DD235261A5 - PROCESS FOR PREPARING ARYL DERIVATIVES OF HETEROVICYCLIC COMPOUNDS - Google Patents

Abstract

The invention relates to processes for the preparation of medically valuable imidazobicyclic compounds. The compounds prepared by the process according to the invention are inotropic agents and serve the treatment and prevention of congestive heart failure or myocardial insufficiency.

Description

-A - 2 -

Field of application of the invention

The invention relates to processes for the preparation of medically valuable compounds and the preparation of pharmaceutical preparations containing these compounds.

Characteristic of the known technical solutions

Various classes of substituted phenylimidazobicyclic compounds have heretofore been found to be positive inotropic agents, i. they are able to stimulate myocardial contractions. In particular. GB Patent 2 132 203 A describes certain substituted phenylimidazopyrimidines, pyrazines and triazines which are said to be inotropic agents with minimal effects on blood pressure and pulse rate. However, some of these compounds show undesirable side effects.

Object of the invention

It was therefore the object and the object of the present invention to provide processes for the preparation of compounds which possess better pharmacological properties without simultaneously occurring undesired side effects.

Explanation of the essence of the invention

The invention relates to the preparation of medically valuable imidazobicyclic compounds and the preparation of pharmaceutical preparations containing these compounds.

The invention is based on investigations which have shown that the group of compounds of the formula I

As defined, surprisingly advantageous inotropic agents are due to their primary inotropic (cardiotonic) action and / or secondary pharmacological effects. Formula I is defined as follows:

η is equal to 1,2 or 3,

m is 0, 1, 2 or 3,

12 3 one of the radicals A, A and A is a nitrogen atom and the other two are CH radicals,

R radicals are independently selected from the radicals indicated below in (a) and (b), namely:

(a) cyano, hydroxy, radicals of the formula -S (O) R, wherein χ

a ^x

is 0, 1 or 2 and R is a C ₁ -alkyl radical, and radicals of the formula -OR in which R represents an allyl or a C 1, -alkyl radical, where the alkyl radical is optionally substituted by one or more radicals, which are selected from halogen, C _1-4 -alkoxy and radicals of the formula -S (O) R ^a , in which χ and

I ~ for X

R ^a correspond to the above meaning,

(b) C, _4- alkanoyl, C, _4- alkanoylamino, 2-methyl-1,3-dioxalan-2-yl, sulfamoyl, NC ₄ -alkylsulfamoyl, N, N-di-C, _4- alkylsulfamoyl, C, ₄ alkylsulfonyloxy, Cj_ ₄ alkylsulfonylamino, Aminsulfonyloxy, NC, ^ Alkylaminosulfonyloxy, N, N-Di-C. .-alkylaminosulfonyloxy, ureido, 3-C ₁ _ ₄ alkylureido, 3,3-di-C ₁ _ ₄ alkylureido, aminosulphonylamino, (C ^ _ ₄ alkylaminosulphonyl) amino, (di-

C,. -Alkylaminosulfonyl) amino, carboxy, carboxylic acid derivatives (selected from carbamoyl, NC., -Alky1-carbamoyl, N, N-di-C ₁ -C -alkylcarbamoyl, carboxylic acid halides, C 1-4 -alkoxycarbonyl, hydroxy-C 1-4 -alkoxycarbonyl and hydroxymethylene) and groups of the formula -0R ^c, wherein R ^c is a linear or branched aliphatic moiety having 1 to 4 carbon atoms, which is optionally substituted by one or more radicals independently selected from halogen, C., .- alkoxy and radicals of the formula -S (O) R ^a , wherein χ and the above meaning, with the proviso that R ^C n

 is

Alkoxy and radicals of the formula -S (O) R ^a , wherein χ and R ^{a are as defined} above, with the proviso, d

b

R is not a radical as defined for R above

R is selected from hydrogen, halogen, amino, hydroxy, C _1-4 -alkyl and C .. -alkoxy,

R radicals are independently selected from halogen, carboxy, amino, C ₁ , -alkylamino, hydroxy, C ₁ -alkoxy, hydroxy-C ₁ -C 4 -alkoxy, C ₁ -C 4 -alkylthio and C ₁ -C -alkylsulfonyloxy,

with the proviso that when R is a hydrogen atom and either m is 0 or m is 1 and R. is a halogen atom, at least one R of the above (b) must be selected.

Unless the context requires otherwise, any reference herein to a compound of formula I should also be read as a reference to the N-oxides of such compound, as well as the salts of the compound and the salts of the N-oxides. In particular, where R does not represent one or more carboxy or carboxylic acid derivative groups, such salts may be acid addition salts. These salts may be formed by protonation of one or more of the basic ring nitrogen atoms in Formula I, and where a therapeutic use is intended, those salts are those that are physiologically acceptable, for example, the salts formed by hydrochloric, hydrobromic, or hydrobromic acid.

are derived from hydrogen peroxide, phosphoric, malic, maleic, fumaric, citric, sulfuric, lactic or tartaric acid.

The present invention provides the compounds of formula I and their physiologically acceptable salts and N-oxides for use as inotropic agents, in particular for the treatment or prevention of congestive heart failure or myocardial insufficiency. The invention also extends to the use of the compounds in the preparation of therapeutic agents for the treatment of these disease states.

The compounds of formula I and their physiologically acceptable salts and N-oxides are valuable inotropic / cardiotonic agents since both in vitro and in vivo experiments have shown that they produce a positive inotropic effect at low concentrations. These particular advantages of the compounds of the invention as compared to the known inotropic agents described in the aforementioned British patent, as demonstrated by test results described below, include one or more of the effects of high inotropic efficacy, pain relief ( mitigation) or a lack of vasodilation and a prolonged duration of action.

Most of the compounds of Formula I (including the physiologically acceptable salts and N-oxides thereof) are considered novel and represent a primary feature of the present invention. The novel compounds are those of Formula I (as defined above) with the proviso that

if η and m are both 1, and R is H, then

1 2 3

Far A is nitrogen, A and A are both CH and R is 4-methoxy, R is not a 7-methoxy group

3 12

and A is a nitrogen atom and A and A are

de are CH and R is a 4-methylsulfonyl group, R is not a 6-methoxy group.

The compound of formula I wherein A is a nitrogen atom

1 2 and A and A are both CH, η and m are both equal to 1

1 2

R is a 4-methylsulfonyl group, R is a hydrogen atom and R is a 6-methoxy group, is described by L. Almirante et al., J. Med. Chem., 9_, 29-33 (1966). It is reported that the compound has analgesic and anti-inflammatory effects in rats. The compound in which A represents a nitrogen atom

2 3 and A and A are both CH, η and m are both

1 2

is 1, R is 4-methoxy, R is H and R is 7-methoxy, is in Rogul'chenko et al., Farm. Zh. (Kiev) 1976, (4), pages 29-32, however, there are no medical therapeutic properties given.

In the case where R represents one or more radicals selected from carboxy and carboxylic acid derivatives, the salts may be those derived from the bases. For therapeutic use, such base salts are those which are physiologically acceptable, such as ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, and salts with organic bases, such as dicyclohexylamine salts.

Like physiologically acceptable salts (derived either from acids or bases), the present invention also encompasses other salts which may be used to purify or characterize the parent compounds of formula I and their N-oxides.

Among the various aspects of the present invention which will be claimed later are all subgroups of the compounds of formula I, i. Subgroups consisting of combinations of the groups specified by the substituents R to R, all permissible ones

1 3 Variants A to A for the imidazobicyclic ring system and all allowed values for η and m.

The subgroups that may be claimed include those listed in the following list which should not be construed as exhaustive or limiting:

1 2

(i) Compounds in which A is N and A and A are both CH, compounds in which both are CH, in which both are CH, compounds in dent

(a) are selected, compounds in whichi

(b) are selected compounds, carbamoyl is,

2 (ii) Compounds in which A is N and A and A

3 (iii) Compounds in which A is N and A and A

(iv) compounds in which the R radicals consist only of (v) compounds in which the R radicals consist only of (vi) compounds in which at least one R radical

(vii) compounds in which at least one R is other than carbamoyl,

2 (viii) compounds in which R is hydrogen, (ix) compounds in which m is 0,

(x) compounds in which at least one radical R is the same

Methoxy, (xi) is any combination of two or more of the groups of compounds listed above under (i) to (xi).

A group of compounds of formula I comprises the compounds in which

η is the same,

m is 0 or 1

the radicals R are independently selected from cyano, hydroxy,

3-a

Radicals of the formula S (O) R, in which χ and R correspond to the definition in formula I, radicals of the formula -OR, wherein R is a C., -alkyl radical, C, ^ alkanoyl, C, .alpha.-alkanoylamino, sulfamoyl, NC , ₄ alkylsulfamoyl, Ν, Ν-di-C ^ _ ₄ alkylsulfamoyl, C,.-alkylsulfonyloxy, C., alkylsulfonylamino, ureido, and carbamoyl (and optionally also aminosulfonylamino), and

R is selected from hydrogen, halogen, amino and hydroxy,

R (if present) is selected from halogen, amino, C 1-6 -alkylamino, hydroxy, C _1-4 -alkoxy, hydroxyC 1- . -alkoxy, C ₁ _ ₄ ~ alkylthio and C ₁ _ ₄ ~ alkylsulfonyloxy.

Another group of compounds of the formula I comprises those Verbindu selects are under

those compounds in which the radicals R are independently

Cyano, hydroxy, radicals of the formula -S (O) R, in which χ is 0, 1 or 2 and R ^{a is} a C _-4 -alkyl radical, sulfamoyl, N-C ₄ -alkylsulfamoyl, N ₇ N-di-C _{1 4-} alkylsulfamoyl, C, _4- alkylsulfonyloxy, C _1-4 -alkylsulfonylamino, aminosulfonyloxy, N _1-4 -alkylaminosulfonyloxy, N, N-di-C ₁ _. -alkylaminosulfonyloxy, carboxy, carboxylic acid derivatives (selected from carbamoyl, NC ₁ _ ₄ alkylcarbamoyl, N, N-di-c._ ₄ alkylcarbamoyl, carboxylic acid halides, C ₁ "alkoxycarbonyl, hydroxyalkoxycarbonyl

d r5

and hydroxymethylene) and radicals of the formula -OR, wherein R is a straight or branched aliphatic moiety of from 1 to 4 carbon atoms, optionally substituted by one or more radicals independently selected from halogen, C _1-4 alkoxy and radicals of the formula -S (O) R, in which χ and R ^{a are as defined} above,

R is selected from hydrogen, hydroxy, C 1 -alkyl and C 1 -alkoxy,

R radicals are independently selected from halogen, carboxy, amino, hydroxy, C _1-4 -alkoxy, C, ₄ alkylthio, and C, ₄ ~ alkylsulfonyloxy, with the further proviso that

2 13

if A is a nitrogen atom and A and A are both CH, R is a radical other than amino or C "alkyl

2 1

sulfonyloxy, and when A is a nitrogen atom and A and A are both CH or A is a nitrogen atom

12 3

and A and A are both CH, R is other than hydroxy.

In general, in formula I, alkyl radicals (both the stand-alone alkyl radicals and those which are part of alkyl-containing radicals, such as alkoxy) may be straight-chain or branched and may be selected from methoxy, ethoxy, propoxy and butoxy groups.

In the definition of R, the aliphatic radical indicated by R may be, for example, a C ₁ , alkenyl (other than alkyl) or a C _1. Alkynyl radical. In particular,

in particular, R may represent, for example, one or more radicals selected from cyano, C 1-5 alkanoyl, carboxy, carbamoyl, methylthio, methylsulfinyl, methylsulfonyl, methoxy, ethoxy, n-propoxy, isopropoxy, propargyloxy, sulfamoyl, NC, C 1 alkylsulfamoyl, N ₇ N-di-C ₁ _ ₄ ~ alkylsulfamoyl, C ₁ _ ₄ alkylsulfonyloxy, C _1-4 alkylsulfonylamino, Aminosulfonyloxy, NC. _{1-Alkylaminosulfonyloxy} and NJN-di-C ₁ alkyl

b c 3 aminosulfonyloxy. In the definitions of R, R and R, the halogen atom may independently be fluorine, chlorine, bromine or iodine.

Some preferred compounds of formula I are those in which η is 1, 2 or 3 (more preferably 2), m is 0. or 1 (more preferably 0), R is a substituent in the 4-position of the phenyl ring represents,

which is selected from cyano, C._ ₄ alkanoyl (especially acetyl) / carboxy or a carboxylic acid derivative (especially carbamoyl), a sulfamoyl, NC,.-Alkylsulfamoyl, N, N-di-C, _4- alkylsulfamoyl, C ^ alkylsulfonyloxy, C, ₄ alkylsulfonylamino, Aminosulfonyloxy, NC ₁ _ ₄ -Alkylaminosulfonyloxy or N ₇ N-di-C _1-4 -alkylaminosulfonyloxy (particularly when the alkyl group (s) in any of the preceding Examples are methyl) and radicals of the formula -S (O) R as defined

Ji

(Especially when χ is 1 and R is a methyl group), and / or one, two or three (as required) C _1-4 alkoxy (in particular methoxy) in the 2- or 3- (and

2 if allowed in the 4-) position of the phenyl ring, R for

3 is hydrogen and R (if present) is a halogen atom or a C, ₄ alkoxy group in the 6- or the 8-position halogen or imidazopyrazine ring system.

A preferred compound due to its advantageous pharmacological properties is 2- (2-methoxy-4-carbamoylphenyl) -imidazo / Ί, 2-a / pyrazine and its N-oxides and physiologically acceptable salts.

Other preferred compounds include the following compounds, their N-oxides and physiologically acceptable salts:

8-methoxy-2- (2-methoxy-4-methylsulfinylphenyl) imidazo / Ί , 2-ajpyrazine ,

2- (4-methylsulfonyloxy-2-methoxyphenyl) -8-methoxy-imidazo [Λ , 2-a_ / pyrazine, and

2- (4-carbamoyl-2-methoxyphenyl) -8-methoxy-imidazo / -1,2-a- pyrazine.

Other examples of compounds of formula I and their acid addition salts include the following bases and their N-oxides and physiologically acceptable salts:

2- (2-methoxy-4-methylsulfonyloxyphenyl) imidazo / -1,2-a / pyrazine, 8-methoxy-2- (2-methoxy-4-methylthiophenyl) imidazo / Ί, 2-a / pyrazine, 8- Methoxy-2- (2-methoxy-4-methylsulfonylphenyl) imidazo / 1,2 -a] pyrazine, 8-chloro-2- (2-methoxy-4-acetylphenyl) imidazo / 1,2-a7pyrazine, 2- 2-methoxy-4-carboxyphenyl) imidazo / 1,2-a-7-pyrazine, 2- (3-methoxy-4-carbamoyl-phenyl) imidazo / 1,2-a-7-pyrazine, 2- (3-methoxy-4-carboxyphenyl) imidazo / Ί, 2-a-pyrazine, 2- (2-methoxy-4-sulfamoyl-phenyl) -imidazo-1,2-a-pyrazine, 2- (2-methoxy-4- (N-methylsulfamoyl) -phenyl) imidazo / _R 2-α- pyrazine, 2- (2-methoxy-4- (Ν, Ν -dimethylsulfamoyl) phenyl) imidazo / Ί, 2-ajpyrazine , 2- (2-methoxy-4-methoxycarbonylphenyl) imidazo / 1,2-a_7pyrazine, 2- 2-methoxy-4-methylsulfonylaminophenyl) imidazo / " 1,2-a- pyrazine, 8-methoxy-2- (2-methoxy-4-methylsulfonylaminophenyl) imidazo / 1" -α-pyrazine, 2- (2-methoxy-4 - (N-methylaminosulphonyloxy) phenyl) imidazo / 1,2-a-pyrazine, 2- (2-methoxy-4-acetylphenyl) imidazo / 1,2-apyrazine, 2- (2-methoxy-4-acetylphenyl) - 8-methoxy-imidazo / i, 2-a_ / pyrazine, 2- (4-hydroxy-2-methoxyphenyl) -8-methoxyimidazo / i, 2-a / pyrazine, 8-methylamino-2- (2-methoxy-4 -methylsulfinylphenyl) imidazo / 1,2-a-pyrazine, 8- (2-hydroxyethoxy) -2- (2-methoxy-4-methylsulfinylphenyl) imidazo / 1,2-a-7-pyrazine, 8-n-propoxy-2- (2- methoxy-4-methylsulfinylphenyl) imidazo / 1,2-a_7pyrazine, 8-methoxy-2- (2-methoxy-4-cyanophenyl) imidazo / 1 _f 2-a-7-pyrazine, 8-hydroxy-2- (2-methoxy-4 -methylsulfinylphenyl) imidazo / 1,2-a- pyrazine, 6-methoxy-2- (2-methoxy-4-methylsulfinylphenyl) imidazo / Ί , 2-a- pyrazine,

8-methylthio-2- (2-methoxy-4-methylsulfinylphenyl) imidazo / Ί, 2-a / pyrazine, 3-bromo-2- (2-methoxy-4-methylsulfinylphenyl) imidazo / Ί, 2-aj ⁷ pyrazine, 2- (2-methoxy-4- / 2-methyl-1,3-dioxalan-2-yl / phenyl) imidazo- / Ί, 2-a-7-pyrazine, 8-methoxy-2- {2-methoxy-4 - / 2-methyl-1,3-dioxalan-2-yl-7phenyl) imidazo / 1,2-a_7pyrazine, 2- (2-methoxy-4-methylsulfinylphenyl) -7-methoxyimidazo / i, 2-aJ- pyrimidine, 3- Amino-2- (2,4-dimethoxyphenyl) imidazo / Ί ^ -aj'pyrimidine, 6-amino-2- (2,4-dimethoxyphenyl) imidazo / ~ 1,2-aJ- ^7- pyrimidine, 2- (2,4 -Dimethoxyphenyl) -3-hydroxyimidazo / -1,2-a7pyrimidine, 6-methoxy-2- (2,4-dimethoxyphenyl) imidazo / Ί, 2-a_7pyrimidine, 2- (2-methoxy-4-methylsulfonyloxyphenyl) imidazo / Ί , 2-a7pyrimi-

2- (2-Methoxy-4-propargyloxyphenyl) imidazo / "1" -a / pyrimidine., 6-Methoxy-2- (2-methoxy-4-methylsulfinylphenyl) imidazo / Ί , 2-aJ- pyrimidine, 6-amino -2- (2-methoxy-4-methylsulfinylphenyl) imidazo / Ί , 2-aJ- pyrimidine, 6-hydroxy-2- (2-methoxy-4-methylsulfinylphenyl) imidazo / Ί , 2-aJ- pyrimidine, 6-methylsulfonyloxy -2- (2-methoxy-4-methylsulfinylphenyl) imidazo / Ί, 2-α7pyrimidine, 6-carboxy-2- (2-methoxy-4-methylsulfinylphenyl) imidazo / 1,2-aJ- pyrimidine, 2- 2-methoxy-4-carboxyphenyl) imidazo / Ί, 2-a / pyrimidine, 2- (2-methoxy-4-carbamoylphenyl) imidazo / 11,2-a7pyrimidine, 2- (3-methoxy-4-carbamoylphenyl) imidazo / Ί, 2- / pyrimidine / 2- (3-methoxy-4-carboxyphenyl) imidazo / ΊΊ -aypyrimidine, 2- (2-methoxy-4-sulfamoylphenyl) imidazo / Ί, 2-a_ / pyrimidine, 2- ( 2-Methoxy-4- (N -methylsulfamoyl) phenyl) imidazo / Ί , 2-aJ- pyrimidine / 2- (2-methoxy-4- (N, N-dimethylsulfamoyl) phenyl) imidazo / Ί , 2-aJ- pyrimidine .

2- (methoxy) methoxycarbonylphenyl) imidazo / Ί, 2-a7pyrimidine, 2- (2-methoxy-4-methylsulfonyl-ininophenyl) imidazo / Ί , 2-aJ- pyrimidine, 2- (2-methoxy-4- (N-) methylaminosulfonyloxy) phenyl) imidazo / Ί, 2-a7pyrimidine, 2- (2-methoxy-4-acetylphenyl) imidazo / Ί, 2-a7pyrimidine, 2- (2-methoxy-4-methylsulfonyloxyphenyl) -6-methoxyimidazole - / Ί, 2-a7pyrimidine, 2- (2-methoxy-4-carbamoylphenyl) -6-methoxy-imidazo / Ί , 2-aJ- pyrimidine, 2- (2-methoxy-4-acetylphenyl) -6-methoxy imidazo / i, 2-a7pyrimi-

2- (2-Methoxy-4-methylsulfonyloxyphenyl) imidazo / Ί, 2-c / pyrimidine,

2- (2-methoxy-4-propargyloxyphenyl) imidazo / Ί, 2-c7pyrimidine, 7-methoxy-2- (2-methoxy-4-methylsulfinylphenyl) imidazo / Ί , 2-cJ- pyrimidine, 7-amino-2- (2-methoxy-4-methylsulfinylphenyl) imidazo / Ί , 2-cJ- pyrimidine, 2- (2-methoxy-4-carboxyphenyl) imidazo / ΊΊ-cjpyrimidine, 2- (2-methoxy-4-carbamoylphenyl) imidazo / Ί, 2-c7pyrimidine, 2- (3-methoxy-4-carbamoylphenyl) imidazo / Ί, 2-c7pyrimidine, 2- (3-methoxy-4-carboxyphenyl) imidazo / Ί, 2-c7pyrimidine, 2- (2-methoxy 4-sulfamoylphenyl) imidazo / Ί, 2-07PyZ ^- imidinyl, 2- (2-methoxy-4- (N-methylsulfamoyl) phenyl) imidazo / Ί , 2-cJ- pyrimidine, 2- (2-methoxy-4- (N, N -dimethylsulfamoyl) phenyl) imidazo / Ί , 2-cJ- pyrimidine, 2- (2-methoxy-4-methoxycarbonylphenyl) imidazo / Ί, 2-c7pyrimidine, 2- (2-methoxy-4-methylsulfonylaminophenyl) imidazo / Ί , 2-cJ- pyrimidine, 2- (2-methoxy-4- (N-methylaminosulfonyloxy) phenyl) imidazo / Ί, 2-c7pyrimidine, 2- (2-methoxy-4-acetylphenyl) imidazo / Ί, 2 -c7pyrimidine, 2- (2-methoxy-4-methylsulfonyloxyphenyl) -7-methoxy-imidazo / Ί, 2-c7pyrimidine,

2- (2-methoxy-4-carbamoyl-phenyl) -T-methoxy-imidazo / 1,2-cJ- pyrimidine,

2- (2-methoxy-4-acetylphenyl / -7-methoxy-imidazo / i, 2-c7pyrimidine,

2- (4-acetamido-2-methoxyphenyl) -8-methoxyimidazole , 2-a- pyrazine,

2- (2-methoxy-4-sulfamoyl-phenyl) -8-methoxy-imidazo / 1,2-a- pyrazine,

2- (2-methoxy-4-N-methylsulfamoylphenyl) -8-methoxyimidazo - / "1,2-a / pyrazine,

2- (2-methoxy-4-N, N-dimethylsulfamoylphenyl) -8-methoxyimidazo / 1,2-a_7pyrazine,

2- (4-acetamido-2-methoxyphenyl) imidazo / Ί, 2-a7pyrazine, 2- (2-methoxy-4-ureidophenyl) imidazo / 1,2-a.7pyrazine, 2- (2-methoxy-4-ureidophenyl ) -S-methoxy-imidazo / Ti, 2-a-7-pyrazine, 2- (2-methoxy-4-ureidophenyl) imidazo / 1,2-a, 7-pyrimidine, 2- (2-methoxy-4-aminosulfonylaminophenyl) imidazole / "1 , 2-a.7pyrazine, 2- (2-methoxy-4-aminosulfonylaminophenyl) -8-methoxy-imidazo / 1,2-a / pyrazine.

The compounds of the formula I and their salts and N-oxides can be administered by oral, rectal or parenteral routes. Generally, these compounds may be administered at a dosage in the range of 1 to 1200 mg per day, although the exact dosage will, of course, depend on a number of clinical factors, such as the species (ie human or animal), age and weight of the disease Patients, the condition to be treated and the severity of the disease, and the particular compound used. For administration of the compounds by oral route, a dosage in the size of 100 to 400 mg, for example about 200 mg per day can be used, while for administration by parenteral route, in particular by intravenous route, a dosage of 20 to 300 mg, advantageously 35 up to 70 mg, eg at about 50 mg per day is generally preferred. The compounds can be administered intravenously by infusion.

be followed, if desired. In this case, a dosage rate of, for example, 1 to 4 mg / min may be used.

The compounds of formula I and their physiologically acceptable acid addition salts and N-oxides of such compounds and salts are preferably administered in the form of pharmaceutical preparations.

The present invention thus further provides pharmaceutically acceptable formulations containing at least one compound of formula I (as defined above) or a physiologically acceptable acid addition salt or an N-oxide of the compound or salt together with at least one pharmaceutical carrier or excipient. The pharmaceutical formulations may be adapted for oral, parenteral (especially intravenous) or rectal administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the known methods in the pharmaceutical field. Such methods include the step of introducing the active ingredient into association with the carrier, wherein one or more additional ingredients may be included. Generally, the formulations are prepared by uniformly and intensively bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product.

Formulations of the present invention suitable for oral administration may be presented as discrete units, such as capsules, dragees or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules, as a solution or suspension in an aqueous liquid

or a non-aqueous liquid, or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.

A tablet may be prepared by compression or molding, optionally with one or more additional ingredients. Compressed tablets can be prepared by pressing in an appropriate machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, smoothing agent, inert diluent, lubricity agent, surfactant or dispersing agent. Shaped tablets may be prepared by humidifying in a suitable machine a mixture of the powdered compound with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated to provide slow or controlled release of the active ingredient therein.

Formulations for rectal administration may be presented as a suppository with the usual carriers, such as cocoa butter.

Formulations suitable for parenteral administration include aqueous sterile injection solutions comprising antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions, suspending agents and May contain thickening agents. The formulations may be presented in unit dose or multi-dose containers, for example in sealed vials and vials, and may be in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example

water for injections, immediately before use. Injection solutions for immediate use and suspensions may be prepared from sterile powder, granules and tablets of the type previously described.

Preferred unit dosage formulations are those containing a daily dose or daily unit underdose, as previously described, or a suitable portion thereof, of an active ingredient.

It should be understood that in addition to the ingredients specifically mentioned above, the formulations according to the invention may contain other agents conventional in the art, taking into account the nature of the formulation in question so that, for example, those suitable for the art oral administration are included, flavors may contain.

The compounds of formula I and their acid addition salts and N-oxides can be prepared by any convenient method which will be apparent to those skilled in the art.

Thus, for example, according to another characteristic of the present invention, there is provided a process for the preparation of the compounds of formula I and their N-oxides and acid addition salts, wherein

a) a compound of formula II

(Π)

12 3 3

(wherein A, A, A, m and R are as defined above and Y is an amino radical or a displaceable radical, for example hydrogen or a halogen atom such as chlorine) with a compound of the formula

(ΠΙ)

(wherein R and η are as defined above or precursor groups therefor and Z is a radical capable of reacting with the radical Y to form an imidazo ring system, with the following formation of a compound of the formula I or an acid addition salt thereof),

b) a compound of the formula

R "a

(IV)

12 3 (in which A, A, A, η and m correspond to the above meaning

1 3 chen and each of the radicals R to R independently one

^aa 13

Rest means as defined for the above radicals R to R or a precursor group thereof, with the proviso that at least one of the radicals R to R is a

a a

represents such precursor group) or an acid addition salt thereof is reacted with an agent which serves to effect a conversion of the precursor group (s) into the desired radical (s),

c) radical arylation of a compound of the formula

2

12 3 2 3 (wherein A, A, A, R, R and m are as defined above) by reaction with a compound of the formula

(VI)

(wherein R and η are as defined above and A is a displaceable radical, for example a diazonium halide, for example the chloride), or

d) reaction of a compound of the formula

(R ¹ )

(Vn)

1 2 (wherein R, R and η are as defined above) with a reagent such that the reagent and Q (in formula VII) are selected to complete the formation of the ring

(R "

12 3 3

to react (in which A, A, A, R and m correspond to the above meaning),

and when a compound of formula I is formed, this compound is optionally converted to the N-oxide and / or acid addition salt thereof.

Where appropriate, methods of the invention may include the steps of protection and subsequent cleavage as known in the art.

The reaction in process a) may optionally be carried out in a solvent, e.g. an organic solvent, such as in ethanol, conveniently at an elevated temperature, e.g. to the reflux temperature of the reaction mixture.

According to a preferred embodiment of the above process a) according to the invention, a compound of the formula II (in which R and m correspond to the above meaning and Y represents an amino radical) is reacted with a compound of the formula III (wherein R and η of the the above meaning and Z is a radical of the formula XCH ₂ CO-, wherein X represents a displaceable radical, preferably halogen, ie fluorine, chlorine, bromine or iodine).

In process a), in which the radical Z in the compound of the formula III is a radical of the formula XCH-CO-, a subsequent reaction with Y can take place and the nitrogen atom in the 1-position of the pyrazine ring in the compound of the formula II, eg with the initial formation of a compound of formula VIII

(Νπΐ)

or a compound of the formula

(IX)

1 3 1 3 (wherein A to A, R to R, X, m and η are as defined above), which can then be cyclized, e.g. by heating to form a compound of formula I.

With respect to process b) above, compounds of formula I in which any R moiety represents a C 1 -C 6 alkoxy radical can be prepared, for example, by alkoxylating a corresponding compound of formula IV wherein the corresponding R group represents chlorine.

Compounds of the formula I in which each R is a C ₁ -alkylsulfinyl or -sulfonyl can be prepared, for example, by oxidation, for example using hydrogen peroxide, organic peracids or bromine or one of its addition compounds, for example an alkali metal hydrobromide (such as it is described in DE-OS 3,044,497) of the corresponding Cj ^ thioverbindung.

Compounds in which each R represents a carbamoyl may be prepared by reacting a corresponding compound of the formula IV wherein the corresponding Rs (e) are 2-methyl-1,3-dioxalan-2-yl with a strong one Acid, such as 2N hydrochloric acid, or by subjecting a corresponding compound of formula IV, wherein the corresponding R group (s) are cyano, to a

Acid hydrolysis under appropriate conditions, e.g. using a strong mineral acid such as sulfuric acid at room temperature.

Compounds in which each R 'is alkoxy can be prepared by treatment of a corresponding compound of Formula IV wherein the corresponding R (s) hydroxy substituents are e.g. an alkyl sulfate.

R-radical (s) are hydroxy, with an alkylation

Third

Compounds in which each R is sulfamoyl, NC, .alpha.-alkylsulfamoyl or N, N-di-C ._.sub .-- alkylsulfamoyl can be prepared by reacting the corresponding compound of formula IV wherein the corresponding R-radicals (e )

egg

a halogen (e.g., chloro) sulfonyl radical, with a

12 12

A compound of the formula Q Q NH, wherein Q and Q are independently hydrogen or C 1 -C 4 alkyl as required.

Compounds wherein each R is a C _{1-.-Alkanoylamino} may be prepared by reacting the corresponding compound of formula IV wherein the corresponding R radical (s) represent amino, with the entsprea,

acidic anhydride, preferably in a suitable medium such as pyridine.

Compounds in which each R is ureido can be prepared by reacting the corresponding compound of formula IV wherein the corresponding R -

el

Residue (s) are amino, with cyanic acid, preferably

is formed in situ, e.g. of an alkali metal cyanate such as a potassium cyanate and a dilute mineral acid such as hydrochloric acid.

Compounds in which each R is C 1 -alkylthio can be prepared by diazotization of a corresponding compound of formula IV wherein

1 R represents an amino radical (eg, by treatment with nitrous acid), followed by the reaction of the product with a corresponding C ₁ -. Alkylmercaptan.

The radical arylation in the above method c) can be conveniently carried out by a method which is the general method of M.H. Hung and L.M. Stock, J. Org. Chem., 1982, 4J7 '448-453. When the compound of formula VI is employed in the form of a diazonium salt, this salt may be prepared in a conventional manner, e.g. from the corresponding amino compound.

In the process d) for the preparation of the compounds according to

1 2 3

Formula I wherein A is a nitrogen atom and A and A are both CH, the substituent Q in the compound of Formula VII may be 2-aminoethyl and the reagent may have the following formula

EtO

EtO

(X)

EtO

(wherein R is a hydrogen atom or a radical as defined above for R).

For the preparation of the compounds of formula I, wherein A is a nitrogen atom and A and A are both CH,

For example, the substituent Q in the compound of formula VII may be formyl and the reagent may then be the formula

OEt NH,

R ⁴

OEt

R '

(XI) 5

4 5

(wherein R and R are independently selected from hydrogen and radicals defined above for R).

For the preparation of the compound of formula I, wherein A is a

1 2

Is nitrogen and A and A are both CH, the substituent Q in the compound of formula VII may be amino and the reagent may then be the formula

(XII)

have (where m is 0, 1 or 2 and the radicals R of

3 4

above definition of R and R is a hydrogen atom or a radical as defined above for R).

The acid addition salts of the compounds of formula I can be prepared in a conventional manner, e.g. by treating the free base with an appropriate acid. The N-oxides of the compounds of formula I can also be prepared in a conventional manner, e.g. by oxidation of the parent compound with a corresponding oxidizing agent, e.g. m-chloroperbenzoic acid.

Compounds of the formula III in which Z is a radical of the formula XCH ₂ CO- can be conveniently prepared by reacting a compound of the formula XIII

(XIII)

(wherein R and η are as defined above) with a halogenating agent such as a cupric halide _f, for example the bromide, or sulphuryl chloride and wherein each residue R represents precursor residue (s), said precursor residue (s) being in the desired group (e) e) are transferred.

Compounds of formula III can also be prepared by reacting the corresponding metal chloride with diazomethane to give the corresponding diazoketone, followed by treatment with an acid of formula HX (wherein X represents a halogen atom).

Compounds of formula XIII can be prepared by reacting the corresponding acid with methyllithium or the corresponding acid chloride with a malonate.

The following examples illustrate the present invention.

Example 1_

2- (2-Methoxy-4-carbamoylphenyl) imidazo / * 1,2-a.7pyrazine and its hydrochloride

(i) 2-methoxy-4-cyanobenzoyl chloride

2-Methoxy-4-cyanobenzoic acid (5.31 g, 30 mmol) was suspended in anhydrous toluene (50 mL) and thionyl

Chloride (8 ml) was added and the mixture was stirred at reflux for 2 hours and heated. The solvent was removed under reduced pressure and excess thionyl chloride was azeotroped with toluene.

(ii) 2-methoxy-4-cyanoacetophenone

(Bis (trimethylsilyDmalonat 15 g, 60 mmol) was added (in anhydrous ether 150 ml) and the solution was stirred under N, and cooled to -6 0 ⁰ C. N-Butyllithium (37.5 ml of a 1.6M solution in hexane, 60 mmol) was added over a period of 15 minutes, which resulted in the formation of a white precipitate of the lithium salt. This was cooled to 0 ⁰ C allowed to warm and then a solution of 2-methoxy-4-cyanobenzoyl chloride (30 mmol in tetrahydrofuran (15 ml) was added dropwise over 10 minutes, stirring was continued for 30 minutes at 0 to 5 ^° C. and then at room temperature for 18 hours.

The resulting mixture was shaken with saturated NaHCO ₃ , the organic phase was dried over MgSO ₄ and evaporated. The aqueous phase was acidified to pH 2 with 2N HCl and extracted twice with ethyl acetate. These extracts were also dried and evaporated and the two residues combined and dissolved in dioxane (80 ml). The solution was heated at reflux for 2 1/2 hours, the solvent was removed under reduced pressure and the residue was dissolved in dichloromethane and washed with saturated NaHCO ₃ solution and with water. The organic layer was dried (MgSO ₄₎ and evaporated under reduced pressure to give the title product having a melting point of 111 ⁰ C.

(iii) 2'-Bromo-^-methoxy-cyanoacetophenone

Copper (II) bromide (19.6 g, 90 mmol) was suspended in ethyl acetate (150 ml) and stirred at room temperature under nitrogen. A solution of 2-methoxy-4-cyanoacetophenone (7.68 g, 40 mmol) in anhydrous CHCl ₃ (150 mL) was added dropwise over 1 1/2 hours. At the end of the addition, the reaction mixture was refluxed for 3 1/2 hours. The mixture was decolorized by charcoal, filtered, and evaporated under reduced pressure to give a pale-green solid which was triturated with ether to give an off-white solid having a melting point of 117-120 ⁰ C.

(iv) 2- (2-methoxy-4-cyanophenyl) imidazo / i, 2-a-7pyrazine

2-Methoxy-4-cyano-2'-bromoacetophenone (20 g) and aminopyrazine (7.41 g) were dissolved in DMF (100 ml) and the mixture was heated at 80 ^° C. under a nitrogen atmosphere for 2 hours. The reaction mixture was poured into water and the insoluble dark brown solid was filtered off and dried. The pH of the filtrate was adjusted to 8.0 with 0.88 ammonia. The solid that precipitated was filtered and dried. Thin layer chromatography indicated that the two solids are identical and thus they were pooled, dissolved in hot chloroform and destained with animal charcoal. Evaporation under reduced pressure gave a tan solid as a product having a melting point of 199 to 201 ^° C.

(v) 2- (2-Methoxy-4-carbamylphenyl) imidazo / Ί, 2-a7pyrazine

2- (2-Methoxy-4-cyanophenyl) imidazo- / "1,2-a-pyrazine (0.5 g) was dissolved in concentrated H ₃ SO ₄ (10 ml) and the mixture stood at room temperature for 24 hours.

the. The mixture was poured onto crushed ice (100 g). The pH of the resulting solution was carefully adjusted to 7.4 with 10N NaOH (with cooling). The precipitated solid was filtered, washed with water and dried. Melting point 262-265 ° C.

(vi) 2- (2-Methoxy-4-carbamoylphenyl) imidazo / Ί, 2-a_7pyrazine hydrochloride

2- (2-Methoxy-4-carbamoylphenyl) imidazo-1, 2-a-pyrazine (0.4 g) was suspended in methanol and anhydrous hydrogen chloride gas was bubbled through the suspension for a few minutes Solid was filtered and dried, m.p. 266-268 ° C.

Example 2

8-methoxy-2- (2-methoxy-4-methylthiophenyl) imidazo / Ί , 2-AJ- pyrazine

(i) 8-chloro-2- (2-methoxy-4-methylthiophenyl) imidazo / Ί, 2-AJ pyrazine

The title compound was prepared in a manner similar to that described in Example 1, but using 2-amino-3-chloropyrazine in place of aminopyrazine.

(ii) 8-methoxy-2- (2-methoxy-4-methylthiophenyl) imidazo / Ί, 2-a.7-pyrazine

The title compound was prepared by treating the compound (i) with sodium methoxide in methanol, melting point 132 to 135 ⁰ C.

Example 3

8-Methoxy-2- (2-methoxy-4-methylsulfinyl! Phenyl) imidazo / Ί, 2-a7 ^ pyrazine

The title compound was prepared by oxidation of the compound of Example 2 with MCPBA (1 ag), mp 184-185 ° C.

Example 4

8-methoxy-2- (2-methoxy-4-methylsulfonyloxyphenyl) imidazo / 1,2-a7pyrazin

The title compound was prepared by mesylation of the compound of Example 24 in a manner analogous to the procedure described in Example 14, m.p. 220-222 ⁰ C.

Example 5

2- (2-methoxy-4-carbamoyl-phenyl) -8-methoxy-imidazo / ~ 1 _f 2-a7-pyrazine hydrochloride

The title compound was prepared from the product of Example 1 in a manner analogous to that described in Example 2, mp 195-197 ° C.

Example 6

2- (2-methoxy-4-acetylphenyl) -e-chloro-imidazo-1,2-a-7-pyrazine

(i) 3-methoxy-4-cyanobenzoic acid

3-Methoxy-4-aminobenzoic acid (19 g) was suspended in a mixture of concentrated HCl (12 ml) and water (245 ml) and stirred at 0 to 5 ^° C. A solution of sodium nitrite (1 eq.) In water (18 ml) was added dropwise to the above suspension, maintaining the temperature between 0 to 5 ^° C. The mixture was stirred at 0 to 5 ⁰ C for 45 minutes.

The greenish brown solution of the diazonium salt was added in portions to freshly prepared copper cyanide solution / prepared from cupric sulfate (34.2g) in water (60ml) containing potassium cyanide (18g), which was heated to 60 ^° C has been. At the end of the addition, the dark brown solution was refluxed for 2 hours.

Insoluble solid was filtered off and the filtrate was acidified with concentrated HCl. Then, insoluble solid was filtered off and redissolved in saturated sodium bicarbonate solution. The solid, which remained insoluble, was filtered off and the filtrate was re-acidified with concentrated HCl. The pale brown solid was filtered and dried (19 g), melting point 237-240 ⁰ C.

(ii) 3-methoxy-4-cyanobenzoyl chloride

3-Methoxy-4-cyanobenzoic acid (14 g) was suspended in anhydrous toluene (800 ml) and thionyl chloride (16 ml) was added and the mixture was heated at reflux for 3 hours. Insoluble solid was filtered off and the filtrate was evaporated under reduced pressure to give the product as a pale brown solid.

(iii) 3-methoxy-4-cyanoacetophenone

Bis-trimethylsilylmalonat (40.35 g) was dissolved in anhydrous ether (250 ml) is entered and the solution was stirred under N ₂ and cooled to -60 ⁰ C. n-Butyllithium (98/5 ml of a 1.6M solution in hexane) was added dropwise over 30 minutes to form a white precipitate of lithium salt. This was allowed to warm to 0 ⁰ C and then a solution of 3-methoxy-4-cyanobenzoyl chloride, the above

in anhydrous THF (80 ml) was added over 10 minutes. Stirring was continued for 1 hour at 0 to 5 ^° C and then at room temperature for 1 hour.

The resulting mixture was acidified with concentrated HCl and extracted with ethyl acetate (200 ml). The organic layer was washed with water, dried and evaporated under reduced pressure, to which was added a brown solid (13 g). The solid was dissolved in dioxane (100 ml) and heated at reflux for 2.5 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (200 ml) and washed with saturated NaHCO 3 solution and water, dried (MgSO 4) and evaporated under reduced pressure to give the title product as a brown solid (9, 3 g) with a melting point of 110-111 ⁰ C.

(iv) 2-methoxy-4-acetylbenzoic acid

3-Methoxy-4-cyanoacetophenone (6 g) was suspended in 2N NaOH (60 ml) and the mixture was refluxed for 40 minutes. The dark brown solution was filtered off to remove traces of the insoluble solid. The filtrate was acidified with glacial acetic acid and extracted with chloroform (3 x 100 ml). The organic layer was dried (MgSO.), Decolorized and evaporated under reduced pressure to give a cream solid (4.6 g) having a melting point of 127-128 ⁰ C.

(v) 2-methoxy-4-acetylbenzyl chloride

2-methoxy-4-acetylbenzoic acid (5.0 g, 0.026 mol) was added.

in toluene (100 ml) and thionyl chloride (5 ml) was added and the mixture was refluxed for 2 hours. The solvent was removed under reduced pressure and excess thionyl chloride was azeotroped with toluene to leave a light tan solid.

(vi) 2'-Bromo-methoxy-'i-acetylacetophenone

Diazomethane, which (15.5 g) was prepared from diazald was stirred at 0 ⁰ C in ether. A suspension of the 2-methoxy-4-acetylbenzoyl chloride in ether (50 ml) was added dropwise to the diazomethane solution. When the addition was completed, the resulting mixture was stirred at ⁰ C for 30 minutes. Excess diazomethane was carefully distilled off and the remaining solution was evaporated under reduced pressure to leave a brownish yellow solid.

The diazoketone obtained above was suspended in anhydrous ether (200 ml) and a saturated solution of HBr in ether was added dropwise at room temperature until the dissolution of most of the solid occurred. The resulting mixture was stirred at room temperature for 30 minutes. Traces of insoluble solids were filtered off and the filtrate was evaporated under reduced pressure to give a solid which was purified through relaxation column chromatography (flash column chromatography) to give the required product with a melting point of 98-100 ⁰ C.

(vii) 2- (2-Methoxy-4-acetylphenyl) -S-chloroimidazole / 1,2-a- pyrazine

2'-Bromo-2-methoxy-4-acetylacetophenone (2.71 g, 0.01 mol) and 2-amino-3-chloropyrazine (1.94 g, 0.015 mol) were dissolved in anhydrous DMF (50 ml) and the dark brown solution was stirred under nitrogen at 80 to 90 ^° C. for 6 hours. The solvent was removed under reduced pressure and the residue was suspended in water and the pH adjusted to 7.0. The insoluble solid was filtered off, dried and purified by relaxation column chromatography to give the title product having a melting point of 213-215 ⁰ C.

Example 7

2- (2-methoxy-4-acetylphenyl) imidazo / Ί, 2-a / pyrazine and its hydrochloride

(i) 2- (2-Methoxy-4-acetylphenyl) imidazo / 1,2-a-7pyrazine

2- (2-Methoxy-4-acetylphenyl) -8-chloro-imidazo / * 1,2-a- pyrazine (0.5 g) was dissolved in anhydrous DMF (30 ml) and triethylamine (1 ml) and A 5% PaI-ladium on carbon catalyst (160 mg) was added and the mixture was hydrogenated until 1 mole equivalent of hydrogen (ca. 40 ml) was taken up. The catalyst was filtered off and the filtrate was evaporated under reduced pressure and the residue was purified by flash column chromatography to give the title compound as a pale cream solid having a melting point of 192-194 ° C.

(ii) 2- (2-Methoxy-4-acetylphenyl) imidazo / * 1,2-a-7pyrazine hydrochloride

2- (2-methoxy-4-acetylphenyl) imidazo / 1,2-a / pyrazine

(0.15 g) was suspended in methanol and 1.5 eq of 2N HCl solution was added and the mixture was stirred at room temperature for 10 minutes. The insoluble residue was filtered off and dried, melting point 225-228 ⁰ C (shrinks at 210 ^{0 c} C).

Example 8

2- (2-Methoxy-4-methylsulfinylphenyl) -7-methoxy-imidazo / Ί, 2-a.7pyrimidine

A suspension of 2-methoxy-4-methylthiophenacyl bromide (4 mmoles, 1.17 g) and 2-amino-4-methoxypyrimidine (5 mmoles, 625 mg) in EtOH (25 ml) was stirred at reflux for 6 hours. The resulting pale yellow solution was then cooled to 0 ^° C. and the hydrobromide salt was filtered off. This was suspended in saturated NaHCO 3 (50 ml), stirred for 30 minutes, filtered and washed with water. Drying at 80 ^° C./10 mm Hg for 2 hours gave a pale yellow solid.

To a solution of the above solid in CHCl ₃ (25 mL) at ⁰ ° C was added MCPBA (1 eq, 368 mg) in CHCl ₃ . After stirring for 1 h, the pale yellow solution was washed with saturated NaHCO ₃ solution and dried over MgSO ₄ . Chromatography on SiO 2 (25 g) eluting with CHCl _{3 followed} by 2% MeOH-CHCl ₃ gave the desired product. This was triturated with EtOAc, filtered and dried at 80 ° C / 10 mm Hg, to obtain a white crystalline solid with a melting point of 234-235 ⁰ C.

Example 9

3-amino- (2- (2,4-dimethoxyphenyl) imidazo / Ί, 2-a7-pyrimidine hydrochloride

2- (2,4-dimethoxyphenyl) imidazo / Ί, 2-a7pyrimidine was added in

prepared analogously to the procedure of Example 8 and was nitrosated with sodium nitrite in acetic acid and the product was reduced by catalytic hydrogenation, m.p.> 200 ° C (decomposition).

Examples 10 to 13

The following compounds were prepared in a manner analogous to that of Example 8:

10) 6-methoxy-2- (2-methoxy-4-methylsulfinylphenyl) imidazo - / * 1, 2-a / pyrimidine, melting point 219-220 ⁰ C.

11) 2- (2-methoxy-4-carbamoylphenyl) imidazo / 1,2-a / pyrimidine

0.9 HCl, m.p. 255-257 ° C.

12) 6-Hydroxy-2- (2-methoxy-4-methylsulfinylphenyl) imidazo / 1,2-a-7-pyrimidine, HCl, 0.6 H ₂ O, m.p. 222-226 ° C (decomp.).

13) 6-methoxy-2- (2, 4-dimethoxyphenyl) imidazo / i, 2-a. / Pyrimidine, mp 200-201 ⁰ C (decomposition).

Example 1_4

2- (2-Methoxy-4-methylsulfonyloxyphenyl) imidazo / Ί, 2-a_7pyrimidine hydrochloride

2- (Methoxy-4-benzoyloxyphenyl) imidazo / Ί, 2-a / pyrimidine was prepared in a manner analogous to that described in Example 8 and debenzylated with thioanisole and trifluoroacetic acid, followed by mesylation with methanesulfonyl chloride in Pyridine was added, mp 244-246 ° C.

Example 15

6-Methylsulfonyloxy-2- (2-methoxy-4-methylsulfinylphenyl) -imidazo / ω-α-pyrimidine hydrochloride

The compound of Example 3 was mesylated analogously to the description in Example 14 to give the title product, mp 184-187 ° C (decomposition).

Example 1_6.

6-Amino-2- (2,4-dimethoxyphenyl) imidazo / Ί, 2-a_7pyrimidine hydrochloride

6- (4-Methoxyphenylazo) -2- (2,4-dimethoxyphenyl) imidazo [\ , 2-a./pyrimidine was prepared from 2-aminopyrimidine-5-azo- (4-methoxybenzene) in a manner similar to that is analogous to Example 8. The resulting protected compound was subjected to catalytic hydrogenation to give the title product, mp 275-278 ° C (decomp.).

Examples 17 to 24

The following compounds were prepared in an analogous manner to the procedure used to prepare the compound of Example 3.

17. 8- (2-Hydroxyethoxy) -2- (2-methoxy-4-methylsulfinylphenyl) imidazo / "1,2-a / pyrazine, mp 190-192 ° C.

18. 8-n-propoxy-2- (2-methoxy-4-methylsulfinylphenyl) imidazo / Ί, 2-a7pyrazin, melting point 150-151 ⁰ C.

19. 8-methoxy-2- (2-methoxy-4-cyanophenyl) imidazo / 1, 2 - &] ~ pyrazine, melting point 237-140 ⁰ C.

20. 8-Methoxy-2- (2-methoxy-4-methylsulphonylphenyl) imidazo / Ί, 2-a7pyrazine (prepared from the starting material).

4-methylsulfonyl-2-methoxyphenacyl bromide), mp 234-236 ° C.

21 8-hydroxy-2- (2-methoxy-4-methylsulfinylphenyl) imidazo [\, 2 -a / pyrazin foams above 150 ⁰ C.

22. 6-Methoxy-2- (2-methoxy-4-methylsulfinylphenyl) imidazo / "1,2-a.Tpyrazine, m.p. 164-165 ° C.

23. 8-methylthio-2- (2-methoxy-4-methylsulfinylphenyl) imidazo / 1,2-a / pyrazine, melting point 160-161 ⁰ C.

24. 8-Methoxy-2- (2-methoxy-4-hydroxyphenyl) imidazo / "1,2 -aJ · pyrazine, mp 275-276 ° C.

Example 25

8-methylamino-2- (2-methoxy-4-methylthiophenyl) imidazo / 1 2 -a / pyrazin

The title compound was prepared by treating the compound of Example 2 (i) with methylamine, melting point 141-143 ⁰ C.

Example 2J5

8-methylamino-2- (2-methoxy-4-methylsulfinylphenyl) imida-ζο / Ί ^ -a / pyrazine dihydrochloride

The title compound was prepared by oxidation of the compound of Example 25 with MCPBA, 1 (eq), melting point 160-161 ⁰ C.

Example 27

2- (2-Methoxy-4-methylsulfonyloxyphenyl) imidazo / i _t 2-yy pyrazine

2- (2-Methoxy-4-benzyloxyphenyl) imidazo / "1,2-a / pyrazine was prepared in a manner analogous to the process of Example 1.

and subjected to debenzylation in a manner analogous to that in Example 14 to give the title compound, mp 197-199 ° C.

Example 28

8-methoxy-2- (2-methoxy-4-hydroxyphenyl) imidazo / Ί, 2-aJpyrazin

8-Methoxy-2- (2-methoxy-4-benzyloxyphenyl) imidazo / Ί, 2-a7-pyrazine was prepared in a manner analogous to the preparation of the compound of Example 3, followed by catalytic hydrogenation to afford the To give title product, mp 275-276 ° C.

Example 2_9

8-Methoxy-2- (2-methoxy-4-methylsulfonyloxyphenyl) imidazo / Ί, 2-a_7pyrazine

The title compound was prepared by mesylation of the compound of Example 28 in an analogous manner to that described in Example 14, m.p. 220-222 ⁰ C.

Example 3J)

3-bromo-2- (2-methoxy-4-methylsulfinylphenyl) imidazo / Ί, 2-a.J- pyrazine

2- (2-Methoxy-4-methylsulfinylphenyl) imidazo / Ί, 2-a / pyrazine was prepared in an analogous manner to that described in Example 1 (iv) and reacted with N-bromosuccinimide to give the title product , Mp 204-205 ⁰ C.

Example 31

2- (2-methoxy-4-carbamoylphenyl) imidazo / Ί, 2-c.7pyrimidine

7-Chloro-2- (2-methoxy-4-cyanophenyl) imidazo / Ί, 2-c / pyrimidine was prepared from 4-amino-6-chloropyrimidine and the corresponding phenacyl bromide in a manner similar to that described in Example 2 (i) is analogous. This was catalytically dechlorinated with 5% palladium on charcoal in the presence of dimethylformamide (DMF) and triethylamine. The dechlorinated product was converted to the title compound in a manner analogous to that described in Example 1 (v), mp 264-266 ° C.

Example 32

7-Methoxy-2- (2-methoxy-4-methylsulfinylphenyl) imidazo / 1,2-c7pyrimidine

The title compound was prepared in a manner similar to that is analogous to the description in Example 31, from 4-amino-6-methoxypyrimidine, m.p. 179-181 ⁰ C.

Example 33

2- (2-Methoxy-4-methylsulfonyloxy) imidazo / Ί, 2-c.7pyrimidine hydrochloride

a) 2- (4-hydroxy-2-methoxyphenyl) imidazo / 1,2-c7pyrimidine

7-Chloro-2- (4-benzyloxy-2-methoxyphenyl) imidazo / 1,2 -cJ- pyrimidine was prepared in a manner analogous to that described in Example 31 and dechlorinated as was also used in Example 31 this step also involves the conversion to the benzyloxy substituent to hydroxy, thereby forming the title compound.

b) 2- (2-Methoxy-4-methylsulfonyloxyphenyl) imidazo / Ί , 2-oJ- pyrimidine hydrochloride

The title compound was prepared from the compound of (a) in a manner analogous to that described in Example 14, mp> 235 ° C (decomposition).

Example 3_4

7-amino-2- (2-methoxy-4-methylsulfinylphenyl) imidazo / Ί , 2-CJ pyrimidine

The title compound was prepared in a manner analogous to that described in Example 31, using as starting material the corresponding diaminopyrimidine, mp 213-215 ° C (decomposition).

Example 35

6-amino-2- (2-methoxy-4-methylsulfinylphenyl) imidazo / Ί , 2-AJ- pyrimidine

6- (4-Methoxyphenylazo) -2- (2-methoxy-4-methylthiophenyl) -imidazo [Λ , 2-a / pyrimidine was prepared in a manner analogous to that described in Example 16. The compound was converted to the corresponding 4-methylsulfinylphenyl compound oxidized by the method which is described in Example 3, followed by cleavage as described in Example 16, joined to give the title product, melting point 219-221 ⁰ C.

Example 3_6

2- (2,4-dimethoxyphenyl) -3-hydroxyimidazo / '1,2-a-pyrimidine and its hydrochloride _#

a) 2-aminopyrimidine N-oxide

This compound was made by the oxidation

of 2-aminopyrimidine as described by L.W. Deady, Synth., Commun., 509 (1977).

b) 2- (2,4-Dimethoxyphenyl) -3-hydroxyimidazole / 1,2-a-7-pyrimidine

2-aminopyrimidine-N-oxide (4.5 g, 40.5 mmol) and 2,4-Dimethoxyphenacylbromid (10.49 g, 40.5 mmol) were combined in dimethylformamide (90 ml) was heated for 2 hours at 8O ⁰ C , After standing overnight, the DMF was evaporated and the residue was taken up and washed with aqueous sodium bicarbonate solution. The organic phase was over Na-SO. dried and the solvent evaporated. The residue was chromatographed over silica using chloroform-methanol (10: 1). The product solidified and was recrystallized from ethanol-chloroform to give 2- (2,4-dimethoxyphenyl) -3-hydroxyimidazo / * 1,2-a / pyrimidine as a yellow solid. 6 (d -DMSO) 8.26 (1H, dd, H-5 or H-7), 8.03 (1H, dd, H-5 or H-7), 7.35 (1H, d, phenyl) , 6.98 (1H, dd, H-6), 6.68 (2H, m, phenyl), 3.84 (3H, s _r OCH _3), 3.78 (3H, s, OCH _3); m / e 271 (M ⁺ ).

c) 2- (2,4-Dimethoxyphenyl) -3-hydroxyimidazo / 1,2-a7pyrimidine hydrochloride

The hydrochloride was prepared by dissolving the free base in ethanol-chloroform and treating with ethereal HCl. The salt was recrystallized from ethanol-ethyl acetate, melting point 225-228 ⁰ C (decomposition). R _f 0.21 (CHCl ₃ -MeOH, 10: 1). Found: C 54.19, H 4.42, N 13.32, Cl 11.57. Calculated for C ₁₄ H ₁₃ NO -HC1-0,2H ₂ O: C 54.00, H 4.63, N 13.50, Cl 11.41.

Example 37

2- (2-methoxy-4-methylsulfonylaminophenyl) imidazo / Ί , 2-AJ- pyrimidine hydrochloride

(i) 4-azido-2-methoxybenzoic acid

A solution of 4-amino-2-methoxybenzoic acid (16.7 g, 0.10 mol) of 11% sodium in 200 ml w / v aqueous sulfuric acid was cooled with stirring to 0 ⁰ C and 15 minutes with a cold solution of sodium nitrite (47.7 g, 0.69 mol) in 100 ml of water. The reaction mixture was stirred for 45 minutes at 0 to 5 ⁰ C and then a solution of sodium azide (73.0 g, 1.12 mol) was added in 300 ml of water in a steady stream over 15 minutes, keeping the temperature below 1O ⁰ C was obtained by vigorous stirring and external cooling. After cooling again to 0 ^° C. and stirring at this temperature for 45 minutes, the suspension was filtered to give a straw-colored solid. This was washed with water and recrystallized from ethanol to give the 4-azido-2-methoxybenzoic acid was obtained, melting point 151-152 ⁰ C.

Analysis: Found C 4 9.9, H 3.50, N, 21.8%. Calculated for C ₀ H ^ NO- C 49.7, H 3.63, N 21.8%.

(ii) 4-azido-2-methoxybenzoyl chloride

The compound of (i) (6.0 g) and thionyl chloride (50 ml) were stirred at reflux and under anhydrous nitrogen for 30 minutes. Removal of excess reagent under reduced pressure followed by azeotropic distillation with benzene gave 4-azido-2-methoxybenzoyl chloride as a pale yellow crystalline solid.

(iii) 2-methoxy-4-azidoacetophenone

Bis-trimethylsilylmalonat (16.3 g) was dissolved in anhydrous ether entered (100 ml) and the solution was stirred under N ₂ and cooled to -60 ⁰ C. n-Butyllithium (42 ml of a 1.6M solution in hexane) was added dropwise over 20 minutes to form a white precipitate of a lithium salt. This was allowed to warm to ⁰ ° C. and then a solution of the above compound (ii) (6.90 g) in anhydrous THF (70 ml) was added over 5 minutes. Stirring was continued at 0 to 5 ^° C for 1 hour. Work-up as in Example 6 (iii) gave the title product as a yellow solid having a melting point of 51-53 ° C; M 191; Analysis: Found C 56.7, H 4.75, N 21.8%. Calculated for CH ₉ H ₃ O ₃ C 56.5, H 4.71, N 22.0%.

(iv) 2-methoxy-4-azidophenacyl bromide

Phenyltrimethylammonium tribromide (4.51 g) was added in a single portion of a solution of the above compound (iii) (1.91 g) in THF (50 ml) with stirring and cooling to 5 ^° C. under nitrogen. The reaction mixture was stirred and cooled to 5 ^° C., filtered, the filtrate and washes diluted with water and then extracted several times with ether. The combined extracts were washed with aqueous saturated NaHCO 4 solution, then with. Water, dried over MgSO ₄ and the solvent was removed under reduced pressure. Trituration of the remaining rubber in hexane containing a little ethanol, gave a solid, which was recrystallized from ether-hexane to give the title compound as a yellow solid with a melting point of 104-106 ⁰ C.

Analysis: Found C 40.2, H 2.94, N 15.4; calculated for C ₉ HgBrN ₃ O ₂ C 40.0, H 2.96, N 15.6%.

(ν) 2- (2-methoxy-4-azidophenyl) imidazo / "1,2-a-pyrimidine hydrobromide

The above compound (iv) (3.24 g) and 2-aminopyrimidine (1.14 g) in ethanol (100 ml) were stirred at reflux and under nitrogen for 5 hours. The reaction mixture was cooled to room temperature and the solid which precipitated was filtered off and recrystallized from aqueous ethanol to give the title compound as a yellow solid, mp 181 ° C (decomp.).

(vi) 2- (2-methoxy-4-aminophenyl) imidazo / Ί, 2-a./pyrimidine

A solution of the hydrobromide of the above (v) (1.30g) in ethanol (60ml) containing triethylamine (0.76g) and 5% palladium-charcoal catalyst was shaken under one atmosphere of hydrogen pressure until thin layer chromatography indicated that all the starting material had been consumed after about 2 hours. The catalyst was removed by filtration over Hyflo and the filtrate was evaporated to dryness under reduced pressure. The remaining material was purified by column chromatography over silica gel using CHCl_-MeOH (8: 1) as eluent to give the title compound was obtained as a yellow solid, melting point 224 ⁰ C (decomposition).

(vii) 2- (2-Methoxy-4-methylsulfonylaminophenyl) imidazo - / * 1,2-a-7-pyrimidine hydrochloride

To a stirred solution of the compound of the above step (vi) (0.50 g) in anhydrous pyridine

(45 mL) at ⁰ ° C was added over 30 minutes a solution of mesyl chloride (0.23 g) in anhydrous pyridine (10 mL). The reaction mixture was stirred for 17 hours at 0 to 5 ⁰ C, the pyridine was removed under reduced pressure and the residue was stirred with water and chloroform. The resulting solid was filtered off and recrystallized from ethanolic hydrogen chloride to give the title compound as a yellow solid having a melting point of 260 to 263 ⁰ C (decomposition). Analysis: Found C 47.1, H 4.20, N 15.7, calculated for C ₁₄ H ₁₄ N ₄ O ₃ S-HCl C 47.3, H 4.23, N 15.8%.

Example 38

2- (4-acetamido-2-methoxyphenyl) -8-methoxyimidazo / 1,2-a7-pyrazine

(i) 2- (4-azido-2-methoxyphenyl) -8-chloroimidazo / '1,2-a / pyrazine

2-Amino-3-chloropyrazine (3.38 g, 26.1 mmol) and 2-methoxy-4-azidophenacyl bromide (4.7 g, 17.4 mmol) were dissolved in DMF (90 mL) and the solution became 6 Heated to 90 ⁰ C hours. DMF was removed under reduced pressure and the residue was triturated with ice-water (100 ml) and with saturated NaHCO ₃ (100 ml). The residue was then in CH 2 Cl 2. (50 ml) and washed with saturated NaHCO ₃ and dried over MgSO ₄ . Chromatography over silica gel eluting with _CHCl3 gave the desired product as a light brown solid having a melting point of 174-182 ⁰ C.

(ii) 2- (4-azido-2-methoxyphenyl) -8-methoxyimidazole, 2,2 -a- pyrazine

The compound according to the above paragraph (i) (1 g,

3.33 mmol) and sodium methoxide (0.36 g, 6.66 mmol) were heated at reflux in methanol (40 ml) for 1 h. The methanol was evaporated and the residue was purified by chromatography on silica using CHCl ₃ as Eluationsmxttel to give the desired product as a light brown solid having a melting point of 154-158 ⁰ C.

(iii) 2- (4-amino-2-methoxyphenyl) -S-methoxyimidazole / 1,2-a- pyrazine

The above compound (ii) (0.82 g, 2.76 mmol) was dissolved in ethanol (45 mL) in the presence of triethylamine (0.77 mL, 5.52 mmol) and 5% palladium on carbon catalyst (82 The catalyst was filtered off and the filtrate was evaporated under reduced pressure, purified by chromatography on silica using CHCl ₃ as eluent to give the desired product as an orange solid having a melting point of 215-226 ° C result.

(iv) 2- (4-acetamido-2-methoxyphenyl) -8-methoxyimidazo [Λ , 2-a_7pyrazine

Acetic anhydride (0.1 ml, 1.1 mmol) was added to a stirred suspension of the above compound (iii) (0.15 g, 0.55 mmol) in pyridine (2.5 ml) at room temperature. After 30 minutes, methanol was added and after a further 15 minutes, CHCl _{3 was} added. The organic solution was washed with saturated NaHCO-. washed and dried over MgSO ₄ . Chromatography on silica with 2% MeOH-CHCl_ as eluent gave the desired product as a light yellow solid having a melting point of 231-235 ⁰ C.

Example 39

2- (2-methoxy-4-sulfamoy! Phenyl) -8-methoxyimidazo / i , 2-AJ- pyrazine

(i) 2- (4-chlorosulfonyl-2-yn-methoxyphenyl) -8-methoxy-iini2o [Λ , 2α / pyrazine

A solution of sodium nitrite (0.20 g, 2.86 mmol) in water (0.5 mL) was added dropwise to a suspension of 2- (4-amino-2-methoxyphenyl) -8-methoxyimidazo / 1,2-a ^ pyrazine (0.52 g, 1.92 mmol) in acetic acid (1 mL) and concentrated HCl (1 mL) at 0 to 5 ⁰ C was added. The reaction mixture was stirred at 5 ⁰ C for 30 minutes and then cooled to 15 ⁰ C. Copper chloride (96 mg, 0.56 mmol) and 6.5M SO- in acetic acid (1.4 ml) were added. The reaction mixture was stirred at 0.5 ^° C. for 48 hours. Water (5 ml) was added and the desired product was filtered off as a yellow solid having a melting point of 284 ° C (decomposition 184 ° C).

(ii) 2- (2-Methoxy-4-sulfamoylphenyl) -8-methoxyimidazo / 1,2-a_7pyrazine

The compound according to the above paragraph (i) (0.1 g, 0.28 mmol) was suspended in THF (1 ml) and cooled in an ice bath. Concentrated ammonia (1.5 ml) was added dropwise and the mixture was allowed to stand at room temperature overnight. The desired product was filtered off as an off-white solid with a melting point of 215 to 240 ⁰ C.

Example 4JD

2- (2-Methoxy-4-N-methylsulfamoylphenyl) -8-methoxyimidazo / Ί, 2-a_7pyrazine

The title compound was prepared in an analogous manner to the

Letters prepared in Example 39, m.p. 218-230 ⁰ C.

Example 41_

2- (4-N _, N-dimethylsulfamoyl-2-methoxyphenyl) -8-methoxyimidazo / * 1,2-a_7pyrazine

The title compound was prepared in an analogous manner to the description in Example 39, mp 167-169 ° C.

Example 42_

2- (4-acetamido-2-methoxyphenyl) imidazo / "1,2-apyrazine

(i) 2- (4-Amino-2-methoxyphenyl) imidazo / "1,2-a7pyrazine

2- (4-azido-2-methoxyphenyl) -8-chloroimidazo / 1,2-a- pyrazine (0.9g, 3mmol) was dissolved in DMF (50ml) in the presence of triethylamine (3.6ml, The catalyst was filtered off and the filtrate was evaporated under reduced pressure, purified by chromatography on silica with 2% MeOH-CHCl ₃ as eluent to give 25.9 mmol) and 10% palladium on carbon catalyst (90 mg) to give the desired product as a yellow solid having a melting point of 208-215 ⁰ C.

(ii) 2- (4-acetamido-2-methoxyphenyl) imidazo / Ί, 2-a_7pyrazine

Acetic anhydride (0.03 ml, 0.33 mmol) was added to a stirred solution of the above compound (i) (40 mg, 0.17 mmol) in pyridine (1 ml). After 3 hours, methanol was added and after a further 15 minutes CHCl _{3 was} added. The organic solution was washed with saturated NaHCO ₃ and dried over MgSO 4. dried. The chromato

chromatography on silica gel eluting with 2% MeOH-CHCl gave the desired product as a light yellow solid having a melting point of 240-254 ⁰ C.

Example 43

2- (2-Methoxy-4-ureidophenyl) imidazo / 1,2-a_7pyrimidine

2- (2-methoxy-4-aminophenyl) imidazo / Ί, 2-a / pyrimidine was prepared in an analogous manner to that described in Example 8 and to the title product by treatment with potassium cyanate in diluted hydrochloric acid, melting point 265 ⁰ C ( Decomposition).

Example 4_4

2- (2-methoxy-4-methylsulfonylaminophenyl) imidazo / Ί, 2-AJ pyrazine

The title compound was prepared in an analogous manner to the description in Example 1, m / e 318 (M), R _f 0.3 (CHCl ₃ MeOH, 10: 1).

Pharmaceutical formulations

The following examples illustrate pharmaceutical formulations according to the present invention, wherein the active compound may be one of the above-defined compounds of formula I, such as 2- (2-methoxy-4-carbamoylphenyl) imidazo / Ί, 2-a_7pyrazine hydrochloride.

Example A Tablet Formulation

Active compound (as base) 100 mg lactose 100 mg

20 mg 4 mg 2 mg

Sodium tar keg Iy co Has polyvinylpyrrolidone magnesium stearate

226 mg

The active compound is mixed with the lactose and the sodium starch glycollate. The mixture is granulated with a solution of polyvinylpyrrolidone in 50% aqueous alcohol. The granules are dried and mixed in the magnesium stearate. The tablets are compressed to an average weight of 226 mg.

Example B

Capsule formulation 100 mg Active connection (as base) 100 mg lactose 30 mg Strength 4 mg methylcellulose 4 mg stearic acid

238 mg

The active compound is mixed with the lactose and the starch. The mixture is granulated with a solution of the methylcellulose in water. The granules are dried and mixed with the stearic acid. 238 mg are poured into a hard gelatin capsule.

Example C IV injection (freeze-dried)

Active compound (as hydrochloride) 50 mg

Mannitol 50 mg

Water for injection to 2 ml

The active compound is dissolved in water for injections. The solution is sterilized by passing it through a membrane filter of 0.2 μ pore size, collecting the filtrate in a sterile glass pick-up device. It is filled into sterile 2 ml glass vials under aseptic conditions and sealed with aluminum caps.

The injection is returned to its original state prior to administration by the addition of an appropriate volume of water for injection or sterile saline solution when large volume infusion is needed.

Example D IV injection (multi-dose ampoule)

Active compound (as hydrochloride) 250 mg benzyl alcohol 0.075 ml

Water for injection 5 ml

The benzyl alcohol is dissolved in water for injection. Then the active compound is added and dissolved. The volume is filled up with water for injection. The solution is then passed through a membrane filter of 0.2 μ pore size, collecting the filtrate in a sterile glass receiving vessel. It is filled into sterile glass ampoules. The ampoules are closed with sterile rubber closures and secured with aluminum caps.

Example E suppository

Compound (as base) 100 mg

Suppository base (Massa Esterinum C) to 2 g

The Suppositorienbase is melted at 40 ⁰ C. The active compound is added to the molten base in the form of a fine powder and mixed until homogeneous. The mixture is poured into appropriate molds using 2 g per mold and allowed to settle.

Biological activity

Determination of inotropic and vasodilator activity in vivo

Compounds of the present invention were evaluated in vivo in comparison with the compound 2- (2-methoxy-4-methylsulfinylphenyl) -imidazo / 1,2-a / pyrazine (hereinafter referred to as Compound ¹ X ¹ described in GB-A-2,132 The compounds were tested on anesthetized open-mouthed Beagle dogs by intravenous injection of a bolus to produce a dose-dependent positive inotropic stimulation over the dose range of 0.003 to 3.0 mg / kg Increasing the maximum rate of change in left ventricular pressure - LV dP / dt) associated with a dose-related increase in aortic blood flow and a drop in systemic blood pressure (see table below) In these preparations, the length of inotropic response was determined by the Measuring the time in which a 50% increase from LV dP / dt returns to pre-dosing levels, the duration is in the wake shown in the table below and given as an area for some of the connections.

TABLE

The effective intravenous dose of the compound to produce a 50% increase in LV dP / dt (ED ₅₀ LV dP / dt), the duration of inotropic response (T) and a 30% drop in diastolic blood pressure (ED ₃₀ DBP ) in anesthetized beagle dogs with open chest.

ED ₅₀ LVdP / dt ED ₃₀ DBP selectivity T r connection MgAg mg / kg ED _5Q LVdP / dt minutes 0.75 0.028 ED ₃₀ DBP 5 X 0.02 0.05 26.8 > 30 example 1 0.91 1.17 0.4 60 Example 3 0.07 0.06 0.08 45-60 Example 4 0.06 0.15 1.22 30-45 Example 5 0.03 0.10 0.39 10 Example 7 0.30

Claims (9)

invention claim and the other two CH radicals are independently R-radicals below those in (a) and (b) are selected, namely: Hydroxy, radicals of the formula -S (O) R _a ^x χ is 0, 1 or 2 and R is a C, .alpha. R 'is radicals and radicals of the formula -OR * ³ , wherein R represents an allyl or a C -.- alkyl radical, where the alkyl radical is optionally substituted by one or more radicals selected from halogen, C, - alkoxy and radicals of the formula -S (0) R, wherein χ and R ^{a of} the above Be correspond to interpretation; C, -alkanoyl., C ₁ _.- alkanoylamino, 2-methyl-1,3-dioxalan-2-yl, sulphamoyl, NC ^ -Alkylsulfairioyl, N, N-di-C_ ₄ alkylsulfamoyl, c._ ₄ - alkylsulfonyloxy, C ^ alkylsulfonylamino, Aminosulfonyloxy, NC. Alkylaminosulfonyloxy-, N, N-di-C ^ -alkylaminosulfonyloxy, ureido, 3-Cj_ ₄ alkylureido, 3,3-di-C., .- alkylureido, aminosulphonylamino, (C. -alkylaminosulfonyl) amino, (di-C ₁ , -alkylaminosulfonyl) amino, carboxy, carboxylic acid derivatives (selected from Carbamoyl, NC ₁ _. Alkylcarbamoyl, N, N-di-C _1-4 alkylcarbamoyl, carboxylic acid halides / C _1-4 alkoxycarbonyl / hydroxy-C-alkoxycarbonyl and hydroxymethylene) and radicals of the formula -OR ^c , wherein R ^{c is} a straight-chain or branched is aliphatic moiety of 1 to 4 carbon atoms, optionally substituted by one or more radicals independently selected from halogen, C, 4-alkoxy and radicals of the formula -S (O) R ^a , wherein χ and R are as defined above with the proviso that R is not a radical according to the above definition for R, R is selected from hydrogen, halogen, amino, hydroxy, C.-alkyl and R radicals are independently selected from halogen, carboxy, amino, C _1-4 -alkylamino, hydroxy, C _1-4 -alkoxy, hydroxy-C, _4- alkoxy, C _1-4 -alkylthio and C _1-4 -alkylsulfonyloxy, with the proviso that when R is a hydrogen atom and either m is 0 or m is 1 and R is halogen, at least one R must be selected from the above (b) and when η and m 2 1 both are 1, and R is H, if then A is 2 3 1 Nitrogen atom, A and A are both CH and R is 4-methoxy, R is not 7-methoxy, and if so 3 1 '2 A is a nitrogen atom and A and A are both CH and R is a 4-methylsulfonyl radical, R is not a 6-methoxy radical, or a physiologically acceptable salt and / or N-oxide thereof, wherein in the process a) a compound of the formula 3 (R) A3 12 3 3 (wherein A, A, A , m and R are as defined above and Y is an amino radical or a displaceable radical, for example hydrogen or a halogen atom such as chlorine) with a compound of the formula (M) (wherein R and η are as defined above or precursor groups therefor and Z is a radical capable of reacting with the radical Y to form an imidazo ring system, with the following formation of a compound of the formula I or an acid addition salt thereof), b) a compound of the formula R ² (IV) 12 3
(in which A, A, A, η and m are as defined above) 1 3 and each of the radicals R to R independently aa ₁ represents a radical as defined for the above radicals R to R or a precursor group therefor, with the proviso that at least one of the radicals R ₌ to R represents such a precursor group) aa or an acid addition salt thereof is reacted with an agent which serves to effect conversion of the precursor group (s) into the desired residue (s), c) radical analogue of a compound of the formula (V) 12 3 2 3
(wherein A, A, A, R, R and m are as defined above) by reaction with a compound of the formula (VI) (wherein R and η are as defined above and A is a displaceable radical, for example a diazonium halide, for example the chloride), or d) reaction of a compound of the formula (R ¹ ) (VIO 12
(wherein R, R and η are as defined above) with a reagent such that the reagent and Q (in formula VII) are selected to complete the formation of the ring (R ³ ) 12 3 3
to react (in which A, A, A, R and m correspond to the above meaning), and when a compound of formula I is formed, this compound is optionally converted to the N-oxide and / or acid addition salt thereof. 2. The method according to item 1, wherein the compound thus prepared is a compound in which η is 2, m is 0 or 1, the radicals R are independently selected from cyano,
Hydro'xy, radicals of the formula S (O) R ^a , wherein χ and R ^a of Definition in formula I, radicals of the formula
-OR, where R _ ₄ alkyl group is a C., C ₁ _ ₄ alkanoyl, C,.-Alkanoylamino, sulfamoyl, NC ._.- alkylsulfamoyl,
N ₇ N-di-C ₁ _ -alkylsulfamoyl, C ₁ _ ₄ -alkylsulfonyloxy,
C 1-6 -alkylsulfonylamino, ureido, carbamoyl and aminosulfonylamino, and R is selected from hydrogen, halogen, amino
and hydroxy, R (if present) is selected from halogen,
Amino, C, .alpha.-alkylamino, hydroxy, C _1-4 -alkoxy, hydroxy-C. , -alkoxy, C 1-4 -alkylthio. and C 1-6 -alkylsulfonyloxy, or a physiologically acceptable salt thereof. 3. The method of item 1, wherein the compound thus prepared a Verbindu
are selected under Bond is a compound in which R radicals are independent Cyano, hydroxy, radicals of the formula -S (O) R ^a , in which χ is O, 1 or 2 and R ^a is a C, ₄ alkyl radical, sulfamoyl, NC ^ alkylsulfamoyl, N, N-di-C, ₄ alkylsulfamoyl, C, ~ ₄ alkylsulfonyloxy, C - ^ - alkylsulfonylamino, Aminosulfonyloxy, NC - ^ - Alkylaminosulfonyloxy, N, N-di-C ₁ _ ₄ -alkylaminosulfonyloxy _/ carboxy, carboxylic acid derivatives (selected from carbamoyl, NC._ ₄ alkylcarbamoyl, ^ N-di-C ^ alkylcarbamoyl, carboxylic acid halides, C ,,. Alkoxycarbonyl, hydroxyalkoxycarbonyl and "~ rl rl Hydroxymethylene) and radicals of the formula -OR, wherein R represents a straight or branched aliphatic moiety of from 1 to 4 carbon atoms, optionally substituted by one or more radicals independently selected from halo, C _1-4 alkoxy and radicals of Formula -S (O) R ^a , wherein χ and R ^a correspond to the above meaning, R is selected from hydrogen, hydroxy, C _1-4 -alkyl and C _1-4 -alkoxy, R radicals are independently selected from halogen, carboxy, amino, hydroxy, C _1-4 -alkoxy, C, ₄ alkylthio and C _{first-alkylsulphonyloxy,} with the further proviso that 2 13 if A is a nitrogen atom and A and A are both CH, R is a radical other than amino or 2 C ₁ -alkylsulfonyloxy, and when A is a nitrogen atom 13 3 and A and A are both CH, or A is 1 2 Is nitrogen and A and A are both CH, R is other than hydroxy, or a physiologically acceptable salt and / or N-oxide thereof. 4. Method according to item 1 or item 3, wherein in the compound of the formula I or of the physiologically tolerable salt and / or N-oxide thereof A is a nitrogen atom and A and A are both CH. 5. The method according to any one of items 1,3 and 4, wherein the compound thus prepared is selected from 8-methoxy-2- (2-methoxy-4-methylsulfinylphenyl) imidazo / Ί, 2-a7pyrazine, 2- (4-methylsulfonyloxy-2-methoxyphenyl) -8-methoxy-imidazo / 1,2-a-7-pyrazine, 2- (4-carbamoyl-2-methoxyphenyl) -8-methoxy-imidazo / 1,2-a- pyrazine and physiologically acceptable salts and / or N-oxides thereof. 6. The method according to any one of items 1, 3 and 4, wherein the compound thus prepared is selected from 2- (2-methoxy-4-carbamoylphenyl) -imidazo / "i, 2-a. / Pyrazine and its N-oxides and physiologically acceptable salts. 7. The method of item 1 (b) or item 7, wherein 2- (2-methoxy-4-cyanophenyl) imidazo / Ί, 2-a_7pyrazin is subjected to acid hydrolysis and optionally the product obtained in a physiologically acceptable salt and / or N Oxide thereof is transferred. 8. The method according to item 1 (d), wherein in the compound of 2 13 Formula I A represents a nitrogen atom and A and A are both CH, wherein the substituent Q in the compound of formula VII is formyl and the reagent is the formula OEt
NH, R ⁴ (XI) R ⁵ 4 5
has (wherein R and R are independently selected from hydrogen and radicals corresponding to the above definition for R). 9. A process for the preparation of a pharmaceutical formulation by a) Preparation of a compound of formula I or a physiologically acceptable salt and / or N-oxide thereof by a method according to any one of items 1 to 8, and b) mixing the resulting product and at least one pharmaceutical carrier or excipient.