FI100801B - Process for the Preparation of New Therapeutically Useful 5-Substituted Thia-Cycloalkyl-1- [1,2,2-Triazolo-1,5-a] Pyrimidine Derivatives - Google Patents

Description

5 100801

Process for the preparation of new therapeutically useful 5-substituted thia-cycloalka- [d] -1,2,4-triazolo [1,5-alpyrimidine derivatives

The present invention relates to novel therapeutically useful 1,2,4-triazolo [1,5-a] pyrimidine derivatives. In particular, the invention relates to a process for their preparation. The specification also describes pharmaceutical compositions containing said compounds and the use of the compounds in the treatment of diseases.

According to the invention there is provided

15 Z

Novel 5-substituted thia-cycloalkane- [d] -1,2,4-triazolo [1,5-a] pyrimidine derivatives according to Q (i) and their pharmaceutically acceptable acid addition salts,

25 wherein in formula I

Q represents a di- (C 1-4 alkyl) amino, (C 1-4 alkyl) thio, phenyl (C 1-4 alkyl) thio or morpholino, piperidino or N-methylpiperazino group attached to the triazole ring of a heterocyclic nitrogen atom Z represents a group of the formula NR7R®, in which R7 and R8 each represent C1-6-alkyl, the latter being optionally substituted by hydroxy or a morpholino, piperidino or pyrrolidino group, and n and m are each 0, 1, 2 or 3 and their sum is 2 or 3.

2 100801

The invention covers all tautomeric forms of the compounds of general formula (I).

The compounds of the present invention have valuable biological properties.

FI patent publication 94344 discloses therapeutically useful thiopyrano-1,2,4-triazolo [1,5-a] pyrimidine derivatives having antidepressant and analgesic activity, respectively. The compounds of the present invention clearly differ in properties from these known compounds; in particular, they have clear inotropic and antianginal effects, supplemented by acute anti-inflammatory, anti-gastric, anti-gastric acid secretion properties and weak sedative, anticonvulsant and analgesic properties.

For the purposes of this application, the term "alkyl" means saturated straight or branched chain saturated aliphatic hydrocarbon groups containing the indicated number of carbon atoms (e.g., methyl, ethyl, tert-butyl, n-butyl, etc.). The term "alkenyl", in turn, refers to straight or branched chain aliphatic carbon-25 live groups having at least one double bond (e.g.

vinyl, allyl, 2-propenyl, methylallyl, butenyl, etc.). The term "phenyl (C 1-4 alkyl)" refers to O-alkyl groups in which at least one hydrogen atom has been replaced by a phenyl group (e.g., benzyl, 1-phenylethyl, 2-30 phenylethyl group, etc.). "Alkylaminoalkyl" and "dialkylaminoalkyl" groups include alkyl groups containing a certain number of carbon atoms (e.g., methylaminomethyl, methylaminoethyl, ethylaminoisopropyl, dimethylaminopropyl, dimethylaminoethyl, diisopropylaminoamino, etc.).

The term "heterocyclic group" refers to 5- or 6-membered 3,100,801 atomic or partially or fully saturated heterocyclic groups having at least one nitrogen and / or oxygen atom, which ring may optionally be fused to a benzene ring (e.g. pipe-5 radyl, morpholinyl, piperazinyl, furyl, imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, pyridazinyl, isoxazolyl, pyrrolidinyl, imidazolidinyl, pyrazolinyl, pyranyl, 1-benzylpiperazin-4-yl, indol-3-yl, etc.). .

"C 1-4 alkoxycarbonyl group" may mean, e.g., methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, etc. "A C 3-8 cycloalkyl group may be, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc."

15 The term halogen atom includes fluorine, chlorine, bromine and iodine.

The pharmaceutically acceptable salts of the compounds of general formula I can be formed, for example, with inorganic or organic acids. Examples of pharmaceutically acceptable acid addition salts include hydrochlorides, hydrobromides, sulfates, citrates, maleates, fumarates and ethanesulfonates.

Of the compounds of general formula I, the following derivatives are preferred: 2- (methylthio) -5- [N- (2-morpholinoethyl)] amino-7,8-dihydro-9H-thiopyrano [3,2-e] ] -1,2,4-triazolo [1,5-a) pyramidine 30 and: 2- (dimethylamino) -5- [N- (3-morpholinopropyl)] amino-7,8-dihydro-9H-thiopyrano [3 , 2-E] -1,2,4-triazolo [1,5-a] pyrimidine and their pharmaceutically acceptable salts.

According to the present invention there is provided a process for the addition of therapeutically useful novel 5-substituted-thia-cycloalkane [d] -1,2,4-triazolo [1,5-a] pyrimidine derivatives of the general formula (I) and their pharmaceutically acceptable acid additions. salts according to which a triazolo derivative of the general formula (II) 5 is prepared

L

wherein R 1 and R 2 represent the same as above and L represents a leaving group, preferably halogen, O-trialkylsilyl, O-alkylsulfonyl or O-arylsulfonyl, is reacted with the general formula With a 20 HZ (III) amine or thiol of formula III wherein Z is as defined above and, if desired, converting a compound of general formula (I) to a pharmaceutically acceptable acid addition salt thereof, or liberating a base of general formula (I) from its acid addition salt, or converting a compound of general formula (I) ) to a second acid addition salt.

When an amine is reacted, i.e. a compound of general formula (III): wherein Z is a compound of formula NR7R®, the excess amine can act as a solvent.

In this case, at least 2 moles of amine are reacted with a triazole derivative of general formula (II) in an amount of 1 mole. When an equimolar amount of amine is used, or when a thiol compound of general formula (III) is reacted, the reaction is carried out in a solvent. Compounds of general formula (II) in which L represents halogen, O-alkylsulphonyl or O-arylsulphonyl are reacted with compounds of general formula (III) in a protic, polar aprotic or apolar aprotic solvent in the presence of an acid scavenger. The protic solvent is preferably an aliphatic alcohol or diol, the polar aprotic solvent is preferably acetonitrile, dimethylformamide or tetrahydrofuran, the apolar aprotic solvent is preferably benzene or a homology thereof, dichloroethane, chlorobenzene or chloroform. As the basic acid scavenger, a tertiary base such as triethylamine is preferably used.

15

When compounds of general formula (II) in which L represents O-trialkylsilyl are reacted with an equimolar amount of an amine or thiol of general formula (III), when the symbol of formula Z represents a group of formula SR9, the reaction is preferably carried out in a polar aprotic state. or in an apolar aprotic solvent. Suitable polar aprotic solvents are mainly acetonitrile, dimethylformamide or tetrahydrofuran, suitable polar aprotic solvents are benzene or a homologue thereof, 1,2-dichloroethane or chloroform. It is also possible to react the O-trialkylsilyl ester of the general formula (III) in situ, i.e. in the reaction mixture in which it is formed, with an amine of the general formula (III) or a thiol. In this case, the solvent may be an excess of the silylating agent used for the preparation of the compounds of general formula (II).

The reaction can be carried out at any temperature between 35 ° C and the boiling point of the solvent used or the excess amine. Preferably, the reaction is carried out at a temperature of 30 to 80 ° C.

6 100801

The obtained compounds of general formula (I) can be separated from the reaction mixture by methods known per se. The compounds crystallize from the reaction mixture either directly or after the addition of water, whereupon they can be filtered off. If they differ in oily form, they can be extracted with a water-immiscible organic solvent, after which the solvent is evaporated off and the residue is clarified by methods known per se.

From the experiments we have performed, it appears that the compounds of general formula (II) used as starting materials can be prepared from known compounds of general formula (IV) for 15 s.

N / N C

s | _I

N (IV) 2 O by converting the oxo group of the compound of general formula (IV) into a leaving group, preferably by means of a mineral halide, a silylating agent, an alkyl or arylsulfonyl halide.

25

The amines and thiols of general formula (III) are commercial products.

The compounds of general formula (I) have valuable positive inotropic and antianginal effects. These effects are complemented by an acute anti-inflammatory effect, an inhibitory effect on gastric ulcer formation and gastric acid secretion, in addition to which the compounds have a weaker sedative, anticonvulsant and Anal-35 genetic effects.

The activities of the compounds of general formula (I) 7 100801 are demonstrated by the following experiments.

1. Positive inotropic effect in anesthetized cats 5

The experiments were performed on male and female cats anesthetized with chloralose urethane (40/300 mg / kg i.p. in a volume of 1 ml per kg). Polyethylene Tetri was injected into the left ventricle through the right subclavian artery. Inotropic activity was measured with the first derivative as a function of left ventricular pressure over time (dP / dt. HSE (Hugo Sachs Eleet-roniese) amplifier The signals thus obtained were recorded on a Lineacorder Mark VII polygraph type WR 3101. Test compounds were administered through a cannula 20 inserted into the femoral vein.

Table I shows the positive inotropic response (dP / dt ,, **) characteristic of the compounds.

25 8 100801

Table I

Positive inotropic effect

Compound Dose dP / dt ^ 5 Example No. mg / kg i.v. % 0.5 35.5 53 1.0 48.0 5.0 95.0 10 10.0 93.6 __ __

Amorin 5.0 53.9 10.0 48.3 15 _ 1.0 56.4

Trapidil 5.0 67.9 10.0 42.3 20

It can be seen from Table I that the compounds of general formula (I) increase the dP / dt values in a dose-dependent manner, said values being characteristic of myocardial force. At the same time, for both reference compounds, the potencies do not exceed 50% even at the highest dose (10 mg / kg). When comparing doses of the same size, the compounds of the invention are about 1.5- to 3.5-fold more potent than the reference compounds.

30 2. Positive inotropic effects measured in guinea pigs

The experiments are performed according to the method of Alous [Alousi, 35 A.A. et al .: J. Cardiovasc. Pharmacol, 5 (1983) 804-811].

Animals weighing 400-600 g were stunned with a head stroke and bled. The heart was excised, the right ventricle was removed and placed in a solution of Tyrod at 37 ° C. It was preloaded with 2.1 g and 40 was electrically stimulated at 2 Hz ... with pulses 9,100,801 for 0.5 ms. The first derivative of the contractile force of the isolated organ as a function of time (dP / dt) and atrial frequency were measured with a polygraph. Percentage changes were calculated from the data thus obtained. The results are shown in Table II.

Table II

Positive inotropic effect in guinea pigs 10 Compound Astringent Frequency

Ex. No. dP / dt (%) (%) 39 51-12

Trapidil 50 - 7 15 Amrinone 33 28

The positive inotropic effect of the compounds is considerably better than that of the reference compounds.

In addition, the compounds of the invention are significantly less tachycardic.

The compounds of the invention may be formulated into pharmaceutical preparations containing as active ingredient at least one compound of general formula (I) or a pharmaceutically acceptable acid addition salt thereof in admixture with a suitable inert solid or liquid carrier.

These pharmaceutical preparations can be obtained by methods known per se by mixing the active ingredient with suitable inert solid or liquid carriers and bringing the mixture into galenic form.

The pharmaceutical compositions of this invention may be administered orally (e.g., tablet, pill, coated tablet, granule, hard or soft gelatin capsule, solution, emulsion, or suspension), parenterally (e.g., solution for injection), or rectally (e.g., suppository). .

Lactose, corn starch, potato starch, talc, magnesium carbonate, magnesium stearate, calcium carbonate, stearic acid 10 or its salts can be used as carriers for the preparation of tablets, coated tablets, granules and hard gelatine capsules. fats, waxes or polyols of suitable composition. Water, polyols (polyethylene glycol), sucrose or glucose can be used, for example, as carriers for solutions and syrups. Solutions for injection may contain as carrier, for example, water, alcohols, polyols, glycerol or vegetable oils. Suppositories can be prepared, for example, by means of oils, waxes, fats or polyols of suitable composition.

20

In addition, the pharmaceutical preparations may contain excipients commonly used in the pharmaceutical industry, e.g., wetting, sweetening, flavoring, salts for regulating the osmotic pressure, buffers, etc. The pharmaceutical preparations may also contain other active ingredients.

The compounds of general formula (I) can be advantageously used in therapy orally in the form of tablets or capsules. Particularly preferred are capsules or tablets containing about 50 mg of active ingredient.

The daily dose of the compounds of general formula (I) may vary widely depending on several factors, e.g. the activity of the active ingredient, the condition and age of the patient, the severity of the disease, etc. The oral dose is generally 10 to 1000 mg / day, preferably 50 to 500 11 100801 mg / day. It should be emphasized that these dose values are for information only and the dose to be administered should always be determined by a physician.

5

The compounds of general formula (I) or their pharmaceutically acceptable salts can be used for the preparation of pharmaceutical compositions which have, in particular, positive inotropic and antianginal effects.

The compounds of general formula (I) or pharmaceutically acceptable salts thereof may be used in cardiotonic and antianginal treatments, wherein an effective amount of said compound or a salt thereof is administered to a patient.

The following non-limiting examples illustrate the invention.

20

Example 1 (outside the invention) 5- (diethylamino) -2- (methylthio) -6,7-dihydro-8H-cyclopenta [dl -1,2,4-triazolo [1,5-a] pyrimidine 4.81 g (0.02 mol) of 5-chloro-2- (methylthio) -6,7-dihydro-8H-cyclopenta [dl-1,2,4-triazolo [1,5-a] pyrimidine is suspended in 30 ml 2-propanol. 2.93 g (0.04 mol) of diethylamine are added to the suspension and the reaction mixture is boiled for 1.5 hours. The resulting solution is evaporated to dryness, after which the crystalline residue is suspended in 40 ml of water, filtered, washed with water, dried and recrystallized from aqueous methanol. Yield 5.32 g (96%)

M.p .: 119-120.5 ° C

35 12 100801

Example 2 5- (Diethylamino) -2- (dimethylamino) -7,8-dihydro-9H-thiopyrano [3,2-d] -1,2,4-triazolo [1,5-a] pyrimidine said compound was prepared according to Example 1 by placing 5-chloro-2- (dimethylamino) -7,8-dihydro-9H-thiopyrano [3,2-e] -1,2,4-triazolo [1,5-a] pyrimidine react with diethylamine.

Yield: 5.43 g (88.5%)

M.p .: 124-126 ° C (recrystallized from ethyl acetate)

Example 3 (outside the invention) 2- (methylthio) -5- [N- (2-morpholinoethyl)] amino-6,7,8,9-tetrahydro-10β-cyclohepta [E] -1,2,4-triazolo - [1,5-a] pyrimidine 4.84 g (0.018 mol) of 5-chloro-2- (methylthio) -6,7,8,9-20 tetrahydro-10H-cyclohepta [E] -1,2,4 -triazolo [1,5-a] pyrimidine is suspended in 15 ml of 2-propanol, 2.02 g (0.02 mol) of triethylamine and 2.60 g (0.02 mol) of 2- aminoethylmorpholine, followed by boiling for 1 hour. The cold sus-25 pension is diluted with water, the separated crystals are filtered and washed with water.

Yield: 6.28 g (96%)

M.p .: 173-174 ° C (recrystallized from acetonitrile) 13 100801

Example 4 2- (Methylthio) -5- [N- (2-morpholinoethyl)] amino-7,8-dihydro-9H-thiopyrano [3,2-dl-1,2,4-triazolo [1,5-a] ] pyrimidine 5

The title compound was prepared according to Example 3 by reacting 5-chloro-2- (methylthio) -7,8-tetrahydro-9H-thiopyrano [3,2-dl -1,2,4-triazolo [1,5-a] pyramidine to react with 2-aminoethylmorpholine.

10

Yield: 5.48 g (83%)

M.p .: 123-124.5 ° C (recrystallized from acetonitrile) Example 5 2- (dimethylamino) -5- [N- (2-morpholinoethyl)] amino-7,8-dihydro-9H-thiopyrano [3, 2-dl -1,2,4-triazolo [1,5-a] pyrimidine To a suspension of 5.40 g (0.02 moles) of 2- (dimethylamino) -5-chloro-7.8 -9H-thiopyrano [3,2-dl -1 / 2,4-triazolo [1/5-a] pyrimidine in 20 ml of 2-propanol, 2.125 g (0.021 mol) of triethylamine and 2.73 g ( 0.021 mol) of 2-aminoethylmorpholine, after which the reaction mixture is boiled for one hour. After cooling, it differs from triethylamine hydrochloride, which is filtered and washed with 2-propanol. The filtrate is evaporated to dryness in vacuo and the residue is dissolved in chloroform. The solution thus obtained is extracted twice with water, dried over dried Na2SO4 and evaporated in vacuo. The oily product is suspended in ethyl acetate. The crystalline product thus obtained is filtered off and washed with ethyl acetate.

Yield: 5.42 g (74.5%) 35 M.p .: 110-113 ° C (recrystallized from ethyl acetate) 14,100801

Following the procedure of Example 3, the following derivative is prepared by reacting a triazolo derivative of general formula (II) with an amine of general formula (III).

5

Example 6 2- (Dimethylamino) -5- [N- (3-morpholinopropyl)] amino-7,8-dihydro-9H-1-pyrano [3,2-dl -1,2,4-triazolo [1, 5-alpyrimidine 10

Yield: 5.35 g (71%)

M.p .: 86-89 ° C (recrystallized from ethyl acetate) Example 7 2-Morpholino-5- [N- (3-morpholinopropyl) amino] -6,8-dihydro-9H-thiopyrano [4,3-dl] -1,2,4-triazolo [1,5-a] pyrimidine

To a solution of 2.43 g (0.0078 mol) of 5-chloro-2-20 morpholino-6,8-dihydro-9H-thiopyrano [4,3-d] -1,2,4-triazolo [1, 5-a] -pyrimidine in 15 ml of acetonitrile, 1.44 g (0.01 mol or about 1.46 ml) of 3-morpholinopropylamine and 1.01 g (0.01 mol or about 1.39 ml) are added. ) triethylamine and the reaction mixture is boiled for 1 hour • with stirring. It is then cooled and the separated product is filtered off and washed with water and acetonitrile. Yield: 3.02 g (92.3%)

M.p .: 173-176 ° C (after recrystallization from acetonitrile) 30

Example 6 2- (Dimethylamino-5- [N- (2-hydroxyethyl) amino] -7,8-dihydro-9H-thiopyrano [3,2-dl -1,2,4-triazolo [1,5-a] pyramidine 35

A mixture of 1.35 g (0.005 mol) of 2- (dimethylamino-Ί 5-7,8-dihydro-9H-thiopyrano [3,2-dl-1,2,4-triazolo [1,5-100,801] a] pyrimidine, 5 ml of isopropanol and 0.61 g (0.01 mol) of ethanolamine are boiled for half an hour with stirring, 10 ml of water are added to the warm solution, the mixture is cooled, then the separated product is filtered off and washed with water and cold isopropanol.

Yield: 1.27 g (86.4%)

M.p .: 187-189 ° C (after recrystallization from acetonitrile) 10

Claims (3)

A process for the preparation of novel therapeutically usable 5-substituted-thia-cycloalka- [d] -1,2,4-triazolo [1,5-alpyrimidine derivatives and pharmaceutically acceptable acid addition salts thereof of the general formula (I) ) z 10 s / (CH ^ y ^N'N «YQ (I) 15 wherein Q represents a group of di- (C ^ g alkyl alkyl) amino, (C 1-6 alkyl) thio, phenyl-CC. β-alkyl) thio or morpholino, piperidino or N-methylpiperazino, which is attached to a triazole ring via the heterocyclic nitrogen atom, 20. represents a group of the formula NR7R8, wherein R7 and R8 are each hydrogen or a C alkyl, the latter being optionally substituted by a hydroxy or a morpholino, piperidino or pyrolidino group, and n and m can each be 0, 1, 2 or 3, their sum being 2 or 3, characterized in that a triazole derivative of the general formula (II) L s / (ch 2 W 2 -n nn (II) x (ch N) 100801 wherein Q means sarana as above and L represents a leaving group, preferably halogen, O-trialkylsilyl, O-alkylsulfonyl or O -arylsulfonyl, is reacted with an amine or thiol of general formula (III) 5 HZ (III) wherein Z means sarana as above, and if desired, the compound of general formula (I) is converted to a pharmaceutically acceptable acid addition salt, or a base of the general formula (I) is released from its acid addition salt, or the acid addition salt of the base of the general formula (I) is converted to another acid addition salt. Process according to claim 1, characterized in that compounds of the general formula (I) are prepared, wherein Q represents dimethylamino, methylthio, benzylthio or morpholino, Z represents a group of the formula Wherein R 4 and R 8 each represent C 1-6 alkyl, possibly containing a hydroxy or morpholine substituent, and n and m mean as above. Process according to claim 1, characterized in that 2- (methylthio) -5- [N- (2-morpholinoethyl)] amino-7,8-dihydro-9H-thiopyrano [3,2-d] -1 is prepared. / 2,4-triazolo [1,5-aipyrimidine or a pharmaceutically acceptable salt thereof. Process according to claim 1, characterized in that 2- (dimethylamino) -5- [n- (3-morpholinopropyl) 3-Jamino-7,8-dihydro-9H-thiopyrano [3,2-d] -1 is prepared. , 2,4-triazolo [1,4-alpyriridine or a pharmaceutically acceptable salt thereof.