WO1989001333A1

WO1989001333A1 - IMIDAZO[1,2-b]PYRIDAZINES

Info

Publication number: WO1989001333A1
Application number: PCT/AU1988/000290
Authority: WO
Inventors: Gordon Bruce Barlin; Leslie Philip Davies; Stephen James Ireland; Maria Mee Leng Ngu
Original assignee: Australian National University
Current assignee: Australian National University
Priority date: 1987-08-07
Filing date: 1988-08-05
Publication date: 1989-02-23
Anticipated expiration: 1990-02-07

Abstract

Imidazo[1,2-b]pyridazine compounds which are substituted in the 2-, 3- and 6-positions, are useful in the treatment of anxiety syndromes, epilepsy, insomnia or skeletal muscle tension, or for the reversal of the sedative effects of the benzodiazepine class of drugs.

Description

"IMIDAZO[1,2-b]PYRIDAZINES"

This invention relates to imidazo[1,2-b]- pyridazine compounds, and in particular it relates to a group of imidazo[1,2-b]pyridazines bearing substituents in the 2-, 3- and 6- positions which have been found to interact with the receptors in the central nervous system which mediate the anxiolytic, anticonvulsant, muscle-relaxant, hypnotic and other activities of the benzodiazepine class of drugs.

Whilst there are a large number of reports in the literature relating to compounds having the imidazo[1,2-b]pyridazine structure (see formula I below), only a small number of these relate to compounds of this structure having a 3-substituent (see formula II). In fact, all of the more relevant reports relate to compounds bearing substituents in both the 2- and 3- positions and in some cases also in the 6- position. these compounds having the general formula III.

Barlin, Brown, I.L., Golic & Kaucic, Aust. J. Chem. 1982, 35. 423, report the preparation of compounds of the general formula III in which X=H, Y=OMe or OEt, Z=Me. None of the compounds disclosed in this paper contain a 2-phenyl substituent. Barlin, Brown, D.J., Kadunc, Petric, Stanovnik & Tisler, Aust. J. Chem. 1983, 36. 1215, report the preparation of a number of compounds of the general formula III, specifically compounds in which: X-Cl, Y=OMe, Z=Ph

X=H, Y=OMe, Z=Ph

X=Cl , Y=OMe, Z=Me

X=H, Y=OMe, Z=Me

Barlin, Brown, D.J. & Fenn, M.D. Aust. J. Chem. 1984, 37, 2391, report the ¹³C n.m.r. spectra of two compounds of the general formula III previously reported in which

X=Cl, Y=OMe and Z=Ph or Me. Finally, Barlin, Aust. J.

Chem. 1986, 39, 1803, reports the preparation of a number of compounds of general Formula III, specifically compounds in which:

X=Ph, Y=OMe, Z=Ph;

X=Br, Y=OMe, Z=Ph;

X-Br, Y=OMe, Z=C₆H₄Br-pp;

X=Br, Y=OMe, Z=C₆H₄Cl-p; X=Cl, Y=OMe, Z=C₆H₄Br-p; X=Cl, Y=OMe, Z=C₆H₄Cl-p;

X=Cl, Y=OMe, Z=C₆H₄OMe-p;

X=Cl, Y=OEt, Z=Ph;

X=Cl, Y=OMe, Z-Ph, 7=Me; X-F, Y=OMe, Z=Ph;

X=OMe, Y-OMe, Z=Ph.

None of these reports contain any disclosure of biological activity of the compounds reported.

Two prior references [Lombardino, J.Heterocycl.Chem. 1968, 5 35 and Chas.Pfieser and

Co. Inc., Brit.Pat. 1, 135, 893, 04 Dec.1968, U.S. Appl. 03 Aug.1966 (Chem.Abstr., 1969, 70, 57870h)] report compounds in which X = OMe, Y = CH₂NMe₂, CH₂NMeCH₂Ph, CH₂N(CH₂CH₂OH)₂, CH₂N⁺Me₃X-,

The second reference reports that some of these compounds were used for the treatment of hypertension and that they were potent antiinflammatory agents. These compounds were either unsubstituted at the 2- position or contained a 2-alkyl group; none contained a 2-phenyl substituent. It has now been found that a class of compounds having the imidazo[1,2-b]pyridazine structure possess useful biological activity, specifically central nervous system activity, and accordingly may be used in methods of treatment and in pharmaceutical compositions. In addition, certain compounds within this class are novel per se, and the present invention encompasses these novel compounds as well as processes for the preparation thereof. According to a first aspect of this invention, there is provided a method for the treatment of anxiety syndromes, epilepsy, insomnia or skeletal muscle tension, or for the reversal of the sedative effects of the benzodiazepine class of drugs, which comprises administration of an effective amount of compound of the general formula V:

in which: X is a halogen atom, or a group of the formula

ER¹, where E is O, S, NH, OCH₂-, SCH₂-, or NHCH₂-, and R¹ is selected from alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, aryl or substituted-aryl (including phenyl or substituted phenyl), arylalkyl or substituted-arylalkyl (including phenylalkyl or substituted phenylalkyl), arylalkenyl or substituted-arylalkenyl (including phenylalkenyl or substituted phenylalkenyl), arylalkynyl or substituted-arylalkynyl (including phenylalkenyl or substituted phenylalkenyl), heteroaryl or substituted-heteroaryl, heteroarylalkyl or substituted-heteroarylalkyl, heteroarylalkenyl or substituted-heteroarylalknyl, heteroarylalknyl or substituted-heteroarylalknyl, cycloalkyl or substituted-cycloalkyl, eyeloalkylalkyl or substituted-cycloalkylalkyl, heterocyclo or substituted-heterocyclo, heterocycloalkyl or substituted-heterocycloalkyl, heterocycloalkenyl or substituted-heterocycloalkenyl or heterocycloalkynyl or substituted-heterocyc oalkynyl;

Y is a group of the formula OR²,

-CH₂NHCOR⁴, or -CH₂NR⁶R⁷, and each of R², R⁴ and R⁶ and R⁷ (which may be the same or different) is selected from alkyl

(including methyl and ethyl), cycloalkyl, or aryl;

Z is selected from aryl or substituted-aryl (including phenyl or substituted-phenyl), arylalkyl or substituted-arylalkyl, (including phenylalkyl and substituted phenylalkyl) heteroaryl or substituted-heteroaryl, heteroarylalkyl or substituted-heteroarylalkyl, cycloalkyl or substituted-cycloalkyl, cycloalkylalkyl or (substituted-cycloalkyl) alkyl, heterocyclo or substituted-heterocyclo, or heterocycloalkyl or substituted-heterocycloalkyl; with the proviso that X is not a group of the formula -OAr or -SCH₂Ar (where Ar is aryl or substituted aryl) when Y is a group of the formula -OAlkyl and Z is aryl or substituted aryl, or heteroaryl or substituted heteroaryl. Preferred aryl groups represented by X, Y and Z are phenyl and α- and β-naphthyl groups, however other aryl groups are encompassed within the scope of this invention. Preferred heteroaryl groups represented by X and Z are α-, ß and γ-pyridyl, and α- and β-thienyl groups, however other heteroaryl groups are also encompassed within the scope of this invention. Preferred optional substituents on the groups represented by X and Z include one or more alkyl (particularly methyl), alkoxy (particularly methoxy), alkylthio (particularly methylthio), halo (particularly fluoro, chloro or bromo), trifluoromethyl, dialkylamino (particularly dimethylamino), nitro or amino groups.

One group of preferred compounds of the general formula V are compounds wherein:

X is a halogen atom, or is selected from alkoxy, alkylthio, phenylalkoxy or substituted- phenylalkoxy, phenylthio or substituted- phenylthio, anilino, phenylalkylamino or substituted phenylalkylamino, α-, β- or γ-picolythio, ß-picolylamino, or benzthiazol-2-ylthio; Y is selected from methoxy or ethoxy; and

Z is selected from phenyl or substituted-phenyl, α- or ß-naphthyl, α-, ß- or γ-pyridyl, or α- or ß-thienyl.

A second group of preferred compounds of the general formula V are compounds wherein:

X is a halogen atom, or is selected from alkoxy, alkylthio, phenoxy or substituted phenoxy, phenylalkoxy or substituted phenylalkoxy, phenylthio or substituted phenylthio, or phenylalkylthio or substituted phenylalkylthio;

Y is selected from -CH₂NHCOMe, -CH₂NHCOPh, and -CH₂NMe₂; and Z is selected from phenyl or substituted phenyl. In another aspect, the present invention provides a pharmaceutical composition for use in treatment of anxiety syndromes, epilepsy, insomnia or skeletal muscle tension, or for the reversal of the sedative effects of the benzodiazepine class of drugs, which comprises a compound of the general formula V as broadly described above, in association with a pharmaceutically acceptable carrier or diluent.

Compounds of the general formula V in which Y represents a group -OR² may be prepared in accordance with one of the two reaction schemes following.

Where the substituent X is a halogen atom, particularly a chlorine atom, this substituent may be readily replaced by other substituents represented by X, such as alkoxy or alkylthio groups, by methods well known in the art.

The starting materials for the reaction schemes as set out above may be prepared from 3,6-dichloropyridazine as follows:

Compounds of the general formula V in which Y represents -CH₂NHCOR or -CH₂NR⁶R⁷ may be prepared by the following reaction scheme:

Further details of the preparation of these compounds will be apparent from the detailed exemplification hereinafter.

As previously noted, certain compounds of the general formula V are novel per se. Accordingly, the present invention also provides compounds of the general formula V as broadly described above, but not including compounds wherein: (i) X=Cl, Y=OMe, Z=Ph; (ii) X=Ph, Y=OMe, Z=Ph; (iii) X-Br, Y=OMe, Z=Ph; (iv) X=Br, Y=OMe, Z=C₆H₄Br-p; (v) X=Br, Y=OMe, Z=C₆H₄Cl-p; (vi) X=Cl, Y=OMe, Z=C₆H₄Br-p; (vii) X=Cl, Y=OMe, Z=C₆H₄Cl-p; (viii) X=Cl, Y=OMe, Z=C₆H₄OMe-p; (ix) X=Cl, Y=OEt, Z=Ph; (x) X=Cl, Y=OMe, Z=Ph, 7 = Me; (xi) X=F, Y=OMe, Z=Ph; or (xii) X=OMe, Y=OMe, Z=Ph.

Tests conducted to determine the biological activity of compounds of the present invention, and specifically tests for activity in the central nervous system, have revealed that these compounds interact with the receptors in the central nervous system which mediate the anxiolytic, anticonvulsant, muscle-relaxant, hypnotic and other activities of the benzodiazepine class of drugs. Specific tests performed to investigate this biological activity include: (i) a test for displacement of H-diazepam from rat brain membranes; and (ii) a rat conflict test for anxiolytic effects. Further details of the present invention including the compounds of the invention, processes for the preparation thereof, and biological activity of compounds of the invention are set out on the following detailed Examples, which are included by way of illustration of this invention.

Experimental

All compounds were examined for the presence of impurities by thin layer chromatography. Solids for analysis were dried at 80-100°/0.1 mm Hg for 3 h unless otherwise specified. Melting points were taken in Pyrex capillaries. Analyses were performed by the Australian National University Analytical Services Unit. 1H n.m.r. spectra were generally recorded at 90 MHz and 30° with a Jeol FX90Q Fourier-transform spectrometer, with tetramethylsilane (in CDCl₃, or CD₃SOCD₃) as internal standard. (In cases where greater peak dispersion was required, spectra were also recorded at 200 or 300 MHz on Varian XL200 or XL300 spectrometers).

Example 1 6-Chloro-3-methoxy-2-(2'-methylphenyl)imidazo[1,2-b]pyridazine

A mixture of 6-chloropyridazin-3-amine (0.1 g), 2-methyl- phenylglyoxal (0.12 g) (prepared by selenium dioxide oxidation of 2-methylacetophenone, as described for acetophenone but for

48 h), ethanol (5.0 ml) and concentrated hydrochloric acid (0.2 ml) was refluxed for 17 h. The solvent was evaporated under reduced pressure, the residue was mixed with water and evaporated, then the residue was suspended in water, chilled and the solid filtered off.

This product was added to ethereal diazomethane (from 2.6 g nitrosomethylurea) and the mixture was stirred initially in ice and then at 20° overnight. The solvent was evaporated and the product subjected to t.l.c. (alumina; chloroform) to give as an oil, 6-chloro-3-methoxy-2-( 2 '-methylphenyl)imidazo[1,2-b] pyridazine (0.1 g) (Found: C, 61.5; H, 4.6. C₁₄H₁₂ClN₃O requires C, 61.4; H, 4.4%). ¹H n.m.r. (CDCl₃): δ 2.41, s, Me; 3.95, s, MeO; 6.97, d, J_{7 8} 9 Hz, H 7; 7.81, d, J_7,8 9 Hz, H 8; 7.31-7.60, complex, H3' ,4' ,5' ,6'.

Example 2

6-Chloro-3-methoxy-2-(2'-methoxyphenyl)imidazo[1,2-b]pyridazine A mixture of 6-chloropyridazin-3-amine (0.2 g), 2-methoxy- phenylglyoxal (0.28 g) (prepared by selenium dioxide oxidation of 2-methoxyacetophenone for 48 h by a method similar to that used for phenylglyoxal), ethanol (8 ml) and concentrated hydrochloric acid (0.2 ml) was refluxed for 8 h. The solvent was evaporated under reduced pressure, the residue was diluted with water, and the red precipitate (0.25 g) was filtered off, washed with water and dried.

Portion (0.15 g) of this product was stirred with ethereal diazomethane (from 1.3 g nitrosomethylurea) in ice and then at 20° overnight. It was evaporated to dryness and the product subjected to t.l.c. (alumina; chloroform) and recrystallised from cyclohexane to give yellow crystals of 6-chloro-3-methoxy- 2-(2 '-methoxyphenyl)imidazo[1,2-b]pyridazine (0.070 g), m.p. 147-150° (Found, for sample dried at 40° amd 0.1 mm Hg for 6 h: C, 58.3; H, 4.1; N, 14.5. C₁₄H₁₂ClN₃O₂ requires C, 58.0; H, 4.2; N, 14.5%). ¹H n.m.r. (CDCl₃): δ 3.90, s, 2'-OMe; 4.06, s, 3-OMe; 6.96, d, J_7,8 9 Hz, H 7; 7.82, d, J_7,8 9 Hz, H 8; 7.03-7.65, complex, H3' ,4' ,5' ,6'. Example 3

6-Chloro-3-methoxy-2-(thien-2'-yl)imidazo[1,2-b]pyridazine

A mixture of 6-chloropyridazin-3-amine (0.5 g), thien-2- ylglyoxal (0.602 g), ethanol (10 ml) and concentrated hydrochloric acid (0.5 ml) was refluxed with stirring for 2.5 h. After chilling the dark red solid [0.3 g. ¹H n.m.r. (CD₃SOCD₃): δ 7.12, d, 7.99, d, 9 Hz, H 7,8; 7.15-7.6, complex H3',4',5'] was filtered off and washed with a little cold ethanol and ether. Portion (0.2 g) of this solid was added to axcess ethereal diazomethane and the mixture stirred initially at 0° and then at 20° overnight. The solvent was evaporated under reduced pressure and the product subjected to t.l.c. (alumina; chloroform) and recrystallised from light petroleum (b.p 60-80°) to give yellow crystals of the title compound, m.p. 175-177° (Found: C, 49.9; H, 3.1; N, 15.7. C₁₁H₈ClN₃OS requires C, 49.7; H, 3.0; N, 15.8%. 1H n.m.r. (CDCl₃): δ 4.20, s, MeO; 6.98, d, J_7,8 9 Hz, H 7; 7.10-7.72, complex, H3',4',5'; 7.80, d, J_7,8 9 Hz, H8.

Example 4

6-Chloro-3-methoxy-2-(3'-nitrophenyl)imidazo[1,2-b]pyridazine. A mixture of 6-chloropyridazin-3-amine (0.2 g), m- nitrophenylglyoxal (0.35 g), concentrated hydrochloric acid (0.12 ml) and ethanol (8.0 ml) was refluxed in an oil bath at 85° for 8 h. After cooling, the red precipitate (0.28 g) was collected and washed with cold water and ether.

This product was stirred with excess ethereal diazomethane initially at 0° and then at 20° overnight. The mixture was then evaporated under reduced pressure and the product subjected to chromatography in chloroform over a column of alumina (30 cm) and recrystallised from methanol to give the title compound (0.14 g), m.p. 230-232°. (Found: C, 51.5; H, 3.0; N, 18.4. C₁₃H₉ClN₄O₃ requires C, 51.2; H, 3.0; N, 18.4%). ¹H n.m.r. (CDCl₃): 4.24, s, Me; 7.03, d, J_7,8 9 Hz, H 7; 7.55-8.99, complex, H2',4',5' and 6'; 7.84, d, J_7,8 9 Hz, H 8.

Example 5

2-(3'-Aminophenγl)-6-chloro-3-methoxyimidazo[1,2-b]pyridazine. A solution of 6-chloro-3-methoxy-3-(3'-nitrophenyl)imidazo

[1,2-b]pyridazine (0.1 g) in methanol (30 ml) was added dropwise to a rapidly stirred mixture of iron powder (0.45 g, freshly washed with dilute acid), methanol (15.0 ml), water (6.0 ml) and concentrated hydrochloric acid (0.6 ml) at 80-85° and then maintained at that temperature for 2 h. The residual solid was filtered off and washed with hot methanol. The combined filtrates were evaporated, the residue diluted with water (10.0 ml) and adjusted with M sodium hydroxide to pH 6-7. This solution was extracted with chloroform and the extract washed with water and dried (Na₂SO₄). After evaporation of the solvent the product was subjected to t.l.c. (alumina; ethyl acetate) and recrystallised from toluene-cyclohexane to give orange needles of the title compound (0.032 g), m.p. 167-169° (Found: C, 56.8; H, 4.0; N, 20.3. C₁₃H₁₁ClN₄O requires C, 56.8; H, 4.0; N, 20.4%). ¹H n.m.r. (CDCl₃): δ 3.7, b, NH₂; 4.15, s, MeO; 6.63- 7.59, complex, H2',4',5' and 6'; 6.96, d, J_7,8 9 Hz, H 7; 7.79, d, J_7,8 9 Hz, H 8. Example 6

6-Fluoro-3-methoxy-2-(4'-methylphenyl)imidazo[1,2-b]pyridazine 6-Fluoropyridazin-3-amine (0.5 g, Barlin, Aust. J. Chem., 1986, 39, 1803), 4-methylphenylglyoxal hydrate (0.74 g) and concentrated hydrochloric acid (0.5 ml) in ethanol (10 ml) were refluxed for 5.5 h. After cooling the orange solid (0.4 g) was filtered off and washed with ethanol and ether. This solid was stirred with excess ethereal diazomethane at 0° and then at 20° overnight and the solvent evaporated. The product was subjected to t.l.c. (alumina; chloroform) and recrystallised from light petroleum (b.p. 60-80°) to give the title compound (0.62 g), m.p. 145-147° (Found, for a sample dried at 110° for 5 h: C, 65.6; H, 4.6; N, 16.4. C₁₄H₁₂FN₃O requires C, 65.4; H, 4.7; N, 16.3%). ¹H n.m.r. (CDCl₃): δ 2.41, s, Me; 4.13, s, MeO; 6.79, d, J_7,8 9 Hz, H7; 7.28, d, 8.01, d, J₂ , 3, 9 Hz, H2',3',5',6'; 8.29, dd, J_7,8 9 Hz, J_H8,F 7 Hz, H8.

Example 7

(a) 6-Methylthio-2-phenγlimidazo[1,2-b]pyridazin-3-(5H)-one Phenylglyoxal (0.34 g) in ethanol (1.0 ml) was added to a mixture of 6-methylthiopyridazin-3-amine (0.35 g) in ethanol (4.0 ml) with concentrated hydrochloric acid (0.2 ml) and the mixture was stirred at 20° for 4 days. The product was filtered off and washed successively with ethanol, water, ethanol and ether to give as a red solid 6-methylthio-2-phenylimidazo

[1,2-blpyridazin-3( 5H)5-one (0.404 g) (Found: C, 59.7; H, 4.3; N, 16.0. C₁₃H₁₁N₃OS requires C, 60.7; H, 4.3; N, 16.3%). 3-Methoxy-6-methylthio-2-phenylimidazo[1,2-b]pyridazine

(b) 6-Methylthio-2-phenylimidazo[1,2-b]pyridazin-3(5H)-one (0.388 g) was added to a solution of diazomethane in ether (prepared from 2.6 g nitrosomethylurea) and the mixture was stirred in ice overnight. The solvent was evaporated and the product subjected to t.l.c. (alumina; chloroform) and recrystallised from cyclohexane to give yellow crystals of 3- methoxy-6-methγlthio-2-phenylimidazo[1,2-b]pyridazine (0.214 g), m.p. 124-125.5° (Found: C, 61.6; H, 4.9; N, 15.5. C₁₄H₁₃N₃OS requires C, 62.0; H, 4.8; N, 15.5%). ¹H n.m.r. (CDCI₃): δ 2.67, s, MeS; 4.17, s, MeO; 6.80, d, J_7,8 9.5 Hz, H7; 7.43, 8.12, complex, Ph; 7.63, d, J_7,8 9.5 Hz, H8.

(c) 6-Chloro-3-methoxy-2-phenylimidazo[1,2-b]pyridazine (0.1 g) and aqueous sodium methanethiolate (prepared by passing methanethiol into 3 ml 1 M sodium hydroxide) was heated in a Teflon-lined screw top bomb at 130-140° for 5 h. The product was extracted into chloroform and subjected to t.l.c. (alumina; chloroform, then developed twice on alumina; ether) to give the title compound (0.006 g). The ¹H n.m.r. was identical with the product described in (b).

Example 8

3-Methoxy-6-methγlsulphonyl-2-phenylimidazo[1,2-b]pyridazine m-Chloroperoxybenzoic acid (1.0 g) in chloroform (15.0 ml) was added to 3-methoxy-6-methylthio-2-phenylimidazo[1,2-b]pyridazine (0.3 g) in chloroform (10.0 ml) and the mixture stirred at 20° for 2 days. The chloroform solution was chilled, shaken with sodium hydrogen carbonate solution and then water, dried (Na₂So₄), and evaporated at 20°. The product was subjected to t.l.c. (alumina; chloroform) and recrystallised from cyclohexane to give yellow crystals of 3-methoxy-6-methylsulphonyl-2- phenylimidazo[1.2-b]pyridazine (0.011 g), m.p. 167-169° (Found, for sample dried at 70° and 0.1 mmHg for 4.5 h: C, 55.6; H, 4.4; N, 13.6. C₁₄H₁₃N₃O₃S requires C, 55.4; H, 4.3; N, 13.8%). 1H n.m.r. (CDCl₃): S 3.40, s, MeSO₂; 4.20, s, MeO; 7.45, 8.22, complex, Ph; 7.62, d, J_7,8 9 Hz, H7; 8.09, d, J_7,8 9 Hz, H8.

Example 9

(a) 6-Propylthiopyridazin-3-amine 6-Chloropyridazin-3-amine (1.942 g) and aqueous sodium propanethiolate (prepared from 1.2 g sodium hydroxide in 25 ml water with 2.28 g propanethiol) were heated at 140° for 17 h. After cooling the solid was filtered off, washed with 1 M sodium hydroxide, dried, and recrystallised from cyclohexane to give white crystals of 6-propγlthiopγridazin-3-amine (1.7 g), m.p. 77-78° (Found, for sample dried at 50° for 4.5 h: C, 49.3; H, 6.5; N, 24.4. C₇H₁₁N₃S requires C, 49.7; H, 6.5; N, 24.8%). ¹H n.m.r. (CDCI₃): S 1.03, t, J 7 Hz, CH₃CH₂CH₂S; 1.71, complex,

CH₃CH₂CH₂S; 3.22, t, J 7 Hz, CH₃CH₂CH₂S; 4.65, bs, NH₂; 6.64, d, J_4,5 9 Hz, H 5; 7.10, d, J_4,5 9 Hz, H4.

(b) 3-Methoxy-2-phenγl-6-propylthioimidazo [1,2-b]pyridazine

Concentrated hydrochloric acid (0.3 ml) was added to a mixture of phenylglyoxal (0.4 g) in ethanol (1.0 ml) with 6- propylthiopyridazin-3-amine (0.5 g) in ethanol (4.0 ml) and the mixture stirred at 20° for 17 days. The orange solid (0.4 g) was filtered off and washed with ethanol and ether. This product was then stirred with excess ethereal diazomethane in ice and at 20° overnight and gave, after t.l.c. (alumina; chloroform) and recrystallisation from light petroleum (b.p. 40-60°), yellow crystals of 3-methoxy-2-phenyl-6- propylthioimidazo[1,2-b]pyridazine (0.18 g), m.p. 128-129° (Found, for sample dried at 20° and 0.1 mmHg for 5 h: C, 64.4; H, 5.8; N, 14.0. C₁₆H₁₇N₃OS requires C, 64.2; H, 5.7; N, 14.0%). 1H n.m.r. (CDCl₃): S 1.10, t, J 7 Hz, CH₃CH₂CH₂S; 1.85, complex, CH₃CH₂CH₂S; 3.24, t, J 7 Hz, CH₃CH₂CH₂S; 4.16, s, MeO; 6.78, d, J_7,8 9.5 Hz, H7; 7.40, 8.10, complex, Ph; 7.63, d, J_7,8 9.5 Hz, H8.

Example 10

(a) 6-Cyclohexylthiopyridazin-3-amine 6-Chloropyridazin-3-amine (0.5 g) with cyclohexanethiol

(1.32 ml) and 0.55 M sodium hydroxide (18.0 ml) at 140° for 20 h gave white crystals of 6-cyclohexylthiopyridazin-3-amine (0.6 g), m.p. 124-125° (from cyclohexane) (Found, for sample dried at 70° and 0.1 mmHg for 3 h: C, 57.8; H, 7.5; N, 20.0. C₁₀H₁₅N₃S requires C, 57.4; H, 7.2; N, 20.1%). ¹H n.m.r. (CDCI₃): s 1.43, 3.87; complex, C₆H₁₁S; 4.60, b, NH₂ ; 6.63, d, J_4/5 9 Hz, H5; 7.09, d, J_4,5 9 Hz, H4.

(b) 6-Cyclohexylthio-3-methoxy-2-phenylimidazo[1,2-b]pyridazine Phenylglyoxal (0.169 g) stirred with 6-cyclohexylthio- pyridazin-3-amine (0.25 g), ethanol (5.0 ml) and concentrated hydrochloric acid (0.125 ml) at 20° for 8 days gave a precipitate (0.2 g) which was filtered off, washed with a little ethanol, and dried at the pump. This product was stirred with excess ethereal diazomethane at 20° for 2 days and gave, after t.l.c. (alumina; chloroform then alumina; ether), 6-cyclohexγlthio-3-methoxy-2- phenylimidazo[1,2-b]pyridazine (0.064 g) as an oil which slowly crystallised. It was dried at 20° and 0.1 mmHg for 5 h for analysis (found: C, 67.0, H, 6.4; N, 11.7. C₁₉H₂₁N₃OS requires

C, 67.2; H, 6.2; N, 12.4%). ¹H n.m.r. (CDCl₃): δ 1.55, 2.18, complex, C₆H₁₁S; 4.16, s, MeO; 6.74, d, J_7,8 9.5 Hz, H7; 7.38,

8.10, complex, Ph; 7.61, d, J_7,8 9.5 Hz, H8.

Example 11

(a) 6-Phenylthiopyridazin-3-amine

6-Chloropyridazin-3-amine (5.0 g) was added to a solution of thiophenol (10.0 ml) in 1.7 M sodium hydroxide (50 ml) and the mixture heated at 130° for 18 h. After cooling the white solid was filtered off washed with 1 M sodium hydroxide and water and dried at the pump. It was divided into two parts and chromatographed separately in chloroform over a column of alumina (12 cm x 4 cm diameter) and recrystallised from benzene to give white crystals of 6-phenylthiopyridazin-3-amine (4.2 g), m.p. 139-140° (lit. 136°).

(b) 2-Phenyl-6-phenylthioimidazo[1,2-b]pyridazin-3(5H-one Phenylglyoxal (0.34 g) in ethanol (6.0 ml) was added to 6- phenylthiopyridazin-3-amine (0.5 g) in ethanol (6.0 ml) containing concentrated hydrochloric acid (0.2 ml) and the mixture stirred at 20° for 3 days. The red solid was filtered off, washed with ethanol, water, ethanol and ether and dried at the pump to give 2-phenyl-6-phenylthioimidazo[1,2-b]pyridazin- 3 (5H)-one (0.284 g) (Found, for sample dried at 100° for 3 h: C, 67.1; H, 3.9; N, 13.2. C₁₈H₁₃N₃OS requires C, 67.7; H, 4.1; N, 13.2%).

(c) 3-Methoxy-2-phenyl-6-phenylthioimidazo[1,2-b]pyridazine 2-Phenyl-6-phenylthioimidazo[1,2-b]pyridazin-3(5H)-one (0.273 g) was added to a solution of excess diazomethane in ether and the mixture stirred in ice and at 20° overnight. The red colour was discharged to give a yellow solution. The product was subjected to t.l.c. (alumina; chloroform) and recrystallised from cyclohexane to give yellow crystals of 3-methoxy-2-phenyl- 6-phenylthioimidazo[1,2-b]pyridazine (0.110 g), m.p. 150-151° (Found, for sample dried at 80° and 0.1 mmHg for 3 h: C, 68.7; H, 4.6; N, 12.7. C₁₉H₁₅N₃OS requires C, 68.4; H, 4.5; N, 12.6%. ¹H n.m.r. (CDCI₃): δ 3.99, s, MeO; 6.71, d, J_7,8 9.5 Hz, H7; 7.45, 8.10, complex 2 x Ph; 7.64, d, J_7,8 9.5 Hz, H8.

Example 12

(a) 6-p-Dimethylaminophenylthiopyridazin-3-amine B-Dimethylaminobenzenethiol (1.3 g; prepared from N,N- dimethylaniline through bis-p-dimethylaminophenyl disulfide by reduction with tin and hydrochloric acid) in 0.55 M sodium hydroxide (18 ml) with 6-chloropyridazin-3-amine (0.5 g) were heated at 150° for 16 h. After chilling the solid (1.0 g) was filtered off, washed with 1 M sodium hydroxide and water, and then recystallised from chloroform to give 6-p- dimethylaminophenylthiopyridazin-3-amine, m.p. 201-202° (Found, for sample dried at 100° for 6 h: C, 58.7; H, 5.8; N, 22.8. C₁₂H₁₄N₄S requires C, 58.5; H, 5.7; N, 22.8%). ¹H n.m.r. (CDCl₃): δ 2.99, s, Me₂N; 4.70, bs, NH₂; 6.65, d, J_4/5 9 Hz, H5;

6.69, d, J₂, 3, 9 Hz, H3',5'; 6.83, d, J_{4 , 5} 9 Hz, H4; 7.42, d, J₂ ' , 3 ' 9 Hz, H2',6'.

(b) 6-p-Dimethylaminophenylthio-3-methoxy-2-phenylimidazo [1,2-b]pyridazine

A mixture of phenylglyoxal (0.06 g), and 6-(p- dimethylaminophenylthio)pyridazin-3-amine (0.1 g), in ethanol (3.0 ml) with concentrated hydrochloric acid (0.1 ml) was refluxed for 24 h. The mixture was then evaporated to dryness under reduced pressure and the yellow residue diluted with water and evaporated twice. The remaining solid was then diluted with water, filtered and dried. This solid (0.106 g) was added to excess ethereal diazomethane and the mixture stirred in ice and at room temperature overnight. The mixture was evaporated to dryness and the solid subjected to t.l.c. ( alumina; chloroform) and recrystallised from cyclohexane to give yellow crystals of 6-(p-dimethylaminophenylthio)-3-methoxy-2-phenylimidazo [1,2-b]pyridazine (0.022 g), m.p. 175-176° (Found, for sample dried at 80° and 0.1 mmHg for 6 h: C, 67.3; H, 5.4; N, 14.9. C₂₁H₂₀N₄OS requires C, 67.0; H, 5.4; N, 14.9%). ¹H n.m.r. (CDCI₃): S 3.03, s, Me₂N; 4.07, s, MeO; 6.60, d, J_7,8 9.5 Hz, H7; 6.74, d, J_7,8 9.0 Hz, H3',5'; 7.37, 8.10 , complex, Ph; 7.48, d, J₂,_{, 3}, 9 Hz, H2',6; 7.71, d, J_7,8 9.5 Hz, H8.

Example 13

6-(Benzyloxy)-3-methoxy-2-phenylimidazo[1,2-b ]Pyridazine

A mixture of 6-benzyloxypyridazin-3-amine (0.5 g), phenylglyoxal (0.34 g), ethanol (5.0 ml) and concentrated hydrochloric acid (0.3 ml) was stirred at 20° for 20 days, then evaporated to dryness under reduced pressure. This residue was broken up with water and the solid (0.6 g) was filtered off and dried. This solid was added to excess ethereal diazomethane and the mixture stirred in ice and at 20° overnight. The solvent was evaporated and the product subjected to t.l.c. (alumina; chloroform) and recrystallised from cyclohexane to give pale yellow crystals of the title compound (0.2 g), m.p. 143-144° (Found, for a sample dried at 110° for 5 h: C, .72.7; H, 5.2; N, 12.7. C₂₀H₁₇N₃O₂ requires C, 72.5; H, 5.2; N, 12.7%). ¹H n.m.r. (CDCl₃): δ 4.11, s, MeO; 5.45, s, CH₂; 6.69, d, J_{7 8} 9 Hz, H7; 7.35-8.16, complex, 2xPh; 7.76, d, J_7,8 9 Hz, H8.

Example 14 6-Benzyloxy-3-methoxy-2-(4'-methylphenylimidazo[1,2-b]pyridazine A mixture of 6-benzyloxypyridazin-3-amine (0.2 g), p-methylphenyl glyoxal monohydrate (0.18 g), ethanol (17 ml) and concentrated hydrochloric acid (0.2 ml) was refluxed for 10 h, then the solvent evaporated under reduced pressure, the residue was methylated with etheral diazomethane and the product subjected to t.l.c. (alumina; chloroform) to give a yellow residue which was recrystallised from light petroleum (b.p. 40- 60°) to give the title compound (0.1 g), m.p. 130-132° (Found, for a sample dried at 90° and 0.1mmHg for 6 h: C, 72.9; H, 5.6; N, 12.1. C₂₁H₁₉N₃O₂ requires C, 73.0; H, 5.6; N, 12.2%).

¹H n.m.r. (CDCI₃): δ 2.40, s, Me; 4.09, s, MeO; 5.44, s, CH₂; 6.66, d, J_7,8 9 Hz, H7; 7.27, d, 8.00, d, J₂ , 3, 9 Hz, H2 ' ,3 ' ,5' ,6'; 7.71, d, J_7,8 9 Hz, H8; 7.33-7.56 complex, Ph. Example 15

(a) 6-(2'-Methoxybenzyloxy)pyridazin-3-amine 2-oxide

Sodium (0.105 g) in 2-methoxybenzylalcohol (6.0 g) was heated gently until all the sodium had reacted. To this was added 6-chloropyridazin-3-amine 2-oxide (0.65 g) and the mixture heated at 135° for 16 h in a screw top reaction vessel.

After cooling, the reaction mixture was poured into cold ether. The light brown precipitate (0.95 g) was filtered off and recrystallised from toluene (charcoal) to give the title compound- (0.4 g), m.p. 189-192° (Found, for a sample dried at

80° and 0.2mmHg for 12h: C, 57.8; H, 5.2; N, 17.1. C₁₂H₁₃N₃O₃ requires C, 58.3; H, 5.3; N, 17.0%). ¹H n.m.r. (CD₃SOCD₃): δ

3.80, s, MeO; 5.18, s, CH₂; 6.38 b, NH₂ ; 6.79, d, 7.28, d, J_4,5

9 Hz, H4 and 5; 6.94-7.43, complex, H3',4',5' and 6'.

(b) 3-Methoxy-6-(2'-methoxybenzyloxy)-2-phenylimidazo [1,2-b]pyridazine

6-(2'-Methoxybenzyloxy)pyridazin-3-amine 2-oxide (0.28 g) and phenacyl bromide (0.24 g) in ethanol (6 ml) were refluxed with stirring for 1.5 h. Ethanol was removed under reduced pressure to give a dark residue which was stirred with ethereal diazomethane at 0°, then at 20° overnight. The crude product was subjected to t.l.c. (alumina; chloroform then toluene) to give an orange solid which was recrystallised from light petroleum (b.p. 60-80°) to give the title compound (0.04 g), m.p. 157-159° (Found, for a sample dried at 90° and 0.2mmHg for 4 h: C, 70.1; H, 5.5; N, 11.9. C₂₁H₁₉N₃O₃ requires C, 69.8; H, 5.3; N, 11.6%). ¹H n.m.r. (CDCl₃): δ 3.89, δ, 2'-OMe; 4.14, s, 3-OMe; 5.49 s,

CH₂; 6.68, d, J_7,8 9 Hz, H7; 6.91-8.16, complex, H3',4',5',6' and Ph; 7.72, d, J_7,8 9 Hz, H8.

Example 16

(a) 6-(3'-Methoxybenzyloxy)pyridazin-3-amine 2-oxide

This compound was prepared from 3-methoxybenzyl alcohol (6.0 g) and 6-chloropyridazin-3-amine 2-oxide (0.65) as for the isomer above.

The precipitate (0.83 g) was recrystallised from toluene (charcoal) to give the title compound (0.47 g), m.p. 143-144° (Found, for a sample dried at 80° and 0.2mmHg for 4 h: C, 58.4; H, 5.3; N, 17.3. C₁₂H₁₃N₃O₃ requires C, 58.3; H, 5.3; N, 17.0%). ¹H n.m.r. (CD₃SOCD₃): δ 3.74, s, MeO; 5.18, s, CH₂ , 6.39 b, NH₂; 6.80, d, 7.28, d, J_4,5 9 Hz, H4 and 5; 6.95-7.39, complex, H2', 4' ,5' and 6'.

(b) 2-(4'-Fluorophenyl)-3-methoxy-6-(3"-methoxybenzyloxy) imidazo[1.2-b1pyridazine

A mixture of 6-(3'-methoxybenzyloxy)pyridazin-3-amine 2- oxide (0.25 g) and ω-bromo-4-fluoroacetophenone (0.22 g) in ethanol (11 ml) was refluxed with stirring for 4 h.

After cooling, etheral diazomethane was added to the reaction mixture and it was stirred at 0° and and then at 20° overnight. The solvents were removed under reduced pressure and the crude product subjected to t.l.c. (alumina; cyclohexane/chloroform, 1:1) to give a light blue crystalline solid which was recrystallized from cyclohexane to give light brown crystals of the title compound (0.06 g), m.p. 113-115°

(Found, for a sample dried at 85° and 0.2mmHg for 12 h: C, 66.8;

H, 4.8; N, 11.2. C₂₁H₁₈FN₃O₃ requires C, 66.5; H, 4.8; N,

11.1%). ¹H n.m.r. (CDCl₃): δ 3.83, s, 3'-OMe; 4.10, s, 3-OMe; 5.41, s, CH₂; 6.67, d, J_7,8 9 Hz, H7 ; 6.68-8.15, complex, H2',

3' ,5' ,6' ,2" ,4" ,5" and 6"; 7.71, d, J_7,8 9 Hz, H8.

Example 17

2-(2'-Aminophenyl)-3-methoxy-6-(3"-methoxybenzyloxy) imidazo[1,2-b]pyridazine

A mixture of 6-(3'-methoxybenzyloxy)pyridazin-3-amine 2- oxide (0.3 g) and ω-bromo-2'-nitroacetophenone (0.3 g) in ethanol (30 ml) was refluxed for 4 h. The solvent was removed in vacuo to leave a dark residue which was stirred with a cold solution of ethereal diazomethane at 0° and 20° overnight. Evaporation of the ether gave a crude product which was subjected to t.l.c. (alumina; toluene, developed twice) to give a yellow oil (0.04 g).

This product was dissolved in methanol (10 ml) and added dropwise to a rapidly stirred mixture of reduced iron powder (0.12 g), methanol (4 ml), water (3 ml) and concentrated hydrochloric acid (0.16 ml). The reaction mixture was maintained at 85-90° for 2 h. The solid was filtered off, washed with hot methanol, and the combined filtrates evaporated to dryness. The residue was diluted with water and the pH adjusted to 7 (with IM sodium hydroxide). The product was extracted into chloroform. Evaporation gave an orange residue which was subjected to t.l.c. (alumina; chloroform) to give a yellowish green residue (0.02 g) which was recrystallised from light petroleum (40-60°) to give the title compound, m.p. 89-90° (Found, for a sample dried at 75° and 0.2mmHg for 4 h: C, 67.5; H, 5.6; N, 14.9. C₂₁H₂₀N₄O₃ requires C, 67.0; H, 5.4; N, 14.9%). ¹H n.m.r. (CDCl₃): δ 3.84, s, 3"-OMe; 4.05, s, 3-OMe; 5.43, s, CH₂; 6.67, d, J_7,8 9 Hz, H7; 6.80-7.91, complex, H3' ,4' ,5' ,6' ,2" ,4" ,5", 6"; 7.68, d, J_7,8 9 Hz, H8.

Example 18

3-Methoxy-6-13'-methoxybenzyloxy)-pyrid-3"-yl imidazo[1,2-b]pyridazine

A mixture of 6-(3'-methoxybenzyloxy)pyridazin-3-amine 2- oxide (0.25 g), 3-bromoacetylpyridin hydrobromide (0.28 g) and sodium hydrogen carbonate (0.084 g) in ethanol (12 ml) was refluxed with stirring for 5.5 h. After cooling, a solution of ethereal diazomethane was added and the mixture stirred at 0° and then at 20° overnight.

Evaporation of the solvents gave a residue which was subjected to t.l.c (alumina; chloroform, developed twice) and the product recrystallised from cyclohexane and light petroleum (b.p. 40- 60°) to give the title compound (0.03 g), m.p. 114-116° (Found, for a sample dried at 80° and 0.2mmHg for 4 h: C, 66.4; H, 4.9;

N, 15.5. C₂₀H₁₈N₄O₃ requires C, 66.3; H, 5.0; N, 15.5%). ¹H n.m.r. (CDCl₃): δ 3.83, s, 3'-OMe; 4.13, s, 3-OMe; 5.42, s, CH₂;

6.71, d, J_7,8 9 Hz, H7; 6.82-8.36, complex, H2' ,4' ,5' ,6' ,2", 4", 5" and 6"; 7.73, d, J_7,8 9 Hz, H8. Example 19

(a) 3-Anilino-6-chloropyridazine

This compound was prepared from 3,6-dichloropyridazine and aniline in ethanol at reflux. It had m.p. 185-186° (from cyclohexane) (lit. 190° , 191.2-192°). ¹H n.m.r. (CDCl₃): δ

7.10, d, J_4,5 9 Hz, H4(5); 7.26, d, J_4,5 9 Hz, H5 (4); 7.30-7.50, complex, Ph.

(b) 3-Anilino-6-hydrazinopyridazine A mixture of 3-anilino-6-chloropyridazine (2.0 g) and hydrazine hydrate (40 ml) was refluxed for 5 h. The hydrazine was evaporated under reduced pressure and the residue suspended in water and the product (0.70 g) collected. It was recrystallised from aqueous methanol to give 3-anilino-6- hydrazinopyridazine. m.p. 204-207° (Found, for a sample dried at 40° and 0.1mmHg for 4 h: C, 59.4; H, 5.7; N, 34.7. C₁₀H₁₁N₅ requires C, 59.7; H, 5.5; N, 34.5%). ¹H n.m.r. (CD₃SOCD₃): δ 4.1, b, NH₂; 6.78, d, J_4,5 9 Hz, H5(4); 6.95, d, J_4,5 9 Hz, H4(5); 6.98-7.69, complex, Ph; 7.79, b, NH.

(c) 6-Anilinopyridazin-3-amine(picrate) 3-Anilino-6-hydrazinopyridazine (0.2 g) in methanol (150 ml) with a little water was shaken with hydrogen over Raney nickel at room temperature and pressure for 6 h. The catalyst was filtered off and the filtrate evaporated to give a solid (0.1 g). ¹H n.m.r. (CD₃SOCD₃): δ 5.71, b, NH₂; 6.77, d, J_4,5 9 Hz, H5(4); 6.97, d, J_4,5 9 Hz, H4 (5); 6.87-7.83, complex, Ph; 8.65, b, NH. Portion of this product with aqueous picric acid gave a yellow precipitate which recrystallised from ethanol to give 6- anilinopyridazin-3-amine picrate, m.p. >250° (Found, for a sample dried at 50° and 0.1mmHg for 6 h: C, 46.5; H, 3.3; N, 23.4. C₁₄H₁₃N₇O₇ requires C, 46.3; H, 3.2; N, 23.6%).

(d) 6-Anilino-3-methoxy-2-(4'-methylphenyl)imidazo[1,2-b]pyridazine

A mixture of 6-anilinopyridazin-3-amine (0.20 g), 4- methylphenylglyoxal (0.18 g) and concentrated hydrochloric acid (0.3 ml) in ethanol (25 ml) was refluxed for 4 h.

After cooling, the solvent was evaporated to give a dark red residue which was stirred with excess ethereal diazomethane at 0° and then at 20° overnight. The mixture was evaporated and the residue was subjected to t.l.c. (alumina; chloroform) and the band showing light blue fluorescence under the 254 nm lamp at low R_f was collected and extracted with chloroform to give the product (0.04 g) which was recrystallised from a mixture of methanol and cyclohexane to give the title compound, m.p. 228- 230° (Found: C, 72.5; H, 5.8; N, 16.5. C₂₀H₁₈N₄0.1/6H₂O requires C, 72.1; H, 5.5; N, 16.8%). % n.m.r. (CDCI₃): δ 2.39, s, Me; 4.14, s, 3-OMe; 6.64, d, J_7,8 9 Hz, H7 ; 6.77, b, NH; 7.11-8.03, complex, H2' ,3' ,5' ,6' and Ph; 7.65, d, J_7,8 9 Hz, H8.

Example 20

(a) 6-Benzylaminopyridazin-3-amine 2-oxide

6-Chlorcpyridazin-3-amine 2-oxide (0.2 g) and benzylamine (2.0 g) were heated in a screw top reaction vessel at 160° for 20 h. After cooling, chloroform (2 ml) was added to the brown residue and the mixture subjected to column chromatography

(alumina: chloroform) and the product eluted with ethanol and methanol, respectively). The light brown residue was precipitated from cold chloroform with ether and the yellow precipitate (0.18 g) recrystallised from acetone to give golden brown crystals of the title compound (0.15 g), m.p. 189-191° (Found, for a sample dried at 90° and O.lmmHg for 4 h:: C, 61.4; H, 5.7; N, 25.9. C₁₁H₁₂N₄O requires C, 61.1; H, 5.6; N, 25.9%). 1H n.m.r. (CD₃SOCD₃): δ 4.32, d, J_{CH NH} 6 Hz, CH₂; 5.85, b, NH₂; 6.52, d, 7.07, d, J_4,5 9 Hz, H4 and 5; 7.30, b, Ph.

(b) 6-Benzylamino-3-methoxy-2-phenylimidazo [1,2-b]pyridazine

A mixture of 6-benzylaminopyridazin-3-amine 2-oxide (0.08 g), phenacylbromide (0.07 g) and ethanol (6 ml) was refluxed, with stirring for 4 h. The solvent was evaporated and the brown residue methylated with excess ethereal diazomethane at 0°, then at 20° overnight. The solvent was evaporated and the residue subjected to t.l.c. (alumina; chloroform, then ether) and the product (0.03 g) recrystallised from light petroleum (b.p. 60-80°) to give the title compound, m.p. 132-134° (Found, for sample dried at 95° and 0.1mmHg for 4 h: C, 73.0; H, 5.7; N, 16.8. C₂₀H₁₈N₄O requires C, 72.7; H, 5.5; N, 17.0%). ¹H n.m.r. (CDCI₃): δ 4.04, s, MeO; 4.59, d, J_{CH NH} 5 Hz CH₂; 6.37, d, J_7,8 9 Hz, H7; 7.36 - 8.12, complex, 2xPh; 7.53, d, J_7,8 9 Hz, H8.

Example 21

(a) 6-( 2'-Methoxybenzylamino)pyridazin-3-amine 2-oxide

This compound was prepared from 6-chloropyridazin-3-amine 2-oxide and 2-methoxybenzylamine as for the benzylamino- analogue. The product was subjected to column chromatography

(alumina; acetone and the product eluted with ethanol and methanol). It was recrystallised from n-propanol and ethyl acetate to give yellow crystals fo the title compound, m.p. 204- 206° (Found: C, 58.9; H, 6.0. N, 22.9. C₁₂H₁₄N₄O₂ requires C,

58.5; H, 5.7. N, 22.8%). ¹H n.m.r. (CDCl₃): δ 3.81, s, OMe;

4.27, d, J_{CH NH} 6 Hz, CH₂; 5.9, b, NH₂; 6.56, d, 7.08, d, J_4,5 9

Hz, H4 and 5; 6.74-7.31, complex, H3',4',5' and 6'.

(b) 3-Methoxy-6-(2'-methoxybenzylamino)-2-phenylimidazo

[1,2-b]pyridazine

6-(2'-Methoxybenzylamino)pyridazin-3-amine 2-oxide (0.20 g) and phenacylbromide (0.18 g) in ethanol (9.0 ml) were refluxed for 2.5 h and then methylated as above. The crude product was subjected to t.l.c. (alumina; chloroform) and recrystallised from a mixture of chloroform and cyclohexane to give the title compound (0.100 g), m.p. 132-134° (Found, for a sample dried at 100° and 0.1mmHg for 4 h: C, 69.9; H, 5.7; N, 15.4. C₂₁H₂₀N₄O₂ requires C, 70.0; H, 5.6; N, 15.5%). ¹H n.m.r. (CDCI₃): δ 3.88, s, 2'-OMe; 4.11, s, 3-OMe; 4.59, d, J_{CH NH} 6 Hz, CH₂; 5.10, t, J_CH,NH 6 Hz' NH; 6.35,d, J_7,8 9 Hz, H7; 6.83 - 8.15, complex, H3' ,4' ,5' ,6' and Ph; 7.48, d, J_7,8 9 Hz, H8.

Example 22

(a) 6-(3'-Methoxybenzylamino)pyridazin-3-amine 2-oxide

This product was prepared as for its 6-(2'- methoxybenzylamino)-isomer above and purified by column chromatography (alumina; chloroform, and eluted with ethanol) and recrystallisation from a mixture of n-propanol and acetone to give the title compound, m.p. 161-163° (Found: C, 58.7; H,

6.0; N, 23.0. C₁₂H₁₄N₄O₂ requires C, 58.5; H, 5.7. N, 22.8%). ¹H n.m.r. (CD₃SOCD₃): δ 3.72, s, OMe; 4.29, d, J_{CH NH} 6 Hz, CH₂; 5.8, b, NH₂; 6.52, d, 7.07, d, J_{4 5} 9 Hz, H4 and 5; 6.71-7.32, complex, H2',4',5' and 6.

(b) 3-Methoxy-6-(3'-methoxybenzylamino)-2-(pyrid-3"-yl)imidazo [1,2-b]pyridazine A mixture of 6-(3'-methoxybenzylamino)pyridazin-3-amine 2- oxide (0.25 g), 3-bromoacetylpyridine hydrobromide (0.28 g) and sodium hydrogen carbonate (0.08 g) in ethanol (7 ml) was refluxed for 1.5 h. After cooling, the red precipitate (0.23 g) was filtered off and methylated with excess ethereal diazomethane at 0° and then at 20° overnight. This mixture was evaporated and the residue subjected to t.l.c. (alumina; chloroform/acetone, 1:1) and recrystallised from chloroform/cyclohexane/light petroleum (b.p. 40-60°) to give the title compound (0.045 g), m.p. 188-189° (Found, for a sample dried at 80° and 0.2mmHg for 4 h: C, 64.6; H, 5.4; N, 18.8. C₂₀H₁₉N₅O₂ 0.5 H₂O requires C, 64.8; H, 5.4; N, 18.9%). ¹H n.m.r. (CDC1₃): s 3.81, s, 3'-OMe; 4.08, s, 3-OMe; 4.57, d,

J_CH,NH 5.5 Hz, CH₂; 4.9, b, NH; 6.42' d, J_7,8 9 Hz, H7; 6.77 - 9.31, complex, H2',4',5',6' and pyrid-3"-yl; 7.56, d, J_7,8 9 Hz, H8. Example 23

2-(2'-Fluorophenyl)-3-methoxy-6-(3"-methoxybenzylamino)imidazo [1,2-blpyridazine ω-Bromo-2-fluoroacetophenone (0.184 g) was added to a solution of 6-(3'-methoxybenzylamino)pyridazin-3-amine 2-oxide (0.2 g) in ethanol (8.0 ml) and the mixture refluxed with stirring for 9 h, then evaporated under reduced pressure.

The residue was dissolved in ethanol (2.0 ml) and ethereal diazomethane (from 5.7 g nitrosomethylurea) added and the mixture stirred at 0° and at 20° overnight. The solvent was evaporated and the product subjected to t.l.c. (alumina; chloroform) and recrystallised from benzene/cyclohexane to give the title compound (0.079 g), m.p. 133-134° (Found, for a sample dried at 100° for 6 h: C, 67.0; H, 4.9; N, 14.5. C₂₁H₁₉FN₄O₂ requires C, 66.7; H, 5.1; N, 14.8%). ¹H n.m.r. (CDCl₃): δ 3.81, s, 3"-OMe; 4.05, s, 3-OMe; 4.57, d, J_CH,_NH 5 Hz CH₂; 4.80, t, J_CH,NH 5 Hz, NH, 6.40, d, J_7,8 9 Hz, H7; 6.80 - 7.90, complex, H3' ,4' ,5' ,6' ,2" ,4" ,5" ,6"; 7.58, d, J_7,8 9 Hz, H8.

Example 24

3-Methoxy-6-(3'-methoxybenzylamino)-2-(3"-nitrophenyl) imidazo[1,2-b]pyridazine

A mixture of 6-(3'-methoxybenzylamino)pyridazin-3-amine 2- oxide (0.37 g) and ω-bromo-3-nitroacetophenone (0.42 g; prepared from 3-nitroacetophenone by bromination in acetic acid) in ethanol (15 ml) was refluxed for 0.5 h. After cooling to room temperature, sodium hydrogen carbonate (0.07 g) was added. After effervescence ceased, the mixture was brought to reflux and continued for a further 3.5 h. After cooling, water (10 ml) was added and the pH adjusted to 7. After chilling in ice, the brown precipitate (0.5 g) was filtered off, washed with water, ether and dried. This solid was added to a cold solution of ethereal diazomethane and the mixture stirred at 0° and 20° overnight. The crude product was subjected to column chromatography (alumina: chloroform) and the product (0.1 g) recrystallised from methanol to give yellow crystals of the title compound (0.095g), m.p. 186-188° (Found, for a sample dried at 90° and 0.1mmHg for 5 h: C, 61.9; H, 4.6; N, 17.1. C₂₁H₁₉N₅O₄ requires C, 62.2; H, 4.7; N, 17.3%). ¹H n.m.r. (CDCl₃): δ 3.78, s, 3'-OMe; 4.11, s, 3-OMe; 4.57, d, J_CH,NH 5.5 Hz, CH₂; 5.20, t, J_CH,NH 5.5 Hz, NH; 6.45, d, J_7,8 9 Hz, H7, 6.76-8.88, complex, H2' ,4' ,5', 6' ,2" ,4" ,5" and 6"; 7.50, d, J_7,8 9 Hz, H8.

2- (3'-Aminophenyl)-3-methoxy-6-(3"-methoxybenzylamino) imidazo[1,2-b]pyridazine

To a rapidly stirred mixture of reduced iron powder (0.08g), methanol (5 ml), water (1 ml) and concentrated hydrochloric acid (0.24 ml), was added a solution of 3-methoxy-6-(3'- methoxybenzylamino)-2-(3"-nitrophenyl)imidazo[1,2-b] pyridazimne (0.05 g) in methanol (20 ml), while the temperature was maintained at 85-90°. After stirring at the same temperature for 3 h, the mixture was filtered and the solid washed with hot methanol. The combined filtrates was evaporated, the residue diluted with water and adjusted to pH 7, and the mixture extracted with chloroform. The extract gave an orange residue which was subjected to t.l.c. (alumina: chloroform) to give a brown product (0.03 g) which was recrystallised from toluene to give yellow crystals of the title compound (0.015), m.p. 84-86°

(Found, for a sample dried at 60° and 0.1mmHg for 12 h: C, 65.7;

H, 5.6; N, 18.3. C₂₁H₂₁N₅O₂.½H₂O requires C, 65.6; H, 5.8; N,

18.2%). ¹H n.m.r. (CDCI₃): δ 3.4, b, NH₂; 3.78, s, 3"-OMe; 4.02, s, 3-OMe; 4.54, d, J_{CH NH} 6 Hz, CH₂; 5.00, t, J_CH/NH 6 Hz' NH;

6.34, d, J_{7 8} 9 Hz, H7, 6.53-7.45, complex,

H2' ,4' ,5' ,6' ,2" ,4" ,5" and 6"; 7.48, d, J_{? 8} 9 Hz, H8.

Example 25 (a) 6-(4'-Methoxybenzyloxy)pyridazin-3-amine

Sodium (0.22 g) in 4-methoxybenzylalcohol (4.1 g) was heated gently until all the sodium had reacted. The temperature- was raised to 120-125°, 6-chloropyridazin-3-amine (1.3 g) was added, and the mixture stirred and heated at this temperature for 4 h.

After cooling, cold ether (100 ml) was added and the brown precipitate (0.9 g) was filtered off, washed with ether and water and dried. It was recrystallised from toluene to give the title compound (0.65 g) , m.p. 159-161° (Found, for a sample dried at 90° and 0.2mmHg for 4 h: C, 62.6; H, 5.9; N, 18.1. C₁₂H₁₃N₃O₂ requires C, 62.3; H, 5.7; N, 18.2%). ¹H n.m.r. (CD₃SOCD₃): δ 3.75, s, MeO; 5.23, s, CH₂; 5.9, b, NH₂; 6.85, d, 6.93, d, J_{4 5} 9 Hz, H4 and 5; 6.95, d, 7.40, d, J_2',3' 9 Hz, H2' ,3' ,5' ,6'.

(b) 3,6-Dimethoxy-2-(4'-methylphenyl)imidazo[1,2-b]pyridazine

A mixture of 6-methoxypyridazin-3-amine (0.42 g), p- methylphenylglyoxal (0.56 g), ethanol (15 ml) and concentrated hydrochloric acid (0.2 ml) was refluxed for 11 h. The reaction mixture was concentrated and the red precipitate (0.65 g) filtered off. A portion of this product (0.15 g) was stirred with a solution of ethereal diazomethane at 0° and then at 20° overnight. The solvent was evaporated and the product subjected to t.l.c. (alumina: toluene/chloroform, 5:1) and recrystallised from light petroleum (40-60°) to give the title compound (0.04 g), m.p. 135-136° (Found, for a sample dried at 95° and 0.2mmHg for 4 h: C, 66.7; H, 5.8; N, 15.8. C₁₅H₁₅N₃O₂ requires C, 66.9; H, 5.6; N, 15.6%). ¹K n.m.r. (CDCl₃): δ 2.39,. s, Me; 4.05, s, 6-OMe; 4.13, s, 3-OMe; 6.60, d, J_{7 8} 9 Hz, H7 ; 7.69, d', J_7,8, 9 Hz, H8; 7.26, d, 7.99, d, J₂, _,3, 9 Hz, H2' , 3' ,5' , 6 ' .

(c) A mixture of 6-(4'-methoxybenzyloxy)pyridazin-3-amine

(0.05 g), p-methylphenylglyoxal monohydrate, ethanol (7 ml) and concentrated hydrochloric acid (0.25 ml) was refluxed for 10 h.

The solvent was removed, the yellow residue suspended in H₂O and filtered off, washed with water and ether. This product (0.02 g) was stirred with a solution of ethereal diazomethane at 0° and

20° overnight. Evaporation gave a residue which was subjected to t.l.c. (alumina; chloroform) to give a product (0.003 g) with

¹ H n.m.r. identical with that from (b). Example 26

(a) 6-(Pyrid-3'-yloxy)pyridazin-3-amine

A solution of 3-hydroxypyridine (6.0 g), sodium hydroxide (1.8 g) and water (45 ml) with 6-chloropyridazin-3-amine (3 g) was heated in a screw top reaction vessel at 170° for 16 h. The reaction mixture was extracted with a 10% mixture of methanol in chloroform to give the product (0.89 g) which crystallised from toluene to give yellow crystals of the title compound. m.p. 155-156° (Found, for a sample dried at 75° and 0.1 mmHg for 5.5 h : C, 57.4; H, 4.2; N, 29.5. C₉H₈N₄O requires C, 57.4; H, 4.3; N, 29.8%). ¹H n.m.r. (CDCl₃) : δ 6.90, d, 7.09, d, J_4,59 Hz, H4 and 5; 7.24-8.53, complex, pyrid-3'-yI.

(b) 3-Methoxy-2-phenyl-6-(pyrid-3'-yloxy)imidazo[ 1,2-b]pyririazine

A solution of 6-(pyrid-3'-yloxy)pyridazin-3-amine (0.2 g), phenylglyoxal (0.17 g), concentrated hydrochloric acid (0.3 ml) and ethanol (7 ml) was refluxed in an oil bath for 16 h. The reaction mixture was evaporated to dryness under reduced pressure and the residue diluted with water and adjusted to pH 6-7. The brown solid (0.19 g) was filtered off and washed with water and ether.

This solid was stirred with excess ethereal diazomethane at 0° and then at 20° overnight The solvent was evaporated and the residue subjected to tl.c. (alumina; chloroform) and the product (0.079 g) recrystallised from cyclohexane to give yellow crystals of the title compound. m.p. 173-175° (Found : C, 68.2; H, 4.5; N, 17.4.

C₁₈H₁₄N₄O₂ requires C, 67.9; H, 4.4; N, 17.6%). ¹H n.m.r. (CDCl₃) : 53.94,s,MeO;

6.87, d,J_7,89 Hz, H7; 7.31-8.14, complex, pyrid-3'-yl and Ph; 7.90,d, J_7,89 Hz, H8. Example 27

(a) 6-(2'-Hydroxyethylamino)pyridazin-3-amine 2-oxide

6-Chloropyridazin-3-amine 2-oxide (0.5 g) and ethanolamine (2.0 g) were heated in a screw top reaction vessel at 160° for 16 h. This mixture was dissolved in methanol and applied to a column of alumina (20 cm x 2.5 cm) packed with chloroform. It was then elute with chloroform containing increasing amounts of methanol. Ethanolamine was eluted first, followed by the product (0.34 g) which was recrystallised from cyclohexane to give the title compound, m.p. 166-168° (Found: C, 42.6; H, 6.0; N, 32.6. C₆H₁₀N₄O₂ requires C, 42.4; H, 5.9; N, 32.9%). ¹H n.m.r. (CD₃SOCD₃) : δ 3.18, t, J 7 Hz, CH₂OH; 3.47, q, NHCH₂; 5.83, b, NH₂; 6.51, d, 7.07, d, J_4,5 9 Hz, H4 and 5.

(b) 6-(2'-Hydroxyethylamino)-3-methoxy-2-phenylimidazo[1,2-blpyridazine

A mixture of 6-(2'-hydroxyethylamino)pyridazin-3-amine (0.2 g), phenacyl bromide (0.3 g) and ethanol (12 ml) was refluxed for 5 h. After cooling, it was stirred with excess ethereal diazomethane at 0° and then at 20° overnight The solvent was evaporated and the product subjected to column chromatography (alumina; ethyl acetate) and then eluted further with ethanol. The product crystallised on addition of chloroform. It was recrystallised from ethyl acetate and light petroleum (b.p. 40-60°) to give crystals of the title compound , m.p. 170-172° (Found: C, ; H, ; N, C₁₅H₁₆N₄O₂ requires C, 63.4; H,

5.7; N, 19.7%). ¹H n.m.r. (CD₃SOCD₃) : δ 3.39, t, J 7 Hz, CH₂OH; 3.63, t, J 7 Hz, NHCH₂: 4.78, b, NH; 6.65, d, J_7,89 Hz, H7; 7.00-8.00, complex, Ph; 7.60, d, J_7,89 Hz, H8. Example 28

(a) 6-(Pyrid-2'-ylmethylthio)pyridazin-3-amine

6-Aminopyridazine-3-thiol (0.44 g) in 0.5 M sodium hydroxide (15 ml) was shaken with pyrid-2-ylmethyl chloride hydrochloride (0.58 g) for 4 h. The aqueous solution was extracted with chloroform, the extract washed with water and dried (Na₂SO₄). Evaporation of the solvent gave a white solid (0.72 g) which was recrystallised from toluene to give the title compound (0.6 g), m.p. 124-126° (Found: C, 55.3; H, 4.6; N, 25.5. C₁₀H₁₀N₄S requires C, 55.0; H, 4.6; N, 25.7%). ¹H n.m.r. (CD₃SOCD₃): δ 4.45, s, CH₂, 6.25 s, NH₂; 6.69, d, 7.24, d, J_4,5 9 Hz, H4,5; 7.16-8.49, complex, H3' ,4' ,5' , 6'.

(b) 3-Methoxy-2-phenyl-6-(pyrid-2'-ylmethylthio)imidazo[1,2-b] pyridazine

A mixture of 6-(pyrid-2'-ylmethylthio)pyridazin-3-amine

(0.24 g), phenylglyoxal (0.16 g) and concentrated hydrochloric acid (0.6 ml) in ethanol (10 ml) was refluxed with stirring, for

9 h.

After cooling, water (10 ml) was added and the pH was adjusted to 7 with 1M sodium hydroxide, and the orange precipitate (0.1 g) was filtered off. This solid was stirred with a cold solution of ethereal diazomethane at 0° and then at

20° overnight. The crude product was subjected to t.l.c.

(alumina: chloroform) to give the title compound as an oil (0.05 g). (Found, for a sample dried at 80° for 5 h: C, 64.5; H, 5.1; N, 15.4. C₁₉H₁₆N₄OS 0.45 H₂O requires C, 64.0; H, 4.8; N, 15.7%). ¹H n.m.r. (CDCl₃): δ 4.08, s, 3-OMe; 4.74, s, CH₂; 6.84, d, J_7,8 9 Hz, H7; 7.12-8.63, complex, H3' ,4', 5', 6', and Ph;

7.66, d, J_7,8 9 Hz, H8.

Example 29 (3) 6-(Pyrid-3'-ylmethylamino)pyridazin-3-amine 2-oxide

6-Chloropyridazin-3-amine 2-oxide (0.4 g) and pyrid-3- ylmethylamine (3.0 g) were heated at 160° for 16 h. The reaction mixture was dissolved in ethanol (3.0 ml) and applied to a column of alumina (22 cm) and washed with n-propanol/acetone (lsl) to remove excess pyridylmethylamine. The product was eluted with methanol and precipitated from chloroform with ether. It was recrystallised from n-propanol/ethylacetate to give yellow crystals of the title compound (0.25 g), m.p. 204- 206° (Found, for a sample dried at 90° and 0.1mmHg for 4 h: C, 55.0; H, 5.3; N, 32.0. C₁₀H₁₁N₅O requires C, 55.3; H, 5.1; N, 32.2%). ¹H n.m.r. (CD₃SOCD₃): δ 4.34, d, J_CH,NH 5.5 Hz, CH₂; 5.87 s, NH₂; 6.51, d, 7.08, d, J_{4 5} 9 Hz, H4 and 5; 6.96-8.55, complex, H2' ,4' ,5', and 6'.

(b) 3-Methoxy-2-(4'-methylphenyl)-6-(pyrid-3"-ylmethylamino) imidazo[1,2-b]pyridazine

To a warm solution of 6-(pyrid-3'-ylmethylamino)pyridazin- 3-amine 2-oxide (0.24 g) in ethanol (5 ml) was added p- methylphenacylbromide (0.24 g) and the mixture was refluxed for 4.5 h. After cooling, this mixture was added to a excess cold ethereal diazomethane and stirred at 0° and and then at 20° overnight. The mixture was evaporated and the residue subjected to t.l.c. (alumina; chloroform) to give a product (0.03 g) which was recrystallised from a mixture of toluene and cyclohexane to give brown crystals of the title compound, m.p. 141-143° (Found, for a sample dried at 90° and 0.1mmHg for 6 h: C, 69.8; H, 5.6;

N, 20.1. C₂₀H₁₉N₅O requires C, 69.5; H, 5.6; N, 20.3%). ¹H n.m.r. (CDCl₃): δ 2.37, s, Me; 3.97, s, 3-OMe; 4.60, d, J_CH,NH 5.5 Hz, CH₂, 5.30 t, J_CH,NH 5.5 Hz, NH; 6.38, d, J_7,8 9 Hz, H7;

7.18-8.69, complex, H2' ,3' ,5' , 6' ,2" ,4" ,5" and 6", 7.95, d. J_7f8

9 Hz, H8.

3-Methoxy-6-(pyrid-3'-ylmethylamino)-2-(pyrid-3"-yl)imidazo [1,2-blpyridazine

A mixture of 6-(pyrid-3'-ylmethylamino)pyridazin-3-amine 2- oxide (0.22 g), 3-bromoacetylpyridine hydrobromide (0.30 g) and sodium hydrogen carbonate (0.09 g) in ethanol (12 ml) was refluxed for 4 h. After cooling, a cold ethereal solution of diazomethane was added and the solution stirred at 0° and then at 20° overnight.

The mixture was evaporated and subjected to t.l.c. (alumina: ethyl acetate/acetone, 1:1) and the product (0.01 g) was recrystallised from a mixture of toluene and cyclohexane to give the title compound (0.005 g) m.p. 153-155° (Found, for a sample dried at 80° and O.lmmHg for 12 h: C, 63.5; H, 4.8; N, 24.4.

C₁₈H₁₆N₆O 0.5H₂0 requires C, 63.3; H, 5.0; N, 24.6%). ¹H n.m.r.

(CDCI₃): δ 4.01, s, MeO; 4.63, d, J_CH,NH 5.5 Hz, CH₂, 5.22, t,

J_CH,NH 5.5 Hz, NH; 6-45, d, J_7,8 9 Hz, H7; 7.22-9.29, complex, H2' ,4' ,5' , 6' ,2" ,4" ,5" and 6"; 7.56, d, J_{7 , 8} 9 Hz, H8. Example 30

(a) 6-Fluoro-2-(4"-methylphenyl)imidazo[1,2-b]pyridazine

A mixture of 6-fluoropyridazin-3-amine (1.13 g) and ω- bromo-4'-methylacetophenone (2.13 g) in ethanol (50 ml) was refluxed for 2 h. After cooling to room temperature, sodium hydrogen carboate (0.42 g) was added. The reflux was contained for a further 20 h.

The reaction mixture was concentrated and chilled. The yellow precipitate was filtered off, washed with water and dried. It was recrystallised from toluene to give the title compound (1.55 g), m.p. 211-213° (Found, for a sample dried at 80° for 5 h: C, 68.9; H, 4.3; N, 18.4. C₁₃H₁₀FN₃ requires C, 68.7; H, 4.4; N, 18.5%). ¹H n.m.r. (CD₃SOCD₃): δ 2.33, s, Me; 7.23, d, J_7,8 9 Hz, H7; 7.25, d, 7.90, d, J₂,_,3, 9Hz,

H2' ,3' ,5' ,6'; 8.29, dd, J_7,8 9 Hz, J_H8,F 10 Hz, H8; 8.74, s, H3.

(b) 3-Benzoylaminomethyl-6-fluoro-2-(4'-methylphenyl)imidazo [1,2-b]pyridazine A solution of N-(hydroxymethyl)benzamide (0.33 g) in glacial acetic acid (6 ml) and concentrated sulphuric acid (0.2 g) was heated in 50° for 15 minutes. 6-Fluoro-2- phenylimidazo[1,2-b]pyridazine (0.43 g) was added and the reaction mixture refluxed for 6 h. Evaporation gave a yellow residue which was dissolved in water and ammonia solution added to pH 10. The precipitate was crushed finely, filtered, washed with water, ether and dried. This product was subjected to column chromatography (alumina; ether and then chloroform) and recrystallised from toluene to give the title compound (0.36 g), m.p. 237-239° (Found, for a sample dried at 80° and 0.2mmHg for

5 h: C, 70.2; H, 4.8; N, 15.4. C₂₁H₁₇FN₄O requires C, 70.0; H,

4.8; N, 15.5%). ¹H n.m.r. (CDCl₃): δ 2.40, s, Me;.5.18, d, J 5.5

Hz, CH₂NH; 6.88, d, J_7,8 9 Hz, H7; 7.35-7.92, complex, H2' ,3' ,5' ,6' and Ph; 8.01, dd, J_7,8 9 Hz, J_H8,F 10 Hz, H8.

Example 31

(a) 6-Benzylthio-2-phenylimidazo[1,2-b]pyridazine

A mixture of 6-benzylthiopyridazin-3-amine (2.17 g) and phenacyl bromide (2.0 g) in ethanol (50 ml) was refluxed for

2 h. After cooling, sodium hydrogen carbonate (0.42 g) was added. After effervescence had ceased, the reaction mixture was further refluxed for 8 h. After chilling in ice, the precipitate was filtered off and the filtrate concentrated to give a second crop. The combined product was washed with water and dried. It was recrystallised from ethanol to give the title compound

(1.5 g), m.p. 155-157° (Found, for a sample dried at 80° and

0.2mmHg for 5 h: C, 72.3; H, 4.9; N, 13.5. C₁₉H₁₅N₃S requires C,

71.9; H, 4.8; N, 13.2%). ¹H n.m.r. (CDCl₃): δ 4.43, s, CH₂,

6.80, d, J_7,8 9 Hz, H7; 7.29-8.00, complex, 2xPh; 7.71, d, J_7,8

9 Hz, H8; 8.17, s, H3.

(b) 3-Acetamido-6-benzylthio-2-phenylimidazo[1,2-blpyridazine N-Hydroxymethylacetamide and 6-benzylthio-2- phenylimidazo[1,2-b]pyridazine gave the title compound, m.p. 240-242° (from ethanol) (Found, for a sample dried at 85° and 0.2mmHg for 5 h: C, 68.0; H, 5.3; N, 14.3. C₂₂H₂₀N₄OS requires C, 68.0; H, 5.2; N, 14.4%). ¹H n.m.r. (CDCl₃): δ 1.93, s, Me; 4.46, s, CH₂S; 4.97, d, J 5.5 Hz, CH₂NH; 6.89, d, J_7,8 9 Hz, H7;

7.29-7.92, complex, 2xPh; 7.67, d, J_7,8 9 Hz, H8.

Example 32 6-Benzylthio-3-dimethylaminomethyl-2-phenylimidazo

[1,2-b]pyridazine

6-Benzylthio-2-phenylimidazo[1,2-b]pyridazine (0.8 g), 33% ethanolic dimethylamine (0.34 g + 0.34 g) and 37% formaldehyde

(0.2 g + 0.2 g) as above gave the title compound (0.55 g), m.p. 102-104° [from cyclohexane/light petroleum (b.p. 40-60°)]

(Found, for a sample dried at 80° and 0.2mmHg for 6 h: C, 70.9;

H, 6.0; N, 14.9. C₂₂H₂₂N₄S requires C, 70.6; H, 5.9; N, 15.0%).

¹H n.m.r. (CDCl₃): δ 2.30, s, 2xMe; 3.95, s, CH₂N; 4.51, s,

CH₂S; 6.85, d, J_7,8 9 Hz, H7; 7.25-8.12, complex, 2xPh; 7.74, d, J_7,8 9 Hz, H8.

Biological Testing

(i) Receptor Binding Assays

Young adult Sprague-Dawley rats were decapitated and their brains removed and placed on ice. Washed synaptosomal membranes were prepared according to a previously published procedure and stored frozen until use. On the day of assay, membrane preparations were thawed, washed once by centrifugation and resuspension in ice-cold distilled water, then resuspended in 50 mM Tris-HCl buffer, pH 7.4 at 2 degrees C. For the receptor bi-nding assays, aliquots of the membrane suspension (approx.0.6-0.8mg protein) were incubated with tritiated diazepam (86.6 Ci/mmol, 0.70 + - 0.05 nM final concentration) and 3 to 5 separate concentrations of the test compounds, in a final volume of 2 ml of 50 mM Tris-HCl buffer. Assays were conducted on ice for an incubation period of 35 min. Unless otherwise stated, assays also contained 100 μM GABA to stimulate the binding of the ligand to the benzodiazepine receptors in the plasma membranes. Nonspecific binding was determined in separate tubes by the addition of a large excess (10 μM) of unlabelled diazepam. Membranes were collected by filtration under vacuum on glass-fibre filters (Whatman GF/B, 2.4 cir.) and washed with 12 ml of ice-cold buffer. Filters were placed in scintillation vials with 1 ml of water and 8 ml of toluene/triton X-100 scintillation fluid; bound radioactivity was determined using conventional techniques. Test compounds (imidazo[l, 2-b]pyridazines) were routinely tested at 4 separate concentrations; within each experiment all assays were performed in triplicate. For each concentration of the test compounds, results were calculated as the percent displacement of specific binding, where specific binding was taken as the amount of radioactive diazepam bound in control tubes (no inhibitor) less the amount bound in the presence of excess unlabelled diazepam. IC₅₀ values (the concentration of the drug causing 50% displacement of radioactive diazepam bound to the brain membranes, under standard assay conditions) were calculated for each test compound using computer-assisted log-logit analysis. The results of these tests are given in Table 3.

(ii) In vivo tests .

(a) In a rat conflict test, GBLD-231 (see Table 3) was found to be active at 0.5 mg/kg, p.o. (no side effects seen). (b) In a test for the prevention of pentylenetetrazol-induced tonic convulsions in rats, it gave ED₅₀ = 4.9 mg/kg, p.o. and

ED₉₀ - 10.8 mg/kg, p.o.

(c) In a continuous avoidance performance test in monkeys, no impairment was observed at 10 or 30 mg/kg, p.o.

(d) The dose separation between desired effects (anticonflict, anticonvulsant) and such side effects as motor impairment, relaxation and sedation generally appeared greater for GBLD-231 than for diazepam.

Claims

CLAIMS:

1. A method for the treatment of anxiety syndromes, epilepsy, insomnia or skeletal muscle tension, or for the reversal of the sedative effects of the benzodiazepine class of drugs, which comprises administration of an effective amount of a compound of the general formula V:

in which:

X is a halogen atom, or a group of the formula ER¹, where E is O, S, NH, OCH₂-, SCH₂-, or NHCH₂-, and R¹ is selected from alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, aryl or substituted-aryl (including phenyl or substituted phenyl), arylalkyl or substituted-arylalkyl (including phenylalkyl or substituted phenylalkyl), arylalkenyl or substituted-arylalkenyl (including phenylalkenyl or substituted phenylalkenyl), arylalkynyl or substituted-arylalkynyl (including phenylalkenyl or substituted phenylalkenyl), heteroaryl or substituted-heteroaryl, heteroarylalkyl or substituted-heteroarylalkyl, heteroarylalkenyl or substituted-heteroarylalknyl, heteroarylalknyl or substituted-heteroarylalknyl, cycloalkyl or substituted-cycloalkyl, cycloalkylalkyl or substituted-cycloalkylalkyl, heterocyclo or substituted-heterocyclo, heterocycloalkyl or substituted-heterocycloalkyl, heterocycloalkenyl or substituted-heterocycloalkenyl or heterocycloalkynyl or substituted-heterocycloalkynyl;

Y is a group of the formula OR²,

-CH₂NHCOR⁴, or -CH₂NR⁶R⁷, and each of R ², R⁴ and R⁶ and R⁷ (which may be the same or different) is selected from alkyl

(including methyl and ethyl), cycloalkyl, or aryl;

Z is selected from aryl or substituted-aryl (including phenyl or substituted-phenyl), arylalkyl or substituted-arylalkyl, (including phenylalkyl and substituted phenylalkyl) heteroaryl or substituted-heteroaryl, heteroarylalkyl or substituted-heteroarylalkyl, cycloalkyl or substituted-cycloalkyl, cycloalkylalkyl or (substituted-cycloalkyl) alkyl, heterocyclo or substituted-heterocyclo, or heterocycloalkyl or substituted-heterocycloalkyl; with the proviso that X is not a group of the formula -OAr or -SCH₂Ar (where Ar is aryl or substituted aryl) when Y is a group of the formula -OAlkyl and Z is aryl or substituted aryl, or heteroaryl or substituted heteroaryl.

2. A method of claim 1, comprising administration of a compound of the general formula V as defined in claim 1, wherein:

X is a halogen atom, or is selected from alkoxy, alkylthio, phenylalkoxy or substituted phenylalkoxy, phenylthio or substituted phenylthio, anilino, phenylalkylamino or substituted phenylalkylamino, α-, ß- or γ- picolylthio, β-picolylalmino, or benzthiazol-2-ylthio; y is selected from methoxy or ethoxy; and

Z is selected from phenyl or substituted phenyl, α- or ß-naphthyl, α-, ß- or γ-pyridyl, or α- or ß-thienyl.

3. A method of claim 1, comprising administration of a compound of the general formula V as defined in claim 1, wherein:

X is a halogen atom, or is selected from alkoxy, alkylthio, phenoxy or substituted phenoxy, phenylalkoxy or substituted phenylalkoxy, phenylthio or substituted phenylthio, or phenylalkylthio or substituted phenylalkylthio; Y is selected from -CH₂NHCOMe, -CH₂NHCOPh, and -CH₂NMe₂; and Z is selected from phenyl or substituted phenyl.

4. A pharmaceutical composition for use in the treatment of anxiety syndromes, epilepsy, insomnia or skeletal muscle tension, or for the reversal of the sedative effects of the benzodiazepine class of drugs, which comprises a compound of the general formula V as defined in ciaim 1, in association with a pharmaceutically acceptable carrier or diluent.

5. A pharmaceutical composition of claim 4, comprising a compound of the general formula V as defined in claim 1, wherein:

X is a halogen atom, or is selected from alkoxy, alkylthio, phenylalkoxy or substituted phenylalkoxy, phenylthio or substituted phenylthio, anilino, phenylalkylamino or substituted phenylalkylamino, α-, ß- or γ-picolythio, ß-picolylamino, or benzthiazol-2-ylthio; y is selected from methoxy or ethoxy; and

6. A pharmaceutical composition of claim 5, comprising a compound of the general formula V as defined in claim 1, wherein:

7. A compound of the general formula V as defined in claim 1, but not including compounds wherein:

(i) X=Cl, Y=OMe, Z=Ph;

(ii) X=Ph, Y=OMe, Z=Ph;

(iii) X=Br, Y=OMe, Z=Ph;

(iv) X=Br, Y=OMe, Z=C₆H₄Br-p;

(v) X=Br, Y=OMe, Z-C₆H₄C1-p;

(vi) X=Cl, Y=OMe, Z=C₆H₄Br-p; (vii) X=Cl , Y=OMe , Z=C₆H₄Cl-p;

(viii ) X=Cl , Y=OMe, Z=C₆H₄OMe-p;

( ix) X=Cl , Y=OEt, Z=Ph;

(x) X=Cl , Y=OMe, Z=Ph, 7 = Me;

(xi) X=F, Y=OMe , Z=Ph; or

(xii) X=OMe, Y=OMe, Z=Ph.

8. A compound of claim 7, wherein:

X is a halogen atom, or is selected from alkoxy, alkylthio, phenylalkoxy or substituted phenylalkoxy, phenylthio or substituted phenylthio, anilino, phenylalkylamino or substituted phenylalkylamino, α-, ß- or γ-picolylthio, ß-picolylamino, or benzthiazol-2-ylthio; y is selected from methoxy or ethoxy; and

9. A compound of claim 7, wherein:

10. A process for the preparation of a compound of the general formula V as defined in claim 1 in which Y represents a group -OR², which comprises reaction of an intermediate compound of the formula:

where X and Z are as defined in claim 1, with a diazoalkane or alkyl halide to form said compound of the general formula V.

11. A process according to claim 10, wherein said intermediate compound is prepared by reaction of a compound of the formula:

where X is as defined in claim 1, with a compound of the formula:

ZCOCHO where Z is as defined in claim 1.

12. A process according to claim 10, where said intermediate compound is prepared by reaction of a compound of the formula:

where X is as defined in claim 1, with a compound of the formula:

ZCOCH₂Hal where Z is as defined in claim 1 and Hal represents a halide.

13. A process for the preparation of a compound of the general formula V as defined ii.claim 1 in which Y represents a group -OH₂NHCOR⁴, which comprises reaction of an intermediate compound of the formula

where X and Z are as defined in claim 1, with a compound of the formula:

HOCH₂NHCOR⁴ where R⁴ is as defined in claim 1.

14. A process for the preparation of a compound of the general formula V as defined in claim 1 in which Y represents a group -CH₂NR⁶R⁷, which comprises reaction of an intermediate compound of the formula

Z where X and Z are as defined in claim 1, with compounds of the formulae

CH₂O and NHR⁶R⁷ where R⁶ and R⁷ are as defined in claim 1.

15. A process according to claim 13 or claim 14, wherein said intermediate compound is prepared by reaction of a compound of the formula:

where X is as defined in claim 1, with a compound of the formula:

ZCOCH₂Hal where Z is as defined in claim 1 and Hal represents a halide.