DK159685B - Imidazothienopyrimidines, pharmaceutical preparations comprising them, a use of the compounds and process for preparing them - Google Patents

Description

in

DK 159685 B

The invention relates to novel therapeutically active imidazothienopyrimidines, pharmaceutical compositions comprising the compounds, the use of the compounds and methods for their preparation. The listed compounds are advantageous for psychopharmaceutical use e.g. in the treatment of central nervous system disorders, for example, as anticonvulsants or anxiolytics.

It is well known (Squires, R.F. and Braestrup, C. in Nature 10 (London) 266 (1977) 732-734) that specific regions of the central nervous system of vertebrates exhibit a strong specific affinity for 1,4- and 1,5-benzodiazepines. These areas are called benzodiazepine receptors.

It has now been found that the compounds of the invention also have strong affinity for the benzodiazepine receptors, making them suitable for use in psychopharmaceuticals.

From Danish Patent Specification No. 155007, imidazoquinazoline compounds are known, as well as affinity for the benzodiazepine receptors. The known compounds, which chemically differ from the subject imidazothienopyrimidines by being derived from the quinazoline skeleton, act agonistically. In contrast, the 25 compounds in question have surprisingly been shown to have an antagonistic or inverse agonistic effect, as evidenced by the test results set forth in Table 2.

The heterocyclic compounds of the invention have the general formula I

o 35 (!) where 2

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wherein R 'is C1-6 alkyl, C8-7 cycloalkyl or C1-6 alkoxymethyl; R5 is C1-6 alkyl; 10

GC "ui" pX

Wherein R and R are independently hydrogen, C 1-6 alkyl or aryl.

The compounds of the invention can be prepared by: a) reacting a compound of formula 11

OyG "" _ α

wherein Y is a leaving group having a compound of formula III

CN - CH2 - R3 (III) 3 wherein R is as defined above to form a compound of formula I according to the invention, or b) reacting a reactive derivative of a compound of 3

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the general formula IV

/ IC ^ • ^ COOH

5 (iv) O * where r and R have the above meanings, with

a compound of the general formula V

R '- C (= NOH) NH 2 (V) wherein R' is as defined above to form a compound of general formula I wherein R is 15 -CX where R 'is as defined above, or

(c) reacting a compound of general formula VI

F \ - CONHj 25 V. (Γ T (VI) No. '

wherein V jry and R have the above meanings, with a compound of general formula VII

r'-c (and3) 2n (ch3) 2 (VII)

wherein R 'is as defined above to form a compound of general formula VIII

CONsCRNC Cloth (VIII) 4

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f = N

Vs ^ Vnn4 * QC * · wherein \ - / r and R * have the above meanings, and reacting the compound of formula (VIII) with NI 2 OH or another aminating agent to give a compound 3 of the general formula Wherein R is C * where R * has the meaning defined above, or

(d) reacting a compound of general formula IX

20 / Λ-CN (IX) nc; where v ^ / r and ΈΓ have the above meanings, with NH 2 OH to form a compound of general formula X 30

/ = N

Ct = N0H) MFE

VwVv <x> 35 0 where α and R ^ have the above meanings, and 5

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reacting the compound of formula (X) with R'-COCl or (R'CO) 00 where R 'has the above meaning, to give Δ 3 a compound of formula I wherein R is -a where R' has the above meaning.

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The leaving group, Y, may be any suitable leaving group and, for example, those disclosed in U.S. Patents 4,031,079 or 4,359,420, for example, halogen, alkylthio, especially, methylthio, aralkylthio, N-nitrosoalkylamino, alkoxy, mercapto , -0P (O) (OR) 2 where R is lower alkyl or -0P (0) (NR '' 'R' ') where R' '' and R '' each represent lower alkyl or phenyl, or together with the nitrogen atom to which they are attached represents a heterocyclic radical such as, for example, morpholine, pyrrolidine, piperidine or methylpiperazine The reaction is best performed under alkaline conditions, i.e. in the presence of a base, and among bases, alkali metal, e.g. The reaction is best carried out in an organic solvent which does not react with the reactants and the products of the reaction under the reaction conditions, in particular an anhydrous solvent and most preferably an anhydrous aprotic acid. solvent such as dimethylformamide (DMF) or the like. The temperature range used may be within any range which allows the reaction to proceed at an appropriate rate and without undue delay or decomposition, and a range from -40 ° C to about room temperature is thus usually particularly appropriate.

The starting materials can be prepared from commercially available 35 thiophene derivatives using well known synthesis methods and as described in Synthesis, Vol. 10, pp. 681 - 682.

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The pharmaceutical compositions of the invention for use in the treatment of diseases of the central nervous system are characterized in that they contain an amount of a compound of the invention which is effective for the relief of such a disease, together with a pharmaceutically acceptable carrier or diluent.

The invention further relates to the use of the imidazothienopyrimidine compounds of formula 1 for the preparation of a pharmaceutical composition for the treatment of diseases of the central nervous system.

The pharmaceutical properties of the compounds of the invention can be illustrated by determining their ability to displace radiolabeled flunitrazepam from benzodiaze-pin receptors.

The displacement activity of the compounds of the invention is found by determining the ED The EDgQ value indicates 20 the dose (mg / kg) of a test substance that causes the specific binding of flunitrazepam to benzodiazepine receptors in a living brain to be reduced to 50% of the control value.

Such an in vivo test is performed as follows: 3

Principle. Twenty minutes after the administration of a dose of H-flunititrepepam (H-FNM) (200 µCi / kg, i.v.), the specific 3 binding of H-FNM to brain benzodiazepine receptors has reached its maximum value. This specific binding of H-FNM can be partially or completely prevented by concomitant or prior administration of pharmacologically active benzodiazepines or some benzodiazepine-like substances (Chang and Snyder, Eur. J. Pharmacol. 48, 212-218 (1978)).

Test Procedure. Test substance solutions (2 mg / ml) are prepared in 5% Duphasol-X (Duphar, castor oil-ethylene oxide 7

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derivative for emulsifying and dissolving oil and other water-insoluble substances) by ultrasound for 10 min using a Branson Bl5 microtip ultrasonic apparatus (option 7). Groups of three mice (females, NMR, 18-22 grams) are injected 5 intraperitoneally with 100 mg / kg of test substance. Fifteen mi nuts after administration of the test substance, mice are injected 4 µCi intravenously by 1 H-FNM (70-90 Ci / mol) in 200 μΐ physiological saline solution. Twenty minutes after H-FNM administration, the mice are sacrificed by cutting off the head; the forebrain 10 is rapidly removed (within 30 sec) and homogenized in 12 ml of ice-cold 25 mM Κί ^ ΡΟ ^, pH 7.1, by means of an UltraTurrax homogenizer equipped with an N 10 shaft. Two portions of 1 ml are immediately filtered through Whatman GF / C fiberglass filters and washed with 2 x 5 ml of the above buffer. The amounts of radioactivity on the filters are determined by conventional scintillation counting. A group of untreated mice acts as a control. One to three mice are injected with 25 µg / kg 3 clonazepam i.p. 30 minutes before H-FNM to determine the amount of non-specific H-FNM binding, which should be between 20 and 8-15% of the total binding. When doses of 100 mg / kg inhibit 3 more than 50% of the specific H-flunitrazepam binding, test substances are administered at doses that are factors of 3.16 times lower than 100 mg / kg. ED ^ for a test substance is defined as the dose which inhibits 50% of the specific 3 H-FNM 25 binding. Specific binding is the amount of binding in control animals minus the amount binding in clonazepam treated mice.

Results. The EDg value is determined from the dose-response curves. If only one dose of test substance is administered, the 30 EDf-Q value is calculated as follows, assuming that the inhibition of specific binding is in the range of 25-75%: ED_n (dose administered) x --- mg / kg 35 Γ 1 U - '] 8

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wherein CQ is specific binding in controls and is specific binding in mice treated with test substance.

Test results obtained by testing some of the compounds 5 of the invention will be shown in the following Table I.

TABLE 1.

Compound No. in Eczema ED5Q (mg / kg) fur material ου 15 8 0.9 3 0.6 10 1.8 9 5.4 11 4.5 20 14 2.7

In order to determine the various effects of the compounds of the invention and a representative selection of the compounds known from OK Publication No. 155007, the following tests were performed.

35 35

Binding of S-TBPS (S-tert butyl-bicyclophosphorus thionate) to rat brain cortex membranes in the absence and presence of test substance 30 S-TBPS is considered to be capable of binding specifically to the chloride ionophore of the GABA-BZ receptor complex.

Since the chloride channel is closely associated with the benzodiazepine binding sites, the binding of a BZ ligand to the receptor complex may allosterially affect the binding of S-TBPS. The effect of benzodiazepines on S-TBPS binding may conveniently be expressed as the TBPS shift, which is defined as the ratio 9.

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between TBPS binding (at a fixed concentration) in the absence and presence of a test substance (Supavilai, P. and Karobath, M., Eur.

J. Pharmacol. 91, 145-146 (1983)).

35 5 BZ receptor agonists increase TBPS binding (shift> 1), antagonists have no effect (shift * 1) and inverse 35 agonists reduce the binding of TBPS (shift <1).

Test Procedure. All preparations are carried out at 0-4 ° C unless otherwise stated. Cerebral cortex (0.1-1 g, frozen overnight at -70 ° C) from male Wistar rats (200-300 g) is thawed and homogenized for 5-10 sec. with an Ultra-Turrax homogenizer in 10 ml of Tris citrate (50 mM), pH

7.1. The homogenizer is purified with 10 ml of buffer and the total suspension is centrifuged for 10 min. at 27,000 x g. The pellet is homogenized as before in 2 x 10 ml buffer and centrifuged for 10 min. at 27,000 x g. The pellet is frozen overnight (at -70 ° C), thawed and washed twice. At each wash, the pellet is homogenized in 2 x 10 ml of 50 mM 20 Tris citrate and centrifuged at 27,000 x g for 10 min.

The pellet is again frozen overnight (at -70 ° C), thawed and washed twice. At each wash, the pellet is homogenized again in 2 x 10 ml of 50 mM Tris citrate and centrifuged at 27,000 x g for 10 min. The pellet is homogenized in Tris citrate 25 (50 mM), NaCl (1M) (100 ml per g of the original tissue) and used for binding samples.

Aliquots of 0.5 ml of tissue suspension are added to 25 µl of the test solution and 25 µl of S-TBPS (1 nM, final concentration), mixed and incubated for 60 minutes. at 25 ° C. Non-specific binding is determined using picrotoxinin twice (10 µg / ml, final concentration) as the test substance. After incubation, the samples are added 10 ml of ice-cold buffer (Tris-citrate (50 mM), NaCl (1M)) and poured directly onto Whatman GF / C glass-fiber filters under suction and immediately washed again with 10 ml of ice-cold buffer. The amount of radioactivity on the filters is determined by conventional liquid scintillation counting.

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xo

Specific binding is the total binding minus non-specific binding.

Test Procedure. Test substances are dissolved in 10 ml of water (about 5 needlessly acidified with 25 µl of 1N HCl and heated on a steam bath for a maximum of 5 minutes) at a concentration of 0.22 mg / ml. Dilutions are made in water at a concentration equivalent to a final concentration of 30 times the IC 2 q values of the benzodiazepine ligands. (The IC ^-Q values are determined from in vitro inhibition of HH-FNM binding to freeze-dried bovine brain membranes).

Results. Test value is specified as 15 TBPS shifts - Specific TBPS binding (1 nM) (+ test substance)

Specific TBPS binding (1 nM) (- test substance)

The results obtained by the test mentioned above are given in the following Table 2.

25 30 35 11

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Table 2

ISLAND

10 Or

x JT TBPS-SHI

Example R3 ratio 15 2c, compound 3 / Y "no 0.94 0 — Η 3, compound 8 AN> ^ 0.89 20 3, compound 10 / Y _ / ° T 0.81 ΧεΛ ~ ^ N ^ CH3 4d, compound 14 0.86 25 @c -O, * · “cl 1 2 3 4 5 6 * 1F (OX 1'13 2

X

3

foi 0 — N

4 * 3B -LX * 1.25 5 oc2H5 6 * Danish submission no. 155007 12

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As can be seen in Table 2, these data show that the compounds in question reduce S-TBPS binding (shift <1) or exhibit neutral effect (shift * 1) and are therefore referred to as inverse agonists or antagonists, whereas 5 from the Danish script, chemically closely related compounds, S-TBPS increases binding (shift> 1) and thus acts agonistically.

The compounds of the invention, together with a conventional excipient, carrier, or diluent, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof, may be used in the form of pharmaceutical preparations and unit doses thereof, and in this form may be used as solids. eg. as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the compound, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injection solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional conditions, with or without additional active compounds or principles, and such unit dosage forms may comprise any suitably effective central nervous system disease-relieving amount of the active ingredient in accordance with daily dose intended to be used. Thus, tablets containing one (1) milligram of active ingredient or, more broadly, one (1) to thirty (30) milligrams, per tablet, are suitably representative unit dosage forms.

Thus, the compounds of this invention can be used for the formulation of pharmaceutical compositions, for example, for oral and parenteral administration to mammals incl. humans, in accordance with conventional methods of galenic pharmacy.

Conventional excipients are pharmaceutically acceptable organic or inorganic carriers suitable for parenteral excipients.

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oral or oral administration and which do not adversely react with the active compound.

Examples of such carriers are water, saline solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid acyl acid and hydroxyl fatty acid esters, hydroxyl

10

The pharmaceutical compositions may, if desired, be sterilized and mixed with excipients, e.g. lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that influence osmotic pressure, buffers and / or dyes or the like, which do not adversely react with the active compound.

For parenteral administration, injectable solutions or suspensions are particularly suitable, preferably aqueous solutions, where the active compound is dissolved in polyhydroxylated castor oil.

Ampoules are appropriate unit dosage forms.

For oral administration, tablets, dragees or capsules with talc and / or carbohydrate as carrier or binder, or the like, are most suitable. The carrier should be lactose and / or corn starch and / or potato starch. A syrup, elixir or the like can be used when a sweetened carrier can be used. Generally, in broader scope, the compound of the invention is dispensed into unit dosage forms containing 0.05-100 mg in a pharmaceutically acceptable carrier per unit dose. 1

A typical tablet which can be prepared by conventional tablet manufacturing techniques contains:

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Active compound 1.0 mg

Lactosum 67.8 mg Ph.Eur.

A vicel® 31.4 mg

Amberiite® IRP 88 1.0 mg 5 Magnesii stearas 0.25 mg Ph.Eur.

Because of their high degree of affinity for the benzodiazepine receptors, the compounds of the invention are extremely useful in the treatment of diseases or disorders of the central nervous system when administered in an amount that alleviates, ameliorates or removes them. The important CNS activity of the compounds of the invention includes both anti-convulsive and anxiolytic activities followed by low toxicity, which together provides an extremely favorable therapeutic index. Thus, the compounds of the invention may be administered to a subject, e.g. a human or animal in need of treatment, relief, amelioration, or removal of a central nervous system disorder associated with the so-called benzodiazepine receptors which require such psycho-pharmaceutical treatment, i.e., especially cramp and / or anxiety disorders, if desired in the form of a pharmaceutically acceptable acid addition salt thereof (such as hydrobromide, hydrochloride, or sulfate, as always prepared in the usual or conventional manner, e.g., evaporation to dry substance of the free base in solution with the acid ), usually in conjunction with, or together with, a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, either orally, rectally, or parenterally (including subcutaneously), in a psychopharmaceutical central nervous system relieving effective dose. , ie an anticonvulsant and / or anxiolytic amount, and in any case an amount effective for relieving such a central nervous system disease because of their benzodiazepine receptor affinity. Suitable dosage ranges are 1-200 milligrams daily, especially 1-100 milligrams daily, and especially 1-30 milligrams daily, as always, depending on the actual manner in which it is used.

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administered in what form it is administered, what symptom the treatment is aimed at, the individual involved and the body weight of the individual involved, as well as the preference and experience of the responsible physician or animal.

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The invention is further illustrated by the following examples: EXAMPLE 1 10 a. Ethyl 4-methyl-2- (N * methylureido) thiophene-3-carboxylate

A stirred ice-cooled solution of ethyl 2-amino-4-methyl-thiophen-3-carboxylate (1.85 g, 10 mmol) and triethylamine (1.4 mL, 10 mmol) in dry tetrahydrofuran (50 mL) was added. dropwise to a phosgene solution (11 mmol, in toluene). The mixture was then heated to reflux for 30 minutes, then cooled to room temperature and poured through gaseous 20 methylamine for 5 minutes. After further stirring for 15 minutes, the mixture was filtered and the filtrate was evaporated to give the title compound as white crystals.

1 H-NMR (60 MHz, CDCl 3) (ppm): (1.5, T 3 H), (2.4, S 3 H), (2.9, D 3 H), (4.4, Q 2 H) ( 5.7, wide NH), (6.2, S 1H) (10.8, wide, NH).

In exactly the same manner, ethyl 4-phenyl-2- (N'-methylureido) thiophene-3-carboxylate was prepared, m.p. 109-12 ° C and ethyl 2- (N'-ethylureido) -4-phenyl-thiophene-3-carboxylate, m.p.

129-33 ° C from ethyl 2-amino-4-phenyl-thiophene-3-carboxylate (Gewald et al., Chem. Ber. 99, 94 (1966) and methylamine and ethylamine, respectively).

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b. 4,5-Dihydro-3,5-dimethyl-6- (5-methyl-1,2,4-oxadiazol-3-yl) -4-oxo-imidazo [1,5-a] thieno [3, 2-e] pyrimidine 5 A stirred solution of ethyl 4-methyl-2- (N'-methylureido) -thiophene-3-carboxylate (2.3 g), triphenylphosphine (2.62 g), triethylamine (1.4 ml ) and carbon tetrachloride (5 mL) in CH 2 Cl 2 (50 mL) was refluxed for 30 min, then evaporated in vacuo. The oily residue was extracted twice with boiling petroleum ether. The combined petroleum ether solutions were evaporated to give N-methyl Ν '- (3-carboe-thoxy-4-methyl-thien-2-yl) -carbodiimide as an oil. The presence of carbodiimide function was confirmed by an IR absorption band at 2140 cm -1.

15

The oil was used as below, without further purification.

A stirred -30 ° C cold solution of potassium t-butylate (1.13 g) in dry DMF (40 ml) was added 3-isocyanomethyl-5-methyl-1,2,4-oxadiazole (1.4 g) . To this solution was added a solution of the carbodiimide described above in dry DMF (20 ml).

The final solution was allowed to reach room temperature before adding acetic acid (1 ml). The solvent was removed in vacuo and the oily residue was then partitioned between ethyl acetate (25 ml) / 2 N HCl (25 ml). The aqueous phase was separated and neutralized with potassium carbonate, precipitating the title compound as oily crystals. The crude product was purified by SiO 2 fractionation with ethyl acetate / methanol-9: 1 as eluent.

This treatment gave the title compound as pale crystals. Mp. 207-208 ° C. (Compound 1).

EXAMPLE 2 17

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a. Methyl 3- (N'-methylureido) thiophene-2-carboxylate 5

A stirred solution of methyl 3-amino-thiophene-2-carboxylate (5 g, 31.8 mmol) and triethylamine (4.43 ml, 31.8 mmol) in dry tetrahydrofuran (100 ml) was added dropwise to a 20% phos gene solution in toluene (31.8 mmol). After the addition was complete, the mixture was heated to reflux for 30 minutes, followed by filtration at room temperature. The filtrate was evaporated in vacuo and the crystalline evaporation residue was suspended in water (200 ml). Filtration of the suspension afforded the title compound as white crystals. Mp. 141-142 ° C.

B. 1,2,3,4-Tetrahydro-3-methyl-2,4-dioxo-thieno [3,2-d] pyrimidine Methyl 3- (N'-methylureido) thiophene-2-carboxylate (4 , 2 g, 20 mmol) was suspended with stirring in 5% aqueous potassium hydroxide (50 ml). Dimethylformamide was added until a clear solution was obtained. Stirring was continued for 30 min, after which the solution was neutralized with acetic acid. This gave a crystalline precipitate of the title compound which was separated by filtration and washed with water. Mp. > 300 ° C.

Similarly, the following compounds were prepared: 1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-5-phenyl-thieno [2,3-d] pyrimidine, m.p. 260-262 ° C, from ethyl 2- (N'-methylureido) -4-phenylthiophene-3-carboxylate 3-ethyl-1,2,3,4-tetrahydro-2,4-dioxo-5-phenyl thieno [2,3-d] -35 pyrimidine, m.p. 255-260 ° C, from ethyl 2- (N'-ethylureido) -4-phenyl-thiophene-3-carboxylate 18

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C. Ethyl 4,5-dihydro-4-methyl-5-oxo-imidazo [1,5-a] thieno- [2,3-e] pyrimidine-3-carboxylate Solution A:

A stirred solution of 1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-thieno [3,2-d] pyrimidine (2.73 g, 15 mmol) in dry DMF (30 ml) was added. sodium hydride (0.87 g 55% in mineral oil, 20 mmol).

After stirring for 20 min. the solution was cooled to 0 ° C and chlorodiethyl phosphate (2.87 ml, 20 mmol) was added. Stirring at 0 ° C was continued for 20 min, then solution B was added (see below).

Solution B:

A -30 ° C cold stirred solution of potassium t-butylate (2.25 g, 20 mmol) in dry DMF (20 ml) was added ethyl isocyanoacetate (2.3 ml, 20 mmol). After stirring for 5 min. the solution was added to solution A.

The final mixture was allowed to reach room temperature before pouring it on water (100 ml). Acetic acid was added to neutral pH. The precipitated crude product was collected by filtration and purified by washing with hot ethanol. Mp. 258-259 ° C. (Compound 2).

Similarly, the following compounds were prepared:

3- (5-Cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-methyl-5-oxo-imidazo [1,5-a] thieno [2,3-e ] pyrimidine, mp. 178-179 ° C

from 1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-thieno [3,2-d] pyrimidine and 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole.

(Compound 3).

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Ethyl 4,5-dihydro-5-methyl-4-OXO-3-phenylimidazo [1,5-a] thieno- [3,2-e] pyrimidine-6-carboxylate, m.p. 268-69 ° C from 1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-5-phenylthieno [2,3-d] pyrimidine and ethyl isocyanoacetate. (Compound 4).

4,5-dihydro-4-methyl-3- (5-methyl-1,2,4-oxadiazol-3-yl) -5-oxo-imidazo [1,5-a] thienof2,3-e] pyrimidine , m.p. 200-201 ° C from 1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-thieno [3,2-d] pyrimidine and 3-isocyanomethyl-5-methyl-1,2, 4-oxadiazole. (Compound 5).

6- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-5-methyl-4-oxo-3-phenyl-imidazo [1,5-a] thieno [3, 2-e] pyrimidine, m.p. 235-236 ° C, from 1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-5-phenyl-thieno [2,3-d] pyrimidine and 5-cyclopropyl-3-isocyanoic acid methyl-1,2,4-oxadiazole. (compound 6).

6- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -5-ethyl-4,5-dihydro-4-oxo-3-phenyl-imidazo [1,5-a] thieno [3, 2-e] pyrimidine, m.p.

190-192 °, from 3-ethyl-1,2,3,4-tetrahydro-2,4-dioxo-5-phenylthieno [2,3-d] pyrimidine and 5-cyclopropyl-3-isocyanomethyl-1 , 2,4-oxadiazole. (Compound 7).

EXAMPLE 3 3- (3-Cyclopropyl-1,2,4-oxadiazol-5-yl) -4,5-dihydro-4-methyl-5-oxo-imidazo [1,5-a] thieno [2,3 -e] pyrimidine 1 2 3 4 5 6 2

Sodium (50 mg) was dissolved in dry ethanol (20 ml). Ethyl 4,5-3 dihydro-4-methyl-5-oxo-imidazo [1,5-a] thieno [2,3-e] pyrimidine-3-carboxylate (0.55 g, 2 mmol) , cyclopropane carboxamide 5 oxime (0.5 g, 5 mmol), and 5 g crushed mol. say 4Å was added.

6

The mixture was refluxed for 6 hours, then cooled to room temperature where methylene chloride was added (30 ml). Moth. si was filtered off and the filtrate was reduced to 5 ml at 20

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evaporation in vacuo. Addition of water (25 ml) gave a crystalline precipitate of the title compound which was collected by filtration. Mp. 215-217 ° C. (Compound 8).

Similarly, the following compounds were prepared: 4,5-dihydro-3- (3-methoxymethyl-1,2,4-oxadiazol-5-yl) -4-methyl-5-oxo-imidazo [1,5-a] thieno [ 2,3-e] pyrimidine, m.p. 206-207 ° C from ethyl 4,5-dihydro-4-methyl-5-oxo-imidazo [1,5-a] thieno [2,3-e] pyrimidine-3-carboxylate and methoxyacetamidoxime. (Compound 9).

4,5-dihydro-4-methyl-3- (3-methyl-1,2,4-oxadiazol-5-yl) -5-oxo-imidazo [1,5-a] thieno [2,3-e] pyrimidine m.p. . 263-265 ° C

15 from ethyl 4,5-dihydro-4-methyl-5-oxo-imidazo [1,5-a] thieno- [2/3-e] pyrimidine-3-carboxylate and acetamidoxime. (Compound 10).

3- (3-Ethyl-1,2,4-oxadiazol-5-yl) -4,5-dihydro-4-methyl-5-oxo-imidazo [1,5-a] thieno [2,3-e ] pyrimidine, m.p. 212-215 ° C, from ethyl 4,5-dihydro-4-methyl-5-oxo-imidazo [1,5-a] thieno- [2,3-e] pyrimidine-3-carboxylate and propionamidoxime. (Compound 11).

4,5-dihydro-5-methyl-6- (3-methyl-1,2,4-oxadiazol-5-yl) -4-oxo-3-phenyl-imidazo [1,5-a] thieno [3 , 2-e] pyrimidine, m.p. 258-61 ° C from ethyl 4,5-dihydro-5-methyl-4-oxo-3-phenyl-imidazo [1,5-a] thieno [3,2-e] pyrimidine-6-carboxylate and acetamidoxime. (Compound 12).

EXAMPLE 4 a. Ethyl 2-amino-thiophene-3-carboxylate 35 was prepared by condensing 1,4-dithian-2,5-diol with * ethyl cyanoacetate according to the literature.

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K. Gewald, Chem.Ber. 98, 3571 (1965) b. Ethyl 2- (N, -methylureido) -thiophene-3-carboxylate 5

A stirred solution of ethyl 2-amino-thiophene-3-carboxylate (5.0 g, 29 mmol) and triethylamine (4.1 mL, 29 mmol) in dry tetrahydrofuran (100 mL) was added to a 20% solution of phosgene. in toluene (16 ml, 32 mmol). The mixture was heated to reflux for 3 hours, then cooled to room temperature and treated with a stream of methylamine for 10 minutes. After further stirring for 30 minutes, the mixture was filtered and the filtrate was evaporated in vacuo, then the crystalline precipitate was suspended in water, filtered and dried to give the title compound as colorless crystals, m.p. 127 ° C.

Similarly, ethyl 2- (N'-ethylureido) -thiophene-3-carboxylate, m.p. 83-87 ° C, using the ethylamine ice cream for methylamine in the above procedure.

20 c. 1,2,3,4-Tetrahydro-3-methyl-2,4-dioxo-thieno [2,3-d] pyrimidine A mixture of ethyl 2- (N-methylureido) -thiophene-3 Carboxylate (4.78 g, 21 mmol), 5% aqueous potassium hydroxide (80 ml) and 96% ethanol (80 ml) were stirred at room temperature for 2 hours, then acetic acid (40 ml) was added. The resulting mixture was stirred at 0 ° C for 30 min, the precipitate filtered from 30 and dried to give the title compound as colorless crystals, m.p. 315-318 ° C.

Similarly, 3-ethyl-1,2,3,4-tetrahydro-2,4-dioxo-thieno [2,3-d] pyrimidine was prepared, m.p. 263-265 ° C, from ethyl 2- (N * -ethylureido) -thiophene-3-carboxylate.

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d. Ethyl 4,5-dihydro-5-methyl-4-oxo-imidazo [1,5-a] thieno- [3,2-e] pyrimidine-6-carboxylate The reaction was carried out under nitrogen.

SOLUTION A;

A stirred suspension of 1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-thieno [2,3-d] pyrimidine (1.0 g, 5.5 mmol) in dry dimethylformamide (25 ml) was added sodium hydride (55% 1 mineral oil solution, 0.31 g, 7.1 mmol). After stirring for 15 min. the solution was cooled to -30 ° C and chlorodiethyl phosphate (1.0 ml, 7.1 mmol) was added. The solution was then allowed to warm to room temperature and then solution B (see below) was added.

SOLUTION B: 20 A stirred solution of potassium t-butoxide (0.8 g, 7.1 mmol) in dry dimethylformamide (10 mL) at -30 ° C was added ethyl isocyanoacetate (0.8 mL, 7.1 mmol) ). After stirring for 5 minutes, the solution was added to solution A.

The final mixture was allowed to reach room temperature. Then acetic acid (3 ml) was added and the solvent removed in vacuo. The precipitate is partitioned between dichloromethane (25 ml) and 1M aqueous sodium hydroxide (25 ml). The organic layer was separated, dried over sodium sulfate and evaporated to give the title compound as colorless crystals, m.p. 191-192 ° C (Compound 13).

Similarly, the following compounds were prepared: 23

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6- (5-Cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-5-methyl-4-oxo-imidazo [1,5-a] thieno [3,2-e] pyrimidine, m.p. 174-176 ° C, from 1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-thieno [2,3-d] pyrimidine and 5-cyclopropyl-3-isocyanoraethyl-1,2 , 4-oxadiazole 5 (Compound 14).

6- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -5-ethyl-4,5-dihydro-4-oxo-imidazo [1,5-a] thieno [3,2-e] pyrimidine, m.p. 154-155 ° C, from 3-ethyl-1,2,3,4-tetrahydro-2,4-dioxo-thieno [2,3-d] pyrimidine and 5-cyclopropyl-3-isocyanomethyl-1, 2,4-oxadiazole (Compound 15).

4.5-Dihydro-5-methyl-6- (5-methyl-1,2,4-oxadiazol-3-yl) -4-oxo-imidazo [1,5-a] thieno [3,2-e] pyrimidine, mp. 221-222 ° C, from 1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-thieno [2,3-d] pyrimidine and 3-isocyanomethyl-5-methyl-oxadiazole ( Compound 16).

EXAMPLE 5 4.5- Dihydro-5-methyl-6- (3-methyl-1,2,4-oxadiazol-5-yl) -4-oxo-imidazo [1,5-a] thieno [3,2-e ] pyrimidine Sodium (50 mg) was dissolved in dry ethanol (50 ml). Ethyl 4,5-dihydro-5-methyl-4-oxo-imidazo [1,5-a] thieno [3,2-e] pyrimidine-6-carboxylate (0.4 g, 1.4 mmol), acetamidoxime ( 0.8 g, 11 mmol) and crushed molecular sieve 4Å (5 g) were added. After the mixture was refluxed for 8 hours, an additional amount of acetamidoxime (0.4 g) was added and heating was continued for an additional 8 hours. The mixture was then cooled to room temperature and dichloromethane (200 ml) was added. The molecular sieve was removed by filtration through a filter and the filtrate was evaporated in vacuo. The residue was dissolved in water (20 ml) and the crystalline precipitate of the title compound was collected by filtration. Mp. 268-270 ° C (Compound 17).

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Similarly, 6- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) -4,5-dihydro-5-methyl-4-oxo-imidazo [1,5-a] thieno [3 2-e] pyrimidine, m.p. 218-219 ° C, from ethyl 4,5-dihydro-5-methyl-4-oxo-imidazo [1,5-a] thieno [3,2-e] pyrimidine-6-carboxylate and cyclopropane carboxamidoxime (Compound 18 ).

Preparation of starting compounds.

EXAMPLE 6 3-Cyclopropyl-5-isocyanomethyl-1,2,4-oxadiazole a. 3-Cyclopropyl-5-formylaminomethyl-1,2,4-oxadiazole

A solution of ethyl formylaminomethyl carboxylate (150 mmol) and cyclopropyl carboxamidoxime (100 mmol) in 100% EtOH (100 mL) was added to Na (200 mg) and crushed molecular sieve (4Å) (10 g). The resulting mixture was stirred and heated to reflux for 8 hours. The mixture was cooled to room temperature, filtered through filter and the filtrate evaporated in vacuo.

The oily residue was partitioned into a CHCl 3 phase which was dried over Na 2 SO 4 and evaporated.

3-Methyl-5-formylaminomethyl-1,2,4-oxadiazole, 3-ethyl-5-formylaminomethyl-1,2,4-oxadiazole, and 3-methoxymethyl-5-formylaminomethyl-1,2,4-oxadiazole were prepared. in exactly the same way from the corresponding carboxamidoximes.

b. 3-Cyclopropyl-5-isocyanomethyl-1,2,4-oxadiazole 35

A stirred solution of 3-cyclopropyl-5-formylaminomethyl-1,2,4-oxadiazole (60 mmol) and triethylamine (176 mmol) for 25 hours.

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CH 2 Cl 2 (100 ml) was added dropwise POCl 2 (60 mmol) at 0 ° C. The mixture was then allowed to stir for 30 minutes at 0 ° C, then a solution of Na 2 CO g (60 mmol) in H2 O (50 ml) was added. The mixture was warmed to room temperature, after which the organic phase was separated, dried and evaporated in vacuo. The residue was treated with ether, decanted and the solution evaporated to give the title compound as an oil. The oil was used without further purification. The compound was characterized by its IR absorption band at 2160 cm -1.

3-Ethyl-5-isocyanomethyl-1,2,4-oxadiazole was prepared from 3-ethyl-5-formylaminomethyl-1,2,4-oxadiazole in a similar manner. IR: cm ”*: 2170.

3-Methyl-5-isocyanomethyl-1,2,4-oxadiazole was prepared from 3-methyl-5-formylaminomethyl-1,2,4-oxadiazole in a similar manner. IR: cm -1: 2170.

3-Methoxymethyl-5-isocyanomethyl-1,2,4-oxadiazole was prepared from 3-methoxymethyl-5-formylaminomethyl-1,2,4-oxadiazole in a similar manner. IR: cm -1: 2170.

EXAMPLE 7 5-Cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole a. Formylaminorethyl-carboxamide oxime 30 - 0.55 mmol or freshly prepared hydroxylamine dissolved in 370 ml of methanol was added 53.6 g (0.638 mmol) of N -formylamino-acetonitrile. An ice bath was used to keep the temperature below 35 ° C during the addition. The solution was allowed to stand at room temperature overnight and then evaporated to give the title compound as pale crystals. Dec.

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104-110 ° C.

b. 3-Formylaminomethyl-5-ethyl-1,2,4-oxadiazole 5

A mixture of 35 ml of ethyl acetate, 20 g of formylamino-methylcarboxamidoxime, 1 g of sodium and 30 g of crushed molecular sieve (4Å) was refluxed in 300 ml of abs. EtOH for 8 hours, then an additional 1 g of sodium was added. The reaction mixture was filtered, and the filtrate was evaporated. The dark oily evaporation residue was dissolved in 300 ml of CHCl 3, filtered and the filtrate evaporated to give the title compound as an oil. H-NMR (60 MHz, CDCl 3) (ppm): 1.4 (3H, t, J-8 Hz), 2.9 (2H, q, J-8 HZ) 4.55 (2H, s), 7, 8 (1H, broad-NH), 8.25 (1H, s).

The following compounds were synthesized from the corresponding ethyl esters in a similar manner: 3-Formylaminomethyl-5-methyl-1,2,4-oxadiazole. 1 H-NMR (60 MHz, CDCl 3) (ppm); 2.6 (3H, s), 4.6 (2H, d, J-3 Hz), 7.4 (1H, wide-NH), 8.25 (1H, s).

3-Formylaminomethyl-5-methoxymethyl-1,2,4-oxadiazole H-NMR (60 MHz, CDCl 3) (ppm): 3.5 (3H, s), 4.7 (4H, s + d, J-6 Hz), 7.8 (1H, broad-NH), 8.25 (H, s).

c. 5-Cyclopropyl-3-formylaminomethyl-1,2,4-oxadiazole O-cyclopropanecarbonylformylaminoethanamidoxime (M »185, 3.13 mol, 1000 g, 58%) was dissolved in demineralized tap water (900 ml).

O-cyclopropanecarbonylformylaminoethanamidoxime was prepared by acylation of the oxime in acetone and contains triethylammonium chloride in the molar ratio of 1: 1.

The solution was refluxed for 4 hours. It was investigated by

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27 HPLC that the reaction was complete. The solution was cooled to 20 ° C, filtered and the filtrate was extracted three times with 400 ml of methylene chloride. The combined methylene chloride extracts were dried over sodium sulfate (120 g) at least 4 times with stirring.

The sodium sulfate was removed by decantation and filtration and the filtrate was evaporated to give the title compound as an oil. H-NMR (60 MHz, CDCl 3) (ppm): 1.2 (4H, m), 2.8 (1H, m), 4.5 (2H, d, J * 6Hz), 7.8 (1H) , wide NH), 8.2 (1H, s).

d. 5-Cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole A stirred solution of 5-cyclopropyl-3-formylamino-methyl-1,2,4-oxadiazole (60 mmol) and triethylamine (176 mmol) in CH 2 Cl 2 (100 ml) was added dropwise POCl 2 (60 mmol) at 0 ° C. The mixture was then allowed to stir for 30 minutes at 0 ° C, then a solution of Na 2 CO 3 (60 mmol) in H 2 O (50 20 ml) was added. The mixture was warmed to room temperature, after which the organic phase was separated, dried and evaporated in vacuo. The residue was treated with ether, decanted, and the solution evaporated to give the title compound as an oil. The oil was used without further purification. The compound was characterized by its IR absorption band at 2160 cm 2

5-Ethyl-3-isocyanomethyl-1,2,4-oxadiazole, 5-methyl-3-isocyanomethyl-1,2,4-oxadiazole, and 5-methoxymethyl-3-isocyanomethyl-1,2,4-oxadiazole were prepared. in a similar way. All compounds were oils and were characterized by their IR stretch bands at 2160 cm -1.

EXAMPLE 8 28

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Methoxyacetamidoxime 5 2.3 g of sodium in 33 ml of dry methanol were mixed with 6.55 g of hydroxylamine hydrochloride in 66 ml of dry methanol. The mixture was filtered and 7.8 g of methoxyacetonitrile were added dropwise to the filtrate. The mixture was allowed to stand for 48 hours. The mixture was then cooled to 4 ° C. Filtration and evaporation of the filtrate gave 8.7 g of the title compound.

The following compounds were synthesized from the appropriate nitriles in a similar manner: 15

Acetamidoxime Propionamidoxime Cyclopropane carboxamidoxime 1sopropylearboxamidoxime 20 Isobutyramidoxime 25 30 35

Claims (10)

29 DK 159685 B 1. Imidazothienopyrimidines of the general formula I wherein: R 1 is or 15 wherein R 1 is C 1-6 alkyl, C 1-4 cycloalkyl or C 1-8 alkoxyraethyl; R 2 is C 1-6 alkyl; 20 g c and g 25 wherein R and R are independently hydrogen, C 1-6 alkyl or aryl. Compound according to claim 1, characterized in that it is 3- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) -4,5-dihydro-4-methyl-5-oxo-imidazo [ 1,5-a] thieno [2,3-e] pyrimidine Compound according to claim 1, characterized in that it is 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5 -Dihydro-4-methyl-5-oxo-imidazo [1,5-a] -thieno [2,3-e] pyrimidine 35 Pharmaceutical composition, characterized in that it contains a compound of formula I according to claims 1-3 and a pharmaceutically acceptable carrier or diluent. Pharmaceutical composition according to claim 4, characterized in that it is in the form of an oral dosage unit containing 1-100 5 mg of the active compound. Pharmaceutical composition for use in the treatment of diseases of the central nervous system, characterized in that it contains an effective amount of a compound of formula I according to claims 1-3, for the relief of such disease, together with a pharmaceutically acceptable carrier or diluent. . Use of a compound of formula 1 according to claims 1-3 for the preparation of a pharmaceutical composition for the treatment of diseases of the central nervous system. Process for the preparation of a compound of formula I according to claims 1-3, characterized in, a) reacting a compound of formula II wherein V, vV and having the meanings given in claim 1, and wherein Y is a leaving group having a compound of formula III CN - CH 2 - R 3 (III) 3 wherein R is as defined in claim 1 to form a compound of formula I, or b) reacting a reactive derivative of a compound having the general formula IV 5 ^ (IV) 0 wherein v - '/ r and having the meanings specified in claim 1, with a compound of the general formula V 10 R'-C (= NOH) NH 2 (V) wherein R 'is as defined in claim 1, to form 3 a compound of general formula I wherein R is 15 wherein R' is as defined in claim 1, or c) reacting a compound with the general formula VI - FNv - CONH, S / Γ T 25 (VI) 30 with a compound of the general formula VII r'-c (and3) 2n (c h3) 2 (VII) wherein R * is as defined in claim 1 to form a compound of the general formula VIII (CONN) Where and R is as defined in claim 1, and reacting the compound of formula (VIII) with NHOOH or another aminating agent to form a compound of general formula I wherein R 3 is O * 15 wherein R 'has the meaning defined in claim 1, or d) reacting a compound of general formula IX 20 GyC, m 25 0 Or wherein V / V and R4 have the meanings specified in claim 1, with N forming a compound of the general formula XC (* NOH) Nt ^ O (X) DK 159685 B QE. wherein V / R and R have the meanings given in claim 1, and reacting the compound of formula (X) with R'-COC1 or (R'CO) 0, where R 'has the meaning given in claim 1, z 3 to form a compound of formula I wherein R is -CL 10 wherein R 'is as defined in claim 1. Process according to claim 8, characterized in that the reaction according to step a) is carried out under alkaline conditions. 15 20 25 30 35