IE910172A1 - New thiazole derivatives - Google Patents

Abstract

New thiazole derivatives which are a substituted 4- or 5-( omega -aminoalkyl)thiazole with formula (1), wherein X represents a nitrogen atom and Y represents a sulphur atom or alternatively X represents a sulphur atom and Y represents a nitrogen atom, n is 1-6, R1 represents a straight or branched alkyl group containing 1-4 carbon atoms and R2 represents an amino group, a process for the preparation of said compounds by ring closure of a 3-bromo- omega -phthalimidoalkan-2-one with thiourea under mild conditions, followed by hydrazinolysis or hydrolysis with diluted hydrochloric acid of the resulting phthalimido derivatives and medicaments containing said derivates with formula (1) for the treatment of congestive heart diseases or for the treatment of allergic disorders.

Description

The invention relates to new thiazole derivatives which are: a. a N-[«-(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 alternatively X represents a nitrogen atom and Y represents a sulphur atom, n is 1-6, Rx 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, z represents a sulphur atom, an oxygen atom or a NH-group respectively, R3 represents a hydrogen atom, a phenyl or an alkyl group with 1-4 carbon atoms respectively and R4 represents a hydrogen atom, a cyano or a benzoyl group respectively/ b. a N-(«-substituted alkyl)-N’~substituted-N-[«-(thiazol-4 or 5-yl)alkyl]guanidine with formula 3, wherein X represents a sulphur atom and Y represents a nitrogen atom or alternatively X represents a nitrogen atom and Y represents a sulphur atom, n is 1-6, Rx represents a hydrogen atom or a straight or branched alkyl group with 1-4 carbon atoms and R2 repre30 sents a hydrogen atom, a straight or branched alkyl group with 1-4 carbon atoms or an amino group, R4 represents hydrogen, a cyano or a benzoyl group respectively, m is 1,2 or 3, A represents a sulphur or an oxygen atom, a -ch2- or a -CH- group respectively and Q represents a R-substituted 5 diphenylmethyl group or a R-substituted (io,n~dihydro) optionally aza 5H-dibenzo-[a,d]-cyolohepten-5-yl group or Q represents a nitrogen atom substituted with Qj and Q2, wherein Qx and q2 represent whether, or not symmetrical R-substituted («-)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’ 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 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-substi20 tuted 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 (condensed) (aromatic) (heterocyclic) rings whether or not symmetrically R-substituted.

Possible present R-substitutad (condensed) (heterocyclic) (aromatic) rings are for example: 2-, 3-, 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, 2-, 3-, 4-(dihydro]pyridyl, 4- or 5-imidazolyl, 2-, 4- or 5-thia2olyl, 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 formulae 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 H2and H3-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 IE 91179 -3organism involved.

In circumstances where a failure cf the normal physiological 5 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 H2-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 H2-receptor aotive, 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 H2-receptor.

N-(«-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 H2receptor.

Both Impromidine (5), the most active guanidine derivatives of formula 7 and Arpromidine (8) all contain under physiological 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 -4IE 91172 been considered in the literature as an element essential for the activity of this type of compounds on the H2-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 H2-receptor and/or to introduce a possibly wanted additional biological activity such as: antagonism of the Ηχ-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 st al., in Arch.Pharm. 338, R49 (1988), or phosphodiesterase inhibition as described in the European patent application 0310737 and illustrated by the guanide derivative (11).

Likewise in these compounds (io and ll), the imidazole moiety can be replaced by a (substituted)aminothiazole.

Thus the invention also relates to a process for the preparation of a ω-aminoalkylthiazole derivative in which one prepares a histamine H2-receptor active compound, whether or not in combination with an additionally wanted biological activity, by preparing from a compound with formula l or its acid addition salt a compound with a substituted 4- or 5-(tothiazolyl-alkyl)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 H2-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 H2-receptor which is -5IE 91172 comparable to that of histamine. Only M.Impicciatore et al. report in Agents and Actions, 20, p.3-4 (1987) about 2-amino5 5-(2-aminoethyl)-thiazole, which according to these authors is able to stimulate through an indirect pathway the histamine H2-receptor (as determined on the fundus of the guinea pig). Zn Zl Farmaco Ed.Sci., 40 (6), p.483-498 (1988) T.Vitali et al. describe this same 2-amino-5-(2-aminoethyl)thiazole io reporting that this compound 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 &>-(thiazol-4 or 5-yl) alkyl 15 derivatives has now been discovered which display a very selective and high histamine H2-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 represen20 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 2amino-5-(2-aminoethyl)-4-methylthiazole (12) can be displaced competitatively 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 H2receptor 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 as high as that of the corresponding 4(5)-3-aminopropyl)-imidazole.

The 2-amino-5-(2-aminoethyl)-4-methylthiazole (12) shows however contrary to histamine (13), in the testing systems used not a single activity towards the Ηχ and H3-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 H2-receptor IE 91172 active compounds with i.a. other combined H^receptor antagonistic, calcium antagonistic, phosphodiesterase inhibitory activity etc, by the more H2-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 H2-receptor.

The 4- or 5-(ω-aminoalkyl)thiazole derivatives mentioned in the introduction with formula l may be obtained using a process not previously described in the literature in high yields by ring closure of a 2-bromo-w-phthalimidoalkanal (18), a 3-bromo-«-phthalimidoalkan-2-one (24) or a l-bromo-ω15 phthalimidoalkan-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) as depicted in reaction schemes A and B.

As will be evident from reaction scheme A one uses as starting materials for the preparation of the 2-bromo-o-phthalimidoalkanals (18) ω-phthalimidoalkanols (16) which may be obtained using processes known from the literature. Conversion 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-«-phthalimidoalkanals (18) are obtained in almost quantitative yield by selective abromination of the obtained ω-phthalimidoalkanals (17) with bromine in carbon tetrachloride.

The preparation of the 3-bromo-o-phthalimidoalkan-2-ones (24) as indicated in reaction scheme (B) takes place by selective bromination with bromine in carbon tetrachloride of the corresponding e-phthalimidoalkan-2-ones (23) which may be obtai40 ned according to a process described in the Dutch patent IE 91172 application 8800998 in which the necessary l-bromd-e-phth&limidoalkan-2-ones (27) have been described as well. The neoes5 sary ω-haloketones (22) which are to be used for the preparation of the 1- and 3-bromo-»-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-[ The corresponding N-(e-(thiazol-4 or 5-yl)alkyl]guanidine derivatives are obtained by reacting a 4- or 5-(,,-[0-(thiazol-4 or 5-yl) alky lguanidines with formula 3 (34) thus obtained are purified and subjected to a mild hydrolysis in diluted hydrochloric acid following which the resulting N-(«-substituted alkyl)-N’-[w-(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)-Ν'substituted-N-[e-(thiazol-4 or 5-yl)alkyl]guanidines with formula 3 may be obtained by reacting a 4- or 5-(ω-aminoalkyl)thiazole with formula 1 together with the corresponding N-(tt-Bubstituted 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-(o-aminoalkyl)thiazole with formula l with a N-(ω-substituted alkyl)-s40 alkylthiouronium derivative (41) as indicated in reaction ® 91172 8scheme ε.

The invention also relates to a medicament or a scientific 5 (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 th£ invention for the treatment of congestive heart diseases whether or not accompanied by io hear failure or for the treatment of allergic disorders.

IE 91172 The invention is illustrated by the following examples: All the chemicals and solvents used are commercially available unless stated otherwise.

Melting points were determined by a Mettler FP 5 5 device for the determination of melting points.

^H-NMR-spectra were determined with a Bruker WH-90 spectrophotometer and the chemical shifts (in ppm) with tetramethylsilane as reference.

Mass spectra are determined on a Varian Mat CHg 10 spectrometer or on a Mat 90 (Finnigan Mat, San Jos6, (J.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-.IJ,, p. 545-550 (1984).

Example I d?-phthal imido-l-alkanol s__(16) General process: A mixture of 148 g (I mole) of particulated phthalic anhydride (15) and 1 mole of a desired w-amino-lalkanol is heated under nitrogen with 3tirring 20 at 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*0 . the viscous mass is poured out in. icewater with stirring,. Subsequently it is extracted with chloroform and the collected chloroformphases are extracted with a 5%-aqueous sodium hydrogen carbonate solution, thereafter it is washed three times with demineralized water. After drying on anhydrous sodium sulfate and filtration the chloroform phase is high-vacuum concentrated.

Thu-s there were obtained: a .4-phthalimido-l-butanol (16 a) in 91% yield, from phthalic anhydride and 4-aminobutanol. ^ft-NMR ( CDCl j ) : 1.38-1.90 ppm .,multiplet, 4H; 2.53 ppm, singlet, IH; 3.51-3.83 ppm, multiplet, 4H; 7.587.94 ppm, multiplet, 4H. b. 5-phthalimido-l-pentanol (16b) in 85% yield, from phtalic anhydride and 5-amino pentanol.

XH-NMR (CDClj): 1.23-1.90-ppm., multiplet, 6H; 2.36 ppm., singlet, IH; 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-1-butanol (lSb^ 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, 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 and the precipitate a rinsed with a.little cold methanol, subsequently the filtrate is vacuum concentrated.

To the residue obtained circa 250 ml of ethylacetate is added and after standing over night at 5®C the resulting residue is removed by filtration.

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 car30 bonate, filtered and. vacuum,concentrated.

IE 91172 - 11 Yield 95%. The so obtained 4-phthalimido-l-butanol is identical to the product obtained by the general process for the -phthalimido-l-alkanols as described in example I. After prolonged standing the viscous oil crystallized.

Melting point 47-49® C.

Example III ^-phthalimido-l-alkanals(17) The preparation of the >*>-phthalimido-l-alkanals (17) 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 1000 ml dry dichloromethane in. a nitrogen atmosphere with vigorous stirring at -50°Q 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 stirring is continued for 15 minutes, subsequently a solution of 0.40 mole of an appropriate CO -phthalimido-l-alkanol (16) in circa 400 ml of dry dichloromethane is dropwise added at such a rata that the temperature is maintained at -50°C. After the addition the stirring is continued at -50°C for 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 the organic phase is removed* and extracted with demineralized water to neutral reaction. The organic phase is subsequently dried on anhydroue sodium sulfate, filtered and vacuum concentrated. The viscous oil obtained is kept in nitrogen atmosphere and is used without any further purification for the preparation of the corresponding 2-bromo-wphthalimido5 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-phthalimidobutanol.

LH-NMR (CDClj): 1.80-2.19 ppm., multiplet, 2H;. 2.56 ppm., triplet (J=7.4 Hz), 2Hj 3.74 ppm, triplet (J=6.8 Hz, 2H; 7.52-7.93 ppm., multiplet, 4H; 9.74 ppm., singlet, IH. b. 5-phthallmido-l-pentanal (17b) in 85% yield, from -phthalimidopentanol.

^H-NMR (CDClj): 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), IH.

Example IV 2-Bromo-L4-phthallmido-l-alkanals__(18) General process: To a solution of 0.5 mole of an appropriate -phthalimico1-alkanol (17) in circa 500 ml of tetrachlorocarbon in a nitrogen atmosphere stirring vigorously 80 g (0.5 mole) of bromine is cautiously added at room temperature. After decoloration of the reaction mixture stirring is continued at room temperature for 2 hours. Subsequently circa 100 ml of > Γ·> 'J'.·’. ·' V»?~ 13chloroform 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 oh 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-<-U -phthalimidoalkylthiazoles (19 ) .

Thus there were obtained: a. 2-Bromo-4-phthalimido-l-butanal (18a) in 78.5 % yield, from 4-phthalimido-l-butanal (17a). 1H-NMR (CDC13: 2.00-2.75 ppm. , .multiplet, 2H; 3.87 ppm., triplet (Js6.8 Hz), 2H; 4.40 ppm, double triplet (.^ = 7.2 Hz, j^= 1.8 Hz), 1H; 7.59-7.96 ppm., multiplet, 4H; 9.45 ppm., doublet (J-1.8 Hz), 1H, b. 2-bromo-5-phthalimldo-l-pentanal__(18b) in 68% yield, from 5-phthalimido-l-pentanal (17b) ^H-NMR (CDClj): 1.76-2.10 ppm.; multiplet, 4H; 3,73 ppm., triplet (J=6,3 Hz), 2H; 4.36 ppm., broad triplet, 1H; 7.607.92 ppm., multiplet, 4H; 9.40 ppm., doublet (J=l,8 Hz),lH. Example V -(u>-phthalimido alkyl) thiazoles (19)__ General process: To a solution of 0.1 mole of an appropriate crude 2-bromophthalimido-1-alkanal (18) in circa 100 ml of dry dimethylformamide in a nitrogen atmosphere a solution of 0.1 mole IE 91172 thioureum, respectively thioformamide, respectively an alkylthioamide 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 filtered off, washed with subsequently ethanol and diethylether, thereafter the precipitate is vacuum'dried.If necessary it is re10 crystallized from an appropriate solvent.

Thus there were obtained: a. 2-amino-5- (2-phthal1ml doethy1)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.

XH-NMR (D6-DMS0): 2.98 ppm., triplet (Js6.8 Hz), 2H; 3.78 ppm., triplet (J-6.8 Hz), 2H; 7.10 ppm., singlet, IH; 2q 7.86 ppm., singlet, 4H; 9.08 ppm., broad singlet, 2H. b_.__2-amlno-5 -( 3-phthalimidopropyl) thiazole__hydrobromide (19b) in 78.5% yield, from 2-bromo-5-phthalimido-l-pentanal (18b) and thiourea:.

XH-NMR (Dg-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, IH; 7.90 ppm.,singlet, 4H; 9.28 ppm., broad singlet, 2H.

IE 91172 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, of. Chem. Abstr. 65, P2O151d.

A mixture of 552 g (4 mole) of particulated anhydrous potassium carbonate, 404 g (2 mole) of freshly distilled 1,3dibromopropane, 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-dihydropyrane together with 140 ml of concentrated aqueous HBrsolution (48%) is refluxed with vigorous stirring for 3 hours, and a violent evolution cf 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 16to 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 102-106eC/18 mm Hg. Reference:(Chem.Abstr., 65, P 20151d). 94-98eC/12 mm Hg.

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

^H-N.MR (CDClj): 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=5.8 Hz), 2H.

Example VII a. 4-phthallmido-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. , 111-1130 C).

^H-NMR (CDClj): 2.22 ppm, singlet, 3H; 2.96 ppm., triplet (J-7,0 Hz), 2H; 3.96 ppm, triplet (J=7.0 Hz), 2H; 7.627.96 ppm., multiplet, 4H. b. 5-phthalimido-2-pentanone (23b) The 5-phthalimido-2-pentanone (23a) is prepared according to Dutch patent application 8800998, April 18,1988.

Yield 53% IE 91172 Melting point 72-74°C.

^H-NMR (CDClg): 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-phthalimldo-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 16,1988.

Yield 80%, viscous oil.

^HaNMR (CDClg): 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-UJ-phthalimido-2-alkanones (24) General process: To a solution of 0,5 mole of an appropriate oo-phthalimido-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 temperature for circa 2 hours. Subsequently there is added circa 100 ml chloroform and 500 ml of demineralized water, thereafter 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-d-methy-5-(CJ-phthallmidoalkyl)thiazoles (25).

Thus there were obtained: a ._ 3-Bromo-5-phthal lmido-2-pentanone ( 24a ) _ yield 95%, from 5-phthalimido-2-pentanone (23b).

^H-NMR (CDClg): 2.10-2.59 ppm., multiplet, 2H; 2.40 ppm., singlet, 3Hj 3.82 ppm;, triplet (J=6.3 HZ), 2H; 4.34 ppm., triplet (Js7.5 Hz), IH; 7,69 ppm., multiplet, 4H. b... 3-Bromo-5-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), IH; 7,60-7.95 ppm., multiplet, 4H.

Example IX -( u) - phthalimidoalkyl)-4-methylthiazoles (25) General process: To a solution of 0.2 mole of a crude 3-bromo-Cu-phthalimido-2-alkanone (24) in circa 100 ml of anhydrous dimethylformamide 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 cirtia 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 precipiate obtained is filtered off, washed subsequently with ethylacetate and diethyl ether, thereafter the precipitate is. vacutim dried.

Thus were obtained: a . 2-Amino-5-(2-phthalimidoethyl)-4-methylthlazolehydrobomide (25a) yield 50%, from 3-bromo-5-phthalimido-2-pentanone (24a) and thioureum.

^H-NMR (Dg-DMSO): 1.98 ppm., singlet, 3H; 2.98 ppm., triplet lg (J-6.5 Hz), 2H; 3.78 ppm., triplet (Jss6.5 Hz) 2H; 7.91 ppm., singlet, 4H; 9.06 ppm., broad singlet, 2H. b. 2-amino-5-(3-phthalimldopropyl)-4-methylthiazole hydrobromide (25b) Yield 51%, from 3-bromo-6-phthalimido-2-hexanone (24b) and thioureum.

^H-NMR (Dg-DMSO): 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, 4Ht 9.23 ppm., broad singlet, 2H. c. 5-(2-phthalimidoethyl)-4-methylthiazole hydrobromide (25c,i yield 40%, from 3-bromo-5-pbthalimido-2-pentanone (24a) and thioformamide. -23 Melting point 207.4-210.6 °C .

^H-NMR (Dg-DMSO): 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-phthallmldoethyl)-2.4-dimethylthiazole hydrobromide i£5dl yield 50%, from 3-bromo-5-phthalimido-2~pentanone (24a) and thioacetamide. 1H-NMR (Dg-DMSO): 2.13 ppm., Singlet, 3H; 2.70 ppm., singlet, 10 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 l-bromo-^ -phthal1mldo-2-alkanone s ( 2 7 ) The l-bromo-<*3-phthal imido-2-al kanones (27) are prepared according to Dutch patent application 8800998, April 18,1968.

Thus there were obtained: a. l-bromo-4-phthalimido-2-butanone (27a). Yield 60%., Melting point 12O-122°C (reference: R.G, Jones et al 20 J.Amer.Chem.Soc., 72, pages 4526-4529 (1950) 119-l20eC).

XH-NMR (CDClj): 3.13 ppm., triplet (J=7.2 Hz), 2H> 3.92 ppm., singlet, 2H; 4.04 ppm., triplet (J=7.2 Hz), 2Hj 7.60-7.96 ppm., multiplet, 4H. b . _l-bromo-5-phthal imido-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.

SE 91172 J. Michalksky et al, Chem.Listy, 49, p. 1379-1384 (1955) cf. Chem.Abstr., 50, 5681 d (1956) 139°C).

^H-NMR (CDClg): 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- (tQ-phthal 1mldoalkyl) thiazoles ( 28 ) The 4-('-0-phthalimidoalkyl) thiazoles (28) are prepared as described for the 5-( °°-phthalimidoalkyl)thiazoles (25) in example IX.

Thus there were obtained: а. 2-amino-4-(2-phthalimldoethyl) thiazole hydrobromide (28a) Yield 95%, from l-bromo-4-phthalimido-2-butanone (27a) and thioureum. 1H-NMR (D-DMSO): 2.95 ppm., triplet (J-5.9 Hz), 2H; 3.87 ppm., triplet (J = 5.9 Hz), 2H;· 6.57 ppm., singlet, IH; 7.86 ppm., singlet, 4H; 8.98 ppm., broad singlet, 2H. b_2-amino-4-( 3-phthalimidopropyl) thiazole hy dr oh rpm Ide (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; б. 56 ppm., singlet, 4H; 9.12 ppm., broad singlet, 2H.

Example XII 4- or 5-M-aminoalky I) thiazoles (20, 26, 29) General process: A solution of 0.1 mole of an appropriateAU-phthalimido 5 alkyIthiazole hydrobromide (25) in circa 400 ml of anhydrous methanol la refluxed 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 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-amlno-5-£2-aminoethy1) thiazole dihydrochloride (20a) Yield 70%, from 2-amino-5-(2-phthalimidoethy1) thiazole hydrobromide (29a).

Crystallized from methanol. Melting point 226-230°C. — 1H-NMR (D -DMSO): 2.88-3.14 ppm, broad singlet, 4H; 7.20 0 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); 5 114 (100).

M*= 143.054 (calculated for CgHgNjS: 143.052) b. 2-amino-5-(3-aminopropyl) thiazole dihydrochloride (20b) Yield 83%, from 2-amino-5-(3-phthalimidopropyl) thiazole hydrobromide (19b).

IQ Crystallized from an ethanol/methanol mixture.

^H-NMR (Dg-DMSO): 1.68-2.10 ppm, multiplet, 2Hj 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); 15 127(100); 113 (9.5) .

M+ = 157.0 63 (calculated for C.H,,N.S: 157.067) Olio c. 2-amino-5-(2-aminoethy1)-4-methylthiazole dlhydrochlqride £26aj._ Yield 82%, from 2-amino-5-(2-phthalimidoethyl)-4-methyl20 thiazole hydrobromide (25a). 1H-NMR (Dg-DMSO): 2.19 ppm., singlet, 3H; 2.32-3.07 ppm. broad singlet, 4H; 8.34 ppm., broad singlet, 3H; 9.32 ppm., broad singlet, 2H.

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

M+ - 157.065 (calculated for C.H.,N.S: 157.067) ,ε 91172 d. 2-amlno-5-(3-aminopropyl)-4-methylthlazole dihydrochloride ( 26b) . Yield 90%, from 2-amino-5-(3-phthalimidopropyl)-4-methyl thi azol e hydrobroimide (25b).

^H-NMR (Dg-DMSO): 1.66-2.02 ppm,, multiplet, 2H·;· 2.16 ppm., 5 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 C7H13N3S: 171.083). e* 2-amino-4-(2-aminoethyl)thiazole dihydrochloride (29 a) Yield 64%, from 2-amino-4-(2-phthalimldoethyl) thiazole hydrobromide (28a). 1H-NMR (Dg-DMSO): 2.96 ppm., triplet (J=6.3 Hz), 2H; 3.12 ppm., triplet (J-6.3 Hz), 2H; 6.72 ppm., singlet, IH; 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,HnN„S: 143.052). □ 9 o f. 2-amino-4-(3-aminopropy1)thiazole dihydrochlorideL (29b) Yield 70%, from 2-amino-4-(3-phthalimidopropy1)thiazole hydrobromide (28b). 1H-NMR (Dg-DMSO): 1.70-2.10 ppm., multiplet, 2H; 2.43-2.95 ppm., multiplet, 4H; 6.58 ppm .,singlet, IH; 8.31 ppm,, •25 broad singlet, 3H; 9.40 ppm., broad singlet, 2H.

IE 91172 - 25 Mass spectrum M/z (intensity in %): 157 (24.2); 140(42.5); 127(8.6); 113(30.0).

M+ = 157.067 (calculated for CcH,,N,S: 157.067) o Id. 4 q. 5-(2-amlnoethyl)-4-methylthiazole dihydrochloride (26c) 5 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 . (Dg-DMSO)ί 2.42 ppm., singlet, 3H; 2.S4-3.40 ppm., 10 multiplet, 4H; 8.01-8.51 ppm., broad singlet, 3H; 8.93 ppm., singlet, IH; 9.55 ppm., singlet, IH.

Mass spectrum M/Z (intensity in %) : 143(12.4); 126(6.8); 113(32.9).

M + = 142.054 (calculated for c6H10N2S: 142.056) 15 · 5-12-aminoethyl )-2,4-dimethylthiazole .dihydrochi or1de (26d) Yield 98%, from 5-(2-phthalimidoethyl)-2,4dimethylthiazole (25d).

Melting point 159.5-163.30C.

^H-NMR (Dg-DMSO): 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 ~(2-aminoethyl)-4-methylthlszole dihydrochloride (26c) The 5-(2-(aminoethyl)-4-methy1thiazoledihydrochloride (26c) may, if desired, also obtained in the following manner: IE 91172 - 26 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 broipi de so.lution ia 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 (Dg-DMSO): 2.46 ppm., singlet, 3H; 3.00 ppm., triplet (J=5.4 Hz), 2H; 3.65 ppm., triplet (J=5.4 Hz), 2Hj 9.95 ppm., singlet, 1H.

A solution of 17.0 g (0.06 mole) of 5-(2-bromoethyl)-4-methylthiazole hydrobromide in circa 150 ml of absolute ethanol is saturated with ammoniek 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 demineralized water, then 11.76 g (0.14 mole) of sodiumhydrogen 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 arid the filtrate is brought at pH - 1 by using a concentrated hydrochloric acid solution. After vacuum concentration the residue is ^91172 - 27 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-amlno-4-methylthiazole-5-yl)propyl]-N1-cyano-0phenyllsoureum (32a) T.o a solution of 4.88 g (0.02 mole) of 2-amino-510 (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. The residue is subsequently taken up in 50 ml of dry freshly distilled pyridine, then 5.76 g (0.02 mole) of diphenyl cyanocarbonimidate (31a) 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 (CDClj); 1.65-2.04 ppm., multiplet, 2H; 2.63 ppm., triplet (J-=7.2 Hz), 2Η-» 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.

IE 91172 - 28 -(^-aminothiazole^S-yl^propyl)-N1-cyano-S-methylisothioureuin (32b) ' To a solution of 4.60 g (0.02 mole) of 2-amino-5(3-amlnopropyl) 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 ( methy1thio]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 (CDClj): 1.54-2,04 ppm., multiplet, 2H; 2.58 ppm., singlet, 3H; 2.68 ppm., triplet (J»5.4 H2), 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-a.mino-4-methylthiazple-5Yyl) propyl j-N’-cyano-Sm ethyl Isothioureum Jggc) .

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 50eC for 15 min.', the inorganic material is filtered off and the filtrate is vacuum concentrated.' Subsequently the the residue ia taken up in 100 ml of dry freshly distilled pyridine, thereto 2.92 g (0.02 mole) of bis (methy1 thio' cyanocarbodiimide (31b) is added. After reflux for 2 hours, the reaction mixture is vacuum concentrated and the residual pyridine ie removed by codistillation with toluene, The residue is subsequently recrystallized front ethanol.

Yield: 85% melting point 172.0-172.4°C.

XH-NMR (Dg-DMSO): 1.50-1.94 ppm., multiplet, 2H; 2.36-2.75 ppm. (under DMSO-signal), 2H; 2.60 ppm., singlet, 3Hj 3.33 ppm., triplet (J=7.2 Hz), 2H; 6.65 ppm., singlet, 2H; 8.40 ppm., singlet, IH.

Exam£le_Xy a. N-[3-(2-amlno-4-methylthiazole-5-yI)propy1jguanidine dihydrobromide (32b) To a solution of 4.88 g (0.02 mole) of 2-amino-5-(3-aminopropyl)-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 50eC 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 is filtered off and acidified with concentrated aqueous hydrogen bromide solution to circa pH = 1, subsequent25 ly there is vacuum concentrated and the residue is.recrystallized from a mixture- of isopropyl alcohol and methanol, Yield 85%.

IE 91172 - 30 1H-NMR (D--DMS0): 1.43-1.88 ppm., multiplet, 2H; 2.08 ppm., 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'-Q, 3-diphenylpropyl )_-0-phenyl i sour eum ( 36a ) A solution of 10.,55 g (0.05 mole) of 3,3-diphenylpropylamine (33a) and 11,90 g (0.05 mole) of diphenylcyano10 carbonimidate (31a) in 100 ml dry dichloromethane is refluxed in nitrogen for 30 minutes. After cooling the reaction 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 minis utes, thereafter the white crystalline material is filtered off, washed with dry diethyl ether and vacuum dried.

Yield 87%, melting point 171-174*0. 1H-NMR (Dg-DMSO): 2.14-2.60 ppm.,multipiet, 2H; 3.00-3.48 ppm., multiplet, 2H; 3.90-4.16 ppm., multiplet, IH; 7.00-7.65 ppm., multiplet, 15H; 8.73 ppm., broad singlet, IH. b. N-cyano-N'-(3.3-diphenylpropyl)-S-methylisothioureum (36b) To a solution of 21.1 g (0.1 mole) of 3.3-diphenylpropylamine (33a) in circa 100 ml of dry diethylether a clear solution of 14.6 g (0.1 mole) of bis[methylthio]cyanocarbodiimide (31b) in circa loo 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% 1H=NMR (CDClg): 2.14-2.58 ppm., multiplet, 2H; 2.30 ppm., singlet, 3H; 3.16-3.50 ppm., multiplet, 2H; 3.95 ppm., tripletfJ=8.1 Hz), IH; 7.26 ppm., multiplet, 10H; 7,58 ppm., broad singlet, IH.

Example XVII a. N-benzoyl-N1-(3,3-dlphenylprogyl)thioureum (38a).

To a solution of 21.1 g (0.1 mole) of 3,3-diphenylpropylamine 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 benzoyl isothiocyanate (37) in circa 50 ml of dry diethyl ethex· 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 (CDClg): 3.26-3.54 ppm., multiplet, 2H; 4.40-4.70 ppm., multiplet, 2H; 5.06 ppm., triplet (J=7.9 Hz), IH; 8.06-8.68 ppm., multiplet, 13H; 8.94 ppm., double doublet. (3^=8.6 Hz, 2.0 Hz), 2H; 11.95 ppm., broad singlet, IH. b, N-(3,3-diphenylpropyl)thioureum (39a) To a solution of 26.2 g (0.07 mole) of Nf-benzoyl-N'(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 cooling 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. 1H-NMR (D -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, lOHj 8.83 ppm., singlet, 1H. c. S-ethy1-N-(3 t 3-diphenylpropyl) isothlouroniumbromide ( 40a) A solution of 13.5 g (0.05 mole) of N-3,3-dipheny1propy1)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 with dry diethyl ether and vacuum dried. Yield 63%, melting point 176-180*0.

XH-NMR (Dg-DMSO): 1.27 ppm., triplet ppm., multiplet, 2H; 3.08-3.40 ppm., ppm,, triplet (J-7.7 Hz), 1H; 7.07-7 1QH; 9,13 ppm., broad singlet, 1H; 9 J=4.5 H2), 1H.

(J=7.2 Hz), 3H; 2.16-2.53 multiplet, 4Hj 4.06 .46 ppm., multiplet, . 56 ppm ., triplet Example XVIII a. N-[2-(2-amino-4-methy1thiazole-5-yl) ethyl]-N*(3.3-dlphenylpropyl) guanidine dipicrate (35a) To a solution of 2.3 g (0.01 mole) of 2-amino-55 (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 504C for 15 min. it is cooled and the inorganic material is filtered off, then 3.55 g (0.01 mole) of N-cyano-N'-(3,3-diphenylpropy1) Q-phenylisoureum (36a) is added thereto. Subsequently it is refluxed for 16 hours. After cooling and vacuum concentration the residue obtained is extracted a few times with dry diethylether. Subsequently circa 50 ml of heat ethylacetate 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-4methy1thiazole-5-yl)e thy1]-N'-cyano-N-(3,3-diphenylpropy1)guanidine (34a) is subsequently taken up without any purif20 ication in 100 ml of 2N aqueous hydrochloric acid, thereafter 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 stirring the precipitate obtained is filtered off andrecrystalized from a mixture of methanol and water.

Yield 10%.

IE 91172 - 34 ^H-NMR (D.-DMSO): 2.12-2.46 ppm, broad multiplet, 2H; 2,70-3.53 ppm., broad multiplet, 6H; 4.02 ppm., triplet (J=7.2 Hz), IH; 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, IH. b. N-[3-(2-amino-4-methylthiazole-5-yl)propyl]-Nl(3,3-diphenylpropyl)guanidine dlpicrate__(35b) The N-(3-(2-amino-4-methy1thiazole-5-y1)propyllΝ' -(3,3-diphenylpropyl)guanidine (35b) was prepared in a manner analogous- to that of the N-[2-(2-amino-4-methylthiazole-5-y1)ethy 1]-N(3,3-diphenylpropyl)guanidine (35a), as described in example XVIIla, from N-cyano-N'-(3,3diphenylpropy1)-0-phenylisoureum (37a) and 2-amino-5-(3aminopropyl)-4-methylthiazole dihydrochloride (26b) with the proviso that the reaction mixture was refluxed for 48 hours .

Yield 45% 1H-NMR (Dg-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, IH; 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, IH.

Example XIX a. N-[3-(2-aminothiazole-5-y1)propy1)]-N1 -(3,3-dlpheny125 propyl) guanidine dip i crarte ( 35c ) To a solution of 2.30 g (0.01 mole) of 2-amino-5(3-aminopropyl) thiazole dihydrochloride (26b) in circa 50 ml IE 91172 of absolute ethanol, a freshly prepared solution of 0.02 male of sodiumethoxide 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 5 the filtrate 3.79 g (0.01 mole) of S-ethyl-N-(3,3-diphenylpropyl ) isothiouronimbromtde (40a) is added. After refluxing for 48 hours the reaction mixture is decolor'sed 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 (Dg-DMSO): 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-amlnothlazole-4-y1)propy1J-N1 -(3,3-diphenylpropy1) guanidine dipicrate (35d) To a solution of 3.14 g (0.02 mole) of 2-amino-4(3-aminopropyl) thiazole (free base of 2-amino-4-(3-amino25 propyl)thiazole dihydrochloride (29b) in circa 100 ml of absolute ethanol 6.18 g (0.02 mole) of N-cyano-N'-(3,3diphenylpropyl)-S-methylisothioureum (36b) is added, IE 91172 - 36 then there is refluxed for 96 hours. After cooling the reaction mixture is decolorised, with activated carbon, 'filtered and vacuum concentrated. Jhe 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 To the filtrate subsequently a solution of 0.04 mole of picric 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% DDMSO.

(DgDMSO}: 1.54-1,95 ppm., multiplet, 2Hj 2.09-2.74 ppm., multiplet, 4H; 2.87-3.30 ppm., multiplet, 4H; 3.98 ppm., triplet (J=7.2 Hz), IH; 6.50 ppm., singlet, IH; 7.15 ppm., broad singlet, 13H; 8.60 ppm., singlet, 4H; 8.96 ppm., broad singlet, 2H.

Example XXI a' N- [ 3-_(_2-amino-4-methy 1 thi azol e-5-yl ) Propyl ]-N'(3,3-diphenylpropyl)guanidine, dipicrate (35b2 A solution of 3.05 g (0.01 mole) of N-[3-(2-amino4.methyl thiazole-5-yi)propylJ-N'-oyano-0-phenylisoureum (32a) and 4.22 g (0,02 mole) of 3,3-diphenylpropy1 amine (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, thereafter the residue is taken up in circa 100 ml of hot ethyl37 Ο**· 5 IE 91172 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-NH-(3,3-diphenylpropyl) guanidine (34b) is hydrolyzed after column chromatography (Kieselgel 60-80, eluent methanol/NHj) by 2N aqueous hydrochloric acid solution and converted into the dipicrate as described for the N-[3-(2aminothiazole-4-yl)propyl]-Ν'- (3,3-diphenylpropyl)guanidine dipicrate (35d) in example XXa.

Yield 65% ^H-NMR (Dg-DMSO): identical to the spectrum as described for the N-(3-(2-amino-4-methylthiazole-5-yl)propyl]-N'-(3,3diphenylpropyl) guanidine dipricate (35b) in example XVIIIb.

Example, XXII a. N , N,1 -b is [3-( 2-amino-4-methylthiazol e-5-y1)prppyll_ 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 sodiumethoxide in 25 ml of absolute ethanol is added. After stirring at 50®C for 15 minutes there ia cooled and the inorganic material is filtered off, then the filtrate ie 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-[3,2amino-4-methylthiazole-5-yl)propyl]-N'-cyano-S-methylisothioureum (32c) is added, thereafter the mixture is refluxed for 12 hours. After cooling the reaction mixture is processed IE 91172 - 38 as described for the N-(3-(2-amino-4-methylthiazole-5-yl)propyl]-N'-(3,3-diphenylpropyl)-guanidine dlpicrate (35b) as described in example XXIa.

Yield 50% ^H-NMR (Dg-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-amlno-4-methyithiazole-5-yl) propyl ] -N 1 -oyanp-Nmethy1guanidine (34c) To a solution of 1.34 g (0.005 mole) of N-(3-(2-amino-4methylthlazole-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*0 (decomposition) ^H=NMR (Dg-DMSO): 1.49-1.82 ppm., multiplet, 2H; 1.97 ppm., 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; 6.8425 7,10 ppm., multiplet, 2H.

Example XXIV N-[3-( 2-amino-4-me thy 1th iazole-5-ylt) £ r opy 12 - N' - c y ano-N[3-( 4-morpholino)propy1) guanidine (34d) To a solution of 1.34 g (0.005 mole) of N-[3-(2-amino-4methylthiazole-5-yl)propyl]-N'-cyano-5-methyl isothioureum (32c) in circa 50 ml of pyridine 1 1.44 g (0.01 mole) of 3- (4-morpholino)propylamine is added, then with stirring in a 5 nitrogen atmosphere for 48 hours there is refluxed. After cooling the reaction mixture is vacuum concentrated, thereafter the residue is extracted a few times with diethylether. Subsequently it is recrystallized from a mixture of absolute ethanol and methanol.

Yield 48%. Melting point 149.0-151.2®C.

^H-NMR (Dg-DMSO); 1.70-1.90 ppm., multiplet,4H; 2.01 ppm., 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^ am in o-4-me thyl thi azo 1 e-5~y l^propy 1 l-N'-cyano-N11(3-phenylbutyl) guanidine__( 34e ) To a solution of 1.34 g {0.005 mole) N-[3-(2-amino4- 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, thereafter 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*0.

IE 91172 - 40 ^H-NMR (Dg-DMSO): 1.30-1.85 ppm., multiplet, 6H; 1.98 ppm., 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-C 3- ( 2-amino-4-methylthlazole-5-yl) propyl 1 -N ’ -cyano-N11(3,3-diphenylpropyl) guanidine__(34f) To a solution of 1.34 g (0.005 mole) N-[3-(2-amino4-methylthiazole-5-yl)propyl]-Ν'-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, thereafter the residue is extracted a few times with diethyl15 ether. Subsequently it is recrystal lize.d from absolute ethanol.

Yield 60% Melting point 164.7-168.8*0.

^H-NMR (Dg-DMSO): 1.44-1.82 ppm., multiplet, 2H; 1.92 ppm., singlet, 3K; 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), IH; 6.58 ppm., broad singlet, 2H; 6.86-7.25 ppm., multiplet, 12H.

Example XXVII N-C 3-(2-aminq-4-methy1thiazole-5-y1) propyl]-N1 -[3-(3,425 dlchloropheny1)-3-(2-pyridyl)propyl]guanidine tripicrate^35f) A solution of 1.34 g (0.005 mole) of N-(3-(2-amino4-methylthiazole-5-yl)propyl]-N'-cyano-S-methy1 isothioureum (32c) and 1.41 g (0.005 mole) of 2-[3-amino-l-(3,4-dichlorophenyl ) 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 2,5 it is recrystallized from an ethanol/acetone mixture.

Yield 53%. 1H-NMR (Dg-DMSO): 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, 9Hj 8.10-8.31 ppm., multiplet, 1H; 8.59 ppm., singlet, 6H; 8.65-8.80 ppm., multiplet, lHj 9.15 ppm., singlet, 2H.

Example XXVIII N-[3-.( 2-amino-4-methylthiazole-5-yl )prqpyl2-N ' -(3-phenyl 25 propyl) guanidine dipicrate__(35g) A solution of 1.34 g (0.005 mole) of N-(3-(2-amino4-methy1 thiazole-5-yl)propyl]-Ν'-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 modif30 ied process as described by A.Buschauer et al. Archiv.der Pharm.,322(3), 165-171 (1989) IE 91172 - 42 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 ie washed a few times with diethylether. Subsequently 25 ml of 6M hydrc5 chloric acid solution is added 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, 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 obtained is filtered of f , then recry s tallized from a methanol/water mixture.

Yield 62%.

^H-NMR (Dg-DMSO): 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--me thyl thlazole-S-y^propyll-N’-fl-imidazolyl·propyjj guanidine dipicrate (35 b) A solution of 1.34 g (0.005 mole) of N-[3-(2-amino-4-methy1thiazole-5-yl)propyl]—N1-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 (Dg-DMSO); 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. ^44Table I H2~activities on the guinea-pig right atrium Compound pO2< ^0,1) nr. ,9 6,4 <5,0 histamine 6,1 I , E 91172 ~~ -45-

Claims (9)

CLAIMS:
1. l. A substituted ω-aminoalkyIthiazole, characterized in that 5 it is a. a N-[«-(thiazol-4 or 5-y1)alkyl]isourea, isothiourea or a guanidine derivative with formula
2. 2. , wherein X represents a sulphur atom and ¥ represents a nitrogen atom or alternatively io x represents a nitrogen atom and Y represents a sulphur atom, n is 1-6, R^ 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 15 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; 20 b. a N-(«-substituted alkyl)-N’-substituted-N”-[«-(thiazol-4 or 5-yl)alkyl]guanidine with formula 3, wherein X represents a sulphur atom and Y represents a nitrogen atom or alternatively X represents a nitrogen atom and Y represents a sulphur atom, n is 1-6, R^ represents a hydrogen atom or a straight 25 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, R^ 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 - or a -CH« IE 91172 -46- group respectively and Q represents a R-subetituted diphenylmethyl group or a R-substituted (10,11-dihydro) optionally
3. 3. A process for the preparation of a histamine H 2 -receptor active compound whether or not in combination with additionally desired biological activity oharaoterized by preparing from a corresponding compound according to formula 40 1 or 2 or an acid addition salt thereof a compound with a IE 91172 -47substituted
4. 4. - or 5-(ω-thiazolylalkyl)guanidine fragment.
5. 5. Use of a compound or medicament according to one of the previous claims for the treatment of congestive heart diseases whether or not accompanied by heart failure or for the treatment of allergic disorders. 5 4. Medicament, or scientific (pharmacological) adjuvant, characterised in that it contains as the active ingredient a compound according to one of the formulas 2-3 or a compound obtained according to claim 3 or an acid addition salt thereof. 0 5 aza 5H-dibenzo-[a,d)-cyclohepten-5-yl group or Q represents a nitrogen atom substituted with Q x and Q 2 , wherein Q x 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 symme10 trical mono-or disubstituted methylidene fragment, wherein R* represents a R-substituted (10,11-dihydro) optionally aza 5Hdibenzo-[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, 15 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-substituted phenyl rings may be replaced by a (heterocyclic) (aromatic) ring whether or not 20 R-substituted or by a combination of a (condensed) (aromatic) (heterocyclic) R-substituted ring with one or more (oondensed) (aromatic) (heterocyclic) rings whether or not symmetrically R-substituted. 25 2. A process for the preparation of an ω-aminoalkylthiazole, characterized in that one prepares a 4- or 5-(a-aminoalkyl)thiazole derivative with formula 1 in which and R 2 have the same meaning as in claim by ring closure of a 2-bromo-wphthalimidoalkanal (18), a 3-bromo-o-phthalimidoalkan-2-one 30 (24) or a l-bromo-e-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).
6. 6. A process for the preparation of 2-bromo-o-phthalimidoalkanals characterized by selective α-bromination of the corresponding ω-phthalimidoalkanals with bromine in carbon tetrachloride.
7. 7. 2-Bromo-»-phthalimido-l-alkanals.
8. 8. A process for the preparation of a compound of claim 1 substantially as hereinbefore described by way of Example.
9. 9. . 9. The product of a process as claimed in any of claims 2, 3, 6 or 8.