CS241503B2 - Method of guanidine derivatives production - Google Patents

Description

The present invention provides guanidine derivatives which are H-2 histamine antagonists and inhibit gastric acid secretion.

It is believed that the physiologically active substance histamine, which is naturally present in the animal organism, is able to bind to certain specific receptors of at least two different and different types when exhibiting its activity. The first of these receptors has been named as the H-1 receptor (see Ash and Schild, Brit. J. Pharmac., 1966, 27, 427) and the effect of histamine on this receptor is blocked (antagonized) by classical "antihistamines" such as mepyramine. The second histamine receptor has been named the H-2 receptor (see Black et al., Nature, 1972, 236, 385), and the effect of histamine on this receptor is blocked by agents such as cimetidine. It is known that one of the results of blocking the effect of histamine on the H-2 receptor is the inhibition of gastric acid secretion and that a compound exhibiting this ability is therefore useful in the treatment of gastric ulcers and other conditions caused or re-induced by gastric acidity.

The British came. No. 2 052 478 A and Japanese Patent Application No. GB 2 052 478 A. No. 56,577,777 (Derwent Accesion No. 74,736 D / 41) discloses H-2 histamine receptor antagonists which are 2-guanidinothiazole derivatives bearing a side chain at the 4-position to which a carbamoyl group is attached. It has now been found that haloalkylguanidinoheterocycles bearing a side chain to which an optionally substituted carbamoyl group is attached at the end are potent antagonists of the H-2 histamine receptors.

The present invention relates to a process for the preparation of guanidine derivatives of the formula I

R

R ¹

G? N Z z- '. O R i V 'π /

·, Ζ-ACN i ** ** (!) Wherein each of R ¹ and R ² , which may be the same or different, represents a hydrogen atom, a branched or unbranched alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having C 3 -C 8 or C 4 -C 14 cycloalkylalkyl, each of which is optionally substituted by alkyl, cycloalkyl or cycloalkylalkyl groups

24150 3

one or more halogen atoms selected from the group consisting of fluorine, chlorine and bromine atoms, with the proviso that at least one of R ¹ and R ² is a halogen-substituted alkyl, cycloalkyl or cycloalkylalkyl group, with the proviso that on the carbon atom alkyl, cycloalkyl or cycloalkylalkyl group which is directly attached to the nitrogen atom, there is no halogen substituent, or R 2 represents a hydrogen atom and R 1 represents a radical of formula II _R 5 _-E - _W (ii) wherein

W represents an unbranched C 2 -C 6 alkylene chain optionally substituted by one or two C 1 -C 4 alkyl groups,

E represents an oxygen or sulfur atom, a sulfinyl group, a sulfonyl group or a radical of the formula NR ⁶ , wherein R ⁶ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms and

R ⁵ represents a hydrogen atom or a straight-chain alkyl group having 1 to 6 carbon atoms, optionally substituted by one or two alkyl groups having 1 to 4 carbon atoms, or are

R 5 and R 6, taken together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidine, morpholine, piperazine or N-methylpiperazine ring, the dotted line in the X ring being a double bond on one side of the nitrogen atom, and

Z represents a carbon or nitrogen atom, such that the ring X is a five- or six-membered aromatic heterocyclic ring containing - at least one nitrogen atom and optionally containing one or two additional heteroatoms selected from oxygen, nitrogen and sulfur atoms, the heterocyclic ring X where appropriate, it may optionally carry one or two substituents selected from the group consisting of fluorine, chlorine and bromine atoms, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethyl, hydroxy and amino,

A represents a phenylene group, a C 5 -C 7 cycloalkylene group or an C 1 -C 8 alkylene group. optionally substituted with one or two alkyl groups of 1 to 3 carbon atoms and optionally containing one or two groups selected from the group consisting of oxygen and sulfur atoms, NH, N-alkyl of 1 to 6 carbon atoms, cis- and trans a vinylene group, an ethynylene group, a phenylene group and a C5-C7 cycloalkylene group, provided that the shortest part of the chain between ring X and C = D consists of at least 3 atoms, the A chain being optionally interrupted by a group directly bonded to - C = D, wherein the group is not oxygen, sulfur, NH or N-alkyl, and wherein no two groups are optionally interrupted by a chain of residue A selected from oxygen and sulfur atoms, NH and N groups -alkyl! are not connected to each other,

D represents an oxygen or sulfur atom,

R3 is hydrogen, hydroxy, amino, (C1-C6) alkylamino, (C1-C6) haloalkylamino, (C1-C6) alkanolamino, (C1-C6) alkyl, (C3-C8) cycloalkyl) C 1 -C 6 cycloalkylalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 hydroxyalkyl C 1 -C 6 alkoxyalkyl, C 2 -C 10 alkoxyalkyl, C 2 -C 10 alkylthioalkyl, C 1 -C 6 aminoalkyl, C 2 -C 8 alkylaminoalkyl, C 3 -C 12 dialkylaminoalkyl, C 2 -C 8 alkanoylaminoalkyl, C 8 -C 14 aroylaminoalkyl, C 3 -C 10 alkoxycarbonylalkyl a carbamoylalkyl group having 2 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, an arylalkyl group having 7 to 11 carbon atoms, a heteroaryl or heteroarylalkyl group, wherein the heteroaryl moiety is a heterocyclic aromatic radical containing one, two or three heteroatoms selected oxygen, nitrogen and sulfur atoms, the alkyl portion of the heteroarylalkyl group having 1 to 6 carbon atoms, wherein when R 3 is or contains an aryl or heteroaryl ring, the ring is optionally substituted with one or two substituents selected from the group consisting of fluorine atoms, chlorine, bromine and iodine, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 2 -C 6 dialkylamino, C 2 -C 6 alkanoyl , trifluoromethyl, hydroxy and amino, and

R4 is hydrogen or

R 3 and R 4 are taken together and together with the nitrogen atom to which they are attached to form a five-, six- or seven-membered saturated ring optionally containing a double bond or an additional oxygen atom, an NH or N-alkyl group, up to 6 carbon atoms, and pharmaceutically acceptable acid addition salts thereof.

It is understood that although in the above general formula (I) and throughout the double bond in the guanidine residue attached to the ring X is located at a particular position, there are other tautomeric forms, at 245050.

Accordingly, the invention includes both tautomeric forms, both as to the particular compounds and to the method for their preparation. When A represents or contains a cycloalkylene radical, the groups attached to this radical may be in the cis- or trans-configuration. When A represents or contains a cycloalkylene residue and / or when A represents an alkylene chain substituted by one or two alkyl groups, such compounds of the formula I will in most cases contain at least one center of asymmetry. Thus, in such cases, the compounds of formula I will exist in at least two enantiomeric forms, the exact number of which is determined by the number of centers of asymmetry. As discussed below, the biological activity of these enantiomeric forms may vary and it should be emphasized that the invention encompasses the racemates of formula I above, including all possible diastereoisomeric forms and all enantiomeric forms exhibiting the desired biological activity, and it is well known how to separate them. diastereoisomeric forms and how racemates can be resolved into individual enantiomers to determine the biological activity of all of these.

Particular halogen-substituted alkyl groups R ¹ or R ² are

2.2.2-trifluoroethyl,

2.2.2-trichloroethyl, 2-chloro-2,2-difluoroethyl,

2.2-dichloro-2-fluoroethyl, 2-bromo-2,2-difluoroethyl,

2.2-dibromo-2-fluoroethyl, 2-fluoroethyl, 2-chloroethyl,

2.2-difluoroethyl,

2.2-dichloroethyl, 2-chloro-2-fluoroethyl, 2-bromo-2-fluoroethyl,

2.2.3.3- tetrafluoropropyl,

2.2.3.3.3.

1.1.1.3.3.3- hexafluorisopropyl,

1,3-dichloro-1,1,3,3-tetrafluoroisopropyl,

1-chloro-1,1,3,3,3-pentafluoroisopropyl,

1,3-difluorisopropyl or

2,2,3,3,4,4 _: 4-heptafluorobutyl.

Particular halogen-substituted cycloalkyl groups R ¹ or R ² are

2.2.3.3- Tetrafluorocyclopropyl,

2-chloro-2,3,3-trifluorocyclopropyl,

2,2-difluorocyclopropyl,

2-chloro-3,3-difluorocyclopropyl,

2,2,3,3,4,4-hexafluorocyclobutyl or 2-chloro-2,3,3,4,4-pentafluorocyclobutyl.

Particular halo-substituted cycloalkylalkyl groups represented by R ¹ or R ² are (1,2,2,3,3-pentafluorcyklopropylJmethylová (2-chloro-l, 2,3,3-tetrafluorcyklopropyljmethylová (1,2,2,3, 3,4,4-heptafluorocyclobutyl] methyl or (2-chloro-1,2,3,3,4,4-hexafluorocyclobutyl) methyl.

Particular alkyl groups for R ¹ and R ² are methyl, ethyl, propyl, isopropyl or butyl.

A particular cycloalkyl group R ¹ or R ² is a cyclopropyl or cyclobutyl group.

A suitable cycloalkylalkyl group R @ ¹ or R @ ² is cyclopropylmethyl or cyclobutylmethyl.

A preferred optional substituent on W is methyl.

A suitable radical R ⁵ is a hydrogen atom or a methyl group.

A suitable radical R ⁶ is a hydrogen atom or a methyl group.

A suitable radical of formula (II) is a 2-methoxyethyl, 2-hydroxyethyl, 2-methylthioethyl or 2-dimethylaminoethyl group.

Particular values for ring X include oxazole, thiazole, imidazole,

1,2.4-thiadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, pyrazole, pyrazine, pyridine, pyrimidine or

A triazine ring, all of which may, where possible, be optionally substituted by one or two substituents selected from the group consisting of fluorine, chlorine and bromine atoms, methyl, methoxy, trifluoromethyl, hydroxy and amino.

A suitable radical for the meaning of the symbol -A- is phenyl, cyclopentylene, cyclohexylene, trimethylene, tetramethylene, pentamethylene, thioethylene, thiotrimetbylene, thiotetramethylene, thiopentamethylene, oxyethylene, oxytrimethylene, methylmethylene, oxytetramethylene, oxytetramethylene, oxytetramethylene, oxytetramethylene, oxytetramethylene, -methylethylene, thiopropylene thiomethylene, oxyethyleneoxymethylene, iminoethylene, iminopropylene, vinylene propylene, oxymethylene vinylene, 1,3-phenylene, 1,3-cyclopentylene, methylene-1,4-phenylene, ethyleneoxymethylene-1,4-phenyl or a thiomethylenethinyllenmethylene group. The writing of these residues in the meaning of the symbol “A” is done by reading from left to right in formula I, so that the former portion of each residue is bonded to the ring X and the latter portion of each residue is bonded to the grouping C = D. for example, if —A— is thiomethy241503

A phenethynylenmethylene group, the compound of formula I comprises a group of formula III

D

- * OZ-S-CH, -C £ C “Cf / -C” in ^{г L} (lil)

Specific R ³ radicals include hydrogen, hydroxy, amino, methylamino,

2,2,2-trifluoroethylamino, acetylamino, methyl, cyclohexyl, cyclohexylmethyl, allyl, propargyl, 2,2,2-trifluoroethyl, methoxy, 2-hydroxyethyl, 2-methoxyethyl, 2-methylthioethyl , 2-aminoethyl, 2-methylaminoethyl, 2-dimethylaminoethyl, 2-acetylaminoethyl, 2-benzoylaminoethyl, methoxycarbonylmethyl, 2-carbamoylpropyl, phenyl, benzyl, heteroaryl and heteroarylmethyl, the heteroaryl portion of the last two is a furan, thiophene, pyrrole, thiazole, oxazole, imidazole, thiadiazole, oxadiazole, triazole, pyrazole, pyridine or pyrimidine ring, wherein when R ³ is or contains a phenyl or heteroaryl ring, the ring is optionally substituted with one or two su substituents selected from the group consisting of fluorine, chlorine, bromine and iodine, methyl, methoxy, methylthio, dimethylamino, acetyl, trifluoromethyl, hydroxy, and amino.

A suitable ring formed by R ³ and R ^{4 together} is a pyrrolidine, piperidine, morpholine, piperazine or N-methylpiperazine ring.

The following are 7 preferred meanings for the guanidine derivatives of formula I. When any of these meanings, either singly or in combination, are considered together with the other general or specific meanings given above for the guanidine derivatives of formula I, suitable subgroups of compounds falling within the above general definition of these compounds which can be prepared by the process of the invention.

1; R ³ and R ⁴ represent hydrogen atoms.

Second R ² is hydrogen and R ^{1 2} is 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, or 2,2,3,3-tetrafluorpropylovou group,

3. Ring X bears no optional substituent.

4. Ring X represents a pyrazole, 1,2,3-triazole or 1,2,4-triazole ring to which residue A is attached at position 1, a pyrimidine ring to which residue A is attached at position A, or a thiazole ring, to which symbol A is attached in position 4.

5. Ring X represents a pyrazole, 1,2,3-triazole or 1,2,4-triazole ring to which residue A is attached at the 1-position.

6. Ring X represents a pyrazole ring.

7. —A— means a tetramethylene, pentamethylene, oxytrimethylene, oxytetramethylene, thiatrimethylene or thiatetramethylene residue.

Specific compounds of the invention are shown in the Examples below. The following is a preferred group of compounds which can be prepared by the process of the invention:

4- [4- (2- / 2,2,2-trifluoroethyl / guanidino) pyrimid-2-ylthio] butyramide (Example 31),

5- (3- (2- / 2,2,2-trifluoroethyl / guanidino) pyrazol-1-yl) valeramide (Example 35),

5- [3- (2- / 2,2,3,3-tetrafluoropropyl / guanidino) pyrazol-1-yl] valeramide (Example 38),

5- [3- (2- / 2-chloro-2,2-difluoroethyl / guanidino) pyrazol-1-yl] valeramide (Example 39),

5- [4- (2- / 2,2,2-Trifluoroethyl / guanidino) -1,2,3-triazol-2-yl] valeramide (Example 40),

5- [4- (2- / 2,2,3,3-Tetrafluoropropyl / guanidino) -1,2,3-triazol-2-yl] valeramide (Example 42),

6- [4- (2- / 2,2,2-trifluoroethyl / guanidino) -1,2,3-triazol-2-yl] hexanamide (Example 43),

4- [4- (2- / 2,2,3,3-tetrafluoropropyl / guanidino) pyrimid-2-yloxy] butyramide (Example 48),

4- [2- (2- / 2,2,3,3-tetrafluoropropyl / guanidino) pyrid-6-ylthio] butyramide (Example 57), as well as pharmaceutically acceptable acid addition salts thereof.

Within this group of compounds, the compounds of Examples 35, 38 and 48 are preferred, and the compound of Example 35 is particularly preferred.

Suitable pharmaceutically acceptable acid addition salts of guanidine derivatives of Formula I of Formula I are, for example, salts with hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid or maleic acid.

The process according to the invention is characterized in that the compound of the general formula (IV ⁾ o

R ² '' C ~ -C = N ^λ / ZAC-DH / ^X N ^Z or an activated derivative thereof with a compound of formula

R ³ R ⁴ NH

The activated derivative may be, for example, an ester such as a C 1-6 alkyl ester, for example a methyl or ethyl ester, or an acid halide, for example an acid chloride or bromide. Alternatively, the activated derivative may be an anhydride, for example a mixed anhydride. Particularly useful mixed anhydrides are those formed by the reaction of a compound of formula IV with a chloroformate, for example ethyl chloroformate or isobutyl chloroformate. The reaction may be carried out in a diluent or solvent such as methanol, ethanol, methylene dichloride, tetrahydrofuran or dimethylformamide and may be accelerated or completed by heating, for example by heating to boiling the diluent or solvent. When the activated derivative is an acid halide, it is preferred to carry out the reaction in the presence of a base such as triethylamine and to use a non-alcoholic diluent or solvent.

When the compounds of formula (I) are obtained in the form of the free bases and the acid addition salts are to be prepared, the compound of formula (I) in the free base form is reacted with an acid to give a pharmaceutically acceptable anion.

The starting materials of formula IV used in the process of the invention can be obtained by separately building two side chains on the respective ring X. Thus, the side chain on the left side of the ring can be built by reducing the nitro group to the amino group by reacting the amino group with an isothiocyanate

R ¹ R ² N = C = S and finally the reaction of the resulting thiourea with ammonia in the presence of mercury oxide. The process of constructing the side chain on the right side of the ring may vary depending on the nature of the ring X, the nature of the ring X atom to which the remainder A (carbon or nitrogen) is attached, and the presence or absence of atoms or groups introduced into In the above construction, it may be necessary to protect the acid functions in the form of cyano or ester groups and, in the final step, hydrolytic regeneration of the carboxyl function. If residue A contains no built-in group or if the built-in group is a phenyl radical and Z represents a carbon atom, it is preferable to build a ring X with a side chain already present on the right side. Thus, when ring X is a thiazole ring, the procedures illustrated in Examples 25, 26, 27 and 28 can be used. Below ring X is a 1,2,3-triazole ring, it can be built by reacting methazonic acid with a suitable azide, as illustrated in Example 10 When ring X is a pyrimidine ring, it can be built by reacting a suitably substituted imino ether with 2-chloroacrylonitrile, as exemplified in Example 15. If the group introduced into the A chain is a vinylene or ethinylene group, the A moiety can be introduced by double or triple bonding condensation methods. When the group introduced into the A chain is a cycloalkylene group, the A chain can be built by conjugation addition to the corresponding cycloalk-2-enone. When the built-in group in the A chain is an oxygen or sulfur atom, or an NH or N-alkyl group, the sidechain on the right side can be built in a manner analogous to that illustrated in Examples 1, 13, 23, 29 and 30.

As mentioned above, the guanidine derivatives of the invention are H-2 histamine antagonists, inhibit gastric acid secretion in warm-blooded animals and are therefore useful in the treatment of gastric ulcers and other conditions caused or re-induced by gastric acidity including ulcers from stress and gastrointestinal bleeding as a result of injury.

The efficacy of antagonizing histamine H-2 receptors can be demonstrated by standard assays, such as the ability of compounds of Formula I to inhibit histamine-induced positive chronotropic responses in spontaneously beating guinea pig atrium or their ability to inhibit histamine-induced aminopyrine consumption in the acidic area of result cells.

The guinea pig atrium test is performed as follows:

The guinea pig's right atrium is suspended in a 25 ml thermostatically controlled (30 ° C) tissue bath containing oxygenated (95% CH, 5% CO 2) Krebs-Henseleit buffer (pH 7.4) at 1 g (isomeric). The tissue is allowed to stabilize for 1 hour, during which time it is washed two to four times. Individual contractions are recorded by a force transfer transducer through a extensometric coupler and the instantaneous velocity is monitored with a cardiotachometer. A control response to 1% histamine is observed, and the tissue is washed three times and allowed to re-equilibrate to baseline. After re-equilibration for 15 minutes, the test compound is added until final concentration is reached. Ten minutes after the addition of the test compound, histamine (1 μΜ) is added again and the response to histamine in the presence of antagonist is compared to the control response to histamine. The results are expressed as a percentage of the control response to histamine. The apparent dissociation constant of the H-2 antagonist is then determined by standard procedures.

The aminopyrine test is performed as follows:

The gastric mucosa of the New Zealand white rabbit is separated from the muscle and washed in buffer 1 [containing 1 liter of 8.007 g of sodium chloride, 0.201 g of potassium chloride, 0.113 g of potassium monohydrogen phosphate, 0.204 g of potassium dihydrogen phosphate, 0.132 g of calcium chloride dihydrate, 0.101 g and 1 g glucose, and is adjusted to pH 7.4 with sodium hydroxide. The tissue is finely chopped, suspended in buffer 1 and washed three times with buffer 1. The tissue is then suspended in a dispersant medium [100 g collagenase (Sigma Chemical Co., type V) and 100 mg bovine serum adbumin (Miles Laboratories Ltd., fraction V) in 100 ml buffer 1; 50 ml medium per 10 g net tissue weight and incubated at 30 ° C and pH 7.4 under continuous stirring in an oxygen atmosphere (conditions continuously monitored and maintained) After 30 minutes, the tissue was allowed to settle and the supernatant was removed, fresh dispersion medium (50 ml per ml) was added. 10 g of wet tissue weight and incubation is continued After 40 to 60 minutes, the tissue dispersion consists predominantly of glands and whole cells, and the remainder of the remaining tissue is removed by filtration through a nylon mesh. in buffer 1 containing 1% bovine serum albumin (Miles Laboratories LTD., fraction V) Finally, the cells and glands were washed three times with buffer 1 and suspended in the buffer. u 2 (contains 500 ml Eagles medium, 10 mg aprotinin (Sigma Chemical 'Co.) and 20 ml (150 mmol) 2- [4- (2-hydroxyethyl) piperazin-1-yl) ethanesonic acid, adjusted to pH 7 with sodium hydroxide, 4; 150 ml, per 10 g net tissue weight. The tissue suspension is stirred at 32 degrees Celsius for at least 1 hour before use.

The tissue suspension was incubated for 20 minutes with test compound and 10 C-labeled aminopyrine μΐηοΐ -dimethylamino ^at (0.1, u ^ i / IML). The consumption of aminopyrine is then stimulated by the addition of histamine and a phosphodiesterase inhibitor ICI 63 197 (Biochem.

Soc. Special Publication 1, 1973, pp. 127-132) to final concentrations of 105, resp. 5 x 10 ^-7 M. After 18 minutes, cells and glands are separated from the incubation medium by filtering the suspension through glass microfiber filters. The mixture of cells and glands is then washed rapidly (in less than 10 seconds) three times with ice-cold buffer 1. The ^H- labeled aminopyrine retained in the tissue is then measured on a scintillation counter and the degree of inhibition of aminopyrine consumption caused by the control is calculated. test compound. From a series of tests performed at different concentrations, the concentrations of the test compound causing 50% inhibition are graphically determined.

All of the compounds exemplified herein were subjected to either a swine fever test or an aminopyrine test. All substances tested in a guinea pig atrium are effective at a bath concentration of 10 μΜ or even lower, with the more active of these compounds showing complete inhibition of responses at that concentration. All compounds tested by the aminopyrine assay show 50% inhibitory consumption of aminopyrine at a concentration of 3 μΜ or below.

Inhibition of gastric acid secretion can be demonstrated by standard tests, such as the ability of the compounds of Formula I to inhibit acid secretion of gastric juices, for example in rats or dogs with gastric fistula or denervated vesicles in the stomach fund, by intravenous, gastric or oral administration. in which gastric secretion has been stimulated by administration of a secretion enhancer, such as pentagastrin, histamine, bethanechol or food.

The rat test is performed as follows:

Female rats weighing 200-230 g are anesthetized by intramuscular administration of urethane at a dose of 1.5 g / kg and cannulated into their trachea. A soft tube is inserted through the esophagus into the stomach of the test animal, which is fastened in the neck region by a ligature. A plastic tube (3 mm diameter) with a plurality of holes is inserted into the anterior region of the stomach by incision in the duodenum and secured by a ligature around the pylorus. The esophagus cannula is washed with saline (9 g of sodium chloride at a dose of 7 ml / min) and the liquid collected from the pyloric duct is collected in beakers at 10 minute intervals.

Acid secretion is stimulated by subcutaneous administration of a specific H-2 antagonist dimaprite at a dose of 10 mg / kg followed by an infusion at a dose of 30 mg / kg / h. Acid secretion is calculated by titrating samples taken after 10 minutes. Titration is performed with 20 mM sodium hydroxide to an end point of pH 6.4. Once the acid secretion has reached uniform values (three consecutive readings are in the range of 5%), the test compound is administered intravenously via a cannula inserted into the left external jugular vein. Secretion is then measured for an additional 2 hours. A stock solution of each of the test compounds (10 mg / ml in dimethylsulfoxide) was prepared first, and an appropriately diluted solution of 1 ml / kg (dimethylsulfoxide concentration less than 2%) was prepared from this stock by dilution with saline.

The test on dogs with chronic fistula is performed as follows:

A 9 to 12 kg beagle purebred bitch, with a chronic stomach fist, is fasted overnight while not restricting drinking water intake. During the experiment, the dog is slightly tied in the stirrups so that he is forced to stand. To determine the effect of the test compound on intravenous administration, the fistula is opened and, following the absence of basal secretion within 30 minutes, continuous intravenous infusion of the secretion enhancer (0.5 µm / kg / h histamine or 2 µm / ml / kg) is initiated. Gastric acid samples are collected every 15 minutes. The volume of each sample is measured and the 1 ml aliquot is titrated with 100 mM sodium hydroxide until neutrality to determine the acid concentration. stable levels of secretion (1-2 hours), the test compound is intravenously administered in saline, and gastric acid samples are taken for an additional 2-3 hours, continuing to infuse the secretion enhancer.

To determine the effect of the test compound on gastric administration, after detection of the absence of basal secretion (within 30 minutes), the test compound contained in the medium consisting of 25 ml 0.5% (w / v) hydroxypropyl methylcellulose and 0.1% ( Tween 80 surfactant in water into the stomach of the animal with the fistula cap After 1 hour, the fistula is reopened and an intravenous infusion of the secretion enhancer as described above is started immediately. observe the gastric acid samples and the approximation of acid secretion to a stable level is compared to that of a control animal with only the vehicle being introduced into the stomach.

To determine the efficacy of oral administration, the test substance is administered in the form of a gelatin capsule rinsed with 15 ml of water. After one hour, the fistula is opened and the intravenous infusion of the secretion enhancer begins immediately. Gastric acid samples are collected and monitored as described above and the approximation of acid secretion to a stable level is compared to that of a control animal to which the test compound has not been administered.

The test on dogs with denervated vesicles in the stomach fund is performed as follows:

Male beagles (14-22 kg) with vague-denerved vesicles in the fundus region were prepared (see Rudick et al., J. Surg. Res. 1967, 7, 383). Animals are allowed to recover for 4 to 6 weeks after surgery, followed by training and standardization of the secretory response for a further 2 to 3 months prior to testing. Before the test, dogs are fasted for 23 hours (water intake is not limited). During the experiments, the dogs are slightly suspended on fabric straps. After washing the sachet with warm water, histamine is infused at a dose of 10 µg / min. This agonist dose induces a submaximal (60-90% of maximum) increase in acid secretion in all experimental dogs. The secretions from the sac are collected at fifteen minute intervals in calibrated glass tubes and measured to the nearest 0.1 ml volume. Dilute a 500 μΐ sample with 5 ml of brine and titrate with 100 mM sodium hydroxide to pH 7.0. The total acid production is calculated from the acid concentration in the secretion and the secretion volume. Test compounds are administered intravenously at a dose of 0.1 ml / kg to the vein of cephalica or orally as a gelatin capsule while the secretion has stabilized (three consecutive readings are in the range of 10%). Secretion is measured for 3 hours after administration of the test substance.

The results obtained in the guinea pig atrium test and the aminopyrine test indicate the efficacy in the rat and dog tests.

No marked signs of toxicity or side effects were observed during rat and dog tests. 5- (4- (2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-yl) valeramide, 5- (4: - [2- (2,2,2-trifluoroethyl) guanidino] - 1,2,3-triazol-2-ylvaieramide, 5- {6- [2 - '(2,2,3,3-etrafluoropropyl) guanidino] pyrid-2-yl valeramide, and 5- (3- [2- (2,2,2-trifluoroethyl) guanidino [pyrazol-1-yl] valeramide was administered intravenously to groups of two anesthetized rats and four awake mice at doses equivalent to 10 and 100 times the dose (in mg / kg) causing approximately 50% inhibition of secretion gastric acid in anesthetized rats No signs of toxicity were noted in any of the test animals receiving these doses.

Many of the compounds disclosed in this assay cause inhibition of gastric acid secretion which, after a few hours, does not deviate from maximum inhibition at all or at all.

The N-methylcyanguanidine moiety in known H-2 receptor antagonists can be converted into a mutagenic N-nitroso-N-methyl-cyanguanidine moiety in mammalian bodies (see Pool et al., Toxicology, 1979,

15, 69). The corresponding group in the compounds of the invention, of the formula CONR ⁵ R ⁴ , is not

1G when R3 and R4 represent hydrogen atoms, potentially for carcinogenic nitroso derivatives.

The guanidine derivatives produced by the process of the invention may be used in the form of pharmaceutical compositions containing guanidine derivatives in combination with non-toxic, pharmaceutically acceptable diluents or carriers.

For example, the pharmaceutical compositions may be in a form suitable for oral, rectal, parenteral or topical administration. For this purpose, the compositions may be formulated in known manner, for example, into tablets, capsules, aqueous or oily solutions or suspensions, emulsions, dispersible powders, suppositories, sterile injectable aqueous or oily solutions or suspensions, gels, creams, ointments or lotions. washing.

In addition to the guanidine derivatives of formula (I), these pharmaceutical compositions for oral, rectal or parenteral administration may contain or be co-administered with one or more known drugs selected from the group consisting of antacldics, such as a mixture of aluminum hydroxide and magnesium hydroxide, antipepsin, such as pepstatin, other histamine H-2 antagonists such as cimetidine or ranitidine, ulcer healing agents such as carbenoxolone or bismuth salts, anti-inflammatory agents such as ibuprofen, indomethacin, naproxen or aspirin, prostaglandins such as 16, Z 2 Taglandin E, classic antihistamines (H1 histamine antagonists) such as mepyramine or diphenhydramine, anticholinergic agents such as atropine or propantheline bromide, anxiolytic agents such as for example diazepam, chlordiazepoxide or phenobarbit al.

The topical pharmaceutical compositions may contain, in addition to the guanidine derivative of the formula I, one or more classical antihistamines (H1 histamine antagonists), such as mepyramine or diphenylhydramine, and / or one or more steroidal anti-inflammatory agents, such as fluocinolone and the like. triamcinolone.

Topical compositions may contain from 1% to 10% (w / w) of a guanidine derivative.

A preferred pharmaceutical composition is a formulation suitable for oral administration in unit dosage form, for example a tablet or capsule containing 5 to 50% of a guanidine derivative, or a formulation suitable for intravenous, subcutaneous or intramuscular injection, for example a sterile injection formulation containing 0.1 to 10% (w / w) guanidine derivative.

These pharmaceutical compositions are normally administered to humans for the treatment of gastric ulcers and other conditions caused or re-induced by gastric acidity in the same vicious manner as used in the administration of cimetidine, taking into account the potency and duration of action of the derivative in terms of dose levels. guanidine compared to cimetidine. Thus, for oral administration, each patient will be administered a dose ranging from 5 to 500 mg, preferably from 10 to 100 mg of the guanidine derivative, and intravenously, subcutaneously or intramuscularly, a dose ranging from 0.5 to 50 mg, preferably from 2 to 20 mg of the guanidine derivative, wherein the respective composition will be administered one to four times, preferably once a day.

The rectally administered dose will be approximately equal to the orally administered dose. The disclosed compositions may be administered less frequently if they contain an amount of the guanidine derivative that is a multiple of the dose effective when administered one to four times daily.

The invention is illustrated by the following non-limiting examples. NMR spectra are reported in terms of δ versus tetramethylsilane (<S = 0) as an internal standard. Signal shapes are indicated by the following abbreviations:

s = singlet d - doublet t - triplet q = quartet m = multiplet w - wide signal.

The term "ether" refers to diethyl ether.

Example 1

A mixture of 0.18 g of ethyl 4- {4- [2- (2,2,2-Crifluoroethyl) guanidino] pyrimid-2-ylthiobutyrate and 5 ml of a 33% (w / v) solution of methylamine in ethanol for 4 days The mixture was stirred at room temperature and evaporated to dryness. The residue was recrystallized from ethyl acetate to give 0.09 g of N-methyl-4- (2,2,2-trifluoromethyl) guanldino] pyrimidin-2-ylthio-butyramide, m.p. 153-155 ° C. ’

The ester used as starting material in the above process can be prepared as follows.

A mixture of 0.64 g of 2-thiocytosine, 1.07 g of ethyl 4-bromobutyrate and 0.84 g of 1,5-diazabicyclo [5.4.0] -undec-5-ene is stirred for 4 hours and then evaporated to a residue. drought. The residue was stirred with water, extracted with ethyl acetate, dried and evaporated to dryness. 1.9 g of a resinous residue are obtained, which is dissolved in 5 ml of acetonitrile, 1.1 g of 2,2,2-C-trifluoromethyl-isolyl-cyanate are added to the solution, and the mixture is heated at 70 DEG C. for 72 hours. 48 hours · add an additional 0.5 g of starting isothiocyanate. The resulting mixture was cooled and the crystallized solid product was filtered off. This gives θ ^ γ1-4- {4- [3241503

(2,2,2-Trifluoroethyl) thioureido] pyrimid-2-yl-thiobutyrate, m.p. 104-106 ° C.

A mixture of 0.25 g of ethyl 4- (4- [3- (2,2,2-trifluoroethyl) thioureido] pyrimid-2-ylthio-butyrate, 2 ml of dimethylformamide, 5 ml of saturated ethanolic ammonia and 0.2 g of yellow oxide The filtrate was evaporated to dryness and the residue was recrystallized from ethyl acetate to give ethyl 4- {4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimidine. 2-ylthio} butyrate, m.p. 120-122 ° C.

Example 2

A mixture of 0.2 g of ethyl 4- {4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-ylthio] butyrate, 0.5 ml of ethanolamine and 5 ml of methanol is heated under reflux for 48 hours. and then evaporated to dryness. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried, evaporated to dryness and the residue was recrystallized from a small volume of ethyl acetate. There was obtained 0.62 g of N- (2-hydroxyethyl) -4- (4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-ylthio) butyramide, m.p. 148-150 ° C.

Example 3

A mixture of 0.2 g of ethyl 4- (4- [2- [2,2,2-trifluoroethyl) guanidino] pyrimid-2-ylthio butyrate, 2 ml of ethylenediamine and 5 ml of methanol was allowed to react at room temperature for 18 hours and then treated with ethyl acetate. Heat to reflux for 4 hours. The reaction solution was evaporated to dryness, the residue was stirred with water and extracted with ethyl acetate. The extract is dried, evaporated to dryness, the residue is dissolved in acetone and this solution is added to an acetone solution of maleic acid. After filtering off the precipitate, 0.22 g of N- (2-aminoethyl) -4- (4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-ylthio] butyramide is obtained.

Using an analogous procedure to that of Example 1, using ethyl 5- (4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-ylthio (valerate (prepared analogously to butyrate used in Example 1)) gives N methyl 5- [4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-ylthio] valeramide, m.p. 148-150 ° C.

Example 5

Analogous to Example 2, using ethyl 5- (4- [2- (2,2,2-trifluorobenzyl) guanidino] pyrimid-2-ylthio; valerate as starting material) gave N- (2-hydroxyethyl). -5- (4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-yithio (valeramide hydrogen maleate), m.p. 179-181 ° C.

Example 6

The procedure described in Example 1 was repeated using hydrazine instead of methylamine. 4- (4- (2- (2,2,2-Trifluoroethyl) guanidino] pyrimid-2-ylthio) butyric acid hydrazide, m.p. 192-195 ° C.

Examples 7 to 9

The procedure described in Example 13 was repeated using 4- (4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-ylthio-butyric acid and the appropriate amine starting material to give the following compounds:

/ N i- ⁰

and..

example —R Example 15: 7 CF3CH2— m.p. 170-178 ° C yield 47%. 8 Example 16: 9 Comment: —ОСНз maleate, m.p. 161-163 ° C, yield 15%. The starting material can be prepared as follows: Example 14: following procedure: maleate temperature mp 202-204 ° C A mixture of 1.03 g of ethyl 4- (4- [2- (2,2,2-trifluoro- yield 50%. ethyl) guanidino] pyrimid-2-ylthioibutyrate a

A solution of 0.13 g of sodium hydroxide in 10 ml of water was heated at reflux for 1 hour and then cooled. The reaction solution was acidified with glacial acetic acid and the crystallized white material was filtered off. There was obtained 0.75 g of 4- [4- (2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-ylthio) butyric acid, m.p. 234-236 ° C.

Example 10

A mixture of 0.2 g of 3 / 4- [2- (2,2,2-trifluoroethyl) guanidino] -1,2,3-triazol-2-yl] benzoic acid, 2 ml of thionyl chloride and 10 ml of tetrahydrofuran was heated to steam for 10 minutes. bath. The reaction mixture is evaporated under reduced pressure, the residue is redissolved in 10 ml of tetrahydrofuran and re-evaporated under reduced pressure. This new dissolution and evaporation is repeated once more. The residue was dissolved in 10 ml of tetrahydrofuran and poured into 20 ml of aqueous ammonia (density 0.880), whereupon a gummy precipitate formed. This precipitate is extracted with ethyl acetate, dried over magnesium sulphate, concentrated to a small volume and treated with a solution of 0.071 g maleic acid in a small volume of acetone, precipitating 0.146 g.

3- {4- [2- (2,2,2-Trifluoroethyl) guanidino) -1,2,3-triazol-2-yl} benzamide, m.p. 199-201 ° C.

The starting material can be prepared as follows:

To a solution of 61 g of sodium hydroxide in 122 ml of water heated to 45-50 ° C was added 61 g of nitromethane at a rate to maintain the above temperature. At the end of the addition, the temperature was raised to 55 ° C for 10 minutes and then allowed to drop again to 50 ° C. The resulting mixture was cooled and neutralized to pH 7 with concentrated hydrochloric acid at a temperature of not more than 10 ° C. The precipitated product was redissolved by the addition of 40 ml of 12.5 N aqueous sodium hydroxide to give a sodium methazonic acid solution.

To a suspension of 68.6 g of 3-aminobenzoic acid in 126.3 ml of concentrated hydrochloric acid and 20 ml of water, a solution is added at 0-5 ° C over about 30 minutes.

36.2 g of sodium nitrite in 300 ml of water. Filtration of the resulting mixture gave a solution

3-carboxybenzenediazonium chloride.

A solution of 3-carboxybenzenediazonium chloride, cooled to 5 ° C, was added to the sodium methazonic acid solution at 10 ° C. A precipitate is immediately precipitated, which is dissolved in 100 ml of 33% (w / w) aqueous sodium hydroxide to a dark red solution, to which 100 ml of acetic anhydride is added while stirring at 25 DEG C., maintaining the basic reaction by adding 200 ml of 33%. % (w / w) aqueous sodium hydroxide. The reaction mixture is acidified with concentrated hydrochloric acid and the precipitated product is filtered off. 101.2 g of a brownish solid are obtained. ml of methanol and 0.5 ml concentrated sulfuric -acid was heated 3 hours at reflux к 'under' reflux condenser ^1. The reaction mixture was neutralized with 1N aqueous sodium hydroxide, concentrated and partitioned between chloroform and brine. The chloroform phase was dried over magnesium sulfate and evaporated to give 5.9 g of a red colored oil which slowly crystallized. The solid product was purified by medium pressure liquid chromatography on a silica gel column using ethyl acetate as eluent. 5.3 g of solid material are obtained which, after recrystallization twice from isopropanol, yields 2.7 g of methyl 3- (4-nitro-1,2,3-triazol-2-yl) benzoate, m.p. 104-106 ° C. .

A mixture of 1.0 g of methyl 3- (4-nitro-1,2,3-triazol-2-yl) benzoate, 0.5 g of 5% (w / w) palladium on carbon and 100 ml of acetic acid was pressurized. 0.1 MPa of hydrogen was stirred until 300 ml of hydrogen were taken up. The reaction mixture was filtered and evaporated to give 0.91 g of methyl 3- (4-amino-1,2,3-triazol-2-yl) benzoate, melting after recrystallization from methanol at 132-134 ° C.

To a warm mixture of 0.44 g of methyl 3- (4-amino-1,2,3-triazol-2-yl) benzoate and 5 ml of acetonitrile is added 0.34 g of 2,2,2-trifluoroethylisothiocyanate, the resulting mixture Allow to cool and react at room temperature for 21 hours. The reaction mixture is filtered, the filter residue is washed with ether and petroleum ether (b.p. 60-80 ° C), and dried. 0.63 g of methyl 3- [4- (3- (2,2,2-trifluoroethyl) thioureido) -1,2,3-triazol-2-yl] benzoate is obtained, m.p. 187-188 ° C.

A mixture of 0.5 g methyl 3- [4- (3- / 2,2,2-trifluoroethyl / thioureido) -1,2,3-triazol-2-yl] benzoate, 0.4 g mercuric oxide and 10 ml 6M ethanolic ammonia was stirred at room temperature for 2 hours, then an additional 0.1 g of mercury oxide was added and stirring was continued for 2 hours. The reaction mixture was filtered and evaporated to give 0.47 g of methyl 3- [4- (2- / 2,2,2-trifluoroethyl / guanidino) -1,2,3-triazol-2-yl] benzoate, melting after recrystallization from ethyl acetate and petroleum ether (b.p. 60-80 ° C) at 177-173 ° C.

A mixture of 0.55 g of methyl 3- [4- (2- / 2,2,2-trifluoroethyl / guanidino) -1,2,3-triazol-2-yl] benzoate, 10 ml of ethanol and 1.7 ml 1N aqueous sodium hydroxide is stirred at room temperature for 18 hours, then 0.6 ml of 1N aqueous sodium hydroxide is added and the resulting mixture is allowed to stand overnight at room temperature. The reaction mixture was diluted with 1N aqueous sodium hydroxide, washed with ethyl acetate, acidified to pH 4, and extracted with a mixture of ethyl acetate and tetrahydrofuran (2: 1 v / v). The extract was dried (MgSO4) and evaporated to give 0.27 g of 3- [4- (2- / 2,2,2-trifluoroethyl / guanidino) -1,2,3-triazol-2-yl] benzoic acid. , which is used without further purification.

Example 11

A mixture of 0.12 g of methyl 3- [4- (2- / 2,2,2-trifluoroethyl) guanidino) -1,2,3-triazol-2-yl] benzoate. 3 ml of ethanol and 1 ml of hydrazine hydrate are allowed to stand overnight at room temperature. The reaction mixture is diluted three times in succession with ethanol and evaporated, the final residue is recrystallized from methanol. 0.03 g of 3- [4- (2- (2,2,2-trifluoroethyl) guanidino] -1,2,3-triazol-2-yl] benzoic acid hydrazide, m.p. 209 DEG-210 DEG C., is obtained.

Example 12

A mixture of 0.2 g of methyl 3- [4- (2- / 2,2,2-trifluoroethyl) guanidino] -1,2,3-triazol-2-yl] benzoate and 5 ml of ethanolamine was heated at room temperature overnight. 80 ° C, then evaporated and the thick oily residue purified by silica gel chromatography using ethyl acetate / isopropanol (6: 1 v / v) as the eluent to give the product after recrystallization from isopropanol N- (2-hydroxyethyl) - 3- [4- (2- / 2,2,2-trifluoroethyl / guanidino) -1,2,3-triazol-2-yl] benzamide, m.p. 171-173 ° C.

Example d 13

To a suspension of 0.25 g of 4- [6- (2- / 2,2,2-1,4] difluoroethyl / guanidino) pyrazin-2-ylthio] butyric acid in 10 ml of tetrahydrofuran at 0 ° C was added 0.082 g first. triethylamine and then 0.088 g. ethyl chloroformate, the resulting mixture was stirred for 30 minutes, 5 ml of tetrahydrofuran ammonia solution was added thereto, and the mixture was stirred again for 30 minutes while allowing the temperature to reach room temperature. The reaction mixture is concentrated in vacuo, 5 ml of aqueous sodium hydrogen carbonate solution are added to the residue, and the mixture is extracted twice with 25 ml of ethyl acetate each time. The extract was dried over magnesium sulphate, filtered and evaporated in vacuo to a pale yellow solid which was purified by medium pressure liquid chromatography on silica gel using methanol / dichloromethane (1:10 v / v) as eluent. The solid obtained is dissolved in ethyl acetate containing an ethanol step and an excess of ethyl acetate solution of maleic acid is added. Excluded. The precipitate was filtered off and recrystallized from ethanol to give 4- [6- (2- / 2,2,2-trifluoroethyl / guanidino) pyrazin-2-ylthio] butyramide maleate in 30% yield, m.p. 171-172 ° C.

The starting material can be prepared as follows:

To a solution of 2-amino-6-chloropyrazine (6 g) in acetonitrile (50 ml) was added 2,2,2-trifluoroethylisothiocyanate (6 ml) and the mixture was refluxed for 6 hours. The reaction mixture was allowed to cool, the precipitated solid material was filtered off and recrystallized from toluene. 222

-chloro-6- [3- (2,2,2-trifluoroethyl) thioureido] pyrazine.

To a solution of 0.7 g of 2-chloro-6- [3- (2,2,2-trifluoroethyl) thioureido] pyrazine in 35 ml of alcoholic ammonia was added 0.65 g of yellow mercury and the mixture was stirred at room temperature overnight. rooms. The reaction mixture is filtered and the filtrate is evaporated in vacuo to a pale yellow solid which, after recrystallization from toluene / petroleum ether (b.p. 60-80 ° C), affords 2-chloro-6- [2- (2,2,2-trifluoroethyl). (guanidino) pyrazine, m.p. 139-140 ° C.

To 1.15 g of a 50% w / w sodium hydride dispersion in oil was added 1.44 g of 4-mercaptobutyric acid, then 1.0 g of 2-chloro-6- [2- (2,2,2- trifluoroethyl) guanidino] pyrazine and the mixture was refluxed overnight on a steam bath. After addition of water, the resulting mixture was washed with ether, the aqueous phase acidified to pH 4 with hydrochloric acid, and the precipitated colorless solid 4- [6- (2- / 2,2,2-difluoroethyl / guanidino) pyrazin-2-ylthiobutyric acid. The mixture is filtered, washed with water and sucked dry. This material is used without further purification.

Example 14

In analogy to Example 13, using aniline instead of ammonia in 28% yield, N-phenyl-4- [6- (2- / 2,2,2-trifluoroethyl / guanidino) pyrazin-2-ylthio] butyramide was obtained at a temperature of 28%. mp 165-167 ° C.

Example 15

To 0.3 g of 5- [4- (2- (2,2,2-trifluoroethyl) guanidino) pyrimid-2-yl] valeric acid was added dropwise 1 ml of thionyl chloride and the mixture was gently heated on a steam bath for 5 minutes. The excess thionyl chloride was evaporated in vacuo and the gummy residue was overlayed with 5 mL of dichloromethane. A solution of 0.105 g of aniline in 0.5 ml of dichloromethane is added first and then triethylamine is added dropwise until the reaction is basic. The resulting mixture was stirred at room temperature for 30 minutes, then poured into water, the organic phase separated and dried over magnesium sulphate. After filtration and evaporation, an oily material was obtained which was dissolved in a small volume of ethanol and excess ethanol was added. maleic acid. The precipitate formed is filtered off, washed with ethanol and recrystallized from ethanol. N-Phenyl-5- [4- (2- (2,2,2-trifluoroethyl) guanidino) pyrimidin-1 H -imidazol-1-yl] -methylamine was obtained in 21% yield. 0.25 Ό.Ό, melting at 169-171 ° C.

The starting material can be prepared as follows:

g of ethyl 5-cyanvalerimidate was stirred in 200 ml of methanol containing for 18 hours

26.4 g ammonium chloride. The mixture is filtered, the filtrate is evaporated to dryness and the residue is heated to reflux in 250 ml of ethanol containing 285 ml of triethylamine and 106 g of 2-chloroacrylonitrile.

After 2 hours, the reaction mixture was cooled, added to 1 liter of water, and the pH adjusted to acetic acid. The aqueous mixture was clarified with charcoal, filtered, and the filtrate was extracted with 300 mL of ethyl acetate. The aqueous phase is separated and adjusted to pH 9 with aqueous sodium hydroxide solution. The aqueous mixture is extracted twice with 500 ml of ethyl acetate each time, the combined extracts are evaporated to dryness and the residue is recrystallized from acetonitrile. 16 g of 5- (4-aminopyrimid-2-yl) valero nitrile are obtained.

A mixture of 30 g of 5- (4-aminopyrimidin-2-yl) valeronitrile and 30 g of 2,2,2-difluoroethyl isothiocyanate in 50 ml of acetonitrile is heated at reflux for 18 hours, the reaction mixture is evaporated to dryness and the residue is dissolved in sat. 48 g of mercuric oxide are added with stirring, after 2 hours the mixture is filtered through a pad of diatomaceous earth and the filtrate is evaporated to dryness, the residue is triturated with ether and the solid product is filtered off to give 39 g of 5- (4- (2- / 2,2,2-trifluoroethyl / guanidino) pyrimid-2-yl) valeronitrile.

To 2 g of 5- (4- (2- (2,2,2-trifluoroethyl) guanidino) pyrimid-2-yllivalononitrile) was added 10 ml of concentrated hydrochloric acid and the mixture was heated on a steam bath for 1.75 hours. by evaporation in vacuo, the residue is dissolved in water and the pH is adjusted to 5 with aqueous sodium carbonate solution. The precipitate formed is filtered off, washed first with water and then with ethanol, and dried under vacuum at 70 ° C. g 5- (4- (2- / 2,2,2-Methoxy-guanidino) pyrimidin-2-yl) valeric acid, which is used without further purification.

Examples 16 to 20

The procedure described in Example 15 was repeated using the appropriate starting materials. The following compounds are obtained:

C-N COR

In the example —R

16 / ~ \ 17 -NH 18 r - \ - ^ - сн _л

Comment:

Example 16:

maleate, m.p. 165-166 ° C (66% yield).

Example 17:

maleate, m.p. 194-196 ° C (25% yield).

Example 18:

bis-maleate, m.p. 162-163 ° C (yield 45%).

Example 19:

M.p. 165 DEG-168 DEG C. 2.5-Maate monohydrate.

Example 20:

187-189 ° C (yield 10%).

Example 2 1

To a suspension of 0.25 g of 5- [4- (2- (2,2,2-trifluoroethyl) guanidino-pyrimidin-4-yl] valeric acid in 10 ml of freshly distilled rerhahndrofuran is added 0.093 g of triethylamine with ice-cooling. g of ethyl chloroformate, the mixture is stirred at 0 ° C for 30 minutes, an additional 0.093 g of triethylamine is added, followed by 0.124 g of 2,2,2-trifluoromethylaminocyl chloride, stirred at 0 ° C for 30 minutes and then left to stand. After evaporation in vacuo, an aqueous sodium carbonate solution was added to the residue, the mixture was extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated in vacuo to an oily residue which was dissolved in a small volume of ethyl acetate and the solution was evaporated. An excess of ethyl acetate solution of maleic acid is added by adding ether and scratching the sides of the vessel with a glass rod to precipitate a colorless solid which is filtered off and recrystallized The residue was triturated with ethyl acetate to give N- (2,2,2-trifluoroethyl) -5- [4- (2- / 2,2,2-fluoroethyl / guanidino) pyrimidin-2-yl] valerole-14503 amide maleate. with 0.25 mol of crystalline water, m.p. 135-140 ° C.

Example 22

In analogy to Example 21, 3-aminopyridazine was used instead

2,2,2-trifluoroethyliniamine is obtained in a yield of 17% of N- (pyridazin-3-yl) -5- (4- (2,2,2-trifluoroethyl) guanidinopyrimidin-2-yl) valeramide maleate, m.p. 163 ° C.

Example 23

To 0.5 g of methyl 3- [2- (2-Z2,2 ₎ 2-thifluoroethyl / guanidino) thiazol-4-ylmethylthio] -propionate in 20 ml of ethanol is added 7 ml of 33% (w / v) of ethanolic methylamine and the mixture was stirred at room temperature for 18 hours. The reaction solution was evaporated and the residue was crystallized from aqueous ethanol. 0.35 g (73%) of N-methyl-3- [2- (2- (2,2,2-trifluoroethyl) guanidino) thiazol-4-ylmethylthio] propionamide, m.p. 152 DEG-154 DEG C., is obtained.

The starting material can be prepared as follows:

To a mixture of 4.6 g of 2- (2,2,2-trifluoroethyl) guanidino-4-chloromethylthiazole hydrochloride in ml of ethanol and 2.47 ml of ethyl 3-mercaptopropionate, solution 1 is added dropwise at 5 ° C over 10 minutes, 8 g sodium hydroxide in 15 ml water. The resulting solution was allowed to warm to room temperature, stirred for 1 hour and then poured into water. The precipitate formed is filtered off and crystallized from ethanol. There was obtained 1.93 g of methyl 3- (2- (2- (2,2,2-trifluoromethyl) pyridinil)) thiazol-4-ylmethylthio] propionate, m.p. 96-98 ° C. .

Example 24

In analogy to Example 23, using the appropriate starting materials, 3- (2- (2- / 2,2,2-trifluoroethyl) guanidino) thiazol-4-yl] propionic acid hydrazide is obtained in a yield of 69%. Mp 125-126 ° C.

Example 25

A mixture of 0.4 g of methyl 5- (2- (3- / 2,2,2-trifluoromethyl / guanidino) thiazol-4-yl) valerate and 60 ml of 33% (w / v) ethanol-methylamine is left for 2 hours. The reaction mixture was evaporated to dryness and the residue was recrystallized from ethyl acetate / ether to give N-methyl-5- [2- (2- / 2,2,2-trifluoroethyl-guanidino) thiazole-4 in 85% yield. m.p. 122-126 ° C.

The starting material can be prepared as follows:

To a solution of 2.0 g of methyl 7-chloro-6-oxoheptanoate in 20 ml of hot ethanol is added a solution of 2.1 g of 2,2,2-trifluoroethylamidinothiourea in 20 ml of hot ethanol. The resulting mixture was heated at reflux for 1 hour, then evaporated to dryness and the residue was partitioned between ether (20 ml) and water (60 ml). The aqueous layer was separated, basified with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate solution was evaporated to dryness and the residue was crystallized from a mixture of ethyl acetate and ether containing a small amount of acetone. There was obtained methyl 5- [2- (2- (2,2,2-trifluoroethyl) guanidino) thiazol-4-yl] valerate which was used without further purification.

Example 26

In analogy to Example 25, N-methyl-4- [2- (2- / 2,2,2-trifluoroethyl) guanidino} thiazol-4-yl] butyramide was obtained using appropriate starting materials.

Analysis:

calculated:

% C, 47.1%;% H, 6.9%;% N, 26.8%.

H, 6.7%; N, 26.8%.

The starting material can be prepared by repeating the procedure described in the second part of Example 25, using methyl 6-chloro-5-oxo hexaneate instead of 7-chloro-6-oxoheptanoate. There was thus obtained methyl 4- [2- (2- / 2,2,2-trifluoroethyl) guanidino] thiazol-4-yl] butanoate

Example 27

A solution of 0.25 g of methyl 3- [2- (2- (2,2,2-trifluoroethyl) guanidino] thiazol-4-yl] cyclopentanecarboxylate in 50 ml of 33% (w / v) ethanolic methylamine was allowed to stand for 5 days The reaction solution was evaporated to dryness and the residue treated with acetic acid in acetone. N-methyl-3- [2- (2- / 2,2,2-trifluoroethyl) guanidino) thiazole was obtained in 63% yield. -4-yl] cyclopentanecarbamide amide hydrogel maleate, m.p. 156-158 cc.

The starting material can be prepared as follows:

A mixture of 18.6 g of cyclopentane-1,3-dicarboxylic acid monomethyl ester and 50 ml of thionyl chloride is allowed to stand at room temperature for 3 hours. The reaction mixture was evaporated to dryness and the residue was dissolved in toluene twice and the solution was evaporated to dryness. The residue is taken up in an excess of ethereal diazomethane solution, allowed to stand at room temperature for 18 hours and then evaporated to dryness. The residue is dissolved in 100 ml of acetone and concentrated hydrochloric acid is slowly added until the evolution of nitrogen ceases. The resulting mixture was concentrated by evaporation and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The ethyl acetate layer was separated and evaporated to dryness to give 16 g of methyl 3- [2-chloro-1-oxoethyl) cyclopentanecarboxylate as a brown oil.

A solution of 3.0 g of the above product in 20 ml of ethanol was added to a solution of 2.8 g

2,2,2-trifluoroethylamide-thiourea in 20 ml of ethanol, refluxing for 2 hours and then evaporating to dryness. The residue was partitioned between 40 ml of water and 60 ml of ethyl acetate, the aqueous layer was basified with sodium bicarbonate and the precipitate was extracted with ethyl acetate. The ethyl acetate extract was evaporated to dryness and the residue was purified by preparative thin layer chromatography using a 90:10: 0.1 (v / v / v) mixture of chloroform, methanol and aqueous ammonia (density 0.880) as a solvent system. Isolation of the appropriate band afforded 0.64 g of methyl 3- [2- (2- (2,2,2-trifluoroethyl) guanidino) thiazol-4-yl] cyclopentanecarboxylate as a resinous material which was used without further purification.

Example 28

A solution of 1 g of crude methyl 3- [2- (2- / 2,2,2-trifluoroethyl / guanidino) thiazol-4-yl] benzoate hydrochloride in 20 ml of 33% (w / v) ethanolic methylamine is left for 4 hours. days at room temperature. The reaction mixture was evaporated to dryness and the residue was triturated with water to give 0.16 g (yield 20%) of N-methyl-3- [2- (2- / 2,2,2-trifluoroethyl) guanidino) thiazole-4- yl] benzamide.

NMR (perdeuterodimethylsulfoxide):

2.8 (d, 3H);

4.1 (m, 2H).

7.3 (s. 1H).

7.0-8.4 (complex 7H).

The starting material can be prepared as follows:

To a solution of 4.0 g of 2,2,2-trifluoroethylamidinothiourea in 30 ml of ethanol, a solution of 3.6 g of 3-cyanophenacyl chloride in 30 ml of warm ethanol is added, the mixture is heated under reflux for 1 hour and then evaporated to a small volume. . After cooling this solution, 4.4 g of 3- (2- (2- (2,2,2-trifluoroethyl) guanidino) thiazol-4-yl) benzonitrile hydrochloride precipitated.

NMR (perdeuterodimethylsulfoxide):

4.4 (m, 2H).

7.5-9.2 (complex, 8H).

4.3 g of the above compound were refluxed in a mixture of 30 ml of acetic acid and 30 ml of concentrated aqueous hydrochloric acid for 2 hours. The reaction solution is evaporated to dryness, the residue is dissolved in 100 ml of methanol and 20 ml of thionyl chloride are added dropwise thereto. Evaporation of the resulting solution to dryness gave crude methyl 3- [2- (2- (2,2,2-trifluoroethyl) guanidino) thiazol-4-yl] benzoate hydrochloride which was used without further purification.

Example 29

To a solution of 84 mg of 4- [6- (2- / 2,2,2-trifluoroethyl / guanidino) pyrid-2-ylthio] butyric acid and 0.2 ml of triethylamine in 5 ml of dimethylformamide was stirred at 0 ° C with stirring. 68 mg of isobutyl chloroformate are added. The reaction solution was cooled to 0 ° C for 0.5 h, then 1 mL of saturated ethanolic ammonia solution was added, and the resulting mixture was stirred at room temperature for 18 h. The reaction solution was evaporated to dryness and the residue was partitioned between 1N aqueous hydrochloric acid and ethyl acetate. The aqueous phase was basified with 10N aqueous sodium hydroxide and extracted with ethyl acetate. The extract was dried and evaporated to dryness to give 60 mg of 4- (6- (2- / 2,2,2-trifluoroethyl) guanidino) pyrid-2-ylthio] butyramide, which crystallized as the hydrogen maleate from acetone and melted. at 138-141 ° C.

The starting material can be prepared as follows:

To a mixture of 0.72 g of 4-mercaptobutyric acid, 0.58 g of a 50% (w / w) sodium hydride dispersion in mineral oil and 5 ml of 2 ethoxyethanol is added 0.35 g of 2-amino-6-bromopyridine, the resulting mixture Heat at reflux for 1.8 hours, then evaporate to dryness. The residue was partitioned between water and ethyl acetate and the aqueous phase was neutralized with acetic acid. Filtration of the precipitated yellow solid gave 0.27 g of 4- (6-aminopyrid-2-ylthio) butyric acid which was used without further purification.

A mixture of 0.21 g of 4- (6-aminopyrid-2-ylthio) butyric acid, 3 ml of dimethylformamide and 0.15 g of 2,2,2-trifluoroethylisothiocyanate was allowed to stand at room temperature for 18 hours and then evaporated to dryness. The residue is dissolved in methanolic ammonia, 0.44 g of yellow mercuric oxide is added, the mixture is stirred at room temperature for 1 hour, then filtered, the filtrate is evaporated to dryness, the residue is stirred with 5 ml of 2N aqueous sodium hydroxide and filtered. . The filtrate is acidified with acetic acid and the precipitate formed is filtered off. There was obtained 0.17 g of 4- [6- (2- (2,2,2-trifluoroethyl) guanidino) pyrid-2-ylthio] butyric acid which was used without further purification.

Example 30

By repeating the procedure described in Example 29, 5- [6- (2- / 2,2,2-trifluoroethyl) guanidinopyrid-2-ylthio] valeramide maleate is obtained in 69% yield, m.p. 138-139 ° C.

The starting material can be prepared by repeating the procedures described in the second and third parts of Example 29 using 5-mercaptic acid instead of 4-mercaptobutyric acid. 5- [6- (2- (2,2,2-Trifluoroethyl) guanidino] pyrid-2-ylthio] valeric acid was obtained.

Examples 31 to 60

The procedure described in Example 13 can be repeated to give the following compounds:

C = N- -z · -C 'z-o-oom. ⁴ N- -

example R circle - X — A— 31 CF3CH2 Jnl 32 CF3CH2 XX, _ey , .. 33 CF3CH2 1> я · 34 CH3OCH2CH2 Λ N S-fCw 3 35 CF3CH2 36 CF3CH2 37 CF5CH2 ÚAcwjs- 38 CHF2CF2CH2 > _n ! / ~ 39 CCIF2CH2 40 CF3CH2 AAch ^ - 41 CF3CH2 42 CHF2CF2CH2 ^(CH W

circle - X — A—

R

CF3CH2

CF3CH2

CF3CH2

CF3CH2

CCIF2CH2

CHF2CF2CH2

CF3CH2

CF3CH2

CF3CH2

CF3CH2

CF3CH2

CF3CH2

CF3CH2

CF3CH2

CHF2CF2CH2

CF 3 CH 2 (CH 2 J 1 j ^X (CH ₅ -

о- | сн ₂ ) зО- (СН _л ) з

s- (cn ₂ ) ₃ -

example

CF5CH2

CF3CH2 ring —X — A—

Legend:

Example 31:

hydrogen maleate, m.p. 202-203 ° C.

Example 32:

hydrogen maleate, m.p. 184-186 ° C.

Example 33:

hydrogen maleate, m.p. 176-177 ° C.

Example 34:

maleate, m.p. 194-195 ^° C.

Example 35:

mp 130 ° C.

Example 36:

1,25-maleate, m.p. 158-159 ° C.

Example 37:

M.p. 130-131 ° C.

Example 38:

dimaleate-0.5 H 2 O, mp 93-95 ° C.

Example 39:

M.p. 162-163 ° C.

Example 40:

maleate, m.p. 156-157 ° C.

Example 41:

maleate, m.p. 159-161 ° C.

Example 42:

maleate, m.p. 141-142 ° C.

Example 43:

maleate, m.p. 146-147 ° C.

Example 44:

Hydrochlorineate-0.5 H2O, m.p. 182-185 ° C.

Example 1 a d 4 5:

mp 179-181 ° C.

Example 46:

mp 192-193 ° C.

Example 47:

maleate, m.p. 149-153 ° C.

Example 48:

maleate, m.p. 161-162 ° C.

Example 1 a d 4 9:

maleate, m.p. 189-191 ° C.

Example 50:

maleate, m.p. 168-169 ° C.

Example 51:

mp 126-128 ° C.

Example 52:

maleate, m.p. 177-179 ° C.

Example 53:

mp 162-164 ° C.

Example 54:

maleate, m.p. 166-168 ° C.

Example 55:

NMR (perdeuterodimethylsulfoxide):

7.5 (m, 4H).

7.5 (d, 1H),

5.8 (d, 1 H),

5.0 (s, 2H).

4.0 (m, 4H);

3.7 (m, 2 H).

Example 56:

m.p. 176-177 hydrogen maleate, degrees Celsius.

Example 57:

maleate, m.p. 173-174 ° C.

Example 58:

maleate, m.p. 143-146 ° C.

Example 59:

mp 192 ° C.

Example 1 a d 6 0:

hydrogen maleate, m.p. 168-170 ° C.

Examples 61 to 65

The procedure described in Example 13 can be repeated to give the following compounds:

example ^Cr i ^Cr v Η _χ

C ring —X — A—

-Nc% *, Z-A-COnuR

R

Legend:

Example 63:

Example 61:

NMR (perdeuterodimethylsulfoxide):

7.41 (d, IH);

5.66 (d, IH);

4.08 (q, 2H);

3.96 (t, 2H).

3.1 (m, 2H).

2.61 (t, 2H).

2.08 (t, 2H).

1.52 (m, 4H).

NMR (perdeuterodimethylsulfoxide):

7.7 (s, 1 H),

3.92 (m, 4H);

2.06 (t, 2H).

1.5 (m, 4H).

Example 64:

the maleate melts at 143-146 ° C.

Example 65:

Example 62:

NMR of dialeate (perdeuterodimethylsulfoxide):

8.4-6.4 (broad m, 10H inclusive)

7.7 [s, 1H])

5.04 (quintet, 1H),

4.35 (q, 2H);

2.85 (quintet, 1H),

2.45-1.9 (m, 6H).

NMR (perdeuterodimethylsulfoxide):

7.5 (m, 5H);

5.73 (d, IH);

4.06 (q, 2H);

5.22 (s, 2 H).

Claims (2)

I will invent the subject (C 1 -C 6) cycloalkyl, (C 3 -C 8) cycloalkyl, (C 4 -C 12) cycloalkyl, (C 2 -C 6) alkenyl, (C 2 -C 6) alkynyl, (C 1 -C 6) haloalkyl , (C 1 -C 6) alkoxy, (C 1 -C 6) hydroxyalkyl, (C 2 -C 10) alkoxyalkyl, (Cth-Cth alkyl) alkylthioalkyl C 2 -C 10, C 1 -C 6 amincalkyl, C 2 -C 8 alkylaminoalkyl, C 3 -C 12 dialkylaminoalkyl, C 2 -C 8 alkanoylaminoalkyl, C 8 -C 14 aroylaminoalkyl C 3 -C 10 alkoxycarbonyl, C 2 -C 10 carbamoylalkyl C 8 -C 10 aryl, C 7 -C 10 aryl, C 7 -C 11 arylalkyl, heteroaryl or heteroarylalkyl, wherein the heteroaryl moiety is a heterocyclic aromatic radical containing one, two or three heteroatoms selected from the group consisting of nitrogen atoms, nitrogen atoms and sulfur, wherein the alkyl portion of the heteroaryl group contains 1 to 6 carbon atoms, wherein when R 3 is or contains an aryl or heteroaryl ring, the ring is optionally substituted with one or two substituents selected from the group consisting of fluorine, chlorine, bromine and iodine; (C 1 -C 6) -alkoxy, (C 1 -C 6) -alkoxy, (C 1 -C 6) alkylthio, (C 2 -C 6) dialkylamino, (C 2 -C 6) alkanoyl, trifluoromethyl, hydroxy, and amino, and R ⁴ represents a hydrogen atom or R 3 and R 4 are taken together and together with the nitrogen atom to which they are attached to form a five-, six- or seven-membered saturated ring containing optionally a double bond or another oxygen atom, an NH or N-alkyl group wherein the alkyl moiety contains 1 to 6 and pharmaceutically acceptable acid addition salts thereof, characterized in that the compound of formula (IV): R 1, R ² , A, D, X and Z are as defined above, or an activated derivative thereof, reacts with a compound of formula R3R4NH wherein R 3 and R 4 are as defined above, whereupon the resulting compound of formula (I) resulting in the free base form is optionally converted by treatment with an acid giving a pharmaceutically acceptable anion to its acid addition salt. A process for the preparation of guanidine derivatives of the formula I in which each of R ¹ and R ² , which may be the same or different, represents a hydrogen atom, a branched or unbranched alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 8 atoms or a C 4 -C 14 cycloalkylalkyl group, each of said alkyl, cycloalkyl or cycloalkylalkyl groups being optionally substituted with one or more halogen atoms selected from the group consisting of fluorine, chlorine and bromine atoms, with the proviso that at least one of R ^{1 is} and R ² represents a halogen-substituted alkyl, cycloalkyl or cycloalkylalkyl group, and with the proviso that no halogen substituent is present on the carbon atom of the alkyl, cycloalkyl or cycloalkylalkyl group directly attached to the nitrogen atom, or R ² represents a hydrogen atom and R ¹ represents the remainder of formula II R ⁵ —E — W— [II] wherein W represents an unbranched C 2 -C 6 alkylene chain optionally substituted by one or two C 1 -C 4 alkyl groups, E represents an oxygen or sulfur atom, a sulfinyl group, a sulfonyl group or a radical of the formula NR ⁶ , wherein R ⁶ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms and R ⁵ represents a hydrogen atom or a straight-chain alkyl group having 1 to 6 carbon atoms, optionally substituted by one or two alkyl groups having 1 to 4 carbon atoms, or are R ⁵ and R ^6, taken together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidine, morpholine, piperazine or N-methylpiperazine ring, the dashed line in ring X represents a double bond on one side of the nitrogen atom, and Z represents a carbon atom or a nitrogen atom, such that the ring X is a five- or six-membered aromatic heterocyclic ring containing at least one nitrogen atom and optionally containing one or two additional heteroatoms selected from oxygen, nitrogen and sulfur atoms; where possible, it may optionally carry one or two substituents selected from the group consisting of fluorine, chlorine and bromine atoms, alkyl groups of 1 to 2 (C 1 -C 6) alkoxy, (C 1 -C 6) alkoxy, trifluoromethyl, hydroxy and amino, A represents a phenylene group, a C 5 -C 7 cycloalkylene group or a C 1 -C 8 alkylene radical optionally substituted by one or two C 1 -C 3 alkyl groups and optionally containing one or two groups selected from the group consisting of oxygen and sulfur atoms, NH, N-C 1 -C 6 alkyl, cis- and trans-vinylene, ethinylene, phenylene, and 5 to 6 cycloalkylene 7 carbon atoms, with the shortest part of the chain between the ring X and the C = D group consisting of at least 3 atoms, the chain of residue A optionally being interrupted by a group directly attached to the C = D group, which is not oxygen, sulfur, NH or N-alkyl and wherein no two groups which optionally interrupt the chain of residue A, selected from oxygen and sulfur atoms, NH and N-alkyl, are connected to each other, D represents an oxygen or sulfur atom, R ³ is hydrogen, hydroxy, amino, (C 1 -C 6) alkylamino, (C 1 -C 6) haloalkylamino, (C 1 -C 6) alkanoylamino, (C 1 -C 6) alkyl 2. A process according to claim 1, wherein the starting materials of the formula IV and R @ ³ R ^{@ 4} NH are those in which R @ 1 is 2,2,2-trifluoroethyl, R @ 2 is hydrogen, the ring X is pyrazole. A represents a tetramethylene group, D represents an oxygen atom and R 3 and R 4 represent hydrogen atoms, and as an activated derivative of the compound of formula (IV) is an alkyl ester thereof having 1 to 6 carbon atoms in the alkyl moiety, halide or mixed anhydride of the corresponding acid.