NL9000132A - NEW THIAZOLE DERIVATIVES. - Google Patents

Description

New thiazole derivatives

The invention relates to new thiazole derivatives, namely

a. A substituted 4- or 5- (tt-aminoalkyl) thiazole of the formula 1, wherein X is a sulfur atom and Y

a nitrogen atom or X is a nitrogen atom and Y is a sulfur atom, n is 1-6, R1 is a hydrogen atom, a straight or branched alkyl group with 1-4 carbon atoms, and R2 is a hydrogen atom, a straight or branched alkyl group with 1-4 carbon atoms or an amino group, b. an N- [- (thiazol-4 or 5-yl) alkyl] isourea, isothiourea or guanidine derivative of the formula 2, wherein X is a sulfur atom and Y is a nitrogen atom and Y is a sulfur atom, n 1-6, R ., a hydrogen atom, or a straight or branched alkyl group having 1 to 4 carbon atoms and R 2 represents a hydrogen atom, a straight or branched alkyl group having 1 to 4 carbon atoms, or an amino group, Z represents a sulfur or oxygen atom, or a NH group, R 3 represents a hydrogen atom , a phenyl or an alkyl group having 1-4 carbon atoms and R4 represents a hydrogen atom, a cyano or a benzoyl group, c. an N- (β-substituted alkyl) -N'-substituted-N "- [[mu] - (thiazol-4 or 5-yl) alkyl] guanidine of the formula 3, wherein X is a sulfur atom and Y is a nitrogen atom, X respectively is a nitrogen atom and Y is a sulfur atom, wherein n is 1-6, R1 represents a hydrogen atom or a straight or branched alkyl group with 1-4 carbon atoms and R2 represents a hydrogen atom, a straight or branched alkyl group with 1-4 carbon atoms or an amino group , R4 represents a cyano or benzoyl group, m 1,2 or 3; A is a sulfur or oxygen atom, a -CH2 or -CH = group and Q is an R-substituted diphenyl-methyl group or an R-substituted (10 , 11-dihydro) al dannite aza is 5H-dibenzo [a, d] -cyclohepten-5-yl group or Qeen with Q1 and Q2-substituted nitrogen atom, wherein Q1 and Q2 are symmetrically R-substituted ((0-) phenyl) (alkyl) groups, is whether Q is an R-substituted>> -phenylalkyl group or Q is an R 'symmetric or disubstituted mono- or disubstituted methylidene fragment, where rin R 'is an R-substituted (10,11-dihydro) aza or not aza 5H-dibenzo [a, d] - <yclohepten-5-yl group or R' represents two phenyl groups already symmetrically substituted with R wherein R is hydrogen, alkyl, alkoxy, amino, monovalent dialkylamino, guanidino, nitro, carboxy, carbalkoxy, halogen, trihalomethyl, etc., while additionally the R-substituted phenyl rings can be replaced by an R or unsubstituted (heterocy Cyclic) (aromatic) ring or by a combination of an R-substituted (condensed) (aromatic) (hot-cyclic) with one or more symmetric or non-symmetrical R-substituted (condensed) (aromatic) (heterocyclic) rings.

For example, R-substituted (condensed) (heterocyclic) (aromatic) rings which may be present are; 2-, 3-, 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2-, 3-, 4- [dihydro] pyridyl, 4 or 5-imidazolyl, 2,4 or 5-thiazolyl, 2- or 3-furyl, 2- or 3-thienyl, dihydropyridazi-non-2 or 6-yl, 2-benzoimidazolyl, etc.

d. an N- ((o-substituted-alkyl) -N '- [»]) - (thia-zol-4 or 5-yl) alkyl] guanidine of the formula 4, wherein Xene is a sulfur atom and Y is a nitrogen atom, and X is a nitrogen atom and Y a sulfur atom, n is 1-6, R 1 represents a hydrogen atom or a straight or branched alkyl group with 1 to 4 carbon atoms and R 2 represents a hydrogen atom or a straight or branched alkyl group with 1 to 4 carbon atoms or amino group, where m 1, 2 or 3 A is a sulfur, oxygen atom, a -CH2- or -CH = group and Q is an R-substituted diphenylmethyl group or an R-substituted (10,11-dihydro) optionally aza 5H-dibenzo [a, d] - cyclohep-5-yl group or Q is a Q1 and Q2-substituted nitrogen atom, Q1 and Q2 being symmetric R-substituted (hi-) phenyl (alkyl) groups or Q being R-substituted ω-phenylalkyl group or Q is a methyl-disubstituted or non-symmetric mono- or disubstituted methylidene fragment, wherein R 'is an R-substituted (10,11-dihydro) aza or not a 5H-dibenzo [a, d] -cycloheptic-5-yl group is whether R 'represents two phenyl groups substituted or not symmetrically substituted with R, wherein R is hydrogen, alkyl, alkoxy, amino, mono or dialkylamino, guanidino, nitro, carboxy, carbalkoxy, halogen, trihalomethylethis, while in addition, the R-substituted phenyl rings may be replaced by an R or unsubstituted (heterocyclic) (aromatic) ring or by a combination of an R-substituted (condensed) ) (aromatic) (heterocyclic) with one or more, if not symmetrical, with R-substituted (condensed) (aromatic) (heterocyclic) rings.

For example, R-substituted (condensed) (heterocyclic) (aromatic) rings which may be present are; 2-, 3-, 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2-, 3-, 4- [dihydro] pyridyl, 4 or 5-imidazolyl, 2,4 or 5-thiazolyl, 2- or 3-furyl, 2- or 3-thienyl, dihydropyridazi-non-2 or 6-yl, 2-benzoimidazolyl, etc.

The invention also relates to acid addition salts of the compounds of formulas 1-4.

Histamine receptors are, according to the current state of knowledge, divided into three classes, which are mainly referred to as historical grounds with the respective qualifications of the H,, H2 and H3 receptor.

Each of these classes of receptors presumably has its own specific biological function depending on the location of such receptor type in the organism concerned.

In those cases where dysfunction of the normal physiological system has taken place, treatment with endogenous or exogenous compounds may be necessary, whereby the receptor system can either be stimulated (agonistic activity) or inhibited (antagonistic activity).

From the above follows the great importance of compounds capable of selectively agonizing or antagonizing the various histamine receptor classes.

Not only from a scientific (pharmacological) point of view, it is important to be able to dispose of overselective histamine receptor active compounds in order to discriminate among the various receptor types, among other things, it also offers therapeutic perspectives with the stimulation of the histamine H2 receptor to treat congestive heart diseases. associated with heart failure and certain allergic conditions, so that there is great interest from the pharmaceutical industry in developing and applying selective histamine H 2 receptor active compounds.

Impromidine (5), described by G.J. Durant etal. in Nature 276, pp. 403-405 (1978) and Dimaprit (6), described by C.R. Ganellin in Pharmacology of Histamine Receptors, pp. 40-44 (1982), Wright Publishers. PSG., Have a moderate to moderately high affinity for the histamine H2 receptor.

N- ((0-substituted-alkyl) -N '- [(imidazol-4-yl) alkyl] guanidines of the formula 7, as described in Dutch patent application 86.01585 and Arpromidine (8) and analogues as described by A. Buschauer in J. Med Chem 32, 1963-1970 (1989), on the other hand, exhibit a high to very high affinity to the H 2 receptor.

Both Impromidine (5), the most active guanidine derivatives of the formula 7 and Arpromidine (8) all contain a protonated N- [3- (imidazol-4-yl) propyl] guanidine fragment under physiological conditions. This fragment, described by MEParsons et al. Under the code SK&F 91486 (9), in Agents and Actions 5, p. 464 (1975), is referred to in literature as an essential element for the activity of this type of compounds on the H2 receptor considered as described by A. Buschauer in J. Med. Chem. 32, 1963-70 (1989). Further substitution to one of the free nitrogen atoms of the guanidine function of this base element can be used to increase the affinity for the H 2 receptor and / or to introduce an optional additional biological activity such as: antagonism of the receptor, as described by G.J. Sterk et al. In Eur. J. Med. Chem. 22, pp. 427-432 (1987) and Dutch Patent Application 86.01585, calcium antagonism as illustrated by the guanidine derivative (10), described by V. Pfahlert et al. In Arch. Pharm. 338, R49 (1988), offosfordiesterase inhibition as described in European patent application 0310737 and illustrated by the guanidine derivative (11).

Thus, the invention also relates to a process for preparing a (O-aminoalkyl-thiazole derivative, wherein a histamine H 2 receptor active compound is prepared, optionally in combination with additional desired biological activity, by a compound of the formula 1, or an acid addition salt thereof, to prepare a compound with a substituted 4- or 5- ((O-thiazolylalkyl) guanidine fragment) Examples of such compounds are the compounds of the formula 2-4 and their acid addition salts.

Additional substitution to the other nitrogen atom can be used to change the activity for the H2 receptor into an antagonist.

Although a large number of (substituted) analogues of histamine have been described in the literature to date, in which the imidazole term has been replaced by another heterocyclic ring system, reference being made to C.R. Ganellin in Pharmacology or Histamine Receptors, pp. 21-31 (1982), Ed. PSG, none of the analogues listed exhibit an activity on the H2 receptor comparable to that of histamine. Only M. Impicciatore et al. Report in Agentsand Actions, 20, pp. 3-4 (1987) the 2-amino-5- (2-aminoethyl) thiazole, which these authors believe is capable of indirectly improving the histamine H2 receptor (as determined on the guinea pig fundus). In IIFarmaco Ed. Sci., 40 (6), pp. 483-498 (1986). Vitali et al. The same 2-amino-5- (2-aminoethyl) thiazole in which this compound is reported to exhibit 0.3% relative activity of histamine on the right atrium of the sCavia, involving this activity in the inotropic effect.

A new series of substituted ft) - (thiazol-4 or 5-yl alkyl) derivatives have now been discovered which exhibit a sea selective and high histamine H 2 receptor activity on the right atrium of the Guinea pig, namely the above compounds of formulas 1-4 and their acid addition salts. This is clearly illustrated by a characteristic representative of the 4- or 5- (amino-alkylalkyl) thiazoles mentioned under formula 1, namely the 2-amino-5- (2-aminoethyl) -4-methylthiazole (12) is essentially a substituted sulfur analog of the endogenous histamine (13) or can be considered a cyclic analog of dimaprit (6).

Is the endogenous histamine (13) able to stimulate all three types of histamine receptors mentioned above, the 2-amino-5- (2-aminoethyl) -4-methylthiazole (12) can be displaced competitively by cimetidine, the intrinsic activity being equal to that of histamine (based on the chronotropic effect) and thus is a full agonist for the H2 receptor with an activity twice as high as that of histamine. The 2-amino-5- (3-aminopropyl) -4-methylthiazole (26b) is a full H2 receptor agonist with an activity 30 times higher than that of the corresponding 4 (5) - (3-aminopropyl) imidazole.

However, at H. | and H3 receptors, the 2-amino-5- (2-aminoethyl) -4-methylthiazole (12), in contrast to histamine (13), shows no activity at all. The essence of the invention now relates to the replacement of the N- [3- (imidazol-4-yl) propyl] guanidine fragment (9) from previously mentioned diverse classes of H 2 receptor active compounds with, inter alia, combined H 1 receptor antagonistic, cal- calcium antagonistic, phosphodiesterase inhibition, etc., by the H 2 receptor specific and more active N- [3- (substituted thiazol-4 or 5-yl) propyl] guanidine fragments.

The thiazole derivatives of formulas 2-4 thus obtained exhibit high to very high activity at the H 2 receptor.

The above-mentioned 4- or 5- (& - - aminoalkyl) -thiazole derivatives of the formula 1 can be obtained in good yields in a manner previously described in the literature, by cyclization of a 2-bromo-phthalimidoalkanal (18), a 3-bromo (O-phthalimi-doalkan-2-one (24) or a 1-bromo-Cü-phthalimidoalkan-2-one (27) with thioformamide, an alkylthioamide or thiourea indimethylformamide under mild conditions, followed by hydrazinolysis or hydrolysis with dilute hydrochloric acid of the obtained phthalimido derivatives (19, 25 or 28) as shown in reaction schemes A and B.

As starting materials for the preparation of the 2-bromo-W-phthalimidoalkanes (18), as shown in Reaction Scheme A, the CO-phthalimidoalkanols (16) appear which can be obtained by the process known in the literature. Conversion of these uphthalimido alkanols (16) to the corresponding aldehydes (17) is carried out by a general method using oxalyl chloride / dimethyl sulfoxide, followed by proton abstraction with a mild base such as triethylamine followed by hydrolysis with water as described by K. Omura et al. in Tetrahedron34, pp. 1651-1660 (1978).

Subsequently, by selective α-bromination of the obtained Oi-phthalimidoalkanes (17) with bromine in carbon tetrachloride, the desired 2-bromo-ft-phthalimidoalkanes (18) are obtained in substantially quantitative yield.

The preparation of the 3-bromo-ft-phthalimidoalkan-2-ones (24) as mentioned in Reaction Scheme B is carried out by selective bromination with bromine in carbon tetrachloride of the corresponding ti> -phthalimidoalkan-2-ones (23) which can be obtained by a process described in Dutch patent application 8800998, which also describes the required 1-bromott-phthalimidoalkan-2-ones (27).

The necessary it) -ha counter ones (22) which are required for the preparation of the 1 and 3-bromo-0) phthalimidoalkan-2-ones (24 and 27) are either commercially available, or may be available at one of the In the manner described in the literature, such as, for example, in Dutch patent application 6511581, good yields are obtained.

The N- [Ol - (thiazol-4 or 5-yl) alkyl] isourea or isothiourea derivatives of the formula 2 are obtained by reacting a 4 or 5- (to-aminoalkyl) thiazole of the formula 1, with a dialkyl-N-cyanoiminodi, respectively -thiocarbonate, a diphenyl-N-cyanocarbonimidate or a diphenyl-N-benzoylcarbonimidate in a suitable solvent according to the methods known in the literature and as indicated in reaction scheme C. The corresponding N- [W- (thiazol-4 or 5-yl) alkyl] guanidine derivatives are obtained by reacting a 4 or 5- (ω-aminoalkyl) thiazole of the formula 1 with an S-alkylisothiouronium derivative.

The N- [0) - (thiazol-4 or 5-yl) alkyl] isurea or isothiourea derivatives (32) obtained are condensed with an appropriate amine (33). The N- ((J-substituted-alkyl) -N'-substituted-N "- [W- (thiazol-4 or 5-yl) alkyl] guanidines of the formula 3 (34) thus obtained are subjected to mild hydrolysis in dilute hydrochloric acid after purification after which the obtained N- (ft) -substituted alkyl) -N '- [(*) - (thiazol-4 or 5-yl) alkyl] guanidines of the formula 4 (35), after optional conversion to a suitable acid addition salt, obtained good yield could be.

Optionally, the desired N- ((o-substituted-alkyl) -N'-substituted-N "- [ft> - (thiazol-4 or 5-yl) alkyl] guanidines of the formula 3 can be obtained by reaction of a 4- or 5- (ω-aminoalkyl) thiazole of formula 1 with the corresponding N- (fc) -substituted alkyl) isourea or isothiourea derivatives (36) according to methods known in the literature and as stated in reaction scheme D or by condensation of a 4 - or 5- (0) -aminoalkyl) thiazole of the formula 1 with an N- (ft) -substituted alkyl) -S-alkylthiouronium derivative (41) as indicated in scheme E.

The invention also relates to a medicament or scientific (pharmacological) auxiliary agent, which contains as active substance a compound of one of the formulas 1-4 or an acid addition salt thereof. The compounds and medicaments of the invention can be used to treat congestive heart disease, which may or may not be associated with heart failure, or to treat allergic conditions.

The following examples illustrate the invention.

All chemicals and solvents used herein are commercially available unless otherwise noted.

Melting points were determined by a Mettler FP 5 melting point determination device.

1H-N.M.R. spectra were determined with a BrukerWH-90 spectrophotometer and the chemical shifts ((ppm) are given relative to tetramethylsilane.

Mass spectra were determined on a Varian Mat CH5 spectrometer or on a Mat 90 (Finnigan Mat, San José, U.S.A.)

Histamine H2 activity was determined on the right atrium of the guinea pig as described by G. J. Strong et al. In Eur. J. Med. Chem., 19, 545-550 (1984).

Example I

fa) -Ftalimido-l-alkanols (16)

General working method:

A mixture of 148 g (1 mole) of finely powdered phthalic anhydride (15) and 1 mole of a desired (0-amino-1-alkanol) is slowly heated under stirring to about 80 ° C under nitrogen after starting the exothermic reaction, whereby the temperature rises to about 140 ° C, it is still heated for about 3 hours at 140 ° C. After cooling the reaction mixture to about 80 ° C, the viscous mass is poured into ice water with vigorous stirring, then extracted with chloroform and the collected chloroform phases are extracted with a 5% aqueous sodium bicarbonate solution and washed three more times with demineralized water After drying over anhydrous sodium sulfate and filtration, the chloroform phase is concentrated in high vacuum.

There was thus obtained: a. 4-Phthalimido-1-butanol (6a) in 91% yield, from phthalic anhydride and 4-aminobutanol.

1H-N.M.R. (CDCl 3): 1.38-1.90 ppm, multiplet, 4H; 2.53 ppm, singlet, 1H; 3.51-3.83 ppm, multiplet, 4H; 7.58-7.94 ppm, multiplet, 4H.

b. 5-Phthalimido-1-pentanol (6bb) in 85% yield, from phthalic anhydride and 5-aminopentanol.

1H-N.M.R. (CDCl3): 1.23-1.90 ppm, multiplet, 6H; 2.36 ppm, singlet, 1H; 3.59 ppm, triplet (J = 5.4 Hz), 2H; 3.67 ppm, triplet (J = 7.2 Hz), 2H; 7.58-7.92 ppm, multiplet, 4H.

Example II

a. 4-Phthalimido-l-butanol (16b)

The 4-phthalimido-1-butanol (16b) can optionally also be obtained in the following manner:

A mixture of 100 g (0.92 mol) of 4-chloro-1-butanol, 135.5 g (0.92 mol) of phthalimide and 127 g (0.92 mol) of finely powdered anhydrous potassium carbonate in about 500 ml of dry dimethylformamide is heated under reflux under nitrogen for 12 hours. After the reaction mixture has cooled, the inorganic salts are filtered off and the precipitate is washed with a little cold methanol, after which the filtrate is concentrated in vacuo. About 250 ml of ethyl acetate are added to the residue thus obtained, after standing overnight at 5 ° C, the initial precipitate is removed by filtration. The filtrate is concentrated under vacuum and the residue is taken up in about 200 ml of chloroform. After extraction with a 5% aqueous sodium bicarbonate solution, it is extracted several more times with demineralized water. The chloroform phase is dried over anhydrous potassium carbonate, filtered and concentrated in vacuo. Yield 95%. The 4-phthalimido-1-butanol thus obtained is identical to the product obtained according to the general procedure for dephthalimido-1-alkanols as described under example I. After standing for a long time, the viscous oil crystallized out. Melting point 47-49 ° C .

Example III

(0-Phthalimido-l-alkanals (17)

The preparation of the ft-phthalimido-1-alkanals (17) is analogous to the method described by K. Omura et al. In Tetrahedron, 34, pp. 1651-1660 (1978) for the preparation of aldehydes from aliphatic or benzyl alcohols .

General working method:

To a solution of 63.5 g (0.5 mol) oxalyl chloride in about 1000 ml of dry dichloromethane is dissolved in a nitrogen atmosphere at -50 ° C with vigorous stirring a solution of 83 g (1.06 mol) of dry dimethyl sulfoxide inca. 200 ml of dry dichloromethane were added dropwise at such a rate that the temperature is maintained at -50 ° C. After stirring, the mixture is stirred for a further 15 minutes, after which a solution of 0.40 mol of a desired 10-phthalimido-1-alkanol (16) in about 400 ml of dry dichloromethane is added dropwise at such a rate that the temperature is maintained at -50 ° C . After addition, the mixture is stirred for another 30 min at -50 ° C, after which 222 g (2.20 mol) of triethylamine are added. The cooling is then removed and the reaction mixture is allowed to slowly warm to room temperature with stirring, after which about 1250 ml of demineralized water is added. After stirring for 30 min at room temperature, the organic phase is separated * and extracted with demineralized water until neutral reaction. The organic phase is then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The viscous oil thus obtained is stored in a nitrogen atmosphere and is used without further purification to prepare the corresponding 2-bromophthalimido channels (18).

* Note: All operations are carried out in a nitrogen atmosphere as much as possible in order to avoid oxidation of the obtained aldehydes by atmospheric oxygen.

There was thus obtained: a. 4-Phthalimido-1-butanal (17a) in 80% yield, from 4-phthalimidobutanol.

1H-N.M.R. (CDCl3): 1.80-2.19 ppm, multiplet, 2H; 2.56 ppm, triplet (J = 7.4 Hz), 2H; 3.74 ppm, triplet (J = 6.8Hz), 2H; 7.52-7.93 ppm, multiplet, 4H; 9.74 ppm, singite, 1H.

b. 5-Phthalimido-1-pentanal (17b) in 85% yield, from 5-phthalimidopentanol.

1H-N.M.R. (CDCl3): 1.50-1.92 ppm, multiplet, 4H; 2.41-2.66 p, p, m., Multiplet, 2H; 3.73 ppm, triplet (J = 6.8 Hz), 2H; 7.62-7.94 ppm, multiplet, 4H; 9.75 ppm , triplet (J = 0.6 Hz), 1H.

Example IV

2-Bromo-to-phthalimido-1-alkanals (18).

General working method:

To a solution of 0.5 mole of a desired Uphthalimido-1-alkanal (17) in about 500 ml of carbon tetrachloride is carefully added in a nitrogen atmosphere with vigorous stirring 80 g (0.5 mole) of bromine at room temperature. After decolorization of the reaction mixture, the mixture is stirred for another 2 hours at room temperature. Then approx. 100 ml of chloroform and 500 ml of demineralized water are added, followed by stirring for another 30 min in a nitrogen atmosphere. The water phase is separated and the organic phase is washed in a nitrogen atmosphere with demineralized water until neutral reaction. After drying over anhydrous sodium sulfate and filtration, the organic phase is concentrated in vacuo. The viscous oil thus obtained is used without further purification to prepare the corresponding 5-W-phthalimidoalkylthiazoles (19). Thus, a. 2-Bromo-4-phthalimido-1-butanal (18a) in 78.5% op¬ yield, from 4-phthalimido-1-butanal (17a).

1H-N.M.R. (CDCl3): 2.00-2.75 ppm, multiplet, 2H; 3.87 ppm, triplet (J = 6.8 Hz), 2H; 4.40 ppm, double triplet (J, = 7.2 Hz, J2 = 1.8 Hz), 1H; 7.59-7.96 ppm, multiplet, 4H; 9.45 ppm, doublet (J = 1.8 Hz), 1H.

b. 2 - Bromo-5-phthalimido-1-pentanal (18b) in 68% yield, from 5-phthalimido-1-pentanal (17b) 1H-N.M.R. (CDCl3): 1.76-2.10 ppm, multiplet, 4H; 3.73 ppm, triplet (J = 6.3 Hz), 2H; 4.36 ppm, broad triplet, 1H; 7.60-7.92 ppm, multiplet, 4H; 9.40 ppm, doublet (J = 1.8 Hz), 1H.

Example V

5- (C-Phthalimidoalkyl ^ thiazoles (19)

General working method:

To a solution of 0.1 mol of a desired crude 2-bromo (ύ-phthalimido-1-alkanal (18) in approx. 100 ml of dry dimethylformamide, a solution of 0.1 mol of thiourea or thioformamide and a alkylthioamide in about 50 ml of dry dimethylformamide. After the light exothermic reaction is complete, the mixture is heated at 100 [deg.] C. for a further 3 hours. After cooling, the reaction mixture is concentrated under high vacuum. To the residue is then added a little ethanol, stirred for 30 minutes, the crystalline material is filtered off, washed successively with ethanol and diethyl ether, and the precipitate is dried in vacuo, if necessary recrystallized from a suitable solvent.

There was thus obtained: a. 2-Amino-5- (2-phthalimidoethhthiazole hydrobromide (19a) in 63% yield, from 2-bromo-4-phthalimido-1-butanal (18a) and thiourea.

The product was recrystallized from an ethanol / methanol mixture.

Srnpt. 221-225 ° C.

1H-N.M.R. (D6-D.M.S.O.): 2.98 ppm, triplet (J = 6.8 Hz), 2H; 3.78 ppm, triplet (J = 6.8 Hz), 2H; 7.10 ppm, singlet, 1H; 7.86 ppm, singlet, 4H; 9.08 ppm, wide singlet, 2H.

b. 2-Amino-5- (3-phthalimidopropyl) thiazole hydrobromide (Ibi in 78.5% yield, from 2-bromo-5-phthalimido-1-pentanal (18b) and thiourea.

1H-N.M.R. (D6-D.M.S.O.): 1.69-2.13 ppm, multiplet, 2H; 2.72 ppm, triplet (J = 7.2 Hz), 2H; 3.66 ppm, triplet (J = 6.3 Hz), 2H; 7.15 ppm, singlet, 1H; 7.90 ppm, singlet, 4H; 9.28 ppm, broad singlet, 2H.

Example VI6-bromo-2-hexanone (22a)

6-Bromo-2-hexanone (22a) is prepared according to a modified method as described in Dutch patent application 6511581, dated March 7, 1966, cf. Chem.

Abstr. 65, P20151d.

A mixture of 552 g (4 moles) of finely powdered anhydrous potassium carbonate, 404 g (2 moles) of freshly distilled 1,3-dibromopropane, 260 g (2 moles) of freshly distilled acetylacetic acid ethyl ester and 700 ml of absolute ethanol is heated with vigorous stirring to about 60 ° C. After the mild exothermic reaction which starts at about 50 ° C, the reaction mixture is heated under reflux for an additional 5 hours. After the reaction mixture has cooled, the inorganic salts are filtered off and the precipitate is washed with absolute ethanol. The combined filtrates are then concentrated in vacuo and about 250 ml of demineralized water are added to the residue. It is then extracted with toluene. The toluene phases collected are combined, dried over anhydrous sodium sulfate, then filtered concentrated in vacuo. Yield 73% based on G.C./M.S. Then, 170.0 g (1.00 mol) of the crude 2-methyl-3-carbethoxy-5,6-dihydropyran together with 140 ml of concentrated aqueous HBr solution (48%) are refluxed with vigorous stirring for 3 hours , in which violent carbon dioxide gas development occurs. After cooling the reaction mixture, the formed 6-bromo-2-hexanone (22a) is extracted with chloroform, the collected chloroform phases are washed with demineralized water until neutral, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is then subjected to fractional distillation. Yield 104 g (0.58 mol) corresponding to 79.4%.

Kpt. 102-106 ° C / 18 mm Hg. Lit: (Chem. Abstr., 65, P20151d).

94-98 ° C / 12 mm Hg

Mass spectrum M / z (intensity in%). 180 (0.14); 178 (0.11), 137 (6.3); 99 (100).

1H-N.M.R. (CDCl3): 1.50-2.06 ppm, broad multiplet, 4H; 2.14 ppm, singlet, 3H; 2.48 ppm, triplet (J = 6.3 Hz), 2H; 3.40 ppm, triplet (J = 6.8 Hz), 2H.

Example VII

a. 4-Phthalimido-2-butanone (23a.)

The 4-phthalimido-2-butanone (23a) was prepared according to a modified procedure after H. Irai et al., Kogyo Kagaku Zasschi, 62, pp. 82-85 (1959) cf Chem.

Abstr., 58, 5659 b (1963) and as described in Dutch Patent Application 8800998, April 18, 1988.

Mp. 108.5-110 ° C (Lit: H. Irai et al. III-11 ° C).

1H-N.M.R. (CDCl3): 2.22 ppm, singlet, 3H; 2.96 ppm, triplet (J = 7.0 Hz), 2H; 3.96 ppm, triplet (J = 7.0 Hz), 2H; 7.62-7.96 ppm, multiplet, 4H.

b. 5-Phthalimido-2-pentanone f23b ^

The 5-phthalimido-2-pentanone (23a) is prepared according to Dutch patent application 8800998, April 18, 1988.

Yield 53%

Mp. 72-74 ° C.

1H-N.M.R. (CDCl3): 1.89-2.12 ppm, multiplet, 2H; 2.15 ppm, singlet, 3H; 2.51 ppm, triplet (J = 7.2 Hz), 2H; 3.72 ppm, triplet (J = 6.6 Hz), 2H; 7.67-7.92 ppm, multiplet, 4H.

c. 6-Phthalimido-2-hexanone (23c ^

The 6-phthalimido-2-hexanone (23b) is prepared as described for the 5-phthalimido-2-pentanone (23a) in Dutch patent application 8800998, April 18, 1988. Yield 80%, viscous oil.

1H-N.M.R. (CDCl3): 1.48-1.80 ppm, multiplet, 4H; 2.14 ppm, singlet, 3H; 2.52 ppm, triplet (J = 6.8 Hz), 2H; 3.70 ppm, triplet (J = 6.3 Hz), 2H; 7.66-7.90 ppm, multiplet, 4H.

Example VIII

3-Bromo-ft-phthalimido-2-alkanones (24)

General working method:

To a solution of 0.5 mole of a desired (ö-phthalimido-2-alkanone (23) in about 500 ml of carbon tetrachloride, 80 g (0.5 mole) of bromine are added with vigorous stirring at room temperature. the reaction mixture is stirred for a further 2 hours at room temperature, then about 100 ml of chloroforms and 500 ml of demineralized water are added, followed by stirring for a further 30 minutes, the water phase is then separated and the organic phase is washed with demineralized water until neutral reaction The organic phase is then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo The residue (viscous oil) is used without further purification to prepare the 2-amino-4-methyl-5- ((ύ- phthalimidoalkyl) thiazoles (25).

There was thus obtained: a. 3-Bromo-5-phthalimido-2-pentanone (24a) in 95% yield, from 5-phthalimido-2-pentanone (23b).

1H-N.M.R. (CDCl3): 2.10-2.59 ppm, multiplet, 2H; 2.40 ppm, singlet, 3H; 3.82 ppm, triplet (J = 6.3 Hz), 2H, 4.34 ppm, triplet (J = 7.5 Hz), 1H; 7.69 ppm, multi-plet, 4H.

b. 3-Bromo-6-phthalimido-2-hexanone (24b) in 93% yield, from 6-phthalimido-2-hexanone (23c) 1H-N.M.R. (CDCl 3): 1.74-2.22 ppm, multiplet, 4H; 2.36 ppm, singlet, 3H; 3.46-3.90 ppm, multiplet, 2H; 4.36 p.p.m., Triplet (J = 7.2 Hz), 1H; 7.60-7.95 ppm, multi-plet, 4H.

Example IX

5- (ίύ-phthalimidoalkyl) -4-methylthiazoles (25)

General working method:

To a solution of 0.2 mol of a crude 3-bromototophthalimido-2-alkanone (24) in about 100 ml of anhydrous dimethylformamide, a solution of 0.2 mol of thiourea or thioformamide and a alkylthioamide in about 100 ml of dry dimethylformamide. After the exothermic reaction, at which the temperature can rise to about 100 ° C, is still ca. Heated at about 100 ° C for 3 hours with stirring. After cooling, the reaction mixture is concentrated under high vacuum and an ethyl acetate / methanol mixture (1: 1 v / v) is added to the residue. After stirring for about 30 minutes, the resulting precipitate is filtered off, washed successively with ethyl acetate and diethyl ether, and the precipitate is dried in vacuo.

There were thus obtained: a. 2-Amino-5- (2-phthalimidoethyl) -4-methylthiazole hydrobromide (25a) in 50% yield, from 3-bromo-5-phthalimido-2-pentanone (24a) and thiourea .

1H-N.M.R. (DO-D.M.S.O): 1.98 ppm, singlet, 3H; 2.98 ppm, triplet (J = 6.5 Hz), 2H; 3.78 ppm, triplet (J = 6.5 Hz), 2H; 7.91 ppm, singlet, 4H; 9.06 ppm, broad singlet, 2H.

b. 2-Amino-5- (3-phthalimidopropyl) -4-methyl-thiazole-hydrobromide (25b) in 51% yield, from 3-bromo-6-phthalimido-2-hexanone (24b) and thiourea.

1H-N.M.R. (D6-D.M.S.O): 1.61-2.04 ppm, multiplet, 2H; 2.15 ppm , singlet, 3H; 2.70 ppm, triplet (J = 8.1 Hz), 2H; 3.64 ppm, triplet (J = 6.6 Hz), 2H; 7.88 ppm, singlet, 4H; 9.23 ppm, broad singlet, 2H.

c. 5- (2-Phthalimidoethyl-4-methylthiazole hydrobromide f25c) in 40% yield, from 3-bromo-5-phthalimido-2-pentanone (24a) and thioformamide.

Mp. 207.4-210.6 ° C.

1H-N.M.R. (D6-D.M.S.O.): 1.99 ppm, singlet, 3H; 2.96 ppm, triplet (J = 6.3 Hz), 2H; 3.76 ppm, triplet (J = 6.3 Hz), 2H; 7.92 ppm, singlet, 4H; 9.23 ppm, broad singlet, 2H.

d. 5- (2-Phthalimidoethyl) -2,4-dimethylthiazole hydrobromide (25d) in 50% yield, from 3-bromo-5-phthalimido-2-pentanone (24a) and thioacetamide.

1H-N.M.R. (D6-D.M.S.O.): 2.13 ppm, singlet, 3H; 2.70 ppm, singlet, 3H; 3.15 ppm, triplet (J = 6.3 Hz), 2H; 3.78 ppm, triplet (J = 6.3 Hz), 2H; 7.84 ppm, singlet, 4H; 8.78 ppm, broad singlet, 1H.

Example X.

1-Bromo-ft) -phthalimido-2-alkanones (27)

The 1-bromo-phthalimido-2-alkanones (27) are prepared according to Dutch patent application 8800998, April 18, 1988.

There was thus obtained: a. 1-Bromo-4-phthalimido-2-butanone (27a) in 60% yield.

Mp. 120-122 ° C (Lit: R.G: Jones et al. J. Amer. Chem.

Soc., 72, 4526-4529 (1950) 119-120 ° C).

1H-N.M.R. (CDCl 3): 3.13 ppm, triplet (J = 7.2 Hz), 2H; 3.92 ppm, singlet, 2H; 4.04 ppm, triplet (J = 7.2 Hz), 2H, 7.60-7.96 ppm, multiplet, 4H.

b. 1-Bromo-5-phthalimido-2-pentanone (27b) in 52% yield. 131-133.4 ° C (Lit: S.Elz and W. Schunack, Z. Natur.Forsch., 42b, pp. 238-242 (1987) 122-125 ° C, J. Michalkskyet al, Chem. Listy, 49, pp. 1379-1384 (1955) cf Chem. Abstr. 50, 5681 d (1956) 139 ° C).

1H-N.M.R. (CDCl3): 1.82-2.24 ppm, multiplet, 2H; 2.74 ppm, triplet (J = 7.2 Hz), 2H; 3.74 ppm, triplet (J = 7.2 Hz), 2H; 3.94 ppm, singlet, 2H; 7.64-7.88 ppm, multiplet, 4H.

Example XI

4- ((0-phthalimidoalkvl) thiazoles f28)

The 4- ((ύ-Phthalimidoalkyl) thiazoles (28) are prepared as described for the 5- (to-phthalimidoalkyl) thiazoles (25) in Example IX.

There were thus obtained: a. 2-Amino-4-ph2-phthalimidoethyl) thiazole hydrobromide 28a, in 95% yield, from 1-bromo-4-phthalimido-2-butanone (27a) and thiourea.

1H-N.M.R. (D6-D.M.S.O.): 2.95 ppm, triplet (J = 5.9 Hz), 2H; 3.87 ppm, triplet (J = 5.9 Hz), 2H; 6.57 ppm, singlet, 1H; 7.86 ppm, singlet, 4H; 8.98 ppm, broadcasting, 2H.

b. 2-amino-4-phthalimidopropyl) thiazole hydrobromide (28b) in 80% yield, from 1-bromo-5-phthalimido-2-pentanone (27b) and thiourea.

H-N.M.R. (D6-D.M.S.O.): 1.72-2.13 ppm, multiplet, 2H; 2.60 ppm, triplet (J = 7.2 Hz), 2H; 3.62 ppm, triplet (J = 6.3 Hz), 2H; 6.56 ppm, singlet, 4H; 9.12 ppm, broad singlet, 2H.

Example XII

4- or 5- (CO-aminoalkyl ^ thiazoles f20.26.29)

General working method:

A solution of 0.1 mole of a desired φ-phthalimidoalkylthiazole hydrobromide (25) in approx. 400 ml anhydrous methanol is heated to reflux with 0.2 mole of an 80% aqueous hydrazine hydrate solution for 5 hours. After cooling in ice, the crystallized phthalhydrazine is filtered off and the clear filtrate is concentrated in vacuo. Then 105 ml of a 1 molar aqueous sodium hydroxide solution is added to the residue and concentrated under high vacuum at room temperature. The residue thus obtained is stirred with warm absolute ethanol, which after-filtration is concentrated in high vacuum. After absorption of the residue in absolute ethanol, the mixture is acidified to approx. 40% with a concentrated 37% aqueous hydrochloric acid solution. pH = 2, after which the mixture is concentrated in high vacuum at room temperature and residues of water are azeotroped using toluene. Acetone is then added to the residue obtained, the crystalline material is filtered off, washed with acetone and diethyl ether, and then dried under vacuum. If necessary, it is recrystallized from a suitable solvent.

There were thus obtained: a. 2-Amino-5-ph2-aminoethyl) thiazole dihydrochloride i20alin 70% yield, from 2-amino-5- (2-phthalimidoethyl) thiazole hydrobromide (29a).

Crystallized from methanol. Mp. 226-230 ° C.

H-N.M.R. (D6-D.M.S.O.): 2.88-3.14 ppm, broad singlet, 4H; 7.20 ppm, singlet, 1H; 8.29 ppm wide singlet, 3H; 9.35 ppm. , singlet, 2H.

Mass spectrum M / Z (intensity in%): 143 (19.3); 127 (3.4), 114 (100).

M + = 143.054 (Calculated for C5 H9 N3 S: 143.052) b. Z-Amino-S-n-aminoprobthhiazole dihydrochloride (20b) in 83% yield, from 2-amino-5- (3-phthalimidopropyl) thiazole hydrobromide (19b).

Crystallized from an ethanol / methanol mixture.

1H-N.M.R. (D6-D.M.S.O): 1.68-2.10 ppm, multiplet, 2H; 2.79 ppm, wide triplet, 4H; 7.20 ppm, singlet, 1H; 8.20 ppm, broad singlet, 3H; 9.46 ppm, broad singlet, 2H.

Mass spectrum M / Z (intensity in%): 157 (13.3); 141 (53.6), 127 (100); 113 (9.5).

M + = 157.0.63 (calculated for C 1 H H Nj S: 157.067) c. 2-Amino-5- (2-aminoethyl) -4-methylthiazole dihydrochloride (26a) in 82% yield, from 2-amino-5- (2-phthalimidoethyl) -4-methylthiazole hydrobromide (25a).

1H-N.M.R. (D6-D.M.S.O): 2.19 ppm, singlet, 3H; 2.82-3.07 ppm, broad singlet, 4H; 8.34 ppm, broad singlet, 3H; 9.32 ppm, broad singlet, 2H.

Mass spectrum M / Z (intensity in%): 157 (5.0); 141 (3.8), 127 (5.0); 114 (8.3).

M + = 157.065 (calculated for C 14 NjS: 157.067) d. 2-Amino-5- (3-aminopropyl) -4-methylthiazole dihydrochloride (26b) in 90% yield, from 2-amino-5- (3-phthalimido-propyl) -4-methylthiazole hydrobromide (25b).

1H-N.M.R. (D6-D.M.S.O): 1.66-2.02 ppm, multiplet, 2H; 2.16 ppm, singlet, 3H; 2.57-3.03 ppm, multiplet 4H, 8.15 ppm, broad singlet, 3H; 9.32 ppm, broad singlet, 2H.

Mass spectrum M / Z (intensity in%): 171 (28.9); 154 (75.1), 127 (100); 115 (9.7).

M + = 171.080 (calculated for C7 H13 N3 S: 171.083) e. 2-Amino-4- (2-aminoethyl) thiazole dihydrochloride (29a) in 64% yield, from 2-amino-4- (2-phthalimidoethyl) thiazole hydrobromide (28a).

1H-N.M.R. (D6-D.M.S.O.): 2.96 ppm, triplet (J = 6.3 Hz), 2H; 3.12 ppm, triplet (J = 6.3 Hz), 2H; 6.72 ppm, singlet, 1H; 8.04 ppm, broad singlet, 3H; 9.28 ppm, broad singlet, 2H.

Mass spectrum M / Z (intensity in%): 143 (4.4); 127 (9.9), 114 (100).

M + = 143.052 (calculated for C 5 H 9 N 3 S: 143.052) f. 2-Amino-4- (3-aminopropyl) thiazole dihydrochloride (29b) in 70% yield, from 2-amino-4- (3-phthalimidopropyl) thiazole hydrobromide (28b).

1H-N.M.R. (D6-D.M.S.O.): 1.70-2.10 ppm, multiplet, 2H; 2.43-2.96 ppm, multiplet, 4H; 6.58 ppm, singlet, 1H; 8.31 ppm, broad singlet, 3H; 9.40 ppm, wide singlet, 2H.

Mass spectrum M / Z (intensity in%): 157 (24.2); 140 (42.5), 127 (8.6), 113 (30.0).

M + = 157.067 (calculated for C ^ NjS: 157.067) g. 5- (2-Aminoethyl) -4-methylthiazole dihydrochloride (26c) in 65% yield, from 5- (2-phthalimidoethyl) -4-methylthiazole (25c) by mild hydrolysis with hydrochloric acid as described by J.W. Black et al., In U.S. Pat. 3,736,331 dated May 29, 1973.

1H-N.M.R. (D6-D.M.S.O.): 2.42 ppm, singlet, 3H; 2.84-3.40 ppm, multiplet, 4H; 8.01-8.51 ppm, broad singlet, 3H, 8.93 ppm, singlet, 1H; 9.55 ppm, singlet, 1H. Mass spectrum M / Z (intensity in%): 143 (12.4); 126 (6.8), 113 (32.9).

M + = 142.054 (calculated for C 6 H 10 N 2 S: 142.056) \ h. 5- (2-Aminoethyl) -2,4-dimethylthiazole dihydrochloride (26d) in 98% yield, from 5- (2-phthalimidoethyl) -2,4-dimethylthiazole (25d).

Srnpt. 159.5-163.3 ° C.

1H-N.M.R. (D6-D.M. S.O.): 2.41 ppm, singlet, 3H; 2.86 ppm, singlet, 3H; 2.94-3.33 ppm, multiplet, 4H; 8.47 ppm, broad singlet, 3H.

Mass spectrum M / Z (intensity in%); 156 (2.1); 127 (100), 85 (3.8).

Example XIII

5-F2-Aminoethyl) -4-Methylthiazole dihydrochloride f 26c)

The 5- (2- (aminoethyl) -4-methylthiazole dihydrochloride (26c) can optionally also be obtained in the following manner:

A solution of 25.0 g (0.175 mol) of 5- (2-hydroxyethyl) -4-methylthiazole (Fluka AG, Chem. Fabrik CH-9470 Buchs) in 150 ml of an aqueous 48% hydrogen bromide solution is stirred for 48 heated at reflux for hours. After cooling, the reaction mixture is concentrated in vacuo and the water present is azeotropically removed with toluene. Then, about 50 ml ethyl acetate and 25 ml absolute ethanol are added to the residue and stirred at room temperature for 30 min. The initial precipitate is then filtered off and dried in vacuum. Yield 64% 5- (2-bromoethyl) -4-methylthiazole hydrobromide.

1H-N.M.R. (D6-D.M.S.O.): 2.46 ppm, singlet, 3H; 3.00 ppm, triplet (J = 5.4 Hz), 2H; 3.65 ppm, triplet (J = 5.4 Hz), 2H; 9.95 ppm, singlet, 1H.

A solution of 17.0 g (0.06 mol) of 5- (2-bromoethyl) -4-methylthiazole hydrobromide in approx. 150 ml of absolute ethanol is saturated with ammonia gas at 0 ° C, after which the mixture is autoclaved for 16 hours. is heated to approx. 100 ° C. After cooling, the reaction mixture is concentrated in vacuo and the residue is taken up in demineralized water, after which 11.76 g (0.14 mol) of sodium hydrogen carbonate are added, followed by stirring at room temperature for about 1 hour. After filtration, the filtrate is concentrated in vacuo and the water present is azeotropically removed with absolute ethanol. The residue is then treated with warm methanol, the inorganic salts are filtered off and the filtrate is brought up to Hp = 1 with a concentrated hydrochloric acid solution. After concentration in vacuum, the residue is then recrystallized from an ethanol / methanol mixture.

Yield 20%, mp. 208-210 ° C.

The 1H-N.M.R. spectrum is identical to the spectrum obtained in the preparation of the 5- (2-aminoethyl) -4-methylthiazole dihydrochloride (26c) as described in Example 11g.

example XIV

a. N-r3- (2-Amino-4-methyl-thiazole-5-propylene-N1-cvano-O-phenyl urea f32a ^

To a solution of 4.88 g (0.02 mol) of 2-amino-5- (3-aminopropyl) -4-methylthiazole dihydrochloride (26b) inca. 50 ml of absolute ethanol are added with stirring 0.04 mole of a freshly prepared sodium ethanolate solution in about 25 ml absolute ethanol. After heating for 15 minutes at about 50 ° C, the inorganic material is filtered off and the filtrate is concentrated under vacuum. The residue is then taken up in 50 ml of dry freshly distilled pyridine and 5.76 g (0.02 mol) of diphenyl cyanocarbonimidate (31a) are added. After heating under reflux for 2 hours, after cooling, the reaction mixture is concentrated in vacuo and the residue is washed several times with dry diethyl ether. The crystalline material is then dried in vacuum.

Yield 100% 1H-N.M.R. (CDCl3): 1.65-2.04 ppm, multiplet, 2H; 2.63 ppm, triplet (J = 7.2 Hz), 2H; 3.41 ppm, triplet (J = 6.3 Hz), 2H; 5.30 ppm, broad singlet, 2H; 7.00-7.19 ppm, multiplet, 2H; 7.19-7.53 ppm, multiplet, 3H.

b. Ν-Γ3-f2-Aminothiazol-5-vl) propyl-Nl-cvano-S-methyliso-thiourea (32b ^

To a solution of 4.60 g (0.02 mol) of 2-amino-5- (3-aminopropyl) thiazole dihydrochloride (20b) in approx. 50 ml of absolute ethanol, 0.04 mol of freshly prepared sodium ethanolate solution in approx. 25 ml absolute ethanol added. After heating for 15 minutes at about 50 ° C, the inorganic material is filtered off and 2.92g (0.02 mol) bis [methylthio] cyanocarbodiimide (31b) is added, followed by refluxing for 12 hours. After cooling the reaction mixture filtered and the filtrate concentrated in vacuo.

Yield 95% 1H-N.M.R. (CDCl3): 1.54-2.04 ppm, multiplet, 2H; 2.58 ppm, singlet, 3H; 2.68 ppm, triplet (J = 5.4 Hz), 2H; 3.30 ppm, triplet (J = 7.2 Hz), 2H; 6.63 ppm, singlet, 1H; 6.70 ppm, singlet, 2H; 8.36 ppm wide singlet, 1H.

c. Ν-Γ3- (2-Amino-4-methyl-thiazole-5-vl) propyll-N1-cvano-S-methyl-isothiourea (32c)

To a solution of 4.88 g (0.02 mol) of 2-amino-5- (3-aminopropyl) -4-methylthiazole dihydrochloride (26b) inca. 50 ml of absolute ethanol are added with stirring 0.04 mol of a freshly prepared sodium ethanolate solution in about 25 ml of absolute ethanol. After heating for 15 minutes at about 50 ° C, the inorganic material is filtered off and the filtrate is concentrated under vacuum. The residue is then taken up in 100 ml of dry freshly distilled pyridine and 2.92 g (0.02 mol) of bis [methylthio] cyanocar bodiimide (31b) are added. After refluxing for 2 hours, the reaction mixture is concentrated in vacuo and residues of pyridine are removed by codeillation with toluene. The residue is then recrystallized from ethanol.

Yield: 85%, mp. 172.0-172.4 ° C.

1H-N.M.R. (D6-D.M.S.O.): 1.50-1.94 ppm, multiplet, 2H; 2.36-2.75 ppm (under D.M.S.O signal), 2H; 2.60 ppm, singlet, 3H; 3.33 ppm, triplet (J = 7.2 Hz), 2H; 6.65 ppm, singlet, 2H; 8.40 ppm, singlet, 1H.

Example XV

a. N-r3-f2-Amino-4-methylthiazole-5-yl) propyl-1au-nidine dihydrobromide (32b)

To a solution of 4.88 g (0.02 mol) of 2-amino-5- (3-aminopropyl) -4-methylthiazole dihydrochloride (26b) inca. 50 ml of absolute ethanol are added with stirring 0.04 mole of a freshly prepared sodium ethanolate solution in about 25 ml absolute ethanol. After heating for 15 minutes at about 50 ° C, the inorganic material is filtered off and 3.70 g (0.02 mol) of S-ethyl isothiouronium bromide is added, followed by refluxing for 6 hours. After cooling, the reaction mixture is filtered and acidified with concentrated aqueous hydrogen bromide solution totca. pH = 1, then concentrated in vacuo and the residue recrystallized from a mixture of isopropyl alcohol and methanol.

Yield 85% 1H-N.M.R. (D6-D.M.S.O.): 1.43-1.88 ppm, multiplet, 2H; 2.08 ppm, singlet, 3H; 2.20-2.72 ppm (partly under D.M.S.O.), multiplet, 2H; 2.83-3.29 ppm, multi-plet, 2H; 7.32-7.88 ppm, broad singlet, 3H; 8.64 ppm, singlet, 4H; 9.10 ppm, singlet, 2H.

Example XVI

a. N-Cvano-N1- (3,3-diphenvlpropyl) -O-phenylsourea (36aï

A solution of 10.55 g (0.05 mol) of 3,3-diphenyl-propylamine (33a) and 11.90 g (0.05 mol) of diphenylcyanocarbonimidate (31a) in 100 ml of dry dichloromethane is added under nitrogen for 30 min heated to reflux. After cooling of the reaction mixture, the vacuum is concentrated and 100 ml of dry diethyl ether are added to the residue. Subsequently, the room temperature is stirred under nitrogen for 15 min, after which the white crystalline material is filtered off, washed with dry diethyl ether and dried in vacuo.

Yield 87%, mp. 171-174 ° C

1H-N.M.R. (D6-D.M.S.O.). 2.14-2.60 ppm, multiplet, 2H; 3.00-3.48 ppm, multiplet, 2H; 3.90-4.16 ppm, multi-plet, 1H; 7.00-7.65 ppm, multiplet, 15H; 8.73 ppm,

wide singlet, 1H

bN-Cvano-N1- (3,3-diphenvlproovl) -S-methylisothiourea (36b) To a solution of 21.1 g (0.1 mol) 3,3-diphenylpropylamine (33a) in approx. 100 ml dry diethyl ether, a clear solution of 14.6 g (0.1 mol) of bis- [methylthiocyanocarbodiimide (31b) in about 100 ml of dry diethyl ether are added, followed by stirring at room temperature for about 30 minutes. The resulting precipitate is then filtered off and washed with dry diethyl ether, after which the crystalline material is dried in vacuo.

Yield 80% 1H-N.M.R. (CDCl3): 2.14-2.58 ppm, multiplet, 2H; 2.30 ppm, singlet, 3H; 3.16-3.50 ppm, multiplet, 2H; 3.95p.p.m., triplet (J = 8.1 Hz), 1H; 7.26 bpm, multiplet, 10H; 7.58 bpm, broad singlet, 1H.

Example XVII

a._N-Benzovl-N1 - (3,3-diphenvlproovl) thiourea f 38a ^

To a solution of 21.1 g (0.1 mole) of 3,3-diphenylpropylamine in 400 ml of dry diethyl ether is slowly dissolved in a nitrogen atmosphere and with vigorous stirring, a solution of 16.3 g (0.1 mole) of freshly distilled benzoyl isothiocyanate ( 37) in about 50 ml of dry diethyl ether and stirring at room temperature for 1 hour. The resulting precipitate is filtered off, washed with dry diethyl ether and dried in vacuo.

Yield 74%, mp. 124-125 ° C

1H-N.M.R. (CDCl3): 3.26-3.54 ppm, multiplet, 2H; 4.40-4.70 ppm, multiplet, 2H; 5.06 ppm, triplet (J = 7.9

Hz), 1H; 8.06-8.68 ppm, multiplet, 13H; 8.94 ppm, double doublet (J1 = 8.6 Hz, J2 = 2.0 Hz), 2H; 11.95 ppm, broad singlet, 1H.

b. N- (3,3-diphenylpropyl) thiourea (39a)

A saturated solution of 10.0 g is added to a solution of 26.2 g (0.07 mol) of N-benzoyl-N '- (3,3-diphenylpropyl) thiourea (38) in 500 ml of anhydrous methanol. (0.072 mol) of potassium carbonate in demineralized water is added, followed by refluxing with stirring for about 6 hours. After cooling, the formed precipitate is filtered off, washed successively with demineralized water and absolute methanol, and the precipitate is dried in vacuo.

Yield 95%, m.p. 198-199 ° C.

1H-N.M.R. (D6 -D.M.S.O.): 3.10-3.28 ppm, multiplet, 2H; 3.94-4.58 ppm, broad multiplet, 2H; 4.22 ppm, singlet, 2H; 5.03p.p.m., triplet (J = 7.7 Hz), 1H; 8.02-8.60 ppm, multi-plet, 10H; 8.83 ppm, singlet, 1H.

c. S-Ethvl-N- (3,3-diphenvlpropyl) isothiouronium bromide (40a)

A solution of 13.5 g (0.05 mol) of N- (3,3-diphenylpropyl) thiourea (39a) in approx. 250 ml of absolute ethanol and 25 ml of bromoethane is refluxed for 5 hours. After cooling, the solution is filtered and the filtrate partially concentrated in vacuo. The crystalline material is filtered off, washed with dry diethyl ether and dried in vacuo. Yield 63%, mp. 176-180 ° C.

1H-N.M.R. (D6-D.M.S.O.): 1.27 ppm, triplet (J = 7.2 Hz), 3H, 2.16-2.53 ppm, multiplet, 2H; 3.08-3.40 ppm, multiplet, 4H; 4.06 ppm, triplet (J = 7.7 Hz), 1H; 7.07-7.46 ppm, multiplet, 10H; 9.13 ppm, broad singlet, 1H; 9.56p.p.m., Triplet (J = 4.5 Hz), 1H.

Example XVIII

a. N-r2 (f2-Amino-4-methyl-thiazol-5-vl) ethll-Nl- (3,3-diphenvloropvl) quanidine dipikrate C35a)

To a solution of 2.3 g (0.01 mol) of 2-amino-5- (2-aminoethyl) -4-methylthiazole dihydrochloride (26a) in 50 ml of absolute ethanol, a freshly prepared solution of 0.02 mol of sodium ethanolate in ca. 25 ml of absolute ethanol added. After stirring for 15 min at approx. 50 ° C, the inorganic material is cooled and filtered, after which 3.55 g (0.01 mol) of N-cyano-N '- (3,3-diphenylpropyl) -0-phenylisourea (36a) will be added. Then it is heated under reflux for 16 hours. After cooling and concentration in vacuum, the obtained residue is extracted several times with dry diethyl ether. Then about 50 ml of warm ethyl acetate is added, stirred for 15 min, the insoluble material is filtered off and the filtrate is concentrated in vacuo. The viscous oil thus obtained, consisting of the crude N- [2- (2-amino-4-methylthiazol-5-yl) ethyl] -N'-cyano-N "- (3,3-diphenylpropyl) guanidine (34a) is then taken up in 100 ml of 2N aqueous hydrochloric acid solution without further purification, after which it is heated under reflux for 3 hours. After cooling, the mixture is concentrated in vacuo and the residue is dissolved in absolute methanol. After filtration, a solution of 0.02 mol of picric acid is dissolved in about 50 ml. methanol added After stirring, the resulting precipitate is filtered off and recrystallized from a mixture of methanol and water.

Yield 10% 1H-N.M.R. (DO-D.M.S.O.): 2.12-2.46 ppm, broad multiplet, 2H; 2.70-3.53 ppm, broad multiplet, 6H; 4.02 ppm, triplet (J = 7.2 Hz), 1H; 7.07-7.60 ppm, multiplet, 13H, 8.64 ppm, singlet, 4H; 8.97 bpm, broad singlet, 2H; 9.06-9.64 bpm, broad singlet, 1H.

\ b. N-r3-f2-Amino-4-methylethiazole-5-yl) propyl-Nl- (3,3-diphenchloroovyl quanidine dipikrate (35b)

The N- [3- (2-amino-4-methylthiazol-5-yl) propyl] -N '- (3,3-diphenylpropyl) guanidine (35b) was prepared in a manner analogous to that of the N- [2- (2-Amino-4-methyl-thiazol-S-yl-methyl-N'-S-diphenyl-propyl-guanidine (35a), as described in Example XVIIIa, from N-cyano-N '- (3,3-diphenylpropyl) - O-phenyl isourea (37a) and 2-amino-5- (3-aminopropyl) -4-methylthiazole dihydrochloride (26b) provided that the reaction mixture was refluxed for 48 hours.

Yield 45% 1H-N.M.R. (D6-D.M.S.O.): 1.54-1.97 ppm, multiplet, 2H; 2.12 ppm, singlet, 3H; 2.22-2.50 ppm, multiplet, 2H; 2.98-3.48 ppm, multiplet, 6H; 4.04 ppm, triplet, 1H, 7.07-7.60 ppm, multiplet, 13H; 8.63 ppm, singlet, 4H; 9.12 ppm, broad singlet, 2H; 9.16-9.45 ppm, broad singlet, 1H.

Example XIX

a. N-r3- (2-Aminothiazol-5-yl) propyl] -N'-f3,3-diphenyl propyl) quanidine dipikrate (35cI)

To a solution of 2.30 g (0.01 mol) of 2-amino-5- (3-aminopropyl) thiazole dihydrochloride (26b) in approx. 50 ml of absolute ethanol, a freshly prepared solution of 0.02 mol of sodium ethanolate in approx. 25 ml of absolute ethanol added. After stirring at 50 ° C for 15 minutes, the mixture is cooled and the inorganic material is filtered off, after which 3.79 g (0.01 mol) of S-ethyl-N- (3,3-diphenylpropyl) -isothiouronium bromide (40a) is added to the filtrate. After refluxing for 48 hours, the reaction mixture is decolorized with activated charcoal, filtered and the filtrate is concentrated in vacuo. The residue is taken up in about 50 ml of methanol, after which a solution of 0.02 mole of picric acid in 50 ml of methanol is added. After stirring for 2 hours, the resulting precipitate is filtered off and recrystallized from a mixture of methanol and water.

Yield 30% 1H-N.M.R. (D6-D.M.S.O.): 1.56-1.98 ppm, multiplet, 2H; 2.00-2.80 ppm, multiplet, 4H; 2.90-3.34 ppm, multi-squeeze, 4H; 4.01 ppm, triplet (J = 7.2 Hz), 1H; 7.13 ppm, singlet, 1H; 7.31 ppm, broad singlet, 13 H; 8.64 ppm, singlet, 4H; 9.12 ppm, broad singlet, 2H.

Example XX

a._N-r3-r2-aminothiazol-4-vl) propvn-Nl- (3,3-diphenvlpropvl) quanidine dipikrate (35d)

To a solution of 3.14 g (0.02 mol) of 2-amino-4- (3-aminopropyl) thiazole (free base of the 2-amino-4- (3-aminopropyl) thiazole dihydrochloride (29b)) in approx. 100 ml absolute ethanol, 6.18 g (0.02 mol) of N-cyano-N '- (3,3-diphenylpropyl) -S-methylisothiourea (36b) are added and refluxed for 96 hours. After cooling, the reaction mixture is decolorized with activated charcoal, filtered and concentrated in vacuo. The residue is then taken up in 100 ml of 2N aqueous hydrochloric acid solution and refluxed for 4 hours. After cooling, the mixture is concentrated in vacuo, the residue is taken up in about 100 ml of absolute ethanol and the inorganic material is filtered off. A solution of 0.04 mol of picric acid in about 50 ml of ethanol is then added to the filtrate. After stirring at room temperature for 3 hours, the resulting precipitate is filtered off and recrystallized from a mixture of methanol and water.

Yield 30% D6-D.M.S.O.

1H-N.M.R. (DóD.M.S.O.): 1.54-1.95 ppm, multiplet, 2H; 2.09-2.74 ppm, multiplet, 4H; 2.87-3.30 ppm, multiplate, 4H; 3.98 ppm, triplet (J = 7.2 Hz), 1H; 6.50 ppm, singlet, 1H; 7.16 ppm, broad singlet, 13H; 8.60 ppm, singlet, 4H; 8.96 ppm, broad singlet, 2H.

Example XXI

a. NTr3-f2-Amino-4-methyl-thiazol-5-yl) propyl-Nt- (3,3-diphenvloronyl-guanidine dipikrate (35b)

A solution of 3.05 g (0.01 mol) N- [3- (2-amino-4-methylthiazol-5-yl) propyl] -N1-cyano-O-phenyl isourea (32a) and 4.22 g ( 0.02 mol) 3,3-diphenylpropylamine (33a) inca. 100 ml of freshly distilled anhydrous pyridine is heated to reflux for 16 hours. After cooling, the reaction mixture is concentrated in vacuo. The residue is then washed with successively demineralized water and diethyl ether, after which the residue is taken up in about 100 ml of warm ethyl acetate. After decolorization with activated carbon and filtration, the filtrate is concentrated in vacuo. The viscous oil thus obtained consisting of the N- [3- (2-amino-4-methyl-thiazol-5-yl) propyl] -N '-cyano-N "- (3,3-diphenylpropyl) guanidine (34b) After column chromatography (Kieselgel 60-80, eluent methanol / NH3) hydrolysed with 2N aqueous hydrochloric acid solution and converted into the dipikrate as described for the N- [3- (2-aminothiazol-4-yl) pro¬ pyl] -Ν- (3,3-diphenylpropyl) guanidine dipikrate (35d) in Example XXa.

Yield 65% 1H-N.M.R. (D6-DMSO): identical to the spectrum as described for the N- [3- (2-amino-4-methylthiazol-5-yl) propyl] -Ν'- (3,3-diphenylpropyl) guanidine dipikrate (35b) example XVIIIb.

Example XXII

a. N.Nl-Bisf3-f2-aiaino-4-methylthiazol-5-yl-propyllauanidine dipikrate f35ei

To a solution of 2.44 g (0.01 mol) of 2-amino-5- (3-aminopropyl) -4-methylthiazole dihydrochloride (26b) inca. 50 ml of absolute ethanol are added with a solution of 0.02 mol of sodium ethanolate prepared in 25 ml of absolute ethanol. After stirring at 50 ° C for 15 min, the mixture is cooled and the inorganic material is filtered off, and the filtrate is concentrated in vacuo. The residue is then taken up in about 100 ml of freshly distilled anhydrous pyridine, after which 2.69 g (0.01 mol) of N- [3,2-amino-4-methylthiazol-5-yl) propyl] -N '-cyano-S- methyl isothiourea (32c) is added and the mixture is refluxed for 12 hours. After cooling, the reaction mixture is worked up as described for the N- [3- (2-amino-4-methylthiazol-5-yl) propyl] -N '- (3,3-diphenylpropyl) -guanidine dipikrate (35b) as described in example XXIa.

Yield 50% 1H-N.M.R. (D6-D.M.S.O.): 1.43-1.88 ppm, multiplet, 4H; 2.08 ppm, singlet, 6H; 2.20-2.72 ppm (partially below D.M.S.O.), multiplet, 4H; 2.83-3.29 ppm, multi-plet, 4H; 7.32-7.88 ppm broad singlet, 3H; 8.64 ppm, singlet, 6H; 9.10 ppm, singlet, 4H.

Claims (5)

1. (ύ-Aminoalkylthiazole, characterized in that it is a. A substituted 4- or 5- (ftJ-aminoalkyl) thiazole of the formula 1, wherein X is a sulfur atom and Y is a nitrogen atom and Y is a nitrogen atom sulfur atom, n is 1-6, R 1 represents a hydrogen atom, a straight or branched alkyl group of 1 to 4 carbon atoms and R 2 represents a hydrogen atom, a straight or branched alkyl group of 1 to 4 carbon atoms or an amino group, or b an N- [0) - (thiazol-4 or 5-yl) alkyl] isourea, isothiourea or guanidine derivative of the formula 2, wherein X is a sulfur atom and Y is a nitrogen atom and Y is a sulfur atom, n1-6 , R represents a hydrogen atom, or a straight or branched alkyl group with 1 to 4 carbon atoms and R 2 represents a hydrogen atom, a straight or branched alkyl group with 1 to 4 carbon atoms or an amino group, Z represents a sulfur or oxygen atom, or an NH group, R 3 a hydrogen atom, a phenyl or an alkyl group with 1-4 carbon atoms and R4 represents a hydrogen atom, a cyano or a benzoyl group, or c. an N- (CO-substituted alkyl) -N'-substituted-Nn- [CO- (thiazol-4 or 5-yl) alkyl] guanidine of formula 3, wherein X is a sulfur atom and Y is a nitrogen atom, respectively X is a nitrogen atom and Y is a sulfur atom, wherein n is 1-6, R represents a hydrogen atom or a straight or branched alkyl group of 1-4 carbon atoms and R2 represents a hydrogen atom, a straight or branched alkyl group of 1-4 carbon atoms or an amino group, R4 represents a cyano or benzoyl group, m 1,2 or 3is; A is a sulfur or oxygen atom, a -CH 2 or a -CH = group and Q is an R-substituted diphenylmethyl group or an R-substituted (10,11-dihydro) al dannite aza 5H-dibenzo [a, d ] -cycloheptic-5-yl group is whether Qeen is a nitrogen atom substituted with Q1 and Q2, wherein Q1 and Q2 are symmetrically R-substituted ((O-) phenyl (alkyl)) groups or Q is an R-substituted (tf-phenylalkyl group is whether Q is an R 'symmetric or disubstituted mono- or disubstituted methylidene fragment, wherein R' is an R-substituted (10,11-dihydro) or not aza 5H-dibenzo [a, d] cycloheps -5-yl group is or R 'is two al though not symmetrically substituted with R phenyl groups, wherein R is hydrogen, alkyl, alkoxy, amino, monovalent dialkylamino, guanidino, nitro, carboxy, carbalkoxy, halogen, trihalomethyl, etc., while in addition, the R-substituted phenyl rings can be replaced by an R or substituted (heterocyclic) (aromatic) ring or by a combination of ation of an R-substituted (condensed) (aromatic) (hot-cyclic) ring with one or more symmetric or non-symmetrical R-substituted (condensed) (aromatic) (heterocyclic) rings, or d. an N- (<0 -substitutedalkyl) -N '- [(J- (thia-zol-4 or 5-yl) alkyl] guanidine of the formula 4, wherein Xene sulfur atom and Y is nitrogen atom, Xene nitrogen atom and Y a sulfur atom, n is 1-6, R 1 represents a hydrogen atom or a straight or branched alkyl group with 1 to 4 carbon atoms and R 2 represents a hydrogen atom or a straight or branched alkyl group with 1 to 4 carbon atoms or amino group, where m 1, 2 or 3 A is a sulfur, oxygen atom, a -CH2- or -CH = group and Q is an R-substituted diphenylmethyl group or an R-substituted (10,11-dihydro) optionally aza 5H-dibenzo [a, d] - cyclohep-5-yl group or Q is a Q1 and Q2-substituted nitrogen atom, wherein Q1 and Q2 are symmetrical R-substituted (ω-) phenyl (alkyl) groups or Q is an R-substituted to-phenylalkyl group or Q is a methyl-disubstituted or non-symmetrical mono- or disubstituted methylidene fragment, wherein R 'is an R-substituted (10,11-dihydro) optionally aza 5H-d ibenzo- [a, d] -cyclohepten-5-yl group is whether R 'represents two phenyl groups, whether or not symmetrically substituted with R, wherein R is hydrogen, alkyl, alkoxy, amino, mono- or dialkylamino, guanidino, nitro, carboxy, carbalkoxy, halogen, trihalomethyl, etc., while, moreover, the R-substituted phenyl rings may be replaced by an alannite with R-substituted (heterocyclic) (aromatic) ring or by a combination of an R-substituted (condensed) (aromatic) (heterocyclic) with one or more symmetric or non-symmetric R-substituted (condensed) (aromatic) (heterocyclic) rings, including the acid addition salts of any of the described compounds of formulas 1-4. 2. Process for the preparation of a (d-amino-alkylthiazole), characterized in that a 4 or 5 - ((0-aminoalkyl) thiazole derivative of the formula 1 as set forth in claim 1 is prepared by ring-closing a 2 -bromo-W-phthalimidoalkanal (18), a 3-bromo (d-phthalimido-alkan-2-one (24) or a 1-bromo-U) -phthalimidoalkan-2-one (27) with thioformamide, an alkylthioamide or thiourea indimethylformamide under mild conditions, followed by hydrazinolysis or hydrolysis with dilute hydrochloric acid of the obtained phthalimido derivatives (19, 25 or 28). 3. Process for the preparation of a (d-amino-alkylthiazole derivative), characterized in that a histamine H2-receptor active compound is prepared, optionally in combination with additional desired biological activity, by means of a compound of the formula 1, or an acid addition salt thereof, to prepare a compound with a substituted 4- or 5- (ö) -thiazolylalkylguanidine fragment. Pharmaceutical or scientific (pharmacological) auxiliary agent, characterized in that it contains as active substance a compound of one of formulas 1-4 or a compound obtained according to claim 3 or an acid addition salt thereof. Use of a compound or medicament according to any preceding claim for treating congestive heart disease, which may or may not be associated with heart failure, or for treating allergic conditions.