CS241537B2 - 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's 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 by gastric acidity.

GB 2 052 478 A and Japanese Patent Application No. J 56 108 777 (Derwent Accesion No. 74 736 D / 41 J) disclose H-2 histamine receptor antagonists which are 2-guanidinothiazole derivatives bearing in position 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 receptors of the histamine.

The present invention provides a process for the preparation of guanidine derivatives of the formula Ih _from nC = NC

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 R5- _{W e} __ ._ (Π) in which

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 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 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, C 8 -C 14 aroylaminoalkyl, C 3 -C 10 alkoxycarbonylalkyl carbamoylalkyl of 2 to 8 carbon atoms, aryl of 6 to 10 carbon atoms, arylalkyl group 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 from 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, chloro , 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

R ⁴ represents a hydrogen atom

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 an additional oxygen atom, NH or N-alkyl, wherein the alkyl moiety contains 1 up to 6 carbon atoms, and pharmaceutically acceptable acid addition salts thereof.

It will be understood that although in the above formula I and throughout the double bond in the guanidine moiety bonded to ring X is located at a particular position, there are other tautomeric forms, and the invention, both with respect to particular compounds and to a process for their preparation it also includes these tautomeric forms.

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 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.

Specific halogen-substituted alkyl groups in the meaning of 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-tetrafluoroisopropyl,

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

1,3-difluoroisopropyl; or

2.2.3.3.4.4.4- heptafluorobutyl group.

Particular halogen-substituted cycloalkyl groups R ⁴ 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 halogen-substituted cycloalkylalkyl groups R ¹ or R ² are:

(1,2,2,3,3-pentafluorocyclopropyl) methyl, (2-chloro-1,2,3,3-tetrafluorocyclopropyl) methyl, (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 cyclopropyl or cyclobutyl.

A suitable cycloalkylalkyl group represented by R ¹ or R ² is a group cykloprůpylmethylová 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 residue of formula II is:

2-methoxyethyl,

2-hydroxyethyl,

2-methylthioethyl or

2-dimethylaminoethyl.

Specific meanings 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, pirimidine 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 residue in the meaning of the symbol “A” is:

phenylene, cyclopentylene, cyclohexylene, trimethylene, tetramethylene, pentamethylene, thioethylenová, thiotrimethylenová, thiotetramethylenová, thiopentamethylenová, oxyethylene, oxytrimethylenová, oxy tetramethylene, methylenthiomethylenová, methylenthioethylenová, methylenthiopropylenová, methylenoxymethylenová, methylenoxyethylenová, ethylenoxyethylenová, oxy-2-methyl ethylene, tliiopropylenthiomethy Lenovo oxyethylenoxymethylenová , 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 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 ring X and the latter portion of each residue is bonded to group C = D. for example, when —A— is a thiomethylenthinylenmethylene group, the compound of formula I comprises a group of formula III

- C 1 -C 5 -CH 2 C = C-CH 2 C (III) 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 part of the last two groups being:

a furan, thiophene, pyrrole, thiazole, oxazole, imidazole, thiadiazole, oxadiazole, triazole, pyrazole, pyridine or pirimidine 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 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 listed above for the guanidine derivatives of formula I above, preferred subgroups of the compounds falling within are obtained

Specific residues in the meaning of the symbol R ³ include:

hydrogen atom,

ÍO

241337 to the above general definition of these substances which can be produced 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-triazolo or 1,2,4-triazole ring to which residue A is attached at the 1-position, a pyrimidine ring to which residue A is attached at the A-position, 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 341,

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

5- [3- {2- / 2,2,3,3-Tetrafluoropropyl / guanidino] pyrazol-1-yl] valeramide (Example 40),

5- (3- (2- / 2-chloro-2,2-difluoroethyl / guanidino) pyrazol-1-yl) valeramide (Example 41),

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

5- {4- {2- (2,2,3,3-Tetrafluoropropyl / guanidino) -1,2,3-triazol-2-yl] valeramide (Example 44),

6- (4- (2- / 2,2,2-trifluoroethyl / guanidino) -1,2,3-triaza-2-yl) hexanamide (Example 45),

4- (4- (2- / 2,2,3,3-tetrafluoropropyl / guanidino) pyrimid-2-yloxy] butyramide (Example 50),

4- [2- (2- / 2,2,3,3-Tetrafluoropropyl / guanidino) pyrid-6-ylthio] butyramide (Example 59), as well as their pharmaceutically acceptable acid addition salts.

Within this group of compounds, the compounds of Examples 3, 40 and 50 are preferred, and the compound of Example 3 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 a guanidine residue is attached to the ring X by reaction of the corresponding cyanamide with a suitable amine. Since the guanidine moiety in the compound of formula I contains only one unsubstituted nitrogen atom, there are two suitable amines for this reaction, namely an amine of the formula R ⁴ R ² NH or an amine of the formula VI x x T 2 -ac-nFr 4 (vi)

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.

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 atom in ring X to which the remainder A is attached (whether carbon or nitrogen 1) and the presence or absence of atoms or groups 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 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.

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

The cyanamide corresponding to the amine (VI) used in the process of the invention can be prepared by reacting a compound (VI) with cyanogen bromide.

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 histamine-induced positive chronotropic responses 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 guinea pig's right atrium is suspended in a 25 ml thermostatically controlled (30 ° C) tissue bath containing oxygenated (95% O 2, 5% CO 2) Krebs-Henseleit buffer (pH 7.4) at 1 g (isometric).

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 transducer through an extensometric coupler and the instantaneous velocity is monitored with a cardiotachometer. A control response to 1.0 µM 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 .mu.m) is added again and the response to histamine in the presence of the 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 potassium monohydrogen phosphate, 0.204 g of potassium dihydrogenphosphate, 0.132 g of calcium chloride dihydrate, 0.101 g). and 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 dispersing medium (50 ml per 10 grams wet tissue weight) was added and incubation 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 is isolated by centrifugation at 200 X g and suspended in buffer 1 containing 1% bovine serum albumin (Miles Laboratories Ltd., fraction Vj.

Finally, cells and glands are washed three times with buffer 1 and suspended in buffer 2 / containing 500 ml Eagles medium (MEM), 10 mg aprotinin (Sigma Chemical Co.) and 20 ml (150 mmol) 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 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 μmηοopy C ¹⁴ -labeled 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 and 10, respectively. 5 X 10 “ ^? 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 are quickly (in less than 10 seconds) washed three times with ice cold buffer 1. At a scintillation counter to measure pa'k labeled aminopyrine C ¹⁴ detained in the tissue, and comparing with a control sample is calculated consumption degree of inhibition of aminopyrine caused by the test compound.

From the series of tests performed at different concentrations, the concentrations of the test substance 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 compounds tested in guinea pig atrium are effective at a bath concentration of 10 µM or even lower, and the more potent of these compounds in 242437 exhibits complete inhibition of responses at that concentration.

All compounds tested by the aminopyrine assay show a 50% inhibition of aminopyrine consumption at a concentration of 3 < M 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 of the test animal, which is attached to the neck area 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 pylor.

The esophagus cannula is flushed with saline (9 g sodium chloride / liter) at a rate 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 specific H-2 antagonists of dimaprite at a dose of 10 mg / kg followed by 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 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) is prepared first and an appropriate dilute solution is prepared from this stock solution by dilution with saline to allow an appropriate injection of 1 ml per kilogram (dimethylsulfoxide concentration less than 2%). .

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 30 minutes, continuous intravenous infusion of the secretion enhancer (0.5, µmol / kg / h histamine or 2 μξ / / kg / h pentagastrin) in brine (15 millliters / 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. After 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 contained in 25 ml of 0.5% (w / v) hydroxypropylmethylcellulose and 0.1% (w / v) is introduced. Tween 80 in water into the stomach of the animal through the fistula cap.

After 1 hour, the fistula is reopened and the intravenous infusion of the secretion enhancer is immediately started 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 to 22 kg) with vagus-denervated vesicles in the fundus region are prepared (see Rudick et al., J. Surg. Res. 1967, 7, 383 J.). Animals are allowed to recover for 4 to 6 weeks after surgery, after which they are trained and standardized for a further 2 to 3 months prior to testing, the dogs are fasted for 23 hours (water intake is not limited), and dogs are lightly suspended on fabric straps during the experiments. histamine is infused at a dose of 10 µg / min, which 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. 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 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- / 2,2,3,3-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 times or 100 times the dose (in mg / kg) causing approximately 50% Inhibition of gastric acid secretion in anesthetized rats No signs of toxicity were noted in any of the test animals receiving 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-methylcyanguanidine 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, 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 16,16-dimethylprostaglandin E2, 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 diphenhydrazine, and / or one or more steroidal anti-inflammatory agents such as fluocinolone and triamcinolone.

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

A preferred pharmaceutical composition is a preparation 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 preparation suitable for intravenous, subcutaneous or intramuscular injection, for example a sterile injection preparation 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 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 500 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 compositions described below may be administered less frequently when 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 as S values versus tetramethylsilane (? = 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 1 and 2) they describe the preparation of the starting materials for work according to the procedure of Example 3.

Example 1

13 g of 5- (3- (2- (2,2,2-trifluoroethyl / guanidino) pyrazol-1-yl) valeronitrile) are added to 65 ml of concentrated sulfuric acid with stirring over a period of 10 minutes and the solution is allowed to react for 18 hours. at 20 ° C, then diluted with 300 ml of ice and basified with 10.8 N sodium hydroxide to pH 9. The mixture is extracted three times with 200 ml of ethyl acetate each time, the extract is dried over magnesium sulphate and evaporated in vacuo to an oily residue. 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. in acetone prepares the maleate melting at 183-184 ° C.

The starting material can be prepared as follows:

To a solution of 17.4 g of 3-nitropyrazole in 150 milliliters of dry dimethylformamide is added portionwise sodium hydride paste (6.16 g of a 61% w / w slurry in ice) to maintain the temperature at 20-30 ° C in portions over 30 minutes. 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-nitropyrazol-1-yl) valeronitrile and 5- (5-nitropyrazole-1-). yl) valeronitrile. The oily material was separated into 15 g portions which were fractionated on a silica gel column (3.5 cm diameter, 100 cm length) eluting at 0.2 MPa with a mixture of ethyl acetate and petroleum ether (bp 60-80 ° C). in a ratio of 3: 7 (v / v). 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. 96-98. Deň: 32 ° C.

12.5 ml of the thiourea prepared above were dissolved in 120 ml of 8M 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- (272,2.2-trifluoroethyl / guanidino) pyrazol-1-yl] valeronitrile. A sample of this oily material was dissolved in acetone and 5 mol equivalents of acid were added. Crystalline maleate precipitates from the resulting clear solution by addition of ether, m.p. 123-125 ° C.

Alternatively, 5- (3- (2- (2,2,2-trifluoroethyl) guanidino) pyrazol-1-yl) valeronitrile can be prepared by reacting 3-aminopyrazole with

2.2.2-trifluoroethyl isothiocyanate, reaction of the resulting thiourea with ammonia in the presence of mercuric oxide and finally alkylation of the nitrogen atom in the 1-position of the obtained product, 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) thiourido) pyrazol-1-yl] valeramide in 6 ml of oni ammonia in ethanol is added 0.56 g of oxide over 5 minutes The filtrate was evaporated in vacuo to an oily residue which was dissolved in ethyl acetate and added to petroleum ether (b.p. 60-80 ° C) to give 5- [3- (2- / 2-chloro-2-ol). 2,2-trifluoroethyl (guanidino) pyrazol-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 40 ^at C. After 4 hours, no longer absorbs more hydrogen. The reaction mixture was filtered and the filtrate was evaporated in vacuo to an oily 5- (3-aminopyrazol-1-yl) valeramide which crystallized. The product (2.5 g) is stirred 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 residue is washed first with acetonitrile and then with ether. 5- (3- (3- (2,2,2-trifluoroethyl) thioureido] pyrazol-1-yl) valeramide, m.p. 172-174 ° C.

Example 3

To a solution of 0.65 g of 2,2,2-trifluoroethyl cyanamide and 0.87 g of 5- (3-aminopyrazol-1-yl) valeramide in 10 ml of ethanol was added 5 drops of concentrated hydrochloric acid and the mixture was heated under reflux for 5 hours. The concentrated hydrochloric acid is maintained at pH 4 by periodic dropwise addition. The volatiles are removed in vacuo and the residue is shaken with 10 ml of 2N aqueous sodium hydroxide and 35 ml of ethyl acetate. The organic layer is separated and the aqueous phase is extracted again. Ethyl acetate (2 x 35 ml) The combined extracts were dried (MgSO 4) and treated with acetic maleic acid to give 5- [3- (2- (2,2,2-trifluoroethyl) -guanidino] pyrazol-1-yl). 180 DEG-182 DEG C. valeramide maleate.

The 2,2,2-trifluoroethyl cyanamide used as the starting material can be prepared as follows.

1.06 g of cyanogen bromide is dissolved in 5 ml of cold ether and this solution is added to a solution of 1.98 g of 2,2,2-trifluoroethylamine in 5 ml of cold ether. The mixture was allowed to warm to 20 ° C over 30 minutes, then filtered, the filter residue was washed with ether, and the combined filtrates were evaporated in vacuo at 20 ° C. 2,2,2-Trifluoromethyl cyanamide is obtained as a mobile oil which solidifies when stored at -15 ° C.

The IR spectrum of the product contained a band at 2280 cm ^-1 (—CN). The NMR spectrum measured in perdeuteromethanol using tetramethylsilane as internal standard (<5 = 0) contains a quartet at 5 - 3.65.

Examples 4 to 62

The following compounds can be prepared in an analogous manner to Example 3:

r ⁴ nh.

^ C = NC X ^X / ZA-CONR ³ R ^lf · ^N Z ^N Example R ¹ circle —X — AR ³ R ⁴

CF3CH2 CH3 H CF3CH2 A ^ N ^ S '(CH ₂ ) ₃ - CH 2 CH 2 OH H CF3CH2 CH2CH2NH? H CF3CH2 jfl CH3 H CF3CH2 n CH2CH2OH H

ring —X — A

R ¹

R3

R ⁴ example

CF3CH2

CF3CH2

CF3CH2

CF3CH2

CF3Cl-I2

CF3CH2

CF3CH2

CF3CH2

CF3CH2

CF3CH2

CF3CH2

CF3CH2

CF3CH2

CF3CH2

XX

WITH

Γ ~ „· ΖΓ Ν

ΑΧ-

s- (CH ₂ ) ₃ ·

^S ~ ( ^{CH2 )} 3

W (CHO

NCH ₂ ^ ·

^(CH / O

(CH 2 NH?

CH2CF3

-M

CH;

OCH3

NH2

H

H

H

H

H

II

CHÍCHžOH h

-o o

C / · / »C / - / 9

CH «CH _€ ^X v-2.

~ ^ ~ ^ν ^ ^η 3 ^} 2

CHsCHz

CH.

\

N-CH &gt;.

Ν—,

A.3

Ν '

H ring —-X — A example

Rl

R ³ R ⁴

CF3CH2

CF3CH2

CF3CH2

26 CF3CH2 CH ^ SC H? CH? ~ CH3 H with- 27 Mar: CF3CH2 X 1 ~ -ch ₂ $ ch ₂ ch ₂ - NH2 H 28 CF3CH2 WITH-, -z 1  í * - · CH3 H 29 CF3CH2 Q “I ^CH ^ 3 CH3 H with- 30 CF3CH2 -in CH3 H S — 1 -Λ 1 31 CF3CH.2 Ai — 1 CH3 H

32 CF3CH2 jfX 33 CF3CH2 34 CF3CH2 Z ^ N X ^ N ^ S- (CH ₂ ) 3 35 CF3CH2 Cl z ^ V ^ s-ICH ^ ' 36 CF3CH2 Px SA S- (CH ₅ - 37 CH3OCH2CH2 λΧ

H

H

H

H

H

H

H

H

H

H

H

H

circle —X — A example

R ¹

Γ— i

CF5CH2

CF3CH2

CHF2CF2CH2

CCIF2CH2

CF :: C! 1 ·

7i ~ (ch ₂ ^ ~

3) - (

Ot ^CH 2't-

JI-ICHA '

N

43 CF3CH2 44 CHF2CF2CH2 p = -N 45 CF3CH2 46 CF3CH2 47 CF3CH2 Q -SrncHA 48 CFsCH? 49 CCIF2CH2 X \ hch ₂ J ₃ - 50 CHF2CF2CH2 AAo-ÍCHA- 51 CF3CH2 0- ( ^c ^ 2 - 3 ") 52 CF3CH2 jH ^x CH ₂ ^sch 2 ^Cμ 2 ~~ 53 CF3CH2 54 CF3CH2

R3

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

R ⁴

H

H

H

H

H

21 22nd example R ¹ ring —X — A R ³ R ⁴ 55 CF3CH2 H H 56 CF3CH2 H H

H

6'2

CK.CH>

CFzCHa

CHF2CF2CH2

CF3CH2

CF3CH2

CF3CH2

'N ^ CHCH ₃ ',

J 1 N 2 N 2 - (C 1 H 2) - Cr

-CHA '';

'2' 3 $ ^ Z

H

H

H

H

H

H

Legend:

Example 4:

mp 153-155 ° C.

Example 5:

mp 148-150 ° C.

Example 6:

m.p. 144-148 ° C.

Example 7:

mp 148-150 ° C.

Example 8:

mp 179-181 ° C.

Example 9:

mp 192-195 ° C.

Example 10:

maleate, m.p. 202-204 ° C. Example 11:

mp 176-178 ° C.

Example 12:

maleate, m.p. 161-163 ° C. Example 13:

mp 199-201 ° C.

Example 14:

mp 209-210 ° C.

Example 15:

mp 171-173 ° C.

Example 16:

maleate, m.p. 171-172 ° C.

Example 17:

mp 165-167 ° C.

Example 18:

maleate-0.25-2 °, mp 169-171 ° C.

Example 19:

maleate, m.p. 165-166 ° C.

Example 20:

maleate, m.p. 194-196 ° C.

Example 21:

m.p. 162 DEG-163 DEG. Example 22:

2,5-maleate-1 H 2 O, mp 165-168 ° C.

Example 23:

maleate-0.5 H2O, mp 187-189 ° C. Example 24:

maleate-0.5 H2O, mp 135-140 ° C. Example 25:

maleate, m.p. 160-163 ° C. Example 26:

mp 152-154 ° C.

Example 27:

mp 125-126 ° C.

Example 28:

mp 122-126 ° C.

Example 29: Analysis calculated:

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

found:

47.0% C,

6.7% H.

26,8% N.

Example 30:

mp 156-158 ° C.

Example 31:

NMR (perdeuterodimethylsulfoxide):

2.8 (d, 3H);

4.1 (m, 2H),

7.3 (s, 1 H),

7.0-8.4 (complex, 7H).

Example 32:

mp-maleate, m.p. 138-141 ° C.

Example 33:

maleate, m.p. 138-139 ° C.

Example 34:

m.p. 202 DEG-203 DEG.

Example 35:

hydrogen maleate, m.p. 184-186 ° C.

Example 36:

176 DEG-177 DEG.

Example 37:

maleate, m.p. 194-195 ° C.

Example 38:

1,25-maleate, m.p. 158-159 ° C. Example 39:

M.p. 130-131 ° C. Example 40:

dimaleate-0.5 PRO, mp 93-95 ° C. Example 41:

M.p. 162-163 ° C. Example 42:

maleate, m.p. 156-157 ° C. Example 43:

maleate, m.p. 159-161 ° C. Example 44:

maleate, m.p. 141-142 ° C.

Example 45:

maleate, m.p. 146-147 ° C. Example 46:

mp-maleate-0.5 H2O, m.p. 182-185 ° C.

Example 47:

mp 179-181 ° C.

Example 48:

mp 192-193 ° C.

Example 49:

maleate, mp 149-153 ^C. 'C. Example 50:

maleate, m.p. 161-162 ° C. Example 51:

maleate, m.p. 189-191 ° C. Example 52:

maleate, m.p. 168-169 ° C. Example 53:

mp 126-128 ° C.

Example 54:

maleate, m.p. 177-179 ° C.

Example 55:

mp 162-164 ° C.

Example 56:

maleate, m.p. 166-168 ° C.

Example 57:

NMR (perdeuterodimethylsulfoxide):

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).

Example 58:

melting point 178-177 ° C.

Example 59:

maleate, m.p. 173-174 ° C.

Example 60:

hydrogen maleate, mp 168-170 ^o C.

Example 61:

maleate, m.p. 113-146 ° C.

Example 62:

mp 192 ° C.

Examples 63 to 67

In analogy to Example 3, the following compounds were obtained:

CF 3 CH 2 NH

2R

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 (CDCl 3): 7.5 (m, 5H),

5.73 (d, 1H),

4.06 (q, 2H);

5.22 (s, 2H).

Example 65:

NMR (perdeuterodimethylsulfoxide):

7.7 (s, 1H).

3.92 (m, 4H);

2.06 (t, 2H).

1.5 (m, 4H).

Example 66:

the maleate melts at 143-146 ° C.

Example 67:

NMR dimalate (perdeuterodimethylsulfoxide):

8.4-6.4 (broad m, 10H including 7.7 [s,

IH]),

5.04 (quintet, IH),

4.35 (q, 2H);

2.85 (quintet, IH),

2.45-1.9 (m, 6H1).

Claims (2)

BACKGROUND OF THE INVENTION A process for the formula of guanidine derivatives of the general formula 1 C ~ N-C D H 1 • C- N (I 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 3 to 8 C 4 -C 14 cycloalkylalkyl, each of which alkyl, cycloalkyl or cycloalkylalkyl is 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 is ¹ and R ² represents a halogen-substituted alkyl, cycloalkyl or cycloalkylalkyl group with the proviso that the carbon atom al241537 an 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 residue 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 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 not connected with 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, C 8 -C 14 aroylaminoalkyl, C 3 -C 10 alkoxycarbonylalkyl carbon, C 2 -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; 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, chloro , bromine and iodine, (C 1 -C 8) 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 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 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 bound to ring X is formed by reacting the corresponding cyanamide with a suitable amine, whereupon the resulting compound of formula I resulting in the free base form is optionally converted by treatment with an acid providing a pharmaceutically acceptable anion to its acid addition salt. 2. The process of claim 1, wherein 2,2,2-trifluoroethyl cyanamide is reacted with 5- (3-aminopyrazol-1-yl) valeramide.