CS241536B2 - 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 capable of binding 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 gastric acidity.

GB 2 052 478 A and Japanese Patent Application No. J 5 610 777 (Derwent Accesion No. 74 736 D / 41) disclose H-2 histamine receptor antagonists which are 2-guanidinothiazole derivatives bearing in position 4 is a side chain 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 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

H _Ž N

C-N-C!

χ AZ-A-C-N

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 3 to 8 carbon atoms or a cycloalkylalkyl group having 4 to 14 atoms 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 and R ² is halo-substituted alkyl, cycloalkyl or cycloalkylalkyl with the proviso that the carbon atom of the alkyl, cycloalkyl or cycloalkylalkyl which is directly attached to a nitrogen atom is present no halogen substituent, or R ² is hydrogen and R ¹ represents a radical of formula II

R ³ —E — W— (II) wherein

W represents an unbranched C 2 -C 4 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 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, the heterocyclic ring X there; 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 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 cycloalkylene of 5 to 7 carbon atoms, with the shortest part of the chain between the rings X and C = D consists of at least 3 atoms, wherein the A chain may optionally be interrupted by a group directly attached to C = D, which is not oxygen, sulfur, NH or N-alkyl, and wherein no two groups are present, optionally interrupting the chain of residue A selected from oxygen and sulfur atoms, NH and N-alkyl groups groups are linked together,

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 8 alkyl, C 3 -C 8 cycloalkyl C 1 -C 6 cycloalkylalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloacyl, 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 C 1 -C 8 carbamoylalkyl, C 6 -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 a heteroaryl moiety; oxygen, nitrogen and sulfur atoms, wherein the alkyl portion of the heteroarylalkyl 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 fluorine, chlorine , bromine and iodine, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, (C 1 -C 6) alkylthio groups, (C 2 -C 6) dialkylamino groups, (C 2 -C 6) alkanoyl, trifluoromethyl, hydroxy and amino, and

R ⁴ represents a hydrogen atom or

R ³ and R ⁴ are joined together and together with

241336 the nitrogen atom to which they are attached 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 carbon atoms, and pharmaceutically acceptable addition salts thereof with acids.

It will be understood that although in the above general formula I and throughout the double bond in the guanidine moiety bonded in the guanidine moiety bonded to ring X is located at a particular position, there are other tautomeric forms, and the invention, as regards particular compounds, thus, the tautomeric forms are also included. 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 radical 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- pentafluoropropyl,

1.1.1.3.3.3- hexafluorisopropyl,

1,3-dichloro-1,1,3,3-tetrafluorisopropyl, 1-chloro-1,1,3,3,3-pentafluorisop: petroleum,

A 1,3-difluoroisopropyl or 2,2,3,3,4,4,4-heptafluorobutylo group.

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 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-tetrafluorocyclopropyl jmethylová (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 particular value for R @ ³ is hydrogen or methyl.

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,

A 1,2,4-thiadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, pyrazole, pyrazine, pyridine, pyrimidine or 1,3,5-triazine ring, all of which the rings may, where possible, be optionally substituted with one or two substituents selected from the group consisting of fluorine, chlorine and bromine atoms, methyl, methoxy, trifluoromethyl, hydroxy and amino.

Suitable radicals A-A are phenylene, cyclopentylene, cyclohexylene, trimethylene, tetramethylene, pentamethylene, thioethylene, thiotrimethylene, thiotetramethylene, thiopentamethylene, oxyethylene, oxytrimethylene, methylene, oxytetramethylene, oxytetramethylene, oxytetramethylene, oxytetramethylene, oxytetramethylene, 2-methylethylene, thiopropylenthiomethylene, oxyethyleneoxymethylene, iminoethylene, iminopropylene, vinylene propylene, oxymethylene vinylene,

1.3- phenylene,

A 1,3-cyclopentylene, methylene-1,4-phenylene, ethyleneoxymethylene-1,4-phenylene, oxy-1,3-phenylenemethylene or thiomethylenethinylenemethylene group. The notation of these residues as " A " is read 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 group C-D. For example, if —A— is a thiomethylenethinylenemethylene group, the compound of formula I contains a group of formula III • C

D

II

IV

Z-S-CH 2 CsC-C HgC (III)

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, genyl, benzyl, heteroaryl and heteroarylmethyl, the heteroaryl part of the latter two being furan, thiophene, pyrrole, thiazole, thiazole, thiazole, , 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 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, preferred subgroups of compounds falling within the above general definition of such compounds that 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 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 36),

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

5- [3- (2- / 2,2,3,3-Tetrafluoropropyl / guanidinoylpyrazol-1-yl) valeramide (Example 42J,

5- (3- (2- / 2-chloro-2,2-difluoroethyl / guanidino) pyrazol-1-yl) valeramide (Example 43),

5- (4- (2- / 2,2,2-trifluoroethyl / guanidino) -1,2,3-triazol-2-yl) valerainide (Example 44),

5- [4- (2- / 2,2,3,3-tetrafluoropropyl / guanidino) -1,2,3-triazol-2-yl] valeramide (Example 46),

6- [4- (2- / 2,2,2-trifluoroethyl / guanidino) -1,2,3-triazol-2-yl) hexanamide (Example 47),

4- [4- (2- / 2,2,3,3-tetrafluoropropyl / guanidino) pyrimidin-2-yloxy] butyramide (Example 52),

4- [2- (2- / 2,2,3,3-tetrafluoropropyl / guanidino) pyrimid-6-ylthio] butyramide (Example 61), as well as their pharmaceutically acceptable acid addition salts.

From this group of compounds, the compounds of Examples 2, 42, 52 are preferred, and the compound of Example 2 is particularly preferred.

Suitable pharmaceutically acceptable acid addition salts of guanidine derivatives of the 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 guanidine moiety bonded to the ring X is built up by reacting the corresponding thiourea or its C 1 -C 6 -alkyl derivative (e.g. S-methyl derivative) or S-benzyl derivative, or a salt thereof, with the corresponding amine.

The guanidine moiety in the compound of formula (I) contains 3 nitrogen atoms, each bearing different substituents. Corresponding amines usable for this reaction may therefore be ammonia, an amine of formula ^R] or ^R2 MW amine of formula VI _with D ** * '\ sl 3 fa (VI)

The reaction may be carried out using an excess of one of the reactants as a diluent or solvent, or with the addition of another diluent or solvent, for example methanol or ethanol. In many cases, a catalyst such as mercuric oxide, lead oxide or sodium hypochlorite is preferably used. The reaction may be carried out at room temperature or may be accelerated or completed by heating, for example by heating to boiling the 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 VI 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 and then optionally reacting the amino group with an isothiocyanate r 1 r ² n = C = S

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 and the ring of the ring X to which the residue A (carbon or nitrogen) is attached, and the presence or absence of atoms or groups introduced into the ring. 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 the built-in group is a phenylene 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. When ring X is a 1,2,3-triazole ring, it can be built by reacting methazonic acid with a suitable azide.

When ring X is a pyrimidine ring, it can be built by reacting a suitably substituted imino ether with 2-chloroacrylonitrile. When the group introduced into the chain A is a vinylene or ethinylene group, the residue A can be introduced by forming a double or triple bond by standard coupling 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, as exemplified in Example 3.

When Z is a nitrogen atom, the right-hand side chain can be built as illustrated in Example 2.

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 the compounds of formula I to inhibit the thiamine-induced positive chronotropic response in spontaneously beating guinea pig atrium or their ability to inhibit histamine-induced aminopyrine consumption in the acid endothelial cells.

The guinea pig atrium test is performed as follows:

The right atrium of the guinea pig is tensioned at 1 g (isometrically suspended in 25 ml thermostatically controlled (30 ° C) tissue bath containing oxygenated (95% C2, 5% CO2J Krebs-Henseleit buffer (pH 7.4)) and allowed to stabilize for 1 hour. Individual contractions are recorded by a force transducer through an extensometric coupler and the instantaneous velocity is monitored by a cardiotachometer, a control response to 1 μΜ histamine is detected, then 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 musculature and washed in buffer 1 (containing 8.007 g of sodium chloride in 1 liter, 0.201 g of potassium chloride, 0.113 g of sodium monohydrogen phosphate, 0.204 g of 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 mg collagenase (Sigma Chemical Co., type Vj and 100 mg bovine serum albumin (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 with stirring under an oxygen atmosphere (conditions continuously monitored and maintained).

After 30 minutes, the tissue is allowed to settle and the supernatant is separated. Fresh dispersion medium (50 ml per 10 g wet tissue weight) is added and incubation is continued. After 40 to 60 minutes, the tissue dispersion consists mainly of glands and whole cells. All remaining major tissue sections are removed by filtration through a nylon mesh. The gland-cell mixture was isolated by centrifugation at 200 g and suspended in buffer 1 containing 1% bovine serum albumin (Miles Laboratories Ltd., fraction Vj.

Finally, the cells and glands were washed three times with buffer 1 and suspended in buffer 2 / containing 500 ml of Eagles medium (MEM), 10 mg of aprotinin (Sigma Chemical Co.) and 20 ml (150 mmol) of 2- [4- (2-hydroxyethyl) piperazin-1-yl] ethanesulfonic acid, adjusted to pH 7.4 with sodium hydroxide; 150 ml per 10 g net tissue weight. The tissue suspension is stirred in an oxygen atmosphere at 32 degrees C for at least 1 hour before use.

The tissue suspension is incubated for 20 minutes with the test compound and 10 μmηοΐ C ¹⁴ aminopyrine on the dimethylamino group (0.1 µCi / ml). Aminopyrine consumption is then stimulated by the addition of histamine and a phosphodiesterase inhibitor ICI 63197 (Biochem. Soc. Special Publication 1, 1973, pp. 127-132) to final concentrations of 10 ^-5 M, respectively. 5 X 10 ^-7 M. After 18 minutes, cells and glands are separated into the incubation medium by filtering the suspension through glass microfibre filters. The mixture of cells and glands is then washed rapidly (in less than 10 seconds) three times with ice-cold buffer 1.

Scintillation counter is then measured labeled aminopyrine C ¹⁴ detained in the tissue, and comparing with a control sample is calculated as the degree of inhibition of aminopyrine consumption caused by the 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 guinea pig atrial 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 test show a 50% inhibition of aminopyrine consumption at a concentration of 3 μΜ or even lower.

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 13 of the test animal and is ligated in the neck region. 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 flushed with saline (9 g of sodium chloride / liter at a dose of 7 ml / min) and the liquid collected from the pyloric duct is collected in beakers at six-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 carried out with 20 mM sodium hydroxide solution to pH 6.4. Once the acid secretion has reached uniform values (three consecutive readings are in the range of 5% J), 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) is first prepared and an appropriately diluted solution is prepared from this stock solution by dilution with saline to inject the appropriate dose at a volume of 1 ml per kg. O).

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 absence of basal secretion within 20 minutes, continuous intravenous infusion of the secretion enhancer (0.5 µmol / kg / h histamine or 2 µg / kg / h pentagastrin) is initiated. saline (15 ml / h).

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. Upon reaching a stable secretion level (1-2 hours), the test compound is administered intravenously in saline and gastric acid samples are taken for a further 2-3 hours, continuing to infuse the secretion enhancer.

To determine the effect of the test compound when administered to the stomach, after detection of the absence of basal secretion (within 30 minutes), the test compound is introduced in an environment consisting of 25 ml 0.5% (w / v) hydroxypropyl methylcellulose and 0.1% (w / w) Tween 80 of the surfactant in water into the stomach of the animal was fed with the fistula and after 1 hour the fistula was reopened and the intravenous infusion of the secretion enhancer was started immediately as described above.

Gastric acid samples are then collected and monitored as described above, 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 is immediately started. 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 lightly suspended on fabric straps, and after washing the pouch with warm water, infusion of histamine is started at a dose of 10 µg / min.

This dose of agonist 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. A 500 μL sample is diluted with 5 ml of brine and titrated 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 in the form of 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 clear 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-yl] valeramide, 5- [6- (2- / 2,15)

2,3,3-Tetrafluoropropyl / guanidino) pyrid-2-yl] valeramide and 5- [3- (2- / 2,2,2-trifluoroethyl / guanidino) pyrazol-1-yl] valeramide were administered intravenously to groups of two anesthetized rats and four awake mice at doses corresponding to 10-fold and 5-fold, respectively. 100 times the dose (in mg / kg) causing about 50% of the gastric acid secretion in anesthetized rats. No signs of toxicity were noted in any of the experimental animals administered these doses.

Many of the compounds disclosed herein inhibit inhibition of gastric acid secretion, which does not deviate from maximum inhibition for a few hours 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 ³ R ⁴ , is not potentially convertible to carcinogenic nitroso derivatives when R ³ and R ⁴ are hydrogen atoms.

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 derivative 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 antacids, such as mixtures of aluminum hydroxide and magnesium hydroxide, antipepsin compound, such as pepstatin, other histamine H-2 antagonists such as imetidine or ranitidine, ulcer healing agents such as cartoenoxolone or bismuth salts, anti-inflammatory agents such as ibuprofen, indomethacin, naproxen or aspirin, prostaglandins such as 16,16-dimethylprostaglandin Classical antihistamines (H1 histamine antagonists) such as mepyramine or diphenhydramine, anticholinergic agents such as atropine or propantheline bromide, anxiolytic agents such as diazepam, chlordiazepoxide or phenobarbital.

The topical pharmaceutical compositions may also contain, in addition to the guanidine derivative of the formula I, one or more classical antihistamines (H-1 histamine antagonists), such as mepyramine or diphenhydramine, and / or one or more steroidal anti-inflammatory agents such as fluocinolone and triamcinolone.

Topical compositions may contain from 1 to 10% (w / w) 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 500 mg 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% ( weight / weight) of the 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 general manner as for cimetidine, taking into account the efficacy and duration of action of the guanidine derivative in terms of dose levels. compared to cimetidine.

Thus, for oral administration, each patient will be administered a dose ranging from 5 mg to 500 mg, preferably from 10 mg to 100 mg of the guanidine derivative, and administered intravenously, subcutaneously or intramuscularly from 0.5 mg to 50 mg, preferably from 2 mg 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 Å versus tetramethylsilane (δ = 0) as an internal standard. Signal shapes are indicated by the following abbreviations:

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

The term "ether" refers to diethyl ether.

It should be noted that in the case of 3-nitropyrazole (Examples 11 and 58)

4 1. 5 3 6 There is a risk of explosion. Example 1 describes the preparation of the starting material for the operation of Example 2.

Example 1

13 g of 5- [3- (2- / 2,2,2-trifluoromethyl / guanldino) pyrazol-1-yl] valeronitrile are added to 65 ml of concentrated sulfuric acid with stirring over 10 minutes. The resulting solution was allowed to react at 20 ° C for 19 hours, then diluted with 300 ml of ice and basified with 10.8 N sodium hydroxide to pH 9. The mixture was extracted three times with 200 ml of ethyl acetate each time, dried over magnesium sulfate and vacuum. Evaporate to an oily residue which crystallizes. Recrystallization of the crude material from ethyl acetate gave 5- [3- (2- (2,2,2-trifluoroethyl) guanidino) pyrazol-1-yl] valeramide, m.p. 130 ° C. From this base, maleate melting at 183-184 ° C is prepared by treatment with maleic acid in acetone.

The starting material can be prepared as follows.

To a solution of 17.4 g of 3-nitropyrazole in 150 ml of dry dimethylformamide is added portionwise sodium hydride paste (6.18 g of a 61% (w / w) suspension) in portions over 30 minutes while maintaining the temperature at 20-30 ° C. liquid paraffin). The resulting mixture was stirred for 45 minutes, to the resulting almost clear solution was added 25 g of 5-bromvaleronitrile at 25-30 ° C over 30 minutes, and the reaction mixture was stirred for 4 hours.

After addition of 450 ml of water and 450 ml of ethyl acetate, the upper layer is separated, dried over magnesium sulphate and evaporated in vacuo to an oily residue consisting of a mixture of 5- (3-nitro-pyrazol-1-yl) valeronitrile and 5- (5-nitropyrazole-1-). The oily material is separated into two 15 g portions which are fractionated on a silica gel column (3.5 cm diameter, 100 cm length) eluted at 0.2 MPa with a mixture of ethyl acetate and petroleum ether (b.p. 60). up to 80 degrees C) in a 3: 7 (v / v) ratio. The 1: 5-isomer is eluted first and then the 1: 3-isomer is eluted. 5- (3-nitropyrazol-1-yl) valeronitrile melts at 32-33 ° C.

To a solution of 9.16 g of 5- (3-nitropyrazol-1-yl) valeronitrile in 200 ml of dry tetrahydrofuran was added 1.8 g of 5% (w / w) palladium on carbon and the mixture was stirred under a hydrogen atmosphere at 20 ° C. 3.2 liters of hydrogen are absorbed in 4 hours. The catalyst was filtered off and the filtrate was evaporated in vacuo to give oily 5- (3-aminopyrazol-1-yl) valeronitrile.

To a solution of 7.0 g of 5- (3-aminopyrazol-1-yl) valeronitrile in 25 ml of acetonitrile was added 6.02 g of 2,2,2-trifluoroethylisothiocyanate. After 15 minutes the solvent was evaporated in vacuo to give 5- [3- (3- (2,2,2-trifluoroethyl) thioureido) pyrazol-1-yl] valeronitrile as a white crystalline solid, m.p. 93-98 ° C. C.

12.5 g of the thiourea prepared above were dissolved in 120 ml of 8 M ammonia in ethanol, 12.8 g of mercury oxide were added and the mixture was stirred at 20 ° C for 30 minutes. The reaction mixture was filtered and the filtrate evaporated in vacuo to give oily 5- (3- (2- (2,2,2-trifluoroethyl) guanidino) pyrazol-1-yl) valeronitrile. of acetone and 5 mol equivalents of maleic acid are added to the solution, and crystalline maleate precipitates from the clear solution obtained by addition of ether, m.p.

Alternatively, 5- (3- (2- (2,2,2-trifluoroethyl) guanidino) pyrazol-1-yl) valeronitrile may be prepared by reaction of 3-aminopyrazole with 2,2,2-trifluoroethylisothiocyanate, by reaction of the resulting thiourea with ammonia in the presence of mercuric oxide and finally alkylation of the nitrogen atom at the 1-position of the product obtained, which is 3- (2- (2,2,2-trifluoroethyl) guanidino] pyrazole, 5-bromvaleronitrile).

Example 2

To a solution of 0.5 g of 5- [3- (3- / 2,2,2-trifluoroethyl / thioureido) pyrazol-1-yl] valeramide in 6 ml of 6 M ammonia in ethanol is added 0.56 g over 5 minutes. The mixture was stirred for 1 hour and then filtered. The filtrate was evaporated in vacuo to an oily residue which was dissolved in ethyl acetate. Addition of petroleum ether (b.p. 60-80 ° C) affords 5- [3- (2- / 2,2,2-trifluoroethyl / guanidinoylpyrazol-1-yl) valeramide as a crystalline solid, m.p. 128-132 ° C. .

The starting material can be obtained as follows.

A solution of 0.2 g of 5- (3-nitropyrazol-1-yl) valeronitrile in 1 ml of concentrated sulfuric acid was allowed to react at 20 ° C for 19 hours. The reaction mixture was diluted with 4 ml of water and basified with 10.8 N sodium hydroxide. to pH 10 and extracted three times with 5 ml of ethyl acetate each time. The extracts were dried over magnesium sulphate and evaporated in vacuo to give a white solid which was recrystallized from ethanol to give 5- (3-nitropyrazol-1-yl) valeramide, m.p. 129-131 ° C.

A mixture of 3.6 g of 5- (3-nitropyrazol-1-yl) valeramide and 0.54 g of 3% (w / w) palladium on carbon is stirred in 20 ml of isopropanol under hydrogen atmosphere while maintaining the temperature below The reaction mixture was filtered and the filtrate evaporated in vacuo to an oily 5- (3-aminopyrazol-1-yl) Jvaleramide, which crystallized to give a 2.5 g product. After stirring in 25 ml of acetonitrile, 2.17 g of 2,2,2-trifluoroethyl isothiocyanate is added, after 18 hours the mixture is filtered and the filter residue is washed first with acetone 241536 with nitrile and then with ether to give 5- (3- (3- / 2,2,2-Trifluoroethyl (thioureido) pyrazol-1-yl] valeramide, m.p. 172-174 ° C.

Example 3

A mixture of 0.34 g of 3- [4- (3- / 2,2,2-trifluoroethyl / thiour eido) -1,2,3-triazol-2-yl] cyclopentanecarboxamide, 0.4 g of mercuric oxide and 20 ml of 6 The methanolic ammonia is stirred at room temperature for 3 hours, then left to stand at room temperature overnight, filtered and evaporated. 0.27 g of 3- [4- (2- (2,2,2-trifluoroethyl) guanidino) -1,2,3-triazol-2-yl] cyclopentanecarboxamide is obtained. To a sample of this product in a small volume of ethyl acetate was added maleic acid equivalent in a small volume of acetone. Addition of ether gave 3- (4- (2- (2,2,2-trifluoroethyl) guanidino) -1,2,3-triazol-2-yl) cyclopentanecarboxamide maleate, m.p. 143-146 ° C.

The starting material can be prepared as follows.

A mixture of 3.5 g of 1,2,3-triazole, 5.0 g of cyclopent-2-enone, 2.0 ml of a 40% w / v solution of benzyltrimethylammonium hydroxide in methanol and 20 ml of dioxane was stirred at room temperature overnight. The reaction mixture is evaporated, the residue is stirred with ethyl acetate, the solution is washed twice with water and once with brine, dried over magnesium sulphate and evaporated. Impure 3- (1,2,3-triazol-2-yl) cyclopentanone was obtained as a pale yellow oil.

NMR (CDCl3):

7.62 (s, 2H).

5.37 (broad quintet, 1H),

3.1 to 1.8 (m, 6H).

A mixture of 0.5 g of impure 3- (1,2,3-triazol-2-yl) cyclopentanone, 0.5 g of lithium aluminum hydride and 20 ml of ether was stirred at room temperature overnight, and the excess lithium aluminum hydride was quenched with aqueous sodium hydroxide solution, filtered. and evaporated to give 0.5 g of unpurified 3- (1,2,3-triazol-2-yl) cyclopentanol as an oil.

To a solution of unpurified 3- (1,2,3-triazol-2-yl) cyclopentanol (0.44 g) in pyridine (5 ml) was added p-toluenesulfonyl chloride (1.1 g) at 5 ° C and cooled to 5 ° C overnight. The extract was washed with water, 2N aqueous hydrochloric acid and brine, dried (MgSO 4) and evaporated to give 0.72 g of unpurified oily 3- (1,2, 3-triazol-2-yl) cyclopentyl-p-toluenesulfonate.

A mixture of 0.7 g of unpurified 3- (1,2,3-triazol-2-yl) cyclopentyl-p-toluenesulfonate, 0.17 g of sodium cyanide and 10 ml of dimethylsulfoxide was stirred at 95 ° C overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4) and evaporated to give 0.33 g of unpurified 3- (1,2,3-triazol-2-yl) cyclopentanecarbonitrile as an oil.

A mixture of 0.3 g of unpurified 3- (1,2,3-triazol-2-yl) cyclopentanecarbonitrile, 2 ml of concentrated sulfuric acid and 1 ml of concentrated nitric acid is allowed to react overnight at room temperature, the initial stage of the reaction being exothermic and requiring cooling. The reaction mixture was poured into water and extracted with ethyl acetate, and the extract was washed with brine, dried over magnesium sulfate and evaporated to give 0.26 g of unpurified 3- (4-nitro-1,2,3-triazole-2-). yl is cyclopentanecarboxylic acid.

A mixture of 3- (4-nitro-1,2,3-triazol-2-yl) -cyclopentanecarboxylic acid (0.3 g) and thionyl chloride (2 ml) was heated at 60 ° C for 30 minutes, then evaporated to dryness under reduced pressure. The volatile residue was stirred with 10 ml of 6M ethanolic ammonia and evaporated to give 0.25 g of unpurified 3- (4-nitro-1,2,3-triazole-2-). A sample of the product purified by medium pressure liquid chromatography on silica gel using ethyl acetate as eluent has a melting point of 127-128 ° C.

To a mixture of 0.28 g of 3- (4-nitro-1,2,3-triazol-2-yl) cyclopentanecarboxamide, 0.3 g of 5% (w / w) palladium on carbon and 20 ml of ethanol at 50 ° C add 0.6 mL of hydrazine hydrate. The reaction mixture was heated at 50 ° C for 15 min, then filtered and evaporated to give 0.22 g of unpurified 3- (4-amino-1,2,3-triazol-2-yl) cyclopentanecarboxamide as a white solid. substances.

A mixture of 0.215 g of 3- (4-amino-1,2,3-triazol-2-yl) cyclopentanecarboxamide, 0.5 g of 2,2,2-trifluoroethylisothiocyanate, 5 ml of acetonitrile and 1 ml of dimethylformamide was stirred at room temperature for 3 hours. The mixture was evaporated, the residue was triturated with ethanol and filtered to give 0.35 g of solid 3- [4- (3- / 2,2,2-trifluoroethyl) thioureido] -1,2,3-triazole-2. -yl] cyclopentanecarboxamide, which is used without further purification.

Example 4

To a solution of 180 mg of 4- [3- (3- (2,2,2-trifluoroethyl) thioureido) pyrazol-1-ylmethyl] benzamide in 5 ml of ethanol saturated with ammonia was added 380 mg of yellow mercuric oxide. The mixture was stirred at room temperature for 17 hours, then centrifuged and the supernatant evaporated in vacuo. There was thus obtained 4- (3- (2- (2,2,2-trifluoroethyl) guanidino) pyrazol-1-ylmethyl) benzamide melting after crystallization from a mixture of ethanol and petroleum ether (b.p. 60-80 ° C) at 192 ° C.

The starting material can be prepared as follows.

To a solution of 3-nitropyrazole (200 ml) in dry dimethylformamide (2.5 ml) was added 70 mg of sodium hydride paste [61% (w / w) dispersion in oil] with stirring, 300 mg of 4-chloromethylbenzamide was added after foaming. The mixture was stirred at room temperature, diluted with 20 ml of water, and the precipitated 4- (3-nitropyrazol-1-ylmethyl) benzamide was isolated by filtration to give 300 mg of product, m.p. 200 DEG-201 DEG.

A solution of 100 mg of the above nitridamide in dry dimethylformamide was hydrogenated at room temperature at atmospheric pressure using 10 mg of 5% (w / w) palladium on carbon catalyst. Filtration followed by evaporation of the filtrate in vacuo gave 4- (3-aminopyrazol-1-ylmethyl) benzamide.

A mixture of 250 mg of the amine prepared above and 0.16 g of 2,2,2-trifluoroethylisothiocyanate in 1 ml of acetonitrile was stirred at room temperature for 3 hours. Filtration of the precipitated solid material gave 180 mg of 4- (3- (3- (2,2,2-trifluoroethyl) thioureido) pyrazol-1-ylmethyl) benzamide, m.p. 205-206 ° C.

Example 5

A mixture of 18.2 mg of 5- (3-aminopyrazol-1-yl) valeramide and 51 mg of (2,2,2-trifluoroethyl) -5-methylisothiourea hydroiodide was heated at 100 ° C for 20 min. Preparative HPLC on silica gel using chloroform / methanol / ammonia (0.880 density) 8: 2: 0.5 (v / v / v) as eluent gave a yield of 40 percent 5- [3- (2)]. (2,2,2-Trifluoroethyl) guanidino [pyrazol-1-yl] valeramide, m.p. 129-130 ° C.

The isothiourea derivative used as the starting material can be prepared as follows.

A solution of 9.12 g of ammonium thiocyanate and 13.6 g of 2,2,2-trifluoroethylamine hydrochloride in 50 ml of water was heated at 100 ° C for 20 hours. Water (50 ml) was added and the mixture was reheated to dissolve the solid. After cooling, the crystalline hydrate of 2,2,2-trifluoroethylthiourea melts at 154-156 ° C in a yield of 52.4%.

A solution of 8.0 g of 2,2,2-trifluoroethylthiourea and 3.5 g of methyl iodide in 40 ml of ethanol was heated at reflux for 70 minutes and then evaporated to dryness in vacuo. Trituration of the residue with ether afforded 2,2,2-trifluoroethyl-5-methylisothiourea hydroiodide of 90% yield, m.p. 154-156 ° C.

Examples 6 to 62

The following compounds can be prepared in an analogous manner to Example 2 or 5:

R NH

C = NC _x

H ,, N 'after-CONR ³ R

R ³

R ⁴

R ¹

CFsCHz

CFsCH?

CFcCHz

Cl (31?

CF.CH i

CF.CHj

CF.5CH2

CF..CII:

CFsCH?

CFsCH?

CF3CH2

CF0CH2

CF3CH2

CF3CH2

CF5CH2 ring —X — A'Ujyy 4

-’Ι ,,.

S ~ (C 3 '

S-fCuUv

ΓΧ

N - (S _{2 -} CH ₂ h).

/ X -., JV t Μ fy _z> ·? '· <A

^N with ₂ ; ₃ n s- _{4 4} ^{N> X} S-1CH ₂ ) ₃ -

A * VV 'f

in 'Network /

<A,

Ϊ <

-N

CH3

CH.CH.OH

CH2CH2NH2

CHs

CH2CH2OH

NH?

CH2CF3

-AND

OCH3

H

NH?

CH3CH2OH

H

UCH ^ ý

R ³

R ⁴ example

R ¹

241536 circle —X — A—

CF3CH2

CF3CH2

CF3CH2

CF3CH2

CF3CH2

CF2CH2

CF3CH2

CF3CH2

CF3CH2 cr.ciiCFjCH2

CF3CH2

CF3CH2

CF3CH2

CF3CH2

CF3CH2

CH ^C

s— “4 I

N

CH _X CH.

N-CH. / ³

h

COCH

N ^s ~ (Ch ₃ K.

CH2CF3

CH3

NH2

CH :;

CHj

CH.3

CH.5

Η

H

H

S-ICH ^ ·

R ³

R ⁴ example

R ¹

4! 3 3 S circle —X — A—

37 CF3CH2 / 1 H H 38 CF3CH2 H H 39 CHOCH2GH2 H H 40 GF.CH; Γ “= Ί H H 41 CF3CH2 H H 42 CHF2CF2CH2 , ..- ¼ .. JH ~ · fCH0r J'j-, 7. -J SeC-A ^ - Pi H H 43 GGllACHj H H

CF..CH2

CF3CH2

CHF2CF2CH2

CF3CH2

CF.5CH2

CF.5CH2

CF3CH2

GGil.'Cil:

CHF2CF2CH2

CF3CH2

CF2CH2

Pf ¹ pf ,.

C HJ ₃ µM

AND

f ^: 'X'

IV f ' ^χ Αί' 1

-F

I want

f, N

W ^ 0 (Ch ^

X \

-N

-3

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

example R ¹ circle —X — A— R3 R ⁴ 55 CF3CH2 Γϊ n ^ ch ^ s-^ ^ j- H H 56 CF3CH2 H H 57 CF3CH2 fci 1 1 1 H 11 uuA J ^ Jhch ₂ v H H 58 CF5CH2 H H

CF ₃ CH ₂

CHFzCFzCHz cf ₃ ch ₂

H

H

H

II

241530

Legend:

Example 6:

mp 153-155 ° C.

Example 7:

mp 148-150 ° C.

Example 8:

m.p. 144-148 ° C.

Example 9:

mp 148-150 ° C.

Example 10:

mp 179-181 ° C.

Example 11:

mp 192-195 ° C.

Example 12:

maleate, m.p. 202-204 ° C. Example 13:

mp 176-178 ° C.

Example 14:

maleate, m.p. 161-163 ° C. Example 15:

mp 199-201 ° C.

Example 16:

mp 209-210 ° C.

Example 17:

mp 171-173 ° C.

Example 18:

maleate, m.p. 171-172 ° C. Example 19:

mp 165-167 ° C.

Example 20:

maleate-0.25 H ₂ O, mp 169-171 ° C. Example 21:

maleate, m.p. 165-166 ° C.

Example 22:

maleate, m.p. 194-196 ° C. Example 23:

m.p. 162 DEG-163 DEG. Example 24:

2,5-maleate-1H ₂ O, mp 165-168 degrees Celsius.

Example 25:

maleate 0.5 H ₂ O, mp 187-189 ° C. Example 26:

maleate-0.5 H ₂ O, mp 135-140 ° C. Example 27:

maleate, m.p. 160-163 ° C.

Example 28:

mp 152-154 ° C.

Example 29:

mp 125-126 ° C.

Example 30:

mp 122-126 ° C.

Example 31: Analysis:

calculated:

H, 6.9; N, 26.8.

found:

H, 6.7%; N, 26.8%.

Example 32:

mp 156-158 ° C.

Example 33:

NMR (perdeuterodimethylsulfoxide):

2.8 (d, 3H);

4.1 (m. 2H);

7.3 (s, 1 H),

7.0 - 8.4 (complex, 7H).

Example 34:

mp-maleate, m.p. 138-141 ° C.

Example 35:

maleate, m.p. 138-139 ° C.

Example 36:

m.p. 202 DEG-203 DEG.

Example 37 _: hydrogen maleate, m.p. 184-186 ° C.

Example 38:

hydrogen maleate, mp 176 to 177 ⁱⁿ C.

Example 39:

maleate, m.p. 194-195 ° C. Example 40:

1,25-maleate, m.p. 158-159 ° C. Example 41:

M.p. 130-131 ° C. Example 42:

dimethyl maleate-0.5 H10, mp 93-95 ° C.

Example 43:

M.p. 162-163 ° C. Example 44:

maleate, m.p. 156-157 ° C.

Example 45:

maleate, m.p. 159-161 ° C. Example 46:

maleate, m.p. 141-142 ° C.

Example 47:

maleate, m.p. 146-147 ° C.

Example 48:

m.p. 182-185 ° C.

Example 49:

mp 179-181 ° C.

Example 50:

mp 192-193 ° C.

Example 51:

maleate, m.p. 149-153 ° C. Example 52:

maleate, m.p. 161-162 ° C. Example 53:

maleate, m.p. 189-191 ° C. Example 54:

maleate, m.p. 168-169 ° C. Example 55:

mp 126-128 ° C.

Example 56:

maleate, m.p. 177-179 ° C.

Example 57:

mp 162-164 ° C.

Example 58:

maleate, m.p. 166-168 ° C. Example 59:

NMR (iperdeuterodimethylsulfoxide):

7.5 (m, 4H),

7.5 (d, 1 H),

5.8 (d, 1 H),

5.0 (s, 2H).

4.0 (m, 4H);

3.7 (m, 2 H).

4 1 5 3 S

Example 60:

176 DEG-177 DEG.

Example 61:

maleate, m.p. 173-174 ° C. Example 62:

168 DEG-170 DEG.

2S

Examples 63 to 67

The following compounds can be prepared in an analogous manner to Example 2 or 5:

example

CP-, C HnN W

Legend:

Example 63:

NMR (CDCl 3): 7.41 (d, 1H),

5.66 ' (d, 1H),

4.08 (q, 2H);

3.96 (t, 2H).

3.1 (m, 2H).

2.61 (t, 2H).

2.08 (t, 2H).

1.52 (m, 4H).

Example 64:

NMR (perdeuterodimethylsulfoxide j):

7.5 (m. 5H);

5.73 (d, IH);

4.06 (q, 2 H),

5.22 (s, 2 H).

Example 65:

NMR (CDCl 3): 7.7 (s, 1H),

3.92 (m, 4H3,

2.08 (t, 2H).

1.5 (m, 4H).

Example 66:

the maleate melts at 143-146 ° C.

Example 67:

NMR dimalate (perdeuterodimethylsulfoxide):

8.4 to 6.4 (broad m, 10H including 7.7 [s, 1H],

5.04 (quintet, 1H),

4.35 (q, 2H);

2.85 (quintet, 1H),

2.45-1.9 (m, 6H).

4 1 5 3 S

Claims (3)

the subject of the invention A process for the preparation of a guanidine derivative of the general 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 10 carbon atoms. C 8 -C 4 cycloalkylalkyl, each of which alkyl, cycloalkyl or cycloalkyl groups are 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 the symbols R ¹ and R ² represent 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 connected to the nitrogen atom, or R ² represents a hydrogen atom and R 2 ¹ represents a residue of formula II r5_e_W— (II where 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 B 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 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, the heterocyclic ring X there; 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 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 cycloalkylene of 5 to 7 carbon atoms, with the shortest part of the chain between ring X and C = D consists of at least 3 atoms, wherein the A-chain may optionally be interrupted by a group directly attached to C = D, which is not oxygen, sulfur, NH or N-alkyl and wherein no two groups optionally interrupting the chain of residue A selected from oxygen and sulfur atoms, NH and N-alkyl groups are not 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, (C 3 -C 8) 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 group, C 1 -C 14 aroylaminoalkyl group, C 3 -C 10 alkoxycarbonylalkyl group carbon atoms, carbamoylalkyl of 2 to 8 carbon atoms, aryl of 6 to 10 carbon atoms, arylalkyl of 7 to 11 carbon atoms, heteroaryl or heteroarylalkyl, wherein the heteroaryl moiety is a heterocyclic aromatic radical containing one, two or three heteroatoms selected oxygen, nitrogen and sulfur atoms, wherein the alkyl portion of the heteroarylalkyl 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 fluoro, 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, amino 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 optionally containing a double bond or an additional oxygen atom, NH or N-alkyl, wherein the alkyl moiety contains 1 to 6 carbon atoms, and pharmaceutically acceptable acid addition salts thereof, characterized in that the guanidine moiety attached to ring X is formed by reacting the corresponding thiourea or its C 1-6 alkyl or S-benzyl derivative, or a salt thereof. , with the corresponding amine, whereupon the resulting compound of formula 1 resulting in the free base form is optionally converted by treatment with an acid giving a pharmaceutically acceptable anion to its acid addition salt. 2. The process of claim 1, wherein 5- [3- (3- (2,2,2-trifluoroethyl) thioureido) pyrazol-1-yl] valeramide is reacted with ammonia. 3. The process of claim 1, wherein 5- (3-aminopyrazol-1-yl) valeramide is reacted with (2,2,2-trifluoroethyl) -5-methylisothiourea or a hydroiodide thereof.