FI64598B - FREQUENCY REQUIREMENT FOR THERAPEUTIC USE OF THERAPEUTIC IMAGE (1,2-A) PURIN-9-ONDERIVAT - Google Patents

Description

//! Γβΐ ^ KUULUTUSJULKAISU / ς o o IJ V) UTLÄGGNINGSSKRIFT 6459 8 P I 7 - *> to i ^ f? · * • g® ~ ^ ^ ^ j (51) Kv.lk. ^ lnt.Ct.3 C O? D 487 / Ί ^ ENGLISH I —Fl N LAN D (21) PktuMtlhukumu * - PKuntansBknlng 7Ö0U27 (22) Hukumlipllvi - AmBkntngvdag 09-02.78 ^ '(23) Alku pilvi — Glltlfhetsdag 09-02-78 / ^ (41) Tullut luik - Bllvlt offuntitg _ 08. 78 ^ PManttl · J * registry managed NihtMtoipumnkuuL) foreign * »n pvm.- ,, '

Patent- och registerstyrelsen Antiikin utligd och utl.Jkrtft * n publktnd ax-y ^ .ua (32) (33) (31) Requested ttuoikeut — Begird priority I'l *. 02.77

USA (US) 76829I

(71) Bristol-ifyers Company, 3 * + 5 Park Avenue, New York, New York 10022, USA (72) Davis L. Temple, Jr., Evansville, Indiana, USA (7 * 1) Qy Roister Ab (5U) Process for the preparation of therapeutically useful imidazo [1,2-a] purine-9-one derivatives - For the preparation of therapeutically useful imidazo [1,2-a] purine-9-one-9-one derivatives

The invention relates to a process for the preparation of novel imidazo [1,2-a] purin-9-one derivatives of the formula I and their pharmaceutically acceptable salts,

R2.! L I

NrY9Nf ^ i 7 «2 - ÄA5 fl · * 2 4 wherein R is hydrogen, lower alkyl or trifluoromethyl, R is lower alkyl, benzyl which may be substituted by halogen or lower alkoxy, pyridylmethyl or phenoxyethyl and R and R are hydrogen , methyl or ethyl. The compounds of formula I and their salts can be prepared so that the compound of formula is 0 ° N 'rs'N__. 111 Ϊ8 NH 2 I 'N XR 6 R 4 4 6 7 wherein R, R and R are as defined above are reduced under formylation conditions to give a monoformyldiamino compound of formula .9

HCO-NH \ IV

Ti --- 7 ϋ [+ - *

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2 I

wherein R, R and R are as defined above, the compound of formula IV obtained is cyclized pyrolytically or by heating with an acid anhydride optionally in the presence of triethyl orthoformate, and if desired the compound of formula I obtained is converted into a pharmaceutically acceptable salt.

The starting materials of formula III can be prepared from R 1, R 2 -substituted 2-methylmercaptoimidazolines of formula V by reacting them with ethyl cyanoacetate or ethyloxyiminocyanate acetate in the presence of a base.

N - CH, I b1

CH3S ^ N ^ 6 H

The compounds of the formula V are obtained in a manner known per se by reacting carbon disulphide with an appropriately substituted ethylenediamine, after which the 2-mercaptoimidazoline obtained 3 64598 is etherified.

To prepare compounds of formula I, a reduction formation of the nitroso group of a compound of formula III is first performed to give a monoformylated diamino compound of formula IV. The reduction formylation can be performed with formic acid as the reaction medium using either catalytic reduction over a palladium on carbon catalyst or using sodium dithionite as the reducing agent, the nitroso compound of formula III is preferably dissolved in 97% formic acid required per 10-30 ml of compound of formula III. Other formylation reaction media of equivalent value may be used. When using catalytic hydrogenation, a suitable hydrogen pressure is between atmospheric pressure and about 6.8 atm, using so much palladium-on-carbon catalyst that complete hydrogenation occurs. Apply a device previously calibrated so that the absorption of hydrogen in moles can be measured. If the calculated amount of hydrogen has not elapsed before the absorption of water ceases, a fresh batch of catalyst is added and the hydrogenation is continued. The hydrogenation is carried out at room temperature, although the reaction is exothermic, as a result of which the temperature rises moderately depending on the size of the batch during the initial stages of hydrogenation. A suitable temperature is 20 to 40 ° C. The time required for hydrogenation is usually relatively short, 15 minutes to 1 hour, depending on the size of the batch and the particular equipment used.

When sodium dithionite (Na 2 S 2 O 4) is used as a reducing agent in the reduction formylation, it is simply added to a solution containing the compound of formula III in concentrated aqueous formic acid (87 to 97% by weight). The reducing agent is used somewhat more than the stoichiometric amount, but a large excess is not necessary because the reduction occurs faster than the decomposition of sodium dithionite.

The cyclization of the formyldiaminoimidazopyrimidinone of the formula IV is carried out either by heating only or also by utilizing a dehydrating agent such as polyphosphoric acid or anhydride. The latter can also act as a reagent for the attachment of the R substituent by taking advantage of the central exchange reaction of the acyl and formyl groups during the cyclization process. When an anhydride of formula 2 2 (R CO) 20 is used, wherein R is lower alkyl, or tri-4 64598 (fluoromethyl, as a cyclizing or dehydrating agent in the presence of pyridine) as a reaction medium, an R substituent is added to the molecule. 2-isopropyl-substituted compound, and using trifluoroacetic anhydride, 2-trifluoromethyl compound is obtained.

The reaction is preferably carried out at the boiling point of the reaction mixture or at a temperature of about 130 to 170 ° C using amounts of soluble anhydride and pyridine, but at least 1 mole part of anhydride, relative to the amount of the compound of formula IV.

To pyrolytically cyclize a formylamino compound of formula IV to a compound of formula I wherein R is hydrogen, a temperature of about 260 ° C is used after diluting the compound of formula IV with a sufficient amount of dimethylformamide to give a flowable, non-viscous liquid on heating. The diluent is removed by evaporation during the process to form the desired product as a residual cake, which is usually colored.

brown. To prepare a compound of formula I wherein R

is hydrogen, triethyl orthoformate may alternatively be used in the cyclization together with alkanoyl anhydride as a dehydrating agent. Ethyl orthoformate inhibits the acyl exchange reaction that occurs when anhydride is used in conjunction with pyridine.

However, the product sometimes contains a small amount of 2-R-substituted product derived from anhyd-2 2 ride (R COJ10) as an impurity. A suitably dissolving amount of liquid anhydride is used in conjunction with about 2 to 5 moles of ethyl orthoformate to 1 mole of the formylamino derivative. The process is carried out at a boiling temperature or at a temperature of about 130 to 170 ° C.

The compounds of formula I are bases and form salts with acids. Pharmaceutically acceptable acid addition salts are those whose anion does not significantly affect toxicity or pharmacological activity. In some cases, they have physical properties that make them better for pharmaceutical purposes (solubility, lack of hygroscopicity, compressibility with respect to tablet modification, and miscibility with other ingredients). The salts are prepared by reacting a base of formula I with an acid, preferably in solution. They can also be prepared by an exchange reaction or by treatment with an ion exchange resin under conditions in which the anion of a salt of a compound of formula I is replaced by an anion of another salt under conditions which allow isolation of the undesired substance, for example by precipitation or solvent extraction or elution. . Pharmaceutically acceptable acids suitable for the formation of a salt of a compound of formula I include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, citric acid, acetic acid, benzoic acid, phosphoric acid, nitric acid, mucic acid, isethionic acid, glycosoric acid, palicoseric acid, palic acid.

The compounds of formula I are amphoteric and also form salts with bases. Such salts include, for example, pharmaceutically acceptable metal, ammonium and amine salts. The cationic moiety generally promotes the utility of the compounds. As with acid addition salts, these salts may be prepared by reacting a compound of formula I with a base, preferably in a solution of a reaction inert medium, or may be prepared by an exchange reaction or treatment with an ion exchange resin under conditions in which the cation of the salt of formula I is not replaced by another cation. the substance is removed or extracted from the solution or extracted into a solvent, or eluted from or retained in an ion exchange resin. Suitable metal salts include sodium, potassium, calcium, barium, magnesium, aluminum and zinc salts. Ammonium and amine salts are prepared in substantially the same manner as metal salts from suitable starting materials. Ammonia, ammonium hydroxide, ammonium salts, various amines, amine salts or quaternary ammonium salts and hydroxides can be used as reagents. Suitable amine types include: (a) primary, secondary or tertiary alkyl and alkenylamines having 1 to 22 carbon atoms and up to 3 carbon-carbon double bonds »(b) hydroxy-substituted primary, secondary and tertiary alkyl amines having 1 to 22 carbon atoms. carbon atoms and up to 3 hydroxyl groups; and (c) alkylenediamines having 1 to 6 carbon atoms »and (d) heterocyclic amines having 3 to 10 carbon atoms and 1 to 3 heteroatoms, at least one of which is nitrogen.

Preferred amine salts are those formed from alkylamines having up to 6 carbon atoms, hydroxy-substituted alkylamines having up to 6 carbon atoms and 3 hydroxyl groups, or salts of alkylenediamines having 2 to 4 carbon atoms. Suitable amines include, for example, ethylenediamine, triethylamine, tris (2-hydroxyethyl) amine, 2-hydroxyethylamine and piperidine.

The compounds of formula I are useful as bronchodilators, as anti-hypersensitivity reactions, as antiallergic agents, as vasodilators and as phosphodiesterase inhibitors. The compounds can be administered orally, parenterally, topically, by inhalation, or rectally. The effective dose range is between about 0.03 mg per kilogram of body weight -> the highest non-toxic dose that can be administered without causing undue side effects.

The maximum non-toxic dose can be determined by standard pharmacological methods using mice. The preferred anti-asthma compound prepared in Examples 1 and 2. the amount is approximately 250 mg per kilogram of body weight administered orally to mice.

The compounds of formula I and their salts are believed to prevent degranulation of sensitized mast cells. Acute hypersensitivity reactions such as asthma, hay fever, allergic rhinitis, urticaria, and food allergy are believed to be caused indirectly by the reaction of immunoglobulin E, sometimes referred to as a reagent antibody, with an antibody in the cell membrane of the mast cell, which triggers reactions mediators such as bradykinin, histamine, serotonin, or slow-reacting substance-A (SRSA). Mediators cause changes in terminal organs such as the airways, blood vessels, skin, and mucous membranes, resulting in symptoms of an allergic seizure. The compounds of formula I are believed to inhibit the release of mediators, thus preventing an allergic seizure. They are therefore useful in the administration of prophylactic treatment to patients who are hypersensitive as described above and prevent sudden allergic seizures such as asthma, hay fever, allergic rhinitis, urticaria and food allergy. Preferred compounds are characterized, in particular, by the fact that they have an orally active effect, a very low toxicity and a bronchodilator effect.

64598

They are therefore useful in the treatment of asthmatic seizures as well as prophylactically in hypersensitive patients, including patients with hypersensitivity to asthma.

The compounds are pulmonary phosphodiesterase inhibitors in rats and are peripheral vasodilators. The vasodilatory effect of the preferred compounds is comparable to that of papaverine in an experiment on a perfused canine hind leg. j

Preferred anti-allergy and anti-asthma agents are compounds of the formula * 4 I in which R is a substituted benzyl group, in particular a halobenzyl group. These compounds are effective antihypertensive agents and bronchodilators with a long duration of action when administered orally. The preferred compound is 4 - ['(4-chlorophenyl) methyl] -6,7-dihydro-3H-imidazo [1,2-a] purin-9 (4H) -one (e.g. 1), which has a more potent an antihypertensive and bronchodilator effect, a longer duration of action, and fewer side effects such as a central nervous system stimulating effect than aminophylline. This substance can be used for bronchodilation purposes in much the same way as aminophylline, taking into account its greater efficacy and longer duration of action. This substance can be used in oral or> parenteral doses in an amount of 0.03-250 mg / kg. i The estimated effective human dose is 10-500 mg orally and can be administered 2-6 times daily. The substance may also be administered topically to a respiratory tract with a single human dose of 20-200 mg administered 2-6 times daily.

The same dosing instructions also apply when the substance is used as a hypersensitivity inhibitor in asthma or allergic rhinitis.

When tested in caged mice orally administered the compound described in Example 1, Compound Ia had no stimulant or depressant effect at doses of 10, 20, 40, 80 or 160 mg / kg body weight, whereas aminophylline had a stimulant effect at the same dose. in the experiment at doses of 15, 30 and 60 mg per kilogram body weight. The effective antihypertensive dose (ED 2) was in rats treated in the passive skin sensitization test by oral administration as prepared in Example 1, and for aminophylline at about 60 mg per kg body weight. The spawning prepared in Example 1 was maintained for more than 6 hours by the corresponding effect of aminophylline f! 8,64598 decreasing in six hours to insignificant. The bronchodilator effect, determined in vitro by guinea pig tracheal spiral (IC 50, the concentration that caused 50% unintentional tendon release, is 14 micrograms / ml for the compound prepared in Example 1 and 19 micrograms / ml for aminophylline.

The bronchodilator effect was determined in vitro (Table I, columns 2-5) using an isolated guinea pig tracheal spiral. The concentration of the substance that causes the spontaneous (Spon) tendency of the tissue to be triggered, as well as the contractions caused by various spasmogens, namely acetylcholine (Ach), histamine (Hist) or barium chloride (BaCl 2), were measured. To achieve 50% inhibition. Values were calculated by interpolating specific dose curves depicting the percentage inhibition as a function of the different concentrations of test compounds in the test solution.

The bronchodilator effect in vivo (Table I, column 6) was determined by determining the dose of test compound required to inhibit methacholine-induced bronchospasm in the rat. The percentages represent the percentage inhibition in the cells of the test compound at the indicated dose. In other cases, the reported value is the dose (mg / kg body weight) required to inhibit bronchospasm by 50% (ED ^ q), the values being obtained by interpolating the specific dose curves. In this experiment, the parameter was pulmonary ventilation pressure (PVP), determined using anesthetized animals. The test compound was administered intraduodenally, followed by an intravenous dose of methacholine every 5, 15, and 30 minutes that had previously been shown to reduce PVP by 50%. Percent inhibition indicates the extent to which the test compound inhibits the decrease in PVP caused by methacholine infusion.

The antiallergic effect, expressed as the ability to inhibit a sudden hypersensitivity reaction, was measured by a passive skin sensitization reaction (PCA) in the rat (Table I, column 7). Animals were passively sensitized by intradermal injection of dorsal spinal cord at various sites from rat reagent, antiserum, and 48 hours thereafter, the test compound was administered. Egg albumin was administered intravenously at regular intervals, usually every 15 minutes, and! ' 9 I 64598 f

Evans blue dye. Evaluation of the skin reaction was performed by measuring the diameter of the spot formed at the sensitized site by intradermal injection. The values shown in the table are either the ED 2 values (mg / kg body weight) of the orally administered test compound or the percentage inhibition values at the dose indicated in parentheses. "I" symbolizes inactivity at the indicated dose.

The antiallergic and bronchodilator effect (Table x size I, column 8) was also studied using rats agitated with egg albumin and the B. pertussis vaccine used to prepare reactive antisera in the CA test. Fifteen days after sensitization, the animals were assayed for PVP in the same manner as above for methacholine-induced bronchospasm, and changes in PVP corresponding to a given amount of egg albumin after experimental drug treatment were determined. The values reported in the table are the ED 2 values (mg / kg body weight) of the orally administered test compound.

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In the following examples, temperatures are expressed in degrees Celsius. Melting points are values corrected according to the USP method when this is reported (corrected). The spectral properties of nuclear magnetic resonance (NMR) refer to the chemical shifts (<£) expressed in parts per million (ppm) with tetramethylsilane as the reference standard. The relative area reported for each transition corresponds to the number of hydrogen atoms of that substituent, and the multiplicity of the nature of the transition is expressed as a broad siglet (bs), siglet (s), multiplet (m), doublet (d), triplet (t), or quadruplet (g) for which the coupling constant is stated when appropriate. The labeling formula is NMR (solvent): ^ (relative area, multiplicity, J-value, and, in some cases, the structural properties referred to). Abbreviations used are EtOH (ethanol), HOAc (acetic acid), Ar (aromatic group), Et 2 O (ethyl ether), DMF (dimethylformamide), MeOH (methanol), i-ProH (isopropanol), (OEt) ^ CH (ethyl orthoformate), Nujol (mineral oil), DMSO-dg (deuterodimethylsulfoxide), IR (infrared), KBr (potassium bromide), EtOAc (ethyl acetate), d (decomposition). Others are common and have a well-established meaning. Only those absorption silon lengths (cm-2) that are relevant for the identification of functional groups are included in the infrared spectra shown. In some cases, attention has been paid to structural properties. Unless otherwise stated, KBr has been used as a diluent in IR spectroscopic assays.

Manufacture of starting materials

Example I-7-Amino-2,3-dihydro-8 - [(4-chlorophenyl) methyl] -6-nitrosoimidazo [1,2-a] pyrimidin-5 (8H) -one

To a solution of 62.30 g (0.44 mol) of 4-chlorobenzylamine in 500 ml of absolute ethanol (dried with a 4A molecular sieve aluminosilicate desiccant) is added 107.40 g (0.44 mol) of 2- ( metyylitlo) -2-imidazoline hydriodide. The mixture is boiled in a water bath in an open bottle and about 150 ml of ethanol are allowed to slowly boil off over 2 hours. This solution is added while still hot to a solution of 1.76 moles of sodium ethylate in 1650 ml of absolute ethanol. To the resulting stirred basic solution of 2 - [(4-chlorophenyl) methyl] amino-2-imidazoline is then added portionwise 61.85 g (0.44 moles) of crystalline (m.p. 129-131 °) ethyloxy oxide. iminocyanate acetate, bright yellow

F

The solution is boiled for 3 hours and then cooled to room temperature. The yellow precipitate is collected, washed with isopropanol, and partially air dried. The wet sodium salt is dissolved in 2000 ml of t-Orta, and acidified with glacial acetic acid. The red precipitate of Kirk rose is filtered off and air dried overnight and then dried in a vacuum oven at 100 ° to give 103.05 g (77%) of a rose powder, m.p. 238-241 ° (dec.). Recrystallization of this material from DMF-EtOH gives red crystals, m.p. 241 ° (dec.).

Anal. 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 (DMSO-d 6), 3.90 / 4, m, (CH 2) δ, 5.15 (2, s, CH 2 AR), 7.32 (4, s, Ar).

Example II 7-Amino-8-benzyl-2,3-dihydro-6-nitrosoimidazo [1,2-a] pyrimidin-5 (8H) -or

The procedure described in Example I is repeated, but 4-chlorobenzylamine is replaced by benzylamine. The product sp. 242 ° (dec.), Yield 68%, recrystallized from DMF.

Example III 7-Amino-2,3-dihydro-8- (2-methylpropyl) imidazo-1H-2,7-pyridimidin-5- (8H) -one

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 absolute ethanol was boiled for 2 hours. The mixture was concentrated in vacuo to a viscous oil which was dissolved in 100 mL of absolute ethanol and added to a solution of 18.40 g (0.80 moles) of sodium and 22.62 g (0.20 moles) of ethyl cyanoacetate in 1200 mL of abs. . ethanol. The mixture was boiled for 3 hours, and then concentrated in vacuo to a viscous oil. Water (400 mL) was added and a white solid slowly crystallized from the mixture. The solid was filtered off and air dried to give 35.43 g (86%) of product, m.p. 235-238 ° (two batches). Recrystallization from CH.jCN gave white crystals, m.p. 230 * 5-232.5 ° (corr.). NMR (DMSO-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, Anal. Found: C, 57.75; H, 7.93; N, 27.14.

Manufacture of finished products

Example 1 4 - [(4-Chlorophenyl) methyl] -6,7-dihydro-3H-imidazo [1,2-a] purin-9 (4H) -one • 13) 64598 a) 7-Amino-p8- [1- (4-Chloro-phenyl) -ethyl] -6- (formylamino) -2,3-dihydro-imidazo [1,2-a] pyrimidin-5- (8H) -one Sample of 40.50 grams (0.133 mol) not recrystallized from Example I the nitroso compound obtained is dissolved in 950 ml of 97% HCOOH and 25.0 g of a dispersion of 5% Pd / C-50% H2O are added under a protective atmosphere of CO2. The mixture is reduced in a Parr hydrogenator at an outlet pressure of 50 psig. About 90% of the calculated H2 consumption is consumed in less than 15 minutes as the temperature rises by 12 °. The remaining part binds within 3 hours and the temperature returns to room temperature. The catalyst is filtered off and the resulting colorless solution is concentrated in vacuo to a thick syrup. The syrup dissolves in 500 ml of H 2 O and is neutralized, with cooling, with concentrated NH 4 OH. The cream solid was filtered off and air dried to give 41.90 g (98%), m.p. 272-275 ° (dec.). Recrystallization from MeOH-i-ProH gives white crystals, m.p. 275.0 ° (dec.) (Corr.).

Anal. Found: C, 52.74; H, 4.46; N, 22.01. IR (Nujol) 3420 cm -1 (NH), 3340, 3200 cm -1 (NH 3), 1680, 1620, 1580 cm -1 (formamide, lactam, C = N), NMR (DMSO-d 6 8.38-7 , 72 (2, multiplex signals according to NHCHO)), 4.00 / 4, m (CH 2) δ 7.90 (2, s, CH 2 AR), 72.5 (4, s, AT).

b) 4- (7-Chlorophenyl) methyl] -6,7-dihydro-3H-imidazo [1,2- a] purine-9 (4H) -one

A suspension of 45.88 g (0.14 mol) of the formylamino derivative obtained in a) in a mixture of 130 ml of acetic anhydride (1.4 mol) and 65 ml of the compound (OEt) ^ CH (0.39 mol) ), boil for 5 hours (the solution is formed after about 30 minutes). Concentration in vacuo to about a quarter of the original volume gives an oil which dissolves in 300 ml of H 2 O. The mixture is treated with charcoal and filtered, and the clear filtrate is neutralized with concentrated NH 4 OH. The white precipitate is filtered off and dried in a vacuum oven to give 28.06 g (66%) of a cream solid, m.p. 285-290 °. Recrystallization from DMF-i-PrOH gave cream crystals, m.p. 289-293 ° (corr. Mp 284.0-285.0 °). If this substance is shown by NMR to contain solvated DMF, it can be removed by stirring the suspended solid in Etoi and then drying again.

14 64598

Anal. Found: C, 55.96 »H, 4.40» N, 23.16. IF (Nujol) 1620 cm-1 (C = N), 1680 cm-1 (C = O). NMR (DMSO-d 6, ppm), 3.84 / 4, m, δ (CH 2 Cl 2, 5.10 (2, s, CH 2 AR), 7.50 (4, s, Ar), 7.91 ( 1 s, CH).

The hydrochloride salt of the product obtained in Method 3 was prepared by dissolving 21.7 g of this material in 75 ml of 3N HCl. Dissolution was not complete when a white solid began to precipitate. Water, 100 ml, was added and the mixture was heated to dissolve the precipitate. The solution was treated with decolorizing carbon and filtered. To the warm filtrate was added isopropanol, 150 mL, and the product precipitated on cooling. It was collected and dried in a vacuum oven at 80 ° overnight »yield 17.05 g, m.p. 249.0-250.0 ° (dec.) (Corr.).

Anal. Found: C, 49.75 »H, 3.83» N, 20.92.

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

A slurry of 7.20 g (0.022 moles) of the product obtained in Example 1a) in a small volume of DMF was kept immersed in an oil bath at 260 °. The DMF was quickly evaporated off and the residual cake was heated with constant stirring for 12 minutes. The remaining light brown solid, m.p. 280-285 °, weighed 6.36 g (93%). Recrystallization from DMF gave a substance identical to that obtained in Example 1 b).

The 4-chlorobenzylamine used in Example I was replaced by various amines and the resulting nitrosoimidazopyrimidinones were converted according to Example 1 a) to the corresponding formylamino imidazopyrimidinones, which were then converted according to either Example 1 b) or Example 2 to compounds of formula I. The compounds prepared are shown in the following Tables II and III.

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Example 13 4 - [(4-Chlorophenyl) methyl] -2-ethyl-6,7-dihydroimidazo [1,2-a] purin-9 (4H) -one

A mixture of 25.00 g (0.078 mol) of the product of Example 1 a) and 50 ml of dry pyridine in 50 ml (0.388 mol) of propionic anhydride was heated at reflux for 3 hours. As the mixture cooled, a white solid precipitated. CH 2 Cl 2 was added and the white solid was filtered off and air dried to give crystals, m.p. 278.0-279.0 ° (corr.). The material was recrystallized from DMF-o-PrOH. NMR (DMSO-d 6): 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.

Anal. Found: C, 58.28 »H, 4.76 *, N, 21.34.

Example 14 4 - [(4-Chlorophenyl) methyl] -6,7-dihydro-2-methylimidazo [1,2-a] purin-9 (4H) -one

The procedure of Example 13 was repeated replacing propionic anhydride with acetic anhydride. The resulting product was recovered as a cream-colored substance, m.p. 311.5-513.5 ° (corr.), Recrystallized from DMF-i-PrOH.

Anal. Found: C, 56.72 »H, 4.36» N, 22.35. NMR (DMSO-d 6) 2.36 (3, s), 3.91 (4, m), 5.20 (2, s), 7.90 (4, m). IR 755, 804, 1020, 1294, 1510, 1630, 1690, 3050, 3160.

Example 15 4 - [(2-Chlorophenyl) methyl] -2- (1-isopropyl-1 H) -6,7-dihydroimidazo [1,2-a] purin-9- (4H) -one The 4-chlorobenzylamine in Example I is replaced by 2- with chlorobenzylamine and the resulting nitrosoimidazopyrimidinone is converted to the corresponding formylamino compound using the procedure of Example 1 a), and the resulting product is then reacted with isobutyric anhydride in a mixture of isobutyric anhydride and pyridine as in Example 13 to give the desired product. Recrystallization from a mixture of chloroform and acetonitrile gave a cloudy, white crystalline solid, m.p. 249.5 to 255.0 ° C.

Anal. Found: C, 59.34 »H, 5.54» N, 20.22. NMR (DMSO-d 6) 2.10 (6 d, 6.5 Hz), 2.94 (2, septet, 6.5 Hz), 3.84 (4, m), 5.12 (2, s) , 730 (4, m), IR 760, 1300, 1505, 1626, 1692, 2980, 3180.

19 64598

Example 16 4- [4- (4-Fluorophenyl) methyl] -6,7-dihydro-3H-imidazo [1,2-a] purin-9 (4H) -one a) 7-Amino-8- [4 (fluorophenyl) methyl-7- (6- (formylamino) -2,3-dihydroimidazo [2,3-a] pyrimidin-5 (8H) -one 7-amino-2,3-dihydro-8 - [(4-fluorophenyl) ) methyl-6-nitrosoimidazo [1,2-a] pyrimidin-5- (8H) -one was prepared as described in Example I, but 4-chlorobenzylamine was replaced by 4-fluorobenzylamine. To a mixture of 8.79 g (0.034 mol) of the product obtained, m.p. 223.5-225.5 ° dec. (corr.) in 100 mL of 97% HCOOH at room temperature, 15.00 g (0.086 moles) of 2828 g are added portionwise over about 5 minutes. During the resulting exothermic reaction, the solution changes from dark purple to light yellow, whereupon some yellow precipitate forms. The mixture is stirred for 10 minutes, after which it is concentrated in vacuo to about 25 ml. The residue is dissolved in 150 ml of HoO, filtered, and neutralized with concentrated NH.OH.

4

The white precipitate is collected, slurried in hot MeOH and filtered. Drying in a vacuum oven gives 9.25 g (90%) of a white solid, m.p. 248-250 °. Recrystallization from fteOH gives white crystals, m.p. 262 ° (dec.).

Anal. Found: C, 55.20; H, 4.62; N 22.87.

b) the formylamino compound obtained in a) was converted as described in Example 2 to a compound identical to the compound of Example 6.

Example 17 4- (Benzyl) -6,7-dihydro-3H-imidazo [1,2-a] purin-9 (4H) -one a) 7-Amino-3- (benzyl) -2,3-dihydro- 6-Formylamino) imidazo [1,2-a] pyrimidin-5- (8H) -one

The procedure of Example 16 is applied to the product obtained in Example II to give the title compound in 86% yield, m.p. 248-250 ° after recrystallization from DMF-i-PrOH.

Anal Found: C, 58.84 »H, 5.38» N, 24.31. NMR (DMSO-d 6) 3.79 (4, m) 5.30 (2, s), 6.66 (2, bs), 7.50 (5, m), 8.36 (1, s), 8.82 (1, s). IR 700, 740, 1305, 1500, 1580, 1612, 1655, 3200, 3320, 3400.

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

The compound obtained in a) is modified in Example 1 b) in Figure 2; 64598 Ί i to give the title compound, obtained in 64% yield as a pale yellow kitbish solid, m.p. 262-264 ° (corr.), After recrystallization from DMF-i-PrOH.

Anal. Found: C, 62.57; H, 5.15; N, 26.13. NMR (DMSO-d 6)

Example 18 4-Isobutyl-6,7-dihydro-3H-imidazo [1,2-a] purin-9 (4H) -one a) 7-Amino-2,3-dihydro-8- (2-isobutyl) - 6-nitrosolim, N, Diazo [1,2-a] pyrimidin-5 (8H) -one

To a solution of 5.00 g (0.024 moles) of the product of Method 30 in 15 mL of IVO and 4 mL of HOAc (0 °) was added (portionwise) 1.72 g (0.24 moles) of NaNCl 2. The mixture was stirred at 24 ° for 30 minutes, cooled to 0 ° and filtered to give 4.44 g (72%) of a purple solid, m.p. 203-205 ° h ..

Recrystallization from H 2 O gave rosy needles, m.p. 205-207 °.

Anal. Found: C, 45.56; H, 7.16; N, 26.93.

b) the compound obtained in a) is converted by reduction into the corresponding formylamino compound as described in Example 1 a), followed by cyclization as described in Example 2 to give a compound which is identical to the compound of Example II.

Example 19 4 - [(4-Chloro-enyl) -methyl] -6,7-dihydro-6,7-dimethyl-3H-imidazo [1,2-a] purin-9 (4H) -one

The procedure described in Example I is repeated, but 2- (methylthio) -2-imidazoline hydroiodide is replaced by 4,5-dimethyl-2- (methylthio) -2-imidazoline hydroiodide. The resulting 7-amino-2,3-dihydro-2,3-dimethyl-8- [4- (4-chlorophenyl) methyl] -6-nitrosoimidazo [1,2-a] pyrimidin-5- (8H) -one is converted to the corresponding 6 -formylamino compound as described in Example 1 a) and the latter is converted to the desired product as described in Example 2.

Example 20 4 - [(4-Chloro-phenyl) -methyl] -2-trifluoromethyl-6,7,7-dihydro-imidazo [1,2-a] purin-9 (4H) -one

A solution of 25.0 g (0.078 mol) of the compound of Example 1a in 50 ml of dry pyridine is prepared and cooled in an ice bath. Trifluoroacetic anhydride, 50 ml (0.355 mol) is then carefully added dropwise. The mixture is then treated to prepare and recover the desired product as described in Example 13.

Claims (2)

A process for the preparation of therapeutically useful imidazo [1,2-a] purin-9-one derivatives of the formula I and their pharmaceutically acceptable salts, wherein R is hydrogen, lower alkyl or trifluoromethyl, R is lower alkyl, benzyl which may be substituted by halogen or lower alkoxy, pyridylmethyl or phenoxyethyl and R and R represent hydrogen, methyl or ethyl, characterized in that the compound of formula ON J) III 1 \ fY7 IR R1 4 6 7 wherein R, R and R are as defined above, are reduced under formylation conditions to give a monoformyldiamino compound of formula, 0 HCO-NH JLI f-IL p7 IV 2. R i1 6. In this case, R, R 3a R are as defined above, and the resulting compound of formula IV is cyclized pyrolytically or by heating with an acid anhydride optionally in the presence of an arthoformate, and if desired the resulting compound of formula I is converted to a pharmaceutically acceptable salt. 1 Claims t f Process according to Claim 1 4- [4- (4-chlorophenyl) methyl] -6,7-dihydro-6,6-dimethyl-3H-imidazo [1,2-a] purin-9 (4H) -one characterized in that the starting material 4 is a compound of the formula III in which R is 4-chloro-67-benzyl and R and R are in the 2-position and denote methyl. 64598 23