WO1995013268A1 - Ulcer-inhibiting triazole derivatives, pharmaceutical compositions containing them and process for preparing same - Google Patents
Ulcer-inhibiting triazole derivatives, pharmaceutical compositions containing them and process for preparing same Download PDFInfo
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- WO1995013268A1 WO1995013268A1 PCT/HU1993/000063 HU9300063W WO9513268A1 WO 1995013268 A1 WO1995013268 A1 WO 1995013268A1 HU 9300063 W HU9300063 W HU 9300063W WO 9513268 A1 WO9513268 A1 WO 9513268A1
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- 0 Cc1nnc(C)[n]1* Chemical compound Cc1nnc(C)[n]1* 0.000 description 6
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
Definitions
- This invention relates to novel 1 , 2 , 4-triazole de ⁇ rivatives of formulae ( la)
- R l and R 2 which are the same or different, stand for hydrogen; - - alkyl or C ⁇ _ 4 alkenyl group; or a phenyl group optionally substituted by C ⁇ - 4 alkyl or alkoxy group; and n is 0, 1 or 2, as well as their acid-addition salts and pharmaceutical compositions containing these compounds.
- n is 0, 1 or 2, as well as their acid-addition salts and pharmaceutical compositions containing these compounds.
- SUBSTITUTESHEET (la) and (lb) of the invention possess valuable pharmaco ⁇ logical effects. Namely, they inhibit the gastric acid secretion, moreover they exert a significant protective effect on the gastric mucose (cytoprotective action) . Thus, they can very preferably be used as active agents of medicaments against ulcer of the digestive system.
- the invention relates also to a method of treatment, which comprises administering a therapeutical- ly effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable acid-addition salt thereof into the organism of a patient for protecting the gastric mucose or against ulcers of the digestive system.
- R ⁇ means hydrogen or methyl group
- R 2 stands for a methyl group
- n is 0 or 1.
- SUBSTITUTESHEET compounds of the latter type are benzimidazole deriva ⁇ tives discussed e.g. in the published European patent applications Nos. 0,005,129 and 0,204,215 as well as in the United States patent specifications Nos. 4,045,564, 4,359,465, and 4,472,409. From these compounds, 2- ⁇ [3,5- -dimethyl-4-methoxypyridin-2-yl)methyl]sulfinyl ⁇ -5- -methoxy-lH-benzimidazole has been recently introduced to therapy.
- imidazole derivatives fused with various heterocycles e.g. in the published European patent applications Nos. 0,234,485 and 0,234,690
- substituted oxazole, thiazole and imidazole derivatives in the published European patent application No. 0,262,845
- imidazole, triazole and tetrazole derivatives in the published Japanese patent application No. 62-207,270
- the triazole derivatives published in the last-mentioned literature reference can well be distinguished from the compounds of general formulae (la) and (lb) of the present invention.
- the aim of the present invention is to prepare com ⁇ pounds, the gastric acid secretion-inhibiting effect of which reaches or exceeds that of active substances of the prior art without adverse side-effects and which exert a significant cytoprotective action, too. It has been found during our investigations that the compounds of the invention, which are structurally different from the gastric acid secretion-inhibiting substances known in the art, entirely satisfy the above demands. Furthermore, it has surprisingly been found that
- SUBSTITUTESHEET compounds of general formulae (la) and (lb) of the in ⁇ vention, wherein R ⁇ and R are as defined above and n is zero, can be prepared in excellent yield and high purity in such a way that, contrary to the usual S-alkylation, a 1,2,4-triazolethiol of general formula (Ila)
- X stands for a leaving group, or with an acid- addition salt thereof without using any base.
- SUBSTITUTESHEET (lb) wherein R ] _, R 2 and n are as defined above, and their acid-additon salts can be prepared by reacting a compound of general formula (Ila) or (lib) , respectively, wherein R ⁇ and R 2 are as defined above, or a tautomer thereof with a compound of general formula (III) , wherein X means a leaving group, or with an acid-addition salt thereof and, if desired, transforming an obtained com ⁇ pound of general formula (la) or (lb) , respectively, wherein and R 2 are as defined above and n is zero, to a compound of general formula (la) or (lb) , respectively, wherein R ⁇ and R 2 are as defined above and n is 1 or 2, by oxidation and optionally by subsequent reduction and/or converting an obtained base to an acid-addition salt by using an organic or inorganic acid or converting an obtained salt to the corresponding free base.
- the leaving group X is meant to be a group which can easily be split by a nucleophilic reagent.
- groups are the halogen atoms, especially chlorine, bromine and iodine; as well as sulfonyloxy groups, e.g. the lower alkylsulfonyloxy and optionally substituted benzenesulfonyloxy or toluene- sulfonyloxy groups.
- the starting substances [of which the compound of general formula (III) is preferably used in the form of an acid-addition salt] are dissolved in a di ⁇ polar aprotic solvent, preferably N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide or aceto- nitrile, and then the components are reacted in a homo ⁇ geneous solution at a temperature between 10 °C and 60 °C, suitably between 20 °C and 40 °C.
- the duration of the reaction varies from 5 minutes to 24 hours depending on the reagents used.
- SUBSTITUTESHEET (la) and (lb) wherein R ⁇ and R 2 are as defined above and n is zero, formed in the alkylation reaction are separated as acid-addition salts or preferably in the base form after liberation by aqueous sodium hydrogen carbonate solution and extraction into a halogenated hydrocarbon, preferably methylene chloride or chloroform.
- a com- pound of general formula (la) or (lb) obtained in the above-described alkylation reaction is treated with an oxidizing agent suitable to oxidize the S atom of the molecule to a sulfinyl or sulfonyl group, respectively.
- an oxidizing agent suitable to oxidize the S atom of the molecule to a sulfinyl or sulfonyl group, respectively.
- the transformation of this type can be accomplished by a number of reagents known in the litera ⁇ ture.
- 3-chloroperbenzoic acid tert-butyl hydroperoxide, sodium hypochlorite or hydrogen peroxide in the presence of metal ions.
- the use of 3- -chloroperbenzoic acid is particularly preferred.
- the oxidizing agent in a small, preferably 0.1 to 0.4 equivalent, excess.
- the reaction can be carried out in organic solvents, pre ⁇ ferably halogenated hydrocarbons at room temperature.
- the final product preferably separated in the base form can be purified by recrystallization or column chromatography, suitably by using silica gel.
- compounds of the general formula (la) or (lb) wherein R ⁇ and R 2 are as defined above and n is 1, can alternatively preferably be prepared by oxidizing a compound of general formula (la) or (lb) , respectively, wherein Ri and R 2 are as defined above and n is zero, obtained in the alkylating reaction, in an organic solvent, preferably in a halogenated hydro- carbon, at room temperature by using 3-chloroperbenzoic
- SUBSTITUTESHEET first case the sulfinyl compound of general formula (la) or (lb) , respectively, obtained by the reduction is re ⁇ covered from the aqueous solution after alkalinization by extracting it with a halogenated hydrocarbon. After combining the extract obtained with the halogenated hydrocarbon solution arising from the original reaction mixture and evaporating it, the desired sulfinyl compound is obtained which is then purified, when necessary, by recrystallization. in the reduction carried out in a heterogeneous system the halogenated hydrocarbon solution containing the sulfinyl compound of general formula (la) or (lb) , respectively, is directly obtained and then worked up as described above. In the above-described combined reaction route (in ⁇ cluding both oxidation and reducing steps) sulfinyl com ⁇ pounds with a suitable quality can be obtained without purification by column chromatography, too.
- the compounds of general formulae (la) and (lb) of the invention can be converted to acid-addition salts by using commonly known and employed processes or, if in the process according to the invention salts are obtained, if desired, the corresponding bases can be liberated.
- the starting substances of the process according to the invention are usually known and commercially avail ⁇ able; or they can be prepared from easily available basic materials by using known methods.
- SUBSTITUTESHEET compounds of Examples 5, 6, 7, 9, 15 and 21 proved to be significantly more active than the reference drugs. 3. Study on the cytoprotective effect The modified method of Robert [Gastroenterology 77 P page 761 (1979) ] was used in these experiments. Twelve animals were used for each dose. The necrotizing agent (containing absolute alcohol and concentrated HC1 in a ratio of 100 ml/2 ml) was orally administered in a final volume of 0.5 ml/100 g of body-weight 30 minutes follow ⁇
- mice and rats were orally treated with various doses of the compounds to be tested. The observation period lasted 14 days. The results are summarized in Table 7.
- the compounds of the invention cannot be considered to be toxic on any of the animal species used.
- the LD 50 value proved to be higher than 1000 mg/kg on mice and higher than 800 mg/kg on rats. Diminution of the spontaneous motor activity and muscular rigidity were observed on mice whereas a slight increase in the spontaneous motor activity and salivation, decrease in the muscular tone and eventually a ptosis were r ⁇ istered on rats.
- the compounds of the invention effectively inhibit the spontaneous gastric-acid secretion and, in addition, they exert a strong stomach wall-protecting action.
- Their therapeutic ratio safety index
- they may be useful for the treatment of ulcers of the digestive system (stomach and duodenal ulcer) .
- the active compounds of the invention are suitably formulated to pharmaceutical compositions in such a way that, after mixing them with known non-toxic inert solid or liguid carriers, diluting.
- SUBSTITUTESHEET binding agents and/or other additives commonly used in the pharmaceutical industry for enteral or parenteral administration they are transformed to one of the usual drug formulations.
- Carriers, diluting or binding agents suitable for the above demands are e.g. water, gelatine, lactose, saccharose, starch, pectin, magnesium stearate, stearic acid, talc, various vegetable oils as well as glycols such as propylene glycol or polyethylene glycol.
- Pharmaceutical additives, auxiliaries are e.g.
- the preservative agents such as methyl 4-hydroxybenzoate, various native or synthetic emulsifying, dispersing or wetting agents, colouring and flavouring agents, buffer substances as well as agents promoting the disintegration or dissolution, and other substances improving the desired effect.
- “Usual drug formulations” are meant to be: oral compositions prepared by using the above-mentioned phar ⁇ maceutical additives; these compositions may be solid forms, e.g. tablets, capsules, powders, dragees, pills or granules or liguid forms, e.g. syrups, solutions, emulsions or suspensions; furthermore rectal compositions such as suppositories; as well as parenteral composi ⁇ tions, e.g. injectable solutions and infusions.
- the preferable dose of the compounds according to the invention is 1 or 2 tablet(s) , capsule(s) or dragee(s) containing 20 mg of the active ingredient each.
- the invention also relates to pharmaceutical compositions containing a compound of the general formula
- the invention furthermore relates to a method of protecting the gastric mucosa or inhibiting ulcers of the digestive system.
- This method comprises administering a therapeutically effective amount of an active agent of
- SUBSTITUTESHEET the general formula (la) or (lb) , respectively, or a pharmaceutically acceptable acid-addition salt thereof to the patient.
- the product is dried over phosphorus pentoxide under reduced pressure to obtain the aimed dihydrochloride as white crystals in a yield of 19.8 g (98.5 %) , m.p.: 172-175 °C, R f : 0.5 (A).
- SUBSTITUTESHEET substance the compounds of general formula (la) shown in Table 10 are obtained.
- R ⁇ and R2 are as given in Table 10 and n is zero.
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Abstract
The invention relates to novel 1,2,4-triazole derivatives of formulae (Ia) and (Ib), wherein R1 and R2, which are the same or different, stand for hydrogen; C1-4 alkyl or C1-4 alkenyl group; or a phenyl group optionally substituted by C1-4 alkyl or alkoxy group; and n is 0, 1 or 2, and acid-addition salts of these compounds. The invention further relates to pharmaceutical compositions containing these compounds as well as a process for the preparation of the compounds of formulae (Ia) and (Ib). The compounds of formulae (Ia) and (Ib) inhibit gastric-acid secretion and exert a significant protective effect on the gastric mucosa (cytoprotective action). Thus, they can be used for inhibiting and treating ulcers of the digestive system.
Description
ULCER- INHIBITING TRIAZOLE DERIVATIVES. PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND PROCESS FOR PREPARING
SAME
This invention relates to novel 1 , 2 , 4-triazole de¬ rivatives of formulae ( la)
Rl and R2, which are the same or different, stand for hydrogen; - - alkyl or Cι_4 alkenyl group; or a phenyl group optionally substituted by C±-4 alkyl or alkoxy group; and n is 0, 1 or 2, as well as their acid-addition salts and pharmaceutical compositions containing these compounds. According to an other aspect of the invention there is provided a process for the preparation of new com¬ pounds of general formulae (la) and (lb) as well as acid-addition salts thereof.
The novel triazole derivatives of general formulae
SUBSTITUTESHEET
(la) and (lb) of the invention possess valuable pharmaco¬ logical effects. Namely, they inhibit the gastric acid secretion, moreover they exert a significant protective effect on the gastric mucose (cytoprotective action) . Thus, they can very preferably be used as active agents of medicaments against ulcer of the digestive system.
The invention relates also to a method of treatment, which comprises administering a therapeutical- ly effective amount of a compound of formula (la) or (lb) or a pharmaceutically acceptable acid-addition salt thereof into the organism of a patient for protecting the gastric mucose or against ulcers of the digestive system.
In a preferable group of the compounds of general formulae (la) and (lb) of the invention R^ means hydrogen or methyl group, R2 stands for a methyl group and n is 0 or 1.
The following compounds are especially preferred:
3-{ [2-(dimethylamino)benzyl]sulfinyl}-4,5-dimethyl- -1,2,4-triazole, 3-{ [2-(dimethylamino)benzyl]thio}-4,5-dimethyl- -1,2,4-triazole,
3-{ [2-(dimethylamino)benzyl]thio}-2-methyl-1,2,4- -triazole,
3-{ [2-(dimethylamino)benzyl]thio}-2,5-dimethyl- -1,2,4-triazole, and the acid addition salts of these compounds.
It is known that compounds inhibiting gastric-acid secretion bear the highest importance in the treatment of ulcers of the digestive system. One type of these co - pounds is represented by the histamine-2-receptor- -blocking agents (such as e.g. ci etidine and ranitidine) ; whereas an other type of these compounds involves substances acting by inhibition of the H+/K+-ATP-ase enzyme. The major part of gastric acid secretion-inhibiting
SUBSTITUTESHEET
compounds of the latter type are benzimidazole deriva¬ tives discussed e.g. in the published European patent applications Nos. 0,005,129 and 0,204,215 as well as in the United States patent specifications Nos. 4,045,564, 4,359,465, and 4,472,409. From these compounds, 2-{[3,5- -dimethyl-4-methoxypyridin-2-yl)methyl]sulfinyl}-5- -methoxy-lH-benzimidazole has been recently introduced to therapy.
Gastric acid secretion-inhibiting pyrimidinone de- rivatives are described in the published Japanese patent applications Nos. 60-228,465 and 60-197,673 as well as in the Hungarian patent specification No. 203,736.
Among the compounds having similar effect, imidazole derivatives fused with various heterocycles (e.g. in the published European patent applications Nos. 0,234,485 and 0,234,690), substituted oxazole, thiazole and imidazole derivatives (in the published European patent application No. 0,262,845) as well as imidazole, triazole and tetrazole derivatives (in the published Japanese patent application No. 62-207,270) have also been disclosed. However, the triazole derivatives published in the last-mentioned literature reference can well be distinguished from the compounds of general formulae (la) and (lb) of the present invention. The aim of the present invention is to prepare com¬ pounds, the gastric acid secretion-inhibiting effect of which reaches or exceeds that of active substances of the prior art without adverse side-effects and which exert a significant cytoprotective action, too. It has been found during our investigations that the compounds of the invention, which are structurally different from the gastric acid secretion-inhibiting substances known in the art, entirely satisfy the above demands. Furthermore, it has surprisingly been found that
SUBSTITUTESHEET
compounds of general formulae (la) and (lb) of the in¬ vention, wherein R^ and R are as defined above and n is zero, can be prepared in excellent yield and high purity in such a way that, contrary to the usual S-alkylation, a 1,2,4-triazolethiol of general formula (Ila)
R1
respectively, wherein Rj_ and R 2 are as defined above, or a tautomer thereof is reacted with a compound of general formula (III) ,
wherein X stands for a leaving group, or with an acid- addition salt thereof without using any base.
Thus, according to the present invention, the 1,2,4-triazole derivatives of general formulae (la) and
SUBSTITUTESHEET
(lb) , wherein R]_, R2 and n are as defined above, and their acid-additon salts can be prepared by reacting a compound of general formula (Ila) or (lib) , respectively, wherein R^ and R2 are as defined above, or a tautomer thereof with a compound of general formula (III) , wherein X means a leaving group, or with an acid-addition salt thereof and, if desired, transforming an obtained com¬ pound of general formula (la) or (lb) , respectively, wherein and R2 are as defined above and n is zero, to a compound of general formula (la) or (lb) , respectively, wherein R± and R2 are as defined above and n is 1 or 2, by oxidation and optionally by subsequent reduction and/or converting an obtained base to an acid-addition salt by using an organic or inorganic acid or converting an obtained salt to the corresponding free base.
According to the definition accepted in the litera¬ ture [T. A. Geissman: Principles of Organic Chemistry, 3rd ed. , ed. . H. Freeman, London (1968)] the leaving group X is meant to be a group which can easily be split by a nucleophilic reagent. Such groups are the halogen atoms, especially chlorine, bromine and iodine; as well as sulfonyloxy groups, e.g. the lower alkylsulfonyloxy and optionally substituted benzenesulfonyloxy or toluene- sulfonyloxy groups. According to a preferred embodiment of the process of the invention the starting substances [of which the compound of general formula (III) is preferably used in the form of an acid-addition salt] are dissolved in a di¬ polar aprotic solvent, preferably N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide or aceto- nitrile, and then the components are reacted in a homo¬ geneous solution at a temperature between 10 °C and 60 °C, suitably between 20 °C and 40 °C. The duration of the reaction varies from 5 minutes to 24 hours depending on the reagents used. The compounds of general formulae
SUBSTITUTESHEET
(la) and (lb) , wherein R^ and R2 are as defined above and n is zero, formed in the alkylation reaction are separated as acid-addition salts or preferably in the base form after liberation by aqueous sodium hydrogen carbonate solution and extraction into a halogenated hydrocarbon, preferably methylene chloride or chloroform. According to the invention, in order to prepare compounds of the general formulae (la) and (lb) , wherein Rl and R are as defined above and n is 1 or 2, a com- pound of general formula (la) or (lb) , respectively, wherein Ri and R are as defined above and n is zero, obtained in the above-described alkylation reaction is treated with an oxidizing agent suitable to oxidize the S atom of the molecule to a sulfinyl or sulfonyl group, respectively. The transformation of this type can be accomplished by a number of reagents known in the litera¬ ture. It is advantageous to use 3-chloroperbenzoic acid, tert-butyl hydroperoxide, sodium hypochlorite or hydrogen peroxide in the presence of metal ions. The use of 3- -chloroperbenzoic acid is particularly preferred.
Furthermore, it is suitable to employ the oxidizing agent in a small, preferably 0.1 to 0.4 equivalent, excess. The reaction can be carried out in organic solvents, pre¬ ferably halogenated hydrocarbons at room temperature. When necessary, the final product preferably separated in the base form can be purified by recrystallization or column chromatography, suitably by using silica gel.
According to the invention compounds of the general formula (la) or (lb) , wherein R^ and R2 are as defined above and n is 1, can alternatively preferably be prepared by oxidizing a compound of general formula (la) or (lb) , respectively, wherein Ri and R2 are as defined above and n is zero, obtained in the alkylating reaction, in an organic solvent, preferably in a halogenated hydro- carbon, at room temperature by using 3-chloroperbenzoic
SUBSTITUTESHEET
acid in an excess of 0.5 to 0.8 equivalent. In this case a mixed oxidation product is obtained which consists mainly of an N-oxide type intermediate of general formula (IVa)
or (IVb) ,
respectively, wherein R^ and R are as defined above, and of a small amount of a compound of general formula (la) or (lb) , respectively, wherein R^ and R2 are as defined above and n is 1. It has been recognized that the part of the reaction mixture consisting of the compound of general formula (IVa) or (IVb) , respectively, can also be transformed to the desired sulfinyl compound (n = l) of general formula (la) or (lb) , respectively, in such a manner that, after termination of the oxidizing reaction, the N-oxide of general formula (IVa) or (IVb) , respect- ively, is extracted with water from the halogenated hydrocarbon used and then it is reduced by using sulfurous acid in an aqueous solution. The reduction by sulfurous acid may be carried out either in the separated aqueous solution or in the heterogeneous reaction mixture containing the halogenated hydrocarbon and water. In the
SUBSTITUTESHEET
first case the sulfinyl compound of general formula (la) or (lb) , respectively, obtained by the reduction is re¬ covered from the aqueous solution after alkalinization by extracting it with a halogenated hydrocarbon. After combining the extract obtained with the halogenated hydrocarbon solution arising from the original reaction mixture and evaporating it, the desired sulfinyl compound is obtained which is then purified, when necessary, by recrystallization. in the reduction carried out in a heterogeneous system the halogenated hydrocarbon solution containing the sulfinyl compound of general formula (la) or (lb) , respectively, is directly obtained and then worked up as described above. In the above-described combined reaction route (in¬ cluding both oxidation and reducing steps) sulfinyl com¬ pounds with a suitable quality can be obtained without purification by column chromatography, too.
The compounds of general formulae (la) and (lb) of the invention can be converted to acid-addition salts by using commonly known and employed processes or, if in the process according to the invention salts are obtained, if desired, the corresponding bases can be liberated.
The starting substances of the process according to the invention are usually known and commercially avail¬ able; or they can be prepared from easily available basic materials by using known methods.
As mentioned in the introduction, the compounds of general formulae (la) and (lb), werein R^, R2 and n are as defined in the introductory part, possess significant in vivo gastric acid secretion-inhibiting and cytoprotec- tive effect.
The gastric acid secretion-inhibiting, ulcer-in¬ hibiting and cytoprotective effects of the compounds of general formulae (la) and (lb) were proven by investiga-
SUBSTITUTESHEET
tions under in vivo conditions by using the methods described hereinafter under items 2 to 4. The compound 2- -{[2-(dimethylamino)benzyl]sulfinyl}-l,4-benzimidazole [Drugs of the Future ϋ, 186 (1988) ; hereinafter compound 5 NC-1300] and omeprazole (see the published European patent application No. 0,005,129) were used as reference drugs.
The fact that the compounds of general formulae (la) and (lb) of the invention exert their above-mentioned
10 effects by inhibiting the H+/K+-ATP-ase enzyme, was supported by in vivo investigations described below under item 1, wherein omeprazole was used as reference drug. 1. Assay of the H+/K+-ATP-ase enzyme inhibition The H+/K+-ATP-ase enzyme was prepared by using the
15 modified method of H. Chang et al. [Biochim. Biophys. Acta 464. 313-327 (1977) ] on swine gastric mucosa. A G2 fraction purified on sugar gradient was used in these measurements. The enzyme activity was measured in 1 ml volume of the reaction mixture containing 2 mM of MgCl2,
20 2 mM of ATP, 20 mM of potassium chloride and enzyme in 40 mM of TRIS acetate (pH = 7.4) buffer solution. The activity of Mg++-ATP-ase enzyme was measured in the absence of potassium chloride. The H+/K+-ATP-ase enzyme activity was obtained as the difference between these
25 two values.
Table 1 Assay of inhibition of the H+/K+-ATP-ase enzyme
Compound Concentration H+/K+-ATP-ase (μmol of ATP/mg of protein/hour) (Example No.) (μM)
Preparation 1 Preparation 2 X±SD Inhibition % X±SD Inhibition %
Baseline 50.4+0.5 55.4±1.1 15 100 4.1±1.3 91 15 50 14.1±1.8 72 4.4±2.2 92
SUBSTITUTESHEET
Table 1 (continued)
Compound Concentration H+/K+-ATP-ase (μmol of ATP/mg of protein/hour) (Example No. ) (μM)
Preparation 1 Preparation 2
X1SD Inhibition % X1SD Inhibition %
15 25 34.210.2 32 28.612.5 48
15 10 50.210.8 0 45.810.1 17
15 5 54.113.8 2
IC50: 34μM IC50: 21 μM
Baseline 63.511.5
17 100 11.512.7 82
17 50 24.514.6 61
17 25 31.315.9 51
17 10 39.516.6 38
17 5 44.315.1 30 IC50: 19μM
Baseline 63.511.5
18 100 2.210.3 96
18 50 2.810.8 95
18 25 6.011.1 90
18 10 22.117.5 65
18 5 37.816.0 40 ICJQ: 6.6 μM
Baseline 43.413.2 31.712.2
21 100 4.411.4 90
21 50 8.911.8 80 2.911.8 91
21 25 15.112.9 65 7.212.0 77
21 10 22.113.0 50 12.811.6 59
21 5 17.711.6 44
21 1 32.715.3 0
IC50: lOμM IC50: 12 μM
Baseline 106.711.2
Omeprazole 100 4.512.8 96
Omeprazole 50 5.110.4 95
Omeprazole 25 21.714.2 80
Omeprazole 10 57.512.4 46 IC50: 10.7 μM n = 3
SUBSTITUTE SHEET
On the basis of the data of Table 1 it can be stated that the compounds described in Examples 18 and 21 are the most effective inhibitors of the H+/K+-ATP-ase enzyme. The average IC50 values of these compounds measured on 5 two preparations are 6.6 μM and 8.5 μM, respectively, which are better than that of omeprazole (IC50 = 10.7 μM) used as reference drug.
2. Determination of the gastric acid secretion-in¬ hibiting effect by using Shay's method 10 After 24-hour starvation female SPRD rats weighing 130 to 160 g each were orally treated with the compounds to be tested. Ten animals were used for each dose. After 1 hour laparotomy and pylorus ligation were carried out under ether anaesthesia according to Shay [Gastro- 15 enterology f>, 43 (1945)]. After 5 hours the animals were killed by an overdose of ether, their stomach was removed and the volume and acid content of the gastric juice were determined. Sodium hydroxide solution (0.1 N) was used for titration in the presence of Tδpfer's indicator. The 20 results are summarized in Table 2.
Table 2 Assay of inhibition of gastric acid secretion by using
Shay's method
Compound Dose Gastric juice (ml) Change Gastric acid (ml) Change ED50
Example mg/kg Control Treated % Control Treated % mg/kg
No. Ό.O. P.O.
5 2.5 7.22 7.32 + 1 3.70 3.14 -15 6.3
5.0 7.22 6.31 -13 3.70 2.86 -23 (4.0-9.9)
10.0 5.36 3.87 -28 3.03 0.74 -76
6 2.5 9.36 8.68 - 3 5.50 4.21 -23 5.0
5.0 9.20 6.08 -34 4.52 3.09 -32 (3.4-7.5)
10.0 9.36 4.54 -51 5.50 1.13 -79
SUBSTITUTESHEET
Table 2 (continued)
Compound Dose Gastric juice (ml) Change Gastric acid (ml) Change ED50
Example mg/kg Control Treated % Control Treated % mg/kg
No. P.O. .O.
7 5.0 8.35 9.79 +17 4.91 3.33 -32 7.5
10.0 9.62 5.55 -42 4.08 1.57 -62 (4.5-12.3)
20.0 10.13 3.82 -62 4.69 0.48 -90
9 1.25 8.71 7.55 -13 4.50 4.11 -10 4.4
2.5 11.37 8.17 -28 6.18 4.11 -33 (2.7-7.3)
5.0 11.37 6.38 -44 6.18 2.89 -53
10.0 10.82 4.73 -56 5.75 1.26 -78
15 2.5 8.71 6.48 -26 4.56 3.00 -33 5.2
5.0 10.45 7.19 -31 5.44 2.76 -49 (2.9-9.3)
10.0 10.35 5.94 -43 5.22 2.00 -62
20.0 9.19 4.42 -52 3.63 0.59 -84
21 5.0 9.61 8.39 -13 4.92 3.14 -36 9.0
10.0 10.13 6.44 -36 4.69 2.07 -56 (4.2-19.3)
20.0 10.13 6.20 -39 4.69 1.62 -66
Reference 10.0 7.30 6.11 -16 4.15 2.74 -34 16.0 drug 20.0 5.61 4.63 -18 3.25 1.36 -58 (11.9-21.4)
(NC-1300) 50.0 5.90 4.50 -24 3.43 0.41 -88
Reference 5.0 6.88 5.40 -22 2.71 1.75 -35 10.5 drug 10.0 6.88 5.47 -22 2.71 1.70 -38 (7.8-14.1)
(O eprazol) 20.0 6.98 4.: 30 ■38 2.81 0.71 -75
It can be seen from Table 2 illustrating the "spontaneous" gastric acid secretion-inhibiting effect of the novel triazole derivatives of the invention that the
SUBSTITUTESHEET
compounds of Examples 5, 6, 7, 9, 15 and 21 proved to be significantly more active than the reference drugs. 3. Study on the cytoprotective effect The modified method of Robert [Gastroenterology 77P page 761 (1979) ] was used in these experiments. Twelve animals were used for each dose. The necrotizing agent (containing absolute alcohol and concentrated HC1 in a ratio of 100 ml/2 ml) was orally administered in a final volume of 0.5 ml/100 g of body-weight 30 minutes follow¬
10 ing administration of the compound to be tested. After 1 hour the animals were killed by an overdose of ether and the size of necrosis appearing on the glandular part of their stomach was evaluated. The results are illustrated in Table 3.
15 Table 3 Investigation of cytoprotective effect
Compound Dose Average length (mm) of the bleedings Change ED50 Example mg/kg Control Treated % mg/kg No. p.o. P.P.
5.0 77.9 56.1 -28 8.5 10.0 67.4 30.8 -54 (5.2-13.8) 20.0 67.4 9.8 -85
13 5.0 76.6 67.2 -12 14.1 10.0 76.6 57.8 -25 (8.9-22.4) 20.0 80.3 23.4 -71
Reference 5.0 107.7 84.4 -22 8.6 drug 10.0 107." 42.3 -61 (6.8-10.9) NC-1300 20.0 88.0 11.7 -87
Reference 5.0 84.8 61.8 -27 10.0 drug 10.0 84.8 46.0 -46 (7.7-13.0) (Omeprazol)
SUBSTITUTESHEET
It is obvious from the data of Table 3 that the compounds of Examples 5 and 13 inhibited in a dose-de¬ pendent manner the stomach-wall necrosis induced by absolute alcohol containing hydrochloric acid. Thus, these compounds possess a favourable cytoprotective effect.
4. Assay of the ulcer-inhibiting effect a) Stomach ulcer-inhibiting effect on rats operated according to Shay ("Shay rats") These investigations were carried out on female
SPRD rats weighing 150 to 170 g each after starvation for 24 hours. The animals were orally treated with a 20 mg/kg dose of the compounds to be tested in a final volume of 0.5 ml/100 g of body-weight. Then, after 1 hour laparotomy and pylorus ligation were performed under ether anaesthesia according to Shay [Gastroenterology 5 , 43 (1945) ] . After 18 hours the number and size of ulcers developed on the membraneous part of the stomach were evaluated under a stereomicroscope by using 8-fold magnification. The size of ulcers was expressed as a score from 0.5 up to 32. The score values of the treated group were compared to those of the group pretreated with the vehicle and expressed as percentage. The results are summarized in Table 4. Table 4
Stomach ulcer-inhibiting effect on Shay rats
Compound ED50 values (mg/kg p.o.) according to
Example No. number severity occurrence of the ulcers
1 5.0 (3.7-6.6) 4.3 (3.2-5.7) 4.7 (3.1-7.2) 5 6.1 (4.3-8.7) 6.6 (4.5-9.8) 13.2 (9.9-17.6) 15 7.0 (5.0-9.7) 4.3 (2.8-6.5) 12.3 (8.8-17.3)
SUBSTITUTESHEET
Table 4 (contd. )
Compound ED50 val es (mg/kg p.o.) according to
Example No. number severity occurrence of the ulcers
Reference drug 7.4 (6.3-8.7) 5.7 (4.7-7.0) 14.5 (13.4-15.7) NC-1300
Reference drug 9.2 (7.0-12.1) 11.0 (8.9-13.5) 17.0 (11.7-24.7) Omeprazole
b) Inhibition of reserpine-induced stomach ulcer
After starvation for 24 hours female SPRD rats were orally treated with a dose of 5 mg/kg and 20 mg/kg, respectively, of the compounds to be tested. Then, the rats were immediately treated with a 5 mg/kg subcutaneous dose of reserpine. After 18 hours the stomach of the animals was observed under microscope. The evaluation was carried out as described under paragraph a) . The results are indicated in Table 5.
Table 5 Inhibition of reserpine-induced stomach ulcer
Compound ED50 values (mg/kg p.o.) based on
Example No. number severity occurrence of the ulcers
1 9.3 (6.6-13.0) 9.2 (6.6-12.9) 10 - 20
5 19.8 (14.3-27.5) 21.4 (16.1-28.3) 37.7 (24.8-57.4)
15 2.8 (1.9- 4.2) 2.6 (1.5- 4.3) 5.8 (3.8- 8.7)
Reference drug 17.0 (12.4-23.3) 20.0 (16.5-24.2) 24.0 (19.4-29.8) (NC-1300)
Reference drug 8.0 ( 5.6-11.4) 6.1 ( 4.1- 9.1) 18.0 (13.3-24.3) (Omeprazole)
SUBSTITUTESHEET
c) Inhibition of indomethacin-induced stomach ulcer These experiments were carried out on female SPRD rats previously starved for 24 hours. During this period the animals were allowed to drink water ad libitum. The animals were orally treated with a dose of 5 mg/kg and 20 mg/kg, respectively, of the compounds to be tested in a final volume of 0.5 ml/100 g, then after 1 hour they were orally treated with a 20 mg/kg dose of indomethacin in the same volume. After 6 hours the rats were killed by an overdose of ether and the ulcers developed on the glandu¬ lar part of their stomach were examined as described in paragraph a) above. The results are summarized in Table 6.
Table 6 Inhibition of indomethacin-induced stomach ulcer
Compound ED50 values (mg/kg p.o. ) based on
Example No. number severity occurrence of the ulcers
1 17.8 (14.9-21.1) 17.2 (13.4-22.0) 27.6 (19.8-38.5)
5 8.6 (5.4-13.6) 8.7 (6.0-12.8) 11.7 (7.2-18.9)
15 6.6 (4.4- 9.9) 7.7 (5.5-10.8) 10 - 20
It can be seen from Tables 4 to 6 that oral doses of 20 mg/kg of the compounds of the invention described in Examples 1, 5 and 15 effectively inhibited the development of stomach ulcer in rats by using various experimental models.
5. Acute toxicity investigations on mice and rats These investigations were carried out on male CFLP mice and female SPRD rats previously starved for 24 hours. The animals were orally treated with various doses of the compounds to be tested. The observation period lasted 14 days. The results are summarized in Table 7.
SUBSTITUTESHEET
Table 7 Investigation of the acute toxicity on mice and rats
Compound Male mice Female rats
Example No. Dose Died/ LD50 Dose Died/ LD50 mg/kg /treated mg/kg /treated
CO. O.
1 1000 0/3 500 0/8
1F00 2/3 1000-1500 800 0/8 >800
5 ** **i 0/6 500 0/8
1000 0/6 >1000 800 0/8 >800
15 500 0/3 500 0/8
1000 1/3 >1000 800 0/8 >800
In the case of oral treatment the compounds of the invention cannot be considered to be toxic on any of the animal species used. The LD50 value proved to be higher than 1000 mg/kg on mice and higher than 800 mg/kg on rats. Diminution of the spontaneous motor activity and muscular rigidity were observed on mice whereas a slight increase in the spontaneous motor activity and salivation, decrease in the muscular tone and eventually a ptosis were r~ istered on rats.
It is obviuos from the above results that, when given even in a low dose, the compounds of the invention effectively inhibit the spontaneous gastric-acid secretion and, in addition, they exert a strong stomach wall-protecting action. Their therapeutic ratio (safety index) is very favourable. Thus, they may be useful for the treatment of ulcers of the digestive system (stomach and duodenal ulcer) .
For the therapeutical use the active compounds of the invention are suitably formulated to pharmaceutical compositions in such a way that, after mixing them with known non-toxic inert solid or liguid carriers, diluting.
SUBSTITUTESHEET
binding agents and/or other additives commonly used in the pharmaceutical industry for enteral or parenteral administration, they are transformed to one of the usual drug formulations. Carriers, diluting or binding agents suitable for the above demands are e.g. water, gelatine, lactose, saccharose, starch, pectin, magnesium stearate, stearic acid, talc, various vegetable oils as well as glycols such as propylene glycol or polyethylene glycol. Pharmaceutical additives, auxiliaries are e.g. the preservative agents such as methyl 4-hydroxybenzoate, various native or synthetic emulsifying, dispersing or wetting agents, colouring and flavouring agents, buffer substances as well as agents promoting the disintegration or dissolution, and other substances improving the desired effect.
"Usual drug formulations" are meant to be: oral compositions prepared by using the above-mentioned phar¬ maceutical additives; these compositions may be solid forms, e.g. tablets, capsules, powders, dragees, pills or granules or liguid forms, e.g. syrups, solutions, emulsions or suspensions; furthermore rectal compositions such as suppositories; as well as parenteral composi¬ tions, e.g. injectable solutions and infusions.
The preferable dose of the compounds according to the invention is 1 or 2 tablet(s) , capsule(s) or dragee(s) containing 20 mg of the active ingredient each.
The invention also relates to pharmaceutical compositions containing a compound of the general formula
(la) or (lb) , respectively, or a pharmaceutically accept- able acid-addition salt thereof as active ingredient; as well as to a process for preparing these compositions.
The invention furthermore relates to a method of protecting the gastric mucosa or inhibiting ulcers of the digestive system. This method comprises administering a therapeutically effective amount of an active agent of
SUBSTITUTESHEET
the general formula (la) or (lb) , respectively, or a pharmaceutically acceptable acid-addition salt thereof to the patient.
The invention is illustrated in detail by the following non-limiting Examples.
The structures of compounds prepared by using the process described in the Examples were proven by 1.3- and 13C-NMR spectra, infrared spectra as well as in a number of cases by mass spectra. The signals of NMR spectra are given in ppm according to the scale related to T S.
Rf values indicated in the Examples were determined by layer chromatography on silica gel (DC-Alufolien Kieselgel 60 F254 Merck, Darmstadt) by using the follow- ing solvent systems:
A: ethyl acetate/methanol = 8:2
B: ethyl acetate
C: ethyl acetate/methanol = 7:3
D: ethyl acetate/carbon tetrachloride = 1:1 Example 1
Preparation of 3-{[2-(dimethylamino)benzyl] hio}-
-4,5-dimethyl-l,2, -triazole dihydrochloride
To a solution containing 7.8 g (60 mmol) of 4,5- -dimethyl-l,2,4-triazole-3-thiol (J. Chem. Soc. 1959. page 3799) in 60 ml of dimethylformamide, 12.0 g (60 mmol) of [2-(chloro ethy1)pheny1]dimethylammonium chloride (J. Chem. Soc. 1954. page 4127) are added at 40 °C under stirring. The ammonium salt is dissolved under stirring within a few minutes and precipitation occurs from the. solution after 10 minutes. After filtering the precipitate is washed 3 times by suspending it in 100 ml of acetone each. The product is dried over phosphorus pentoxide under reduced pressure to obtain the aimed dihydrochloride as white crystals in a yield of 19.8 g (98.5 %) , m.p.: 172-175 °C, Rf: 0.5 (A).
SUBSTITUTESHEET
Examples 2 to 5
By following the process described in Example l above and using the corresponding 1,2,4-triazolethiol as starting substance, the compounds of general formula (la) or (lb) , respectively, indicated in Table 8 are obtained. In these compounds R^ and R2 are as shown in Table 8 and n is zero.
Table 8
Example General Rl R2 M.p.* Rf Solvent
5 (lb) CH3 CH3 147-152 0.85 A
* In the Table the melting point of the dihydrochloride salt of the compounds is given.
Example 6
Preparation of 3-{[2-(dimethylamino)benzyl]thio}- -4 ,5-dimethyl-l,2 - -triazole
12.0 g (36 mmol) of dihydrochloride prepared according to Example 1 are portionwise added to a mixture of 250 ml of 5 % aqueous sodium hydrogen carbonate solution and 250 ml of chloroform. After cessation of the effervesence the mixture is shaken and then separated. After extracting the aqueous phase twice with 125 ml of chloroform each, the combined chloroform solution is dried over anhydrous sodium sulfate, then evaporated under reduced pressure. The aimed base is recrystallized from ethanol to give a yield of 9.1 g (97 %) , m.p. 54-55 °C, Rf: 0.5 (A). The aimed base forms colourless lamellar crystals.;
SUBSTITUTESHEET
Examples 7 and 8
By following the procedure described in Example 6 the bases of general formula (la) shown in Table 9 are obtained. In these compounds R^ and R2 are as given in Table 9 and n is zero.
Table 9
Example Ri 2 M.p.* Rf Solvent
No. °C svste
7 H CH3 oil 0.45 A
8 CH3 Φ- 130-132 0.15 B
Example 9 Preparation of 3-{[2-(dimethylamino)benzyl]thio}- -2-methyl-l,2,4-triazole
After dissolving 1.76 g (16 mmol) of 2-methyl- -l,2,4-triazole-5-thiol [Ann. 641/ 121-128 (1961)] in 16 ml of dimethylformamide, 3.2 g (16 mmol) of [2-(chloro- methyl)phenyl]dimethylammonium chloride are added at room temperature. The mixture is stirred at room temperature for 2 hours, then evaporated under reduced pressure. The thick oily residue is shaken with a mixture of 100 ml of 5 % aqueous sodium hydrogen carbonate solution and 100 ml of chloroform. The aqueous phase is extracted twice with 50 ml of chloroform each, the organic solution is dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product obtained is purified by chromatography on a silica gel column by using ethyl acetate as eluent. After evaporating the fractions containing the aimed compound, a thin oil is obtained in a yield 3.5 g (88 %) , Rf: 0.7 (B) . Examples 10 to 14 By following the process described in Example 9 and using the corresponding 1,2,4-triazolethiol as starting
SUBSTITUTESHEET
substance the compounds of general formula (la) shown in Table 10 are obtained. In these compounds R→ and R2 are as given in Table 10 and n is zero.
Table 10
Example Rl 2 M.p. Rf Solvent No. °C system
10 CH3 H 104-108 0. 3 B
11 H H 48-52 0.25 B
12 H <i 79-83 0.25
13 <£> CH3 57-59 0.5 B
14 H3co- e - CH- 52-56 0.4 B
Example 15
Preparation of 3-{[2-(dimethylamino)benzyl]- -sulfinyl}-4,5-dimethyl-l,2,4-triazole Method a)
10.0 g (30 mmol) of the compound prepared according to Example 1 are transformed to the free base by a mix¬ ture of 240 ml of 5 % aqueous sodium hydrogen carbonate solution and 240 ml of chloroform as described in Example 6. The chloroform solution is dried, supplemented to 1200 ml with anhydrous chloroform and then 12.0 g (33 mmol) of 55 % 3-chloroperbenzoic acid are portionwise added to the obtained solution at 25 °C under stirring. After stirring for further 2 hours the reaction mixture is washed 3 times with 300 ml of 5 % aqueous sodium hydrogen carbonate solution each. The chloroform solution is dried over anhydrous sodium sulfate and evaporated. The residue is subjected to chromatography on a silica gel column by using ethyl acetate first and then a 8:2 mixture of ethyl
SUBSTITUTESHEET
acetate and methanol as eluent. After evaporating the fractions containing the aimed compound, a yellow oily residue is obtained in a yield of 2.5 g (30.1 %) , Rf: 0.4 (A). Method b)
3.50 g (15 mmol) of 3-{[2-(dimethylamino)benzyl]- -thio}-4,5-dimethyl-l,2,4-triazole dihydrochloride salt (see Example 1) are added in small portions to a mixture containing 120 ml of 5 % aqueous sodium hydrogen carbon- ate solution and 120 ml of chloroform under stirring. After separation the aqueous phase is extracted twice with 60 ml of chloroform each. The chloroform solution is filled up to 600 ml with chloroform and 8.0 g (22 mmol) of 55 % 3-chloroperbenzoic acid are added in one portion. After 3 minutes following the dissolution of perbenzoic acid the reaction mixture is washed 3 times with 50 ml of water each and the chloroform phase is set aside. 1.9 g
(15 mmol) of sodium sulfite are dissolved in 50 ml of water and 15 ml of 2 N (30 mmol) hydrochloric acid are added. The solution smelling of sulfur dioxide is immediately dropwise added to the previously separated aqueous phase during about 5 minutes at room temperature. The pH value of the intensely yellow solution is adjusted from 1 to a value of 7 to 8 by adding 5 % aqueous sodium hydrogen carbonate solution. The mixture is extracted 3 times with sodium hydrogen carbonate solution, then the mixture is extracted 3 times with 120 ml of chloroform each. The chloroform phases are combined with the chloroform phase previously set aside, cautiously shaken once with 20 ml of water, dried over anhydrous sodium sulfate and evaporated. The residue is crystallized from ethyl acetate, filtered and dried on air to give the aimed product in a yield of 2.4 g (57 %) , m.p.: 104-106 °C.
SUBSTITUTESHEET
Examples 16 and 17
By following the process described in Example 15, Method a) or b) , compounds of general formulae (la) and (lb) shown in Table 11 are obtained. In these compounds Ri, R2 and n are as given in Table 11.
Table 11
Example General *1 R2 M.p. Rf Solvent Method No. formula °C system
16 ( la) CHn <£ 145-148 0.6 B a)
17 ( lb) CH, CH3 oil 0.3 ) or b) , resp.
15 Example 18
Preparation of 3-{ [2- (dimethylamino) benzyl] -
-sulfinyl}-2-methyl-l, 2 , 4-triazole
Method a)
After dissolving 7.0 g (28 mmol) of the compound
20 prepared according to Example 9 in 850 ml of methylene chloride, 9.6 g (31 mmol) of 55 % 3-chloroperbenzoic acid are added at 25 °C under stirring. After 30 minutes the reaction mixture is washed 3 times with 250 ml of 5 % aqueous sodium hydrogen carbonate solution each, then 5 dried over anhydrous sodium sulfate. After evaporating the organic solution under reduced pressure, the oily residue is subjected to chromatography on silica gel by using ethyl acetate as eluent. After evaporating the fractions containing the aimed compounds an oily residue 0 is obtained in a yield of 1.5 g (20.2 %) , Rf: 0.45 (B) . Method b)
After dissolving 3.75 g (15 mmol) of the compound prepared according to Example 9 in 600 ml of chloroform, 6.0 ml (27 mmol) of 78 % 3-chloroperbenzoic acid are 5 added at, 25 °C. After vigorously stirring the reaction
SUBSTITUTESHEET
mixture for 5 minutes, 56 ml of 5 % aqueous sodium hydro¬ gen carbonate solution (33 mmol) are added, then the two- phase mixture is vigorously stirred for additional 5 min¬ utes. Simultaneously, 4.5 g (35 mmol) of sodium sulfite are dissolved in 50 ml of water, 36 ml of 2 N (72 mmol) hydrochloric acid are dissolved in 50 ml of water, 36 ml of 2 N (72 mmol) hydrochloric acid are added and the thus-prepared sulfurous acid solution is quickly dropped to the above reaction mixture. The yellow heterogeneous reaction mixture is vigorously stirred for 5 minutes, then, after separating the two phases, the chloroform phase is washed 3 times with 120 ml of 5 % sodium hydrogen carbonate solution each. The aimed product is obtained by using the procedure described under Method a) of Example 18. A yield of 1.2 g (32 %) is obtained. Examples 19 to 24
By following the procedure described in Example 18 compounds of general formula (la) shown in Table 12 are obtained. In these compounds Rj_, R2 and n are as given in Table 12.
Table 12
Example l R2 n M.p. Rf Solvent Method
No . °C system
19 CH3 H 1 94- 96 0.2 B a) or b ) , resp.
20 H H 1 143-146 0. 1 B a) or b ) , resp.
21 H CH3 1 oil 0.35 A a) or b ) , resp.
22 <°> CH3 1 121-124 0.45 B a ) or b ) , resp.
23 H 3 CO- c CH3 2 165-168 0.9 c a )
24 H3co" θ CH3 1 oil 0.65 c b )
SUBSTITUTESHEET
Claims
1. 1,2,4-Triazole derivatives of the general formulae (la)
Rl and 2, which are the same or different, stand for hydrogen; Cι_4 alkyl or C _4 alkenyl group; or a phenyl group optionally substituted by C _4 alkyl or alkoxy group; and n is 0, 1 or 2, and acid addition salts of these compounds.
2. A compound selected from the group consisting of 3-{ [2-(dimethylamino)benzyl]thio}- ,5-dimethyl- -1,2,4-triazole, 3-{[2-(dimethylamino)benzyl]sulfinyl}-4,5-dimethyl- -1,2,4-triazole,
3-{[2-(dimethylamino)benzyl]thio}-2-methyl-l,2,4- -triazole,
3-{ [2-(dimethylamino)benzyl]thio}-2,5-dimethyl- -1,2,4-triazole
SUBSTITUTESHEET and the acid addition salts of these compounds.
3. A pharmaceutical composition, which comprises as active ingredient a novel 1,2,4-triazole derivative of general formula (la) or (lb) , respectively, wherein Ri, R2 and n are as defined in claim 1, or a pharma¬ ceutically acceptable acid-addition salt thereof in admixture with carriers and/or additives commonly used in the pharmaceutical industry.
4. A process for the preparation of novel 1,2,4- -triazole derivatives of general formulae (la)
and
Rl and R2, which are the same or different, stand for hydrogen; C _4 alkyl or Cι_4 alkenyl group; or a phenyl group optionally substituted by C1..4 alkyl or alkoxy group; and n is 0, 1 or 2, and acid addition salts of these compounds , which comprises reacting a compound of general formula (Ila)
SUBSTITUTE SHEET 
or (lib) ,
R2
respectively, wherein Ri and R2 are as defined above, or a tautomer thereof with a compound of general formula (III),
wherein X means a leaving group, or with an acid-addition salt thereof and, if desired, transforming the obtained compound of general formula (la) or (lb) , respectively, wherein Ri and R2 are as defined above and n is zero, to a compound of general formula (la) or (lb) , respectively, wherein Ri and R2 are as defined above and n is 1 or 2, by oxidation and optionally by subseguent reduction and/or converting an obtained base to an acid-addition salt by using an organic or inorganic acid or converting an obtained salt to the corresponding free base.
SUBSTITUTESHEET
5. A process as claimed in claim 4, which comprises reacting the compound of general formula (III) in the form of one of its acid-addition salts.
6. A process as claimed in claim 4 or 5, which comprises reacting the compound of general formula (Ila) or (lib) , respectively, or a tautomer thereof with the compound of general formula (III) or an acid-addition salt thereof in a dipolar aprotic solvent.
7. A process as claimed in claim 6, which comprises using dimethylformamide, dimethylacetamid or dimethyl- sulfoxide as solvent.
8. A process as claimed in any of claims 4 to 7, which comprises carrying out the oxidation with 3-chloro¬ perbenzoic acid in a halogenated hydrocarbon.
9. A process for the preparation of a pharma¬ ceutical composition, which comprises mixing as active ingredient a novel 1,2,4-triazole derivative of the general formula (la) or (lb), respectively, wherein Ri, R2 and n are as defined in claim 4, or a pharmaceutically acceptable acid-addition salt thereof, prepared by using the process claimed in claim 4, with carriers and/or additives commonly used in the pharmaceutical industry and transforming them to a pharmaceutical composition.
10. A method for protecting the gastric ucosa and inhibiting the ulcers of the digestive system, character¬ ized by administering to a patient to be treated a thera¬ peutically effective amount of an 1,2,4-triazole deriva¬ tive of the formula (la) or (lb) , respectively, wherein Rl, R2 and n are as defined in claim 1, or a pharma- ceutically acceptable acid-addition salt thereof alone or in the form of a pharmaceutical composition.
SUBSTITUTESHEET
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU55333/94A AU5533394A (en) | 1993-11-12 | 1993-11-12 | Ulcer-inhibiting triazole derivatives, pharmaceutical compositions containing them and process for preparing same |
| PCT/HU1993/000063 WO1995013268A1 (en) | 1993-11-12 | 1993-11-12 | Ulcer-inhibiting triazole derivatives, pharmaceutical compositions containing them and process for preparing same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/HU1993/000063 WO1995013268A1 (en) | 1993-11-12 | 1993-11-12 | Ulcer-inhibiting triazole derivatives, pharmaceutical compositions containing them and process for preparing same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1995013268A1 true WO1995013268A1 (en) | 1995-05-18 |
Family
ID=10982877
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/HU1993/000063 WO1995013268A1 (en) | 1993-11-12 | 1993-11-12 | Ulcer-inhibiting triazole derivatives, pharmaceutical compositions containing them and process for preparing same |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU5533394A (en) |
| WO (1) | WO1995013268A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6323230B1 (en) * | 1997-06-05 | 2001-11-27 | Geange Ltd. | Use of nitrogen heterocyclic aromatic derivatives in the topical treatment of the epithelial tissues diseases |
| WO2002064135A1 (en) * | 2001-02-09 | 2002-08-22 | Telik, Inc. | Heterocyclic inhibitors of glycine transporter 2 |
| JP2005513035A (en) * | 2001-11-28 | 2005-05-12 | ソシエテ・ド・コンセイユ・ド・ルシエルシエ・エ・ダアツプリカーション・シヤンテイフイツク・（エス．セー．エール．アー．エス） | 5-sulfanyl-4H-1,2,4-triazole derivatives and their use as pharmaceuticals |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0354788A1 (en) * | 1988-08-10 | 1990-02-14 | Nippon Chemiphar Co., Ltd. | Novel imidazole derivatives |
-
1993
- 1993-11-12 WO PCT/HU1993/000063 patent/WO1995013268A1/en active Application Filing
- 1993-11-12 AU AU55333/94A patent/AU5533394A/en not_active Abandoned
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0354788A1 (en) * | 1988-08-10 | 1990-02-14 | Nippon Chemiphar Co., Ltd. | Novel imidazole derivatives |
Non-Patent Citations (2)
| Title |
|---|
| CHEMICAL ABSTRACTS, Vol. 114, No. 3, issued 1991, 21 January (Columbus, Ohio, USA), HONMA, YASUSHI et al., "Preparation of Imidazole Derivatives as Antiulcer Agents", page 709, the Abstract No. 23964d; & JP,A,02 049 727. * |
| CHEMICAL ABSTRACTS, Vol. 116, No. 5, issued 1992, 03 February (Columbus, Ohio, USA), YAMAKAWA, TOMIO et al., "Synthesis and Structure-Activity Relationships of N-Substituted 2-([2-Imidazolylsulfinyl]Methyl)Anilines as a New Class of Gastric Hydrogen/Potassium Ion-ATPase Inhibitors", page 18, the Abstract No. 33918x; & CHEM. PHARM. BULL., * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6323230B1 (en) * | 1997-06-05 | 2001-11-27 | Geange Ltd. | Use of nitrogen heterocyclic aromatic derivatives in the topical treatment of the epithelial tissues diseases |
| WO2002064135A1 (en) * | 2001-02-09 | 2002-08-22 | Telik, Inc. | Heterocyclic inhibitors of glycine transporter 2 |
| US6894054B2 (en) | 2001-02-09 | 2005-05-17 | Telik, Inc. | Heterocyclic inhibitors of glycine transporter 2 |
| JP2005513035A (en) * | 2001-11-28 | 2005-05-12 | ソシエテ・ド・コンセイユ・ド・ルシエルシエ・エ・ダアツプリカーション・シヤンテイフイツク・（エス．セー．エール．アー．エス） | 5-sulfanyl-4H-1,2,4-triazole derivatives and their use as pharmaceuticals |
Also Published As
| Publication number | Publication date |
|---|---|
| AU5533394A (en) | 1995-05-29 |
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