RU2036924C1 - Method of synthesis of imidazo-(1,2-b)-pyridazine or their salts and imidazo-(1,2-b)-pyridazine derivatives or their salts - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: method of synthesis of derivatives of imidazo-(1,2-b)-pyridazine of the formula (I)

where R₁, R₂, R₃, X - as indicated in description is carried out by interaction of compound of the formula (II)

where R₁ and Z - as indicated in description with compound of the formula (III)

where Alk, X, R₂, R₃ - as indicated above. EFFECT: improved method of synthesis. 3 cl, 3 tbl

Description

 The invention relates to new derivatives of imidazopyridazines, their preparation and use.

 The inventive imidazopyridazine derivatives have anti-allergic and anti-inflammatory effects, as well as activity in inhibiting platelet activating factor and are used as anti-asthma drugs by controlling bronchospasm and narrowing of the bronchi.

 Japan Patent Publication No. SNO 61 (1986) 152684 discloses that the compounds of the imidazo [1,2-b] pyridazine group have antithrombogenic activity as well as cardiovascular activity, especially cardiotonic activity. However, there are no reports of any imidazo [1,2-b] pyridazine derivatives that have anti-allergic and anti-inflammatory effects, as well as activity in inhibiting platelet activation factor.

 On the other hand, the development of highly effective anti-asthma drugs is a promising area, although various types of anti-asthma drugs have been released to the markets.

 As a result of extensive research in the field of chemical modification of imidazo [1,2-b] pyridazine at position 6, until now unknown derivatives of imidazo [1,2-b] pyridazine have been discovered to have anti-allergic and anti-inflammatory effects and activity in inhibiting platelet activation factor.

 It was also found that these derivatives control bronchospasm and narrowing of the bronchi.

где R₁ представляет собой атом водорода или галогена или низшую алкильную группу, возможно содержащую заместитель (заместители); R₂ и R₃независимо друг от друга представляют собой атом водорода, низшую акильную группу, возможно содержащую заместитель (заместители), циклоалкильную группу или фенильную группу, возможно содержащую заместитель (заместители), или R₂ и R₃ вместе с атомом азота, с которым они связаны, могут образовывать гетероциклическое ядро, возможно содержаее заместитель (заместители); Х представляет собой атом кислорода или S(O)n (n принимает значения 0-2); AlK представляет собой алкиленовую группу с прямой или разветвленной цепью, содержащую 1-10 атомов углерода и, возможно содержащую заместитель (заместители), при условии, что Х представляет собой атом кислорода, когда R₁ представляет собой атом водорода, любой из R₂ и R₃ представляет собой атом водорода, а оставшийся атом водорода или низшую алкильную группу, и AlK представляет собой алкиленовую группу с прямой цепью, содержащую 2-4 атома углерода; или соль этого соединения.The invention provides imidazo [1,2-b] pyridazine of formula I

where R ₁ represents a hydrogen or halogen atom or a lower alkyl group, possibly containing a substituent (s); R ₂ and R ₃ independently represent a hydrogen atom, a lower alkyl group, possibly containing a substituent (s), a cycloalkyl group or a phenyl group, possibly containing a substituent (s), or R ₂ and R ₃ together with a nitrogen atom, with which they are connected, they can form a heterocyclic nucleus, possibly containing a substituent (s); X represents an oxygen atom or S (O) n (n is 0-2); AlK is a straight or branched chain alkylene group containing 1-10 carbon atoms and optionally containing substituent (s), provided that X represents an oxygen atom when R ₁ represents a hydrogen atom, any of R ₂ and R ₃ represents a hydrogen atom, and the remaining hydrogen atom or lower alkyl group, and AlK represents a straight chain alkylene group containing 2-4 carbon atoms; or a salt of this compound.

где R₁ предсталяет собой атом водорода или галогена или низшую алкильную группу, возможно содержащую заместитель (заместители); R₂ и R₃независимо друг от друга представляют собой атом водорода, низшую алкильную группу, возможно содержащую заместитель (заместители), циклоалкильную группу или фенильную группу, возможно содержащую заместитель (заместители), или R₂ и R₃ вместе с атомом азота, с которым они связаны, могут образовывать гетероциклическое ядро, возможно содержащее заместитель (заместители); Х представляет собой атом кислорода или S(O)_n (n принимает значение 0-2); AlK представляет собой алкиленовую группу с прямой или разветвленной цепью, содержащую 1-10 атомов углерода, и возможно содержащую заместитель (заместители); или соль этого соединения.The invention also contemplates an anti-asthma composition comprising a compound of the following formula I '

where R ₁ represents a hydrogen or halogen atom or a lower alkyl group, possibly containing a substituent (s); R ₂ and R ₃ independently represent a hydrogen atom, a lower alkyl group, possibly containing a substituent (s), a cycloalkyl group or a phenyl group, possibly containing a substituent (s), or R ₂ and R ₃ together with a nitrogen atom, with which they are bound, they can form a heterocyclic core, possibly containing a substituent (s); X represents an oxygen atom or S (O) _n (n is 0-2); AlK is a straight or branched chain alkylene group containing 1-10 carbon atoms and optionally containing substituent (s); or a salt of this compound.

 In addition, the invention provides a method for producing a compound of formula I or I ′, or a salt thereof. When the compounds of formula I or I 'contain an asymmetric carbon atom, they can be active compounds; racemic mixtures are also included in the scope of the invention.

 As used herein, the term “lower alkyl group” means a straight or branched chain alkyl group containing 1 to 6 carbon atoms. Examples of lower alkyl groups are methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl groups.

 The term "cycloalkyl group" means a cycloalkyl group containing 3-6 carbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.

H₂-CH₂-, -

, -(CH₂)₃-, -CH

, -

-CH

CH₂-, -CH

-, -CH₂-

H₂-, -CH₂-

-, -(CH₂)₅-,
-CH

-

H₂-, -(CH₂)₆-, -(CH₂)₇-, -(CH₂)₈-, -(CH₂)₉- и -(CH₂)₁₀
Предпочтительными группами являются алкиленовые группы с прямой или разветвленной цепью, содежащие 1-6 атомов углерода, например -СН₂-, -СН₂СН₂-, -(СН₂)_3-, -(СН₂)₄-,
-CH

H₂-, -CH

- и -CH₂-

H₂
Примерами заместителей в низшей алкильной группе, возможно содержащей заместитель (заместители), являются гидроксильня группа, аминогруппа, моно(низший алкил)аминогруппа, низшая алкоксигруппа и атом галогена. Число таких заместителей составляет 1-4. Примерами заместителей в фенильной группе, возможно содержащей заместитель (заместители), являются аминогрупа, моно- или ди(низший алкил)аминогруппа, низшая алкоксигруппа и атом галогена. Число таких заместителей составляет 1-5. Примерами заместителей в алкиленовой группе с прямой или разветвленной цепью, содержащей 1-10 атомов углерода и, возможно содержащей заместитель (заместители), являются гидроксильная группа, аминогруппа, атом галогена, фенильная группа, бензильная группа, моно(низший алкил)аминогруппа, низшая алкоксигруппа или гетероцикл. Количество таких заместителей составляет 1-5. Примерами упомянутой моно(низший алкил)аминогруппы являются моно(С₁-С₄-алкил)аминогруппы, например метиламиногруппа, этиламиногруппа и пропиламиногруппа. Примерами ди(низший алкил)аминогруппы являются ди(С₁-С₄-алкил)аминогруппы, например диметиламиногрупппа и диэтиламиногруппа. Примерами низшей алкоксигруппы являются алкоксигруппы С₁-С₆, например, метоксигруппа, этоксигруппа, пропоксигруппа и гексилоксигруппа. Под атомом галогена подразумеваются фтор, хлор, иод и бром. Термин "гетероцикл" включает 5- или 6-членный гетероцикл, например, тиенил, фурил, пиридил, морфолино или тиазолил.Examples of groups denoted by the term "straight or branched chain alkylene group containing 1-10 carbon atoms" are the following groups:

H ₂ -CH ₂ -, -

, - (CH ₂ ) ₃ -, -CH

, -

-Ch

CH ₂ -, -CH

-, -CH ₂ -

H ₂ -, -CH ₂ -

-, - (CH ₂ ) ₅ -,
-Ch

-

H ₂ -, - (CH ₂ ) ₆ -, - (CH ₂ ) ₇ -, - (CH ₂ ) ₈ -, - (CH ₂ ) ₉ - and - (CH ₂ ) ₁₀
Preferred groups are straight or branched chain alkylene groups containing 1 to 6 carbon atoms, for example —CH ₂ -, —CH ₂ CH ₂ -, - (CH ₂ ) _3- , - (CH ₂ ) ₄ -,
-Ch

H ₂ -, -CH

- and -CH ₂ -

H ₂
Examples of substituents in a lower alkyl group, possibly containing substituent (s), are a hydroxyl group, an amino group, a mono (lower alkyl) amino group, a lower alkoxy group and a halogen atom. The number of such substituents is 1-4. Examples of substituents in a phenyl group, possibly containing substituent (s), are an amino group, a mono or di (lower alkyl) amino group, a lower alkoxy group and a halogen atom. The number of such substituents is 1-5. Examples of substituents in a straight or branched chain alkylene group containing 1-10 carbon atoms and possibly containing substituent (s) are a hydroxyl group, an amino group, a halogen atom, a phenyl group, a benzyl group, a mono (lower alkyl) amino group, a lower alkoxy group or heterocycle. The number of such substituents is 1-5. Examples of said mono (lower alkyl) amino group are a mono (C ₁ -C ₄ alkyl) amino group, for example a methylamino group, an ethylamino group and a propylamino group. Examples of the di (lower alkyl) amino group are the di (C ₁ -C ₄ alkyl) amino group, for example a dimethylamino group and a diethylamino group. Examples of the lower alkoxy group are C ₁ -C ₆ alkoxy groups, for example, a methoxy group, an ethoxy group, a propoxy group and a hexyloxy group. By a halogen atom is meant fluorine, chlorine, iodine and bromine. The term “heterocycle” includes a 5- or 6-membered heterocycle, for example, thienyl, furyl, pyridyl, morpholino or thiazolyl.

A heterocyclic core, in the case when R ₂ and R ₃ together with the nitrogen atom to which they are attached form a heterocyclic core, is a 4-7 membered heterocyclic core containing at least one nitrogen atom, and possibly oxygen and / or sulfur atoms . A 5- or 6-membered heterocyclic ring is generally preferred. Examples of 5- or 6-membered heterocyclic nuclei are pyrrolidine, piperidine, morofoline, piperazine and homopiperazine. These 5- or 6-membered heterocyclic nuclei can be substituted with one or five substituents, examples of which are the substituents indicated for the lower alkyl and phenyl groups.

CH₂- или -СH₂-

H₂-
Представляющая интерес группа соединений (I') или их солей включает в себя соединение формулы Ia

где AlK₁ представляет собой алкиленовую группу с прямой или разветвленной цепью, содержащую 1-6 атомов углерода, или соль этого соединения;
соединение формулы Ib:

где Х₁ представляет собой атом кислорода или серы, а AlK представляет собой алкиленовую группу с разветвленной цепью, содержащую 2-6 атомов углерода, или соль этого соединения, и соединение формулы Ic:

где Х₁ имеет то же значение, что и выше, а AlK₃ представляет собой алкиленовую группу с прямой или разветвленной цепью, содержащую 3-5 атомов углерода, или соль этого соединения.Preferably R ₁ represents hydrogen and so on, and R ₂ and R ₃ represent a hydrogen atom and so on. Preferably X is an oxygen or sulfur atom. Preferably, AlK is, for example, a straight or branched chain alkylene group containing 1-6 carbon atoms, such as, for example
- (CH ₂ ) ₃ - -CH

CH ₂ - or -CH ₂ -

H ₂ -
A group of compounds of interest (I ′) or salts thereof includes a compound of formula Ia

where AlK ₁ represents a straight or branched chain alkylene group containing 1-6 carbon atoms, or a salt of this compound;
compound of formula Ib:

where X ₁ represents an oxygen or sulfur atom, and AlK represents a branched chain alkylene group containing 2-6 carbon atoms, or a salt of this compound, and a compound of formula Ic:

where X ₁ has the same meaning as above, and AlK ₃ represents a straight or branched chain alkylene group containing 3-5 carbon atoms, or a salt of this compound.

, -(CH₂)₃-, -CH

, -(CH₂)₄-, -CH

CH₂-,

-

, -(CH₂)₅-, -CH₂-

H₂- и -(CH₂)₆-
AlK₂ может быть алкиленовой группой с разветвленной цепью, содержащей 2-6 атомов, например
-

, -CH

, -

-CH

H₂-, -

H

, -CH

H₂-,
-CH₂-

H₂- и -

H₂CH

.
AlK₃ может быть алкиленовой группой с прямой или разветвленной цепью, содержащей 3-5 атомов, например

CH₂)₃-, -CH

, -

-CH

H₂-, CH₂-

H₂- и -CH

-
Заявляемое соединение формулы I' можно получить способом А), который включает в себя конденсацию соединения формулы II

где R₁ и Х имеют те же значения, что и в формуле I', или соли этого соединения, с соединением формулы III
y-AlK-SO

где R₂, R₃ и AlK имеют те же значения, что и в формуле I', а представляет собой реакционноспособную группу, или ее соль, обычно в присутствии основания.Specifically, AlK ₁ may be a straight or branched chain alkylene group containing 1-6 atoms, for example
-CH ₂ -, -CH ₂ CH ₂ -, -

, - (CH ₂ ) ₃ -, -CH

, - (CH ₂ ) ₄ -, -CH

CH ₂ -,

-

, - (CH ₂ ) ₅ -, -CH ₂ -

H ₂ - and - (CH ₂ ) ₆ -
AlK ₂ may be a branched chain alkylene group containing 2-6 atoms, for example
-

, -CH

, -

-Ch

H ₂ -, -

H

, -CH

H ₂ -,
-CH ₂ -

H ₂ - and -

H ₂ CH

.
AlK ₃ may be a straight or branched chain alkylene group containing 3-5 atoms, for example

CH ₂ ) ₃ -, -CH

, -

-Ch

H ₂ -, CH ₂ -

H ₂ - and -CH

-
The inventive compound of formula I 'can be obtained by method A), which includes the condensation of the compounds of formula II

where R ₁ and X have the same meanings as in formula I ', or salts of this compound, with a compound of formula III
y-AlK-SO

where R ₂ , R ₃ and AlK have the same meanings as in formula I ', and represents a reactive group, or its salt, usually in the presence of a base.

 Examples of the reactive groups Y in formula III are halogen (e.g. chlorine, iodine or bromine), an arylsulfonyloxy group with 1-10 carbon atoms (e.g. phenylsulfonyloxy or p-tolylsulfonyloxy) and an alkylsulfonyloxy group with 1-4 carbon atoms (e.g. methanesulfonyloxy). Examples of bases are alkali metal hydrides (e.g. sodium hydride or potassium hydride), alkali metal alkoxides (e.g. sodium hydroxide or potassium hydroxide), and carbonates (e.g. sodium carbonate or potassium carbonate).

This reaction is carried out in an inert solvent, for example alcohol (e.g. methanol or ethanol), ether (e.g. dioxane or tetrahydrofuran), an aromatic hydrocarbon (e.g. benzene, toluene or xylene), nitrile (e.g. acetonitrile), amide (e.g. dimethylformamide or dimethylacetamide ) and sulfoxide (e.g. dimethyl sulfoxide). Temperatura reaction is 10-200 ^C, preferably 50-100 ^C. The reaction time is from 30 minutes to 24 hours, preferably 1-6 hours. The product obtained in this reaction can be isolated and purified by known methods, for example by solvent extraction, a change in basicity, redistribution, salting out, crystallization, recrystallization or chromatography.

где R₁ имеет то же значение, что и в формуле I', а Z представляет собой реакционноспособную группу, или соли этого соединения, с соединением формулы V
HX-AlK-SO₂N

где R₂, R₃, Х и AlK имеют те же значения, что и в формуле I', или его соли, обычно в присутствии основания. Реакционноспособные группы и основания, указанные для упомянутого способа А), применимы также и к этой реакции.In addition, the compound of formula I 'claimed in the invention can be obtained by method B), which includes the condensation of the compounds of formula IV

where R ₁ has the same meaning as in formula I ', and Z represents a reactive group, or salts of this compound, with a compound of formula V
HX-AlK-SO ₂ N

where R ₂ , R ₃ , X and AlK have the same meanings as in formula I ', or its salt, usually in the presence of a base. The reactive groups and bases indicated for the aforementioned method A) are also applicable to this reaction.

This reaction is carried out at 20-200 ^{° C,} preferably at 50-150 ^{° C,} more preferably at 50-100 ^{° C} for 30 minutes to 24 hours, preferably for 1-10 hours, in an inert solvent such as, for example, an alcohol (e.g. methanol or ethanol), ether (e.g. dioxane, tetrahydrofuran), a promising hydrocarbon (e.g. benzene, toluene or xylene), nitrile (e.g. acetonitrile), amide (e.g. dimethylformamide or dimethylacetamide), or sulfoxide (e.g. dimethyl sulfoxide). The resulting product can be isolated and purified by known methods specified for method A).

где R1, AlK и Х имеют те же значения, что и в формуле I', а W представляет собой атом галогена, или соли этого соединения, с амином формулы VII
NH

где R₂ и R₃ имеют те же значения, что и в формуле I', или с солью этого амина.Further, compound I 'can be prepared by method C), which includes the reaction of a compound of formula VI

where R1, AlK and X have the same meanings as in formula I ', and W represents a halogen atom, or salts of this compound, with an amine of formula VII
NH

where R ₂ and R ₃ have the same meanings as in formula I ', or with a salt of this amine.

This reaction is carried out in an inert solvent specified for methods A) or B), for example in alcohol (for example methanol, ethanol), ether (for example dioxane, tetrahydrofuran), a halogenated hydrocarbon (for example dichloromethane, chloroform), nitrile (for example acetonitrile) or a sulfoxide (e.g. dimethyl sulfoxide) at (-20) - (+ 100 ° ^C), preferably (-10) -. (+ 50) ^{° C} for 30 minutes to 5 hours, preferably for 1-3 h The resulting product can be isolate and purify by known methods indicated for methods A) or B).

 The compound of formula I ′ thus obtained can be converted, if desired, into its salt using standard methods.

 Salts of compounds I or I 'are usually pharmaceutically or physiologically acceptable salts. Examples of such salts are salts with inorganic acids, for example with hydrochloric, sulfuric or phosphoric acid, or with organic salts, for example with methanesulfonic p-toluenesulfonic, lactic, tartaric or citric acid. These salts can also be used as salts of compounds II, III, IV, V, VI and VII used as starting materials for the preparation of compounds of formula I '.

A

lK-

AcO-

-SON

AcO

-SO₂Cl

AcO

SO₂N

HO-AlK-SO

В приведенных формулах AlK, Y, R₂ и R₃ имеют те же значения, что и выше, а Ас представляет собой ацетильную группу. Далее, соединение формулы VI можно получить реакцией между соединением формулы II или его солью и соединением формулы XIII
y AlK SO₃H, где y и AlK имеют те же значения, что и выше, с последующим галогенированием полученного таким образом соединения, или реакцией между соединением IV или его солью с соединением формулы XIV
HX AlK SO₃H, где Х и AlK имеют те же значения, что и выше, с последующим галогенированием полученного таким образом соединения. Соединение формулы VII можно получить способом, описанным, например, в Comprehensike Organic Chemistry Vol 2 (1979), или аналогичными ему способами.As for the starting materials used in the methods for producing compounds of the formula I 'or their salts, the compounds of the formula II can be obtained by the method described in the auxiliary example 1 or similar methods; the compounds of formula III can be obtained by methods disclosed, for example, in Chem. Ber. 91, 2130 (1958), I. Org. Chem. 52, 2162 (1987) and Japanese Patent Publication No. HO 62 (1987) 48687 or similar methods; compound (IV) can be obtained by methods disclosed, for example, in Tetra hedrov 24, 239 (1968) and in Heterocyclic 2, 53 (1965) or similar methods; Compound (V) can be prepared by converting the reactive group of a compound of formula III into a mercapto group or hydroxyl group in accordance with standard methods. Compounds of formula V in which X is O can be prepared according to the following reaction scheme or in a similar manner

A

lK-

AcO-

-Son

Aco

-SO ₂ Cl

Aco

SO ₂ N

HO-AlK-SO

In the above formulas, AlK, Y, R ₂ and R ₃ have the same meanings as above, and Ac represents an acetyl group. Further, a compound of formula VI can be prepared by the reaction between a compound of formula II or a salt thereof and a compound of formula XIII
y AlK SO ₃ H, where y and AlK have the same meanings as above, followed by halogenation of the compound thus obtained, or by reaction between compound IV or a salt thereof with a compound of formula XIV
HX AlK SO ₃ H, where X and AlK have the same meanings as above, followed by halogenation of the compound thus obtained. The compound of formula VII can be obtained by the method described, for example, in Comprehensike Organic Chemistry Vol 2 (1979), or by analogous methods.

 When a compound of formula I ′ or a physiologically acceptable salt thereof is administered to a mammal, for example a human, as an anti-asthma agent, the dosage varies depending on age, body weight, disease state, route of administration, frequency of administration, etc. but, as a rule, is 0.1-100 mg / kg / day, preferably 0.1-50 mg / kg / day, more preferably 0.5-10 mg / kg / day at a frequency of 2-3 times a day.

 The route of administration can be either oral or parenteral.

 The compound of formula I 'can be administered in pure form, but it is usually administered in the form of a pharmaceutical preparation prepared on the basis of a pharmaceutically acceptable carrier or diluent. Examples of pharmaceutical preparations are tablets, capsules, granules, finely divided granules, powders, syrups, injectable or inhaled preparations. These drugs can be prepared in the usual way. Examples of carriers for oral administration are starch, mannitol, crystalline cellulose, and sodium carboxymethyl cellulose, which are commonly used for the manufacture of pharmaceutical preparations. The carriers used for the preparation of injectable preparations are distilled water, physiological saline, glucose solution and an infusion agent. Other components commonly used for the preparation of pharmaceutical formulations may be added to said preparations.

 Supporting Example I.

 Preparation of 6-mercaptoimidazo [1,2-b] pyridazine.

6-Chlorimidazo [1,2-b] pyridazine (13.5 g), a 28% solution (by weight) of sodium methylate in methanol (17.5 g) and thioacetic acid (7.0 g) are dissolved in 70 ml of methanol and the resulting solution was heated at 150 ^C in a sealed tube for 6 hours. The reaction mixture was cooled to room temperature and subjected to distillation to remove the organic solvent. The residue was washed three times with chloroform, and the insoluble matter was extracted six times with 50 ml of a solution of chloroform-methanol (1: 1). The collected extracts are distilled to remove the organic solvent. Precipitated crystals were isolated by filtration; 3.7 g of 6-mercaptoimidazo [1,2-b] pyridazine are obtained.

Calculated, C 47.11; H 3.43, N 27.47
C ₆ H ₅ N _3,5
Found, C, 46.97; H 3.25; N, 27.25.

 Auxiliary example 2.

 Preparation of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide.

a) A mixture of 16.7 g of 3-bromo-2,2-dimethyl-1-propanol, 14.6 g of potassium thiocyanate and 60 ml of dimethylformamide was stirred for 4 hours at 130-140 ^C. The reaction solution was cooled to room temperature ( hereinafter means 5-20 ^about C), and add to it a mixture of 200 ml of diethyl ether and 200 ml of water. Separate the ether layer. The aqueous layer was extracted with 150 ml of diethyl ether. The collected ether layers were washed with brine, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was distilled under reduced pressure to obtain 12.4 g of 3-hydroxy-2,2-dimethyl-1-propylthiocyanate.

T.kip. 133-134 ^about C / 4 mm Hg

NMR (CDCl ₃ ) δ 1.03 (6H, s), 1.72 (1H, t, I 5 Hz), 3.46 (2H, d, I 5 Hz).

 A mixture of 58.7 g of 3-hydroxy-2,2-dimethyl-1-propylthiocyanate, 400 ml of acetic anhydride and 400 ml of pyridine was stirred for 16 hours at room temperature. The reaction solution was concentrated under reduced pressure. The residue was dissolved in 50 ml of diethyl ether. The resulting solution was washed sequentially with 1 m hydrochloric acid solution, water, an aqueous solution of sodium bicarbonate, water and dried over anhydrous magnesium sulfate. After removing the solvent, the residue was purified by distillation under reduced pressure to obtain 53.2 g of 3-acetoxy-2,2-dimethyl-1-propylthiocyanate.

T.kip. 126-128 ^about With 3 / mm RT.article

NMR (CDCl ₃ ) δ 1.09 (6H, s), 2.07 (3H, s), 3.02 (2H, s), 3.90 (2H, s).

c) Through a mixture of 71.3 g of 3-acetoxy-2,2-dimethyl-1-propylthiocyanate and 550 ml of water at room temperature for 6 hours, chlorine gas is bubbled under vigorous stirring. The reaction solution was extracted with diethyl ether (2 times 400 ml); the extracts are washed with saturated saline (5 times 300 ml each) and dried over anhydrous magnesium sulfate. After removal of solvent, the residue was purified by distillation under reduced pressure; 54.6 g of 3-acetoxy-2,2-dimethyl-1-propanesulfonyl chloride are obtained;
T.kip. 125-126 ^about C / 0.4 mm RT.article

NMR (CDCl ₃ ) δ 1.27 (6H, s), 2.10 (3H, s), 3.86 (2H, s), 3.98 (2H, s).

d) To a solution of 20.3 g of 3-acetoxy-2,2-dimethyl-1-propanesulfonyl chloride in 300 ml of dichloromethane for 1 h, ammonia gas was bubbled, keeping the reaction temperature at not higher than 13 ^{° C,} under ice-cooling and stirring. The precipitate was filtered off, the filtrate was concentrated and subjected to silica gel column chromatography using a methanol chloroform mixture (1:20) as an eluent. The desired fractions are concentrated under reduced pressure; 10.8 g of 3-acetoxy-2,2-dimethyl-1-propanesulfonamide are obtained.

T.kip. 106-109 ^about S.

NMR (CDCl ₃ ) δ 1.19 (6H, s), 2.08 (3H, s), 3.22 (2H, s), 3.99 (2H, s).

 c) To a solution of 10.0 g of 3-acetoxy-2,2-dimethyl-1-propanesulfonamide in 80 ml of methanol, 9.2 g of a 28% (by weight) solution of sodium methylate in methanol are added; the addition is carried out at room temperature with stirring. With stirring for 30 minutes, the reaction mixture was concentrated to dryness and the residue was subjected to silica gel column chromatography using a chloroform-methanol mixture (9: 1) as aluent. The desired fractions were concentrated to give 6.2 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide.

Mp 57-59 ^about S.

NMR (CDCl ₃ ) δ 1.00 (6H, s), 2.97 (2H, s), 3.17 (2H, d, I 5 Hz), 4.64 (1H, t, I 5 Hz), 6.69 (2H, br).

Calculated, C 35.91; H 7.84; N, 8.38
C ₆ H ₁₃ NO ₃ S
Found C, 35.97; H 8.02; N, 8.08.

In the same manner as described in Supporting Example 1, the following alkyl sulfonamide derivatives were prepared: 3-hydroxy-1-propanesulfonamide
NMR (CDCl ₃ + d ₆ -DMCO) δ 2.07 (2H, m), 3.22 (2H, m), 3.71 (2H, m), 3.99 (1H, t), 6.04 (2H , with).

(R) - (-) - 3-hydroxy-2-methyl-1-propanesulfonamide
[α] _D ²⁴ 25.1 ^about (s 1.0, methanol)
NMR (d ₆ DMCO): 1.01 (3H, d), 2.10 (1H, m), 2.71 (1H, q), 3.16 (1H, q), 3.32 (2H, m ), 4.70 (1H, s), 6.77 (2H, s)
3-hydroxy-2-ethyl-1-propanesulfonamide
NMR (CDCl ₃ ) δ 0.86 (3H, t), 1.47 (2H, q), 1.8-2.0 (1H, m), 2.7-3.2 (2H, m), 3.3-3.6 (2H, m), 4.59 (1H, t), 6.77 (2H, s).

 Supporting Example 3.

 Obtaining 3-mercapto-2,2-dimethyl-1-propanesulfonamide.

a) To a solution of 5.0 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide in 18 ml of pyridine, 6.3 g of p-toluenesulfonyl chloride are added while cooling with ice. After 2 hours, the reaction mixture was poured into a mixture of 300 ml of chloroform and 100 ml of ice water. The separated chloroform layer is washed successively with dilute hydrochloric acid and water, dried over anhydrous magnesium sulfate and distilled under reduced pressure; 8.5 g of 3-tosyl-hydroxy-2,2-dimethyl-1-propanesulfonamide are obtained
Mp 59-61 ^about With
Calculated, C 44.84; H 5.96; N, 4.36
C ₁₂ H ₁₉ NO ₅ S ₅
Found C, 44.84; H 6.01; N, 4.27.

b) A solution of 6.2 g of 3-tosyloxy-2,2-dimethyl-1-propanesulfonamide and 3.75g of potassium thiocyanate in 30 ml of dimethylformamide was stirred at 130-140 ^C for 6 hours, then concentrated to dryness. A mixture of dichloromethane and methanol (9: 1) was added to the residue, after which the insoluble matter was filtered off. The filtrate was concentrated and the residue was subjected to column chromatography using chloroform-ethyl acetate (2: 1) as an eluent. The desired fractions were concentrated to give 0.87 g of 3-thiocyanato-2,2-dimethyl-1-propanesulfonamide as a yellow oil.

NMR (CDCl ₃ ) δ 1.33 (6H, s), 3.27 (2H, s), 3.31 (2H, s), 5.23 (2H, s).

 c) to a solution of 5.15 g of 3-thiocyanato-2,2-dimethyl-1-propanesulfonamide in 100 ml of ethanol, while stirring in an atmosphere of nitrogen gas, gradually in small portions of 0.79 g of sodium borohydride, the procedure takes 1 hour. The reaction mixture is boiled with reflux for one hour and concentrate under reduced pressure. 20 ml of water and 30 ml of 1N are added to the residue. of hydrochloric acid. The organic layer was separated, the aqueous layer was washed with ethyl acetate (3 times 50 ml). The collected organic layers were dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was subjected to silica gel chromatography using a mixture of chloroform-methanol (10: 1) as an eluent; 0.76 g of 3-mercanto-2,2-dimethyl-1-propanesulfonamide is obtained.

Mp 83-86 ^about S.

NMR (CDCl ₃ ) δ 1.20 (6H, s), 1.41 (1H, t), 2.69 (2H, d), 3.28 (2H, s), 4.83 (1H, s) .

 Auxiliary example 4.

 Preparation of 3-bromo-2-ethyl-1-propanesulfonamide

 a) To a solution of 4.2 g of 2-ethyl-1,3-propanediol in 60 ml of dichloromethane is added 10.5 g of triphenylphosphine, to which 7.17 g of N-bromosuccinimide was gradually added in small portions while cooling with ice and stirring. The resulting mixture was stirred for 30 minutes while cooling with ice and for one hour at room temperature, after which it was concentrated under reduced pressure. The residue was subjected to column chromatography using n-hexane-ethyl acetate (7: 3) as an eluent. The desired fractions are concentrated; 5.19 g of 3-bromo-2-ethyl-1-propanol are obtained as a colorless oil.

NMR (CDCl ₃ ) δ: 0.95 (3H, t), 1.43 (2H, q), 1.5-1.9 (1H, m), 1.60 (1H, w), 3.4 -3.8 (4H, m)
A solution of 5.19 g of 3-bromo-2-ethyl-1-propanol and 6.02 g of potassium thiocyanate in 30 ml of dimethylformamide was stirred for 70 minutes at 100 ° ^C. To the cooled reaction solution was added 100 ml of ice water and the mixture was extracted with ethyl acetate (3 times 50 ml each). The extracts are washed with water, dried and distilled to remove the solvent. The residue was subjected to silica gel column chromatography using a mixture of n-hexane and ethyl acetate as an eluent. The desired fractions are concentrated; 3.30 g of 2-ethyl-3-hydroxy-1-1-propanethiocyanate are obtained as a colorless oil.

NMR (CDCl ₃ ) δ 0.98 (3H, t), 1.50 (2H, q), 1.66 (1H, w), 1.7-2.0 (1H, m), 3.0- 3.3 (2H, m), 3.5-3.9 (2H, m).

 c) To a solution of 3.3 g of 2-ethyl-3-hydroxy-1-propanethiocyanate and 5.96 g of triphenylphosphine in 40 ml of dichloromethane, 4.04 g of N-bromosuccinimide are added with stirring and ice-cooling. The resulting mixture was stirred for 10 minutes under ice-cooling and for one hour at room temperature, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using n-hexane-ethyl acetate (10: 1) as an eluent. The desired fractions were concentrated to give 4.70 g of 3-bromo-2-ethyl-1-propantiocyanate as a colorless oil.

NMR (CDCl ₃ ) S: 1.00 (3H, t), 1.4-1.7 (2H, m), 1.9-2.1 (1H, m), 2.9-3.1 ( 2H, m), 3.4-3.8 (2H, m).

 d) Through a solution of 2.09 g of 3-bromo-2-ethyl-1-propanethiocyanate in 30 ml of a 50% aqueous solution of acetic acid, chlorine gas was bubbled under stirring at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with dichloromethane (2 times 50 ml). The extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 25 ml of dichloromethane, through which ammonia gas was bubbled for 30 minutes. The reaction solution, to which 50 ml of ice water was added, was extracted with dichloromethane (2 times 50 ml). The extracts are washed with water, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was subjected to silica gel column chromatography using n-hexane-ethyl acetate (3: 2) as an eluent. The desired fractions are concentrated; 1.58 g of 3-bromo-2-ethyl-1-propanesulfonamide are obtained as a colorless oil.

NMR (CDCl ₃ ) δ 0.97 (3H, t), 1.4-1.8 (4H, m), 2.1-2.4 (1H, m), 3.5-3.9 (2H , m) 4.80 (2H, s).

 In the same manner as described in Supporting Example 4, 3-bromo-2-phenyl-1-propanesulfonamide was obtained.

NMR (CDCl ₃ ) δ 3.4-3.9 (5H, m), 4.29 (2H, s), 7.1-7.5 (5H, m)
Supporting Example 5.

 Preparation of 3,6-dichlorimidazo [1,2-b) pyridazine.

 6-Chlorimidazo [1,2-b) pyridazine (7.68 g) was added to 150 ml of carbon tetrachloride, to which 7.0 g of bromosuccinimide was added, and the resulting mixture was refluxed for 2 hours. After cooling, it was filtered off. precipitated crystals. The filtrate is washed sequentially with 1 aqueous sodium hydroxide solution, 1 N. hydrochloric acid and water, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was washed with diethyl ether; 7.13 g of 3,6-dichlorimidazo [1,2-b) pyridazine are obtained.

Melting point: 120-121 ° ^C.

NMR (CDCl ₃ ) δ 7.12 (1H, d), 7.75 (1H, s), 7.92 (1H, d).

Example 1 Preparation of 6- (3-sulfamylpropylthio) imidazo [1,2-b] pyridazine 6 Merkaptoimidazo [1,2-b] pyridazine (1.5 g) and a 28% solution (by weight) sodium methoxide in methanol (2.1g) was stirred in 30 ml of methanol ^at 50 ° C for 3 hours The mixture was cooled to room temperature, 3.0 g of 3-aminosulfonyl-1-iodopropane was added and stirred at room temperature for 1.5 hours. The mixture was distilled to remove the solvent, and the residue was subjected to silica gel chromatography using successive solutions as eluent 2 (vol.) Methanol in chloroform, 2.5 (vol.) Methanol in chloroform and 3.2 (vol.) Methanol in chloroform. Fractions containing the desired product are collected and concentrated. The precipitate was isolated by filtration to obtain 1.6 g of 6- (3-sulfamylpropylthio) imidazo [1,2-b) pyridazine.

Mp 147-148 ^about S.

 Calculated, C 39.69; H 4.44; N, 20.57.

C ₉ H ₁₂ N ₄ O ₂ S ₂ .

 Found, C 39.62; H 4.42; N, 20.50.

 PRI me R 2. Obtaining 6- (3-sulfamylpropylthio) imidazo [1,2-b] pyridazine.

Ammonia gas was bubbled through a solution of 3-chloropropanesulfonyl chloride (25 g) in ether (20 ml) for 30 minutes under ice-cooling. Then, 50 ml of water was added to the reaction mixture. The ether layer was separated, the aqueous layer was extracted with 100 ml of ethyl acetate. The ether layer and the ethyl acetate layer are combined, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was recrystallized from n-hexane to give 21 g of 3-hlorpropansulfonamida (m.p. 64-65 ° ^C).

The resulting product was dissolved in 150 ml of methanol and 150 ml of 2N was added to the resulting solution. a solution of potassium hydrosulfide in ethanol. The resulting mixture was heated for one hour at ⁷⁰ ° C and then distilled under reduced pressure to remove the solvent. 20 ml of water are added to the residue. The pH of the mixture was adjusted to 3 by adding hydrochloric acid, followed by extraction with 200 ml of chloroform. The chloroform layer is dried over magnesium sulfate and distilled to remove the solvent; 10.8 g of crude 3-mercapto-propanesulfonamide are obtained.

 The resulting product was dissolved in 200 ml of methanol, to which 11.8 g of a 28% (by weight) solution of sodium methylate in methanol and 8.0 g of 6-chlorimidazo [1,2-b] pyridazine were added. The resulting mixture was refluxed for 3 hours, concentrated to dryness under reduced pressure. 100 ml of water was added to the residue, and the resulting aqueous solution was extracted with 100 ml of a mixture of ethyl acetate tetrahydrofuran (1: 1). The organic layer was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was subjected to silica gel column chromatography using a solution of methanol in chloroform (vol.) As an eluent. Collect target fractions. The residue was recrystallized from methanol; 5.6 g of the expected product are obtained.

 PRI me R s 3-24. Using the method described in example 2, the compounds of examples 3-24 were obtained, these compounds are shown in table 1 (approx. Translation: see table 1).

 PRI me R 25. Obtaining 6- [2- (N-cyclopropylsulfamyl) ethylthio] imidazo [1,2-b] pyridazine.

 To a solution of 1.35 g of 6-chlorimidazo [1,2-b] pyridazine in 30 ml of methanol, 1.45 g of sodium 2-mercaptoethanesulfonate and 1.80 ml of a 28% (by weight) solution of sodium methylate in methanol are added; then the resulting mixture was refluxed for 5 hours. The precipitated crystals are separated by filtration and washed with methanol; 1.98 g of 2 - [(imidazo [1,2-b] pyridazin-6-yl) thio] ethanesulfonate are obtained.

Mp 263-266 ^about S.

 The resulting product is suspended in 10 ml of phosphorus oxychloride. The resulting mixture was refluxed for 2 hours, after which it was concentrated to dryness under reduced pressure. To the residue was added 50 ml of dichloromethane, to which 2.7 g of cyclopropylamine was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes. After the completion of the reaction, 50 ml of water are added. The dichloromethane layer was separated. the aqueous layer was extracted with 50 ml of chloroform. The layers of dichloromethane and chloroform are combined, dried over anhydrous magnesium sulfate and the solvent is removed by evaporation. The residue was subjected to silica gel chromatography using a 20% (by volume) solution of acetic acid in chloroform as an eluent, followed by ethyl acetate. The desired fractions were concentrated, the residue was recrystallized from chloroform-ether; 0.30 g of expected product is obtained.

Mp 121-123 ^about S.

 Calculated, C 44.28; H 4.73; N18.78.

C ₁₁ H ₁₄ N ₄ O ₂ S ₂ .

 Found, C, 43.90; H 4.82; N, 18.82.

 PRI me R s 26-28. Using the method described in example 25, the obtained compounds of examples 26-28, these compounds are shown in table 1 (approx. Transl. See table 1).

 PRI me R 29. Obtaining 6- (5-sulfamoylpentylthio) imidazo [1,2-b] pyridazine.

To a solution of 1.57 g of 5-hlorpentansulfonamida in 40 ml of methanol was added 40 ml of 2N potassium hydrosulfide in ethanol, and the resulting mixture was heated at ⁷⁰ ° C for 45 minutes. To the reaction mixture was added 1.54 g of a 28% sodium methoxide solution in methanol and 1.16 g of 5-chlorimidazo [1,2-b] pyridazine; the resulting mixture was refluxed for one hour. The reaction mixture was concentrated to dryness under reduced pressure. The residue is extracted with 40 ml of chloroform and 40 ml of 0.1 N. of hydrochloric acid. The aqueous layer was extracted three times with chloroform. Then, the combined organic layers are dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was subjected to silica gel column chromatography using a mixture of methanol chloroform (1:35) as an element. The desired fractions are concentrated. The residue was recrystallized from methanol; 0.62 g of the expected compound are obtained.

Mp 120-121 ^about S.

 Calculated, C 43.98; H 5.37; N, 18.65.

C ₁₁ H ₁₆ N ₄ O ₂ S ₂ .

 Found, C, 43.97; H 5.45; N, 18.45.

 The compounds of examples 30-34 are shown in table. 2, obtained by reaction of 4-chlorobutanesulfonamide, 3-chloro-2-methyl-1-propanesulfonamide, 3-bromo-2-ethyl (or 2-phenyl) -1-propanesulfonamide (obtained by the method described in supporting example 4), or 3 β-bromo-3-phenyl-1-propanesulfonamide (obtained in the same manner as in auxiliary example 4), with 6-chlorimidazo 1,2-pyridazine in accordance with the method described in example 2.

 PRI me R 35. Obtaining (+) - 6 - [(2- (S) -methyl-3-sulfamilyropyl) thio] imidazole [1,2-b] pyridazine.

To a solution of 0.78 g of 2- (S) -methyl-3-chloro-1-propanesulfonamide in 20 ml of methanol was added 20 ml of 2 N. a solution of potassium hydrosulfine in ethanol; the resulting mixture was refluxed at ⁷⁰ ° C for one hour in nitrogen flow. Then, 1.0 g of a 28% solution of sodium methylate in methanol and 0.73 g of 6-chloro-imidazo [1,2-b] pyridazine were added to the mixture, and the resulting mixture was refluxed for 3 hours. Reaction mixture concentrated under reduced pressure. 10 ml of water was added to the residue, and the pH of the resulting solution was adjusted to 6.0 by the addition of 1N. hydrochloric acid, followed by extraction with a mixture of tetrahydrofuran-ethyl acetate (1: 1). The extract was dried over anhydrous magnesium sulfate and distilled to remove the solvent under reduced pressure. The residue was subjected to silica gel column chromatography using a chloroform-methanol mixture (10: 1) as an eluent. The desired fractions were concentrated under reduced pressure to obtain 0.29 g of the target compound. The resulting product was dissolved in 2 ml of a mixture of hydrochloric acid-methanol, and the resulting solution was concentrated under low pressure. The residue was recrystallized from methanol-ethyl ether to give 0.2 g of the hydrochloride salt of the target compound.

Mp 154-157 ^about S.

[α] _D ²⁴ + 13.6 (s = 1.0, water)
Calculated, C 36.59; H 4.79; N, 17.07.

C ₁₀ H ₁₄ N ₄ O ₂ S ₂ ˙CHl˙ 0.3H ₂ O.

 Found, C, 36.80; H 4.74; N, 17.21.

 PRI me R 36. Obtaining hydrochloric acid (-) - 6- (2- (R) -methyl-3-sulfamylpropyl) thio imidazo [1,2-b] pyridazine.

 The target compound is obtained from 2- (R) -methyl-3-chloro-1-propanesulfonamide in accordance with the method described in example 35.

Mp 157-160 ^about S.

[α] _D ²⁴ -13.2 ^about (s = 1.0 water).

 PRI me R 37. Obtaining 6 - [(3-sulfamyl-2,2-dimethylpropyl) thio] imidazo [1,2-b] pyridazine.

To a solution of 1.67 g of 2,2-dimethyl-3-totsianato-1-propanesulfonamide in 50ml of ethanol with stirring in a stream of nitrogen was added portionwise 0.41 g of sodium borohydride and the resulting mixture was heated at 80-85 ^{° C} for 1 , 5 hours. To the reaction mixture was added 0.62 g of 6-chlorimidazo [1,2-b] pyridazine and 0.81 ml of a 28% solution of sodium methylate in methanol, after which the resulting mixture was heated at reflux for 2 hours. The reaction solution is concentrated to dryness. 30 ml of soda was added to the residue and extracted with a mixture of tetrahydrofuran-ethyl acetate (1: 1). The extract was dried over anhydrous magnesium sulfate and distilled under reduced pressure, removing the solvent. The residue was subjected to silica gel column chromatography using a chloroform-methanol mixture (10: 1) as an eluent. The desired fractions were concentrated, the residue was recrystallized from ethanol; 0.32 g of the expected compound is obtained.

Mp 198-199 ^about S.

 Calculated, C 43.98; H 5.73; N, 18.65.

C ₁₁ H ₁₆ N ₄ O ₂ S ₂ .

 Found, C, 43.94; H 5.48; N, 18.18.

 PRI me R 38. Obtaining -6 - [(3-sulfamyl-2,2-dimethylpropyl) thio] imidazo [1,2-b] pyridazine.

To a solution of 0.37 g of 3-mercapto-2,2-dimethyl-1-propylsulfonamide and 0.37 g of a 28% solution of sodium methylate in methanol in 50 ml of methanol, 0.31 g of 6-chlorimidazo [1,2- b] pyridazine, and the resulting mixture was refluxed at 80-85 ^{° C} for 3 hours. The reaction solution was concentrated under reduced pressure. 30 ml of water was added to the residue and extraction was carried out with a mixture of tetrahydrofuran-ethyl acetate (1: 1). The extract was dried over anhydrous magnesium sulfate and distilled under reduced pressure, removing the solvent. The residue was recrystallized from ethanol to give 0.4 g of the target compound.

 PRI me R 39. Obtaining 6 - [(2,2-dimethyl-3-sulfamylpropyl) oxy] imidazo [1,2-b] pyridazine.

To a solution of 3.5 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide in 30 ml of DMF, 0.85 g of sodium hydride (60% in oil) was added portionwise. To the resulting mixture was added 3.18 g of 6-chlorimidazo [1,2-b] pyridazine, and then 0.85 g of sodium hydride. The reaction solution was heated at ⁷⁰ ° C for 1.5 h and then for 1 hour at ¹⁰⁰ ° C (heating is performed while stirring) and concentrated under reduced pressure. The residue was taken up in 100 ml of ice-water, extracted with ethyl acetate and tetrahydrofuran (1: 1) (4 times 100 ml), dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was recrystallized from ethanol to give 5.18 g of the target compound.

Mp 165-167 ^about S.

 Calculated, C 46.47; H 5.67; N, 19.70.

C ₁₁ H ₁₆ N ₄ O ₃ S.

Found, C 46.20; H 5.75; N, 19.44
Example 40. Preparation of (+) - 6 - [(2- (R) -methyl-3-sulfamylpropyl) oxy] imidazo [1,2-b] pyridazine.

To a solution of 0.93 g of 2- (R) -methyl-3-hydroxy-1-propilsulfonamida in 50 ml of DMF was added portionwise 0.48 g of sodium hydride and the resulting mixture was stirred for 30 min at 70 ° ^C. To the mixture is added 0.98 g of 6-chlorimidazo [1,2-b] pyridazine, and the mixture was refluxed for 5 hours. After cooling the reaction mixture, its pH was adjusted to 6.0 with 1N hydrochloric acid and concentrated under reduced pressure to dryness. The residue was subjected to silica gel column chromatography using a chloroform-methanol mixture (10: 1) as an eluent. The desired fractions were collected and concentrated to give 1.06 g of the target compound.

[α] _D ²⁴ + 8.7 (c = 1.0, methanol).

 Calculated, C 44.43; H 5.22; N20.73.

C ₁₀ H ₁₄ N ₄ O ₃ S
Found, C, 44.36; H 5.16; N, 20.70.

 The compounds of examples 41 and 42 (shown in table 2) were obtained by reaction of 3-hydroxy-1-propylsulfonamide or 2-ethyl-3-hydroxy-1-propylsulfonamide with 6-chlorimidazo [1,2-b] pyridazine in accordance with the method described in example 40.

 Example 43. Preparation of 3-chloro-6 - [(3-sulfamylpropyl) thio] imidazo [1,2-b] pyridazine.

To a solution of 1.57 g of 3-chloro-1-propanesulfonamide in 20 ml of methanol was added 20 ml of 2N. a solution of potassium hydrosulfide in ethanol, after which the resulting mixture is heated at 70 ^about C for 50 minutes To the reaction mixture were added 1.48 g of 28% sodium methoxide in methanol and 1.32 g of 3,6-dihlorimidazo [1,2-b] pyridazine and the mixture refluxed at ¹⁰⁰ ° C for 3 h. The mixture was concentrated under reduced pressure, 20 ml of water, adjusted to pH 7.0 1 N, was added to the residue. hydrochloric acid. The precipitated crystals are separated by filtration and recrystallized from methanol and ethyl ether; 1.12 g of the target compound are obtained.

Mp 136-137 ^about S.

 Calculated, C 35.23; H 3.61; N18.26.

C ₉ H ₁₁ N ₄ O ₂ S ₂ Cl.

 Found, C, 35.12; H 3.68; N, 18.39.

 Example 44. Preparation of 2-chloro-6 - [(sulfamylpropyl) thio] imidazo [1,2-b] pyridazine.

To a solution of 1.57 g of 3-chloro-1-propanesulfonamide in 20 ml of methanol was added 20 ml of 2N. potassium hydrosulfide solution and the resulting mixture is heated at 70 ^about C for 50 minutes Then, 1.48 g of a 28% sodium methoxide solution in methanol and 1.32 g of 2.6 dichlorimidazo [1,2-b] pyridazine (Japan Patent Publication No. HO 64 (1989) -38091) and the resulting the mixture was heated at ¹⁰⁰ ° C for 3 hours. The mixture was concentrated under reduced pressure. Then, 20 ml of water was added to the residue, and the pH was adjusted to 7.0 with 1 N hydrochloric acid. The precipitated crystals are separated by filtration and subjected to silica gel column chromatography using a mixture of chloroform and methanol (50: 1) as eluent. The desired fractions are collected, concentrated, the residue is recrystallized, and 1.1 g of the expected product is obtained.

Mp 117-118 ^about S.

 Calculated, C 35.23; H 3.61; N, 18.26.

C ₉ H ₁₁ N ₄ O ₂ S ₂ Cl.

 Found, C 35.39; H 3.71; N, 18.25.

 PRI me R 45. Obtaining 3-chloro-6 - [(2,2-dimethyl-3-sulfamylpropyl) oxy] imidazo [1,2-b] pyridazine.

To a solution of 1.67 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide in 30ml of DMF was added 0.8 g of sodium hydride, after which the resulting mixture was heated at ⁷⁰ ° C for one hour. To this mixture was added 1.88 g of 6-chlorimidazo [1,2-b] pyridazine and the resulting mixture was heated for 4.5 hours. The reaction mixture was distilled to remove the solvent (under reduced pressure), and 50 ml of a mixture of water was added to the residue. With ice, the pH of the resulting mixture was adjusted to 6.0 1N. hydrochloric acid, followed by extraction with a mixture of tetrahydrofuran and ethyl acetate (1: 1). The extract was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to silica gel column chromatography using a mixture of chloroform and methanol (20: 1) as an eluent. The collected target fractions are concentrated; 1.56 g of the expected product are obtained.

Mp 197-200 ^about S.

 Calculated, C 41.45; H 4.74; N, 17.58.

C ₁₁ H ₁₅ N ₄ O ₃ SCl.

 Found, C 41.21; H 4.65; N, 17.57.

 PRI me R 46. Obtaining hydrochloric acid 6 - [(2,2-dimethyl-3-sulfamylpropyl) oxy] imidazo [1,2-b] pyridazine.

 To a solution of 1.71 g of 6 - [(2,2-dimethyl-3-sulfamylpropyl) oxy) imidazo [1,2-b] pyridazine in 100 ml of methanol was added 5 ml of a 30% solution of hydrochloric acid in methanol. The resulting mixture was concentrated under reduced pressure to dryness. The residue was recrystallized from ethanol; 1.7 g of the target compound are obtained.

Mp 206-207 ^about S.

 Calculated, C 41.18; H, 5.38; N, 17.46.

C ₁₁ H ₁₆ N ₄ O ₃ S HCl.

 Found, C 41.10; H, 5.30; N, 17.30.

 Example 47. Preparation of 3-methyl-6- [2,2-dimethyl-3-sulfamoylpropyl) hydroxy] imidazo [1,2-b] pyridazine.

3-Hydroxy-2,2-dimethyl-1-propanesulfonamide (1.67 g) was dissolved in dimethylformamide (25 ml), to which sodium hydride (60% in oil) (0.4 g) was added with stirring. To this mixture was added 6-chloro-3-methylimidazo [1,2-b] pyridazine (1.68 g), followed by sodium hydride (0.4 g). The reaction solution was heated at ⁸⁰ ° C for 2 hours and then at ¹⁰⁰ ° C for 0.5 hours with stirring, and concentrated under reduced pressure. The residue was placed in water (30 ml) in order to remove precipitated crystals, which were then washed with ether and dissolved in an aqueous solution of hydrochloric acid with pH1. The resulting solution was treated with activated carbon and adjusted to pH 6. The precipitated crystalline material was collected and recrystallized from ethanol to give 1.9 g of the title compound.

Mp 194-196 ^about S.

 Calculated, C 48.31; H, 6.08; N, 18.78.

C ₁₂ H ₁₈ N ₄ O ₃ S.

 Found, C, 48.27; H, 6.16; N, 18.61.

 Below are the results of pharmacological testing of the claimed compounds.

Measurement Method:
Effect on narrowing of the bronchi caused by platelet activating factor for guinea pigs.

 For tests, male Hartley guinea pigs (live weight 500 g) were used. The bronchial constriction reaction in guinea pigs, which received intravenous platelet activation factor (1 μg / kg), was determined by the Konzett-Rosster method. In the guinea pig trachea, the back of which was fixed, under conditions of anesthesia with urethane (intravenous administration, 1.50 mg / kg), the cannula was dissected and connected to an artificial respirator. The outlet of the tracheal cannula was connected to a sensor (type 7020, Ugebasile). Air was supplied into the trachea at a speed of 3-7 ml impulse, 70 impulses per minute, with an overpressure in the lungs of 10 cm, a water column; the outgoing air flow was recorded using a Rectegraph (Recte-Hori-8s, Sanei Sduki) through a sensor. After administration of calamine to guinea pig (1 mg / kg, intravenously), a solution of platelet activating factor (1 μg / kg) in physiological saline was injected through the cannula in the jugular vein; the bronchial constriction reaction thus induced was recorded within 15 minutes. The drug was suspended in a 5% solution of gum arabic (30 mg / kg of drug), was orally administered 1 hour before the introduction of platelet activation factor. The results are shown in table. 3.

 As follows from the data table. 3, the compounds of formula I have an exceptionally beneficial effect in narrowing the airways, and therefore can be used as anti-asthma agents.

 As for the comparative data, the table is supplemented by the description data on the inhibition of the anti-asthmatic agent "/ KS-404 /".

Tab. 3 and 4 show that a typical compound of the target compounds (1) has a bronchospasm inhibitory effect three or more times higher than the known anti-asthma agent. The toxicity of the target compound is low, since the LD ₅₀ is about 200 μg / kg (when administered orally to mice).

Claims (2)

1. The method of obtaining derivatives of imidazo (1,2 b) pyridazine of the General formula

where R _{1 is} hydrogen, halogen or a lower alkyl group;
R ₂ and R _{3 are} independently hydrogen, a lower alkyl group, optionally substituted with a hydroxyl group, naphthyl or a nitrogen-containing heterocyclic group, optionally substituted with a lower alkyl group, a lower alkoxy group, a cycloalkyl group or a phenyl group optionally substituted with a halogen or lower alkoxy group ,
or R ₂ and R ₃ together with an adjacent nitrogen atom form a 6-membered nitrogen or oxygen containing heterocyclic ring, provided that when R ₂ and R ₃ form a piperazine ring, it may be substituted with lower alkyl, phenylalkyl or a nitrogen or oxygen containing heterocyclic a group;
X oxygen or sulfur;
Alk C ₁ C ₅ straight or branched chain alkylene group optionally substituted by a phenyl group, provided that when R _{1 is} hydrogen, one of R ₂ and R _{3 is} hydrogen and the other is hydrogen or a lower alkyl group, and, in addition to Moreover, Alk C ₂ - C ₄ straight chain alkylene group, X oxygen,
or their salts, characterized in that the compound of General formula

where R ₁ has the indicated meanings;
Z is halogen,
or its salts are reacted with a compound of the general formula

where R ₂ , R ₃ , X and Alk have the indicated meanings,
in the presence of an alkali metal hydride or alkali metal alcoholate. 2. Derivatives of imidazo (1,2-b) pyridazine of the General formula

where R _{1 is} hydrogen, halogen or a lower alkyl group;
R ₂ and R _{3 are} independently hydrogen, a lower alkyl group optionally substituted with hydroxyl, naphthyl or a nitrogen-containing heterocyclic group, optionally substituted with a lower alkyl group, a lower alkoxy group, a cycloalkyl group or a phenyl group optionally substituted with a halogen or lower alkoxy group, or R ₂ and R ₃ together with an adjacent nitrogen atom form a 6-membered nitrogen or oxygen containing heterocyclic ring, provided that when R ₂ and R ₃ form a piperazine ring, it may be substituted lower alkyl, phenylalkyl or a nitrogen or oxygen containing heterocyclic group;
X is oxygen or sulfur;
Alk C ₁ C ₅ straight or branched chain alkylene group optionally substituted by a phenyl group, provided that when R _{1 is} hydrogen, one of R ₂ and R _{3 is} hydrogen and the other is hydrogen or a lower alkyl group, and, in addition to Moreover, Alk C ₂ - C ₄ straight chain alkylene group, X oxygen,
or their salts.

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