CS207499B2 - Method of making the heterocyclic aminopyrimidine compounds - Google Patents

Description

The present invention relates to a process for the preparation of aminopyrimidine compounds with a condensed heterocyclic kiruheim on an ipyrimidine ring. The invention also relates to medicaments ¹ and agents affecting biological functions comprising these heterocyclic pyrimidimine compounds as active ingredients.

The compounds of the invention correspond to the general formula I

in which

R @ ¹ represents a hydrogen atom, a C1 -C4 alkyl group or a C2 -C4 phenoxyalkyl group in the alkyl moiety,

R ² represents a hydrogen atom, an alkyl group ι3 1 to 4 carbon atoms or a halogen atom and ·

R @ ⁴ represents a hydrogen atom, a C1 -C4 alkyl group, a pyridyl methyl group, a phenylalkyl group having 1 to 3 carbon atoms in the alkyl moiety optionally substituted in the phenyl moiety with one or two halogen atoms or one or two alkoxy groups containing 1 to 2 Or - represents a phenoxyalkyl group having 2 to 4 carbon atoms in the alkyl moiety.

The compounds of formula (I) according to the invention are preferably hydrogen atoms in the meaning of R ^{@ 1} and R @ ² and preferably in the meaning of R ^{@ 4,} halobenzyl as 4-chlorobenzyl.

The compounds of formula I are basic and form salts with acids. The invention includes not only the free compounds of formula (I) but also their acid addition salts. Pharmaceutically acceptable acid addition salts are those whose ainion does not significantly contribute to the toxicity or pharmacological activity of the salt itself and are therefore fairly pharmacologically equivalent to the bases of formula (I), but are preferred for use as medicaments.

In some cases, these salts have physical properties which make them more advantageous in the preparation of dosage forms such as solubility, absence of hygroscopicity, the possibility of being compressed in the preparation of tablets and their

Compatibility with other ingredients with which the compounds of the invention may be used for pharmaceutical purposes. The salts are prepared by reacting a basic compound of formula I with an acid, preferably by contacting the components in solution. The described salts can also be prepared by double decomposition (meta-mixtures) or by ion exchange under conditions in which the anion of one salt of the compound of formula I is replaced by the anion of the other salt, the undesirable component being separated such as precipitation or solvent extraction or elution from the ion exchanger, optionally by retaining · on the ion exchanger.

Suitable pharmaceutically acceptable acids for the preparation of the salts of the compounds of formula (I) include hydrochloric acid, hydrobromic acid, hydroiodic acid, citric acid, acetic acid, benzoic acid, phosphoric acid, nitric acid, mucic acid, isethioic acid, glucocucic acid, acid palimitic acid, heptainioic acid and the like.

Compounds of formula I in which R @ ¹ is hydrogen are amphoteric and can also form salts with bases. Accordingly, the invention also includes pharmaceutically acceptable salts of the compounds of formula I wherein R 1 is hydrogen, metals, ammonium salts with amines. Here again, the definition of a pharmaceutically acceptable salt is practically consistent with the above definition of a pharmaceutically acceptable acid addition salt, with the cation not contributing significantly to the toxicity or pharmacological efficacy of the present case. The cationic portion of these compounds generally contributes to the usefulness of the active ingredients since the resulting salts impart physical properties suitable for processing into dosage forms.

These salts can be prepared, as in the case of acid addition salts, by reacting a compound of formula I in which R 1 is hydrogen with a base, preferably in solution in an inert liquid medium, or can be prepared by rheeathesis or ion exchange with conditions in which a cation of one salt of a compound of formula I is replaced by another cation and the undesired component is eliminated, for example by precipitation from solution or solvent extraction, or by elution from the ion exchanger or by retention on the ion exchanger.

Suitable metal salts include sodium, potassium, calcium, barium, magnesium, aluminum and zinc salts. Analogously, ammonium salts and amine salts are prepared from the corresponding starting materials in substantially the same manner as the metal salts. Ammonium, air-ammonium hydroxide, ammonium salts, various targets, amine salts or quaternary ammonium salts or hydroxides can be used as reactants in this case. Suitable types of amines include:

(a) primary, secondary, tertiary alkyl and alkenylamines containing 1 to 22 carbon atoms and up to 3 double bonds carbon · - - carbon,

(b) hydroxy-substituted primary, secondary and tertiary alkylamines containing 1 to 22 carbon atoms and up to 3 hydroxyl groups;

(c) C 1 -C 6 alkylenediamines; and (d) C 3 -C 6 heterocyclic amines

1 to 3 heteroatoms, at least one of which is a nitrogen atom.

Preferred amine salts are those with alkylamines containing up to 6 carbon atoms or hydroxy-substituted alkylamines containing up to 6 carbon atoms and up to 3 hydroxyl groups, and alkylenediamines having 2 to 4 carbon atoms. Suitable amines include ethyl demialmin, triethylamine, triis (2-hydroxyethyl amine, 2-hydroxyethylamine, pipetidine, and the like).

The compounds of formula I are useful as bromolytic agents, antiallergic agents for immediate hypersensitivity reactions, vasodilators, and phosphodiesterase enzyme inhibitors. The invention encompasses a method of treating a mammal in need of inducing bronchodilation, vaisodilation or allergy suppression with a nontoxic bronchodilator or vasodilator, or suppressing immediate hepeirsenisivity by administering an inhibitory dose of either compound.

The disclosed compounds may be administered orally, parenterally, topically, by inhalation, or rectally. Effective doses which can be administered without undesirable side effects range from about 0.03 mg / kg body weight up to the maximum non-toxic dose.

Maximum non-toxic doses can be determined by standard pharmacological methods in mice. This one. the dosage for the compound prepared as described in Examples 3 and 4 below, which is a preferred antiasthmatic agent, is about 250 mg / kg body weight when administered orally to mice.

The compounds of formula (I) and their salts are believed to inhibit degrainization of sensitized connective cells. Immediate hypersensitivity reactions such as asthma, seine rhinitis, allergic rhinitis, urticaria and food allergy are believed to be mediated by the reaction of immunoglobulin E, sometimes referred to as a reagin-type antibody, with the cell membrane antigen of the connective cells, resulting in wherein the connective cell eventually releases imediators such as bradykinin, hiisHaimin, seroteinin or slower acting substance A (SRS-A).

Mediators cause changes in target organs such as the airways, blood vessels, skin and mucous membranes to produce an allergic reaction. It is believed that the disclosed compounds prevent the release of mediators, thereby preventing the occurrence of an allergic attack. They are therefore useful for the prophylactic treatment of persons suffering from hypersensitivity of the above-mentioned types and for the inhibition of acute allergic attacks such as asthma, hay fever, allergic rhinitis, urticaria and food allergies.

The difference between the preferred compounds is that they are effective when administered orally, have very low toxicity, and are bionodially active. Such compounds are therefore useful in the treatment of asthma attacks as well as in the prophylactic treatment of patients with hyperseinsitivity, including those in whom hypersensitivity is manifested by asthma. These compounds are inhibitors of rat lung phosphodiesterase and act as peripheral vaisodiating agents. Preferred compounds exhibit an isolated washed backing in the assay. paw dog vasodilatory efficacy comparable to papaverine.

Preferred antiallergic and anti-antistatic agents are those compounds of formula I wherein R 4 is a halobenzyl group and most preferred are compounds of formula I wherein R 4 is a hailogenbenzyl group and R ¹ and R ² are hydrogen. These compounds are orally administered in effective inhibitors hypionis ^ a ^ ^a, it ^ i ^^ j ^ 'and the picking bronchodilators with duration of action. A preferred compound is 4 - [(4-chlorophenyl) methyl] -6,7-dihydrO-3H-imidazo [1,2,2-a] purin-9 ((4H) -one (see Example 3 below)), which exhibits stronger antihypertensive and a bronchodilation activity than aminophylline has a longer duration of action and lower side effects as an effect on central nervous system stimulation, which can be used as a bronchodilation agent in much the same way as aminophylline, but taking into account its increased efficacy and longer duration duration of action.

For oral or parenteral administration, the compound may be used at doses of Ό, ϋ3 to 250 250 mg / kg. In humans, a predicted unit effective dose for oral administration may range from about 10 to about 500 mg, and may be administered two to six times daily. The compound can also be administered topically to the airways using a suitable device, in a unit dose ranging from 20 to 200 milligrams in humans, which can be administered two to six times daily. Similar dosages may be used when administering the compound as an antioxidant for asthma or allergic rhinitis.

In the cage-closed mouse efficacy test, the product of Example 3 shows neither stimulatory nor depressive efficacy at orally administered doses of 10, 20, 40, 80 and 160 mg / kg body weight, whereas aminophylline exhibits a stimulatory efficacy at doses of 15 , 30 · and 60 mg / kg body weight.

In the rat passive skin anaphylaxis test, when administered orally, the antihypertensively effective dose (ED 50) of the product of Example 3 is 34 mg / kg body weight and aminophylline of about 60 mg / kg body weight. The effect of the product of Example 3 on the depression of hypersensitivity viity persists after. for more than 6 hours, whereas the same effect aminophylline ¹ within 6 hours falls to insignificant value.

According to an in vitro test on an isolated guinea pig tracheal ring, the bronchoidiation effect value (IC 50, concentration resulting in a 50% release of spontaneous stress j for the product of Example 3 is 14 µg / ml and for aminophylline 19 µu / ml.

The performance and results of the biological activity assays of a number of compounds of the invention are described below.

Bronchodilatation The lactating activity is examined in vitro (Table 1, Columns 2 to 5) using an isolated guinea pig tracheal ring. The concentration of test compound required to release the spontaneous tissue (Spon) and the contractions caused by various spasmogens, namely acetylcholine ( The values are given in IC 50 values, which is the concentration of test compound required to inhibit contraction by 50%, as determined by interpolation from dose-response curves. curves are obtained by plotting the inhibition in percent versus concentrations, for various concentrations of test compounds in solution.

The in vivo brilliant efficacy (Table 1, column 6) is examined by detecting the dose of test compound required to inhibit methachiolto-induced bronchospasm in rats. The percentages represent the percent inhibition on application of the test compound at the dose indicated in parentheses. The values shown are the doses in mg / kg body weight required to inhibit 50% of bromine pubasma (ED 50). These doses are determined by interpolation from dose-response curves.

The test is performed on anesthetized animals and the lung pressure at breathing (PVP) is measured. The test compound is administered intoaduode intravenously at intervals of 5, 15 and 30 minutes after intravenous administration of methacholine in a dose which has been previously shown to cause a 50% reduction in PVP. Percent inhibition indicates to what extent the test compound inhibits PVP reduction caused by methacholine infusion.

Antiallergic efficacy as the ability to inhibit an immediate hypersensitivity reaction is determined by a passive skin anaphylactic reaction (PCA) in rats (Table 1, column 7). The test animals are passively senititized by intradermal injection of a rat reaginl antiserum at various sites on the shaved back, and 48 hours thereafter the test compound is administered. This is followed by administration of the allergen at a predetermined interval, usually 15 minutes, by intraveinous injection of egg albumin and Evans blue. A skin reaction is detected at the sensitized site, which is evaluated by measuring the diameter of the spot formed at the site sensitized by intradermal injection. Hod207499 notes shown in the table are either ED50 values in mg / kg body weight for oral administration of the test compound or percent inhibition values when the test compound is administered at the dose indicated in parentheses. The symbol "I" indicates that the substance is ineffective at the indicated dose.

Combined antiallergic and bromo-activity tests (Table 1, column 8) were also performed on rats actively segregated with ovalbumin and B. pertuissis as well as with the reagin aintiser in the PCA assay. 15 days after isiensitisation, animals are prepared for PVP measurement as in the methacholine-induced broinchospasm assay and measured for PVP resulting in response to egg albumin administration followed by administration of test compound. The ED50 values in mg / kg body weight for oral administration of the test compound are given in Table 1.

Table 1 Bronchodilatory and anti-alialic efficacy

(1) test substance (.example no. (2) (4) (5) guinea pig tracheal ring Sípon Ach HiiSit BaCh ) (6) • methacholiin - induced spasm (7) PCA (&) allergy // broinch'0spaisimus theaphylin 18.5 19.3 12.1 41.5 19.2 41.5 22.4 3 11.4 23 3 35 5.2 33.7 2.9 5 12, δ - - 64% (9) 43% (49) 6 49 - - - - 25% (49) - 7 12.6 - - - - I (25) - 8 17.5 - - 55.5% (10) 29% (9) - 9 - - - - - I (10) - 10 1'28 - - - - 50% (25) - 11 46 - - - - 25% (9) - 12 50 4.8 - 86 2.3 27% (24) - 13 6.3 - - 63% (9) I (25) - 14 13 - - -. 26% (16) 20% (49) - 15 Dec 5.3 3.5 9.9 19.1 1.79 40% (38) - 16 > 7.0 - - - - I (25) - 17 54 - - - - 34% (24) - 20 May > 200 - - - - 46% (24) - 23 22.5 - - - - I (25) - 24 15.5 - - - 1: 3% (3) I (W) - 27 Mar: 11.3 - - - 34.7% (10) I (25) -

Subject. The invention is a process for the preparation of the compounds of the above formula (I) and their pharmaceutically acceptable acid addition salts, as well as the pharmaceutically acceptable salts of those compounds, wherein R ¹ is hydrogen, anchor, ammonium and amine, characterized by: by cyclizing the compound of formula II

in which

R ⁴ is as defined above, and then, in order to obtain a compound of formula I in which R ² is a halogen atom, the compound of formula I in which R ² is a hydrogen atom is reacted with a halogenating agent known to the introduction of a halogen atom for the aromatic compounds, and in order to obtain a compound of the formula I in which R @ ¹ represents a radical A representing a C1 -C4 alkyl group or a C2 -C4 phenoxyalkyl group in the alkyl moiety. the compound of formula (I) in which R @ ¹ is hydrogen is converted by treatment with a strongly basic alkali metal compound to an alkali metal salt which is reacted with a hailogeinide, phosphate or sulfate reagent of formula AX. where A has the aforementioned meaning and X represents the corresponding reactive ester residue, in order to obtain a pharmaceutically acceptable acid addition salt of a compound of formula I, the compound of formula I is reacted with a pharmaceutically acceptable acid, and to obtain a pharmaceutically acceptable alkali metal salt, an ammonium salt or an amine salt of a compound of formula (I) with a compound of formula (I) wherein R ¹ is hydrogen. is reacted with a pharmaceutically acceptable base.

The process according to the invention, together with the preparation of the starting materials of the general formula II, illustrates the following reaction scheme and further details of the individual reaction steps in this scheme are given in connection with this scheme. In the above scheme, R 4 is as defined above and R ² is hydrogen or C 1 -C 4 alkyl.

Ammonia or the corresponding primary amine is reacted with 2'-methylmercaptoimidazoline to form -2-amidatazolazole, wherein the amine substituent corresponds to the formula -R 4 NH-. The latter, preferably without isolation, is subjected to a condensation reaction with ethyl oximiinocyanoctaine to form 7-amino-2,3- ^{| dihydroh8-4-6-in!} iti-imidimidiazo [12-a] pyrtinidin-6 (8H) -On-labeled in the above reaction scheme by Formula III. The condensation reaction is carried out without aqueous conditions in an anhydrous liquid inert reaction medium, in the presence of a common base, capable of forming the anion of an amino imidazoline intermediate. When a lower alkanol such as ethanol, isopropanol or butanol is used as the solvent, a suitable base is sodium ethoxide or potassium tert-butoxide. Other alkali metal alkoxides, amides or hydriflues, such as sodium amide in conjunction with a liquid and / or aprotic liquid medium and sodium hydride in an aprotic liquid medium, may also be used for this purpose. This reaction yields intermediates of formula III in high yields which, when R 4 is a phenylalkyl group as defined above and optionally substituted, range from about 75 to 100 ° C.

The alternative procedure, which is preferred when R4 is an alkyl group as defined above, consists in using ethyl cyanate instead of oximino cyanocyanate. The resulting 7-a! Mia-2, 3-dihydro-8-R ⁴ -imidazo [l, 2-a] pyrilmidiin-5- (8H j -one SE- then -nitroisuje * sodium nitrite in aqueous acetic - acid to give intermediates of formula III.

The next reaction step consists in the reductive formylation of the nitro group in the compound of formula (III) to give the mono-formulated dialminoderivative of formula (II). Reductive formylation is carried out in formic acid as the reaction medium, either by catalytic reduction using palladium on carbon as the catalyst or by using sodium dithionite as the reducing agent. Briefly, the nitro compound ¹ of Formula III is dissolved preferably in 97% acetic formic ·, wherein the housing is generally necessary to use · 10 - 30 ml of 97% formic acid per one gram compound of formula III. Other equivalent reaction media suitable for the formation reaction may also be used. In catalytic hydrogenation, the hydrogen pressure may conveniently range from atmospheric pressure up to 0.7 MPa, using palladium on carbon as a catalyst in an amount sufficient to complete the hydrogenation. Suitably, a pre-calibrated hydrogenation device is used which allows the measurement of the molar amount of absorbed hydrogen. If hydrogen uptake ceases at the time when the calculated amount of hydrogen is not consumed, an additional portion of fresh catalyst is added and the hydration is continued. Hydrogenation is carried out at room temperature, although the reaction is exothermic, resulting in a slight to moderate temperature increase in the first stage of hydrogenation, depending on the batch size. Temperatures of 20 to 40 ° C are suitable. Depending on the size of the batch and on the hydroger used, the hydrogenation is usually completed in a relatively short time ranging from 15 minutes to 1 hour.

To use sodium dithionite as a reducing agent in reductive polymerization, it is simple to add it to a solution of the intermediate of formula III in concentrated aqueous formic acid (87-97 wt%), using a slightly higher amount of sodium dithionate. · A stoichiometric amount, however, a higher excess is not necessary because the reduction proceeds faster than the decomposition of the sodium dithionite. since this reducing agent has been used in the basic art only since it is known that the dithiomethate is decomposed in an acidic medium as a by-product formed during the reaction. Cite amount of sulfur. ^Pofps: any access is generally useful for the reduction of aromatic nitroisloučenin Arno corresponding to formula wherein Ar is an aromatic carbocyclic or aromatic heterocyclic radical, to aromatic amines of the formula · Arnhem, where Ar is as defined above.

· As already mentioned above, takes place · cyclization foirmyl-diaminoimidazopyrimidin-one of the general formula · · II 4-R4-6,7-dihydro-2-R ² '-3H-imidazo [1,2-a] purin 9 (4H) -one of formula vzorce either by heating the starting material alone or by using a dehydrating agent such as polyphosphoric acid or anhydride. The latter may also serve as an agent for introducing a 2-R 2 '-' substitueint into compounds of formula (Γ) by exchanging a formyl group during cyclization to an acyl residue. When using an anhydride of the general formula · (R2'CO) 2 O wherein R 2 'is alkyl of 1 to 4 carbon atoms such as cyklodéhydraaačního agent in the presence of pyridine as the reaction medium, ·, result in the introduction of R ^2', corresponding to the anhydride used. For example, using isobutyric anhydride yields the product bearing the isopropyl substituent at the 2-position. The reaction is preferably carried out at reflux or in a temperature range of about 130 ° C to 170 ° C, using appropriate amounts of anhydride and pyridine relative to the amount of the starting compound of formula II, wherein the amount of anhydride is at least 1 mol equivalent .

In the pyrolytic cyclization of the formylthaine compound of formula II to the product of formula Γ in which R 2 'is hydrogen, a temperature of about 26 ° C is used, the starting material of formula II being diluted with a sufficient amount of dimethylformamide prior to the reaction · Heating gives a non-viscous liquid. During the reaction, the diluent is evaporated to give the desired product as a solid residue, which is usually brown in color. Alternatively, for the cyclization to give compounds of formula (I) wherein R 2 is hydrogen, triethynyl (II) onthromate in combination with alkanoic anhydride may be used as a dehydration. · Reagent. It also suppresses the acyl exchange that occurs when an anhydride is used along with pyridine. However, the product is sometimes contaminated with a small amount of the product containing the 2 'substituent R 2' originating from the (R 2 'CO) 2 O anhydride. Suitably a liquid anhydride is used for each mol equivalent of the formyl amino derivative in an amount sufficient to dissolve the solids, in combination with about 2 to 5 mol equivalents of orthoformate ^. atého. In this case too, the reaction is carried out under reflux or at a temperature in the range of from 130 ° C to 170 ° C.

The products of formula (I) in which R ¹ is other than hydrogen are readily prepared by reacting a salt of a compound of formula (I) in which R 1 represents a hydrogen atom with an alkali metal reagent of formula (AX) wherein A represents a C 1 -C 4 alkyl group or a C 2 -C 4 phenoxyalkyl group and an X represents a reactive ester group such as a chloride, bromido, iodide, phosphate or sulfate moiety. The desired alkali metal salt is obtained by reacting a compound of formula I wherein R 1 is hydrogen with a strong alkali metal compound 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 methoxide, potassium tert-butoxide, sodium amide, and sodium hydride. Suitable reactive esters include butylbromide, methylbutyl, dimethylsulfate, triethylphosphate, hexylbromide, tert-butyl chloride, benzylbromide,

2-phenoxyethyl chloride, 4-fluorobenzylbroimide,

3-chlorobenzyl bromide and 2-methoxybenzyl chloride. It is desirable to operate at elevated temperatures in the range of about 89 to 150 ° C.

In order to prepare compounds of formula I in which R2 is chlorine, bromine or iodine, compounds of formula I in which R2 is hydrogen are subjected to hailogenation under the usual conditions for introducing a chlorine, bromine or iodine atom. For example, if a solution of a compound of formula I in which R2 is hydrogen in acetic acid is treated with elemental bromine, the bromine atom is introduced into the 2-position.

N-bromosuccinimide, N-chloromiccinimide or N-chloroacetamide can also be used for halogenation. The S-chloro derivatives can be converted to the 2-iodo or 2-fluoro derivatives by reaction with a concentrated (47%) iodo group at a temperature of 0 ° C or by conversion to. triethylammonium salt followed by treatment with potassium hydrofluoride in the absence of diluent.

The invention is illustrated by the following non-limiting examples. If the abbreviation 'kor' is given in parentheses after the melting point, the melting point should be corrected as usual. The NMR spectra show the chemical shifts (ΰ), expressed in ppm relative to tetnamethylethylsilane as an internal standard The relative areas reported for each shift correspond to the number of hydrogen atoms in the respective substituent, the signal shapes being expressed by abbreviations "ss" (broad singlet), " s ”(singlet),“ m ”(multiplet),“ d ”(doublet),“ t ”(triplet) and“ q ”(quartet), with interaction constants (J) being given where applicable and In the IC spectra, only the absorption at wavelengths (cm ^-1 ) for functional groups relevant for the identification of the compound is reported, and in some cases the structural characteristics are given. spectra using the KBr technique (potassium bromide tablets).

Example 1

7-Amino-2,3-dihydro-8 - [(4-chlorophenyl) methyl] -B-nitrosoimidazo [1,2-a] pyrimidin-5 (8H) -one

To a solution of 62.30 g (0.44 mol) of 4-chlorobenzylaimine in 500 ml of absolute ethanol dried over an aluminosilicate molecular sieve is added 107.40 g (0.44 mol) of 2-methylthio-2- imidazole-1-ol. of hydroiodide. The mixture is heated in an open reaction vessel to a noticeable boiling bath and about 150 ml of ethanol are slowly evaporated over 2 hours. The resulting solution was added while still hot to 1.76 moles of sodium ethoxide in 1650 moles of absolute ethanol and to the resulting basic solution of 2 - [(4 - [(4 - [(4 - [(4 - (biphenyl) phenyl) methyl] methyl] methyl] 6.15 g (0.44 mol) of crystalline oximinocyanoacetic acid ethyl ester of melting point 129 DEG-131 DEG C. are added in portions with stirring. The bright yellow solution was refluxed for 3 hours, then cooled to room temperature, the yellow precipitate was filtered off, washed with isopropanol and partially air dried. The wet sodium salt obtained is dissolved in 2000 ml of water and the solution is acidified with glacial acetic acid. The bright pink precipitate is filtered off, air-dried over n and then dried in a vacuum oven at 100 ° C. 103.06 g (77%) of a yellow powder, m.p. ¹ with decomposition at 238 DEG-241 DEG C., is obtained, which, after recrystallization from a mixture of dimethylphormarnide and ethanol, yields red crystals, melting on decomposition at 241 DEG.

NMR (perdeuterodimethylisulfoxide):

3.90 [4, m, (CH 2) 2],

5.15 (2, s, CH2), .....

7.32 (4, s, Ar). “.....

Example 2

7-amino: 10-8- [(4-chlorophenyl (methyl) -6-formylamino-2,3-dihydroimidazo [1,2-a] pyrimidin-5 (8H) -one]

40.50 g (0.133 mol) of the non-recrystallized nitroisilo compounds of Example 1 are dissolved in 950 ml of 9-7% formic acid and 25.0 g of 5% palladium on carbon with 50% water are added under a carbon dioxide atmosphere. The mixture was reduced in a Parr hydrogenation apparatus at an initial pressure of 50 psi. In less than 15 minutes approximately 90% of the calculated amount of hydrogen is consumed, increasing the temperature by 12 ° C. The remainder of the hydrogen was absorbed within 3 hours and the temperature dropped again to room temperature. The catalyst is filtered off and the colorless filtrate is concentrated in vacuo to a thick syrup residue which is dissolved in 500 ml of water. The solution was neutralized with concentrated ammonium hydroxide while cooling, the off-white solid product was filtered off and air dried. 41.90 g (98%) of a melting point at 272 DEG-275 DEG C. is obtained, which, after recrystallization from a mixture of methanol and isopropyl alcohol, yields a white crystalline product, melting at 275.0 DEG. ^; ° C (corr.).

Analysis:

found:

C: 52.74%, H: 4.46%, N: 2'2.01%.

IC (nujol):

3420 cm -1 (NH),

3340, 3200 cm -1 (NH2),

1680, 1629, 1580 cm ^-1 (formamide, lactam, G = N).

NMR (perdeuterodimethylsulfoxide):

8.32 to 7.72 (2, multiple signals for NHCHO conformers),

4.00 [4, m, (CH2)],

5.90 '(2, s, CH3);

7.25 (4, s, Ar).

Example 3

Analysis:

found:

C: 50.68%, H: 3.93%, N: 22.59%.

IC (nujol):

1600 · up to r7u0 · cm ^-1 (C = O, C = N),

3550 cm < -1 > (NH).

4 - ((4-chlorophenyl) methyl] 6,7-dihydro-3 H -imidazo [1,2- a] purin-9 (4 H ') -one

A suspension of 45.88 g (0.14 mol) of the formyl imo derivative prepared in Example 2 in a mixture of 130 ml (1.4 mol) of acetic anhydride and 65 ml (0.39 mol) of ethyl ethyl formate is added

The mixture was refluxed for 18 hours (after 30 minutes the suspension became a solution). Concentration of the reaction mixture in vacuo to about 1/4 of the original volume gave an oily residue which was dissolved in 300 ml of water. The solution is clarified with activated carbon, filtered, and the clear filtrate is neutralized with concentrated ammonium hydroxide. The precipitated white precipitate was filtered off and dried in a vacuum oven to give 28.06 g (66%) of an off-white solid, m.p. 285-290 ^and C. Recrystallization from dimethylformamide / isopropyl alcohol gave an off-white crystalline product. mp 289 DEG-293 DEG C. (co. 284.0 DEG-285 DEG C., 0 DEG C.) If the product contains NMR-solubilized dimethylforimamide, this solvent can be removed by suspending the solid product in diethyl ether with stirring. and evaporate again to dryness.

Analysis:

found:

C: 55.9%, H: 4.40%, N. 23.16%.

IR (nujoil):

1620 cm ^-1 (CN), 1680 ^cm-1 (C = 0).

NMR (perdeuterodimethylsulfoxide):

3.84 (m, (CH2)),

5.10 (2, -s, cm @ -1),

7.59 (4, s, Ar);

7.91 (1, s, CH).

The hydrochloride of the product of Example 3 was prepared by dissolving 21.7 g of this product in 75 mL of 3N hydrochloric acid. Dissolution is not yet complete when white solid material begins to precipitate. 100 ml of water are added and the mixture is heated to dissolve the precipitate. The solution is decolorized with activated carbon, filtered, 150 ml of isopropyl alcohol is added to the warm filtrate and the product is precipitated by cooling. Filtration followed by drying in a vacuum oven overnight at 80 ° C yielded 17.05 g of the product melting at 249.0-250.0 ° C (dec) with decomposition.

Analysis:

found:

C 49.75%, H 3.83%, N 20.92%.

Example 4

Preparation of the product of Example 3 by pyrolysis

A suspension of 7.20 g (0.022 mol) of the product prepared in Example 2 in a small volume of dimethylformamide was placed in an alley bath at 260 ° C. Dimethylformaimide was rapidly evaporated and the solid residue was heated with stirring for 12 minutes. There were obtained 6.36 g (93%) of brownish-solid residue, mp 280-285 C ^and that after .překrystalování dimethylfoirmamldu provide a material identical to that prepared in Example 3rd

In the procedure of Example 1, the 4-chlorobenzylamine was replaced with various other amines, and the resulting nitroisoiridazopyrimidinones were converted into the procedure of Example 2. the corresponding fortoyl-aminolimidazopyrimidinones, which are then converted into one of the products according to the invention by the procedure of Example 3 or 4. The characteristics and reaction conditions for the preparation of these products are given in the following table:

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Example 14

4 - [(4-chlorophenyl) methyl] -2-ethyl-6,7-dihydroiimidazo [1,2-a] purin-9 (4H) -one

A mixture of 25.0 g (0.078 mol) of the product of Example 2 and 50 ml of dry pyridine in 50 ml (0.388 mol) of priopionic anhydride was refluxed for 3 hours, then cooled, whereupon a white solid precipitated. . Acetonitrile was added, the white solid product was filtered off and air dried. M.p. 278.0-279.0 ° C (coir.), Which can be recrystallized from a mixture of dimethylformamide and isopropyl alcohol.

NMR (perdeuterodiimethylsulfioxide):

I, 22 (3, t, 1.5 Hz), 2.67 (2, d, 7.5 Hz),

3.98 (4, m), 5.08 (2, s), 7.43 (4, m),

II, 3 (1, SS).

Company ID:

756, 805, 1295, 1510, 1630, 1695, 3050, 3100, 31160 cm &^lt; -1 ^&gt;.

Analysis:

found:

C: 58.28%, H: 4.76%, N: 21.34%.

Example 1 and 4 15

4 - [(4-chlorophenyl) methyl] -6,7-dihydro-2-methyltoidazo [1,2-a] purin-9- (4H) -oin

The procedure described in Example 14 was repeated except that acetainhydride was used in place of proipioinic anhydride. The resulting product is obtained in the form of a cream-colored solid melting after recrystallization from mixtures of dimethylformamide and isopropyl alcohol at 311.5 to 313.5 ° C (co.).

Analysis:

found:

C: 56.72%, H: 4.36 θ / ο, N: 22.35%;

NMR (perdeuterodimethylsulfoxide):

2.3-6 (3, s), 3.91 4, m), 5.20 (2, s),

7.90 (4, m);

Company ID:

755, 894, 1020, 1294, 1510, 1630, 1690,

3) 050, 3160.

Example 16

4 - [(2-chlorophenyl) methyl] -2 - [(1-methylethyl) -6,7-dihydroimidazo [1,2- a ]purin-9 (4 ') -απ

Using the procedure described in the Example, except that 2-chlorobenzyl amine was used instead of 4-chlorobenzylamine, the resulting nitrosoimidazoipyrimidinone was converted to the corresponding formylamino compound by the procedure of Example 2, which was then reacted with isobutyric anhydride according to Example 14. in a mixture of isobutyric anhydride and pyridine to give the desired product, which results in the form of a white, fluffy crystalline solid, m.p.

Analysis:

found:

C: 59.34%, H: 5.54%, N: 20.22%;

NMR (Perdeutenoidimethylsulfoxide):

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);

Company ID:

7'60, 1300, 150'5, 1626, 1692, 298'0,3180.

Example 17

2-bromo-4 - [(4-chlorophenyl) methyl] -6,7-dihyidro-3H-imidazole [1,2-a] purin-9 (4H) -one hydrobiromide

To a solution of 2.00 g (0.006-6 mmol) of the product of Example 3 in 10 ml of acetic acid was added 1.60 g (0.010 mol) of bromine and the resulting solution was heated on a steam bath for 10 minutes. A yellow flocked product precipitated, which was filtered off and air dried to give 3.29 grams of a white solid melting at 212 ° C with decomposition. Heating a suspension of this material in aicetonitrile yields a white powder melting at 248 ° C with decomposition, which, after recrystallization from a mixture of dimethylfortoamide and acetoinitrile, yields fine white needle crystals melting with decomposition at 228.5-229.5 degrees Celsius (cf. ).

Analysis:

C: 36.48%, H: 2.92 ° / o, N: 15.01%,

Example 18

7-a ^and I-ethylamino-8-BE: 2,3-Benzyl-6-diihydro niitrosoimidazo [1,2-a] pyrimidin-5 (8H] -one

The procedure described in Example 1 was repeated except that benzylamine was used instead of 4-chlorobenzylamine. The product obtained in a yield of 68% melts with decomposition at 242 ° C (after recrystallization from dimethylformamide).

Example 19

-am in-2,3-dBh-d-dr-6-sulfamino-imidazo [1,2-a] pyrimidin-5 '(8H) -one

The product prepared in Example 18 is subjected to the reaction described in Example '2' to give the desired product, m.p. The product obtained is not further crystallized.

Example 20

6,7-dihydro-2- (1-methylethyl) -4- (2-methylpropionyl) -3H-imidazo [1,2-a] purin-9 (4H) -one

The product prepared in Example 19 is subjected to the reaction described in Example 14 except that isobutyric acid anhydride is used instead of the propionic anhydride used in Example 14. The product is obtained in a yield of 35% and melts at 271.0 to 273.0 ° C (rec.

Analysis:

found:

C: 58.50%, H: 6.25%, N: 24.39%;

NMR (Perdeutebiodimeithylsulfoxide):

1.20 (6, d), 1.34 (6, d), 3.00 (i, m),

4.10 (5, m), 13.2 (1, bs);

IC:

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

Example 2 1

7-Amino-e - [(4-fluorophenyl) methyl] -6-formylthio] -2,3-dihydroxyimidazo [2,3-a] pyrimidin-5 (8H) -one

Using the procedure described in Example 1, substituting 4-fluorobenzylamine for 4-chlorobenzylamine, 7-amino-2,3-dihydro-8- [[4-fluorophenyl] methyl] -6-nitrosoimido [o] [0.24] was prepared. 1 ·] ^ JУ * ri ^ li ^^ in- · 5 [<1 H] -on. To 9.79 g (0.034 mol) of the product obtained, melting with decomposition at 223.5 to 225.5 ° C (corr.), In 1010 ml of 97% formic acid, is added at room temperature over a period of about 5 minutes after in portions of 15.00 g (0.086 mol) of sodium disionite.

An exothermic reaction occurs during which the original dark-blooded color of the solution becomes 'light yellow' and some yellow precipitate is formed. The mixture is stirred for 10 minutes and then concentrated in vacuo to a volume of about 25 ml. The residue is dissolved in 150 ml of water, the solution is filtered and the filtrate is neutralized with concentrated ammonium hydroxide. The white precipitate formed is filtered off, stirred in hot methanol and the suspension is filtered. Drying in vacuo gave 9.25 g (190% of a white solid, mp 248-250 ° C), which after recrystallization from methanol gave a white crystalline product melting at 262 ° C.

Analysis:

found:

C: 55.52%, H: 4.62%, N: 22.87%.

The formyl amino compound prepared in Example 21 was converted to the product identical to that prepared in Example 8 by the procedure described in Example 4.

Example 2 2

7-a _m · TNO-8-2,3-aenylm.ethyl · dihy0ro-6- ^and αlта: ^y ^ L l.aimiini πtmioaz ^ [1 ^ 1 ^l ^ 2 t ^αj JyrtЫιdin-5 (8H] -he

The product prepared in Example 18 was subjected to the reaction described in Example 21 to give the title compound in a yield of 86%, after recrystallization from dimethylformamide / isopropanol at 248-250 ° C.

Analysis:

found:

C: 58.84%, H: 5.38%, N: 24.31%;

NMR (perO · euterodimethylsulfoxide):

3.79 (4, m), 5.30 (2, sj, 6.66 (2, ss), 7.50 (5, mj, 8.36 (1, s), 8.82 (1, s) );

IC:

700, 740, 1305, 1500, 1580, 1612, 1655 ,. 3200, 3320, 3400.

Example 23

4-methyl-6,7-diidyl-6,7-diidyl-ZH-midazo [1,2-a] purin-9 (4H) -one

By the method described in Example 3 with the difference that as starting formylaminosloučenina using the product prepared in Example 22. The title compound was obtained in 64% yield as a yellowish crystalline solid, mp after recrystallisation from diisopropyl ^^ ^| methyl-l ^^ a ^ i ^ n ^^ ^ lm IIId and isopropanol at 262 to 264 ^Q C (corr.).

Analysis:

found:

C: 62.57%, H: 5.15%, N: 26.13%;

NMR (perdeute.'rodi.methylsulfoxide):

3.88 (4, m), 5.16 (2, s), 7.45 (5, m), 8.00 (1, s);

IC:

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

EXAMPLE 24 1-Buityl-4 - [(4-chlorophenyl) methyl] -6,7-dihydroimidazo [1,2- a] purin-9 (4H) - [beta] -11,6-dihydroxybenzo [10-a]

To a suspension of 1.77 g (0.0059 mol) of the product of Example 3 in 20 ml of dry dimethylformalrnide was added 0.27 g (0.0065 mol) of sodium hydride in stirring. 57% dispersion in mineral oil. After complete dissolution, 0.69 g (0.0065 mol) of n-butyl bromide was added, the mixture was heated at 100 ° C for 3 hours, 200 ml of water were added thereto, and the aqueous portion was decanted from the precipitated gum residue.

The resinous residue was dissolved in 1N hydrochloric acid (100 mL) and filtered. The resulting yellow solution was basified with ammonium hydroxide and the resulting resinous material was taken up with isopropyl alcohol. The isopropanol solution is acidified with etihartolic hydrochloric acid and allowed to evaporate. The solid residue yielded recrystallization from a mixture of acetonitrile and ethyl acetate of 0.65 g (28%) of pale yellow crystals, m.p. 223 DEG-225 DEG C. (205.5 DEG-206.5 DEG C.).

IC:

770, 1310, 1400, 1500, 1608, 1660, 1720

2710 and 3110 ·;

NMR (CDCl3):

0.83, (3, t, 6.2 Hz), 1.27 (2, m),

1.73 (2, m) 4.28 (6, m), 5, · β (2, s),

7.39 (2, m), 8.04 (1, S);

Analysis:

found:

C: 54.48%, H: 5.56%, N: 17.8-4%.

Example 2 5

7-Amino-2,3-dihydro-8- (2-methyl-piperidin) imidazo [. 1- (2-a) pyrimidin-5 (8) -one

A mixture of isobutylamine (29.25 g, 0.40 mole) and 48.82 g (0.20 mole) of 2-methylithto-2-imidazoline hydroiodide in 250 ml of absolute elthianol is refluxed for 2 hours then The mixture is concentrated in vacuo to a viscous oil which is dissolved in 100 ml of absolute ethanol and added to a solution of 18.40 g (0.80 mol) of sodium and 22.62 g (0.20 mol) of ethyl cyanoacetate. ml of absent eithanol. The mixture was refluxed for 3 hours and concentrated in vacuo to a viscous, oily residue. Upon addition of 400 ml of water, a white solid slowly crystallized, the kitelry was filtered off and air dried. 35.43 g (86%) of a material with a melting point of 2'35 to 238 ° C (two fractions) are obtained, which, after recrystallization from acetonitrile, gives a white crystalline product, m.p. ikor.).

NMR (perdeuterodimethylsulfoxide):

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);

IC:

770, 1.190, 1280, 1-490, 1610, 1655, 3160, and 3300;

Analysis:

found:

C: 57.75%, H: 7.93%, N: 27.14%.

Example 2 6

7-Amino-2,3-cyclohexyl-8- (2-methylpropyl) -6- [1,2-a] pyrimidin-5 (8H) - he

To a solution of 5.00 g (0.024 mol) of the product prepared in Example 25 in 15 ml of water and 4 ml of acetic acid is added portionwise at 0 ° C 1.72 g (0.024 mol) of sodium nitrite. The mixture was stirred at 24 ° C for 1 minute, then cooled to 0 ° C and filtered. 4.44 g (7-2%) of a purple solid are obtained. M.p. 203 DEG-205 DEG C. (decomposition).

Purification from water gave the product as pink needle crystals, mp 205-207 ° C.

Analysis:

found:

C: 45.56%, H: 7.16%, N: 26.93%

The product of Example 26 was converted to the corresponding product of Example 1 by reduction to the corresponding compound of Example 2 and cyclization of Example 4.

Example 27

The product prepared in Example 13 is subjected to the reaction described in Example 24 except that 2-phenoxyethylb (rolmid) is used instead of n-butylamide. In a yield of 53%, 1- (2-phenoxyethyl) -Y-dihydro- 1-P-Methylpropyl) imidazo 1,2-a] purin-9 (4H) -one melting after recrystallization from acetonitrile at 228 to 2130 ° C.

NMR (CDCl3):

1.10 · (6, -d, 6.2 Hz), 2.40 (1, m),

4.41 (8, m), 4.83 (2, t, 6.0 Hz),

7.21 (5, m), 8.06 (1, s), 13.7 (1, bs);

IC:

709, 760, 1250, 1460, 1600, 1645, 1715, 2600, 2980;

Analysis:

found:

C: 58.75%, H: 6.18%, N: 17.88%.

0 7 4 9 8

Example · 2 · 8

Solution for injection

The components listed below are dissolved in a volume of water for injection, the resulting solution having a volume of 1 liter, filtered through a 0.5 pxa Mieimibran filter, placed in clean sterile ampoules, which are then sealed over a flame and sterilized in a flame. autoclave.

ingredient quantity maize Škr ob 6.0g microcrystalline cellulose · 40.0g magnesium stearate 1.0g

The above dose is intended to produce 1000 tablets weighing 370 mg each containing 59 img of the active ingredient. Tablets containing from 25 to 200 mg of active ingredient can be made using the same ingredients with the appropriate weight and tablet size.

the product of Example 27 sodium chloride tris (hydroxymethyl) aminomethane buffer at pH 8.5

0.2 to 5.0 g 'as needed to isootonize the solution as desired

Powder for inhalation

The components listed below are mixed after asep. In quiet conditions and mixtures, the hard gelatin capsules are sawed so that each capsule serves 50 mg of the mixture, corresponding to 25 mg of the active ingredient.

Example 29 quantity component

Tablets for oral administration

The ingredients listed below are dry blended in a suitable mixer and compressed into a tablet press using a 8.7 mm screen and a concave punch.

a component of the amount of the product of Example 3 sucrose, pre-granulated for direct compression

50,0 g

210.0 g micronized product 25.0 g of Example 4 powdered lactose 25.0 g

The above dose is intended for the manufacture of 1000 capsules. The capsules produced are suitable for dispensing the powder into the inhaled air through the use of a respiratory-controlled device. By suitably adjusting the composition and amount of the composition, it is possible to produce capsules containing from 0.5 to 40 mg of active ingredient.

Claims (3)

A process for the preparation of heterocyclic amiinopyrimidine compounds of the general formula I R ** in which. R @ ¹ represents a hydrogen atom, a C1 -C4 alkyl group or a phenoxyalkyloxy group having from 2 to 4 carbon atoms in the alkyl moiety, R ² represents hydrogen, alkyl with 1-4 <alkyl or halogen and R ⁴ represents a hydrogen atom, a C 1 -C 4 alkyl group, a pyridylmethyl group, a C 1 -C 4 phenylialkyl group 3 carbon atoms in the alkyl moiety optionally substituted in the phenyl ring by one or two halogen atoms or one or two alkoxy groups each containing 1 to 3 carbon atoms, or a phenoxyalkyl group having 2 to 4 carbon atoms in the alkyl moiety, and their pharmaceutically acceptable addition salts acid and pharmaceutically acceptable Stoll those above compounds wherein R ¹ is hydrogen, metal, ammonium salts and amine salts characterized by cyclising a compound of formula II HCONH z nh ₂ in which R ⁴ has from above. defined above, followed in the event that one wishes to obtain a compound of vzobce I in which R ² represents a halogen atom, the obtained compound of formula I in which R2 is hydrogen is reacted with halogemačním známým- reagent for introducing a halogen atom into aromatic compounds, and in order to obtain a compound of the formula I in which R @ 1 is a radical A representing a C1 -C4 alkyl group or a C2 -C4 phenoxyalkyl group in the alkyl moiety, the compound of the formula I is obtained. I, in which R @ 1 is hydrogen, is converted by treatment with a strongly basic alkali metal compound into an alkali metal salt, which is then reacted with a halide, phosphate or sulfate reagent of formula AX wherein A is as defined above and X is the corresponding reactive residue. of an ester when a pharmaceutically acceptable acid addition salt of a compound of formula (I) is to be obtained, the compound of formula (I) is reacted with a pharmaceutically acceptable acid, and when a pharmaceutically acceptable alkali metal salt is obtained, an ammonium salt or an amine salt of a compound of formula I, a compound of formula I wherein R 1 is hydrogen is reacted with a pharmaceutically acceptable base. 2. Process according to claim 1, characterized in that the cyclization of the compound of the formula II is carried out pyrolytically by heating to 25 (0 ^: 270 ° C) in the presence of a high-boiling solvent, preferably dimethylformamide. 3. The process according to claim 1, wherein the cyclization of the compound of formula II is carried out in the presence of a dehydrating agent such as polyphosphoric acid or a C1 -C4 alkanoic acid anhydride, optionally in combination with ethyl ortho-mercanol, at a temperature of 130 DEG-170 DEG C., preferably under reflux.