FI74004C - FRAME FOR THE PREPARATION OF THERAPEUTIC ANIMAL PRODUCTS PIPERAZINYLPYRIDO / 2,3-B / -CH - / 3,4-B / PYRAZINE DERIVATIVES. - Google Patents

Description

1 74004

Process for the preparation of therapeutically useful piperazinyl-pyrido ε-2,3-b7 and β-4-fe7pyrazine derivatives 5 Separated from patent application 831790

The present invention relates to a process for the preparation of therapeutically useful piperazinylpyrido [2,3-b] 7- and β-3,4-b7-pyrazine derivatives of formula I

10 "^> - Χ - (<: Η2> 3-Ν ^ Ν- ^ βΑν Xr2 111 15 wherein one of A and B is N and the other is CH; and R £ represents hydrogen, methyl or ethyl or R 1 and R 2 together represent tetramethylene, and X is -CO- or -O-, and to prepare their acid addition salts.

F is preferably in the para position with respect to the X moiety. A suitable X is -O-, but more preferably X is -CO-. R 1 and R 2 are primarily the same.

The process according to the invention for the preparation of the compounds of the formula I is characterized in that the compound of the formula IV

5 74004 a ^ V-nh2 ^ g> -X-.CH2,3-N_ ^ N-WbJLhh2

wherein A, B and X are as defined above, optionally reacting a carbonyl group with a compound of formula VI

10 V 1 (VI) 0 R 2 wherein and R 2 are as defined above and then the carbonyl protecting group which may be present is removed. The process can be carried out in the usual manner used in analog ring condensations. The process is expediently carried out at a temperature in the range 40-160 °, preferably in the range 60-120 °. Suitable solvents are methanol, tetrahydrofuran, dioxane, toluene or n-propanol.

When X is -CO- in the resulting compound of formula I, it is convenient to use a carbonyl protecting group, e.g. a dialkyl ketal group such as dimethyl or diethyl ketal group or an alkylene ketal group such as ethylene or n-propylene ketal group. Removal of such a group can be performed in a known manner.

For example, compounds of formula IV can be obtained according to the following reaction scheme: 74004 3 ÄNO, R, -NH A NO 2

x I T

6 Rf * ^ NH2 + F _

10 ^ MCH2) 3-OH

-Οθζ I CH3 20 l

IV

Rg = bromine or especially chlorine.

Each carbonyl protecting group can be removed in a known manner either before or after condensation with a compound of formula VI.

Insofar as the preparation of the starting materials is not specifically described, these compounds are known or can be prepared in the same manner as the known compounds or by the methods described herein.

The compounds of formula I can be converted into their acid addition salts in the customary manner and vice versa. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, succinic acid, maleic acid or fumaric acid.

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In the following examples, all temperatures are reported in degrees Celsius and are uncorrected.

The following abbreviations are used in the table: 1) oxalate 5 2) bis-maleate 3) hydrochloride 4) dihydrochloride 5) decomposes

Example 1 10- [4- (2,3-Dimethyl-pyrido [2,3-d] pyrazin-6-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1-butanone (Compound I)

A mixture of 9 g of 4- [4- (2,3-diaminopyridin-6-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1-butanone and 2.6 g of butane-2, 3-dione in 250 ml of methanol, stirred at reflux for 15 hours. The solvent is evaporated off. The residue is dissolved in hot ethyl acetate and treated with activated carbon, filtered and cooled to give the title compound, m.p. 155-156 °.

The starting material can be obtained as follows: A mixture of 6 g of 2-amino-6-chloro-3-nitropyridine, 12.6 g of 1- (4-fluorophenyl) -4- (1-piperazinyl) -1-butanone- dihydrochloride and 20 g of potassium carbonate in 120 ml of n-propanol, stirred at reflux for 21/2 hours. The mixture is then treated with 400 ml of water, stirred for a further 10 minutes and cooled in an ice bath. The precipitate obtained is filtered off, washed with water, dissolved in methylene chloride, dried over sodium sulfate and evaporated to dryness. Obtained 1- (4-fluorophenyl) -4- [4- (2-amino-3-nitropyridin-6-yl) -1-piperazinyl] -1-butanone, m.p.

128-130 °, dissolved without further purification in 400 ml of methanol. To the solution is added 3 g of palladium on charcoal (5%) and the mixture is hydrogenated under normal conditions. The catalyst is filtered off and the solvent is distilled off to give 1- (4-fluorophenyl) -4- [4- (2,3-diaminopyridin-35-yl) -1-piperazinyl] -1-butanone, which is used without further purification.

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Example 2

In analogy to Example 1, the following compounds of formula I with hydrogen are prepared:

Eg A B R- | R2 X Sp.

a CH NHH CO 4-F 130-131 b CH N C2H5 C2H5 CO 4-F 99-100 10 c N CH CH3 CH3 CO 4-F 138-139 d N CH HH CO 4-F 124-126 e N CH C2H5 C2H5 CO 4-F 118-121 f N CH - (CH2) 4 - CO 4-F 138-140 15 g N CH HHO 4-F 98-100

The compounds of the formula I have a pharmacological effect and are therefore indicated for use as pharmaceuticals, e.g. for therapeutic purposes. In particular, the compounds have a tension-triggering effect, which has been demonstrated by standard experiments, e.g., by inhibiting the movement of mice. In this experiment, groups of three male mice (18-24 g, OF-1, Sandoz Basle) were orally administered 3.2, 10, 32, 25, 100, and 320 mg of the test herb. One hour after drug administration, mice were examined individually and their movements were compared to those of control animals.

In addition, the compounds of formula I bind to the 1 H-spiperone binding sites of the brain. Modified method of Leysen et al., Biochem. Pharmac. 27, 307 (1978)

The experiment was performed as follows: fresh calf striated tissue was homogenized in 25-fold volume of Tris buffer (pH 7.4, 50 mmol, 120 mmol sodium chloride) and centrifuged. The granules were suspended in 22-fold volume of Tris buffer, incubated for 15 minutes at 6 74004 at 37 ° C and centrifuged. The granules were suspended in 300-fold volume of Tris buffer, incubated for 15 minutes at 37 ° C and centrifuged. The granules were suspended in 300-fold volume of Tris buffer. The composition of the test mixtures 5 was as follows: 45 mmol Tris buffer pH 7.7, 108 mmol sodium chloride, membranes corresponding to 6 mg weight of the original tissue, 0.1 nanomole H 2 -spiperone, -7 5 x 10 moles cinaserin 5- To eliminate the contribution of HT2 receptors and 1 .mu.mol of unlabeled spipe to determine non-specific binding. To determine the inhibition of specific binding of H-spiperone, test plants were added to give 5-9 different concentrations, ranging from 1 nanomolar to 10 μmol, in two experimental batches. After incubation for 40 minutes at 15 room temperature, the test mixtures were rapidly filtered

Through a Whatman GF / B filter, the filters were washed twice with 5 ml of ice-cold Tris buffer and counted on a scintillation counter.

The compounds are therefore indicated for use as stress-triggers. The daily dosage indicated for this use is from about 25 to about 600 mg of the compounds, administered in appropriately divided doses 2-4 times a day in unit dosage form containing from about 6 to about 300 mg or in sustained release form.

Furthermore, the compounds of the formula I have an antihypertensive effect, which has been demonstrated by standard experiments, for example as a binding assay for H-prazosin for O 2 receptors / P. Modified method of Greengrass et al., 30 Eur. J. Pharmac. 55, 323-326 (1979), 7. The experiment was performed as follows:

Fresh calf cortical tissue is homogenized in 20 volumes of Tris-HCl buffer (50 mmol, pH 7.7) using a Polytron PT 20 and centrifuged at 35,000,000 x g for 25 minutes. The granules are resuspended in 13 times the volume of the same buffer, incubated for 7 minutes at 37 ° C and centrifuged at 50,000 x g for 11 minutes. The granules from this centrifugation are frozen at -20 ° C and resuspended in 60 times the volume of the same buffer as above before being used in the binding assay. The composition of the test mixtures (total volume = 2 ml) is as follows: 50 mmol Tris-HCl buffer pH 7.7, membranes corresponding to 30 mg of original tissue weight and 0.3 nanomoles of H-prazosin. Test samples for the determination of non-specific binding further contain phentolamine at a concentration of 10 .mu.mol. To determine the efficacy of the herbs to prevent specific binding of H-prazosin (difference between total binding and non-specific binding), test compounds are added to give 5-9 different concentrations between 1 nanomolar and 10 μmol, in two test portions. After 40 minutes of incubation at room temperature, the test mixtures are rapidly filtered through Whatman GF / B filters and washed twice with 5 ml of ice-cold Tris buffer. The radioactivity of the filters is estimated by counting with a scintillation-20 counter.

The compounds are therefore indicated for use as antihypertensive agents. The daily dosage to be administered for this use is from about 5 to about 100 mg of the compounds, administered in appropriately divided doses 2 to 4 times a day in unit dosage form containing from about 1 to about 50 mg or in sustained release form.

In addition, the compounds of formula I have an anti-pulse effect, as shown by standard experiments. For example, in a guinea pig atrium in vitro /R.P. The method of Hof and G. Scholtysik, J. of Carciovascular Pharmacology 5, 176-183 (1983), a decrease in spontaneously pulsating heart rate has been observed at a bath concentration of between about 1 and about 100 .mu.mol.

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The compounds are therefore indicated for use as antipruritics. The daily dose to be administered for this use is about 10 to 100 mg of the compounds, suitably administered 2 to 4 times a day in the form of divided dosage units containing about 2 to about 50 mg or in a sustained-release form.

The compounds of formula I may be administered in the form of a pharmaceutically acceptable acid addition salt. The effect of such acid addition salts is of the same order of magnitude-10 as that of the free base forms. The present invention also provides a pharmaceutical combination comprising a compound of formulas I and VII, or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutically acceptable carrier or diluent. Such combinations may be in the form of, for example, a solution or a tablet.

The stress-triggering effect is the primary indication for the compounds of formula I.

Claims (1)

A process for the preparation of therapeutically useful piperazinylpyrido [3,3-f] and?-3,4-phenyrazine derivatives of formula I wherein one of A and B is N and the other is CH; R 1 and R 2 represent hydrogen, methyl or ethyl or R 1 and R 2 together represent tetramethylene; and X is -CO- or -O-; and their acid addition salts, characterized in that the compound of formula IV 20 <J ^ - (CH2> 3- {3 ^ bXh2 <IV) 25 in which A, B and X have the same meaning as above, optionally with a carbonyl group is protected, reacted with a compound of formula VI ° Y * 1 (VI, 30 r2 wherein R1 and R2 are as defined above, and then any carbonyl protecting group present is removed and the compound of formula I is recovered as free base-35). form or in the form of an acid addition salt.