DE2806199A1 - AMINOPYRIMIDINE COMPOUNDS, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS - Google Patents

Description

PATENT LAWYERS

PROF. DR. DR. J. REiTSTOTTER

DR.-ING. WOLFRAM BUNTE

DR. WERNER KINZEBACH

BAUERSTRASSE 22. D-60O0 MUNICH ΛΟ - FERNRUF (O89) 37 65 83 · TELEX 52152O8 ISAR D POSTAL ADDRESS: POSTFACH 78O. D-8OOO MUNICH

Munich, February 14, 1978 M / 19 025

BRISTOL-MYERS COMPANY 345 Park Avenue

New York, N.Y. 10022 / USA

Aminopyrimidine compounds, method too their manufacture and medicinal products

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The invention relates to aminopyrimidine compounds with a heterocyclic ring attached to the pyrimidine ring. The invention also relates to a method for producing the inventive Compounds, as well as a drug containing these heterocyclic pyrimidine compounds.

The compounds according to the invention correspond to the following Formulas I and II:

(, ^CH 2> n

II

In these formulas, R stands for hydrogen or the group A, in which A is a lower alkyl or lower alkenyl group each up to 8 carbon atoms, a pyridylmethyl group, an aralkyl group having 7 to 12 carbon atoms, one substituted aralkyl group with 7 to 12 carbon atoms, an aryloxyalkyl group having 8 to 12 carbon atoms, or a substituted aryloxyalkyl group having 8 to 12 carbon atoms means, where the substituted aralkyl and substituted Aryloxyalkyl groups as substituents 1 or 2 Carry halogen, alkoxy and / or Al kyl groups, the alkoxy and contain alkyl groups up to 6 carbon atoms.

2
In formulas I and II, R represents hydrogen, trifluoromethyl, halogen (including fluorine, chlorine, bromine, iodine), azido

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Cyano, amino, lower alkylamino, di-lower-alkylamino, or lower alkyl wherein each of the lower alkyl groups has up to 8 carbon atoms.

In formulas I and II, R means mass, low Alkyl with up to 8 carbon atoms, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, lower alkanoyl or lower Alkenoyl with up to 8 carbon atoms each, aroyl with up to 10 carbon atoms, substituted aroyl with 7 to 12 Carbon atoms, aralkyl with 7 to 12 carbon atoms, substituted aralkyl with 7 to 12 carbon atoms, aryloxyalkyl with 8 to 12 carbon atoms, or substituted Aryloxyalkyl of 8 to 12 carbon atoms, each of the substituted aroyl, substituted aralkyl and substituted Aryloxyalkyl groups as substituents 1 or 2 halogen, Have alkoxy and / or alkyl groups, each of the alkoxy and contains alkyl groups up to 6 carbon atoms.

In the case of compounds with a bronchodilator effect

12 4

R and R are preferably hydrogen and R is preferably a substituted benzyl group, most preferably for a Haiogenbenzylg ^ group, like 4-chlorobenzyl.

In the formulas I and II, the radicals R and R are ring substituents which are bonded to a carbon atom are. R and R stand for hydrogen, methyl and / or ethyl. The radicals R and R can be attached to any ring carbon atoms be bound.

In formulas I and II, η denotes an integer, namely 1, 2 or 3.

In formulas I and II, Z stands for the 0xo (= 0), or imino (= NH) group.

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The compounds of the formulas I and II are bases. They form salts with acids j. The invention includes not only the substances of the formulas I and II, but also their acid addition ^! salts. The pharmaceutically acceptable acid addition salts are those in which the anion: is not essential for toxicity or pharmacological activity

I j

ι did the salt contributes. They thus represent the pharmacological

j see equivalents of the bases of formulas I and II. For the

• They are preferred for medical use. In some cases ^;

I do they have physical properties * which their use i dung for pharmaceutical formulation purposes cheaper er j

! lets shine. The properties are, for example, -j

^! wise about solubility, lack of hygroscopicity, compressibility j

I ability with regard to the manufacture of tablets and

i compatibility with other constituents shared with the ! Substances can be used for pharmaceutical purposes, The salts are prepared by reacting a base of formula I or formula II with an acid. This is preferably done by bringing into solution. You can also by metathesis or treatment with an ion exchange resin under conditions under which the j Anion of a salt of the substance of formula I or formula II

is replaced by the anion of another salt. This is done under conditions that allow separation of the undesired species _; ; for example by precipitation from the solution or extraction into a solvent, or elution from or retention on an ion exchange resin. Pharmaceutically acceptable acids for salt formation from the substances of the formulas I and II include hydrochloric acid and hydrobromic acid. Hydroiodic acid, citric acid, acetic acid, j benzoic acid, phosphoric acid, nitric acid, mucic acid, j isethionic acid, glucaric acid (glucosaccharic acid), palmitic acid, heptanoic acid, and other acids.

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- 12 -

The substances of the formula I and of the formula II in which R stands for hydrogen, are amphoteric and also form salts with bases. Accordingly, those are pharmaceutically acceptable Metal, ammonium and amine salts of the substances of the formulas

I and II, in which R is hydrogen, are encompassed by the present invention. Again, the definition is one pharmaceutically acceptable salt substantially in accordance with the previous discussion of pharmaceutically acceptable acid addition salts. In this case, however, it is the cation that did not make a significant contribution to toxicity or has pharmacological activity. The cation of these salts generally contributes to their usefulness active ingredients. This is for pharmaceutical reasons and is the result of the physical properties of the salt. As in the case of the acid addition salts, the salts by reaction of the substance of the formula I or of the formula II, in which R is H, with the base, preferably in solution in a reaction-inert liquid medium. You can also get it through metathesis or through treatment with produce an ion exchange resin under conditions under which the cation of a salt of the substance of the formula I or

II is replaced by another cation, and among which the undesired species, for example by precipitation from the Solution or by extraction into a solvent, or by Eluting or by retention on an ion exchange resin. Suitable metal salts include the sodium-potassium, Calcium, barium, magnesium, aluminum and zinc salts. The ammonium and amine salts are in the same way Part of the invention. These salts are made from corresponding starting materials in essentially the same manner as the metal salts manufactured. One can use ammonia, ammonium hydroxide, ammonium salts, various amines, amine salts or quaternary Use ammonium salts and hydroxides as reactants.

Suitable classes of amines include:

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(a) primary, secondary or tertiary alkyl and alkenyl amines having 1 to 22 carbon atoms

and with up to 3 carbon-carbon doubles! - ties;

(b) primary, secondary substituted by hydroxyl and tertiary alkyl amines having 1 to 22 carbon atoms and having up to 3 hydroxyl groups;

(c) the alkylenediamines having 1 to 6 carbon atoms; and

(d) the heterocyclic amines having 3 to 10 carbon atoms and having 1 to 3 heteroatoms, at least one of which is nitrogen.

Preferred amine salts are those of the alkylamines with up to 6 carbon atoms or alkylamines substituted by hydroxyl groups with up to 6 carbon atoms and up to 3 hydroxyl groups and those of the alkylenediamines with 2 to 4 carbon atoms, j Suitable amines include ethylenediamine, triethylamine,; tris (2-hydroxyethyl) amine, 2-hydroxyethylamine, piperidine, and ι like that. j

The compounds of formulas I and II are useful as bronchodilator and antiallergic agents in inhibition the immediate hypersensitivity reaction, as vasodilatoric agents and as inhibitors of enzyme phosphodiesterase. According to the invention, bronchodilation or vasodilation can be induced in mammals. Treatment too allergy in mammals is possible. According to the invention, this is done with the aid of a dose of the compounds according to the invention, the bronchodilator or vasodilator effective is or an inhibition effect over the immediate

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Causes hypersensitivity reaction. The compounds can be administered orally, parenterally, topically by inhalation, or rectally will. Effective doses range from about 0.03 mg / kg body weight to the maximum, non-toxic Dose that can be administered without undesirable side effects. The maximum non-toxic doses can be determined by pharmacological Standard methods can be determined using mice. The value for the following examples Substance prepared 3 or 4 is approximately 250 mg / kg body weight per os in mice. This connection is for you Use against asthma preferred.

It is believed that the compounds of the formulas I and II and their salts cause the degranulation of sensitized mast cells inhibit. It is believed that immediate hypersensitivity reactions, such as asthma, hay fever, allergic rhinitis, urticaria and food allergy Reaction of the immunoglobulin E, which is sometimes called reagin-like Antibody is referred to, are mediated with an antigen of the cell membrane of a mast cell, with innerhalt The mast cell reactions are initiated that eventually become mediators, such as bradykinin, histamine, or serotonin Release "slow reacting substance-Α" (SRS-A). The mediators cause changes in the so-called end organs, such as the Airways, blood vessels, skin and mucous membranes. This leads to the symptoms of an allergic attack. It is believed that the substances according to the invention j prevent the release of mediators. This prevents the j allergic attack. They are therefore used for prophylactic purposes Treating patients who have hypersensitivities of previously have mentioned types, useful. They also inhibit acute allergic attacks such as asthma, hay fever, allergic ones Rhinitis, urticaria and food allergies. Preferred Connections are characterized in particular by the

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they were orally active, had very low toxicities and had a bronchodilatory effect. She ; are therefore useful for treating asthma attacks. They are also used prophylactically in hypersensitive patients; Patients, including those whose hypersensitivity is manifested by asthma, are useful. The connections ! are inhibitors of phosphodiesterase in the rat lung, > and they are also peripheral vasodilators. The vasodilatory capacity of preferred compounds of the invention is the perfused dog hindleg similar in 'the preparation of the papaverine.

Preferred compounds for anti-allergy and anti-asthma treatment are those substances of the formula I in which R is the substituted aralkyl group, preferred for the halobenzyl group. It is most preferably those compounds of the formula I in which R is

1 2 is the halobenzyl group and R and R are hydrogen. These substances are orally effective hypersensitivity Reaction inhibitors and bronchodilators. You own one Long-term effect. A preferred species is 4- / T (4-chlorophenyl ) methyl7-6,7-dihydro-3H-imidazoA, 2-a / purin-9 (4H) -one (see example 3 here). This connection is in anti-hypersensitivity and bronchodilator effect stronger than aminophylline, has a longer duration of action and brings reduced side effects, for example a reduced one Stimulation of the central nervous system, with itself. This substance can be used in bronchodilator Use in a very similar way as the aminophylline, taking into account the increased effectiveness and the longer duration of action is. Oral or parenteral doses ranging from 0.03 to 250 mg / kg of this substance can be used. In humans, the estimated, effective single dose is im Range from 10 to 500 mg orally, you can take two to six times

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administered daily. The substance can also be administered topically ■ with the aid of a suitable device in a single dose; which is 20 to 200 mg in humans and two to six times _; given daily. Similar dosage regulations can also be used when using this compound as an anti-hypersensitivity agent in asthma or allergic rhinitis.

In the activity cage test using a mouse to which oral doses were administered, the substance according to Example 3 resulted in neither a stimulation effect nor a depression effect. Doses of 10, 20, 40, 80 or 160 mg / kg body weight were used in this test. In the same test, the aminophylline stimulated at doses of 15, 30 and 60 mg / kg body weight. The effective anti-hypersensitivity dose (ED ₅₀ ) in the rat which was treated orally in the passive cutaneous anaphylaxis test with the substance according to Example 3 is 34 mg / kg body weight. That for the aminophylline is approximately 60 mg / kg body weight. The hypersensitivity inhibitory effect of the substance according to Example 3 persisted for a period longer than 6 hours. In contrast, the effect of the aminophylline decreased to a non-significant level within 6 hours. The bronchodilatory effect measured in vitro on the guinea pig tracheal coil (ICg ₀ , concentration which leads to 50% relaxation of the spontaneous tone) has a value of 14 C ⁷ VmI for the compound of Example 3 and a value of 14 C 7 VmI for aminaphylline 19th

The actual intermediates for making the compounds of the formulas I and II are the substances represented by the formula III. Herein, B denotes hydrogen or

It

the ON, H ₂ N, or HCNH group. The compounds of the formula

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III and their acid addition salts are part of the present invention. Some compounds of the formula III have a blocking or stimulating effect on the smooth muscles. Mention should be made here of the 7-amino-8-Z "(4-chlorophenyl Jmethylj e-formylamino-Za-dihydroimidazo ^ l ^ - ^ pyrimidin-BiSHy-one and; the 7-amino-2,3-dihydro-6- nitroso-8- (2-phenoxyethyl) imidazo- ■ A, 2-a7pyrimidin-5- (8H) -one. Those compounds in which! B stands for hydrogen or the ON group are derived from the j through R ⁶ and R ⁷ substituted 2-methylmercaptoimidazolines, 2-methylmercapto-3,4,5,6-tetrahydropyrimidines or 2-methylmercapto-S ^ .Be-tetrahydro-IS-diazepines are produced. These are represented by the formula IV. The production takes place by their Reaction in the presence of a base with ethyl cyanoacetate, Äthyloximinocyärfacetat, malonitrile, or Oximinomalononitril. The last two reactants mentioned lead to the intermediate products in which Z stands for the imino group. In the formulas III and IV the symbols n, Z, R and R have the same Meanings as given above. R in formula III has the same meaning as R in formula I.

III

IV

The intermediates of the formula IV are according to known procedures by reacting carbon disulfide with the appropriately substituted ethylenediamine, trimethylenediamine or tetramethylenediamine, followed by etherification of the corresponding

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chenden 2-mercaptoimidazoline, 2-mercapto-3,4,5,6-tetrahydro-; pyriraidins or 2-mercapto-4,5,6,7-tetrahydro-! ^ - 1,3-diacezpins. _t

The following discussion of the synthesis procedure; of the substances of the formulas I and II is mainly aimed at those substances in which η is 1 and R ⁶ and R are hydrogen. Nevertheless, the method is equally applicable to all compounds. The process is shown schematically below. R ¹ and R ⁸ have the same meanings as described above with reference to formulas I and III.

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3 = ■

co cc

3Ξ · 0Ο CO

ZZL O

CM

CO

cc

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Bring ammonia or a primary amine with 2-methylmercapto-i imidazoline to the reaction. This gives 2-aminoimidazoline,;

8 ί

in which the amino substituent of the formula R NH- corresponds. The latter compound is preferably made into one without isolation; Condensation reaction with Äthyloximinocyanacetat brought to implementation. This gives a 7-amino-2,3-dihydro-8-R -6-nitroso-imidazoΛ> 2-a / -pyrim ^ din-5 (8j ^) - one, which is represented by formula V in the reaction scheme. This compound is the intermediate of the formula III, in which B is ON-, Z is oxo, η is 1 and R ⁶ and R ^{7 are} hydrogen. The condensation reaction is carried out in an anhydrous, inert, liquid reaction medium under anhydrous conditions in the presence of a strong base capable of forming the anion of the aminoimidazoline intermediate. If you use a lower alkanol, such as ethanol, isopropanol or Buta-j no! as a solvent, sodium ethylate or potassium tert-butylate is a satisfactory base. Other alkali metal alkylates, amides, or hydrides can also be used. For example, sodium amide can be used with liquid ammonia or an aprotic liquid medium, and sodium hydride in an aprotic liquid medium. The reaction leads to the intermediate products of the formula V. High yields are obtained

th when R is from about 75 to 100% of aralkyl or \ substituted aralkyl. A preferred alternative way of working in the event that R represents an alkyl or alkenyl group j consists in using ethyl cyanoacetate instead of ethyloximinocyanacetate. The 7-amino-2,3-dihydro-8-R ⁸ -imidazo _J ri »2-a7pyrimidin-5 (8] i) -one (formula III, B, R ⁶ , R ⁷ = H, η = 1) , Z = Oxo) is then nitrosated with sodium nitrite in aqueous acetic acid. The intermediate products of the formula V are obtained here.

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In the manufacture of the substances of the formula I, the second stage of the process comprises the reductive formylation of the nitroso group of the substance of the formula V. This gives the monoformylated diamino substance of the formula VI. This is the intermediate of the formula III, in which B is HCONH-, Z is Oxo, η is 1 and R ⁶ and R are hydrogen. The reductive formylation is carried out in formic acid as the reaction medium. In this case, either a catalytic reduction is carried out using a palladium catalyst on carbon, or sodium dithionite as the reducing agent. In this operation, the nitroso compound of the formula V is preferably dissolved in 97% formic acid. This may require 10 to 30 ml of 97% formic acid per gram of formula V substance. It is also possible to use other equivalent formylating reaction media. Using catalytic hydrogenation, hydrogen pressures from atmospheric pressure up to about 7 kg / cm (100 psi) are useful, using a sufficient amount of palladium on carbon catalyst to make the hydrogenation complete. It is beneficial to use a pre-calibrated device so that hydrogen absorption can be measured on a molecular basis. If the calculated amount of hydrogen is not taken up before the uptake of hydrogen ceases, a fresh portion of catalyst is added and the hydrogenation is continued. The hydrogenation is carried out at room temperature, although the process is exothermic, resulting in a slight to moderate increase in temperature, depending on the batch size, during the initial stages of the hydrogenation. Temperatures of 20 ^° C. to 40 ^° C. are favorable. The hydrogenation usually only requires a relatively short period of time of 15 minutes to 1 hour, depending on the batch size and the particular device used.

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Sodium dithionite (Na ₂ S ₂ O ₄ ) is used as a reducing agent
in reductive formylation, it just becomes one
Solution of the intermediate of formula V in concentrated
(87 to 97% w / w) formic acid was added. One uses
little more than a stoichiometric amount, however, are large
Surplus is not required as the reduction is faster than
the decomposition of the sodium dithionite takes place. !

i If one wishes to reduce an aromatic nitroso compound to the corresponding I the aromatic amino compound, two j molar proportions of sodium dithionite as the stoichiometric amount are to be regarded j. This is a new and surprising process, given the fact that
that according to the prior art, this reducing agent was used only 'borrowed in basic solution. It is namely loading. knows that sodium dithionite decomposes in acidic media. ^! Some sulfur is produced as a by-product during the reaction

educated. The process is generally applicable to the reduction of aromatic nitroso compounds of the formula ArNO to aromatic amines i of the formula ArNH ₂ , where Ar is an aromatic carbocyclic group or an aromatic heterocyclic group, j

The cyclization of the formyldiaminoimidazopyrimidinone
Formula VI to the 4-R ⁸ -6,7-dihydro-2-R ⁹ -3F [-imidazon, 2-a7purin-9 (4] i) -one of the formula VII is converted either by heat alone | effect or by the action of a dehydrating agent, i such as polyphosphoric acid or an anhydride, achieved. The latter ¹

Q j

can also be used as a reactant for the introduction of the 2-R -Substi- j tuenten in the substances of the formula VII with the help of a
Acyl exchanges are used with the formyl group during the cyclization process. If an anhydride of the formula j (R ⁹ CO) ₂ O, in which R ^{9 is} lower alkyl having 1 to 8 carbon atoms or trifluoromethyl, is used, as cyclization
or dehydrating agent in the presence of pyridine as a reactant

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tion medium, the anhydride corresponding R substituent is introduced. For example, isobutyric anhydride leads to a 2-isopropyl substituted product and trifluoroacetic anhydride leads to the 2-trifluoromethyl product. The reaction is j preferably carried out at the reflux temperature of the reaction mixture, or in the range of about 130 ⁰ C to 170 ⁰ C to obtain quantities suitable of anhydride and pyridine as a solvent, based on the amount of the converted intermediate of formula VI used. However, at least a molar proportion of anhydride is used.

For the pyrolytic cyclization of the formylamino compound

of the formula VI to the product of the formula VII, in which R is hydrogen, a temperature of approximately 260 ^° C. is used after the intermediate of the formula VI has been diluted with a sufficient amount of dimethylformamide to produce a fluid, non-viscous liquid when heated to obtain. During the process the diluent is removed by evaporation; this results in the formation of the desired product as a residue cake, which is usually brown in color. Alternatively, one can use the cyclization to BiI-

preparation of substances of the formula VII, in which R is H, Triethyl orthoformate in conjunction with an alkanoyl anhydride dehydrating agent use. The ethyl orthoformate is suppressed the acyl exchange reaction that occurs when the anhydride is used with pyridine. Nonetheless, it is Product sometimes due to low percentages of the

9 9

hydride (R CO ^ O contaminated 2-R -substituted product derived from. An appropriate amount of a liquid anhydride is used in conjunction with approximately 2 to 5 molar proportions of ethyl orthoformate per molar portion of formylamino derivative. Again, the process is carried out at the reflux temperature or approximately within the Range from 13O ⁰ C to 17O ⁰ C carried out.

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4 In the preparation of the substances of the formula I ₁ in which R is alkanoyl, aroyl or substituted aroyl, a favorable method is to use the intermediate of the formula VI, in which R is a hydrogen atom, and the desired alkanoyl, aroyl or to use substituted aroyl anhydride as a dehydrating or cyclizing agent in the conversion of the intermediate of the formula VI into the product of the formula VII as described above. If pyridine is used, an R substituent which corresponds to the anhydride used is also introduced. The same conditions as described above are used. If, for example, 7-amino-6-formylamino-2,3-dihydroimidazo- / ri, 2-a / pyrimidin-5 (8H) -one is refluxed with equal volumes of pyridine and isobutyric anhydride, the 6,7-dihydro- 2- (1-methylethyl) '4- (2-methylpropionyl) -3iH-iniidazo-Z'l, 2-a7-purin-9 (4ji) -one formed.

A compound of the formulas I or II in which R is H can be acylated in a conventional manner to prepare alkanamides, arylcarboxamides or ring-substituted arylcarboxamides using the corresponding carboxylic acid halide, anhydride, or mixed anhydride. Preferred conditions are those comparable to those known to be effective in acylating a weakly basic aniline derivative. In any case, it should be determined whether the N ⁴ - (formula I or II, in which R ^{4 stands} for alkanoyl, aroyl or substituted aroyl) or the N -acyl product is formed.

The products of the formulas I and II, in which R is different from hydrogen, are in a simple manner by reacting an alkali metal salt of a substance of the formula I or II in which R ^{1 is} a hydrogen atom with a reagent of the formula AX, in which A has the same meaning as before and X

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a reactive ester group such as chloride, bromide, iodide, phosphate] or sulfate. You get the required; Lent Al kaiimetall salt by reaction of the substance of the formula j I, in which R is H, with a strong Al kaiimetal1 base in an inert organic solvent, such as an aromatic or aliphatic hydrocarbon, ether, alcohol, or amide, such as dimethylformamide. Suitable bases include sodium hydride, sodium methylate, potassium tert-butylate, sodium amide or lithium hydride. Suitable reactive esters include butyl bromide, methyl iodide, dimethyl sulfate, triethyl phosphate, hexyl bromide, tert-butyl chloride, benzyl bromide, 2-phenoxyethyl chloride, 4-fluorobenzyl bromide, 3-chlorobenzyl bromide and 2-methoxybenzyl chloride. Higher temperatures in the range from approximately 80 to 150 ^° C. are desirable.

2 The compounds of the formula I in which R is hydrogen,

can be halogenated under normal conditions. As a result; a chlorine, bromine or iodine atom is introduced, whereby one

Compounds of the formula I are obtained in which R is chlorine, bromine or iodine. For example, treating a

2 Solution of a product of the formula I, in which R is hydrogen, in acetic acid solution with elemental bromine to introduce a bromine atom in the 2-position. N-bromosuccinimide, N-chlorosuccinimide or N-chloroacetamide can also be used for halogenation. Other suitable halogenating agents and conditions include phosphorus oxychloride or phosphorus tribromide to convert a 2-hydroxy group to the corresponding 2-chloro or 2-bromo compound. The 2-chloro-compounds can be prepared by reaction with concentrated (47%) aqueous HJ at ⁰ ° C or by converting the Trimethylammoniumsalzes, followed by reaction of this product with KHF2 at 5O ⁰ C in the presence of any diluent, into the corresponding 2-iodo - Or 2-fluorine compounds are transferred.

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The 6,7-dihydro-3H-imidazo- / 2 '1': 5,67-v-triazole - / 4,5-d / -pyrimidin-9 (4HJ-ones of the formula II substituted in the 4-position are eliminated the intermediates of the formula V converted into an amino group by reduction of the nitroso group. This is shown in the above reaction scheme for the compound of the formula VIII, which is the intermediate of the formula III, wherein B for H ₂ N-, Z for oxo, η is 1 and R ⁶ and R represents hydrogen, is. the reduction may be in the same manner as the reductive formylation in the preparation of intermediates of formula VI are performed, except that the formic acid is replaced by another reaction medium is inert under the reaction conditions. An acidic medium is preferred for the catalytic reduction. Aqueous mineral acid is very useful as the reaction medium. The use of dilute, aqueous hydrochloric acid is preferred. Other methods that are known to those skilled in the art for reducing a nitroso group into an amino group are known are applicable. The diamino intermediate of the formula VIII obtained is then converted into the product of the formula IX. This is done by treatment under conditions commonly used to diazotize aromatic amines, for example using sodium nitrite and aqueous hydrochloric acid. It is not necessary to isolate and purify the intermediates of the formula VIII. The solution resulting from the reduction can, after the catalyst has been separated off, treated with an aqueous solution of sodium nitrite and then. simply be evaporated. This gives the desired product, which is then purified by recrystallization.

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According to the invention, intermediate products of the formula III and a process for converting them into compounds of the formulas I and II are thus created. This process consists in that first the aminopyrimidine compound of the formula III, in which B is hydrogen or the ON group, by condensation of malonitrile, oximinomalonitrile or a lower alkyl ester of cyanoacetic acid or oximinocyanoacetic acid with a 2-R ⁸ NH-I , 3-Diazacycloalk-2-en and then! in the case where cyanoacetic ester or malononitrile is used as the reagent, the nitroso group is introduced by reaction of the product with nitrous acid and then the nitroso compound of the formula III (B stands for ON-) in the case where a compound of the Formula I is desired, reduced under formylation conditions and, in the case in which a compound of the formula II is desired, reacted under non-formylating conditions, the monoformyldiaminopyrimidine of the formula III, in which B stands for the HCONH group,; or the diaminopyrimidine of the formula III, in which B stands for the H ₂ N group, is obtained, and then the V compound of the formula III (B = H ₂ N- or HCONH-) is cyclized, a compound of the formula I or a compound of formula II is obtained, wherein the cyclisation for preparing the compounds of formula I by heating the substance of formula III (B = HCONH-) to a temperature of about 26O ⁰ C in the presence of a sufficient quantity sufficient of a to form a liquid reaction mixture Performs amount of a reaction-inert diluent, or, alternatively, the substance mentioned in the presence of a cyclodehydrogenating agent such as polyphosphoric acid or carbocyclic acid anhydride to a temperature in the range of about 13O ⁰ C to 170 ⁰ C, and, in this process, the cyclization for production the compound of the formula II by diazotizing the substance of the formula III (B = NH ₂ ) by treatment with a diazotizing agent el under- conditions of which are known

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is that they are useful for the diazotization of aromatic amines \ , treated and then, if a compound of the;

4 Formula I or II is desired _s in which R stands for alkanoyl, aroyl or substituted aroyl, a substance of the formula I \ or II, in which R stands for hydrogen, with an acylie- \

converting agent that said alkanoyl, aroyl or J substituted aroyl group under conditions which are necessary for the production ■ development of amides from aromatic amines are known,

2 leads. Compounds of the formula I »where R is a water ' Substance atom stands, can be effective with one known for the introduction of a chlorine or bromine atom into an aromatic compound!

Haiogenating agents are treated to be a substance of the

2
To form formula I in which R is chlorine or bromine.

The chlorine or bromine compound can then be converted into the corresponding Fluorine or iodine compound are transferred. Furthermore, substances of the formulas I or II, in which R is hydrogen by treatment with a strong alkali metal base be converted into an alkali metal salt in a reaction-inert, liquid reaction medium. The obtained alkali! metal salt can be mixed with a reactive ester of the formula AX, | for example a halide, phosphate or sulfate: This gives a substance of the formula I or II in which R is the group A as defined above.

In the following procedures, the temperatures are expressed ^{in 0 C.} The melting points are values that have been corrected according to the US Pharmacopoeia, if the information: (Corr.) Is found. The spectral characteristics expressed by nuclear magnetic resonance (NMR) relate to the chemical shifts (d "), expressed in parts per million (ppm) against tetramethyl si! An as standard. The relative area given for the various shifts corresponds to the number the hydrogen atoms in the respective substituent.

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Lent multiplicity is given as a broad singlet (bs), singlet J (s), multiplet (m), doublet (d), triplet (t) or quadruple (q). When indicated, the coupling constant is also indicated. The notation used is: '■ NMR (solvent): / (relative area, Mui tipiizität, J-value i and in some cases an indication of the structural characteristics). Abbreviations used: EtOH (ethanol), HQAc (acetic acid), Ar (aromatic group), Et ₂ O (ethyl ether), DMF (dimethylformamide), MeOH (methanol), v-PrOH (isopropanol), (OEt) ₃ CH (ethyl orthoformate ), Nujol (mineral oil), DMSO-dg (deuterodimethyl sulfoxide), IR (infrared), KBr (potassium bromide), EtOAc (ethyl acetate), d (decomposition). Other abbreviations are common and have fixed meanings. The infrared spectra described only include the absorption wavelengths (cm ~) which are valuable for identifying functional groups. In some cases, structural characteristics are given. Unless otherwise stated, KBr was used as the diluent in the IR spectroscopic determinations.

example 1

7-Amino-2,3-dihydro-8 - / "(4-chlorophenyl) methyl 17-6 -nitro so -imidazo / *!, 2-a7pyrimidin-5 (8H) -one

To a solution of 62.30 g (0.44 mol) of 4-chlorobenzylamine in 500 ml absolute ethanol (via 4A molecular sieve aluminosilicate desiccant dried) are given 107.40 g (0.44 mol) of 2- (methylthio) -2-imidazoline hydroiodide. One heats up the mixture on a steam bath in an open flask for Boil and slowly boil away approximately 150 ml of the ethanol over the course of 2 hours. While this solution is still hot it is added to 1.76 mol of sodium ethylate in 1650 ml of absolute EtOH. To the resulting stirred, basic solution

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of 2 - one / "(4-ChI orphenyl) methyl_7ami no-2-imi dazol i ns then, 61.85 g (0.44 mol) of crystalline (melting point 129 to 131 ⁰ _C): Äthyloximinocyanacetat portionwise to is maintained. The light yellow solution is refluxed for 3 hours and then cools to room temperature. The yellow precipitate is collected, washed with J ^ -PrOH and partially air-dried. The moist sodium salt is dissolved in 2000 ml of H ₉ O and acidified with glacial acetic acid The healing pink precipitate is filtered off and dried
overnight in air, then in a vacuum at 100 ^° C. in the oven. This gives 103.05 g (77 I) pink powder with j melting point 238-241 ⁰ C (d). Recrystallization of this material from DMF-EtOH gives red crystals with a melting point; 241 ⁰ C (d). !

Analysis : Found C, 50.68; H 3.93; N 22.59 IR (Nujol) 1600-1700 cm " ¹ (C = O, C = N), 3550 cm" ¹ (NH).

NMR (DMS0-d ₆ ) 3.90 / _ ~ 4, m, (CH ₂ J ₂ J, 5.15 {2, s _s C ^ 7.32 (4, s, Ar).

example

7-Amino-8- / T (4-chlorophenyl) methyl 7-6- (formylamino) -2,3- dihydro-J imidazo / "1,2-a7-pyrimidin-5 (8H) -one

A sample of 40.50 g (0.133 mol) is not recrystallized ^! Sized nitroso compound of Example 1 in 950 ml of 97% strength i HCOOH and 25.0 g of 5% Pd / C-50 % H ₂ O are added under a CO ₂ atmosphere. The mixture is on a Parr hydrogenator!

ο reduced with an initial pressure of 3.5 kg / cm (50 psig).

About 90 % of the calculated H ₂ consumption takes place in less! than 15 minutes, the temperature increasing ^{by 12 ° C.} Of the
The rest is absorbed over the course of 3 hours. Then prevails

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MJ-440!

room temperature again. The catalyst is filtered off and the colorless solution obtained is concentrated in vacuo to give a thick syrup. The syrup is dissolved in 500 ml of water and neutralized with concentrated NH * OH while cooling. The whitish solid is filtered off and air-dried. This gives 41.90 g (98%) of product with melting point 272-275 ⁰ C (d). Umkristal1 isation from MeOH-v-PrOH affords white crystals with melting point 275, ⁰ ° C (d) (corr.).

analysis

found: C, 52.74; H 4.46; N 22.01

IR (Nujol) 3420 cm " ¹ (NH), 3340, 3200 cm" ¹ (NH ₉ ), 1680, 1620, 1580 cm (formamide, lactam, C = N)

! NMR (DMSO-d ₆ ) 8.38-7.72 (2, multiple signals for NhICF [O conformers), 4.00 / ~ 4, m, (CjH ₂ ) ₂ 7, 5.90 (2, s, ClH 7.25 (4, s, Ar).

example

4- / ~ (4-chlorophenyl) methyU-6,7-dihydro-3H-imi dazo / l , 2-aJ- purin-9 (4H) -one

A suspension of 45.88 g (0.14 mol) of the formylamino derivative from Example 2 in a mixture of 130 ml of acetic anhydride (1.4 mol) and 65 ml (OEt) ₃ CH (0.39 mol) is refluxed for 5 hours held (after 30 minutes a solution is formed). Concentrate in vacuo to approximately 1/4 of the original volume to an _oil-s which is dissolved in 300 ml of water. The mixture is treated with activated charcoal and filtered. The clear filtrate is made with conc. NH ₄ OH neutralized. The white precipitate is filtered off and dried in the oven in vacuo,

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28.06 g (66 %) of whitish solid with a melting point of 285 to 290 ^° C. being obtained. Umkristall isation from DMF-V-PrOH gives off-white crystals with melting point 289-293 ⁰ C; corrected Melting point: 284.0 to 285, O ⁰ C. When the NMR shows that this material contains as DMF solvate, this can of suspended solid in ETNO and then another drying are removed by stirring.

analysis

Found: C, 55.96; H 4.40; N 23.16

IR (Nujol) 1620 cm " ¹ (C = N), 1680 cm" ¹ (C = O)

NMR (DMS0-d ₆ , ppm) 3.84 / "4, m, (CH ^) ₂ 7, 5.10 (2, s, CH ₂ AR),

7.50 (4, s, Ar), 7.91 (1, s, CHI).

The Hydrochloridsalζ of the product is prepared according to Example 3 by dissolving 21.7 g of this material in 75 ml of 3N HCl. The dissolution is not yet complete while the precipitation of a white solid begins. 100 ml of water are added and the mixture is heated to dissolve the precipitate. The solution is treated with decolorizing charcoal and filtered. Then 150 ml of isopropanol are added to the warm filtrate. The product is precipitated on cooling. Collecting the product, and dried overnight in a vacuum oven at 80 ⁰ C. The yield was 17.05 g, mp 249.0 to 250.0 ⁰ C (d) (corr.)

analysis

Found: C, 49.75; H 3.83; N 20.92

'■; η -e.

MJ-440

Example 4 Pyrolysis of the product according to Example 3

It is a slurry of 7.20 g (0.022 mol) of the product of Example 2 in a small volume of DMF in a befindliches at 260 ⁰ C ■ oil bath. The DMF evaporates very quickly = heat up; the residue cake with constant stirring for 12 minutes. The light brown solid that remains has a melting point of 280 to 285 ^° C. Weight: 6.36 g (93 %). Recrystallization from DMF gives a material which is identical to the material obtained in Example 3.

The 4-chlorobenzylamine in the method according to Example 1 was replaced by various amines, and the nitrosoimidazopyrimidinones obtained were converted into the corresponding formylaminoimidazopyrimidinones according to Example 2, which then either according to Example 3 or Example 4 were converted into one of the products according to the invention. The identifying data and the manufacturing conditions are in the following Table listed.

809833/1063

Examples 5-13

ο ro cn

6,7-dihydroimidazo / 1,2-a7purin-9- (4H) -ones of the formula I, n = 1, R ¹ , R ² , R ⁶ , R ⁷ = H

at
game
No. R ⁴ NS up. ⁰ C
rr,) , 0 Metho de OO υ 3-chlorobenzyl 262 , 0-267 , 0 Ex .3 09833 / 6th 2-chlorobenzyl 292 , 0-293 Ex .3 __i
ο cn
Ui 7th 3,4 dichior 279 , 0-280 Ex .3

benzyl

4, fluorobenzyl HC1 salt

2-methoxybenzyl

296.0-298.0 251.0-252.0

228.5-233.5 d * Example 4 solvent element

% DMF

% DMF

% MeOH

Example 4 71 %

DMF
MeOH-i-PrOH

NMR

IR

C 56.05 (DMSO-d,) 3.89 (4. m) 760, 800, 1400

H 4.14 5.15 (2, s), 7.48 (4, m), 155O ₅ 1625 * 1700,

N 23.20 7.98 (1, s), 13.5 2600, 2880, 2975,

(1, bs) 3110 j

C 55.60 (DMSO-d,) 3.84 (4, m) 756, 1295, 1360,

H 4.01 5.20 (2, s), 7.42 (4, m) 1550, 1620, 1700,

N 23.21, 8.01 (1, s), 13.4 (1, bs) 2880, 2960, 3100

C 50.09 (DMSO-d.) 3.86 (4, m), 770, 114O ₅ 1305

H 3.29, 5.10 (2, s), 7.54 (3, m), 1440, 1480, 1560,

N 20.53 7.89 (1 _s s) ₉ 13.4 (s, bs) 1635, 1700, 2900,

3140. ,

C 58.98 (DMSO-d,) 3.85 (4. m)
H 4.30 5.14 (2, s), 7.49 (4, in) () ()

,, (,),, (,), N 24.41 8.01 (1, s), 13.5 (1, bs) 3130

835, 1220, 1450 155O ₅ 1625, 1690

% 1n HCl-NI-LOH C 58.62 (DMSO-d,) 3.79 (3, s)
^H H 5.18 4.15 (4>), 5.39 (2, s) () ()

755, 1240, 1292 1490, 1550, 1610

N 23.23 7.20 (4, ni), 8.22 (1, s) 1700 _s 2600, 3130

example
No.

M.p. ⁰ ° C
(corr.)

method

( η ! ¹¹ 2- (3,4-dimethoxy-
pheny-ethyl 218 , 0-224 , 0 * CD
OT
ω ι
[ 12 2- (phenoxy) -
ethyl 223 , 5-224 , 5 ■ ***>. ο j 13 isobutyl 230 , 5-231 , 5

Removing solvent elemene L-I for the Umkri-tarana- ^deuterons stall ization analysis

NMR

IR

-ti CD -P CD

ο ro cn

Example 4 52

2-pyridylmethyl 258.0-260.0 * Ex. 4 50 % DHF

C 56.28 (DMS0-d _fi ) 3.80 (4. m) 796, 1360, 1472

H 4.38 5.18 (2, s), 7.24 (2, m), 1560, 1610, 1705,

N 29.95 7.76 (1, m), 7.85 (1, s), 2980, 3130, 3520 8.70 (1. m) i

1n HCl-NH-OH C 54.80 (DMSO- (U 2.90 (2, m), 760, 1265, 1520, ⁴ H 5.68 3.78 (6, s), 3.90 (9, m), 1630, 1690, 2970 N 18.55 4.70 (2, m), 6.90 (3, m), ι

7.98 (1, s) j

Ex. 3 58% MeOH

Ex. 4 34 % i ~ PrOH C 60.56 (DMSO- (U 3.90 (4, m), 690, 752, 1240, H 5.09 4.37 (4, m), 7.26 (5 , m), 1500, 1625, 1705, N 23.48 8.04 (1, s) 2960, 3060, 3120

(DMS0-d ₆ ) 0.92 (6, d

C 56.53

H 6.54 6.5 Hz) ° 2.32 (1, m),

N 29.84 3.82 (6, m), 7.90 (1, s)

765, 895, 1300, 1436, 1550, 1620, 1700, 2970

M / 19 025 - 36 -

Example 14 4 - / (4-ChI orphenyl) methyl7-2-ethyl-6,7-dihydroindazo / l »2-

A mixture of 25.00 g (0.078 MqT) of the product according to Example 2 and 50 ml of dry pyridine in 50 ml (0.388 mol) of propionic anhydride is refluxed for 3 hours. A white solid precipitates out on cooling. It is CH ₃ CPf to, filtered off the white solid, and dried in air to give crystals of melting point 278.0 to 279.0 receives ⁰ C (corr.). The material can be recrystallized from DMF-v-PrOH.

analysis

Found: C, 58.28; H 4.76; N 21.34

NMR (DMSO-dg): 1.22 (3, t, 7 * 5 Hz), 2.67 (2, 9, 7.5 Hz),

3.98 (4, m), 5.08 (2, s), 7.43 (4, m, 11.3 (1, bs).

IR: 756, 805, 1295, 1510, 1630, 1695, 3050, 3100, 3160.

Example 15

4 - // (4-ChIorphenyl) methy17-6, 7-di hydro-2-me thy! -Imidazo / "!» 2-a7 ~ purin-9 (4H) -one

The method of Example 14 is repeated, the propionic anhydride being replaced by acetic anhydride. The product is obtained in the form of a cream-colored solid with Schmeli point 311.5 to 313.5 ⁰ C (corr.). recrystallized from DMF-v-PrOH.

analysis

found: C, 56.72; H 4.36; N 22.35

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H / 19 025 - 37 -

MJ-440

NMR (0MS0-d ₆ ): 2.36 (3, s), 3.91 (4, m), 5.20 (2, s), 7.90

<4, ra)

IR: 755, 804, 1020, 1294, 1510, 1630, 1690, 3050, 3160.

Example 16

4- / ~ (2-chlorophenyl) methylI-2- (1-methylathy!) -6,7-dihydroimidazo / "1» 2-a7purin-9 (4H) -one

In the procedure of Example 1, the 4-chlorobenzylamine is replaced by 2-chlorobenzylamine and the corresponding nitrosoimidazopyrimidinone is converted by the method of Example 2 into the corresponding formylamino compound. The product obtained is then reacted with isobutyric anhydride in a mixture of isobutyric anhydride and pyridine by the method of Example 14, the desired product being obtained. This is as flocJciger, white crystalline-j ner solid with melting point 249.5 to 255, ⁰ ° C to Umkristal! Ization obtained from a mixture of chloroform and acetonitrile.

analysis

Found: C, 59.34; H 5.54; N 20.22

NMR (DMS0-d ₆ ): 2.10 (6, d, 6.5 Hz), 2.94 (2, septet, 6.5 Hz), 3.84 (4, m), 5.12 (2 , s) ,. 7.30 (4.m)

IR: 760, 1300, 1505, 1626, 1692, 2980, 3180.

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MJ-440

Example 17 ι

2-bromo-4-Z "(4-chlorophenyl) methyl7 ~ 6, 7-di hydro-SH-imidazo / i , 2-nJ- ' purine-9 (4H) -one-hydrobronnd ;

1.60 g (0.010 mol) of bromine are added to a solution of 2.00 g
(0.0066 mol) of the product according to Example 3 in 10 ml HOAc and j heated the solution obtained for 10 minutes on a steam bath. Yellow flakes fall out. These are filtered off and at the; Air dried. 3.29 g of solid with a melting point are obtained
212 ⁰ C (d). A suspension of the material CH ₃ CN _{5 is} heated; one obtains a white powder of melting point 248 ⁰ C (d), S Umkristal1 isation from DMF-CHoCN resulting fine white needles
with melting point 228.5 to 229.5 ⁰ C (d) (corr.).

analysis

found: C, 36.48; H 2.92; N 15.01

Example 18

7-Amino-8-benzyl-2,3-dihydro-6-nitrosoimidazo - / '1,2-a7pyrimidin-5 (8H) -one j

The procedure of Example 1 is repeated, the 4-chlorobenzylamine being replaced by benzylamine. The received
Product melts at 242 ^° C. (d). After recrystallization from
DMF, the yield is 68 %.

Example 19

7-Amino-2,3-dihydro-6-formylaminoimidazo / 1,2-a7-pyrimidin - 5 (8H) -one

The procedure of Example 2 is applied to the product
according to Example 18, where the title product with melting

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Ηα-440

point 268 ⁰ C (d) in a yield of 40 % . This product is fully crystallized. [

B ~ eis ρ i el · 2 <T f

6,7-dihydro-2- (1-methylethyl) -4- (2-methylpropiony1 J-3H-imidazo- j fl »2-a7purin-9 (4H) -one

The method of Example 14 is applied to the product of Example 19, the propianic anhydride mentioned in Example 14 being replaced by isobutyric anhydride. The product is obtained in a yield of 35 %. Melting point 271.0 to 273, ⁰ ° C (corr.) According Umkristal Msation from isopropanol.

Analysis found: C, 58.50; H 6.25; N 24.39

NMR (DMS0-d ₆ ): 1.20 (6, d), 1.34 (6, d), 3.00 (1, m.), 4.10

(5, m), 13.2 (1, bs)

IR: 780, 1250, 1275, 1365, 1410, 1540, 1580, 1700, 2980, 3200.

Example 21

7 - Amino - 8- / ~ (4-f Iu or phenyl) methyl7-6- (formylamino) -2,3-dihydroimidazo / ~ 2,3-a7pyrimidin-5 (8H) -one

The 7-amino-2,3-dihydro-8 - / "(4-fluorophenyl) methyl7-6-nitrosoimidazoA.2-a7pyrimidin-5 (8H) -one is prepared by the method of Example 1, whereby the one used in this example, 4-chlorobenzylamine with 4-fluorobenzylamine replaced. to 9.79 g 0.034 mol) of the product obtained with melting point 223.5 to 225.5 ⁰ C (d) (corr.) in 100 ml 97 35-acetic 15.00 g (0.086 mol) of NaoSpO «are added in portions to HCOOH at room temperature

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M / 19 025 - 40 -

MJ-440

Course of about 5 minutes. During the exothermic reaction, the color of the solution changes from dark purple to light yellow and some yellow precipitate forms. The mixture is stirred for 10 minutes and then concentrated in vacuo to approximately 25 ml. The residue is dissolved in 150 ml of water, filtered and neutralized with concentrated NH ^ OH. Collect the white precipitate, slurry in hot MeOH and filter. Upon drying in vacuo, 9.25 g (90%) of white solid is obtained with melting point of 248 to 25O ⁰ C. Recrystallization from MeOH gives white crystals, melting point 262 ⁰ C (d).

analysis

found: C, 55.20; H 4.62; N 22.87

If the formylamino compound prepared according to Example 21 is converted according to the method described in Example 4, a product is obtained which is the same as that prepared according to Example 8 Product is identical.

Example 22

7-Amino-8- (phenyl methyl ) 2,3-dihydro-6- (formylamino) imidazo- / 1,2-a7-pyrimidin-5 (8H) -one

The procedure of Example 21 is applied to the product of Example 18, this material being obtained in 86% yield. Melting point 248 to 25O ⁰ C after recrystallization from DMF-j ^ -PrOH.

analysis

found: C 58.84; H 5.38; N 24.31

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M / 19 025 - 41 -

MJ-440

NMR (DMS0-d ₆ ): 3.79 (4, m), 5.30 (2, s), 6.66 (2, bs), 7.50 i

(5, m), 8.36 (1, s), 8.82 (1, s) ^:

IR: 700 _S 740 ₉ 1305, 1500 _s 1580, 1612, 1655, 3200, 3320, 3400. ■

Example 23 4- (Phenylmethyl) -6,7-dihydro-3H-imidazoZ'l, 2-a7purin-9 (4H) -one

In the procedure of Example 3, the formylamino starting material is replaced by the product according to Example 22. The title product is obtained in 64% yield in the form of a pale yellow, crystalline solid with a melting point of 262 to! 264 ⁰ C (corr.) According Umkristall isation from DMF-J _- -PrOH.

analysis

Found: C, 62.57; H 5.15; N 26.13

NMR (DMS0-d ₆ ): 3.88 (4, m), 5.16 (2, s), 7.45 (5, mj, 8.00 (1, s)

IR: 715, 764, 1300, 1435, 1550, 1620, 1700, 3150.

Example 24

1-Butyl-4 - / '(4-ChIorphenyl) met hy IJ-6, 7 -dihydro i mi dazo / Ί, 2-a7-purin-9 (4H) -one hydrochloride

0.27 g (0.0065 mol) of NaH (57% mineral oil dispersion) are added to a stirred suspension of 1.77 g (0.0059 mol) of the product according to Example 3 in 20 ml of dry DMF. After completion of dissolution, 0.69 g (0.0065 mol) of n-butyl bromide are added and the mixture heated for 3 hours at 100 ⁰ C. Add water (200 ml) and decant the aqueous

809833/1063

M / 19 025 - 42 -

MJ-440

part of the fancy, rubbery product. The> gum is dissolved in 100 ml of In HCl and filtered. The yellow solution obtained is made basic with NH ^ OH and the gum obtained is taken up in j_-PrOH. The ^ -PrOH solution is acidified with HCl ethanol extinguisher and allowed to evaporate. The solid residue from EtOAc-CHgCN is recrystallized to give 0.65 g (28%) of pale yellow crystals, melting point 223-225 ⁰ C; (corrected melting point 205.5 to 206.5 ⁰ C (d)) is obtained. '

Analysis ;

found: C, 54.48; H 5.56; N 17.84

NMR (CDCl ₃ ): 0.83 (3, t, 6.2 Hz), 1.27 (2, m), 1.73 (2, m),

4.28 (6, m), 5.88 (2, s), 7.39 (2, m), 8.04 (1, p

IR: 770, 1310, 1480, 1500, 1608, 1660, 1720, 2710 and 3110.

Example 25

4 - / "(4-chlorophenyl) methyl7-6,7-dihydro-3H-imidazo / 2 ', 1': 5,67-vtriazo1oZ4,5-d7pyrimidin-9 (4H) -one

A solution of 1.00 g (0.0033 mol) of the product according to Example 1 in 50 ml in HCl is hydrogenated over 0.50 g of 10% Pd / C. The catalyst is filtered off and the filtrate is cooled to ⁰ ° C. A solution of 0.24 g (0.0035 mol) of NaNOo in 2 ml of HpO is added in one portion and the solution is stirred; For 30 minutes at 25 ^° C. The solution is concentrated in vacuo to a solid residue. This is slurried in MeOH and filtered. The filtrate is concentrated in vacuo and the crystalline residue is _{slurried in CH 3} CN and filtered, giving 0.60 g of pink crystals with a melting point of 252 ^° C. (d). The material is dissolved in 1 η NaOH and neutralized with HOAc. Filter the white solid

809833/1063

M / 19 025 - 43 -

MJ-440

, and it dries in the air to give 0.50 g (50%) of product is obtained with melting point 300.0 ⁰ C.

analysis

found: C, 51.30; H 4.02; N 27.65

NMR (DMS0-d ₆ + CF ₃ CO ₂ H): 4.26 (4, m), 5.57 (2, s), 7.79 (5, m) IR: 770, 810, 1305, 14, 95, 1585, 1640, 1720 and 2700.

The various nitrosoimidazole pyrimidinones used in here The various examples described can be converted into the corresponding Imidazotriazolpyrimidinones are transferred. Compare Examples 5 to 13, 18, 31 and 41, for example to 43. In the same way, the 1-substituted imidazotriazolopyrimidinones can be prepared from the corresponding unsubstituted compounds by following the steps in the examples 24 and 32 to 44 applied methods. The identifying dates and manufacturing conditions are for some of these products are listed in the table below.

809833/1063

ο σ> co

Examples 26-29

6 ₎ 7-Dihydro-3JH-imidazo / 2 ⁱ r: 5,67-_v-triazolo / 4,5- ^ 7-pynmidin-9 (4H) -one of the formula II, n = 1, R ¹ , R ⁶ and R ⁷ = H

Example no.

M.p. ⁰ C (corr.)

. solvent

beuie for the Urakri. stallization

26 3,4-dimethoxy-286.0-287.0 phenethyl

51 % 1η NaOH-HOAc

27 4-fluorobenzyl 294.0-295.0 d. 29 % 1η NaOH-HOAc

28 3,4-dichloro-247.5-249.5 d. 43 % water benzyl

29 hydrogen

■ 300

9% in NaOH-HOAc

Elemental analysis

C 55.46 H 5.27 N 24.07

C 54.30 H 3.86 N 29.08

C 40.05 H 3.62 N 46.27

NMR

(CF3CO0H) 4.03 (6, s),
3.32 (2. m), 4.50 (6. m)
7.08 (3. m)

(DMSO-d,), 4.00 (4, m),
5.21 (2 ° s), 7.41 (4. m)

(DMSO-d,) 4.21 (4, m)
5.72 (2, s), 7.85 (3, m)

(DMSO-d ^b ) 3.90 (4.m)
8.20 (1, bs)

IR

775, 1305, 1520

1580, 1650, 1725, 2700

770, 830, 1300

1510, 1580, 1640,

1720, 2700

825, 1320, 1590,

1665, 1755, 2800, 3000

780, 1280, 1540

1620, 1700, 308O ₁ 3160

-P » CD

* produced by the compound used there in the method of Example 1 o-Methoxybenzylamine is replaced, followed by reduction and cyclization of this product by the method of Example 25; there is debenzylation leading to the formation of the specified Product in which R is hydrogen, leads.

M / 19 025 - 45 -

MJ-440

Example 3Ό

7-Ami 110-2,3- (Ji hydro-8- (2-methy 1 propyi) imidazo / ~ 1,2-α-7-pyrimidin-5 (8H) -one

"ι

A mixture of 29.25 g (0.40 mol) of isobutylamine and 48.82 g (0.20 mol) of 2- (methylthio) -2-imidazoline hydroiodide in 250 ml of abs. EtOH is refluxed for 2 hours. One concentrates! the mixture in vacuo to a viscous oil, which is in 100 ml of j abs. EtOH dissolved and to a solution of 18.40 g (0.80 mol) of sodium and 22.62 g (0.20 mol) of ethyl cyanoacetate in 1200 ml of abs. EtOH admits. The mixture is refluxed for 3 hours and then concentrated in vacuo to a viscous oil. Water (400 ml) is added. Gradually a white solid crystallizes out. Is filtered off the white solid, and dried in air to give 35.43 g (86%) of product with melting point 235-238 ⁰ C is obtained (two Cristal 1fraktionen). Recrystallization from CH ^ CN gives white crystals with a melting point of 230.5 to 232.5 C (corr.). -

analysis

found: C, 57.75; H 7.93; N 27.14

NMR (DMS0-d ₆ ): 0.89 (6, d, J 6.0 Hz), 2.04 (1, m), 3.68 (2, d),

3.76 (4, m), 4.38 (1, s), 7.68 (2, bs)

IR: 770, 1190, 1280, 1490, 1610, 1655, 3160 and 3300.

Example 31 7-amino-2,3-dihydro-8- (2-methylpropyl) -6-nitrosoimidazo / 1,2-a7-

pyrimidin-5 (8H) -one

To a solution of 5.00 g (0.024 mol) of the product from Example 30 in 15 ml of H ₂ O and 4 ml of HOAc (O ⁰ C) are added (in portions

809833/1063

M / 19 025 - 46 -

MJ-440

wise) 1.72 g (0.024 mol) NaNO ₂ . The mixture is stirred for 30 minutes at 24 ^° C., cooled to ⁰ ° C. and filtered, giving 4.44 g (72 %) of a purple solid with a melting point of 203 to 205 ^° C. (d).

Recrystallization from f ^ O yields pink needles with a melting point of 205 to 207 ^° C.

analysis

found: C, 45.56; H 7.16; N 26.93

The product according to Example 31 is then reduced to the corresponding formylamino compound by the method of Example 2 and cyclization by the method of Example 4 converted into the product of Example 13.

Examples 32 to 40

The procedure of Example 24 is applied to the product of Example 13 using the n-butyl bromide used there replaced by the reagents listed below. Those listed in the table below are obtained analog products.

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Examples 32 to

lR ¹ -6,7-dihydro-4- (2-methylpropyl imidazo // !, 2-a7 pure in-9 (4H) -one

example
32

reagent

4-fluorobenzy! Chloride rf \

33 3,4-dichlorobenzyl chloride Cl 34 2-methoxybenzyl chloride 35

2- (4-chlorophenyl) ethyl bromide

CH ₂ -

Cl- / V-CH ₂ CH ₂ -

36 3-chloromethyl pyridine

37 4-chloromethylpyridine

σ-

H ₂ -

CH ₂ -

38 3-Bromo-2-methylpropene CH ₂ = C

'CH ₂ -CHo

39 2-phenoxyethyl bromide

OCH ₂ CH ₂ - *

40 2-naphthylmethyl bromide

CH ₂ -

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* Yield 53%; recrystallized from CH ₃ CN ₅

Melting point 228 to 230 ⁰ C.

NMR (CDCl ₃ ): 1.10 (6, d, 6.2 Hz), 2.40 (1, m), 4.41 (8, m), 4.83 (2, t, 6.0 Hz ) ₉ 7.21 (5, m), 8.06 (1, s), 13.7 (1, bs).

IR: 700, 760, 1250, 1460, 1600, 1645, 1715, 2600, 2980.

analysis

found: C, 58.75; H 6.18; N 17.88.

Example 41

4-ZT (4-chlorophenyl) methyl 17 -6,7-dihydro-6,7-di-methyl 1-3H-imidazo-j A, 2-a7-purin-9 (4H) -one

The procedure of Example 1 is repeated, using the 2- (methylthio) -2-imidazoline hydroiodide used there 4,5-Dimethyl-2- (methylthio) -2-imidazo! In-Hydroiodide replaced. The 7-amino-2, 3-dihydro-2,3-dimethyl -8- / f (4-chlorophenyl ) -methyl7-6-nitrosoimidazoA, 2-a7-pyrimidin-5 (8h [) - one is converted into the corresponding 6-formylamino compound according to the procedure of Example 2; the latter is after the procedure of Example 4 converted into the desired product.

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Example 42

4-Z ~ (4-chlorophenyl) methyl 17-7, 8-dihydro-3H, 6H-pyrimido A , 2-aJ- purine-10 (4H) -one

The procedure of Example 1 is repeated, using the 2- (methy1thio) -2-imidazoline hydroiodide used there Replaced 2- (methylthio) -3,4,5,6-tetrahydropyrimidine hydroiodide. The 8-amino-3, 4-dihydro-9 - / '(4-chlorophenyl) methyl7-7- i obtained

nitroso-2H ^ 5H ^ pyrimido (l, 2-a.) pyrimidi n-6 (9_H) -one becomes after the | Procedure of Example 2 converted into the corresponding 7-formyl amino ¹ compound. The latter is then cyclized according to procedure i of Example 4 to give the desired product.

Example 43

4 - / "(4-ChIorphenyl) methyl 17-6,7,8,9-tetrahydro-3H-1,3-diazepino- / 1,2-a7-purine-II (4H) -one

The procedure of Example I _{5 is} repeated, the 2- (methylthio) -2-imidazoline hydroiodide used there by 2- (methyl thio) -4, 5, 6,7-tetrahydro-IIH-l, 3-diazepine Hydroiodide replaced. The obtained 9-amino-10- / ~ (4-chlorophenyl) methyV7-8-n itroso-2, 3,4,5-tetra hydro-1,3-diazepino / 1,2-a7-pyHra'i ^c Hn-7 (10HJ-one is converted into the corresponding 8-formylamino compound according to the procedure of Example 2 - the latter is then cyclized according to the procedure of Example 4 to give the desired product.

I Example 44

1 , 4- Di / "(4-fluorophenyl) methyl7-6, 7-di hydro imi dazo / 1.2 - a7 P u r i η - 9 (4H ) -on Man applies the working method of the By S game s 24 on the product

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of Example 8, the n-butyl bromide used in Example 24 being replaced by 4-fluorobenzyl chloride. The product is obtained in a 53 % yield. It is recrystallized from isopropyl acetate-hexane. Melting point 186.0 to 188, ⁰ ° C (corr.) ·

analysis

found: C, 63.76; H 4.54; N 17.50;

NMR (CDCl ₃ ): 4.03 (m, 4), 5.25 (s, 2), 5.45 (s, 2),

7.34 (m, 8) and 7.57 (s, 1),

IR: 760, 775, 834, 1230, 1520, 1648 and 1690.,

Example 45

4-Z ~ (4-chlorophenyl) methyU-2-trif1 uormethy 1-6,7-dihydroimidazo-

/ 1> 2-a7purine-9 (4H) -one

A solution of 25.0 g (0.078 mol) of the product according to Example 2 in 50 ml of dry pyridine is prepared and cooled in an ice bath. 50 ml of trifluoroacetic anhydride (0.355 mol) are then carefully added dropwise. Subsequently treated the mixture as described in Babeispiel 14 to produce and recover the desired product.

example

6,7-dihydro-9-imino-4- (2-methylpropyl) -3H ₁ 4H-imidazoA, 2-a7-purine

The procedure of Example 30 is repeated, replacing the ethyl cyanoacetate used in this example by 0.2 mol of malonitrile. The obtained 7-amino-2,3-dihydro-5-imino-8- (2-methylpropyl) -8H_-imidazo / Ί , 2- & 7pyrimi din is then

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converted into the 6-nitroso compound according to the procedure of Example 31. The latter is reduced and formylated according to the procedure of Example 2 and then according to the working _; as of Example 4 cyclized, giving the desired j product. ι

Example 47

4 - / "(4-chlorophenyl) methyl 17-6, 7-dihydro-9-imino-3H, 4H-imidazo- CL ^X , Γ: 5,67-v-triazole / "4,5-dJpyrimidiη

The procedure of Example 1 is repeated, except that the Ethyloximinocyanacetat used there by Oximinomalonitril replaced. Then the 7-amino-2,3-dihydro-8-Z "(4-chlorophenyl ) methyl7-5-imino-6-nitroso-8F [-imidazo - / "1,2-a7pyrimidine converted into the desired product by the procedure of Example 25.

B e is ρ ie 1 48

2-Azido-4 - / "(4-chlorophenyl) methyl 17-6, 7-dihydroimidazo / 1,2-a7- \ purin-9 (4H) -one

1.31 g (0.0028 mol) of the product according to Example 17 are dissolved in 10 ml of DMF, 0.65 g (0.01 mol) of NaN ₃ are added and the mixture is heated to 100 ^° C. for 1 hour before the mixture. The crude product is obtained from the reaction mixture by dilution with 50 ml HgO. The yield is 0.45 g. This material is dissolved in the minimum amount of DMF ₅ , 25 ml of CHoCN are added, the precipitate is removed

I -J

hit by filtration and dilute the filtrate with 50 ml of H ₂ O, the desired product having a melting point of 200 to 212 ^° C. (d) being obtained.

IR: 2175, characteristic of the azido group.

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Example 49

4- / f (4-Ch1orphenyT) methy17-2-cyano-6,7-dihydroimidazo / 1,2-aJ- j purine-9 (4H) -one f

The procedure of Example 48 is repeated, replacing the NaN ₃ with NaCN.

Example 50 I.

i 2-dibutylamino-4 - / "(4-chlorophenyl) methyU-6,7-dihydroimidazo-

/ ~ 1,2-a7-purin-9 (4H) -one

The procedure of Example 48 is repeated, replacing the NaNg with dibutylamine.

If the corresponding compounds in Example 50 are replaced by low-boiling amines, such as, for example, fithylamine, or ammonia to form a 2-lower alkylamino or a 2-amino-j To obtain compound, the procedure is carried out in a closed vessel under pressure to obtain the required To be able to obtain reaction temperature. You can also use higher-boiling starting amines, such as Benzylmethylamine, then the benzyl group hydrolyzed and, for example, the 2-methylamino compound receives.

Example 51 Solution for injection

Dissolve the following ingredients in sufficient water for injection to make one liter and filter the solution through a membrane filter with a

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MJ-440

Pore size of 0.5 / in.

component

Product according to Example 27 0.2 to 5.0 g

Sodium chloride as much as necessary

to isotonic j

Tri s (hydroxymethyl) aminomethane buffer
as much as required for pH 8.5

The filtered solution is filled into clean, sterile ampoules, fused with the flame and sterilized in an autoclave

Example 52 Oral tablets

The following ingredients are mixed in dry Condition in a double-shell mixing device and pressed on a tablet press using a 0.87 cm (11/32 inch) die and concave ram.

Constituent quantity

Product according to Example 3 50.0 g

Cane sugar, for direct pressing

pre-granulated 210.0 g

Corn starch 6.0 g

microcrystalline cellulose 40.0 g

Magnesium stearate 1.0 g

This batch size is intended for 1000 tablets and provides one tablet with a weight of 370 mg. Any tablet contains 50 mg of active ingredient. One can use tablets containing 25 to 200 mg of active ingredient Make the same ingredients by adding the weight

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MJ-440 and adjust the tablet size accordingly.

Example 5J3 j

ι I

I.

Inhalation powder j

The following ingredients are mixed aseptically and j

them in hard gelatin capsules. Each capsule contains 50 mg of the j

Mixture, of which 25 mg are the active ingredient. !

Component quantity |

Product according to Example 4, micronized 25.0 g

Lactose powder 25.0 g ι

The above approach is sufficient for 1000 capsules. These
Capsules are suitable for taking the powder in an inhaled air stream
to be dispensed using a breath actuated device. With given capsules, the agent can be adjusted accordingly so that the capsules contain 0.5 to 40 mg of active ingredient. >

809833/1063

Claims (1)

Claims R represents hydrogen or the group A, wherein A is lower alkyl or lower alkenyl with in each case to to 8 carbon atoms, pyridylmethyl, aralfcyl with 7 to 12 carbon atoms, substituted aralkyl with 7 to 12 carbon atoms, aryloxyalkyl with 8 to 12 carbon atoms, or substituted aryloxyalkyl of 8 to 12 carbon atoms, wherein each of substituted aralkyl and substituted aryloxyalkyl groups as substituents one or two halogen, Alkoxy and / or Al kyl res te have, the alkoxy and alkyl groups contain up to 6 carbon atoms; R ^{2 represents} hydrogen, trifluoromethyl, halogen, azido, cyano, amino, lower alkylamino, di-lower alkylamino, or lower alkyl, the lower alkyl groups 809833/1063 M / 19 025 MJ-440 have up to 8 carbon atoms; R is hydrogen, lower alkyl or lower alkenyl each with up to 8 carbon atoms, pyridylmethyl, lower alkanoyl or lower alkenoyl with each up to 8 carbon atoms, aroyl with 7 to 10 carbon atoms, substituted aroyl with 7 to 12 carbon atoms, Aralkyl with 7 to 12 carbon atoms, substituted aralkyl with 7 to 12 carbon atoms, Aryloxyalkyl of 8 to 12 carbon atoms, or substituted aryloxyalkyl with 8 to 12 carbon atoms, where the substituted aroyl, substituted aralkyl and substituted aryloxyalkyl groups as substituents have one or two halogen, alkoxy and / or alkyl groups, the alkoxy and alkyl groups contain up to 6 carbon atoms; R ⁶ and R ^{7 represent} ring substituents attached to carbon and represent hydrogen, methyl and / or ethyl; η is the integer 1, 2 or 3; and Z is oxo or imino; and the pharmaceutically acceptable acid addition salts of the foregoing compounds, as well as the pharmaceutically acceptable metal, ammonium and amine salts of the foregoing Compounds in which R is hydrogen. 2. 4- / T (4-chlorophenyl) methy 1.7-6,7-dihydro-3H-imidazo /; i, 2-a7-purin-9 (4H) -one. 3. 4 - / '4-Chlorophenyl) methyl (7-6,7-dihydro-3h [-imi dazo / Ί, 2-a / -purine-9 (4HJ-one hydrochloride. 809833/1063 M / 19 025 MJ-440 4. Compounds of the formula III (CH ₉ ) 2> n III wherein: Is hydrogen or the group A, in which A is lower! ges alkyl or lower alkenyl each with up to 8 carbon atoms, pyridylmethyl, aralkyl with 7 to 12 carbon atoms, substituted aralkyl with 7 to 12 carbon atoms, aryloxyalkyl with 8 to 12 carbon atoms, or substituted aryloxyalkyl with 8 to 12 carbon atoms, the substituted aralkyl and substituted aryloxyalkyl radicals have one or two halogen, alkoxy and / or alkyl groups as substituents, the alkoxy and alkyl groups contain up to 6 carbon atoms; B represents hydrogen, nitroso, amino or formylamino; R and R represent ring substituents attached to carbon and represent hydrogen, methyl and / or ethyl; η is the integer 1, 2 or 3; and Z is oxo or imino; and their acid addition salts. 809833/1083 M / 19 025
MJ-440 - -flT- 5. 7-Amino-8 - / "(4-chlorophenyl) -me thy IJ-6- (formyl ami η ο-2, 3-dihydroimidazoZl, 2-a7pyrimidin-5 (8H ^) - one. 6. Process for the preparation of the compounds according to claim 1, characterized in that a compound of the formula IHa: HIa R ⁶ , , 7 - wherein Z, R, R, R 'and η have the meanings given in claim 1, in the case in which a compound of the formula I according to claim 1 is desired under Formy-1ierungsbedingungen, and in the case in which a compound of Formula II according to claim 1 is desired, reduced under non-formylating conditions, using the monoformyldiaminopyrimidine of the formula III, in which B stands for the HCONH group, or the di aminopyrimidine of the formula III, in which B stands for the F ^ N group , and then the compound of the formula III (B stands for H ₂ N- or HCONH-) is cyclized to form a compound of the formula I or II, and, if a compound of formula I or II is desired 4th
is, in which R is alkanoyl, aroyl or substituted aroyl, a substance of the formula I or II with an acylating agent which is capable of introducing the alkanoyl, aroyl or substituted aroyl group mentioned, under conditions which are necessary for the preparation of 809833/1063 m / 19 025 - jT- 28Q6199 MJ-440 ζ Amides are known from aromatic amines, and, if a compound of the formula I is desired in which R is halogen, a compound of the formula I, wherein R is hydrogen, with a halogenating agent, which is known to be useful for introducing a halogen atom into an aromatic compound, nimble! t, and, if a compound of formula I or II is desired in which R is the group A defined above, a Compound of formula I or II in which R. is hydrogen j by treatment with a strong alkali metal base and reacting the obtained alkali metal salt with a Halide, phosphate or sulfate reagents of the formula AX (X = halogen, phosphate, sulfate; A = as previously defined) converted into an alkali metal salt, and, when a pharmaceutically acceptable acid addition salt a compound of the formula I or II is desired, the compound of the formula I or II with a pharmaceutically converts compatible acid, and, if a pharmaceutically acceptable metal, ammonium or amine salt of a compound of formula I or II is desired, a compound of formula I or II wherein R is hydrogen
table-compatible base implements. II, in which R is hydrogen, with a pharmaceutical Process for the preparation of compounds according to Claim 4, characterized in that malonitrile, oximinomalonitrile or a lower alkyl ester of cyanoacetic acid or oximinocyanoacetic acid with a 2-R NH-1,3-diazacycloalk-2-ene condensed and then in the 809833/1063 M / 19 025 MJ-440 8th. 9. Case in which cyanoacetic ester or malononitrile are used as a reagent, with nitrous acid the nitroso group introduces into the product, and, if a compound of the formula III in which B is amino or formylamino is desired, the compound of formula III, wherein B is ON-, to form a compound of formula III, wherein B is formylamino stands, reduced under formylation and available Formation of a compound of formula III in which B is amino, reduced under non-formylating conditions. Process for reducing an aromatic nitroso compound of the formula ArNO to an aromatic amine of the formula ArNF ^ J where Ar is an aromatic carbocyclic or aromatic heterocyclic group, thereby ge ■ indicates j that the nitroso compound is at least j two molar proportions of sodium dithionite in concentrated I. Reacts aqueous formic acid as the reaction medium. Process according to claim 8, characterized in that aromatic nitroso compounds of the formula IHb: IHb wherein: R is hydrogen or the group A, wherein A is lower alkyl or lower alkenyl with each up to 8 carbon atoms, pyridylmethyl, aralkyl 809833/1063 MJ-440 having 7 to 12 carbon atoms, substituted aralkyl of 7 to 12 carbon atoms, aryloxyalkyl having 8 to \ 12 carbon atoms or substituted aryloxyalkyl having 8 to 12 carbon atoms, wherein the substitutable j-substituted aralkyl and substituted aryloxyalkyl ■ as substituents one or two halogen , Alkoxy and / or alkyl groups, each of the alkoxy and alkyl groups containing up to 5 carbon atoms; R ⁶ and R ^{7 represent} ring substituents bonded to carbon and represent hydrogen, methyl and / or ethyl, are used. 10. Medicaments containing at least one compound according to any one of claims 1 to 5 with conventional pharmaceuticals Formulation agents and additives. 809833/1063