexane. 4.5 g of the title compound are obtained.

Melting point 92-93 ° C

Mass spectrum (+ ve APCI) ((M + H) +) ^395: H NMR (DMSO- d _s) δ 0.21-0.23 (2H, m), 0.43 to 0.50 (2H, m) 1.04-1.08 (1H, m), 2.60 (2H, d), 3.67 (3H, s), 4.26 (2H, s), 7.56-7.64 (3H) m, 7.67 (1H, s), 9.27 (1H, s).

b) 7-Cyclopropylmethyl -5-methyl-3- [2- (methylthio) ethyl-2 - [(3-trifluoromethylphenyl) methyl] thieno [2,3-d] pyridazin-4 (5H) -one

To 5 ml of dry tetrahydrofuran was added 0.64 ml of a 1M solution of triphenylphosphine in tetrahydrofuran and then 0.64 ml of a 1M solution of diethyldiazodicarboxylate in tetrahydrofuran and then 0.64 ml of a 1M solution of 2,6-di-t -butylphenol in tetrahydrofuran. This was stirred for 5 minutes and then 1.23 ml of a 0.5 M solution of thylthioethanol in tetrahydrofuran was added. The solution was stirred for 5 minutes and then a solution of 243 mg of 7-cyclopropylmethyl-3-hydroxy-5-methyl-2 - [(3-trifluoromethylphenyl) methyl] thieno [2,3-d] pyridazin-4 (5H) -one was added. in 1 ml tetrahydrofuran. The solution is stirred periodically for 24 hours and then purified by chromatography on silica gel, eluting with a gradient of isohexane and ethyl acetate. 77 mg of the title compound are obtained.

Mass spectrum (SS + ve, TOF) ((M + H)) found: 469.1241; calculated for: 469.1231

ΘιΘ S ΞΘ

- in ~ -

NMR 1, 02 (DMSO -1.03 d _s ) 50 (1H, m, 2, , 21-0.23 11 (3H, (2H, s), 2, (m) , 66 , 0,48-0150 (2 Κ, d), 2, N 5 (2H, (2H, 3, 69 (3H, s), 4.30 ( 2H, t) 4.40 (2H, s), 7.56-7.64 (3H / , / of. (H J -

m,

(t)

The following compounds were prepared as described in Example 50 using the appropriate alcohol as reactants.

· * · · «« · · · ·

Pharmacology of human lymphocyte reaction (MLR)

The MLR assay is performed in a 96-well flat bottom microtiter plate. Compounds are prepared as a 10 mM stock solution in dimethylsulfoxide. 50 dilutions are made in a culture RPMI 1640 cell solution. Serial dilutions are prepared from this solution. Place 10 μΐ of these 50 diluted samples in each well so that the test concentration starts at 9.5 µm and further decreases. 1.5x10 ⁼ cells from both corresponding donors are plated in each well in a final volume of 0.2 ml RPMI 1640 medium supplemented with 10% human serum, 2 mM L-glutamine and penicillin./ strepcomycin. Cells are incubated at 37 ° C in a humidified atmosphere with 5% carbon dioxide for 120 hours. ³ H-thymidine (0.5 pCi level of cell-absorbed radioactivity, T-cell profiling) is added for the last 6 hours of incubation.

Then it is measured coz is the bar

In the above assay, the title compound examples 1 to 57 exhibited hoanccy IA _S0 less than lxl0 ^'Ì M.

Claims (12)

PATENT CLAIMS A compound of formula I wherein 3 is CH or a nitrogen atom (Ν), a sulfur atom (S) or an oxygen atom (O); D is carbon atom (C) or nitrogen atom (Ν); Ξ is CR ³ or a nitrogen atom (N); when D is carbon then 3 is sulfur or oxygen and Ξ is CR ³ , and if D is nitrogen then either 3 is CH and E is CR ³ or nitrogen, or 3 is nitrogen and E is CR ³ ; R ¹ is a group NR'R where R 'is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R is an alkyl group having 1 to 6 carbon atoms, or R' and R together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated heterocyclic ring, or R is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkyloxyalkyl group having 1 to 3 carbon atoms in each alkyl moiety, a cycloalkyloxyalkyl group having 3 to 6 cycloalkyl moieties C 1 -C 3 -alkyl, C 3 -C 6 -alkenyl, phenyl, C 3 -C 7 -cycloalkyl, C 3 -C 5 -cycloalkylmethyl or C 3 -C 5 -cycloalkenyl; 3-7 carbon atoms, each of which may be optionally substituted by one or several halogens; R ² is methyl or C 2 -C 6 alkyl optionally substituted with C 1 -C 6 alkoxy other than in the 1-position; R ³ is hydrogen or XR ³ or X-Ar ¹ ; X is -O-, S (O) _n , SO, N (R 0) or C (= O) N (R ⁵ ); n is 0, 1 or 2; R is an optionally substituted alkyl or alkenyl group, or further when X is SO _; N (R c), or C (= ^ 0) N (R ^{S), R} and R ⁶ form together with the nitrogen atom to which they are attached, an optionally substituted three- to seven-membered heterocyclic ring; Ar is an optionally substituted phenyl or pyridyl group; ^R is hydrogen, alkyl of 1-6 carbon atoms, or is linked to R ⁵ as defined above; R ⁴ is CHR ⁷ Ar ² or Ar ³ , or further when D is carbon, C (O) Ar ² or CR ⁷ (OH) Ar ² ; Ab is an aryl or heteroaryl group which may be optionally substituted; Ar ³ is acenaphthenyl, indanyl or fluorenyl, each of which may be optionally substituted; 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 R ⁷ is hydrogen or alkyl having 1 carbon atom; or a pharmaceutically acceptable salt or solvate thereof. 2. A compound according to claim 1, wherein ^R is alkylamino having 1 to 4 carbon atoms, or R ¹ is an alkyl group containing 3-5 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkyloxyalkyl group having in each alkyl part 1-3 carbon atoms, cycloalkyloxyalkyl group containing 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 3 carbon atoms in the alkyl portion, alkenyl group containing 3 to 6 carbon atoms, phenyl, cycloalkyl group containing 3 to 5 carbon atoms, cycloalkylmethyl group containing in cycloalkyl or C 3 -C 5 cycloalkenyl or C 3 -C 5 cycloalkenyl, each of which may be optionally substituted with one to four halogen atoms. A compound according to claim 1 or 2, wherein R ² is a methyl or C 2 -C 6 alkyl group optionally substituted with a C 1 -C 4 alkoxy group other than the 1-position. A compound according to any one of claims 1 to 3, wherein R ⁴ is CHR ⁷ Ar ² , C (O) Ar ² or CR ⁷ (OH) ArV A compound according to claim 4, wherein Ar ^{2 is} phenyl, naphthyl, pyridyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, thienyl, benzothienyl, furanyl , benzofuranyl, thiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl; Indolyl, indolizinyl, pyrazolyl, indazyl, imidazolyl, benzimidazolyl, imidazopyridyl, triazolyl, benzatriazolyl or triazolopyriayl groups, each it may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, trif lucromethyl, trifluoromethoxy, amino, cyano, carboxyl, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, (di) C 1 -C 6 alkylamino, acylamino C 1 -C 6 alkylamino; C 2 -C 6 alkylsulfonamido, C 1 -C 6 alkyls, C 1 -C 6 alkyl (CONH) (C 1 -C 6 alkyl) and C 1 -C 6 alkoxycarbonyl. A compound according to any one claim 1 to 5 in which X is -O- group, S (0) _{n group} , where n Yippee 0, 1 or 2, or C (= O) N (R ⁵ ). A compound according to any one claim 1 to 6, wherein R ⁵ is alkyl group containing 2 and z 6 atoms carbon or C 2 -C 6 alkenyl optionally substituted with one or more substituents independently selected from the group consisting of amido, amino, carboxyl, cyano, hydroxyl, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms , (C1-C6) -alkylcarbonyl, (C1-C6) -alkoxycarbonyl, (C1-C6) -alkoxycarbonyl 100 ALIGN! 44 99 l- · · · · · · · · (C)-C)) alkylamino group, (C)-C alky) alkylamino group, (C až-C ac) acylamino group, (C až-C alkyl) alkylsulfonamido group, tetrahydrofuranyl, dioxclanyl, imidazolyl, haloalkylsulfonamido group C 1-6 carbon atoms and a tetrazolyl group. A compound according to any one of claims 1 to 11 A phenyl or pyridyl group or a substituent is independently selected from hydroxy, 2-6 carbon atoms, carbon atoms and in each alkyl group one or more substituents selected from the group consisting of: consisting of a carboxyl group, an acvlamino group having a carbon atom, an alkylamido group having 1 to an alkylsulfonamido group having 1 to 6 (di) alkylsulfamoyl groups having 1 to 6 carbon atoms The compound of claim 1 which is 2,6-dihydro-2-methyl-4- (2-methylpropyl) -6- (1-naphthylmethyl) -1H-pyrrolo [3,4-d] pyridazin-1-one, 2,6-dihydro-2- (2-methoxyethyl) -4- (2-methylpropyl) -6- (1-naphthylmethyl) -1H-pyrrolo [3,4-d] pyridazin-1-one, 2,6-dihydro-7 - [(3-hydroxypropyl) thio] -2-methyl-4- (2-methylpropyl) -6- (1-naphthylmethyl) -1H-pyrrolo [3,4-d] pyridazine-1 -he, 4 - {[2,6-dihydro-2-methyl-4- (2-methylpropyl) -6- (1-naphthylmethyl) 1-oxo-1H-pyrrolo [3,4-d] pyridazin-7-yl] thio } butanoic acid, 2,6-dihydro-7 - [(3-hydroxypropyl) sulfinyl] -2-methyl-4- (2-methylpropyl) -6- (1-naphthylmethyl) -1H-pyrrolo [3,4-d] pyridazine-1 -he, 101 ♦ · · · · · · · · · 2,6-dihydro-7 - [(3-hydroxypropyl) sulfonyl] -2-methyl-4- (2-methylpropyl) -S- (1-naphthylmethyl) -1H-pyrrolo [3,4-d] pyridazine-1 -he, 2- (1-hydroxy-1- (1-naphthyl) methyl) -5-methyl-7- (2-methylpropyl) thieno [2,3-a] pyridazin-4 (5H) -one, 5-methyl-7- (2-methylpropyl) -2- (1-naphthylmethyl) thieno [2,3-d] pyridazin-4 (5H) -one, 3 - [(3-hydroxypropyl) thio] -5-methyl-7- (2-methylpropyl) -2- (1-naphthylmethyl) thieno [2,3-d] pyridazin-4 (5H) -one, 5-methyl-7- (2-methylpropyl) -2- (1-naphthylcarbonyl) thieno [2,3-d] pyridazin-4 (5H) -one, 3 - ((3-hydroxypropyl) sulfinyl] -5-methyl-7- (2-methylpropyl) 2- (1-naphthylmethyl) thieno [2,3-d] pyridazin-4 (5H) -one, 4- | [4,5-dihydro-5-methyl-7- (2-methylpropyl) -2- (1-naphthylmethyl) 4-oxothieno [2,3-d] pyridazin-3-yl] thio] butanoic acid, 5-methyl-7- (2-methylpropyl) -2- (1-naphthylmethyl) -3- (2-pyridinylthio) thieno [2,3-d] pyridazin-4 (5H) -one, 3 - [(3-hydroxypropyl) sulfonyl] -5-methyl-7- (2-methylpropyl) 2- (1-naphthylmethyl) thieno (2,3-d) pyridazine-4 (5H) -cn, 2- [1-hydroxy-1-phenylmethyl] -5-methyl-7- (2-methylpropyl) thieno [2,3-d] pyridazin-4 (5H) -one, 5-methyl-7- (2-methylpropyl) -2-phenylmethylthieno [2,3-d] pyridazin-4 (5H) -one, 3 - [(3-hydroxypropyl) thio] -5-methyl-7- (2-methylpropyl) -2-phenylmethylthieno [2,3-d] pyridazin-4 (5H) -one, 102 • 9 * tt 9 »99 9 »··» · · 9999 9 9 9 · 9999 9 9 9 9 99 ··. 999 ·· 9 99 · 9 * 99 9999 • 99999 99 99 99 99 3 - [(3-hydroxypropyl) sulfonyl] -5-methyl-7- (2-methylpropyl) -2-phenylmethylthieno [2,3-d] pyridazin-4 (5H) -one, 2,6-dihydro-2-methyl-4- (2-methylpropyl) -6-phenylmethyl-1H-pyrroio [3,4-d] pyridazin-1-one, 2,6-dihydro-2-methyl-4- (2-methylpropyl) -6-phenylmethyl-7- (2-pyridinylthio) -1H-pyrrolo [3,4-d] pyridazin-1-one, 2,6-dihydro-7 - [(3-hydroxypropyl) thio] -2-methyl-4- (2-methylpropyl) -β-phenylmethyl-1H-pyrrolo [3,4-d] pyridazin-1-one, 2,6-dihydro-2-methyl-4- (2-methylpropyl) -6- (3,4,5-trimethoxyphenyl) methyl-1H-pyrrolo [3,4-d] pyridazin-1-one, 2,6-dihydro-2-methyl-6- (1-naphthyimethyl) -4- (1-methylethyl) amino-1H-pyrrolo [3,4-d] pyridazin-1-one; 2,6-dihydro-2-methyl-4- (2-methylcyclyl) -6- (4-oyridinvi) methyl-1H-pyrrolo [3,4-d] pyridazin-1-one, 6- (2-chlorophenyl) methyl-2,6-dihydro-2-methyl-4- (2-methylpropyl) -1H-pyrrolo [3,4-d] pyridazin-1-one, 6- (3,5-difluorophenyl) methyl-2,6-dihyaro-2-methyl-4- (2-methylpropyl) -1H-pyrrolo [3,4-d] pyridazin-1-one, 6- (2-chloro-6-fluorophenyl) methyl-2,6-dihydro-2-methyl-4- (2-methylpropyl) -1H-pyrrolo [3,4-d] pyridazin-1-one, 6- (3-chloro-2-fluorophenyl) methyl-2,6-dihydro-2-methyl-4- (2-methylpropyl) -1H-pyrrolo [3,4-d] pyridazin-1-one, 2,6-dihydro-2-methyl-4- (2-methylpropyl) -6- (2-quinolinylmethyl) -1H-pyrrolo [3,4-d] pyridazin-1-one, 99 99 99 9 9 9 9 · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99,999 99,999 · 99 103 2,5-dihydro-2-methyl-4- (2-methylpropyl) -6- (2-trifluoromethylphenyl) methyl-1H-pyrrolo [3,4-d] pyridazin-1-one; 2,6-dihydro-6- (2-imidazo (1,2-a) pyridinyl) methyl-2-methyl-4- (2-methylpropyl) -1H-pyrrolo [3,4-d] pyridazin-1-one, 2,5-dihydro-N- [3- (1-1H-imidazolyl) propyl] -2-methyl-4- (2-methylpropyl) -1-oxo-6-phenylmethyl-1H-pyrrolo [3,4-d] pyridazin-1-one; on-5-carboxamide, 2,5-dihydro-5-methyl-7- (2-methylpropyl) -2- (1-naphthylmethyl) 4H-pyrazolo [3,4-d] pyridazin-4-one, 2,6-dihydro-6-methyl-4- (2-methylpropyl) -2- (1-naphthylmethyl) -7H-pyrazolo [3,4-d] pyridazin-7-one, 2,5-dihydro-3 - [(3-hydroxypropyl) thio] -5-methyl-7- (2-methylpropyl) -2- (1-naphthylmethyl) -4H-pyrazolo [3,4-d] pyridazine-4 -he 2- [1-hydroxy-1- (1-naphthyl) methyl] -5-methyl-7- (2-methylpropyl) furo [2,3-d] pyridazin-4 (5H) -one, 5-methyl-7- (2-methylpropyl) -2- (1-naphthylmethyl) furo [2,3-d] pyridazin-4 (5H) -one, 2- [1-hydroxy-1- (3-cyanophenyl) methyl] -5-methyl-7- (2-methylpropyl) furo [2,3-d] pyridazine-4 (5H) cn, 2- (3-cyanophenyl) methyl-5-methyl-7- (2-methylpropyl) furo [2,3-d] pyridazin-4 (5H) -one, 2- (2-Trifluoromethylphenyl) methyl-5-methyl-7- (2-methylpropyl) thieno [2,3-d] pyridazin-4 (5H) -one hydrochloride 2 - [(1-hydroxy-1-pyridine- 3-yl) methyl] -5-methyl-7- (2-methylpropyl) thieno [2,3-d] pyridazin-4 (5H) -one; 104 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 5-methyl-7- (2-methylpropyl) -2- (3-pyridinylmethyl) thieno [2,3-d] pyridazin-4 (5H) -one, 2- (2-chloro-5-fluorophenyl) methyl-5-methyl-7- (2-methylpropyl) thieno [2,3-d] pyridazin-4 (5H) -one, 2 - [(1-hydroxy-1-quinolin-3-yl) methyl] -5-methyl-7- (2-methylpropyl) thieno [2,3-d] pyridazin-4 (5H) -one, 5- methyl 7- (2-methylpropyl) -2- (3-quinolinylmethyl) thieno [2,3-d] pyridazin-4 (5H) -one, 2- (3-chlorophenyl) methyl-3- (2-hydroxyethoxy) -7- (methoxymethyl) 5-methylthieno [2,3-d] pyridazin-4 (5H) -one, 2 - [(3-chlorophenyl) methyl] -7-cyclohexyl-3- (2-hydroxyethoxy) -5-methylthieno [2,3-d] pyridazin-4 (5H) -one, 2 - [(3-chlorophenyl) methyl] -3- (2-hydroxyethoxy) -5-methyl-7-phenylthieno [2,3-d] pyridazin-4 (5H) -one, 2 - [(3-chlorophenyl) methyl] -7-cyclopentyl-3- (2-hydroxyethoxy) -5-methylthieno [2,3-d] pyridazin-4 (5H) -one, 7-Cyclopropylmethyl-3-methoxy-5-methyl-2 - [(3-trifluoromethylphenyl) methyl] thieno [2,3-d] pyridazin-4 (5H) -one, 7-cyclopropylmethyl-5-methyl-3- [2- (methylthio) ethoxy] 2 - [(3-trifluoromethylphenyl) methyl] thieno [2,3-d] pyridazin-4 (5H) -one, 7-cyclopropylmethyl-3- (2-methoxyethoxy) -5-methyl-2 - [(3-trifluoromethylphenyl) methyl] thieno [2,3-d] pyridazin-4 (5H) -one, 3-cyclopentylmethoxy-7-cyclopropylmethyl-5-methyl-2 - [(3-trifluoromethylphenyl) methyl] thieno [2,3-d] pyridazin-4 (5H) -one, 105 • · · · · · · · · · · · · · · · · · · · · · · Cykl-cyclopropylmethyl-5-methyl-3- (tetrahydrofuran-2-ylmethoxy) -2 - [(3-trifluoromethylphenyl) methyl] thieno [2,3-d] pyridazin-4 (5H) -one, 7-cyclopropylmethyl-3- (3-hydroxy-3-methylbutoxy) -5-methyl-2 - [(3-trifluoromethylphenyl) methyl] thieno [2,3-a] pyridazin-4 (5H) -one, N- {3- [7-cyclopropylmethyl-5-methyl-4-oxo-2- (1-trifluoromethylphenyl) methyl] -4,5-dihydrothieno [2,3-d] pyridazin-3-yl] oxypropyl} acetamide, 7-cyclopropylmethyl-3 - ([1,3] aioxolan-4-ylmethoxy) -5-methyl-2 - [(3-trifluoromethylphenyl) methyl] thieno [2,3-d] pyridazin-4 (5H) -one, or 7-Cyclopropylmethyl-5-methyl-3- (4-oxopentyl) oxy-2 - [(3-trifluoromethylphenyl) methyl] thieno [2,3-d] oyricazin-4 (5H) -one. A process for the preparation of a compound of formula I according to claim 1, comprising: (a) when X is S (O) _n and _n is 1 or 2, oxidizing a compound of formula II (II) wherein R ₃ 'is SR ⁵ or S-Ar ¹ and B, D, R ¹ , R ² , R ^{4, R} and Ar ¹ are as defined in claim 1, or 106 (b) when X is S (O) _n and _n is 0, reacting a corresponding compound of formula I in which E is CR ³ and R ³ is hydrogen with a compound of formula III R ^{3 -} SSR ³ (III) ve in which both R ^and also represent a group R ³ or with the buyer Ar ¹ as defined in claim 1, or with a compound common formulas IV, LSR (IV) wherein L is a leaving group and the radical R is as defined above, or (c) when X is SO ₂ N (R ^a) reacting a compound of formula V wherein L is a leaving group and R 3, D, R ¹ , R ² and R ⁴ are as defined in claim 1, with a compound of formula VI HNR ^S R ³ (VI) wherein R ^{6 is} as defined in claim 1 and R ³ is as defined above in step (b), or (d) when X is C (= O) N (R ⁶ ), reacting the compound of formula VII 107 in which there are 3 in which there are 3, D, R ¹ , R ² and R ^{4 are a} compound of formula VI defined by (e) when D is carbon, E is s and R ⁴ is a CH (CH) Ar ² group of formula VIII as defined in claim 1, ) Kupina or CR ^3, R ³ is hydrogen, reacting a compound of 3 wherein R ¹ and R ^z are defined in nárkoku 1 above with a compound of formula IX Ar ² CHO (ix) wherein Ar ^{2 is} as defined in claim 1, or (f) when D is carbon, E is CR ³ , R ³ is hydrogen and R 'is CHR ⁷ Ar ² , a reduction corresponding to a compound of formula I wherein R ⁴ is CR ⁷ (OH) Ar ² , or (g) when D is carbon, E is CR ³ , R ³ is hydrogen and R ⁴ is C (O) Ar ² , oxidizing the corresponding compound of formula I wherein R ⁴ is CH (OH) Ar ² , or (h) when D is carbon, E is CR ³ , R ³ is hydrogen, R ⁴ is CR ⁷ (OH Ar ² and R ⁷ are alkyl Containing 1 to a reaction corresponding to 2 compounds of the formula: (i) a carbon atom, in which R ⁴ is a C (O) Ar ^{2 group} , with an alkylating agent containing an alkyl group having 1 to 4 carbon atoms, or if D is a carbon atom, e is CR ^J, R ³ is hydrogen and R ⁴ is Ar ^3, reacting a compound of formula VIII as defined above in step (e) with 1-indanone, 2-indanone, 9-fluorenone or 1-acenaphthenone and subsequent reduction, or (j) when D is nitrogen, B is CH, Ξ is CR ³ and R ³ is hydrogen, reacting a compound of formula X R 'wherein R ⁹ is an alkyl group and R ¹ and R ⁴ are as defined in claim 1, with a compound of formula XI, r ² nh-nh, (XI) wherein R is as defined in claim 1, or (k) if D is N, B is CH and E is N, reacting a compound of Formula XII, N — R (XII) Wherein R ^{10 is an} alkyl group and R ¹ and R ⁴ are as defined in claim 1, with a compound of formula XI as defined above in step (j); (1) when D is a nitrogen atom, 3 is a nitrogen atom, E is a CR ³ group and R is a hydrogen atom, reacting a compound of formula XIII wherein R ^{11 is an} alkyl group and R ¹ and R ⁴ are as defined in claim 1, the compound of formula XI defined above in step (I, if X is -O-), reacting the compound of formula XIIIA (XIIIA) wherein B, D, R ¹ , R ² and R ⁴ are as defined in claim 1, with a compound of formula (XIIIB) R ^and -L (XIIIB) wherein L is a leaving group such as a halogen atom, and R ⁸ is as defined in step (b) above; or 110 · pokud pokud D D D D D D D D D D D D D D D D D D D D D D D D D D D is a carbon atom, B is a sulfur atom or an oxygen atom, R ³ is a -OR ⁵ group and R ⁴ is a CH ₂ Ar ² residue, reacting a compound of formula XIIIC wherein 3 'is a sulfur or oxygen atom and R ¹ , R ³ and Ar ² are as defined in claim 1, with a compound of formula XI as defined in step (j) above; and optionally subsequently converting the compound of formula I to another compound of formula I and / or forming a pharmaceutically acceptable salt or solvate of the compound of formula ΐ. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 9 in association with a pharmaceutically acceptable additive, diluent or carrier. A process for the preparation of a pharmaceutical composition according to claim 11 comprising mixing a compound of formula I or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 9 with a pharmaceutically acceptable additive, diluent or carrier. A compound of formula I or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 9 for use in therapy. • · · · 111 Use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 9 for the manufacture of a medicament for use in therapy. 15. A method of treating immunosuppression comprising administering to a patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 9. A method of treating or reducing the risk of reversible c-bstructive airway diseases in patients suffering from or at risk of said diseases, comprising administering to a patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof.