CZ307796B6 - Arylbenzothiazolylurea derivatives, preparing and using them - Google Patents

Abstract

The invention provides new general formula I arylbenzothiazolylurea derivatives and pharmaceutically acceptable alkali metal salts, ammonia or their amines, or acid addition salts where Ris selected from -COOH, -COO (C 1 -C 4 alkyl), -CONH, -CONH (C 1 -C 4 alkyl), -CON (C 1 -C 4 alkyl), -NH, -NH (C 1 -C 4 alkyl), -N (C 1 -C 4 alkyl), -NHCO (C 1 -C 4 alkyl), -N (C 1 -C 2 alkyl) CO (C 1 -C 4 alkyl). These new aryl benzothiazolyl urea derivatives are inhibitors of betaamyloid alcohol dehydrogenase (ABAD) enzymatic activity. The invention also includes a method of preparing them and their therapeutic use in treating Alzheimer's disease and / or dementia.

Description

Technical field

The present invention relates to novel inhibitors of beta-amyloid-binding alcohol dehydrogenase (ABAD) enzymatic activity based on arylbenzothiazolylurea derivatives, to a process for their preparation and to their therapeutic use.

BACKGROUND OF THE INVENTION

Alzheimer's disease (AD) is the most common form of senile dementia and its treatment involves high financial and social costs. Current treatment is palliative at best, it treats symptoms, not causes of the disease. Thus, further disease development and patient death are inevitable. The development of more effective therapeutics against this disease is therefore extremely important.

Amyloid beta peptide (Αβ) is a widely recognized factor causing the development of AD. This peptide has been found to interact with a mitochondrial enzyme called beta-amyloid binding alcohol dehydrogenase (ABAD) (Yan, SD, Fu, J., Soto, C., Chen, X., Zhu, H., Al. Mohanna, F., Collison, K., Zhu, A., Stern, E., Saido, T., Tohyama, M., Ogawa, S., Roher, A., and Stern, D. (1997) Nature 389, 689-695). ABAD is a 27 kDa multifunctional mitochondrial matrix enzyme that catalyzes the reduction of aldehydes and ketones and the oxidation of alcohols (He, XY, Yang, YZ, Schulz, H., and Yang, SY (2000) Biochem. J. 345 Pt 1, 139-143 Powell, AJ, Read, JA, Banfield, MJ, Gunn-Moore, F., Yan, SD, Lustbader, J. Stern, A. R. Stern, D. M. and Brady, RL (2000) J. Mol Biol. 303, 311-327). In vitro experiments have shown that the interaction between ABAD and Αβ is cytotoxic and causes mitochondrial dysfunction, reactive radical production and subsequent cell death (Lustbader, JW, Cirilli, M., Lin, C., Xu, HW, Takuma, K. Wang, N., Caspersen, C., Chen, X., Pollak, S., Chaney, M., Trinchese, F., Liu, S., Gunn-Moore, F., Lue, L.-F. Walker, DG, Kuppusamy, P., Zewier, ZL, Arancio, O, Stern, D., Yan, SS, and Wu, H. (2004) Science 304, 448-452). Interestingly, for this cytotoxicity, the ABAD enzyme needs to be catalytically active (Yan, SD, Shi, Y., Zhu, A., Fu, J., Zhu, H., Zhu, Y., Gibson, L. Stern, E., Collison, K., Al-Mohanna, F., Ogawa, S., Roher, A., Clarke, SG, and Stern, DM (1999) J. Biol Chem 274, 2145-2156 ).

Thus, direct inhibition of ABAD may lead to a new strategy for the treatment of Alzheimer's disease.

In 2006, Xie et al. frentizole as a compound capable of inhibiting ABAD-ββ interaction (Xie, Y., Deng, S., Chen, Z., Yan, S., Landry, D. W. (2006) Bioorg. Med. Chem. Lett. 16, 46574660).

Frentizole is a weak inhibitor with an IC50 of approximately 200 μΜ. Xie et al. also reported frentizole analogs, two of which showed 30-fold higher activity in inhibiting ABAD-Αβ interaction compared to frentizole (IC50 less than 10 μΜ):

- 1 GB 307796 B6

Musilek et al. (patent CZ 305633) and Hroch et al. (Hippo, L., Benek, O., Guest, P., Aitken, L., Soukup, O., Janockova, J., Musil, K., Dohnal, V., Dolezal, R., Kuca, K. , Smith, TK, Gunn Moore, F., Musilek, K. (2016) Bioorg. Med. Chem. Lett. 26, 3675-3678) described structurally different compounds based on the benzothiazole structural skeleton:

R ^{1 '3} = H, OH, Cl

R ⁴ = F, Cl

Some of these compounds (eg K690, K691) were able to reduce ABAD activity to 38-39% at 25 μΜ concentration. 3-Chloro-4-hydroxyphenyl linked to a benzothiazolylurea skeleton has been identified as an important structural fragment for the inhibition of ABAD.

In 2017, Hroch et al. (Hippo, L., Guest, P., Benek, O., Soukup, O., Janockova, J., Dolezal, R., Kuca, K, Aitken, L., Smith, TK, Gunn-Moore, F. , Zala, D., Ramsay, RR, Musilek, K. (2017) Bioorg. Med. Chem. 25, 1143-1152) indolylthiourea derivatives:

H

R

Some of these compounds were able to reduce ABAD activity to 39-49% at 100 μΜ concentration.

In 2017, Benek et al. (Benek, O., Hippo, L., Aitken, L., Dolezal, R., Guest, P., Benkova, M., Soukup, O., Musil, K, Kuca, K., Smith, TK, Gunn -Moore, F., Musilek, K. (2017) Med. Chem. 13, 345-358) derivatives of benzothiazolylurea, benzothiazolylthiourea and benzothiazolylguanidine with 4-substitution on distal phenyl:

Some of these compounds (eg K8O8) were able to reduce ABAD activity to 17% at 25 μΜ concentration.

-2GB 307796 B6

SUMMARY OF THE INVENTION

The present invention provides novel ABAD activity inhibitors based on arylbenzothiazole urea derivatives.

The present invention provides compounds of formula I,

OH

C (I) and their pharmaceutically acceptable salts with alkali metals, ammonia or amines, or their acid addition salts, wherein R ¹ is selected from -COOH, -COO (C 1 -C 4 alkyl), -CONH ₂ , -CONH (C1 C4 alkyl), -CON (C1 -C4 alkyl) _2, -NH _2, -NH (C1-C4 alkyl), -N (C1 -C4 alkyl) _2, -NHCO (C1 -C4 alkyl), -N ( C1-C2 alkyl) CO (C1-C4 alkyl).

In particular, the compounds of formula I are intended for use as medicaments, preferably for use in the treatment of Alzheimer's disease and / or dementia.

Alkyls are linear, branched, or cyclic saturated hydrocarbon radicals having a range of carbon numbers in a particular case. Alkyls are especially methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl.

In a preferred embodiment, the compound of formula I is selected from the group consisting of: ^V

R? Name skm & iiiiiY (CH ₃ ) ₂ N 1- (3-chloro-4-hydroxyoxyphenyl) -3- [6- (dimethylamino) -1,3-benzothiazal-2-yl] urea ch ₃ conh N - (2 - {[(3-chloro-4-hydroxyphenyl) carbamoyl] amino} -1,3- benzothiazol-6-yl) acetamide COOH 2 - {[(3-chloro-4-hydroxyphenyl) fcu: bamoyl] amino} -1,3- benzothiazole-6-carboxylic acid CONH _Ž 2 - {[{3-chloro-4-hydroxyphenyl) kaitamoyl] amino} -1,3- benzothiazole-6-carhaxamide _{(CH3) 2} NCO 2 - {[(3-chloro-4-hydroxyphenyl) carbamoyl] amine} - AGV- dimethyl-1,3-benzothiazole-6-carboxamide

In one embodiment, the invention provides arylbenzothiazolylureas of formula I and pharmaceutically acceptable alkali metal, ammonia, or amine salts thereof, or acid addition salts thereof, preferably arylbenzothiazolylureas selected from the group consisting of 1- (3-chloro-4-hydroxyphenyl) -3- [6- (dimethylamino) -1,3-benzothiazol-2-yl] urea, N- (2 - {[(3-chloro-4-hydroxyphenyl) carbamoyl] amino} -1,3-benzothiazol-6-yl) acetamide, 2 - {[(3-chloro-4-hydroxyphenyl) carbamoyl] amino} -1,3-benzothiazole-6-carboxylic acid, 2 - {[(3-chloro-4-hydroxyphenyl) carbamoyl] amino} -1,3-benzothiazole-6-carboxamide 2 - {[(3-chloro-4-hydroxyphenyl) carbamoyl jamino} - N, N-dimethyl-1,3-benzothiazole-6-carboxamide, and their pharmaceutically acceptable salts with alkali metals, ammonia or amines, or their acid addition salts, for use in inhibiting beta-amyloid alcohol-binding dehydrogenase (ABAD) activity.

In the compounds of the invention, R ^{1 is a} carboxyl group, a derivative thereof, an amino group, or a derivative thereof. Surprisingly, it has been found in the present invention that these groups at the R ¹ substituent position exhibit a significantly higher ABAD enzyme inhibitory activity than the structurally closest compounds with halogens, hydroxyls or alkoxyls at this position.

In one embodiment, the invention relates to arylbenzothiazolylureas of formula I and pharmaceutically acceptable alkali metal, ammonia, or amine salts thereof, or acid addition salts thereof, preferably arylbenzothiazolylureas, selected from the group consisting of 1- (3-chloro-4-hydroxyphenyl) -3 - [6- (dimethylamino) -1,3-benzothiazol-2-yl] urea, N - (2 - {[(3-chloro-4-hydroxyphenyl) carbamoyl] amino} -1,3-benzothiazol-6-yl) acetamide 2 - {[(3-chloro-4-hydroxyphenyl) carbamoyl] amino} -1,3-benzothiazole-6-carboxylic acid, 2 - {[(3-chloro-4-hydroxyphenyl) carbamoyl] amino} -1,3 - benzothiazole-6-carboxamide, 2 - {[(3-chloro-4-hydroxyphenyl) carbamoyl] amino} -N, N-dimethyl-1,3-benzothiazole-6-carboxamide, and their pharmaceutically acceptable alkali metal salts, ammonia or amines, or acid addition salts thereof, for the manufacture of a medicament for the treatment of Alzheimer's disease and / or dementia.

The present invention also provides a pharmaceutical composition comprising at least one arylbenzothiazolyl urea derivative of the Formula I and pharmaceutically acceptable alkali metal, ammonia or amine salts thereof, or acid addition salts thereof, preferably at least one arylbenzothiazolyl urea derivative selected from the group consisting of 1- (3). -chloro-4-hydroxyphenyl) -3- [6- (dimethylamino) -1,3-benzothiazol-2-yl] urea, N- (2 - {[(3-chloro-4-hydroxyphenyl) carbamoyl] amino} -1, 2 - {[(3-chloro-4-hydroxyphenyl) carbamoyl] amino} -1,3-benzothiazole-6-carboxylic acid, 3-benzothiazol-6-yl) acetamide, 2 - {[(3-chloro-4- hydroxyphenyl) carbamoyl] amino} -1,3-benzothiazole-6-carboxamide, 2 - {[(3-chloro-4-hydroxyphenyl) carbamoyl] amino} - N, N-dimethyl-1,3-benzothiazole-6-carboxamide , and at least one pharmaceutically acceptable carrier. Suitable carriers are, in particular, fillers such as carbohydrates, starches, carboxymethyl starch, cross-linked polyvinylpyrrolidine, alginic acid and its salts, solvents, binders, and the like.

Clarification of drawings

Giant. 1: Relative ABAD enzyme activity in the presence of arylbenzothiazolylurea derivatives at a concentration of 10 μΜ.

DETAILED DESCRIPTION OF THE INVENTION

The invention is described in the following non-limiting examples. Starting materials for the preparation of compounds of formula I are available from commercial sources.

Example 1: Preparation of ABAD inhibitors

N'-Carbonyldiidinidazole (12 mmol) was added to a solution of 2-amino-6- (N-diylthylainino) benzo-1,3-thiazole (10 mmol) in anhydrous dichloromethane (50 mL) and the reaction was refluxed for 20 h. was cooled to 2-8 ° C, precipitated and filtered under reduced pressure and washed with cooled dichloromethane. The crude product (6-N-diylthylamino-benzo-1,3-thiazol-2-yl) -1H-imidazole-1-carboxamide was dried under reduced pressure and used in the next reaction step without further purification. ^IN

Next, 4-amino-2-chlorophenol (1.1 mmol) was added to a suspension of (6-N, N-dimethylaminobenzo-1,3-thiazol-2-yl) -1H-imidazole-1-carboxamide (1 mmol). ) in anhydrous

Acetonitrile (15 mL) was added and the reaction mixture was refluxed for 20 h. The reaction mixture was cooled to room temperature, 1 M HCl (15 mL) was added and the precipitate was filtered under reduced pressure. The crude product was recrystallized from diethyl ether / methanol, dried under reduced pressure to give 1- (3-chloro-4-hydroxyphenyl) -3- [6- (dimethylamino) -1,3-benzothiazol-2-yl] urea .

The following derivatives have been prepared in this and analogous manner, the characterization of which is given:

1- (3-chloro-4-hydroxyphenyl) -3- [6- (dimethylamino) -1,3-benzothiazol-2-yl] urea (K1151) Yield 92%, mp 130-132 ° C. 1 H NMR (500 MHz, DMSO- d 6) δ 10.56 (br s, 1H), 9.89 (s, 1H), 8.98 (s, 1H), 7.60 (d, J = 2.6Hz, 1 H), 7.46 (d, J) = 8.8 Hz, 1H), 7.19 (d, J = 2.6Hz, 1H), 7.17 (dd, J = 8.8, 2.6Hz, 1H), 6.93 (d, J = 8.7Hz, 1H), 6.86 (dd, J) = 8.9, 2.6 Hz, 1H), 2.91 (s, 6H). ¹³ C NMR (126 MHz, DMSO- d 6) δ 156.08, 152.15, 148.79, 147.47, 139.62, 132.72, 130.92, 120.65, 119.33, 118.04, 116.65, 115.30, 112.69, 103.97, 40.89. HRMS (ESI) calcd for C ₁₆ H ₁₆ ClN ₄ O ₂ S [M + H] ⁺ 363.06770, found 363.0673. Elemental analysis (EA): Calc'd for C16H15ClN4O2S: C, 52.97; H 4.17; N 15.44; S 8.84; Found C, 52.69; H 4.18; N 15.54; S 8.77.

N- (2 - {[(3-Chloro-4-hydroxyphenyl) carbamoyl] amino} -1,3-benzothiazol-6-yl) acetamide (K1152) Yield 71%, mp 190.5-191.5 ° C. 1 H NMR (500 MHz, DMSO- d 6) δ 10.06 (s, 1H), 9.33 (s, 1H), 8.23 (d, J = 2.1Hz, 1H), 7.59 (d, J = 2.6Hz, 1H) 7.56 (d, J = 8.7Hz, 1H), 7.44 (dd, J = 8.7Hz, 2.1Hz, 1H), 7.18 (dd, J = 8.8Hz, 2.6Hz, 1H), 6.94 (d, J = 8.7Hz, 1 H), 2.06 (s, 3H). ¹³ C NMR (126 MHz, DMSO- d 6) δ 168.15, 158.61, 152.17, 148.89, 143.73, 134.88, 131.43, 130.82, 120.59, 119.35, 119.26, 119.17, 118.21, 116.70, 111.40, 23.96. HRMS (ESI) calcd for C 16 H 14 ClN 4 O 3 S [M + H] ⁺ 377.04697, found 377.0465. EA: Calcd. For C16H13ClN4O3S: C 51.00; H 3.48; N 14.87; S 8.51; Found C, 50.65; H 3.64; N 14.56; S 8.20.

2 - {[(3-Chloro-4-hydroxyphenyl) carbamoyl] amino} -1,3-benzothiazole-6-carboxylic acid (K1153)

Yield 94%, mp 265 ° C (dec.). 1 H NMR (500 MHz, DMSO- d 6) δ 9.95 (br s, 1H), 9.36 (s, 1H), 8.52 (s, 1H), 7.95 (dd, J = 8.4, 1.2 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1 H), 7.60 (d, J = 2.3 Hz, 1 H), 7.20 (dd, J = 8.7, 2.3 Hz, 1 H), 6.95 (d, J = 8.7 Hz, 1 H). ¹³ C NMR (126 MHz, DMSO- d 6) δ 167.09, 162.63, 152.26, 149.05, 131.23, 130.65, 127.31, 125.08, 123.54, 120.75, 119.41, 119.37, 118.77, 116.71. HRMS (ESI) calcd for C 15 H 11 ClN 3 O 4 S [M + H] ⁺ 364.0153, found 364.0149. EA: Calcd. For C15H10ClN3O4S: C, 49.53; H 2.77; N 11.55; S 8.81; Found C, 49.23; H 2.68; N 11.66; S 8.97.

2 - {[(3-Chloro-4-hydroxyphenyl) carbamoyl] amino} -1,3-benzothiazole-6-carboxamide (K1156)

Yield 42%, m.p. Mp 185-186 ° C. 1 H NMR (500 MHz, DMSO- d 6) δ 9.93 (br s, 1H), 9.25 (s, 1H),

8.42 (d, J = 1.8Hz, 1 H), 7.97 (br s, 1H), 7.91 (dd, J = 8.4, 1.8 Hz, 1 H), 7.66 (d, J = 8.4 Hz, 1 H), 7.61 (d, J = 2.6 Hz, 1 H), 7.33 (br s, 1 H), 7.20 (dd, J = 8.7, 2.6 Hz, 1 H), 6.94 (d, J = 8.7 Hz, 1 H). ¹³ C NMR (126 MHz, DMSO- d 6) δ 167.49, 161.67, 152.34, 150.03, 149.01, 130.86, 130.67, 128.90, 125.71, 121.24, 120.76, 119.43, 119.35, 118.46, 116.68. HRMS (ESI) calcd for C 15 H 12 ClN 4 O 3 S [M + H] ⁺ 363.03132, found 363.03082. EA: Calcd. For C15H11ClN4O3S: C, 49.66; H 3.06; N 15.44; S 8.84; Found: C, 49.81; H 3.11; N 15.49; S 8.68.

2 - {[(3-Chloro-4-hydroxyphenyl) carbamoyl] amino} -N, N-dimethyl-1,3-benzothiazole-6-carboxamide (K1157)

Yield 92%, m.p. Mp 266-267 ° C. 1 H NMR (500 MHz, DMSO- d 6) δ 11.08 (br s, 1H), 9.94 (s, 1H), 9.06 (s, 1H), 7.99 (d, J = 1.7Hz, 1 H), 7.65 (d) J = 8.3 Hz, 1H), 7.61 (d, J = 2.6Hz, 1H),

7.42 (dd, J = 8.3, 1.8 Hz, 1 H), 7.20 (dd, J = 8.8, 2.6 Hz, 1 H), 6.94 (d, J = 8.7 Hz, 1 H), 2.98 (s, 6 H). ¹³ C NMR (126 MHz, DMSO- d 6) δ 169.87, 161.21, 152.36, 149.01, 148.39, 130.85, 130.79, 130.66, 125.29, 120.84, 119.53, 119.33, 119.33, 118.56, 116.65, 34.99. HRMS (ESI) calcd

-5 CZ 307796 B6 for C 17 H 16 ClN 4 O 3 S [M + H] ⁺ 391.06262, found 391.0620. EA: Calcd. For C17H15ClN4O3S: C, 52.24; H 3.87; N 14.34; S 8.20; Found C, 51.98; H 3.91; N 14.29; S 9.91.

Example 2: Production of ABAD (beta-amyloid-binding alcohol dehydrogenase)

To achieve high expression of recombinant protein in bacterial cells, the codons of the DNA sequence of the human hsd17b0 gene were optimized by the Gene Optimizer. The DNA sequence thus prepared was prepared de novo as a DNA fragment, then amplified by PCR and specific primers (known in the art) and inserted into plasmid pET28b. A recombinant protein carrying an A-terminal histidine tag was expressed in E. coli BL21 cells (DE3) at a reduced temperature of 25 ° C for 16 hours. The cell pellet was resuspended in lysis buffer (50 mM Tris-HCl, pH 8.0, 500 mM NaCl, 30 mM imidazole, 1 mg / ml lysozyme, 100 U / mL benzonase and protease inhibitors EDTA free) and the bacteria were disrupted using an ultrasonic homogenizer. (ten pulses for 15 seconds followed by a 30 second pause for ice cooling). Cell debris was removed by centrifugation (12,000 x g, 10 min, 4 ° C) and the supernatant was applied to a Sepharose Affinity Carrier (Ni Excel Sepharose) for 2 hours for subsequent affinity purification of the protein. The affinity support was washed with wash buffer (50 mM Tris-HCl, pH 8.0, 500 mM NaCl, 40 mM imidazole) and the protein was eluted with elution buffer (50 mM Tris-HCl, pH 8.0, 500 mM NaCl, 300 mM imidazole). Purified recombinant protein was desalted with PD10 desalting column in storage buffer (50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 30% glycerol), aliquoted at 100 µL and stored at -80 ° C for further analysis. The purity of the recombinant protein was verified by polyacrylamide gel electrophoresis, the protein concentration was determined by the bicinchonine method (MicroBCA kit).

Example 3: Testing of compounds

10 mM stock solutions in DMSO of all the new compounds prepared in Example 1 were prepared. These solutions were further diluted to 1 mM in DMSO and then diluted to 100 mM with demineralized water. NADH and acetoacetyl-CoA solutions were prepared by dissolving the compound in water to a concentration of 3.16 mM. Test buffer (10 mM Tris; 150 mM NaCl; 1 mM DTT; 0.01% BSA; 0.001% Tween) was prepared and adjusted to pH 7.4 with NaOH solution.

60 ml of buffer, 10 ml of diluted enzyme and 10 ml of inhibitor solution were added to the assay well (resulting concentration of compound in the assay well was 10 mM). This mixture was incubated at 37 ° C for 5 min. Then 10 ml of NADH solution and 10 ml of acetoacetyl-CoA solution were added. Absorbance at 340 nm was measured. Each sample was measured in triplicate and an enzyme reaction without added inhibitor solution was used as a control.

The resulting relative activities of the ABAD enzyme are shown in Table 1 and FIG. 1, and a comparison with prior art substances (referred to as control and standard) is also provided. From the results, it is clear that the novel compounds of the present invention have a higher ABAD inhibitory activity, which is an important factor in the development of Alzheimer's disease and dementia, i.e., they exhibit therapeutic activity against Alzheimer's disease and / or dementia.

Table 1: Relative activity of ABAD enzyme in the presence of arylbenzothiazolylurea derivatives at a concentration of 10 μΜ.

The general formula is used to describe each derivative:

-6EN 307796 B6 --NR @ 1 R @ 2 S @ 1 - @ 1 H @ 1 R @ 2 S

Compound number R ^{1 2} R? R ³ R ⁴ % ABAD activity at i <µM PULL control - - - - 100 ALIGN! 0.78 standard K690 F O Cl OH 60.25 2.63 standard K691 Cl O Cl OH 55/75 1.69 standard K808 CHjO NH - OCH3 69.82 2.63 Κ115Ϊ _(CH}) N O Cl OH 27.03 1.69 K1152 CHjCONH O Cl OH 21.96 3.3 8 K1153 HOOC O Cl OH 20.27 0 Kil 56 H ₂ NCO O Cl OH 38.29 1.88 K1157 (CH 2 NCO O Cl OH 30.97 1.88

PATENT CLAIMS

Claims (6)

Arylbenzothiazolylurea derivatives of the general formula I: OH Cl (I) and pharmaceutically acceptable salts thereof with alkali metals, ammonium or amines, or their addition salts with acids, wherein R ¹ is selected from -COOH, -COO (C1 -C4 alkyl), -CONH2, -CONH (C1- C4 alkyl), -CON (C1 -C4 alkyl) _2, -NH _2, -NH (C1-C4 alkyl), -N (C1 -C4 alkyl) _2, -NHCO (C1 -C4 alkyl), -N (C1 -C2 alkyl) CO (C1-C4 alkyl). A compound according to claim 1, selected from the group consisting of 1- (3-chloro-4-hydroxyphenyl) -3- [6- (dimethylamino) -1,3-benzothiazol-2-yl] urea, A- (2- { [(3-chloro-4-hydroxyphenyl) carbamoyl] amino} -1,3-benzothiazol-6-yl) acetamide, 2 - {[(3-chloro-4-hydroxyphenyl) carbamoyl] amino} -1,3-benzothiazol-6 -carboxylic acids, 2 - {[(3-chloro-4-hydroxyphenyl) carbamoyl] amino} -1,3-benzothiazole-6-carboxamide, 2 - {[(3-chloro-4-hydroxyphenyl) carbamoyl] amino} - N, N -dimethyl-1,3-benzothiazole-6-carboxamide, and their pharmaceutically acceptable salts with alkali metals, ammonia or amines, or their acid addition salts. Arylbenzothiazolylurea derivatives according to claim 1 or 2 for use as medicaments. Arylbenzothiazolylurea derivatives according to claim 1 or 2 for use in the treatment of Alzheimer's disease and / or dementia. Arylbenzothiazolylurea derivatives according to claim 1 or 2 for use in inhibiting alcohol-binding alcohol-amyloid dehydrogenase binding activity. 6. A pharmaceutical composition comprising at least one derivative The arylbenzothiazolylurea of claim 1 or 2 and at least one pharmaceutically acceptable carrier.