CS241000B2 - Production method of heterocyclic guanidine derivatives - Google Patents

Description

(54) A method for producing heterocyclic guanidine derivatives i

The present invention provides a process for the preparation of heterocyclic 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 was named as the H-1 receptor (see Ash & 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 as 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.

One of the results of blocking the effect of histamine on the H-2 receptor is known to inhibit 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.

GB2O52478A and GB2O558OOA disclose histamine H-2 receptor antagonists which are 2-guanidinothiazole derivatives bearing a 4-side chain at the end of which a substituted amidino group is attached.

It has now been found that haloalkylguanidinoheterocycles do not sense a side chain to which an optionally substituted amidino group is attached at the end are potent histamine H-2 receptor antagonists.

Accordingly, the invention provides guanidine derivatives of formula (I)

- And

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 groups are optionally substituted by one or more halogen atoms selected from the group consisting of fluorine, chlorine and bromine atoms, with the proviso that at least one of s ^ym> ol ^for R ¹ and R ² is alkylated halogensubs ^^ a ^ ^yl-cyclo- cvou ^b loal.kylovou not a cycloalkylalkyl group as - tm limitation that - on - carbon - carbon alkyl, cycloalkyl or groups cykioalkyialkylové which - is directly attached to the nitrogen atom,

1, there is no halogen substituent, or R represents a hydrogen atom and R- represents a radical of formula II ^r5 -E-W (11) wherein:

W represents a straight-chain alkylene chain of 2 to 6 carbon atoms optionally substituted by one or more alkyl groups of 1 to 4 carbon atoms,

E represents a hydrogen - oxygen or sulfur, a sulfinyl group, a sulfonyl group or a radical vzorce'NR® where 'represents hydrogen R®' and ^{plurality of projections,} frequent or alkoxycarbonyl having ¹ to ⁶ carbon atoms, - and

R ⁵ hydrogen znamená.atcm not on nerozv ^b ^ Vena asylum with ^{the pi} nu u ^- 1 and ^{F - 6} alkyl, ^- O- * r ^ sub case stiju <нлaneu - one or two alkyl groups having 1 to 4 - or carbon atoms

R ^{5 -} and ^- R® ^ o ^ ny ^{- al} ol with the nitrogen atom to ^the esters are attached form a pyrrolidine, piperidine, - morolinový, piperazine or N - nethylpiperazinový circle dotted line in the ring represents a double bond -X on the one hand, a 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 the group consisting of oxygen, nitrogen and sulfur atoms; whereby this ring may, if possible, carry one or two substituents selected from the group consisting of fluorine, chlorine and bromine atoms, alkyl groups of 1 to 6 carbon atoms, alkoxy groups - having 1 to 6 carbon atoms, a hydroxy group, a hydroxyl group and an amino group,

A represents a phenylene group, a C 5 -C 7 cycloalkylene group or an C 1 -C 8 alkylene radical, optionally substituted by one or two C 1 -C 3 alkyl groups, and optionally containing as part of it yen chains - or - two groups - selected from the group consisting of oxygen and sulfur atoms, an NH group, an N-alkyl group having from 1 to 6 carbon atoms, a cis- and trans-vinylene group, and a Unyleno3 group;

241000, phenylene and C 5 -C 7 cycloalkylene, provided that the shortest part of the chain between ring X and C (R ⁴ ) = NR ³ consists of at least 3 atoms, provided that the chain of residue A is optionally interrupted by any of the aforementioned groups directly bonded to C (R ⁴ ) = NR ³ , this group is not NH or N-alkyl and provided that there are no two groups optionally interrupted by the chain of residue A selected from atoms oxygen and sulfur, NH and N-alkyl groups, are not directly linked to one another,

R is hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 14 cycloalkylalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, (C 1 -C 6) aminoalkyl, (C 2 -C 10) alkylaminoalkyl, (C 3 -C 14) alkylaminoalkyl, (C 2 -C 6) carboxyalkyl, (C 1 -C 6) alkanoyl; C 1 -C 11 aryl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkanoyl, (C 1 -C 6) thioalkanoyl, (C 7 -C 11) thioaroyl, cyano, carbamoyl, thiocarbamoyl, alkylcarbamoyl C 2 -C 6 dialkyl, C 3 -C 10 dialkylcarbamoyl, C 2 -C 6 alkylthiocarbamoyl, C 3 -C 10 dialkylthiocarbamoyl, carboxyl, C 2 -C 6 alkoxycarbonyl, alkoxythiocarbonyl 2 to 6 carbon atoms, oxamoyl, sulfamoyl, alkylsulfanoyl of 1 to 6 carbon atoms, dialkylsulfamoyl of 2 to 10 carbon atoms, arylsufamoyl of 6 to 10 carbon atoms, aralkylsulfamoyl of 7 to 11 carbon atoms, alkanesulfonyl C 1 -C 6 arenesulfonyl, C 6 -C 10 arensulfonyl, hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 -alkylamino, C 2 -C 10 dialkylamino, C 6 -alkylamino up to 10 carbon atoms, 2 to 6 carbon alkoxycarbonylamino, 7 to 11 aryloxycarbonylamino carbon atoms, C 1 -C 6 alkanoylamino, C 7 -C 11 aroylamino, C 1 -C 6 thioalkanoylamino, C 7 -C 11 thioaroylamino, heteroarylcarbonylamino, C 1 -C 6 heteroarylalkylcarbonylamino, (C 1 -C 6) alkylsulfonyl (C 1 -C 6), (C 6 -C 10) arenesulfonylamino, ureido, thioureido, oxamoylamino, heteroaryl or (C 1 -C 6) heteroarylalkyl;

7 7

R represents a radical of the formula NHR in which R represents a hydrogen atom, a (C 1 -C 6) alkyl group, a (C 2 -C 6) alkenyl group, a (C 2 -C 6) alkynyl group, a cyano group, a (C 1 -C 6) alkanoyl group , carbamoyl, C 2 -C 6 alkylcarbamoyl or C 4 -C 6 alkanoylamino, or

-R is a 4cm hydrogen or C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group, and R is a carboxyl group, wherein when R ³ is or contains a heteroaryl radical, the heteroaryl radical consisting of a five or six membered heterocyclic ring containing one, two, three or four heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms, the ring optionally being substituted with one or two substituents selected from the group consisting of methyl and amino, and pharmaceutically acceptable acid addition salts.

It will be understood that although in the above general formula (I) and throughout the text, the double bonds in the radicals bonded to the ring X are located at particular positions, there are other tautomeric forms, and both inventive and contemplated compounds are contemplated. these tautomeric forms are also included.

It will further be appreciated that when A is or contains a cycloalkylene moiety, the moieties to such a moiety may be linked 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 is to be understood that the invention encompasses the racemates of formula (I) above, including all possible diasteatoisomeric forms and all enantiomeric forms exhibiting the desired biological activity. It is known how diastereoisomeric foils can be separated and how racemates can be resolved into individual enantiomers and the biological activity of all these substances can be determined.

2

Cross-substituted halogen-substituted alkyl groups in the meaning of R or R are 2,2,2-trifluoromethyl, 2,2,2-trichloroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-4-fluoroethyl; -bromo-2,2-difluoroethyl, 2,2-diben-1-fluoroethyl, 2-fluoroethyl, 4-chloroethyl, 2'-difluoroethyl, 2,2-dichloroethyl, 2-chloro-2-fluoroethyl, 2- bromo-4-fluoroethyl, 2,2,3,3-tetrafluoropentyl, 2,2,3,3,3-p-trifluoromethyl, 1,1,1,3,3,3-trifluoromethylpentyl, 1,3-dichloro-1, 1,3,3-tetrafluoroisopropyl, 1-chloro-1,1,3,3,3-pentafluoroisopropyl, 1,3-difluoropropyl or 2,2,3,3,4,4-heptafluorobutyl.

Kontortoírni halo nsubstiunovanými c ^ ^yk loal ^alkyl radials hundred us @ R @ ³ or R @ ² are 2,2,3,3-tttéafUuorcy ^to lo ^{p p} en Nva ^{yl, 2-chloro-2,} 3, ³ -t ^f f ^u néccyk ^with pprn ylnvá ^{P, 2, 2-difluoro} Lusaka ^to lnpénpylnvá 2-chlné-3,3-dflUnéccy ^to nopénpylnvá, 2,2,3,3,4,4-htxαflunécyklnbutylnvá or 2-chloro-2, 3,3,4,4-pentcflunéCy ^to lnbutylová group.

Corinate lip^Gefsubstituted c^yrlnclk^ylclky^withFirst hundred^Friby the meaning of the symbol R¹^ or R² are / 1^,2^,2^,3^,3-^pentaflunéc^ykOpeopropyl / Met^hylnvá, /²-C^hl · or ·^andl^{, 2,3},³-tt^téC^Flunéc^ykln for methyl, 1,2,2,3,4,4,4-heptaptifluoro-butyl-methyl^yor 2, 2, 3, 3, 3, 4, 4-hexafluorin^yklnbut^yl / etth^ygroup.

i 2

The alkyl groups R and R are methyl, ethyl, propyl, isopropyl or butyl.

Kcbntortní klnclr ^{cy y} sk catch ^up with another represented by R ^{1, R 2} is C Neto ^y k ^l o ^p ro ^p Neto yl ^and cyclobutyl.

2

Suitable C rlnclr ^{y y y} lclr group of gears · When R or R is cyclopropylmethyl or cyclobutylmethyl.

A preferred optional substituent on W is methyl.

A particular value for R @ ⁵ is atomvod ^Cart with or methyl ^and quick match.

Suitable zbyttom ^R6 is hydrogen or methyl vodíito] ^á hylnv quick match.

· A suitable radical of formula II is ² -methonχethylová, hydroxychloroquine ² ^ (j ^ 5 ^ t ^^ H ^^ oic acid, 2-methylthioethyl or ² -dimethylcminoethylnvá group.

Representative meanings for ring X include oxazole, thiazole, imidazole, 1,2,4-thiadiazole, 1,2-oxadiazole, 1,2,3-thiazole, 1,2,4-thiazole, pyrazole, pyrazole, pyridine, a pyrimidine or 1,3,5-triazine ring, all of which may be optionally substituted by one or two substituents selected from the group consisting of fluorine, chlorine and bromine, methyl, methoxy, trifluoromethyl, hydroxy and amino.

A suitable radical for -A- is phenylene, cyclopentylene, cyclohexylene, trimethylene, tetramethylene, pentamethylene, thioethylene, thiotrimethylene, thiotetramethylene, thiopentamethylene, oxyethylene, oxytrlmethylene, oxytenthiethylene, oxytetramethylene, oxytetramethylene, oxytetramethylene, oxytetramethylene, methylethylene, thiopropylenthiomethylene, oxypropylenoxy-, oxyethylenoxymethylene, oxyethylenthio-, oxypropylenthio-, iminoethylene, iminopropylene, vinylene-propylene, oxymethylene-vinylene, 1,3-phenylene, 1,3-cyclopentylene, methylene-1,4-phenylene, 4-methylene-1,4-phenylene, a phenylene, oxy-1,3-phenylenmethylene or thiomethylenethinylenmethylene group.

Writing these radicals represented by -A- is designed so that it is read from left to right in formula I such that the first named part of each residue is bonded to the ring X and the last mentioned ^{part to} a ^{ždéh would} oz t ^to u is bound to you ^k u ^{p s} C en / ^R4 / -NR ^third

For example, when -A- is a thiotrimethylene group, the compound of formula I comprises a moiety of formula V

/IN/

As ^to TN onkr ^{é í} ZB ^sition in meaning with mbo ^{l y} u R ³ UV ^ADE j ^í atom ^paddlers. Me ^^ c ^ o ^y klohexylová, cyclobutylmethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 2-aminoethyl, 2-methylaminoethyl, 2-dimethylaminoethyl, 2 "carboxy ^y eth ^y _r Nominal acetyl, benzoyl, phenyl, benzyl , allyl, propargyl, trifluoroacetyl, thioacetyl, thiobenzoyl, cyano, carbamoyl, thiocarbamoyl, methylcarbamoyl, dimethylcarbamoyl, methylthiocarbamoyl, dimethylthiocarbamoyl, carboxyl, methoxycarbonyl, methoxythiocarbonyl. sulfamoyl, methylsufamoyl, dimethyisufansuyl, phenylsulfamoyl, benzylsulfamoyl, methanesulfonyl, benzenesulfanyl, hydroxy, methoxy, amino, methylamino, dimethylamino, phenylamino, methoxycarbonylamino, thenoxycarbonylamino, phenoxycarbonylamino, phenoxycarbonylamino, phenoxycarbonylamino, phenoxycarbonylamino, , heteroarylcarbonylamino-, heteroarylacetylamino-, methanesulfonylamino-, benzenesulfonylamino-, ureido-, thioureido-, oxamoylamino-, heteroaryl- or heteroarylmethyl, wherein the heteroaryl moiety is furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, thiazolyl, imidazolyl, imidazolyl, imidazolyl, imidazolol , a pyrazolyl, pyridyl or pyrimidyl radical, optionally substituted with one or two substituents selected from the group consisting of methyl and amino.

K ^k r ^s t n ^r M. zb ^y t ^to em in meaning symlbo ^ ^R4, Z b ^y te ^to NHR ^2, therein ^of R ^{2 BC} edsta ⁱⁿ U is hydrogen or methyl, allyl, propargyl, cyano, acetyl, carbamoyl, methylcarbamoyl or acetylamino.

Another IconJcrétaím zbyttem When R ^{4 is} arbox ^yl OC ^and with ^the at ^PI in ^Preparation pad ^ R ³ represents a hydrogen atom or a methyl, allyl or propargyl. .

The following are 9 preferred meanings for the guanidine derivatives of Formula I.

When any of these meanings, either singly or in combination, are taken together with the other general or specifically mentioned meanings given above for the guanidine derivatives of formula I, preferred subgroups of compounds falling within the above general definition of these compounds are obtained.

24IOOO

4 7 7

1. R represents cyano and R represents a radical of formula NHR ', wherein R 6 represents a hydrogen atom.

1

Second R ² is hydrogen and R ¹ is 2,2,2-trifluoroethyl or 2,2,3,3-tetrafluorpropylovou group.,

3. Ring X bears no optional substituent.

4. Ring X is a pyrazole, 1,2,3-triazole, pyridine or pyrimidine ring to which the A chain is attached at the 2-position.

5. -A- represents a tetramethylene, pentamethylene, oxytrimethylene, oxytetramethylene, thiotrimethylene or thiotetramethylene residue.

6. -A- represents a tetramethylene, oxytrimethylene or thiotrimethylene residue.

7. Ring X is a pyridine or pyrimidine ring to which residue A is attached at the 2-position, and A is a thiotrimethylene residue.

8. Ring X is a pyrimidine ring,. to which residue A is attached at position 2, and A represents an oxytrimethylene residue.

9. Ring X is a pyrazole or 1,2,3-triazole ring and A is a tetramethylene group.

Specific compounds of the invention are described in the Examples. The following are preferred compounds of the invention:

Nk ^y an-4- [S - ^ - ^^^ - trifluorethj / Guanidine / p ^ azole ltylJbutonaimLdin / ^RIK p Ia ^d 60 /.

An nk ^y 4- [4- / 2- / ^2, 2,2-trifluoroeth ^y l / ^d guanidino amino / -l, ^{2, 3-triazol-2- ylJb} anamiďin u ^t / ^d la lecture ^Cart

And pharmaceutically acceptable acid addition salts thereof.

Suitable pharmaceutically acceptable acid addition salts of guanidine derivatives according to the invention are, for example, salts with hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid or maleic acid.

The present invention relates to a process for the preparation of compounds of the above-mentioned general formula (I), characterized in that

(VI) in which

3 7

R has any of the meanings given above for R or R a

R 6 represents a replaceable residue, reacted with a compound of formula VII

R ¹⁴ - NH 2 (VII) wherein

R ¹⁴ has one of the meanings uvedenýc ^h above for R ⁷ a R ^b no ^third

When R is hydrogen, the compound of formula (VII) is ammonia which is conveniently used for the reaction in the form of a salt such as ammonium chloride. R ¹³ can be, for example, C 1 -C 6 alkoxy, such as methoxy. . . . or ethoxy.

The reaction may be carried out in a diluent or in a solvent such as methanol or ethanol. The reaction generally takes place at room temperature, but in some cases heating may be required to accelerate or complete the reaction, for example heating to the boiling point of 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 most important intermediate for the preparation of starting materials. for the process according to the invention, the starting material of the general formula (XVII) is used

/ КПЛ /

This starting material can be prepared by separate construction of the two side chains on the appropriate ring X. Thus, for side chain on the left side of a ring to build up reducing the nitro group to an amino group by reacting the amino group with an isothiocyanate of the formula R ³ R ² N = OS 'and finally reacting the resulting ammonia in the presence of mercuric oxide. The process of constructing the side chain on the right side of the ring may vary depending on the nature of the ring X, the nature of the atom in the ring X to which the remainder A (carbon or nitrogen) is attached, and the presence or absence of atoms or groups introduced into chain A.

If residue A contains no established group, or if the introduced group is a phenylene residue and Z represents a carbon atom, it is. advantageous to build a circle X with a side chain already present on the right side.

Thus, when ring X is a pyrimidine ring, it can be built by reacting a suitably substituted amidine with 2-chloroacrylonitrile to give the corresponding 4-aminopyrimidine derivative, as exemplified by Examples 8 and 14.

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. If the group introduced into the A chain is a vinylene or ethinylene group, it can be introduced into the remainder of A by double or triple bond formation by standard coupling methods. .

When the built-in group in the A-chain is an oxygen or sulfur atom, or an NH or a group. N-alkyl, the right-hand side chain can be built as illustrated in Examples 1, 7, 16 and 21. When z is N, the right-hand side chain can be built as illustrated in Examples 3, 4, 18, and 19.

^{Baseline la sition generally} the formula VI ^P ro ^p RAC ^and caused em ^b e ^p o ^dl vynáiezu in one ^of R ¹² is

3 is hydrogen and R @ 1 is alkoxy, may be prepared from the starting materials of formula XVII by treatment with anhydrous hydrogen chloride in a diluent or solvent of formula R @ ¹³ OH, as exemplified by Examples 1, 2, 3, 4, 6, 7, 8, 9, 14, 15, 16, 17, 19 and 21.

As mentioned above, guanidine derivatives produced by the method 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 stress ulcers and gastrointestinal bleeding due to injury.

The activity 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 acidic area of endothelial cells.

The guinea pig atrium test is performed as follows:

Guinea pig right atrium at a tension of 1 g / isometrically / suspended in 25 ml of a thermostatically-controlled / 30 ° C / tk ^and the new ^{e la} marks ^{of their} content ^of C ^s okysMčený / 9 ^{5% 5%} CO ^ ^b Kre with ^-H enseleit ^U V buffer (pH 7.4).

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 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 / l 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, 0.201 g of potassium chloride, 0.113 g of sodium monohydrogen phosphate, 0.204 g of potassium dihydrogen phosphate, 0.132 g of calcium chloride dihydrate in 1 liter. 0.101 g magnesium chloride 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 dispersing medium. 100 g collagenase (Sigma Chemical Co., type V) and 100 mg bovine serum albumin (Miles Laboratories Ltd., fraction V) in 100 ml buffer 1: 50 ml medium ^per 10 ^g or ^at the weight of tissue and agitated ^{s ky} in the ^phorous b ^s mos ^{t FER} e ^{b i} nto uj ^e at ³⁰ ° C and pH 7.4 / 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 g wet 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 mixture of glands and cells is isolated by centrifugation at 200 xg and suspended in buffer 1 containing 1% bovine serum albumin * iles Laboratoies Ltd. fraction V. Finally, the cells and glands are washed three times with buffer 1 and the suspension is contained in buffer 2 500 ml of Eagles medium / MEM / 10 mg N otintau / Si Chemtoal Co./ ° and ²⁰ ml ^{/ 150 mm} / 2- [4- / 2-hydrsxyethyl ^/ p ⁱ Perazim-yl] ttaansufSonsvé acid adjusted to pH 7.4 with sodium hydroxide? 150 ml and 10 g net weight! tissue.

The tissue suspension is stirred in an oxygen atmosphere at 32 ° C for at least 1 hour before use.

The tissue suspension was incubated for 20 minutes with test compound and 10 / j ^ C ^ I-labeled aminopyrine C for ^{14 h} y ^d ioet ^to aminos ^and UPIN ^E / 0,1 / uCi / ml /. ^The sweat ^{of b} and e is ^p, and aminopyrine stimulates ^the addition histmlnua phosphodiesterase inhibitor ICI 63197 / Biochem. Soc. S ^p ecial PuUiicatiso 1 1973 ^, pp. 127 to ¹³ 2 / to Anal concentrations 10 ^-5 M res ^p . 5 x 10 “ ⁷ M.

After 18 minutes, the cells and glands are separated from the incubation medium by filtering the suspension through glass microfiber filters. Mixture ·. The cells and glands are then rapidly (in less than 10 seconds) washed three times with ice-cold buffer.

At Scion NiO ^and C ^{o after} the ^J ^ i ^ ⁱ · ^p and the změiří ^to amino ^^ n C-labeled ^14, is seized in tkánty and ^p of ^- flattening the control sample is calculated degree of inhibition of aminopyrine consumption caused by the test compound.

From the series of tests performed at different concentrations, the concentration of the test compound causing 50% inhibition is graphically determined.

All of the compounds exemplified in this test were subjected to either a guinea pig test or an aminopyrine test. All substances tested in the urinary urinary tract are effective at a bath concentration of 10 µM or even lower, and more effectively demonstrate from these compounds in this complete inhibition of responses.

All compounds tested by the aminopyrine assay showed a 50% inhibition of amine pyrrine consumption at 33M or even lower.

Inhibition of gastric acid secretion can be demonstrated by standard assays, such as the ability of the compounds of formula I to be administered intravenously, to the stomach, or orally, to inhibit acid gastric secretion in, for example, rats or dogs with gastric stomachs or gastric sacs in which gastric secretion has been stimulated by administration of a secretion enhancer, such as pentagastrin, histamine, bethanechol or food.

The rat test is carried out as follows:

Rat female of weight! 200 to 230 g are anesthetized by intramuscular administration of urethane at a dose of 1.5 g / kg and into their trachea. · Introduces the cannula. A soft tubing is inserted through the esophagus into the stomach of the test animal and secured by a ligature in the embrace of the neck.

A plastic tube (3 m in diameter) with a plurality of holes is inserted into the anterior region of the stomach by incision in the duodenum and its position is ligated around the pylorus. The esophagus cannula is washed with saline (9 g of chloride chloride / liter) at a dose of 7 ° C and the liquid removed from the outlet is collected in beakers at intervals of ten minutes. ^: .

Acid secretion is stimulated by subcutaneous administration of the specific H-2 antagonist dimaprite. at a dose of 10 mg / kg followed by an infusion at a dose of 30 mg / kg / h. Acid secretion is calculated by titrating samples taken after 10 minutes.

Titration is performed with 20 mM sodium hydroxide to an end point of pH 6.4. Once the acid secretion has reached a uniform value (three consecutive readings are in the range of 5%), the test compound is injected intravenously through the left external jugular vein.

Secretion is then measured for an additional 2 hours. A stock solution of each of the test compounds (10 mg / ml in dimethylsulfoxide) was prepared first and an appropriately diluted solution was prepared from this stock solution by dilution with saline to allow an appropriate injection of 1 ml / kg (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, after detecting absence of basal secretion within 30 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. Measure the volume of each sample and titrate a 1 ml aliquot with 100 mM sodium hydroxide until neutrality to determine the acid concentration.

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

In the stomach 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 a medium consisting of 25 ml 0.5% (w / v) hydroxypropyl-methylcellulose and 0.1% (w / v) Tween 80 surfactant 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 loaded 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 opens and immediately ceases with the intravenous infusion of a secretion enhancer.

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 the 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) were prepared with vague-denerved vesicles in the fundus region (see Rudlick et al., J. Surg. Res. 1967, Λ 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 hung on cloth. · Straps. .

After washing the pouch warm. with water at a dose of 10 µg / min, infusion of histamine is started. This agonist dose induces a submaximal / 60-90% of the maximal / increase in all experimental dogs. acid secretion.

^To re ^ACK for ^those vol take place in patnáctiminutovýýh ntervalech ^ ^d of ^{the H} and ^IIb rovanýc sk ^l eněných tubes with 0,1 ml is measured by its volume. The 500 µm sample was diluted with 5 mL of brine and titrated with 100 mM sodium hydroxide to pH 7.0. . '

Total acid production is calculated from the acid concentration in the secretion and the secretion volume. The test compounds are administered intravenously at a dose of 0.1 ml / kg to the cephalica vein or orally as a gelatin capsule at the time the secretion stabilizes / three The following readings are in the range of 10%. Secretion is measured for 3 hours after administration of the test substance.

From the results obtained in the guinea pig atrial test and the aminopyririne test, one can conclude on the efficacy in the rat and mouse tests. on · dogs.

No clear signs of toxicity or side effects were observed during rat and dog tests.

A number of compounds listed. in this test, it causes an inhibition of gastric acid, which does not deviate from maximum inhibition for a few hours or at all.

The compounds produced by the process of the invention may be used in the form of pharmaceutical compositions containing the guanidine derivatives of the invention 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, this can be mentioned. for example, tablets, capsules, aqueous or oily solutions or suspensions, emulsions, dispersible powders, suppositories, sterile injectable aqueous or oily solutions or suspensions, gels, creams, ointments. or washing means.

In addition to the guanidine derivative of the present invention, 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 antadetic agents, such as mixtures of aluminum hydroxide and magnesium hydroxide, antipepsin compound. such as pepstatin, other histamine H-2 antagonists such as cimetidine or ranltidine, 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 E ₂ , classical antihistamines (histamine H-1'antagonists), such as. for example, mepyramine or diphenhydramine, anticholinergic agents such as atropine or propantheline bromide, anxiolytic agents such as diazepam, chlordiazepoxide or phenobarbital. '* i, t ·

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

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

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.

The pharmaceutical compositions described above are normally administered to humans for the treatment of gastric ulcers and other conditions caused or re-induced by the stomach. In a general manner such as that used for the administration of cimatidine, the efficacy and duration of action of the guanidine derivative of the present invention as compared to cimetidine should be considered in terms of dose levels.

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 of the invention, intravenously, subcutaneously. or by intramuscular administration, a dose ranging from 0.5 to 50 mg, preferably from 2 mg to 20 mg of the guanidine derivative of the invention is administered one to four times, preferably one, daily. .

The rectal dose administered will be approximately equal to the orally administered dose. The disclosed compositions may be administered less frequently when the amount of guanidime 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 of the invention. NMR spectra are given in delta versus triethylsilane.

/ delta = 0 / as internal standard. Signal shapes are indicated by the following abbreviations:

s = singlet, d-doublet, t-triplet ,.

q »kvaaret, m - muuttppet,.

By ether is meant diethyl ether. It should be noted that the fact that y case ^

3-trspopazszolu (example 3) and 4-oitrttrijzttu (example 4) risk of explosion. Example 4 describes the preparation of the starting material for the process of Example 5.

Example 1 and -dl / ·,

· A solution of 0.65 ^g of 4- [4- / 2- / 2,2,2-triftutrethyl / ^g ethylguanidine / ^sl pyrimidd22ylthls utyros tri- ^{n t in} 15 ml of mmthanolu and 30 ml ^of ether were s t ^ ⁰ C lotto saturated with c · ^{d hl} orovo guard and ^p and ^{k NEC} hook ¹⁸ hours ^{STAT p} s 0 ° C.

· · The reaction solution was evaporated to dryness and the residue content jícímu iminoether was added a solution of 0.22 g of sodium methoxide in 10 ml mmthanolu then added a mixture of 0.21 g ^hy-d roxylαmi.o hydrothloridu, 10 mL and 0.16 mmthanolu g of sodium methoxide, the resulting mixture was stirred at room temperature for 3 hours and then evaporated to dryness. The residue is shaken between water and ethyl acetate, the ethyl acetate phase is dried and evaporated to dryness.

The residue is purified by preparative thin layer chromatography using Merck GF 254 plates and a mixture of ethyl acetate, methanol and ammonia (density 0.88) in a 6: 1: 0.5 by volume ratio as the solvent for the system.

^{About 48} g of 4- ^{[4- /} 2- ^/ 2,2,2-tf ^ljS uoteth / l ^j gunn DIS ^d / P ^p yiiаid ^{2-ylthSoJ-L-Ox а} I ^O O ^l utylaminu characterized as press 137 DEG-139 DEG.

The starting material used in the above reaction can be prepared as follows:

To a solution of 0.25 g of 2-thiocytosine in 5 ml of 0.5 N aqueous sodium hydroxide is added 0.23 g

Of 4-chlorobutyronitrile in 2 ml of ethanol and stirred for 18 hours. After adding another 0.23 g

The reaction solution was concentrated in vacuo to a volume of 2 ml and cooled. 0.3 g of 4- / 4-tminopytlnid-2-ytrhio / ^b ubyroh0trilb on te ^ OTE point ^{of 99} DEG to 100 DEG C., isolated ^odřl-l-yl compound act in enhanced ^é ^ precipitate.

A mixture of 0.25 g of 4- / 4-2-aminohptlmid ylttinr-bubytlh0ttirb 3 ml acetonOtlirb and 0.21 g of 2,2,2-tlifiuorethylSrttn ^R 7 okyaoátb ² hours while stirred ^{and y} te ^pl OTE 70 ° C, then evaporated to dryness. .Kytsaiizací z ^ TKU from ether and ^{p r} etlh ethelb / pulse of boiling ^60-80 ° C / to give 0.37 g of 4- (4- / 3-2,2,2alniilrllrtttyl / thiblrniho / pyrimidin-2-tlthih] 125 DEG-126 DEG.

A mixture of 0.32 g 4- (4- / 3- / 2,2,2-alifiuhlethtl / -thioblendh / ^y p rlnnin-2- ^yl tthio] 0ub ^y toh0irirb 20 ml sat. Ethanolic ammonia solution and 0.5 g yellow oxide ^ u ^ ATEH stirred for 20 hours at m ^ t ^ t ^ c ^ ott ^., filtered and the filtrate evaporated to dryness. the residue postytne ^C o pekrYstatov ^ i SJ ° of acetone and petroleum ^ e ^ / toptota boiling ^60-8 0 ° C / 0.29 g of 4- [4- / 2- / 2,2,2-trifrbhleah ^yl / gbanidioo / ^y p ^y riminl 2- lthihJbub ^y tlontrirb mp 137 Deň: 32 ° C.

Example 1 a d 2.

To a mixture of 1.5 g of 4- [4-72- / 2,2,2-brifrbhrebhyl / gbanidino / P-22 ^y timid tbhio ^y | ^y OUB tlhOnrirb, 10 ml methanol and 20 ml · c ^ is orotormu 'is a temperature at 0 ° C while dry p ^^ characterized ^hrolooo c d ^s for ^{up to} saturation. The resulting solution was ^two days ne'chá ^y st ^ate at ° C and then concentrated in к Suc ^h. The residue was partitioned between a solution of 5 g of potassium carbonate in 25 ml water and three times with 25 ml of chloroform. The combined chloroform extracts were evaporated to dryness and 0.25 g of ammonium chloride was added in 5 ml of methanol to the remaining n-alcohol. The resulting mixture was stirred at room temperature for 2 hours then. Evaporate to dryness and triturate with ether.

Gains ^and 4 - [4- / 2- / ^2,2,2-fri hreat yl ^t / h ^b uoni ^NN // ^tr n ^{m [t} NID-2-ylthio ^0b utonадidin dlhchlol ^t h ⁱ d.

NMR / ^y peldeuterolimeth lstilootd / 9.1 / šrroký s, 2H /, '8,8 / br s, 2И /, 8.1 / d, H /,

6.4 (d, 1H), 4.2 (g, 2H), 3.1 (t, 2H), 2.5 (m), including methylmethoxide (2.08) (m, 2H).

Example 3

A solution of 0.94 g 5- (3- / 2- / 2,2,2 .tlifibh> lethtr / ^p gbtnidinor ytltol-yl] oaleronOtrirb in 10 ml and 10 ml chlorofomiu metoanolu toptotě at 0 ° C and saturated with gaseous C ^hr orooh guard and ^{d. MES y} 24 h cooled to ⁵ ° C, NACE ^z to ^t ^ e ^ ^s, and ^the proportion of ^{y d} steamed in cotton-Ptot at ⁴⁰ ° C.

The syrupy residue is cooled in ice and 50 ml of ice-cold 10% (w / v) aqueous potassium carbonate solution are added. The resulting precipitate was extracted with chloroform, dried over magnesium sulphate and evaporated in vacuo to give a brown ether.

0.5 g of the latter is dissolved in 5 ml of methanol and. 0.73 g of hydrobromic acid hydrazide is added to the solution. Results The ^d Nu ^The organic solution was allowed to react ^{and 48} Todina toploto at 20 ° C for ^No. EZ doused volatiles removed in vacuo.

The syrupy residue is crystallized by filtration with a mixture of ether and ethanol (9: 1, v / v). To give N-acetylamino-N- [3 - // 2 / 2,2,2-tlfrihorethy / gbuaoi ^d IOH / ptlazol L-yl0vallrami ^d io of warm-up to 142 I counting. 144 ° C.

The starting material can be prepared as follows:

To a solution of 17.4 g of 3-orthopyrtyl in 150 ml of dry dnmethylhormamideb was maintained at ²⁰ to ²⁰ ° C while maintaining the temperature by external ice cooling. ³⁰ ° C was added portionwise over ³⁰ min 6 ¹⁶ g of paste natriímhydridu / 61 »[hmoOnnot / hmoOnoot] suspension in liquid paraffin /. After 45 minutes mu ^c HA to the resulting almost clear solution at ^T emperature ^of 2 ⁵ to 30 ° C, ^runs through 30 ^minutes, 25 ^g

Of 5-bromo-phenylterrile and the resulting mixture was added. stir 4 clearings.

After the addition of 45 ml of water and 450 ml of ethyl acetate, the upper layer was separated, dried over magnesium sulphate and evaporated in vacuo to an oily residue consisting of a mixture of S-4-nitropyraazoll-yl / valeronntril and S1 (S-oitropyrrzO-1-yl). valeronOtrilu.

Maaterál The oil was divided into two doused with 15 g which was fractionated on a column silkkagelu / diameter 3.5 cm, length 100 cm / column eluted with a pressure of 0.2 bar and ^p Société ettylacetátu etroletheru / boiling point 60, and ^a 8 ⁰ ° C / at ratio of 3: 7 ^/ ^ ^b ^ _/ ^/ a is ^b ^.

First, the 1, S-10oer is eluted, followed by the 1,3-isooereo. S / ^P 3lOinro yyrfo0ll ^<yl / valeronitail melts at 32-33 ° ^C.

To a solution of 9.16 g · Sl / 3 · oinropyj rfzOll-yl / valeronOtrilu in 200 ml of dry netrahydrofurfou at 1.8 g of 5% / hooOnoot / hooOnooS / palladium on carbon and the mixture was stirred in a hydrogen atmooféře ^p · s tep mp 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 an oily S- (3-hexanol) -alcohol-1-ol.

To a solution of 7.0 g of S- (3-azinooyrazflol-1) valeroontril in 25 ml of acetonntril is added

6.02 g of 2,2,2-trifluoroethylthiocyanate. After 15 minutes, the solvent was evaporated in vacuo. vacuo to give S- [3- / 3- / ^2-2,2 nrifluoaetlyl / t ^f oOpyjafol iouaei ^l-yl '] valeroittail. the ^f orm ^of a white ^{substance to} rystalic ^Ké yo, Melting ^t even 96 and ⁹⁸ ° C.

12.5 g of the above prepared t ^ hi ^ c ^^ m ^ o ^ ins rozpuutí in 120 ml of 8M ammonia in EtOH, treated with ^E 12 ^{8 g} carbon lip ^ n ^^ o and the mixture was stirred for ³ 0 minutes at, Melting ²⁰ ° C. The reaction mixture was filtered and the filtrate was evaporated in vacuo to give an oily salt of [3- (2- / 2,2,2-trifluoroenlyl) guanofino] ylazolol-1-yeastol-3-ol.

A sample of this oily maaerial is dissolved in acetone. to the solution was added 5,000 equivalents of raspic acid. Ether was added to the thus vlniklOou · clear solution was precipitated torystalický ma ^ maleate melting at 1 ^23, and ^{from 125} ° C.

Example 4

A solution of 0.5 g of unpurified [eta] &lt; 5 &gt;- [4- [2- (2,2,2-trifluoroenol) guanofino-1,2,3-thiialol-2-yl] valerimidate and 0.2 ml of acetonitrile acetone in 10 ml. mL of methanol was stirred at room temperature overnight.

The resulting mixture is evaporated to dryness, the residue is dissolved in 10 ml of concentrated aqueous hydrochloric acid and the mixture is heated on a steam bath for 10 minutes. The reaction mixture was odpaaí, the residue basified with saturated aqueous sodium lydrQ ^g · gnoUličitfnu solution and extracted with etlýlfcétáteo.

This extract was extracted with 2N aqueous hydrochloric acid, the acidic extract was basified with 2.5 N aqueous sodium hydroxide and extracted with ethyl acetate. The latter extract is dried over magnesium sulphate, turned to a small volume and a solution of 0.36 g of madeinic acid in a small volume of acetone is added to the residue.

Gains ^and 0.35 ^g of 2- / 4- [4- / 2- / ^{l 2,2,2} luoaen ^if the ^l-yl / ^NIF guan ino- ^{l, 2, 3} -trifloll ² jl ^{l] b u} y ^j / ^{L-ioidazol·l} dihydrogenooleátu mp 137-139 ^o C.

The default material can be obtained as follows:

241000 ·:

To a solution of 23.0 g of 4-oxo-1,2,3-triazole in 135 ml of dry dimethylformamide, a dispersion of 4.8 g of sodium hydride in 4.8 g of mineral oil is added while stirring at room temperature.

The mixture was stirred for 30 minutes and then stirred at room temperature overnight

The product was extracted with ethyl acetate and

33.0 g of 5-bromvaleronitrile is poured into water. <

purified via column chromatography on 1 kg of the gel using a mixture of equal volumes of ethyl acetate and petroleum ether / temperature and ⁸⁰ ° ^{C /} I ^for the elution of ^¹H čtei ^ a. ^From IS ^Ka otejovitého ^{22.3 g of 5} - / 4 it ^^ ^ (O &apos; ^l-3-tri azole-2- ^yl / valeronitrile.

silikavaru 60

A suspension of 0.5 g of 5% (w / w) palladium on carbon-triazol-2-yl) valeronitrile in 20 ml of acetic acid was added until 420 ml of hydrogen were taken up.

in pressure solution '0.1

5- (4-nitro-1,2,3)

1,0 9

MPa of hydrogen stir until

The mixture was filtered and evaporated. 0.85 g of -triazol- ² -yl] valeronitrile is obtained.

oily-5-amino-4-ol ^; A solution of 0.35 g of 5- (4-amino-1,2,3-triazol-2-yl) valeronitrile and -0.5 g · 2.2; -TrifÍuorethylisothiokyanátu ² in 5 ml of acetonitrile was stirred overnight at room temperature inclu-I.: _Reaction: · ^mixture: about ^dp and ^R 'from ^the TE ^to the pr ^{y p} ticular are installing from a mixture ^{of it} with the ^l e and ^p uenu ^{t h} shutters ERU / teptete boiling ⁶ · 0-80 · ^ ° to ^yield 0 ^{50 g} of 5- ^[4 - / ³ - / ^{2, 2,2-tri fluoroethyl yl} / ^well into thioure / L ^{2, 3-triazol-2- yi]} vialerO ^'- r · n ^{il it} at Tej ^^ o ^p o ^{p t} and ^l řekrys OC ^and it of toluene ^{at 86} and ⁸⁸ ° C ·. :. . ; ;

To a solution ^of 0.45 ^g of 5- [4- / 3- / 2,2,2-tri ^fluoroethyl l / thioureido / -l, ^2, 4-triazol-2- ^yl lÍvaleronit.rilu in 10 ml of 6N ethanolic ammonia solution 0.6 g grams of mercury is added with stirring at room temperature. .

The mixture was stirred at room temperature for 2 hours, then filtered and evaporated. There were obtained 0.41 g of 5- [4- / 2- / 2,2,2-trifluoroethyl / Guanidine / -l, ^2, 3-triazol-2-yl] valeronitrll.

Thaw ^to 1.0 ^{g of} y, ^ ^ are assured of 5- [4- / 2- / ^{2 2} _ ^{2-tri fl} uore ^IHY l / ^{g and} Uan DIØ / ^-l, 2,3-triazpl ^{- 2yl} j va ^l Eron tr ^{i il} at the sites. 15 ml C ^hl oro ormu ^f and 10 ml of the meteanolu ^EXAMPLE teptete ⁰ ° C with sat ^{yl ootin} lynným chloride.

^{The currency} was left in a closed ^Eb ance ^{2 d} n ^YR e ^g OVA ^{t at t} e ^p lo ^I 5 ° C to ^p e ^z is a ^DP and ^R · ^to dryness to give the product as a salt with hydrochloric acid . This hydrochloride was basified with a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with dichloromethane.

The extract was dried over magnesium sulfate and evaporated to give 1.0 g of methyl 5- [4- / 2- / ² _Z ^{2 2} ~ trifluoroethyl / guanidinoZ-l, ^{2, 3-tri} azo ^{l "2} - ^yl] va ^l er ⁱ z ^e d ^{i ate} in the ^f orm ^of an oil that · is used without further purification.

Example 5

A mixture of 1.0 g Meihu ^yl-5 - [N ^{4/2/2, 2,} 2-trifluoroethyl / ^g ethylguanidine / -l, 2,3-triazol-2-yl] valerimidate chloride and 0.18 g of ammonium ammonium chloride in 15 ml of methanol was stirred at room temperature for 18 hours. evaporate to dryness. 1.0 g of unpurified 5- ^[4 - / ² - / ^{2, 2, 2} -irifluoreth ^yl / ^g uaoidino / -l, ^2,3-tri azo ^l - ² - ^yl] va ^{l id} Eram inu in the form of the hydrochloride.

A mixture of 0.40 ml of ethyl formate, 0.57 ml of ethyl propionate, 0.25 g of sodium hydride, 0.25 g of mineral oil and 4 drops of ethanol was stirred and refluxed in 15 ml of ether for 4 hours.

Rea ^{CZK tup} was zfilteuje and ^p evný of EC to ^be fi ^ ru was added ^and the flowable к ^{0.5 g of 5} - ^[4- / 2- / 2 г ^ - ^^^ огеЬЬ ^ / ^ о диапМ / - !, ^{2 'S-1-2-} same basic ^] aroC vateramitHn- ^ ^ or ^ uv ^{5 1} п ^meth anol.

241000 16

The mixture was heated under reflux for 18 hours and then evaporated to dryness. The residue was partitioned between ethyl acetate and water, the aqueous phase was separated, acidified with acetic acid, basified with aqueous sodium bicarbonate solution and extracted with ethyl acetate.

The extract was dried over magnesium sulphate and evaporated to dryness. The residue was triturated with ethyl acetate and filtration, 0.11 g of 4-hydroxy-5-methyl-2- / 4 - [ '4- / 2- / 2,2,2-trifluoroethyl / Guanidine / -l, ^2, 3- ^{tri azole-2-yl yl} Jbut / pyrimidine as the acetate, ^and o. te ^pl ot ^{th of} the 1 ^{52-1 54} ° C.

The filtrate was concentrated to a small volume, and after adding a solution of 0.06 g of maleic acid in a small volume of acetone, an additional 0.17 g of the same product was obtained as the hydrogen maleate, m.p. 173-175 ° C. ‘

Examples of ^R in its capacity ^{to 0.23} g acetanh Drazi ^{d y} u ^{methylquinoline} 1.0 ^g of L ^- 5- ^{[4 -} / 2 ^- / ^{2,2, 3,3-t} Etra ^{fluorine pollen P} ro / ^g Uani ^d ino tert-1,2,3-triazol-2-yl] valerimidate in 15 ml of methanol was stirred at room temperature for 5 days, then evaporated to dryness.

The residue was dissolved in ethanol, refluxed for 18 hours, and then evaporated to give a crude product which was purified by medium pressure liquid chromatography on a silica gel column using a mixture of dichloroethane, methanol and aqueous ammonia (density 0.88 / v). ratio 9: 1: 0.1 (v / v / v) as eluent.

: Give ⁰ 7 ^g δ-ι ^^^^ - / ^4- ^ - / ² - / ^ ^{2, 3,} 3-tetrafluoro luorpropyl / Guanidine / - !, 2 3-triazol-2-yljbutyl / -L 2,4-triazole as an oil. A sample of this product was converted to the 'di / hydrogenma ^L E ^and T / ^I C ^s taj ^{EXAMPLE 9} až.112 10 ° C.

The starting material can be prepared as follows:

A solution of 2.2 g of 5- (4-amino-1,2,3-triazol-2-yl) valeronitrile and 2.3 g of 2,2,3,3-tetrafluoropropyl isothiocyanate in 20 ml of acetonitrile was stirred at room temperature overnight. rooms. The reaction mixture was evaporated to dryness, the residue was triturated with ethanol and light petroleum / b.p. 60-80 ° C / ^l and U is ^straight ekrysta from ethanol ·.

September ^KA-2, 7 ^{g of} 5- [4- / 3- / ^{2, 2, 3, 3-tetra-yl} luorprop ^f / th ⁱ oureido / ^{-l, 2,3} -triene ⁱ azo ^{l "2-yl} JVA ^{1 of} eronitrile melting after recrystallization from ethanol at 99-101 ^° C.

To solution 2^,0 g 5- [4- / 3- / 2.2^,3^,3 “tetrafluor^pro^pyl / th^andourei^dα-1,2,3-triazo^l-²"^yl]va^lero of nitrile in 50 ml of 6M methanolic ammonia solution was added with stirring at room temperature

2.5 g of mercury oxide. The mixture was stirred at room temperature for 3 days, then filtered and evaporated.

^KA September ^2, 0 ^{g of} uncleaned it ^Star 5- [4- / 2- / ^{2, 2, 3,} 3-tetra ^fl uorpro ^P y ^L / ^G Uan ino ^id / ^{-l, 2,} 3 "triazole"" ² - ^{yl il} va ^l eronit.r u.

A solution of 1.0 g of the above nitrile in a mixture of 15 ml of chloroform and 10 ml of methanol was saturated with hydrogen chloride gas at 0 ° C. Mixture. Allow to react for 2 days in a sealed flask^vat at te^plot^E 5 ° C, at^Csince then^pand^r k suc^hat^{, whose}mz z ^^{ká žá}given^pgenus^kt in^E .^Form^E h^ydro chloride.

A solution of this hydrochloride in dichloromethane was washed with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate and evaporated. Ose. . 1.0 g of methyl "5" £ 4 "· '·' - / 2- / ^{2, 2, 3,} 3-yl tetrafluorpro ^P / Guanidine / ^{-l, 2, 3-triazol-2-yl]} ^ ^ va Rimi herein in Orme ^f o ^ · jovitého material which was used without dalšího.čištění.

Example 7

A mixture of 22.2 g of ethyl formate, 15.3 g of ethyl propionate, 1 ml of ethanol, 15 g of a 50% (w / w) sodium hydride dispersion in mineral oil and 300 ml of ether is stirred at room temperature for 18 hours, then filtered. the filter was dissolved in 150 ml of methanol and 38 g of 4- (2- [2- (2,2,2-trifluoroethyl) guanidino] pyrid-6-ylthio] butanamidine hydrochloride was added.

The reaction mixture was stirred under reflux for 5 hours, then evaporated to dryness and the residue was partitioned between ether and water. The aqueous phase was acidified to pH 1, washed with ether and then neutralized with saturated aqueous sodium bicarbonate.

The precipitate formed is filtered off, dissolved in methanol, acidified with ethereal hydrogen chloride solution, the precipitated hydrochloride is filtered off and recrystallized from methanol. Gains ^{and 4-y} H ^y -hydroxy ^-5-methyl-2- / ^3- [2- / ^2- / 2,2, ² trifluoroethyl -TR ^{IFL h} y ^l / well guan ^idi / pyrid-6 ^{- ylthio} o] propyl ^l / ^py r ⁱ midin- ^dihydro droc ^hl ori taj ^{d s} c ^s maiden name for ^{KL du} pH ²⁴⁴ and ^{from 246} ° C.

The starting material can be obtained as follows:

To a solution of 83.7 ml of benzyl mercaptan and 16.4 g of sodium in ethanol was added 40 g of 2-amino-6-bromopyridine, and the mixture was heated under reflux for 72 hours with stirring. The reaction mixture is evaporated to dryness, the residue is stirred with a mixture of 1.4 l of water and 700 ml of ethyl acetate, and acidified to pH 1 with concentrated aqueous hydrochloric acid.

The precipitated solid was filtered to give 30 g of 2-amino-6-benzylthiopyridin-hydrocHor CS ^ te ^pl ol ^{E t} U ^{s. Mp 189-191} ° C.

To a solution of 47.2 g of 2-amino-6-benzylthiopyridine hydrochloride in 700 ml of liquid ammonia is added, in small portions, 17.0 g of sodium. After the sodium addition is complete, 21.9 g of ammonium chloride are added and the mixture is evaporated to dryness.

The residue was dissolved in a mixture of 100 ml of ethanol and 100 ml of water, 23 ml of 4-bromobutyronitrile was added, and the mixture was stirred for 18 hours. at room temperature. The reaction solution was evaporated to dryness and the residue was partitioned between 2N aqueous hydrochloric acid and ether.

The aqueous phase was basified with 10 N aqueous sodium hydroxide and extracted with ethyl acetate. The extract was dried over sodium sulfate and evaporated to dryness to give 36.1 g of 4- (2-aminopyrid-6-ylthio) butyronitrile which was used without further purification.

A solution of 4- (2-aminopyrid-6-ylthio) butyronitrile (36 g) and 2,2,2-trifluoroethylisothiocyanate (22 ml) in acetonitrile (100 ml) was allowed to stand at room temperature for 18 hours. Filtering the crystalline precipitate and washing with cold ethanol to give 4- [2- / 3- / 2,2,2-trifluoroeth ^yl / ^d of thiourea / ^py ri ^d-6-yl t ^h io] ^b ut ^{s t} ri ^l roni EPLO of ^{t th t h} e n ^{e of 133} and ¹³¹ ° C.

A mixture of 29 ^{g of} 4- £ 2- / 3- / ^{2, 2, 2-trifluoro-yl} flureth / ^thi Oure ^into / p ^y r ^id -6- ^{ylth io] b} u ^t yron ^IT ri ^l with ^{29 g of} yellow mercuric oxide and 100 ml of saturated ethanolic ammonia solution were stirred at room temperature for 24 hours and then filtered.

The filtrate from the dry Ari ^p ^ ^y ZB tek triturated with ^p etro.let ^H ER / te ^p lota boiling point ^60-80 ° C / and filtered. 24 g of 4- (2- / 2- / 2,2,2-trifluoroeth ^y l / ^g ethylguanidine / ^py rid-6- ^ylthio] butyro.nitrilu ^pl of TE counting revolutions ^{of 89-9 s} 1 ° C .

A solution of 36.5 ^{g of} 4- [2- / 2- / ^2, 2, ^2- trifluoroethyl ^hy l / ^Guanidine amino / ^py rid-6- ^y lth ⁱ o] ut ^{b y} ron ⁱ tr ⁱ lu 150 ml chboroformu 50 m and ^{1 l th} Me yes ^l u ^t e ^{pl at} about ^the 0 ° C with sat ^y children. ^pl ynným chlorovodítem ^p and ^k NEC ^h and 72 h ^y rea ^g OVA ^{t pl with} TE OTE 0 ° C. ^R ea n ^{s CZK} mixture of ^P and ^{R to be} suc ^h as demodulation ^to e was partitioned between aqueous potassium carbonate and chloroform.

241000 18

The aqueous phase is extracted twice more with chloroform, the chloroform extracts are combined and, after drying and evaporated to dryness, the residue is dissolved in 200 ml of methanol, added to the solution.

Ammonium chloride (8.6 g) was stirred at room temperature for 2 hours and then evaporated to dryness.

The residue was triturated with acetonitrile and the insoluble material was filtered off to give 38 g of 4- [2- / 2- (2,2,2-trifluoromethyl) guanidino] pyrid-6-ylthiobutanamidine hydrochloride which was used without further purification. A sample of the product characterized as the dihydrochloride melts at 118-120 ° C.

Example 8

A mixture of 0.37 g ethyl formate, 0.6 g ethyl propionate and 0.5 g 50% (w / v) sodium hydride dispersion in mineral oil was heated to reflux in 15 ml of ether containing 1 drop of ethanol.

After 2 hours, the precipitated white precipitate was filtered off with exclusion of moisture and heated at reflux for 24 hours with 0.75 g of 5- [4- / 2- / 2,2,2-trifluoroethyl] guanidino / pyrimid-2-yl. ] valeramidine hydrochloride in 10 mL of methanol.

The reaction mixture was evaporated to dryness and the residue was partitioned between dilute aqueous acetic acid (20 mL) and ethyl acetate (10 mL). The aqueous layer was separated and adjusted to pH 7 with aqueous sodium bicarbonate solution.

The aqueous mixture is extracted twice with 20 ml of ethyl acetate each time, the ethyl acetate layers are combined, evaporated to dryness and the residue is purified by preparative thin layer chromatography using chloroform / methanol / aqueous ammonia (0.88 density) 8: 2: 0 Volume (v / v) as eluent.

Appropriate material isolated from the plates yields, after trituration with acetonitrile, 0.1 g of 4-hydroxy-5-methyl-2- [4- / 4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-yl]. m.p. 210-212 ° C.

The starting material can be prepared as follows:

g of ethyl 5-cyanvalerimidate was stirred in 200 ml of methanol containing 26.4 g of ammonium chloride for 18 hours, then the mixture was filtered and the filtrate was evaporated to dryness. The residue was heated to reflux in 250 ml of ethanol containing 285 ml of triethylamine and 106 g.

Of 2-chloroacrylonitrile.

After 2 hours, the reaction mixture was cooled, added to 1 liter of water, adjusted to pH 4 with acetic acid, charcoal was added to the aqueous mixture, the mixture was filtered and the filtrate was extracted with 300 ml of ethyl acetate.

The aqueous layer is separated, adjusted to pH with aqueous sodium hydroxide solution and extracted twice with 500 ml of ethyl acetate each time. The combined extracts were evaporated to dryness and the residue was recrystallized from acetonitrile to give 16 g of 5- (4-aminopyrimid-2-yl) valeronitrile.

A mixture of 5- (4-aminopyrimid-2-yl) valeronitrile (30 g) and 2,2,2-trifluoroethylisothiocyanate (30 g) in acetonitrile (50 ml) was heated at reflux for 18 h, then evaporated to dryness and dissolved in sat. methanolic ammonia solution.

48 g of mercuric oxide are added to the resulting solution, after 2 hours the mixture is filtered through a pad of diatomaceous earth and the filtrate is evaporated to dryness. The residue was triturated with ether and the solid product was filtered off to give 39 g of 5- [4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-yl] valeronitrile.

A solution of 39 g of 5- [4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-yl] valeronitrile in a mixture of 250 ml of chloroform and 150 ml of methanol is cooled to -10 DEG C. and saturated with hydrogen chloride gas. The mixture is left to stand at 0 ° C for 60 hours, then evaporated to dryness and a mixture of 100 g of potassium carbonate and 300 ml of water cooled to 5 ° C is added to the residue.

The resulting mixture is extracted twice with 200 ml of chloroform each, the combined organic extract is dried over magnesium sulphate and evaporated to dryness. The residue is stirred in 150 ml of methanol with 7 g of ammonium chloride, after 3 hours the mixture is filtered and 500 ml of ether are added to the filtrate.

Filtration of the precipitated solid material gave 30 g of 5- [4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-yl] valamidamidine hydrochloride which was used without further purification.

Example 9

To a mixture of 3.0 g of 4- [4- [2- (2,2,2-trifluoroethyl) guanidino / pyrimid-2-ylthio] butyronitrile, 40 ml of chloroform and 20 ml of methanol was added excess hydrogen chloride gas at 0 ° C. . The resulting mixture was allowed to stand at room temperature for 2 days, evaporated to dryness, dissolved in a solution of 10 g of potassium carbonate in 50 ml of water and extracted three times with 50 ml of chloroform each. The organic layer was evaporated to dryness and the crude imino ether was used without further purification.

1.6 g of the above material was dissolved in 5 ml of methanol, 0.2 g of cyanamide was added, the resulting solution was stirred at room temperature for 1 hour, and the white precipitate was filtered off. 1.1 g (yield 66%) of N-cyano-4- [4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-yl] butanamidine, m.p.

Example 10

A solution of 0.5 g of methyl 4- [4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-ylthio] butyrimidate and 0.2 g of 2,2,2-trifluoroethylamine hydrochloride in 3 ml of methanol The mixture is allowed to stand at 20 DEG C. for 2 hours, then the solvent is evaporated off under vacuum and the gummy residue is purified by preparative thin layer chromatography on silica gel using a mixture of ethyl acetate, methanol and aqueous ammonia (density 0.880) 6: 1: 1 / volume / volume / as a solvent system.

The product is dissolved in acetone and converted to N- (2,2,2-trifluoroethyl) -4- 4- (2- (2,2,2-trifluoroethyl) guanidino) pyrimid-2-ylthio butyramidine monohydrate by addition of maleic acid. m.p. 138-140 ° C.

Example 11

To a solution of 0.5 g of methyl 5- [4- / 2- (2,2,2-trifluoroethyl) guanidino / pyrimid-2-yl] valerimidate, in 6 ml of methanol, 0.28 g of ethyl carbazate is added, reaction The mixture was allowed to stand for 18 hours, then evaporated to dryness and the residue triturated with a mixture of ether and ethanol.

0.39 g (65%) of N-ethoxycarbonyl-5- [4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-yl] valeramidrazone, m.p. 137 DEG-139 DEG C., is obtained.

Example 12

A solution of 0.55 g of methyl 5- [4- / 2- (2,2,2-trifluoroethyl) guanidino / pyrimid-2-yl] valerimidate and 0.26 g of 2-amino-4-methylimidazole acetate in 5 ml The mixture is evaporated to dryness and the residue is purified by medium pressure liquid chromatography using a mixture of chloroform, methanol and aqueous ammonia (density 0.880) in a ratio of 9: 1: 0.05 (v / v / v) as eluent.

0.18 g of N- (4-methylpyridazol-2-yl) -5- [4- / 2- (2,2,2-trifluoroethyl) guanidino] pyrimidine was obtained from the appropriate fraction by treatment with an excess of maleic acid in acetone. * 2-yljvaleramidin ih ^ ro ^ ^ ^ tep nmateátu about the point of 18 ^4-187 ° C.

Example 13

A solution of 0.12 g of methyl 2 N-cyano-2- [4- [2- (2,2,22-trifluoroethyl) uulium] -pyrimidin-2-yl] hydrimidamide and 15 ml of 33% (wt / vol) ethanolic methyl in 3 ml of methanol is left to stand. After standing for 24 hours, the solvent was evaporated and the residue was purified by chromatography on silica gel.

A resinous solid mat is obtained, which is converted into the malic acid salt in acetone. After filtering off and washing with acetone, 0.027 g of N, N-methyl-N-cyano-5-4- (2,2,2,2-trifluoromethyl) lithium polyolefin is obtained. ·

Default small! can be prepared as follows:

To a solution of 0.5 g meteh ^ - 5 [4-22- / 2,2, 2-trifluoro iuorthУyi / guliiaiio / pyriiid-2-yl] vlltrϋiaáty ydihydrochloridu in 10 ml of methanol was added 0.125 g trieУh ^y Lmin and 0.08 g of cyanamide, the mixture 18 hours at mícW teptoté ² 0 ° C.

Volatile laundry is evaporated in vacuo and was triturated The rest SIIS ether and ethanol to afford the crude mettyllN У ^y-yn-i - [ '4-77- / 3.2, -yhrflUuo: metУyl / guaiiaiio / p ^y devises -2- ^yl ] vinylidide as a white solid which is used without further purification.

Example 14

A mixture of 0.37 g of 6- [4- [2- (2,2,2-trifluoromethyl) glycol] pyrimidin-2-yl] hexanediol (0.1 g), 0.17 g of 22-chloroacrylonitrile and 0.4 g of triethylamine was added. in ethanol (5 ml) was refluxed for 6 hours, then evaporated to dryness and the residue was shaken with dilute aqueous sodium hydroxide solution and concentrated.

The ethyl acetate layer was evaporated to dryness and the residue was triturated with acetonitrile. 0.2 g of 4 - ^^^ 2-255 / 4- [2- / ^2,2,2-y // triiUorthУh glaniainoJp ^gamma RIII-2-li / ptit ^y i] pyrimidine Tepe T ^and the 11 ^{4 and} 11 ⁷ ° C.

Default Measure! may be prepared in an analogous manner to that described above. is described in the second to fourth parts of Example 8, using ethyl 66-cyanotinimiaate instead of ethyl 5-cyanivaleridate.

Example. 15 Dec

To 0.4 g of methyl-propionic acid in 5 ml of methanol is added 0.16 g of a 50% (moisture) / water (dispersion) hydride-in-oil dispersion. 0.6 g of 3-T2- [ ^4- [2- / 2,2,2,2-trifluorotoluyl] guliidino / pyridin-2-ylthio-2-ylthiocyanate] was added to the resulting solution, and the resulting mixture was heated under reflux for 6 hours. reflux condenser and then evaporated to dryness.

The residue was shaken between aqueous sodium hydrogen carbonate solution and the ethyl acetate layer was evaporated to dryness and the residue was treated with mm-amino acid in acetone. 0.14 g of 4-Уydaroχl5, б6yamithyУl22 / 2222- / 4 2/2 - - hrflUorreУУyl / guliiaiiO pyrimidin-2-yl / eУhox ^{yl] thy} l t / ^y p ⁱ imido nyУ ^and drogerlíalt ^Ah uo Tepee reading of 150 and ^{1 53} ° C.

-72- ⁴ 32-2- 5 / 2.2, ² 2TrrfiuoretУ ^yl / guliiaiio / ^y p IIId-2- ^y Ij tthoxy / propaiamidan-УydaochУorid used as the starting ma ^ Erml may be prepared as follows:

SiS ^ 62 g of bis / 2-kylietУyl / ttУtru ethanol and 23 g in 300 ml ether at 0 ° C for 1 uvtóe ^{eighth g of} hydrogen chloride. After NEC ^ 3 ^d b ^y at stet te ^ OTE 0 ° C with PA ^{to P d} of the layer was separated, treated at -10 DEG C. к solution of 140 g of potassium carbonate in 400 ml of water and the resulting mixture was extract with 200 ml of chloroform. The chloroform extract was evaporated to dryness to give an oily residue from which 35 g of ammonium chloride (12 g) was stirred for 18 hours in 100 ml of ethanol.

The mixture is filtered, the filtrate is evaporated to dryness and the residue is refluxed for 2 hours in 150 ml of ethanol with 16.5 ml of 2-chloroacrylonitrile and 55 ml of triethylamine. The reaction mixture was evaporated to dryness, the residue was partitioned between aqueous acetic acid and ethyl acetate, the aqueous layer was separated, basified with dilute sodium hydroxide and extracted three times with ethyl acetate.

The combined extracts were evaporated to dryness and the residue purified by medium pressure liquid chromatography using a mixture of chloroform, methanol and aqueous ammonia (density 0.880) in a ratio of 15: 1: 0.05 (v / v / v) as eluent. 4.7 g of 3- [2- (4-aminopyrimid-2-yl) ethoxy] propionitrile are obtained.

NMR (Perdeuterodimethylsulfoxide): 2.7 (t, 2 N), 2.8 (t, 2 N), 3.5 (t, 2 N), 3.8 (t, 2 N), 6.2 (d, 1 N) 6.6 (broad s, 2 N), 7.9 (d, 1 N).

4.5 g of this material was refluxed with 5 g of 2,2,2-trifluoroethylisothiocyanate in 5 ml of acetonitrile for 2 hours. The reaction mixture is evaporated to dryness, the residue is dissolved in 100 ml of saturated ethanolic ammonia solution and 9 g of mercuric oxide are added with stirring.

After 30 minutes the mixture was filtered and the filtrate was evaporated to dryness to give 3.5 g

3- [2- [4- (2- (2,2,2-trifluoroethyl) guanidino] pyrimid [2] yl) ethoxy] propionitrile.

NMR (Perdeuterodimethylsulfoxide): 2.7 (t, 2 N), 2.9 (t, 2 N), 3.6 (t, 2 N), 3.8 (t, 2 N), 4.15 (q, 2 N), 6.5 (d, 1N), 7.3 (wide, 1N), 7.9 (wide, 2N), 8.15 (d, 1N).

3.5 g of this material are dissolved in a mixture of 30 ml of methanol and 30 ml of chloroform, saturated with hydrogen chloride at -10 DEG C., the resulting solution is allowed to stand at 0 DEG C. for 2 days and then evaporated to dryness.

The residue is taken up in a solution of 30 g of potassium carbonate in 70 ml of water and the resulting mixture is extracted with 50 ml of chloroform. The organic layer was evaporated to dryness and the residue (1 g) in 4 ml of methanol was stirred with 0.16 g of ammonium chloride for 6 hours.

Evaporation of the mixture to dryness gave 3- [2- [4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-yl] ethoxy] propanamidine hydrochloride which was used without further purification.

Example 16

To a solution of 0.352 g of ethyl acetate and 0.07 g of sodium hydride in 6 ml of methanol is added 0.5 g of 5- [4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-yloxy] valeramidine hydrochloride . The resulting solution was refluxed for 18 hours, then the solvent was evaporated, the residue was taken up in aqueous acetic acid and extracted with ethyl acetate.

The aqueous layer was basified with potassium carbonate and extracted with ethyl acetate. After work-up, a sticky solid is obtained which, after crystallization from acetonitrile, yields 0.22 g

4-hydroxy-6-methyl-2- [4- (4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-yloxy] butyl pyrimidine as white crystals, m.p. 191-193 ° C C.

The starting material can be prepared as follows:

To 2.75 g of sodium hydride in 95 ml of tert-butanol is added 10 g of 4-cyanobutanol, the solution is

methylsulfinylpyrimidine (see European Patent Publication No. 30092). The resulting solution was reacted first at 40 ° C for 2 hours and then at room temperature for 18 hours.

The solvent was evaporated in vacuo and the residue was washed first with water and then with ether to give 8.5 g of 5- [4- / 2- (2,2,2-trifluoroethyl) guanidino / pyrimid-2-yloxy] valeronitrile at a temperature of mp 134-136 ° C.

g of the above nitrile is dissolved in 40 ml of dry chloroform and 20 ml of methanol, cooled to 0 DEG C. and saturated with hydrogen chloride gas. The resulting mixture was allowed to react for 60 hours at 0 ° C, then the volatiles were removed in vacuo, the residue was shaken with 50 ml of cold aqueous potassium carbonate solution and extracted three times with 50 ml of chloroform each.

The combined extracts were dried over magnesium sulphate and evaporated in vacuo to give methyl 5- [4- (2- (2,2,2-trifluoroethyl) guanidino) pyrimid-2 valerimidate as a resin material which was used without further purification. cleaning.

To 1.5 g of methyl 5- [4- (2- (2,2,2-trifluoroethyl) guanidino) pyrimid-2-yloxy] valerimidate in 15 ml of methariol is added 0.25 g of ammonium chloride and the solution is stirred at room temperature for 2 hours room temperature.

Ether was added to the reaction solution until turbidity and stirring continued to precipitate a solid material. Filtration gave 1.52 g of 5- (4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-yloxy] valeramidine hydrochloride, m.p. 156-15 ° C.

Example 17

To a solution of 330 mg of 1- [2- (2-cyanethoxy) ethyl] -3- [2- (2,2,2-trifluoroethyl) guanidino] pyrazole in 15 ml of methanol and 15 ml of chloroform is added at 0 ° C until saturation indicates dry hydrogen chloride gas. The resulting mixture was allowed to stand at 0 ° C for 24 hours, then the solvent was evaporated in vacuo and the residue basified with 10 ml of ice-cold 10% (w / v) aqueous potassium carbonate solution.

The mixture is extracted three times with 10 ml of chloroform each, the extracts are dried over magnesium sulphate and evaporated in vacuo to a light yellow oil of 330 mg. This oil was dissolved in 10 mL of methanol, 100 mg of cyanamide was added, and the mixture was stirred at room temperature for 17 hours.

The reaction solution was evaporated to dryness and the residue was purified by preparative thin layer chromatography using 1: 9: S (v / v / v / v) triethylamine / ethanol / ethyl acetate as eluent. 0.21 g of N-cyano-3- [2- / Z- [2- (2,2,2-trifluoroethyl) guanidino pyrazole-propionamidine] is obtained.

NMR (Perdeuterodimethylsulfoxide): 7.4 (d, 1 N), 5.6 (d, 1 N), 4.0 (broad m, 4 N), 3.65 (broad m, 4 N), 2.5 (m, 2 N) /.

The starting material can be prepared as follows:

To a solution of 13.8 g of potassium carbonate in 40 ml of water, 7.6 g of 2-hydroxyethylhydrazine are slowly added, the mixture is cooled to 0 ° C and 8.75 g of 2-chloroacrylonitrile is slowly added with vigorous stirring.

Stirring was continued for a further 17 hours and the mixture was continuously extracted with ethyl acetate for 20 hours. Evaporation of the solvent gave 7.7 g of 60% 3-amino-1- (2-hydroxyethyl) pyrazole, b.p. 170 DEG C./0.1 mbar.

A mixture of 13.8 g of 2,2,2-trifluoroethylisothiocyanate and 12.5 g of 3-amino-1- (2-hydroxyethyl) pyrazole in 30 ml of acetonitrile dried over a 4.10 molecular sieve is stirred for ¹⁰ hours at room temperature.

241000 at room temperature, after 30 minutes a precipitate began to form. Filtration gave Κ, Ι g / 46% / ^{L-72-hydrate,} xyethhl / 3- 3- £ / 2,2,2-trlflorrtthyl / ^{h of} hioreei O7 ^P yrazolu rpm ^EP ture mp 145-146 ° C .

^K ° ^from R ^to it in ^20.0 g of L / 2 ^- hydrox ^y eth ^yl / ^- 3 ^- £ 3 ^- / ^{2, 2, 2 "t} r ⁱ f ^l trifluoroethyl / thioureido] ^p yrazolu

In 700 ml of 5N ethanolic solution. 64.8 g of yellow mercuric oxide are added with stirring and stirring is continued for 2 hours. .

The mixture was filtered through a pad of diatomaceous earth and the solvent was evaporated to dryness in vacuo. O ^l ejov ^as those from ^{thee Kp} axis ^ky tne ^p of ^tri Turac with ether ^and 1 ^8, 5 ^g / 99% / L / h of 2-Hydroxy ^{y y} eth ^y 1 / -3- ^ 2- / 2 Mp 82 ° C; j ·

I ^{To extensible to} about 1 ^g in ^2.5 L / hr ^{of 2-} Hydroxy ^{y y} eth ^y l / -3- ^[2 - / ^{2, 2, 2-t} ri ^fl uoreth ^yl / ^Guanidine inojp Razo ^{y l} uo te ^pl OTE T ^and the ⁸² ° C.

The mites on ^the two ^{51 gl} - / ² -h DROXI ^{y y} e ^t h ^yl / -3 ^{- [2} - / ^2,2,2 -TR f ^{i l -yl} uoreth / ^g Uani ^{di ethylamino] pyridine} Razo ^l uv 10 ml. Acetonitrile (0.8 g) was added, followed by the addition of 10 [mu] l of a 40% (w / v) aqueous solution of benzyltrimethylammonium hydroxide, the resulting solution was stirred at room temperature for 1 hour, then evaporated to dryness in vacuo. liquid chromatography eluting with triethylamine: ethanol: ethyl acetate = 1: 1: I ^to about 9./objan/objem/objem/ · u ^l e n ^{e No No} ini him ^{dL. ka} CIS 1.0 ^{g of l-} ^ ² "/ ^2-cyano] ^ <Bth <^ ^ y ^{/ <t} B H ^{J-3-yl -} ^ ^2" / ^{2, 2, 2 at} the -triflates ^R et ^hy l / ^g Uan no ^{idi l} p ^y razo ^l u.

NMR (CDCl 3): 7.6 (d, 1H), 5.8 (d, 1H), 4.2 (m, 2H), 4.1 (t, 2H), 3.8 (t, 2 H) 3.6 (t, 2H); 2.7 (t, 2H).

Example 18

A mixture ^of s 0, ^{6g methylcarbazole} -5- ^| 5-- ² 2 ^{2, 2, 2-Trifluoro} uoreth ^f l ^y / ethylguanidine ^g / ^l tetrazol-2- ^yl] valerimidate, 0.2 g of acetic acid hydrazide and 20 ml of methanol was stirred for 2 hours at room temperature, then evaporated, triturated with ether containing a trace of ethanol and filtered.

Z ^it is 0 ^KA ^ ^g N ^- Acer ^yl ain ^even no ^- 5 ^- p5 ^- 2 ^{2 t} 22 ^2,2tt r ^t h ^ffl uoie ^yl 2guan ^Ldi no2retrazolt2t ^y lj alert ^the amidine. A sample of the product after trituration with ethanol and filtration melted with decomposition at 159-161 ° C.

The starting material can be prepared as follows:

To a mixture of 8.5 g of 5-amfnorerrazole, 4.0 g of sodium hydroxide and 40 ml of water is added, while stirring at room temperature, a solution of 16.2 g of 5-bromvaleronframe in 160 ml of acetone. The resulting mixture was heated at reflux for 4 hours, then the solvent was evaporated. ; zb ^y tek is partitioned between water and ethyl acetate.

The organic phase is separated, dried over magnesium sulphate and evaporated to a oily solid which is triturated with ether. The mixture was filtered and the filtrate was evaporated to yield

11.5 g of an oily material which was purified by silica gel column chromatography using ethyl acetate as eluent. 2.7 g of partially purified from 5-25tamfnoteriat ^^ y ^ va ^ ron ^ r ^ uo ot te ^{pl of} T ^ck 1 ^59-6 ° C.

1.0 g of 5-25-amphnotetrazol-2-yl-2-isolithion was melted, 1.0 ml of 2,2,2-trifluoroethyl isothiocyanate was added and the mixture was allowed to stand overnight. The white solid product was triturated with ttokUerem ..Ae ^ ^ OTA bp ⁴⁰ and ⁶⁰ ° C / sm and ^E ^^ of oestrus.

AND

Z with ^k and 1.5 ^{g of} Part ^C them vypištěného 5- ^ 5- / 3 ^{-22 2 2} -trffluorerh ^yl / thiouie do2tet ^{r i} azole-2- ^y 1] VA ^ ron ^ r ^ uo ^{pl t} e rt ^{th of} the ⁹⁴ to ⁹⁶ ° C.

A mixture of 1.5 g of partially purified 5-β- [3- (2,2,2-trifluoroethyl) thioureido] tetrazol-2-yl] valeronitrile, 1.5 g of mercuric oxide and 20 ml of 6M ethanolic ammonia was stirred overnight, then stirred filtered and evaporated.

The residue was recrystallized from ethanol to give 1.1 g of 5- [5- (2- (2,2,2-trifluoroethyl) guanidino) tetrazol-2-yl valeronitrile, m.p. 140-141 ° C.

A mixture of 0.5 g of 5- [5- (2- (2,2,2-trifluoroethyl) guanidino) tetrazol-2-yl] valeronitrile, 15 ml of chloroform and 10 ml. of methanol was saturated with hydrogen chloride gas at 0 ° C. The reaction mixture was allowed to react at 5 ° C for 48 hours, then evaporated to dryness and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate.

The organic layer was separated, dried over magnesium sulphate and evaporated to give 0.6 g of methyl 5- [s- [2- (2,2,2-trifluoroethyl) guanidino] tetrazol-2-yl] valerimidate. without further cleaning.

Example 19

To a solution of 1 g of 5- [2- (2,2,2-trifluoroethyl) guanidino] -1,2,4-triazol-1-yl] valeramidine hydrochloride in 14 ml of methanol was added 1.95 g of sodium sodium salt -2-formylpropionate, the resulting suspension was heated at reflux for 3.5 hours, evaporated and the residue was partitioned between water and ether.

The aqueous layer was acidified to pH 3 with glacial acetic acid and extracted again with ether. Neutralization with aqueous ammonia solution (density 0.880) and extraction with ethyl acetate gave a white solid which, after crystallization twice from acetonitrile, gave 0.127 g (12%) of 4-hydroxy-5-methyl-2- [4- / 3- ^ 2- (2,2,2-Trifluoroethyl) guanidino] -1,2,4-triazol-1-yl) butyl pyrimidine, m.p. 235-237 ° C.

The starting material can be prepared as follows:

To a solution of sodium methoxide in methanol (1.2 g of sodium in 30 ml of methanol) was added 4.2 g of 3-amino-1,2,4-triazole, the resulting solution was stirred at room temperature for 0.5 h, then 5-bromvaleronitrile (8.1 g) was added and the mixture was heated under reflux for 12 hours.

The reaction mixture was evaporated, the residue was partitioned between water and ethyl acetate, the extracts washed with brine, dried over magnesium sulfate and evaporated to a pale yellow oil (6.5 g) which was purified by medium pressure liquid chromatography using a mixture of ethyl acetate and methanol. 6: 1 (v / v) as eluent. The colorless oil thus obtained is used without characterization for the following reaction.

To 5.45 g of crude 1- (4-cyanobutyl) -3-amino-1,2,4-triazole in 80 ml of acetonitrile is added:

4,4 g of 2,2,2-trifluoroethylisothiocyanate and the resulting solution was refluxed for 3.5 hours.

Evaporation gave a white sticky solid residue which, after trituration with ether / ethanol, gave 4.04 g of 5- [3- (3- (2,2,2-trifluoroethyl) thioureido] -1,2,4-triazole- 1-yl] valeronitrile as a white solid, m.p. 136-138 ° C.

To 3.6 g of this nitrile in ⁸⁰ methanol and 5 ml of acetonitrile was added 3.06 g of mercuric oxide and 15 ml of methanolic ammonia solution. The mixture was stirred for 1.5 hours, the resulting black suspension was filtered through a pad of diatomaceous earth and the filtrate was evaporated to a white solid residue.

This residue was washed with ether and filtered to give 5- [3 '- [2- (2,2,2-trifluoroethyl) guanidino] -1,2,4-triazol-1-yl] valeronltril as a white solid Recrystallizers from ethanol at 200 to 201 ° C. Yield 2.87 g.

A solution of 2 g of 5- (3- (2- (2,2,2-trifluoroethyl) guanidino) -1,2,4-triazol-1-yl) valeronitrile in 15 ml of methanol and 35 ml of chloroform is saturated at 0 ° C. and then allowed to stand at 0 ° C for 62 hours.

The solvent was evaporated and the residue was partitioned between aqueous potassium carbonate solution and chloroform. The chloroform extracts were washed and evaporated to give methyl 5- [3- (2- (2,2,2-trifluoroethyl) guanidino) -1,2,4-triazol-1-yl] valerimidate as pale yellow oil.

A solution of 1 g of methyl 5- [3- [2- (2,2,2-trifluoroethyl) guanidino] -1,2,4-triazol-1-yl] valerimidate in 12 ml of methanol containing 0.162 g of ammonium chloride was added for 3 hours Stir at room temperature.

Evaporation of the solvent gave 5- [3- (2- (2,2,2-trifluoroethyl) guanidino] -1,2,4-triazol-1-yl] valeramidine hydrochloride as a yellow gum which was used without further cleaning.

Example 20

A solution of 0.5 g of methyl 5- [3- (2- (2,2,2-trifluoroethyl) guanidino) -1,2,4-triazol-1-yl] valerimidate in 5 ml of methanol and 0.17 g of hydrazide of acetic acid was allowed to stand at room temperature for 3 hours.

The reaction solution was evaporated to a sticky solid residue which, after trituration with an ether / ethanol mixture, yielded 0.71 g of N-acetylamino-5- [3- (2- (2,2,2-trifluoroethyl) guanidino) -1,2, 4-triazol-1-yl] valeramidine as a white solid, m.p.

Example 21

A mixture of 0.3 g of methyl 4- (2- [2- (2,2,2-trifluoroethyl) guanidino / pyrid-6-yloxy] butyrimidate, 0.054 g of ammonium chloride and 5 ml of methanol is stirred at room temperature for 1 hour, then ethyl 2-formylpropionate sodium [prepared from 0.37 g of ethyl formate, 0.51 g of ethyl propionate and 0.5 g of a 50% (w / w) sodium hydride / oil dispersion as described in the first section is added thereto. of Example 7], the resulting mixture was heated under reflux for 18 hours and then evaporated to dryness.

The residue was partitioned between ether and water, the aqueous phase was acidified to pH 1 and washed with ether. After neutralization with sodium bicarbonate, the aqueous phase is extracted three times with ethyl acetate, the combined ethyl acetate extracts are dried and evaporated to dryness.

The residue is dissolved in acetone, this solution is added to an acetone solution of maleic acid, the precipitate formed is filtered off and crystallized from aqueous ethanol. 0.1 g of 4-hydroxy-5-methyl-2- [3- [2- / 2- (2,2,2-trifluoroethyl) guanidino] pyrid-6-yloxypropyl] pyrimidine hydrogen maleate is obtained, m.p. to 210 ° C.

The imidate used as starting material can be prepared as follows:

A mixture of 0.85 g of 4-hydroxybutyronitrile, 0.48 g of 50% (w / w) sodium hydride dispersion in mineral oil and 5 ml of sulfolane was stirred at room temperature for 1 hour. After addition of 0.87 g of 2-amino-6-bromopyridine, the mixture was heated to 130 ° C with stirring for 18 hours, then cooled, diluted with 20 ml of water, acidified with concentrated aqueous hydrochloric acid and washed with ether.

The aqueous phase was basified with 10 N aqueous sodium hydroxide, extracted three times with ethyl acetate, the combined extracts were dried and evaporated to dryness.

2,2,2-Trifluoroethyl isothiocyanate was added to a solution of the residue in 5 ml of acetonitrile, and the resulting solution was heated under reflux for 1 hour and then evaporated to dryness. The residue is stirred with 20 ml of 2N aqueous hydrochloric acid and 20 ml of ether, and the insoluble material is filtered off.

This solid was dissolved in methanolic ammonia solution, 2 g of yellow mercury oxide were added, the mixture was stirred at room temperature for 18 hours, filtered and the filtrate evaporated to dryness. There was obtained 1.0 g of 4- [? - [2- (2,2,2-trifluoroethyl) guanidino] pyrid-2-yloxy] butyronitrile.

A solution of 4- (2- [2- (2,2,2-trifluoroethyl) guanidino] pyrid-6-yloxy] butyronitrile in a mixture of 10 ml of chloroform and 5 ml of methanol is saturated with hydrogen chloride at 0 DEG C. and left to stand at room temperature for 3 days. Low: 14 ° C.

The reaction solution was evaporated to dryness and the residue was shaken with a mixture of chloroform and aqueous potassium carbonate solution. The chloroform phase was dried and evaporated to dryness to give 0.8 g of methyl 4- [2- [2- (2,2,2-trifluoroethyl) guanidino] pyrid-6-yloxy] butyrimidate which was used without further purification .

Example 22

A solution of 0.2 g of methyl 4- [2- [2- (2,2-trifluoroethyl) guanidino] pyrid-6-ylthio] butyrimidate and 0.2 g of sulfamide in methanol was allowed to stand at room temperature for 24 hours and then stirred at room temperature. evaporate to dryness. The residue is partitioned between water and ethyl acetate, the ethyl acetate phase is dried and evaporated to dryness.

The residue is dissolved in acetone, this solution is added to an acetone solution of maleic acid, the precipitate formed is filtered off and crystallized from aqueous ethanol. There was obtained N-sulfamoyl-4- [2- (2- (2,2,2-trifluoroethyl) guanidino) pyrid-6-ylthio] butyramidine hydrogen maleate, m.p. 176-177 ° C.

Examples 23 to 30

The following compounds were prepared as described above:

Example R ¹ · <

^CF 3 ^CH 2

^CH 3

CHF ₂ CF ₃ CH ₂ ^CF 3 ^CH 2

- / CH _2/4 O / CH _2/3 ^CH 3

CH ₃

CHFgCFgCR

^CH 3 continued table

Example ¹ R -Het- -AND- R ² 'r ³ 27 CF ₃ CH ₂ - / CH _2/4 ^CH 3 H 28 CHF ₂ CF ₂ CH ₂ - / CH _2/4 ^CH 3 H

Example 23: mp 182-183 ° C, yield 28%. Intermediary. 6- [4- (2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-yl] hexanamidine can be prepared by a procedure analogous to that described in Parts 2 to 5 of Example 8, using 6-cyanohexanimidate instead of ethyl 5-cyanvalerimidate .

Example 24: mp 128-130 ° C, yield 36%. Intermediate 5- [4- / 2- / 2,2,3,3-tetrafluoropropyl / guanidino / pyrimid-2-yl] valeramidine can be prepared by a procedure analogous to that described in Part Two to Five of Example 8 using 2,2,3, 3-tetrafluoropropylisothiocyanate instead of 2,2,2-trifluoroethylisothiocyanate.

Example 25: mp 217-219 ° C, yield 54%. Intermediate 4- [4- (2- (2,2,2-trifluoroethyl) guanidino) pyrimid-2-yloxy] butyramidine can be prepared by a procedure analogous to that described in the second to fourth parts of Example 16 using 3-cyanopropanol instead of 4-cyanobutanol.

Example 26: maleate, m.p. 182-184 ° C, yield 25%. The 4- [4- [2- (2,2,3,3-tetrafluoropropyl) guanidino] pyrimidin-2-yloxy] butyramidine used as starting material can be prepared as follows.

The procedure described in the second, third and fourth parts of Example 34 of European Patent Publication No. 30092 is repeated, using 2,2,3,3-tetrafluoropropyl isothiocyanate instead of 2,2,2-trifluoroethyl isothiocyanate to give 4- [2-]. 2,2,3,3-tetrafluoropropyl / guanidino] -2-methylsulfinylpyrimidine.

By repeating the second, third and fourth parts of Example 16 using the above intermediate and 3-cyanopropanol instead of 4-cyanobutanol, the desired starting material is obtained.

Example 27: The NMR spectrum of the product, measured in perdeuterodimethylsulfoxide, contains the following signals: 7.7 (d, 1 N), 7.5 (d, 1 N), 5.7 (d, 1 N), 4.05 (q, 2 N). , 3.95 (t, 2N), 1.85 (s), ZN /, 1.7 (m, 4N).

Yield 29%. Intermediate 5- (3- (2- (2,2,2-trifluoromethyl) guanidino) pyrazol-1-yl) valeramidine may be prepared from methyl-5- (3- (2- (2,2,2-trifluoroethyl) guanidino) pyrazole). 1-yl] valerimidate in an analogous manner to that described in the second part of Example 2 using the above imidate instead of methyl 4- [4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-ylthio] butyrimidate.

Example 28: maleate, melting point 152 ° C, yield 32%. Intermediate 5- [4- (2- (2,2,3,3-tetrafluoropropyl) guanidino) -1,2,4-triazol-2-yl] valeramidine may be prepared in an analogous manner to that described in the second to sixth parts of Example 4. and in the first part of Example 5, using 2,2,3,3-tetrafluoropropyl isothiocyanate instead of 2,2,2-trifluoroethyl isothiocyanate.

Example 29: maleate, m.p. 169-170 ° C, yield 42%. Intermediate 5- (2- [2- (2,2,3,3-tetrafluoropropyl) guanidino / pyrid-6-ylthio] valeramidine may be prepared in an analogous manner to that described in Parts 2 to 6 of Example 7 using 5- bromvaleronitrile instead of 4-bromobutyronitrile and using 2,2,3,3-tetrafluoropropyl isothiocyanate instead of 2,22-trifluoroethyl isothiocyanate.

Example 30: maleate, m.p. 189-191 ° C, yield 56%. Intermediate 5- (2- [2- (2,2,2-trifluoroethyl) guanidino] pyrid-6-ylthio] valeramidine may be prepared in an analogous manner to that described in the second to sixth parts of Example 7 using 5-bromvaleronitrile instead of 5-bromvaleronitrile. Of 4-bromobutyronitrile.

Examples 31 to 50

The procedure described in Example 3 was repeated using the appropriate starting materials. The following compounds are obtained.

^ NNHCOR ² \ h ₂

R ¹ NH 4 CN-Het-AC ^H 2 ^{N 4}

Example R ¹ -Het- 31 ^CF 3 ^CH 2 XX 32 ^CF 3 ^CH 2 Xx 33 ^CF 3 ^CH 2 Xx 34 ^CF 3 ^CH 2 XX

-As / CH _2/3 -s / CH _2/3 S / CH _2/3 S / CH _2/4 -

-CH ₃

-CH ₃

35 chf ₂ cf ₂ ch ₂ XX 36 chf ₂ cf ₂ ch ₂ Xx 37 ^CF 3 ^CH 2 XX 38 ^CF 3 ^CH 2 XX

-s / CH _2/4 -s / CH _2/4 - / CH _2/5 - / CH _{2/4 -CH3} ^{П_ СдНд-}

-CH ₃

-CH ₃

continued table Example R ¹ chf ₂ cf ₂ ch ₂ ^CF 3 ^CH 2

-Hetx <XX

-A- / CH _2/4 -о / сн ₂ / з41 ^CF 3 ^CH 2

-о / сн _2/3 43 CF3CH2

CF3CH2

CF ₃ CH ₂

CF ₃ CH ₂

7 CF3CH2

CClF ₂ CH2

CHF ₂ CF ₂ CH 2

Comment:

-CH3

-CH3

O / CH _2/3 O / CH2 / 4-O / CH _2/3 O / CH2 / 4-o / CH _2/3 S / CH2 / 3

-S (CH 2) ₄

-S / C ^H2 / ⁴

-S (CH 2) 4

-CH ₃

-CH ₂ CH

-CH3

CH3

- ^{C 3} • ^{CH 3}

In the above table there is a grouping

R ¹ NH _X 2 h ₂ n ^{/ Z} on the right side of the heterocyclic radical is bonded to the bond located on the left side of the heterocyclic radical as Het and residue A is attached to the bond found as Het.

Similarly, the heterocyclic Het radical is attached to the -A- moiety and the amidine moiety is attached and the bond For example, the product of Example 31 corresponds to the formula on the left-hand side located on the right-hand side of the -A- moiety.

CF ₃ CH ₂ NH 4

Example 31: The NMR spectrum measured in perdeuterodimethylsulfoxide contains the following

2N /, 4.15 / q, 2N /, 6.34 / d, ЗN /, 7.25 / s /, 1N /, 10.1 / s, 1N /.

signals: 1.95 / m, 2N /, 2.2 / m, 2N /, 3.05 / t, 7.59 / m, 1N /, 7.8-8.2 / m, 5N /, 8, 63 / m

Example 32: temperature thaw 149 to 152 ° C, yield 67 Example 33: temperature thaw 183 to 185 ° c, yield 47 Example 34: temperature thaw 156 to 158 ° c, yield 86

%.

%.

%. Intermediate methyl 5- [4- [2- (2,2,2-trifluoroethyl) guanidino] pyrimid-2-ylthio] valerimidate may be prepared in an analogous manner to that described in the second to fourth parts of Example 1 and the second part of Example 2, using 5-bromvaleronitrile instead of 4-chlorobutyronitrile.

Example 35: mp 15 3-155 ° C, 36% yield. Intermediate methyl 5- [4- (2- / 2,2,3-tetrafluoropropyl) guanidino] pyrimid-2-ylthio] valerimidate may be prepared in an analogous manner to that described in the second to fourth parts of Example 1 and the first part of Example 2. using 5-bromvaleronitrile instead of 4-chlorobutyronitrile and 2,2,3,3-tetrafluoropropyl isothiocyanate instead of 2,2,2-trifluoroethylisothiocyanate.

Example 36: temperature thaw 170 to 172 Example 37: temperature thaw 123 to 126 Example 38: temperature thaw 187 to 189 Example 39: temperature thaw 163 to 164 Example 40: temperature thaw 149 to 152 Example 41: temperature thaw 151 to 153 Example 42: temperature thaw 191 to 193 Example 43: temperature thaw 156 to 158 Example 44: temperature thaw 82 to 86 ° Example 45: temperature thaw 130 to 133

° C, ° C, ° C, ° C, ° C, yield ° C, ° C, Yield Yield Yield Yield Yield 65 ° C, Yield 89

%.

%.

%.

C, yield 31%.

° C, yield 55 »

Severography, n. P., MOST, ··

Price 2,40 Kčs

Example 46: thaw 15 9 to 161 ° c, yield 7-4 % Example 47: temperature thaw 173 to 175 ° c. yield 61 * Example 48: tt ^ oot thaw 132 to 134 ° c. yield 63 %

Intermediate methyl 5- [2- (2- (2-chloro-2,2-difluoroethyl) guanidino) pyrid-6-ylthio] valerimidate may be prepared by a method analogous to that described in the second to fifth and first half of the sixth part of Example 7. using 5-bromomethylitrile instead of 4-bromouloylittil and using 2-chloro-2,2-difluoroethil18-thiocyanate instead of 2,2,2-trifluoroethylsilyl thiocyanate.

Example 49: mp 136-137 ° C, yield 82%.

Example ^50: t ^ lota mp 134-135 ° ^{C e} ýtěž to 54%.

Example 51

The procedure described in Example 11 was repeated using the appropriate iminoehhtou as the starting material. In 12% yield was obtained 55tyldoiy-l- / 5- 54- / ² 2-2 -, - toflluorttty0 / guaiidiio / mido ^ ^^ l-oxy] Uulyl / -l, ⁵ 2,4h0i ^and z8O -íalt ^HOT ^ lo ^ ² point 06 and ^Z 20 ⁸ ° C.

Example 52 to 66

The procedure described in Example 9 is repeated using the appropriate immunity as the starting material. The following compounds are obtained:

example ^r1

-Het-A52

CF ₃ CH ₂

-S (CH 2) ₄

CHF2CF2CH2

-S / CH2 / 3 '

CHF ₂ CF ₂ CH ₂

-S / CH2 / ₄ ^CF 3 ^{CH 2}

- (CH 2) 2 O / CH 2/2

CF ₃ CH ₂

^ / CH2 / ₄ 57

CF ₃ CH ₂

^- / ^{CH2 /} ₅ continued table example Jft ^{1 CF} 3 ^CH 2

-Het-

-AO / CH _2/4 59 ^CF 3 ^CH 2

O / CH _2/3 60 CF ₃ CH ₂ ^CF 3 ^CH 2 ^CF 3 ^CH 2 CF ₃ CH ₂

CClF ₂ CH ₂

CHF ₂ CF ₃ CH ₂ ^CF 3 ^CH 2

- / CH _2/4 - / CH _2/4 -s / CH _2/3 S / CH _2/4 S / CH _2/4 -s / CH _2/4 Notes:

In the above table, the ^{r 1} group is NH

H ₂ N is attached to the bond located on the left side of the -Het- heterocyclic moiety and the -A group is bonded to the bond located on the right side of the -Het- heterocyclic moiety. Similarly, the bond on the left side of the -A- moiety is attached to the heterocyclic ring -Het- and the bond on the right side of the -A- moiety is attached to the N-cyanamidine moiety. For example, the product of Example 52 corresponds to the formula CF ₃ CH ₂ NH

C = N

NH ₂ h ₂ n

Example 52: maleate monohydrate, m.p. 148 ° C, yield 28%.

Example 53: temperature thaw 197 to 198 ° C, yield 16 %. Example 54: 1,25-maleate, mp 168-169 ° C Z, yield 40% Example 55: temperature thaw 175 to 177 ° C / yield 48 %. Example 56: temperature thaw 162 to 164 ° C, yield 30 %. Example 57: temperature thaw 180 to 183 ° C, yield 37 %. Example 58: temperature thaw 168 to 170 ° C, yield 70 %. Example 59: temperature thaw 172 to 174 ° C, yield 73 %. Example 60: monomaleate hemihydrate, melting point 129 M.p. 1 - 130 ° C. Example 61: temperature thaw 181 to 183 ° C, yield 53 %.

Example 62: maleate, m.p. 142-144 ° C, yield 33%.

Example 63: maleate, mp 129-130 ° C, yield 61%.

Example 64: maleate, m.p. 125-127 ° C, yield 73%.

Example 65: maleate, mp 123-125 ° C, yield 54

Example 66: maleate, m.p. 118-119 ° C, yield 63%.

Examples 67 to 71

The process described in Example 22 was repeated using the appropriate imino ether as the starting material. The following compounds are obtained:

R ¹ NH ₄ ^H ₂ ^ n ^{/ X}

CsN

-Het-A-C

NSO ₂ NH ₂ NH ₂

Example R

-Het-A-

-s / CH _2/3 -

^CF 3 ^CH ₂

continued table example R -HHt- . "AND- 70 ^с р зсн ₂ phi ^ N -O (CH 2) 4 71 CHF2ČF2CH2 XX -S / CH2 / 3 “

Comment:

The table above is a grouping

R ^X NH ^H 2 ^N

attached to the bond located on the left side of the -HHt- heterocyclic moiety, and the -A group is bonded to the bond over the right side of the -HHt- heterocyclic moiety. likewise, the bond on the left side, the -A- moiety is linked to the heterocyclic ring -HHt-, and the bond on the right side of the -A- moiety is linked to the sulfmoylamidine moiety. For example, the product of Example 64 corresponds to the formula ^CF 3 ^CH 2 ^NH

H2N

--SlCH ^ -c ^ NSO2NH ₂ NH ₂

Case 67:, 25-maleate ^and t-monohydd ^Ra, a ^{heat-T, and} the OTA ¹²⁴ to ¹²⁷ ° C / ^{characterized} in that t ^{of a 15%} /.

Example 68: IAEA, having ^a melting ^{point 178-1} 8 ⁰ ° C, ^to yield off ^from the e 11%.

^comm ice 69: ^l, maleate, pulse ^L T, ^and the OTA ¹⁴⁹ and ^{15 2} C. Even in ^{yield was 3%.}

Example 70: te ^{T P} Lot 1 ⁹³ it and ^{from 195} ° C above ^{Photogene, white} e ^3.5%.

More also 71: mal.eát te ^pl OTA ^th the H ^8-120 'C,' e ^{Photogene, white} above ^19%. ·

Examples 72 to 77

The following compounds were obtained using the appropriate imino ether starting material as described above:

R ^X NH _X • XceN-HHT-AC ^H ₂ N?

NSO2CH3

Example R

-Het-A72 ^CF 3 ^CH 2

- / CH _2/5 73 CHF ₂ CF ₂ CH ₂

- / CH _2/4 74 CF ₃ CH ₂

- / CH _2/2 O / CH _2/2 75 ^CF 3 ^CH 2

-o / CH _2/4 76 ^CF 3 ^CH 2

-s / CH _2/3 -

-s / CH _2/3 Notes:

In the above table there is a grouping

attached to the bond located on the left side of the -Het- heterocyclic moiety, and -A is attached to the bond located on the right side of the -Het heterocyclic moiety. Similarly, the bond on the left side of the -A- moiety is attached to the heterocyclic ring -Het and the bond on the right side of the -A- moiety is attached to the methylsulfonylamidine moiety. For example, the product of Example 75 corresponds to the formula

Example 72: Maleate; The NMR spectrum, measured in perdeuterodimethylsulfoxide, contains the following signals: 1.5 (m, 6 N), 2.1 (t, 2 N), 2.8 (t, 2 N), 4.3 (q, 2 N), 6.1 / s, 2N /, 6.8 / d, 1N /, 8.4 / d, 1N /.

Example 73: maleate,

Example 74: Maleate,

Example 75: Maleate,

Example 76: Maleate

Example 77: maleate, melting point 142 to melting point 109 to melting point 169 to melting point 131 to melting point 145 to

146 ° C, yield 18%

112 ° C, 21% yield

170 ° C, 7% yield.

132 ° C, 40% yield

147 ° C, yield 50%

Example 78

The process described in Example 12 was repeated using the appropriate imino ether as starting material. N- (4-Methylimidazol-2-yl) -3- [2- [4- / 2- (2,2,2-trifluoromethyl) guanidino] pyrimid-2-yl-ethoxy] -propionamidine trimaleate was obtained in 8% yield. mp 138-141 ° C.

Example 79

The procedure described in Example 11 was repeated using the appropriate imino ether as starting material. N-ethoxycarbonyl-5- [4- (2- (2,2,2-trifluoroethyl) guanidin-4-pyrimid-2-yloxy] valeramidrazone (m.p. 117-119 ° C) was obtained in 69% yield.

Claims (4)

SUBJECT OF THE INVENTION Process for the preparation of heterocyclic guanidine derivatives of the general formula I N R @ ² * H ₂ N ^{/ Z} = N / I / in which 12 each of R and R, 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 carbon 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 2 and R 2 is halo-substituted alkyl, cycloalkyl or cycloalkylalkyl with the proviso that no halogen substituent is present on the carbon atom of the alkyl, cycloalkyl or cycloalkylalkyl group that is directly attached to the nitrogen atom, or R ² represents a hydrogen atom and R ¹ represents a radical of formula II R ⁵ - E - W - (II) 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 ⁸ , wherein R 6 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and r5 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 r5 and r6 are joined together to form a pyrrolidine, piperidine, together with the nitrogen atom to which they are attached , a morpholine, piperazine or N-methylpiperazine ring, the dotted line in the ring X represents a double bond on one side of the nitrogen atom, and Z represents a carbon atom or a nitrogen atom, such that the ring X is a five- or six-membered aromatic heterocyclic ring containing at least one nitrogen atom and optionally containing one or two additional heteroatoms selected from oxygen, nitrogen and sulfur atoms, the heterocyclic ring where optionally, it may optionally have one or two substituents selected from the group consisting of fluorine, chlorine and bromine, 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 / R ⁴ / NR ³ consists of at least 3 atoms, provided that if the chain of residue A is optionally interrupted by one of the aforementioned groups directly linked to C / R ⁴ / NR ³ , it is not that group NH or N-alkyl and with no two groups optionally interrupting the A chain selected from oxygen and sulfur atoms, NH and N-alkyl groups are not directly linked to each other, R ³ is hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 14 cycloalkylalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl , C 1 -C 6 aminoalkyl, C 2 -C 10 alkylaminoalkyl, C 3 -C 14 dialkylaminoalkyl, C 2 -C 6 carboxyalkyl, C 1 -C 6 alkanoyl, 7-aroyl C 1 -C 11 aryl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkanoyl, theoalkanoyl group having 1 to 6 carbon atoms, theoaroyl group having 7 to 11 carbon atoms, a cyano group, a carbamool group, a thiocarbamoyl group, an alkylcarbimoyl group 2 to 6 carbon atoms, 2 to 6 carbon atoms alkylcarbamoyl, 2 to 6 carbon atoms alkylthilcarbamoyl, 2 to 6 carbon atom alkylcarbamoyl, 3 to 10 carbon atoms dealhthylcarbamoyl, kaab < C 2 -C 6 alkoxycarbonyl, C 2 -C 6 alkoxycarbonyl, oxamoolivo, sulfamoyl, C 1 -C 6 cycloalkyl, C 2 -C 10 alkylsulfonyl. (C 6 -C 10) arylsulfmiyl group, (C 7 -C 11) aralkylsufmoyl group; up to 6 carbon atoms, creosollooyl of 6 to 10 carbon atoms, hydroxyl group, clkoxeskopino of 1 to 6 carbon atoms, fminoscuoin, C 1 -C 6 -alkoxy, C 2 -C 10 dialkylamino, C 6 -C 10 -alkylamino C 2 -C 6 alkoxycarbonylamino, C 7 -C 11 aayloxyxynabonylaminoscin, C 1 -C 6 alkanoylamino, C 7 -C 11 aroylaminoscin, C 1 -C 6 thioalkanoylamino, thio-C ^ th ^ carbon atoms, heteroarylcarbonylcarbonyl, alkylthiocarbonyltinitropino having 1 to 6 carbon atoms in the alkyl moiety; C 1 -C 6 alkanesolfonyl amino group, C 6 -C 10 arensolfonylamino group, oaeeditkopino, theioaeldosclpioo, oxamoolamino, heteriaaelS1 or hettaicrelclkyl group having 1 to 6 carbon atoms; 6 carbon atoms in the alkyl moiety; and R ^{4 preferences} unnecessary ^to Formula HNR ⁷ where R ⁷ represents a hydrogen vi ^d I ^{к o,} and ^{o yl} Ovoo group · having 1-6 carbon atoms, alkenyl> Vou group having 2-6 carbon atoms, clkioylovoo group 2 up to 6 carbon atoms, cyano, C 1 -C 6 alkyl, carabamoyl, C 2 -C 6 alkylcarbamoyl or C 1 -C 6 alkanoyl isoisopino; or R ³ represents a water-in non ^b of Al tulle group is ^from 1 to ⁶ carbon OHL ^Cart on ^{and lк} eoy ^l an Mo sku ^ nu 2 to 6 carbon ^y coal this or and ^o in ^y nominal Lupine 2 to ⁶ · ^y uhlíto atom and R ⁴ for VUJE ^^ kааrox Livio ^y group, wherein R ³ represents ask not ^b oo ^b is ^h e ^{t h} U is taoaa lovУ ^{e ry} of ^{the TT,} this hettaiaaelovy residue consisting of a five or - štttčltonyýi a heterocyclic ring containing. one, two, three or four heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms, which ring is optionally substituted with one or two substituents selected from the group consisting of methyl and amino, and pharmaceutically acceptable acid addition salts thereof; A compound of formula VI X х'Ч ^H 2 ^{n /} . ·, - C ^χ · Ζ - A NR ¹² - ^c T Xr ¹³ (VLt in which 1 2 R *, R *, A, X and / / are as defined above, 12 3 7 R * * has any of the meanings given above for R 6 or R 6a R ¹³ is a vermin residue, reacted with a compound of formula VII R ¹⁴ - NH ₂ / VII / in which ^R14 my one of the meanings given above for R ⁷ or. R @ ³ , whereupon the optionally formed compound in the free-freely reacted acid is reacted with an acid-scooping pharmaceutically acceptable anion to form a pharmaceutically-acceptable acid addition salt. 2. A process according to claim 1, wherein the corresponding compounds of the formulas VI and VII are used as starting materials to form the compounds of the formula. I, in which 1 2 R, R, Z and X 'have the same meaning as in 1, o R @ 1 is hydrogen, C1 -C6 alkyl, cycloalkyl having 1 to 6 carbon atoms; Up to 3 - 8 carbon atoms, having cykloclkylclkylovou ^e - 4 GB 14 carbon atoms, halogenoalkyl - group having 1 to 6 carbon atoms, - hydroxyalkyl - having first C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 10 alkyl aminoalkyl, C 3 -C 14 di-alkylaminoalkyl, C 2 -C 6 alkyl, carboxy In the case of a 1 to 6 carbon atom, a 7 to 11 carbon atom group, a 6 to 10 carbon atom group, a 7 to 11 carbon atom group, a C1-C4 carbon group, 2 to 6 carbon atoms, 11 to 6 carbon atoms, 2 to 6 carbon atoms, haloalkanoyl of 2 to 6 carbon atoms, thioalkanoyl of 1 to 6 carbon atoms, thioiroyl of 7 to 11 carbon atoms, cyano, crbam> - C 2 -C 6 dialkylcarbamoyl, - C 3 -C 10 dialkylcarbamoyl, C 2 -C 6 -alkylcarbamoyl, C 3 -C 10 dialkyllhioaramethyl. , carbox groups u, C 2 -C 6 -alkoxycarbonyl, - ilkoxy-thiocarbonyl> (C 2 -C 6), oxamoyl, sulfimoyl, (C 1 -C 6) alkylsulfoyl, (C 2 -C 10) dimethylsulfonyl group, (C 6 -C 10) alkylsulfonyl group, (C 1 -C 10) alkylsulfonyl group; (C až-C 11 ir), (C ir-C ir ir) irenesulfonyl, hydroxyl, C až-C il il (C až-C il il) alkoxy, Cmin-C, cl, C až až-C cl cl (Cky-Ckylam) amino, Cžž-C 10il di (Cž-C di di) amino group (C až-C 10 alko) alkoxy, C,-C 6 alko (C alko-C alko alko) alkoxycarbonyl (C,-C 6 alko), Clo-C 11 cry (Clo-C cry cry) alkoxycarbonylamino, C al-C až al (Clan-Clan al) allanotlamino, C c-C 11 l (Crot-Crot l) thioalkanoyl C 6-C c th, C 11-C 11 th (thioiroyl) amino, Col-Col,, Col-Col,, Col-C heter heter) (C 1 -C 6) phonylamino, (C 6 -C 10) -sulfonyl-amino, ureido, thioureido, oxamoyl, heteroiryl or C 1 -C 6 letherolryl-C 1 -C 6 alkyl R ⁴ předst ^IWU is a radical of the formula HNR ⁷ where R ⁷ znimsn ^and read wire ^{to u} cltylovou with ^k u ^p yne with 1-6 carbon atoms, - llkentlyvyu group having 2-6 carbon atoms, lllintlovyu group 2-6 carbon atoms, cyano, C 1 -C 6 alkyl, carbamoyl, C 2 -C 6 -alkylcarbamoyl or C 1 -C 6 -alkylamino, or r 3 is hydrogen or C 1 -C 6 -alkyl; 6 carbon atoms, 11-alkenyl 4 groups of 2 to 6 carbon atoms or lllintlyvou group having 2-6 carbon atoms, - R c 'represents kcrboxylovou group, wherein ^R3 ^ Kud ^zncm ^^ o ⁿ eb ^oo bs Huj ^{c t e} heterylr lyvý ^- residue is ^- this ^ Bteroiryl unnecessary ^for AC-TV ^courser © ⁿ five or six membered heterocyclic ring containing one, two, three or four heteroatoms selected from zahrnnjící oxygen, nitrogen and sulfur, Pril ring is optionally substituted with one or two substituents selected from methyl zalhrniuící and amino groups, and pharmaceutically acceptable acid addition salts thereof.