Aminoalkyl-substituted 5-mercaptothiazoles, the preparation and use thereof

Aminoalkyl-substituted 5-mercaptothiazoles of the formula ##STR1## where R.sup.1, n and A have the meanings stated in the description, and the preparation thereof are described. The compounds are suitable for controlling diseases.

This application is a 371/of PCT/EP92/01004 filed May 8, 1992. 
The present invention relates to novel amino-alkyl-substituted 
5-mercaptothiazoles, the preparation thereof and the use thereof for 
controlling diseases. 
U.S. Pat. No. 3,717,651 describes, inter alia, 5-mercapto-substituted 
thiazoles which have herbicidal properties. 
We have now found that aminoalkyl-substituted 5-mercaptothiazoles of the 
formula I 
##STR2## 
where R.sup.1 is H, C.sub.1 -C.sub.5 -alkyl, phenyl which is unsubstituted 
or substituted by halogen, C.sub.1 -C.sub.5 -alkyl or C.sub.1 -C.sub.5 
-alkoxy, or is thienyl, 
n is an integer from 2 to 6, 
A is NR.sup.2 R.sup.3 where R.sup.2 and R.sup.3, which can be identical or 
different, are each hydrogen, C.sub.1 -C.sub.5 -alkyl, which is 
unsubstituted or substituted by phenyl or thienyl, or is 
##STR3## 
where Ar is phenyl which is unsubstituted or mono-substituted by C.sub.1 
-C.sub.5 -alkyl, C.sub.1 -C.sub.5 -alkoxy, halogen, nitro, hydroxyl, 
trifluoromethyl or cyano, or is pyridyl, pyrimidinyl or thienyl, 
and their salts with physiologically tolerated acids are very suitable for 
controlling diseases. 
In the formula I, R.sup.1 is preferably H or C.sub.1 -C.sub.5 -alkyl, A is 
preferably 
##STR4## 
or C.sub.1 -C.sub.5 -alkyl A.sub.r is unsubstituted phenyl or phenyl 
monosubstituted by and n is preferably 2 or 3. 
The compounds of the formula I can be prepared by 
a) reacting a 5-mercaptothiazole of the formula II 
##STR5## 
where R.sup.1 is as defined above, or a salt of this compound, with an 
.omega.-X-alkylamine of the formula III 
EQU X--(CH.sub.2).sub.n --A III 
where A and n are as defined above, and X is a leaving group such as 
chlorine, bromine or R.sup.4 SO.sub.2 O--[R.sup.4 =C.sub.1 -C.sub.4 -alkyl 
or phenyl which is unsubstituted or substituted by C.sub.1 -C.sub.3 -alkyl 
or halogen], or 
b) reacting an .omega.-alkyl-substituted 5-mercaptothiazole of the formula 
IV 
##STR6## 
where R.sup.1, n and X have the stated meanings, or a salt of this 
compound, with an amine of the formula V 
EQU HA V 
where A is as defined above, or 
c) reacting an .omega.-mercaptoalkylamine of the formula VI 
EQU HS--(CH.sub.2).sub.n --A VI 
where A and n are as defined above, with a 5-Y-substituted thiazole of the 
formula VII 
##STR7## 
where R.sup.1 is as defined above, and Y is chlorine or bromine, or with 
a hydrohalic acid salt of this compound, 
and converting the resulting compounds where appropriate into their salts 
with physiologically tolerated acids. 
The reactions in process a) preferably take place in a solvent at from room 
temperature to the boiling point of the solvent, where appropriate in the 
presence of an acid acceptor. Examples of solvents which can be used are 
dimethylformamide, or ketones such as acetone or butanone, and of acid 
acceptors are inorganic bases such as sodium or potassium carbonate or 
tertiary organic bases such as triethylamine or pyridine. In excess, the 
latter can also act as solvent. 
The crude product is isolated in a conventional way, eg. by filtration, 
removal of the solvent by distillation, or extraction from the reaction 
mixture. The resulting compound is purified in a conventional way, for 
example by recrystallization from a solvent, chromatography or conversion 
into an acid addition compound. 
The 5-mercaptothiazoles of the formula II used as starting materials are 
known from the literature or can be prepared by treating a thiazole of the 
formula VIII 
##STR8## 
where R.sup.1 is as defined above, or a hydrohalic acid salt of this 
compound, with bases such as aqueous ammonia solution or sodium hydroxide 
solution, if required also in a two-phase mixture. Another possibility for 
the synthesis comprises reacting the thiazoles of the formula VII with 
inorganic sulfides such as potassium hydrogen sulfide. The 
mercaptothiazoles of the formula II need not be isolated for subsequent 
reactions. Thus, for example, it is also possible to obtain the compounds 
of the formula I according to the invention by treating a mixture of the 
thiazoles of the formula VIII and of the .omega.-X-alkylamines of the 
formula III with a base, in which case the mercaptothiazole of the formula 
II which is formed in situ immediately reacts with the alkylamines of the 
formula III. 
The reactions in process b) take place in the melt, if required also in the 
presence of a solvent such as ethyl acetate, tetrahydrofuran, 
dimethylformamide, dimethoxyethane, toluene or xylene, at from room 
temperature to the boiling point of the solvent, preferably in the 
presence of a base such as sodium methylate, sodium ethylate, sodium 
hydride, sodium carbonate, potassium carbonate, or of an amine such as 
pyridine. It is also possible where appropriate for the amine component IV 
in excess to act as reagent, base and solvent. 
The reactions in process c) take place in a solvent at from room 
temperature to the boiling point of the solvent. Examples of suitable 
solvents are dimethylformamide, dimethoxyethane, tetrahydrofuran or a 
ketone such as acetone or butanone. It is beneficial to add a base such as 
sodium or potassium carbonate, sodium hydroxide, or a tertiary amine such 
as pyridine or triethylamine. 
The thiazoles of the formula VII and mercaptoalkylamines of the formula VI 
which are used as starting materials can, where they are not known from 
the literature, be prepared by conventional methods. 
The resulting compounds according to the invention are, where appropriate, 
converted into their addition salts with physiologically tolerated acids. 
Examples of suitable physiologically tolerated organic and inorganic acids 
are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, 
oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic 
acid and benzoic acid. Others are to be found in Fortschritte der 
Arzneimittelforschung, Vol. 10, pp. 224 et seq., Birkhauser Verlag, Basel 
and Stuttgart, 1966. 
The acid addition salts are usually obtained in a conventional way by 
mixing the free base or solutions thereof with the appropriate acid or 
solutions thereof in an organic solvent, for example a lower alcohol such 
as methanol, ethanol or propanol, a halohydrocarbon such as methylene 
chloride, an ether such as methyl t-butyl ether or diisopropyl ether, a 
ketone such as acetone or butanone or an ester such as ethyl acetate. It 
is also possible to use mixtures of the said solvents to improve 
crystallization. In addition, pharmaceutically acceptable aqueous 
solutions of acid addition compounds of the compounds I according to the 
invention can be prepared by dissolving the free bases in an aqueous acid 
solution. 
The compounds according to the invention are suitable for controlling 
diseases, especially for treating disorders of the central nervous system 
(eg. parkinsonism, schizophrenia) and high blood pressure. They have, in 
particular, valuable properties as dopamine receptors, in some cases with 
selectivity for presynaptic dopamine receptors, or as dopamine 
antagonists. The compounds of the formula I show affinity for the dopamine 
receptor in receptor binding assays; they inhibit motility in mice 
(measured in cages with a photoelectric beam) and influence the pivoting 
behavior of rats with unilateral 6-hydroxydopamine lesions of the 
substantia nigra (Brain Research 24, (1970) 485-493). 
The effects of the novel compounds can be shown in the receptor binding 
assay as follows: 
Striata from rats (Sprague Dawley, Charles River) were homogenized 
immediately after removal in 0.32M sucrose solution (0.degree. C.). The 
homogenate was filtered through gauze, the filtrate was centrifuged at 
1000 .times.g (5 min at 4.degree. C.) and the resulting supernatant was 
centrifuged at 40000 .times.g (4.degree. C., 10 min). The residue 
(membranes) was taken up in incubation buffer (50 mM tris-HCl, 1 mM 
MgCl.sub.2 and 0.1% ascorbic acid, pH 7.4) and incubated at 37.degree. C. 
for 20 min. The residue was subsequently washed 2.times. with incubation 
buffer by resuspension and recentrifugation. The membranes were frozen in 
portions in liquid nitrogen. 
The assay mixtures (1 ml) were composed of membranes (380 .mu.g of 
protein), 1 nM .sup.3 H-ADTN (NEN, Dreieich Germany, specific 
radioactivity 1.4 TBq/mmol) and 0.1 .mu.M SCH 23390 (total binding) or a) 
with the addition of 50 nM spiperone (non-specific binding) or b) with 
test substance. The mixtures were prepared in triplicate. 
After the incubation (40 min at 25.degree. C.) the mixtures were filtered 
through glass fiber filters (Whatman GF/B) and briefly washed with 
ice-cold washing buffer (tris-HCl, pH 7.4). The radioactivity retained on 
the filters was determined by liquid scintillation counting. The 
non-specific binding comprised about 40-50% of the total binding. 
The evaluation of the competition plots and the determination of the 
dissociation constant took place by iterative non-linear regression 
analysis based on the "ligand" program (Muson and Rodbard: Anal. Biochem. 
107 (1980) 220). 
Affinity of the test substances for the dopamine D.sub.2 receptor 
______________________________________ 
Example 
Ki (nM) 
______________________________________ 
1 12 
2 3 
3 19 
5 18 
7 9 
______________________________________ 
The compounds according to the invention can be administered orally or 
parenterally ( subcutaneously, intravenously, intramuscularly, 
intraperitoneally ) in a conventional way. Administration can also take 
place through the nasopharyngeal space using vapors or sprays. 
The dosage depends on the age, condition and weight of the patient and on 
the mode of administration. The dose of active substance is, as a rule, 
about 10-500 mg per patient and day on oral administration and about 1-100 
mg per patient and day on parenteral administration. 
The novel compounds can be used in the conventional solid or liquid 
pharmaceutical forms, eg. as uncoated or (film) coated tablets, capsules, 
powders, granules, suppositories, solutions or sprays. These are produced 
in a conventional way. The active substances can be processed with 
conventional pharmaceutical aids such as tablet binders, fillers, 
preservatives, tablet disintegrants, flow regulators, plasticizers, 
wetting agents, dispersants, emulsifiers, solvents, retarding agents, 
antioxidants and/or propellant gases (cf. H. Sucker et al.: 
Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The 
pharmaceutical forms obtained in this way normally contain the active 
substance in an amount of from 1 to 99% by weight.

The following Examples illustrate the invention: 
EXAMPLE 1 
4-Methyl-5-[3-(1,2,3,6-tetrahydro-4-phenylpyridyl)propyl]-thiazole-2-one 
hydrochloride 
EXAMPLES 
1. 2-Amino-4-methyl-5-[2-(4-phenylpiperidinyl)ethyl-thio]thiazole 
hydrochloride 
9.65 g of 2-amino-5-bromo-4-methylthiazole, 11.1 g of 
2-(4-phenyl-1-piperidinyl)ethyl mercaptan and 20.7 g of potassium 
carbonate in 50 ml of dimethylformamide were stirred at 80.degree. C. for 
30 minutes. The mixture was poured into ice-water and extracted with 
methylene chloride, and the organic phase was washed with water, dried and 
concentrated. The residue was purified by chromatography (SiO.sub.2 ; 
CH.sub.2 Cl.sub.2, CH.sub.3 OH (0-20%)). The hydrochloride was prepared by 
dissolving the free base in methanol and adding ethereal HCl. 
Yield: 4.8 g (26%); melting point: 205.degree.-210.degree. C. 
The following were prepared in a similar way: 
2. 
2-Amino-5-[2-(1,2,3,6-tetrahydro-4-phenylpyridinyl)-ethylthio]-4-methylthi 
azole hydrochloride Yield: 17%; melting point: 204.degree.-206.degree. C. 
3. 2-Amino-4-methyl-5-[2-(4-phenylpiperazinyl)ethylthio]thiazole 
hydrochloride Yield: 20%; melting point: 235.degree.-237.degree. C. 
4. 2-Amino-5-[2-(4-phenylpiperazinyl)ethylthio]thiazole hydrochloride 
Yield: 15%; melting point: from 55.degree.C. (decomposition) 
5. 2-Amino-4-methyl-5-[2-(N-phenethyl-N-propylamino)-ethylthio]thiazole 
hydrochloride Yield: 25%; melting point: 104.degree. C. 
6. 2-Amino-4-methyl-5-[2-(4-pyridin-2-ylpiperazinyl)ethylthio]thiazole 
tartrate Yield: 20%; melting point: 122.degree.-123.degree. C. 
7. 2-Amino-4-methyl-5-[3-(N-phenethyl-N-propylamino)propylthio]thiazole 
tartrate Yield: 31%; melting point: 118.degree.-120.degree. C. 
Examples of pharmaceutical forms: 
A) Tablets of the following composition are made in a tableting machine in 
a conventional way. 
40 mg of substance of Example 1 
120 mg of corn starch 
13.5 mg of gelatin 
45 mg of lactose 
2.25 mg of Aerosil.RTM. (chemically pure silica in submicroscopically fine 
distribution) 
6.75 mg of potato starch (as 6% paste) 
B) 
20 mg of substance of Example 4 
60 mg of core composition 
60 mg of coating composition 
The core composition comprises 9 parts of corn starch, 3 parts of lactose 
and 1 part of 60:40 vinylpyrrolidone/vinyl acetate copolymer. The coating 
composition comprises 5 parts of sucrose, 2 parts of corn starch, 2 parts 
of calcium carbonate and 1 part of talc. The coated tablets produced in 
this way are subsequently provided with an enteric coating. 
c) 10 g of substance of Example 2 are dissolved in 5000 ml of water with 
the addition of NaCl and adjusted to pH 6.0 with 0.1N NaOH to produce a 
solution isotonic with blood. 1 ml portions of this solution are 
introduced into ampoules and sterilized.