NEW THIAZOLE DERIVATIVES

Abstract: A N-[ omega -(thiazol-4 or 5-yl)alkyl]isourea, isothiourea of a guanidine derivative with formula (II) and a N-( omega -substituted alkyl)-N'-substituted-N''-[ omega -(thiazol-4 or 5-yl)alkyl]-guanidine with formula (III), a process for the preparation of said compounds by ring closure of a 2-bromo- omega -phthalimidoalkanal, or of a 3-bromo or 1-bromo omega -phthalimidoalkan-2-one with thioformamide, an alkylthioamide or thiourea followed by hydrazinolysis or hydrolysis of the resulting phthalimido derivates and medicaments containing said derivatives with formulas (II) and (III) and use of said medicaments for the treatment of congestive heart diseases or for the treatment of allergic disorders.

Description: New thiazole derivatives. The invention relates to new thiazole derivatives which are: a. a N-[ω-(thiazol-4 or 5-yl)alkyl]isourea, isothiourea or a guanidine derivative with formula 2 , wherein X represents a sulphur atom and Y represents a nitrogen atom or alternati¬ vely X represents a nitrogen atom and Y represents a sulphur atom, n is 1-6, R x represents a hydrogen atom or a straight or branched alkyl group with 1-4 carbon atoms and R 2 repre¬ sents a hydrogen atom, a straight or branched alkyl group with 1-4 carbon atoms or an amino group, Z represents a sulphur atom, an oxygen atom or a NH-group respectively, R 3 represents a hydrogen atom, a phenyl or an alkyl group with 1-4 carbon atoms respectively and R represents a hydrogen atom, a cyano or a benzoyl group respectively; b. a N-(ω-substituted alkyl)-N--substituted-N n -[ω-(thiazol-4 or 5-yl)alkyl]guanidine with formula 3, wherein X represents a sulphur atom and Y represents a nitrogen atom or alternati¬ vely X represents a nitrogen atom and Y represents a sulphur atom, n is 1-6, R x represents a hydrogen atom or a straight or branched alkyl group with 1-4 carbon atoms and R 2 repre¬ sents a hydrogen atom, a straight or branched alkyl group with 1-4 carbon atoms or an amino group, R 4 represents hydrogen, a cyano or a benzoyl group respectively, m is 1,2 or 3, A represents a sulphur or an oxygen atom, a -CH 2 ~ ox a -CH= group respectively and Q represents a R-substituted diphenylmethyl group or a R-substituted (10,11-dihydro) optionally aza 5H-dibenzo-[a,d]-cyclohepten-5-yl group or Q represents a nitrogen atom substituted with Q_ and Q 2 , whe¬ rein Q-L and Q 2 represent whether or not symmetrical R-substituted (ω-)phenyl(alkyl) groups, or Q represents a R-substituted (ω-)phenyl(alkyl) group or Q represents a whether or not symmetrical mono-or disubstituted methylidene fragment, wherein R 1 represents a R-substituted (10,11-dihy- dro) optionally aza 5H-dibenzo-[a,d]-cyclohepten-5-yl group or R* represents two whether or not symmetrically with R substituted phenyl groups, wherein R represents hydro gen, alkyl, alkoxy, amino, mono- or dialkylamino, guanidino, nitro, carboxy, carbalkoxy, halogen (fluoro, chloro, bromo, iodo) , mono-, di- and trihalogenmethyl or -methoxy (halogen = fluoro, chloro, bromo) etc., while in addition the R-substi- tuted phenyl rings may be replaced by a (heterocyclic) (aromatic) ring whether or not R-substituted or by a combina¬ tion of a (condensed) (aromatic) (heterocyclic) R-substituted ring with one or more (condensed) (aromatic) (heterocyclic) rings whether or not symmetrically R-substituted. Possible present R-substituted (condensed) (heterocyclic) (aromatic) rings are for example: 2-, 3-, 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, 2-, 3-, 4-[dihydro]pyridyl, 4- or 5-imida- zolyl, 2-, 4- or 5-thiazolyl, 2- or 3-furyl, 2- or 3-thienyl, dihydropyridazinon-2 or 6-yl, 2-benzoimidazolyl, etc. The invention also relates to the acid addition salts of the compounds with the formulas 2 and 3. Histamine receptors are classified according to the present knowledge into three categories which are described, mainly for historical reasons, with the qualifications of Εl_- f H 2 - and H 3 -receptor. Each of these classes of receptors presumably has its own and biologically specific function, in as far as they are present and dependent on the location of such a receptor type in the organism involved. In circumstances where a failure of the normal physiological system has occurred a treatment with endogenous or exogenous compounds may be necessary which may stimulate (agonistic activity) or inhibit (antagonistic activity) the receptor system. From the above follows the great importance of compounds capable to agonize or to antagonize in a selective way the different classes of histamine receptors. It is important to be able to dispose of selective histamine receptor active compounds in order to discriminate between the different receptor types not only from a scientific (pharma-cological) point of view, but also on therapeutic respect notably the stimulation of the histamine H 2 -receptor offers wide perspectives for the treatment of congestive heart diseases, accompanied by heart failure, and certain allergic disorders so that there exists a large interest from within the pharmaceutical industry for the development and application of selective, histamine H 2 -receptor active, compounds. Impromidine (5) , described by G.J. Durant et al. in Nature 276, p.403-405 (1978) and Dimaprint (6), described by C.R. Ganellin in Pharmacology of Histamine Receptors, p.40-44 (1982), publishers Wright.PSG. , exhibit a moderately to fairly high affinity for the histamine H 2 -receptor. N-(ω-substituted alkyl)-N'-[imidazol-4-yl]alkyl)guanidines with formula 7, as described in the Dutch patent application 86 01585, and Arpromidine (8) and analogues, as described by A.Buschauer in J.Med.Chem. 32, p.1963-1970 (1989) on the contrary exhibit a high to very high affinity for the H 2 - receptor. Both Impromidine (5) , the most active guanidine derivatives of formula 7 and Arpromidine (8) all contain under physiolo¬ gical circumstances a protonated N-[3-(imidazol-4-yl)propyl]- guanidine fragment. This fragment, which has been described as SK&F 91486 (9) by M.E. Parsons et al. in Agents and Actions 5, p.464 (1975) has been considered in the literature as an element essential for the activity of this type of compounds on the H -receptor as described by A.Buschauer in J.Med.Chem. 32, p.1963-1970 (1989) . Further substitution at one of the free nitrogen atoms or the guanidine function of this basic element may be applied in order to increase the affinity for the H 2 -receptor and/or to introduce a possibly wanted additional biological activity such as: antagonism of the H i -receptor, as described by G.J.Sterk et al. in Eur.J.Med.Chem. 22, p.427-432 (1987) and the Dutch patent application 86 01585, calciumantagonism as illustrated by the guanidine derivative (10) described by V.Pfahlert et al. , in Arch.Pharm. 338, R49 (1988), or phosp- hodiesterase inhibition as described in the European patent application 0310737 and illustrated by the guanide derivative (11). Likewise in these compounds (10 and 11) , the imidazole moiety can be replaced by a (substituted)aminothiazole. Thus the invention also relates to a process for the prepara¬ tion of a ω-aminoalkylthiazole derivative in which one prepa¬ res a histamine H 2 -receptor active compound, whether or not in combination with an additionally wanted biological activi¬ ty / by preparing from a compound with formula 1 or its acid addition salt a compound with a substituted 4- or 5-(ω- thiazoly1-alky1)guanidine fragment. Examples of such compounds are the compounds with formulas 2 and 3 and their acid addition salts. Additional substitution at the other nitrogen atom may be applied in order to change the activity for the H 2 -receptor into an antagonistic activity. Although thus far a large number of (substituted) analogues of histamine, in which the imidazole term has been replaced by another heterocyclic ring system, has been described in the literature, for a review of which reference may be made to C.R. Ganellin in Pharmacology of Histamine Receptors, p.21-31 (1982), publishers Wright.PSG, none of the mentioned analogues displays an activity at the H 2 -receptor which is comparable to that of histamine. Only M.Impicciatore et al. report in Agents and Actions, 20, p.3-4 (1987) about 2-amino- 5-(2-aminoethyl)-thiazole, which according to these authors is able to stimulate through an indirect pathway the histam¬ ine H 2 -receptor (as determined on the fundus of the guinea pig). In II Farmaco Ed.Sci., 40 (6), p.483-498 (1986) T.Vita- li et al. describe this same 2-amino-5-(2-aminoethyl)thiazole reporting that this compoun exhibits an activity on the right atrium of the guinea pig of 0.3% relative to the activity of histamine whereas this activity is related to the inotropic effect. A new series of substituted ω-(thiazol-4 or 5-yl)alkyl derivatives has now been discovered which display a very selective and high histamine H 2 -receptor activity on the right atrium of the guinea pig, namely the above mentioned compounds with formulas 1-4 and their acid addition salts. All this is clearly illustrated by a characteristic represen- tative of the 4- or 5-(ω-aminoalkyl)thiazoles reported under formula 1, viz. the 2-amino-5-(2-aminoethyl)-4-methylthiazole (12) which is essentially a substituted sulphur analogue of the endogenous histamine (13) or which alternatively may be considered as a closed ring analogue of dimaprit (6) . Whereas endogenous histamine (13) is able to stimulate all previously mentioned types of histamine receptors, the 2- amino-5-(2-aminoethyl)-4-methylthiazole (12) can be displaced co petitatively by cimetidine, while the intrinsic activity (related to the chronotropic effect) is equal to that of histamine, thus rendering it to be a full agonist for the H 2 - receptor with an activity twice as high as that of histamine. The 2-amino-5-(3-aminopropyl)-4-methylthiazole (26b) is a full H 2 -receptor agonist with an activity 30 times as high as that of the corresponding 4(5)-3-aminopropyl)-imidazole. The 2-amino-5-(2-aminoethyl)-4-methylthiazole (12) shows how¬ ever contrary to histamine (13) , in the testing systems used not a single activity towards the H j , and H 3 -receptors. The essence of the invention now relates to the replacement of the N-[3-(imidazol-4-yl)propyl]guanidine fragment (9) from the previously mentioned different classes of H 2 -receptor active compounds with i.a. other combined Hi-receptor antago¬ nistic, calcium antagonistic, phosphodiesterase inhibitory activity etc, by the more H 2 -receptor specific and more active N-[3-(substituted thiazol-4 or 5-yl)propyl]guanidine fragments. The thiazole derivatives with formulas 2-4 thus obtained show a high to very high activity on the H 2 -recep¬ tor. The 4- or 5-(ω-aminoalkyl)thiazole derivatives mentioned in the introduction with formula 1 may be obtained using a pro¬ cess not previously described in the literature in high yields by ring closure of a 2-bromo-ω-phthalimidoalkanal (18) , a 3-bromo-ω-phthalimidoalkan-2-one (24) or a 1-bromo-ω- phthalimidoalkan-2-one (27) with thioformamide, an alkylthio¬ amide or thiourea in dimethylformamide under mild conditions, followed by hydrazinolysis or hydrolysis with diluted hydro¬ chloric acid of the resulting phthalimido derivatives (19, 25 or 28) as depicted in reaction schemes A and B. As will be evident from reaction scheme A one uses as star¬ ting materials for the preparation of the 2-bromo-ω-phthali- midoalkanals (18) ω-phthalimidoalkanols (16) which may be obtained using processes known from the literature. Conversi¬ on of these ω-phthalimidoalkanols (16) into the corresponding aldehydes (17) is being carried out according to a general method using oxalylchloride/dimethylsulphoxyde, followed by proton abstraction with a mild base such as triethylamine followed by hydrolysis with water as described by K.Omura et al. in Tetrahedron 34, p. 1651-1660 (1978). Subsequently the desired 2-bromo-ω-phthalimidoalkanals (18) are obtained in almost quantitative yield by selective α- bromination of the obtained ω-phthalimidoalkanals (17) with bromine in carbon tetrachloride. The preparation of the 3-bromo-ω-phthalimidoalkan-2-ones (24) as indicated in reaction scheme (B) takes place by selective bromination with bromine in carbon tetrachloride of the cor¬ responding ω-phthalimidoalkan-2-ones (23) which may be obtai- ned according to a process described in the Dutch patent application 8800998 in which the necessary 1-bromo-ω-phthali- midoalkan-2-ones (27) have been described as well. The neces- sary ω-haloketones (22) which are to be used for the prepara¬ tion of the 1- and 3-bromo-ω-phthalimidoalkan-2-ones (24 and 27) are either commercially available or may be obtained in good yield according to a process described in the literature such as for example the process described in the Dutch patent application 65 11581. The N-[ω-(thiazol-4 or 5-yl)alkyl]isourea or isothiourea derivatives with formula 2 are obtained by reaction of a 4- or 5-(ω-aminoalkyl)thiazole with formula 1, with a dialkyl-N- cyano-iminodithiocarbonate, a diphenyl-N-cyanocarbonimidate or a diphenyl-N-benzoylcarbonimidate respectively in a suitable solvent according to methods known from the litera¬ ture and as indicated in reaction scheme C. The corresponding N-[ω-(thiazol-4 or 5-yl)alkyl]guanidine derivatives are obtained by reacting a 4- or 5-(ω-aminoal- kyl)thiazole with formula 1 together with a S-alkylisothiou- ronium derivative. The N-[ω-(thiazol-4 or 5-yl)alkyl]isourea or isothiourea derivatives thus obtained (32) are condensed with a suitable a ine (33). The N-(ω-substituted alkyl)-N 1 - subtituted-N M -[ω-(thiazol-4 or 5-yl)alkyIguanidines with formula 3 (34) thus obtained are purified and subjected to a mild hydrolysis in diluted hydrochloric acid following which the resulting N-(ω-substituted alkyl)-N'-[ω-(thiazol-4 or 5-yl)alkyl]-guanides with formula 4 (35) can be obtained in good yield eventually after conversion to a suitable acid addition salt. Alternatively the desired N-(ω-substituted alkyl)-N'substitu- ted-N w -[ω-(thiazol-4 or 5-yl)alkyl]guanidines with formula 3 may be obtained by reacting a 4- or 5-(ω-aminoalkyl)thiazole with formula l together with the corresponding N-(ω-substitu- ted alkyl)isourea or isothiourea derivatives (36) according to methods known from the literature and as indicated in reaction scheme D or by condensation of a 4- or 5-(ω-aminoal- kyl)thiazole with formula l with a N-(ω-substituted alkyl)-s- alkylthiouronium derivative (41) as indicated in reaction scheme E. The invention also relates to a medicament or a scientific (pharmacological) adjuvant which contains as the active ingredient a compound according to one of the formulas 2-3 or an acid addition salt thereof. One may use the compounds or the medicaments according to the invention for the treatment of congestive heart diseases whether or not accompanied by hear failure or for the treatment of allergic disorders. The invention is illustrated by the following examples: All the chemicals and solvents used are commercial¬ ly available unless stated otherwise. Melting points were determined by a Mettler FP 5 device for the determination of melting points. H-NMR-spectra were determined with a Bruker WH-90 spectrophotometer and the chemical shifts -S (in ppm) with tetramethylsilane as reference. Mass spectra are determined on a Varian Mat CH- spectrometer or on a Mat 90 (Finnigan Mat, San Jose, U.S.A.) . Histamine H -activity was determined on the right-side atrium of the guinea pig as described by G.J. Sterk et al in Eur.J.Med. Chem. ,19. ' , p. 545-550 (1984) . Example I vϋ-phthalimido-l-alkanol s (16) General process: A mixture of 148 g (1 mole) of particulated phthalic anhydride (15) and 1 mole of a desired t -amino-1- alkanol is heated under nitrogen with stirring a circa 80°C. After starting the exothermal reaction with which the temperature is rising to circa 140° C, there is heated at 140° C for three hours.After cooling the reaction mixture until circa 80°C the viscous mass is poured out in. icewater with s irring. . Subsequently it is extracted with chloroform and the collected chloroform- phases are extracted with a 5%-aqueous sodiumhydrogen carbonate solution, thereafter it is washed three times with demineralized water. After drying on anhydrous sodium sulfate and fil¬ tration the chloroform phase is hjgh-vacuum concentrated. Thu-s there were obtained: a.4-phthal imido-1-butanol (16a) in 91% yield, from phthalic anhydride and 4-aminobutanol . 1 B*-NMR (CDC1 ) : 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-l-pentanol (16b) in 85% yield, 5 from phtalic anhydride and 5-amino pentanol. 1 H-NMR (CDC1 3 ) : 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. 10 Example II a. 4-Phthalimido-l-butanol (16b) 4-Phthalimido-l-butanol (16b) can, if desired, also be obtained in the following way: A mixture of 100 g (0.92 mole) of 4-chloro-l-butanol , 15 135.5 g (0.92 mole) phthalimid and 127 g (0.92 mole particulated anhydrous potassium carbonate in circa 500 ml dry dimethylformamide is refluxed under nitrogen for 12 hours. After cooling the reaction mixture the inorganic salts are filtered off 20 and the precipitate s rinsed with a. little cold methanol , subsequently the filtrate is vacuum concentrated. To the residue obtained circa 250 ml of ethyl- acetate is added and after standing over night at 5°C the resulting residue is removed by filtration. 25 The filtrate is vacuum concentrated and the residue is taken up in circa 200 ml chloroform. After extraction with a 5%-aqueous sodium hydrogen carbonate solution there is extracted a few .times in demineralized water. The chloroform phase is dried on anhydrous potassium car- 0 bonate, filtered and vacuum concentrated. Yield 95%. The so obtained 4-phthalimido-l-butanol is identical to the product obtained by the general process for the <• * -• • -phthalimido-1-alkanols as described in example I. After prolonged standing the viscous oil 5 crystallized. Melting point 47-49° C. Example III O -phthalimido-l-alkanals (17) The preparation of the -phthalimido-1-alkanals (17) 10 occurs analogous to the method as described by K.Omura et al in Tetrahedron, 34, pages 1651-1660 (1978) for the preparation of aldehydes from aliphatic or benzylic alcohols. General process: To a solution of 63.5 g (0.5 mole) oxalylchloride in circa 15 1000 ml dry dichlororaethane in* a nitrogen atmosphere with vigorous stirring at -50°C a solution of 83 g (1.06 mole) of dry dimethylsulfoxide in circa 200 ml of dry dichloromethane is dropwise added at such a rate that the temperature is maintained at -50°C. After the addition the 0 stirring is continued for 15 minutes, subsequently a solution of 0.40 mole of an appropriate UJ -phthalimido-1-alkanol (16) in circa 400 ml of dry dichloromethane is dropwise added at such a rate that the temperature is maintained at -50°C. After the addition the stirring is continued at -50°C for 25 30 minutes, subsequently 222 g (2.20 mole) of triethylamine is added thereto. Subsequently the cooling is removed and the reaction mixture is slowly brought with stirring at room temperature, thereafter circa 1250 ml of demineralized water is added. After stirring for 30 minutes at room temperature 30 the organic phase is removed* and extracted with demineralized water to neutral reaction. The organic phase is subsequently dried on anhydrous sodium sulfate, filtered and vacuum con¬ centrated. The viscous oil obtained is kept in nitrogen at¬ mosphere and is used without any further purification for the preparation of the corresponding 2-bromo-c phthalimido- alkanales (18) . * Nota bene: All the actions are carried out as much as possible in a nitrogen atmosphere to prevent oxidation of the aldehydes obtained by atmospherical oxygen. Thus there were obtained: a. 4-phthalimido-l-butanal (17a) in 80% yield, from 4-phthal- imidobutanol . " " " H-NMR (CDC1 ): 1.80-2.19 ppm., multiplet, 2H;. 2.56 ppm., triplet (J=7.4 Hz), 2H; 3.74 ppm, triplet (J=6.8 Hz, 2H; 7.52-7.93 ppm., multiplet, 4H; 9.74 ppm., singlet, 1H. b. 5-phthalimido-l-pentanal (17b) in 85% yield, from 5-phthalimidopentanol . 1 H-NMR (CDC1 ): 1.50-1.92 ppm., multiplet, 4H; 2.41-2.66 ppm., 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-Bromc- a-phthalimido-l-alkanals ( 18 ) General process: To a solution of 0.5 mole of an appropriate -- -phthalimido- 1-alkanol (17) in circa 500 ml of tetrachlorocarbon in a nitrogen atmosphere stirring vigorously 80 g (0.5 mole) of bromine is ca_utiously added at room temperature. After decolor¬ ation of the reaction mixture stirring is continued at room temperature for 2 hours. Subsequently circa 100 ml of chloroform and 500 ml of demineralized water are added, thereafter stirring takes place in a nitrogen atmosphere for 30 minutes. The water phase is removed and the organic phase is washed in a nitrogen atmosphere with demineralized water to neutral reaction. After drying on anhydrous sodium sulfate and filtration the organic phase is vacuum concentrated. The viscous oil obtained is used without any purification for the preparation of the corresponding 5- ) -phthalimidoalkyl- thiazoles ( 19 ) . Thus there were obtained: a. 2-Bromo-4-phthalimido-l-butanal (18a) in 78.5 % yield, from 4-phthalimido-l-butanal (17a). H-NMR (CDC1 3 : 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, J 2 = 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-l-pentanal (18b) in 68% yield, from 5-phthalimido-l-pentanal (17b) 1 H-NMR (CDC1 ) : 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),lH. Example V 5-( >-phthalimidoalkyl )thiazoles (19) General process: To a solution of 0.1 mole of an appropriate crude 2-bromo- phthalimido-1-alkanal (18) in circa 100 ml of dry dimethyl- formamide in a nitrogen atmosphere a solution of 0.1 mole thioureum, respectively thioformamide, respectively an alkyl¬ thioamide in circa 50 ml of dry dimethylformamide is added with stirring. After the light exothermal reaction heating takes place at 100°C for 3 hours. After cooling the reaction mixture is high vacuum concentrated. Subsequently a little ethanol is added to the residue, it is stirred for 30 minutes, thereafter the crystalline material is fil¬ tered off, washed with subsequently ethanol and diethylether, thereafter the precipitate is "cacuum dried.If necessary it is re- crystallized from an appropriate solvent. Thus there were obtained: a. 2-amino-5-(2-phthalimidoethyl ) thiazole hydrobromide (19a) in 63% yield, from 2-bromo-4-phthalimido-l-butanol (18a) and thiourea. The product was crystallized from an ethanol/methanol mixture. Melting point 221-225°C. " " " H-NMR (Do.-DMSO): 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., broad singlet, 2H. b. 2-amino-5-(3-phthalimidopropyl ) thiazole hydrobromide (19b) in 78.5% yield, from 2-bromo-5-phthalimido-l-pentanal (18b) and thiourea. 1 H-NMR (D D.-DMSO): 1.69-21.13 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 VI 6-bromo-2-hexanone (22a) 6-Bromo-2-hexanone (22a) is prepared according to a modified process as described in Dutch patent application 6511581 dated March 7,1966, cf. Chem. Abstr. 65, P20151d. A mixture of 552 g (4 mole) of particulated anhydrous potassium carbonate, 404 g (2 mole) of freshly distilled 1,3- dibromopropane , 260g (2 mole) of freshly distilled acetyl acetic ester and 700 ml of absolute ethanol is heated with vigorous stirring until circa 60°C. After the mild exothermal reaction beginning at circa 50°C, the reaction mixture is refluxed for circa 5 hours. After cooling the reaction mixture the inorganic salts are filtered off and the residue is rinsed with absolute ethanol. The combined filtrates are subsequently vacuum concentrated, thereafter to the residue circa 250 ml of demineralized water is added. Subsequently it is extracted with toluene. The collected toluene phases are combined, dried on anhydrous sodium sulfate, filtered and subsequently vacuum concentrated. Yield 73% on the basis of G.C./M.S. Subsequently 170.0 g (1.00 mole) of the crude 2-methyl-3-carbethoxy-5 ,6-dihydro- pyrane together with 140 ml of concentrated aqueous HBr- solution (48%) is refluxed with vigorous stirring for 3 hours, and a violent evolution αf carbondioxide gas takes place. After cooling the reaction mixture the formed 6-bromo-2-hexanone (22a) is extracted by means of chloroform, the collected chloroform phases are washed with demineralized water to neutral reaction, thereafter dried on anhydrous sodium sulfate, filtered and vacuum concentrated. Subsequently the residue is subjected to fractionated distillation. Yield 104 g (0.58 mole) which corresponds with 79.4%. Boiling point 102-106°C/18 mm Hg. Reference:(Chem.Abstr. , 65, P 20151d) . 94-98°C/l2 mm Hg. Mass spectrum M/Z (intensity in %) . 180(0.14): 178(0.11); 137(6.3) ; 99 (100) . " ""H-NMR (CDC1 ) : 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. Examole VII a. 4-phthalimido-2-butanone (23a) The 4-phthalimido-2-butanone (23a) was prepared according to a modified process by H.Irai et al . , Kogyo Kagaku Zasschi, 62, pages 82-85 (1959) cf. Chem.Abstr., 58, 5659 b (1963) and such as described in Dutch patent application 8800998, April 18,1988. Melting point 108.5-110°C (Reference: H.Irai et al . , 111-113°C). H-NMR (CDC1 ) : 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-phthal imido-2-pentanone ( 23b ) The 5-phthalimido-2-pentanone ( 23a) is prepared according to Dutch patent app lication 8800998 , April 18 , 1988. Yield 53% Melting point 72-74°C. " ""H-NMR (CDC1 ): 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. H=NMR (CDC1 3 ): 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- ^ -phthal imi do-2-alk nones ( 24 ) General process: To a solution of 0.5 mole of an appropriate c- -phthal- imido-2-alkanone (23) in circa 500 ml of tetrachlorocarbon is cautiously added, with vigorous stirring, 80 g (0.5 mole) bromine at room temperature. After decoloration of the reaction mixture the stirring is continued at room temperat¬ ure for circa 2 hours. Subsequently there is added circa 100 ml chloroform and 500 ml of demineralized water, there¬ after it is stirred for 30 minutes. The water phase is subsequently removed and the organic phase is washed with demineralized water until neutral reaction. The organic phase is subsequently dried on anhydrous sodium sulfate, filtered and vacuum concentrated. The residue (viscous oil) is used without any purification for the preparation of the 2-amino-4-methy-5-( Co-phthalimidoalkyl) thiazoles (25). Thus there were obtained: a. 3-Bromo-5-phthalimido-2-pentanone (24a) yield 95%, from 5-phthalimido-2-pentanone (23b). 1 H-NMR (CDC1 ): 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., multiplet, 4H. b. 3-Bromo-6-phthalimido-2-hexanone (24b) yield 93%,from 6-phthalimido-2-hexanone (23c). ■ " " H-NMR (CDClg): 1.74-2.22 ppm, multiplet, 4H; 2.36 ppm., singlet, 3H; 3.46-3.90 ppm., multiplet, 2H; 4.36 ppm., triplet, (J=7.2 Hz), 1H; 7.60-7.95 ppm., multiplet, 4H. Example IX 5- ( j -phthalimidoalkyl )-4-methy1thiazoles (25) General process: To a solution of 0.2 mole of a crude 3-bromo-OJ-phthal- imido-2-alkanone (24) in circa 100 ml of anhydrous dimethyl- formamide a solution of 0.2 mole of thiourea respectively thioformamide, respectively an alkylthioamide in circa 100 ml of dry dimethylformamide is added with stirring. After the exothermal reaction the temperature may rise to circa 100°C, there is heated at circa 100°C for circa 3 hours. After cooling the reaction mixture is high vacuum concentrat¬ ed, thereafter to the residue an ethylacetate/methanol mixture (1:1 v/v) is added. After stirring circa 30 minutes the precipifete obtained is filtered off, washed subsequently with ethylacetate and diethyl ether, thereafter the precipitate is vacuum dried. Thus were obtained: a. 2-Amino-5- _2-ph^ha1imi_άoethyl )-4-methylthiazole- hydrobomide (25a) yield 50%, from 3-bromo-5-phthalimido-2-pentanone (24a) and thioureum. H-NMR (D.-DMSO) : 1.98 ppm., singlet, 3H; 2.98 ppm., triplet o (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 hiazole hydrobromide (25b) Yield 51%, from 3-bromo-6-phthalimido-2-hexanone (24b) and thioureum. 1 H-NMR (D -DMS0): 1.61-2.04 ppm. , multiplet, 2H, 2.15 ppm. , o 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 (25c) yield 40%, from 3-bromo-5-phthalimido-2-pentanone (24a) and thioformamide. -23 - Melting point 207. -210.6°C. 1 H-NMR (D.-DMSO) : 1.99 ppm. , singlet, 3H; 2.96 ppm. , triplet o (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) yield 50%, from 3-bromo-5-phthalimido-2-pentanone (24a) and thioacetamide. " " " H-NMR (D ^ -DMSO) : 2.13 ppm. , singlet, 3H; 2.70 ppm. , singlet, b 3H; 3.15 ppm. , triplet (J=6.3 Hz) , 2H; 3.78 ppm. , triplet (J=6.3 Hz9, wH; 7.84 ppm. , singlet, 4H; 8.78 ppm. , broad singlet, 1H. Example X 1-bromo-U -phthalimido-2-alkanones ( 27) The l-bromo-<-0-phthalimido-2-alkanones (27) are prepared according to Dutch patent application 8800998, April 18,1988. Thus there were obtained: a. l-bromo-4-phthalimido-2-butanone (27a). Yield 60%.. Melting point 120-122°C (reference: R.G. Jones et al J.Amer.Chem.Soc. , 72, pages 4526-4529 (1950) 119-120°C). 1 H-NMR (CDC1 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. l-bromo-5-phthalimido-2-pentanone (27b ) . Yield 52%. Melting point 131-133.4°C (Reference: S.Elz and W.Schunack, Z.Natur. Forsch., 42b, p. 238-242 (1987) 122-125°C, J. Michalksky et al , Chem.Listy, 49, p. 1379-1384 (1955) cf. Chem.Abstr. , 50, 5681 d (1956) 139°C) . H-NMR (CDC1 ): 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-( ( U-phthalimidoalkyl ) thiazoles (28) The 4-( l.-phthalimidoalkyl ) thiazoles ( 2 ' 8 ) are prepared as described for the 5-( <^->-phthalimidoalkyl ) thiazoles (25) in example IX. Thus there were obtained: a^_2-amino-4-( 2-phthalimidoethy1 ) thiazole hydrobromide_(_28a) Yield 95%, from l-bromo-4-phthalimido-2-butanone (27a) and thioureum. " H-NMR (D 6 -DMS0): 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. , broad singlet, 2H. _ _ 2-amino-4-( 3-phthalimidopropyl ) thiazole hydrobromide (28b) Yield 80%, from l-bromo-5-phthalimido-2-pentanone (27b) and thioureum. H-NMR (Dg-DMSO): 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-(--*>-aminoalkyl )thiazoles (20, 26, 29) General process: A solution of 0.1 mole of an appropriate -J-phthalimido- alkyl hiazole hydrobromide (25) in circa 400 ml of anhydrous methanol is refluxed with 0.2 mole of an 80%-aqueous hydra- zine-hydrate solution for 5 hours. After cooling in ice the crystallized phthalhydrazine is filtered off and the clear filtrate is vacuum concentrated. Subsequently 105 ml of a 1 molar aqueous sodium hydroxide solution is added to the residue, thereafter there is high-vacuum concentrated at room temperature. The residue obtained is stirred with warm absolute ethanol, which is high-vacuum concentrated after filtration. After taking up the residue in absolute ethanol there is acidified with a concentrated aqueous 37%- hydrochloric acid solution until circa pH = 2, thereafter the mixture is high-vacuum concentrated at room temperature and residual water are azeotropically removed by using toluene. To the residue obtained acetone is subsequently added, thereafter the crystalline material is filtered off, rinsedwith acetone and diethylether , thereafter it is vacuum dried, If necessary there is recrystallized from an appropriate solvent. Thus were obtained: a. 2-amino-5-( 2-aminoethyl)thiazole dihydrochloride (20a) Yield 70%, from 2-amino-5-(2-phthalimidoethyl) hiazole hydrobromide (29a). Crystallized from methanol. Melting point 226-230°C. 1 H-NMR (D . .-DMS0): 2.88-3.14 ppm, broad singlet, 4H; 7.20 6 ppm., singlet, 1H; 8.29 ppm, broad 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 C_H g N S: 143.052) b. 2-amino-5-( 3-aminopropyl )thiazole dihydrochloride (20b) Yield 83%, from 2-amino-5-(3-phthalimidopropyl ) hiazole hydrobromide (19b). Crystallized from an ethanol/methanol mixture. " " " H-NMR (Do-DMS0): 1.68-2.10 ppm, multiplet, 2H; 2.79 ppm, broad 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 b_H 1„1,N 3_S: 157.067) c. _2-amino-5-(2-aminoethyl)-4-methylthiazole dihydrochloride (26a) Yield 82%, from 2-amino-5-( 2-phthalimidoethyl ) -4-methyl- thiazole hydrobromide (25a). " " " H-NMR* (D b.-DMS0) : 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 c bH 1 11 π N3„S: 157.067) d. 2-amino-5-(3-aminopropyl)-4-methylthiazole dihydro¬ chloride (26b) . Yield 90%, from 2-amino-5-(.3-phthalimido- propyl )-4-methylthiazole hydrobromide (25b). 1 H-NMR (D c -DMS0): 1.66-2.02 ppm., multiplet, 2H;- 2.16 ppm., 6 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 C 7 H 13 N 3 S: 171.083 ) . e. 2-amino-4-(2-aminoethyl)thiazole dihydrochloride (29a) Yield 64%, from 2-amino-4-(2-phthalimidoethyl ) thiazole hydrobromide (28a). " " " H-NMR (D c b-DMS0): 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_ DH Q yN.S: 143.052). f. 2-amino-4-( 3-aminopropyl )thiazole dihydrochloride (29b) Yield 70%, from 2-amino-4-(3-phthalimidopropyl )thiazole hydrobromide (28b). " " " H-NMR (D 6 -DMS0): 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., broad 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_H N S: 157.067) o li q. 5-( 2-aminoethyl )-4-methylthiazole dihydrochloride (26c) Yield 65%, from 5-(2-phthalimidoethyl )-4-methylthiazole (25c) by mild hydrolysis with hydrochloric acid as described by J.W. Black et al . in U.S.patent specification 3 736 331 dated May 29,1973. " " " H-NMR (D D.-DMS0): 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_H-._N_S: 142.056) b 10 2 h. 5-( 2-aminoethyl )-2.4-dimethylthiazole dihydrochloride (26d) Yield 98%, from 5-(2-phthalimidoethyl )-2 ,4- dimethylthiazole (25d). Melting point 159.5-163.3°C . " " " H-NMR (D 6 -DMS0): 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-( 2-aminoethyl )-4-methylthiazole dihydrochloride (26c) The 5-(2-( aminoethyl )-4-methylthiazoledihydro- chloride (26c) may, if desired, also obtained in the following manner: A solution of 25.0 g (o,175 mole) of 5-(2-hydroxyethyl )- 4-methylthiazole (Fluka A.G., Chem.Fabrik,CH-9470 Buchs ) in 150 ml of aqueous-48% hydrogen bromide solution is refluxed for 48 hours. After cooling the reaction mixture is vacuum concentrated and the residual water is removed azeotropically with toluene. Subsequently to the residue circa 50 ml of ethylacetate and 25 ml of absolute ethanol are added and stirred for 30 minutes at room temperature. The obtained precipitate is subsequently filtered off and vacuum dried. Yield 64% 5-( 2-bromomethyl )-4-methylthiazole hydrobromide. H-NMR (Db_-DMS0): 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 mole) of 5-(2-bromo- ethyl )-4-methylthiazole hydrobromide in circa 150 ml of absolute ethanol is saturated with ammonia*-: gas at 0°C, thereafter the mixture is heated in an autoclave at circa 100°C for 16 hours. After cooling the reaction mixture is vacuum concentrated and the residue is taken up in deminer¬ alized water, then 11.76 g (0.14 mole) of sodium- hydrogen carbonate is added thereto, subsequently there is stirred at room temperature for circa one hour. After filtering the filtrate is vacuum concentrated and the residual water is removed azeotropically by absolute ethanol. The residue is subsequently treated with warm methanol, the organic salts are filtered off and the filtrate is brought at pH = 1 by using a concentrated hydrochloric acid solution. After vacuum concentration the residue is subsequently crystallized from an ethanol/methanol mixture.. Yield 20%. Melting point 209-210°C. The H-NMR-spectrum is identical to the spectrum as obtained with the preparation of the 5-( 2-aminoethyl ) -4-methylthiazole- dihydrochloride (26c) as described in example Xllg. Example XIV a. N-[ 3-(2-amino-4-methy1thiazole-5-yl ) propyl ] -N ' -cyano-0- phenylisoureu (32a) T.o a solution of 4.88 g (0.02 mole) of 2-amino-5- ( 3-aminopropyl )-4-methylthiazole dihydrochloride (26b) in circa 50 ml of absolute ethanol 0.04 mole of a freshly prepared sodium ethoxide solution in circa 25 ml of absolute ethanol is added with stirring. After heating at cir¬ ca 50°C for 15 min. , the inorganic material is filtered off and the filtrate is vacuum concentrated. The residue is subsequently taken up in 50 ml of dry freshly distilled pyridine, then 5.76 g (0.02 mole) of diphenyl cyanocarbon- imidate Ola) is added thereto. After reflux for 2 hours, after cooling the reaction mixture is vacuum concentrated, thereafter the residue is washed a few times with dry diethylether . The crystalline material is subsequently vacuum dried. Yield 100%. H-NMR (CDC1 3 ) : 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 . N-[3-(2-aminothiazole-5-yl )propyl ]-N ' -cyano-S-methyliso- thioureum (32b) To a solution of 4.60 g (0.02 mole) of 2-amino-5- (3-aminopropyl )thiazole dihydrochloride (20b) in circa 50 ml of absolute ethanol 0.04 mole of a freshly prepared sodium ethoxide solution in circa 25 mol of absolute ethanol is added with stirring. After heating at circa 50°C for 15 minutes the inorganic material is filtered off and 2.92 g (0.02 mole) of bis [methylthio]cyanocarbodiimide (31b) is added thereto, subsequently there is refluxed for 12 hours. After cooling the reaction mixture is filtered and the filtrate is vacuum concentrated. Yield 95%. " " " H-NMR (CDC1 3 ): 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., broad singlet, 1H. c . N-[3-(2-amino-4-methylthiazole-5-yl )propyl]-N '-cyano-S- methylisothioureum (32c) . To a solution of 4.88 g (0.02 mole) of 2-amino-5- (3-aminopropyl )-4-methylthiazole dihydrochloride (26b) in circa 50 ml of absolute ethanol 0.04 mole of a freshly prepared sodium ethoxide solution in circa 25 ml of absolute ethanol is added with stirring. After heating at circa 50°C for 15 min . , the inorganic material is filtered off and the filtrate is vacuum concentrated. Subsequently the the residue is taken up in 100 ml of dry freshly distilled pyridine, thereto 2.92 g (0.02 mole) of bis[methylthio]- cyanocarbodiimide (31b) is added. After reflux for 2 hours, the reaction mixture is vacuum concentrated and the residual pyridine is removed by codistillation with toluene. The residue is subsequently recrystallized from ethanol. Yield: 85% melting point 172.0-172.4°C . 1 H-NMR (Dg-DMSO): 1.50-1.94 ppm., multiplet, 2H; 2.36-2.75 ppm. (under DMSO-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-[3-(2-amino-4-methy1thiazole-5-yl )propyl]guanidine dihydrobromide_ (32b ) To a solution of 4.88 g (0.02 mole) of 2-amino-5-(3-amino- propyl )-4-methylthiazoledihydrochloride (26b) in circa 50 ml of absolute ethanol 0.04 mole of a freshly prepared sodium ethoxide solution in circa 25 ml of absolute ethanol is added with stirring. After heating at circa 50°C for 15 min. , the inorganic material is filtered off and 3.70 g (0.02 mole) of S-ethylisothiouroniumbromide is added, then there is refluxed for 6 hours. After cooling the reaction mixture isfiltered off and aicidified with concentrated aqueous hydrogen bromide solution to circa pH = 1, subsequent- ly there is vacuum concentrated and the residue is.recrystall- ized from a mixture of isopropyl alcohol and methanol. Yield 85%. H-NMR (D ^ -DMSO): 1.43-1.88 ppm., multiplet, 2H; 2.08 ppm. , 6 singlet, 3H; 2.20-2.72 ppm. (partially under DMSO) , multiplet, 2H ; 2.83-3.29 ppm., multiplet, 2H; 7.32-7.88 ppm. , broad singlet, 3H; 8.64 ppm., singlet, 4H; 9.10 ppm., singlet, 2H. Example XVI a. N-cyano-N ' - ( 3.3-dipheny_lpropyl )-O-phenylisoureum (36a) A solution of 10.55 g (0.05 mole) of 3 ,3-diphenyl- propylamine (33a) and 11.90 g (0.05 mole) of diphenylcyano- carbonimidate (31a) in 100 ml dry dichloromethane is refluxed in nitrogen for 30 minutes. After cooling the react¬ ion mixture , it is vacuum concentrated, thereafter 100 ml of dry diethylether is added to the residue. Subsequently there is stirred in nitrogen at room temperature for 15 min- utes, thereafter the white crystalline material is filtered off, washed with dry diethyl ether and vacuum dried. Yield 87%, melting point 171-174°C. " " " H-NMR (D.-DMS0) : 2.14-2.60 ppm.,multiplet , 2H; 3.00-3.48 o ppm. , multiplet, 2H ; 3.90-4.16 ppm. , multiplet, 1H; 7.00-7.65 ppm. , multiplet, 15H; 8.73 ppm. , broad singlet, 1H. b. N-cyano-N '-( 3.3-diphenylpropyl )-S-methylisothioureum (36b) To a solution of 21.1 g (0.1 mole) of 3.3-diphenyl- propylamine (33a) in circa 100 " ml of dry diethylether a clear solution of 14.6 g (0.1 mole) of bis [methylthio] cyanocarbo- diimide (31b) in circa 100 ml of dry diethylether is added, then there is stirred at room temperature for circa 30 min. The precipitate obtained is subsequently filtered off and washed with dry diethyl ether, thereafter the crystalline material is vacuum dried. Yield 80% H=NMR (CDC1 ): 2.14-2.58 ppm., multiplet, 2H; 2.30 ppm., singlet, 3H; 3.16-3.50 ppm., multiplet, 2H; 3.95 ppm., triplet(J=8.1 Hz), 1H; 7.26 ppm., multiplet, 10H; 7.58 ppm., broad singlet, 1H. Example XVII a. N-benzoyl-N '-( 3, 3-diphenylpropyl )thioureum (38a). To a solution of 21.1 g (0.1 mole) of 3 , 3-diphenyl- propylamine in 400 ml of dry diethyl ether in nitrogen atmosphere slowly and vigorously stirring a solution of 16.3 g (0.1 mole) of freshly distilled benzoylisothiocyanate (37) in circa 50 ml of dry diethyl ether* is added, then it is stirred at room temperature for 1 hour. The precipitate obtained is filtered off, washed with dry diethylether and vacuum dried. Yield 74%, melting point 124-125°C. " " " H-NMR (CDC1 3 ): 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. (J 1 =8.6 Hz, J = 2.0.Ha), 2H; 11.95 ppm., broad singlet, 1H. b. N-( 3 ,3-diphenylpropyl ) thioureum (39a) To a solution of 26.2 g (0.07 mole) of N-benzoyl- ' - (3.3-diphenylpropyl )thioureum (38) in 500 ml of anhydrous methanol a saturated solution of 10.0 g (0.072 mole) of potassium carbonate in demineralized water is added, then it is refluxed with stirring for circa 6 hours. After cool¬ ing the formed precipitate is filtered off, washed with successively demineralized water and absolute methanol, then the precipitate is vacuum dried. Yield 95%, melting point 198-199°C. H-NMR (Db.-DMSO): 3.10-3.28 ppm. , multiplet, 2H; 3.94-4.58 ppm., broad multiplet, 2H; 4.22 ppm., singlet, 2H; 5.03 ppm., triplet (J=7.7 Hz) , 1H; 8.02-8.60 ppm., multiplet, 10H; 8.83 ppm., singlet, 1H. c. S-ethyl-N-(3 ,3-diphenylpropyl ) isothiouroniumbromide (40a) A solution of 13.5 g (0.05 mole) of N-3 ,3-diphenyl- propyl)thioureum (39a) in circa 250 ml of absolute ethanol and 25 ml of bromomethane is refluxed for 5 hours. After cooling the solution is filtered and the filtrate is partially vacuum concentrated. The crystalline material is filtered off, washed w ith dry diethyl ether and vacuum dried. Yield 63%, melting point 176-180°C. " " " H-NMR (Dg-DMSO): 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; 9.56 ppm., triplet J=4.5 Hz) , 1H. Example XVIII a. N-[2-( 2-amino-4-meth lthiazole-5- l ) ethyl ] -N ' - (3.3-diphenylpropyl ) guanidine dipicrate (35a) To a solution of 2.3 g (0.01 mole) of 2-amino-5- ( 2-aminoethyl ) -4-methylthiazole dihydrochloride (26a) in 50 ml of absolute ethanol a freshly prepared solution of 0.02 mole of sodium ethoxide in circa 25 ml of absolute ethanol is added. After stirring at circa 50°C for 15 min. it is cooled and the inorganic material is filtered off, 0 then 3.55 g (0.01 mole) of N-cyano- '-( 3 , 3-diphenylpropyl ) - 0-phenylisoureum (36a) is added thereto. Subsequently it is refluxed for 16 hours. After cooling and vacuum concentrat¬ ion the residue obtained is extracted a few times with dry diethylether. Subsequently circa 50 ml of heat ethylacetate 5 is added, stirred for 15 minutes, the insoluble material is filtered off and the filtrate is vacuum concentrated. The viscous oil obtained, comprising crude N-[ 2-( 2-amino-4- methylthiazole-5-yl ) ethyl ]-N' -cyano-N"-( 3, 3-diphenylpropyl )- guanidine (34a) is subsequently taken up without any purif- o ication in 100 ml of 2N aqueous hydrochloric acid, there¬ after there is refluxed for 3 hours. After cooling there is vacuum concentrated and the residue dissolved in absolute methanol. After filtration a solution of 0.02 mole of picric acid in circa 50 ml of methanol is added. After 5 stirring the precipitate obtained is filtered off andrecrystal- ized from a mixture of methanol and water. Yield 10%. 1 H-NMR (D -DMSO): 2.12-2.46 ppm, broad multiplet, 2H; 6 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 ppm., broad singlet, 2H; 9.06-9.74 ppm, broad singlet, 1H. b . N-[3-(2-amino-4-methylthiazole-5-yl )propyl]-N ' - (3 ,3-diphenylpropyl) guanidine dipicrate ( 35b ) The N-[3-(2-amino-4-methylthiazole-5-yl)propyl]- ' -(3 ,3-diphenylpropyl )guanidine (35b) was prepared in a manner analogous to that of the N-[2-( 2-amino-4-methyl- thiazole-5-yl ) ethyl ] -N '-( 3 , 3-diphenylpropy 1 ) guanidine (35a) , as described in example XVIIIa, from N-cyano-N '-( 3 , 3- diphenylpropy 1 ) -0-phenylisoureum (37a) and 2-amino-5-( 3- aminopropyl ) -4-methylthiazole dihydrochloride (26b) with the proviso that the reaction mixture was refluxed for 48 hours. Yield 45% " " " H-NMR (D -DMSO): 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; 7.04-7.60 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-[3-(2-aminothiazole-5-yl )propyl) ]-N'-(3,3-diphen l- propyl )guanidine dipicrate (35c) To a solution of 2.30 g (0.01 mole) of 2-amino-5- (3-aminopropyl )thiazole dihydrochloride (26b) in circa 50ml of absolute ethanol, a freshly prepared solution of 0.02 mole of sodium ethoxide in circa 25 ml of absolute ethanol is added. After stirring at 50°C for 15 min. there is cooled and the inorganic material is filtered off, thereafter to the filtrate 3.79 g (0.01 mole) of S-ethyl-N-(3 ,3-diphenyl- propyl) isothiouronimbromide (40a) is added. After refluxing for 48 hours the reaction mixture is decolorised with activated carbon, filtered and the filtrate is vacuum concentrated. The residue is taken up in circa 50 ml of methanol, then a solution of 0.02 mole of picric acid in 50 ml of methanol is added. After stirring for 2 hours the precipitate obtained is filtered off and recrystallized from a mixture of methanol and water. Yield 30% H-NMR (Db.-DMS0): 1.56-1.98 ppm., multiplet, 2H; 2.00-2.80 ppm., multiplet, 4H; 2.90-3.34 ppm., multiplet, 4H; 4.01 ppm., triplet (J=7.2 Hz) , 1H; 7.13 ppm., singlet, 1H; 7.31 ppm., broad singlet, 13H; 8.64 ppm., singlet, 4H; 9.12 ppm., broad singlet, 2H. Example XX a. N-[3-(2-aminothiazole-4-yl)propyl]-N'-(3,3-diphenylpropyl) guanidine dipicrate (35d) To a solution of 3.14 g (0.02 mole) of 2-amino-4- (3-aminopropyl) hiazole (free base of 2-amino-4-(3-amino- propyl )thiazole dihydrochloride (29b) in circa 100 ml of absolute ethanol 6.18 g (0.02 mole) of N-cyano-N'-(3 ,3- diphenylpropyl)-S-methylisothioureum (36b) is added, then there is refluxed for 96 hours. After cooling the reaction mixture is decolorised with activated carbon, filtered and vacuum concentrated. The residue is subsequently taken up in 100 ml of 2N aqueous hydrochloric acid solution and refluxed for 4 hours. After cooling there is vacuum concentrated, thereafter the residue is taken up in circa 100 ml of absolute ethanol and the inorganic material is filtered off Tothe filtrate subsequently a solution of 0.04 mole of picri c acid in circa 50 ml of ethanol is added. After stirring at room temperature for 3 hours, the precipitate obtained is filtered off and recrystallized from a mixture of methanol and water. Yield 30% D c DMS0. 6 Ή-NMR (Db.DMSO 1.54-1.95 ppm. , multiplet, 2H ; 2.09-2.74 ppm. , multiplet, 4H; 2.87-3.30 ppm. , multiplet, 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. N-[ 3-( 2-amino-4-meth lthiazole-5-y1 )propyl]-N'- ( 3, 3-diphenylpropyl)guanidine dipicrate ιn ( , 35b ) A solution of 3.05 g (0.01 mole) of N-[3-( 2-amino- 4.methylthiazole-5-yl)propyl]-N'-cyano-0-phenylisoureum (32a) and 4.22 g (0.02 mole) of 3 , 3-diphenylpropylamine (33a) in circa 100 ml of freshly distilled anhydrous pyridine is refluxed for 16 hours. After cooling the reaction mixture is vacuum concentrated. The residue is subsequently washed with successively demineralized water and diethyl ether, there¬ after the residue is taken up in circa 100 ml of hot ethyl- acetate.After decoloration with activated coal and filtration the filtrate is vacuum concentrated. The viscous oil obtained comprising N-[3-(2-amino-4-methylthiazole-5-yl )propyl]-N' - cyano-N"-(3 ,3-diphenylpropyl )guanidine (34b) is hydroly zed after column chromatography (Kieselgel 60-80, eluent methanol/NH„ ) by 2N aqueous hydrochloric acid solution and converted into the dipicrate as described for the N-[3-(2- aminothiazole-4-yl )propyl]-N'-(3,3-diphenylpropyl )guanidine dipicrate (35d) in example XXa. Yield 65% H-NMR (D 6-DMSO): identical to the spectrum as described for the N-[ 3-( 2-amino-4-methylthiazole-5-yl )propyl ]- ' -( 3 ,3- diphenylpropy1)guanidine dipricate (35b) in example XVIIIb. Example XXII a. N,N'-bis[3-(2-amino-4-methylthiazole-5-yl)propyl] guanidine dipicrate (35e) To a solution of 2.44 g (o.Ol mole) of 2-amino-5- (3-aminopropyl )-4-methylthiazole dihydrochloride (26b) in circa 50 ml of absolute ethanol a solution of 0.02 mole of freshly prepared sodium ethoxide in 25 ml of absolute ethanol is added. After stirring at 50°C for 15 minutes there is cooled and the inorganic material is filtered off, then the filtrate is vacuum concentrated. Subsequently the residue is taken up in circa 100 ml of freshly distilled anhydrous pyridine, thereto 2.69 g (0.01 mole) of N-[3,2- amino-4-methy1thiazole-5-yl)propyl ]-N ' -cyano-S-methy1isothio¬ ureum (32c) is added, thereafter the mixture is refluxed for 12 hours. After cooling the reaction mixture is processed as described for the N-[3-( 2-amino-4-methylthiazole-5-yl )- propyl]-N '-(3 ,3-diphenylpropyl )-guanidine dipicrate (35b) as described in example XXIa. Yield 50% 1 H-NMR (D c -DMS0): 1.43-1.88 ppm. , multiplet, 4H ; 2.08 ppm. , singlet, 6H; 2.20-2.72 ppm., (partially under DMSO) , multiplet, 4H; 2.83-3.29 ppm. , multiplet, 4H ; 7.32-7.88 ppm., broad singlet, 3H; 8.64 ppm. , singlet, 6H; 9.10 ppm. , singlet, 4H. Example XXIII N-[3-(2-amino-4-methylthiazole-5-yl )propyl ]-N ' -cyano-N"- methylguanidine (34c ) To a solution of 1.34 g (0.005 mole) of N-[ 3-( 2-amino-4- methylthiazole-5-yl )propyl ]-N • -cyano-3-methylisothioureum (32c) in circa 25 ml of absolute ethanol 5 g of methylamine in 50 ml of absolute ethanol is added, thereafter with stirring for circa 5 hours there is refluxed. After cooling the reaction mixture is vacuum concentrated, thereafter the residue is crystallized from absolute ethanol. Yield 92%. Melting point 167.8-172°C (decomposition) ■ " " HsNMR (D_-DMS0): 1.49-1.82 ppm., multiplet, 2H; 1.97 ppm., b singlet, 3H; 2.32-2.50 ppm. , multiplet, 2H; partially under DMSO) ; 2.67 ppm. , doublet (J= 5.0 Hz) , 3H; 2.95-3.28 ppm., multiplet, 2H; 6.60 ppm., broad singlet, 2H; 6.84- 7.10 ppm. , multiplet, 2H. Example XXIV N-[3-(2-amino-4-methylthiazole-5-yl )propyl ]- ' -cyano-N"- [3-(4-morpholino )propyl lguanidine (34d) To a solution of 1.34 g (0.005 mole) of N-[3-(2-amino-4- methylthi zole-5-yl )propyl]-N' -cyano-5-methyl isothioureum (32c) in circa 50 ml of pyridine 1.44 g (0.01 mole) of 3-(4-morpholino)propylamine is added, then with stirring in a nitrogen atmosphere for 48 hours there is refluxed. After cooling the reaction mixture is vacuum concentrated, there¬ after the residue is extracted a few times with diethyl¬ ether. Subsequently it is recrystallized from a mixture of absolute ethanol and methanol. Yield 48%. Melting point 149.0-151.2°C . H-NMR (D ^ -DMS0) ; 1.70-1.90 ppm. , multiplet ,4H; 2.01 ppm., b singlet, 3H; 2.11-2.70 ppm., multiplet, 8H; 3.00-3.36 ppm. , multiplet, 4H; 3.54-3.78 ppm. , multiplet, 4H; 6.65 ppm., singlet, 2H; 7.12-7.46 ppm, multiplet, 2H. Example _XXV N-[-3-( 2-amino-4-methylthiazole-5-y1 )propyl ]-N ' -cyano-N"- (3-phenylbutyl )guanidine ( 34e) To a solution of 1.34 g (0.005 mole) N-[3-( 2-amino- 4-methylthiazole-5-yl)propyl]-N'-cyano-S-methylisothioureum (32c) in circa 50 ml of pyridine 1.499 (0.01 mole) of 4-phenylbutylamine is added, thereafter with stirring in a nitrogen atmosphere for 48 hours there is refluxed. After cooling the reaction mixture is vacuum concentrated, there¬ after the residue is extracted a few times with diethyl ether. Subsequently it is recrystallized from absolute ethanol . Yield 51%. Melting point 159.3-161.9°C . H-NMR (D c -DMS0): 1.30-1.85 ppm. , multiplet, 6H; 1.98 ppm., b singlet, 3H; 2.32-2.75 ppm. , multiplet, 4H (partially under DMSO) : 2.96-3.38 ppm, multiplet, 4H; 6.62 ppm. , singlet, 2H; 6.97-7.18 ppm., multiplet, 2H; 7.26 ppm., singlet, 5H. Example XXVI N-[3-( 2-amino-4-methylthiazole-5-yl )propyl]-N'-cyano-N"- (3, 3-diphenylpropyl)guanidine (34f) To a solution of 1.34 g (0.005 mole) N-[3-(2-amino- 4-methylthiazole-5-yl) ropyl ]-N' -cyano-S-methylisothioureum (32c) in circa 50 ml of pyridine 2.11 g (0.01 mole) of 3 , 3-diphenylpropylamine is added, then with stirring in a nitrogen atmosphere for 48 hours there is refluxed. After cooling the reaction mixture is vacuum concentrated, there¬ after the residue is extracted a few times with diethyl- ether. Subsequently it is recrystallize.d from absolute ethanol . Yield 60% Melting point 164.7-168.8°C . " " " H-NMR (D_-DMS0): 1.44-1.82 ppm. , multiplet, 2H; 1.92 ppm. , b singlet, 3H; 2.14-2.50 ppm., multiplet, 2H (partially under DMSO); 2.86-3.24 ppm., multiplet, 4H; 3.24-3.60 ppm. , multiplet, 2H; 3.98 ppm., triplet (J=8.0 Hz), 1H; 6.58 ppm., broad singlet, 2H; 6.86-7.25 ppm., multiplet, 12H. Example XXVII N-[3-(2-amino-4-methylthiazole-5-yl ) propyl ] -N '-[ 3-( 3 ,4- dichlorophenyl)-3-( 2-pyridyl ) propyl] guanidine tripicrate(35f) A solution of 1.34 g (0.005 mole) of N-[3-(2-amino- 4-methy1thiazole-5-yl )propyl]-N ' -cyano-S-methylisothioureum (32c) and 1.41 g (0.005 mole) of 2-[3-amino-l-(3 , 4-dichloro- phenyl )propyl ]pyridine* in circa 50 ml of pyridine is refluxed with stirring in a nitrogen atmosphere for 72 hours. After cooling the reaction mixture is vacuum concentrated and the residue is washed a few times with diethyl ether. Subsequently 25 ml of 6M hydrochloric acid solution is added thereto and there is refluxed for 6 hours. After cooling the reaction mixture is vacuum concentrated and the residue is taken up in circa 25 ml of methanol, thereto 4.5 g of pitric acid in circa 50 ml of hot methanol is added. Subsequently circa 5 ml of demineralized water is added and the precipitate obtained is filtered off, then it is recrystallized from an ethanol/acetone mixture. Yield 53%. " " " H-NMR (D c b-DMS0): 1.59-1.83 ppm., multiplet, 2H; 2.10 ppm., singlet, 3H; 2.30-2.71 ppm., multiplet, 4H; 3.00-3.39 ppm., multiplet, 4H ; 4.42 ppm., triplet (J=6.7 Hz), 1H; 7.20-8.97 ppm., multiplet, 9H; 8.10-8.31 ppm., multiplet, 1H; 8.59 ppm., singlet, 6H; 8.65-8.80 ppm., multiplet, 1H; 9.15 ppm., singlet, 2H. Example XXVIII N-[ 3-( 2-amino-4-methylthiazqle-5-yl )propyl]-N '-(3 -phenyl propyl ) guanidine dipicrate (35g) A solution of 1.34 g (0.005 mole) of N-[3-( 2-amino- 4-me thy 1 thiazole- 5-yl ) propyl ]-N ! -cyano-S-methylisothioureum (32c) and 1.35 g (0.01 mole) of 3-phenylpropylamino in circa * 2-[3-amino-l-( 3, 4-dichlorophenyl) propyl] pyridine was obtained in a modif- ied process as described by A.Buschauer et al. Archiv.der Pharm. ,322(3) , 165-171 (1989) 50 ml of pyridine with stirring in a nitrogen atmosphere for 72 hours there is refluxed. After cooling the reaction mixture is vacuum concentrated and the residue is washed a few times with diethylether. Subsequently 25 ml of 6M hydro- chloric acid solution is added and there is refluxed for 6 hours. After cooling the reaction mixture is vacuum con¬ centrated and the residue is taken up in circa 25 ml of methanol, then 3.05 g of picric acid in circa 50 ml of methanol is added thereto. Subsequently circa 5 ml of demineralized water is added thereto and the precipitate ob¬ tained is filtered off,then recrystallized from a methanol/water mixture . Yield 62%. " " " H-NMR 1.53-2.20 ppm., multiplet, 4H; 2.07 ppm., singlet, 3H; 2.40-2.78 ppm., multiplet, 4H (partially under DMSO); 3.00-3.76 ppm., multiplet, 4H; 7.00-7.26 ppm., multiplet, 8H; 8.62 ppm., singlet, 4H; 9.14 ppm. , singlet, 2H. Example XXIX N-[3-(2-amino-4-methylthiazole-5-yl)propyl ]-N'-( 1-imidazolyl- propyl )guanidine dipicrate (35h) A solution of 1.34 g (0.005 mole) of N-[3-( 2-amino-4-methyl- thiazole-5-yl )propyl]-N' -cyano-S-methylisothioureum (32c) and 1.25 g (0.01 mole) of N-(3-aminopropyl ) imidazole in circa 50 ml of pyridine is refluxed with stirring in a nitrogen atmosphere for 72 hours. After cooling the reaction mixture is vacuum concentrated and the residue is washed a few times with cold methanol. Subsequently 25 ml of 6M hydro- chloric acid solution is added thereto and there is refluxed for 6 hours. After cooling the reaction mixture is vacuum concentrated and the residue is taken up in circa 25 ml of methanol, thereto 3.05 g of picric acid in circa 50 ml of methanol is added. Subsequently circa 5 ml of demineralized water is added thereto and the precipitate obtained is filtered off, then it is recrystallized from a methanol/water mixture . Yield 38%. " " " H-NMR ; 1.60-1.90 ppm., multiplet, 2H; 2.06 ppm. , singlet, 3H; 2.06-2.34 ppm. , multiplet, 2H; 2.54-2.98 ppm. , multiplet, 4H ; 3.14-3.60 ppm., multiplet, 2H; 4.28 ppm. , triplet (J=7.2 Hz) , 2H; 7.22-7.92 ppm., multiplet, 5H ; 8.59 ppm., singlet, 4H; 9.10 ppm., singlet, 2H. Tαble I H2- activities on the guinea-pig right atrium nr. Compound pD2(-0,1 ) hist mine 51

Claims: CLAIMS: 1. A substituted ω-aminoalkylthiazole, characterized in that it is a. a N-[ω-(thiazol-4 or 5-yl)alkyl]isourea, isothiourea or a guanidine derivative with formula 2 , wherein X represents a sulphur atom and Y represents a nitrogen atom or alternative¬ ly X represents a nitrogen atom and Y represents a sulphur atom, n is 1-6, R-L represents a hydrogen atom or a straight or branched alkyl group with 1-4 carbon atoms and R 2 represents a hydrogen atom, a straight or branched alkyl group with 1-4 carbon atoms or an amino group, Z represents a sulphur atom, an oxygen atom or a NH-group respectively, R 3 represents a hydrogen atom, a phenyl or an alkyl group with 1-4 carbon atoms respectively and R 4 represents a hydrogen atom, a cyano or a benzoyl group respectively; b. a N-(ω-substituted alkyl)-N*-substituted-N M -[ω-(thiazol-4 or 5-yl)alkyl]guanidine with formula 3, wherein X represent a sulphur atom and Y represents a nitrogen atom or alternati vely X represents a nitrogen atom and Y represents a sulphu atom, n is 1-6, R represents a hydrogen atom or a straigh or branched alkyl group with 1-4 carbon atoms and R 2 repre sents a hydrogen atom, a straight or branched alkyl grou with 1-4 carbon atoms or an amino group, R 4 represents hydro gen, a cyano or a benzoyl group respectively, is 1,2 or 3, A represents a sulphur or an oxygen atom, a -CH 2 - or a -CH= group respectively and Q represents a R-substituted diphenyl- methyl group or a R-substituted (10,11-dihydro) optionally aza 5H-dibenzo-[a,d]-cyclohepten-5-yl group or Q represents a nitrogen atom substituted with Q_ and Q 2 , wherein Q_ and Q 2 represent whether or not symmetrical R-substituted (ω-)- phenyl(alkyl) groups, or Q represents a R-substituted (ω- )phenyl(alkyl) group or Q represents a whether or not symme- trical mono-or disubstituted methylidene fragment, wherein R 1 represents a R-substituted (10,11-dihydro) optionally aza 5H- dibenzo-[a,d]-cyclohepten-5-yl group or R' represents two whether or not symmetrically with R substituted phenyl groups, wherein R represents hydrogen, alkyl, alkoxy, amino, mono- or dialkylamino, guanidino, nitro, carboxy, carbalkoxy, halogen (fluoro, chloro, bromo, iodo) , mono-, di- and triha- logenmethyl or - ethoxy (halogen = fluoro, chloro, bromo) etc. , while in addition the R-substituted phenyl rings may be replaced by a (heterocyclic) (aromatic) ring whether or not R-substituted or by a combination of a (condensed) (aromatic) (heterocyclic) R-substituted ring with one or more (conden¬ sed) (aromatic) (heterocyclic) rings whether or not symmetri¬ cally R-substituted. 2. A process for the preparation of an ω-aminoalkylthiazole, characterized in that one prepares a 4- or 5-(ω-aminoalkyl)- thiazole derivative with formula 1 in which R- j^ and R 2 have the same meaning as in claim by ring closure of a 2-bromo-ω- phthalimidoalkanal (18) , a 3-bromo-ω-phthalimidoalkan-2-one (24) or a l-bromo-ω-phthal-imidoalkan-2-one (27) with thioformamide, an alkylthioamide or thiourea in dimethylformamide under mild conditions, followed by hydrazinolysis or hydrolysis with diluted hydrochloric acid of the resulting phthalimido derivatives (19, 25 or 28). 3. A process for the preparation of a histamine H 2 -receptor active compound whether or not in combination with additionally desired biological activity characterized by preparing from a corresponding compound according to formula 1 or 2 or an acid addition salt thereof a compound with a substituted 4- or 5-(ω-thiazolylalkyl)guanidine fragment. 4. Medicament, or scientific (pharmacological) adjuvant characterized in that it contains as the active ingredient compound according to one of the formulas 2-3 or a compoun obtained according to claim 3 or an acid addition sal thereof. 5. Use of a compound or medicament according to one of th previous claims for the treatment of congestive hear diseases whether or not accompanied by heart failure or fo the treatment of allergic disorders. 6. A process for the preparation of 2-bromo-ω-phthalimido alkanals characterized by selective α-bromination of th corresponding ω-phthalimidoalkanals with bromine in carbo tetrachloride. 7. 2-Bromo-ω-phthalimido-l-alkanals.

Inventors: ERIKS JOHN CHARLES, STERK GEERT JAN, TIMMERMAN HENDRIK, VAN DER GOOT HENDERIKUS, ERIKS, JOHN, CHARLES, STERK, GEERT, JAN, TIMMERMAN, HENDRIK, VAN DER GOOT, HENDERIKUS
Applicants: CEDONA PHARM BV, CEDONA PHARMACEUTICALS B.V.
Application year: 1991
Main classification: C07D277
IPC codes: A61K31, A61K39, A61P9, A61P37, A61P43, C07D209, C07D277, C07D417