前苏联专利SU1419518A3 Method of producing derivatives of 1,2,5-thiadiazole or nontoxic pharmaceutically acceptable salts,

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专利摘要:
Histamine H2-receptor antagonists of the formula <IMAGE> wherein A, m, Z, n and R<1> are as defined herein, and their nontoxic pharmaceutically acceptable salts, hydrates and solvates are novel anti-ulcer agents which are prepared by ring closure of a substituted ethanediimidamide of the formula <IMAGE>
公开号:SU1419518A3
申请号:SU833568849
申请日:1983-03-28
公开日:1988-08-23
发明作者:Рей Креншо Ронни；Антонио Алджери Альдо
申请人:Бристоль-Мейерз Компани (Фирма)；
IPC主号:

专利说明:

The invention relates to a method for producing 1,2,5-thiadiazole derivatives of the general formula
A- (CH2) t - g- (CH2) n - NH-v-NHR,
R
in which R is hydrogen, s, -Cj-alkyl, Q
benzyl; ha - O or 1; n - 2 or 3;
; - hydrogen, sulfur, methylene; And - groups "with
t% ij
d - ° -d-in - ° "-f
N-CH5-0-N-CH2-G-.
where Rj and R - C, -C, -alkyl or together with nitrogen form a piperidine, pyrrolidine or tetrahydropyridyl ring or their non-toxic pharmaceutically acceptable salts, hydrates or solvates.
The purpose of the invention is to develop a preparative method for producing new 1,2,5-thiadiazole derivatives having H-receptor histamine antagonists activity that inhibit gastric acid absorption and are useful for the treatment of peptic ulcers and other pathological hypersecretory conditions .
Example 1. 3-Amino-A- 3- (3-pyperidinomethylphenoxy) propylamine 6 -1, 2, 3-thiadiazole.
A. (3-Piperidinomethylphenoxy) propyl ethanediimidamide trihydrochloride.
A suspension of 1-oxide of 3-amino-4- 3- (3-piperidinomethylphenoxy) propyl-, 2,5-thiadiazole (17.1 g, 47.0 mmol) in 450 ml of methanol is treated with 38 ml of concentrated HCl. The resulting solution is stirred for 3 hours at ambient temperature. Concentration of the solution followed by azeotropy. Distillation of water with absolute ethanol gives colorless crystals. They are suspended in 200 ml of absolute ethanol, filtered and dried under vacuum, yielding 16.6 g (82.6%).
with
J
0
0
50
H
Q
compound, m.p. 205-222 ° C (decomp.). Recrystallization from a 50% mixture of methanol with ethyl acetate gives an analytical sample, m.p. 206-216 with (decomp.).
Calculated,%: C, 47.84; H 7.08; N 16.41.
CnH NyO-3HCl.
Found,%: C 47.56; H 7.18; N 16.75.
B. 3-Amino-4- 3- (3-piperidinomethylphenoxy) propylamino -1,2,5-thiadiazole.
A stirred suspension of N- 3- (3-piperidinomethylphenoxy) trihydrochloride was propyl ethanediimidamide (2.13 g,
5.0 mmol) (prepared in stage A) in 20 ml of dimethylformamide (DMF) is treated with sulfur monochloride (2.02 g, 15.0 mmol) and stirred for 4 hours. The resulting mixture is poured carefully
in 200 ml of water and alkalinized with potassium carbonate. The mixture is extracted with three portions of 50 ml of methylene chloride and, after drying over magnesium sulfate. neither concentration is obtained
2.1g of dark resinous substance containing the product. The product is purified by preparative high pressure liquid chromatography on silica using methylene chloride (100): 2-propanol (10): ammonium hydroxide (0.5) as the mobile phase. Corresponding fractions give 0.89 g of the title compound, which gives, with fumaric acid in n-propanol, 0.76 g (21.4%) of the title compound.
in the form of crystalline fumarate salt, so pl. 187-187.5 ° C. High pressure liquid chromatography (HPLC) shows a purity greater than 99%.
Calculated,%: C 56.27; H 6.71; N 17.27; S 7.90 ..
(C H gNsOS). .
Found,%: C 56.09; H 6.36; N 16.98; S 8,08.
A portion of the fumarate is suspended in water, neutralized with potassium carbonate and extracted with methylene chloride. The methylene chloride is concentrated, and the free base of the target compound crystallizes out; m.p. 43-. A portion of the free base is converted to the hydrochloride salt, m.p. 138-140 C.
Calculated,%: C 53.18; H 6.83; N 18.24; S 8.35.
With „H j fOS-HCl.
Found,%: C 53.14; H 6.88; N 18.49; S 8.74.
EXAMPLE 2. H-lmino-4- 2- (5 dimethylamino-methyl-2-fyp Lp) methyloethyl ethylamino 1,2,5-thiadiazole.
A. Trihydrochloride hydrate (5-dimethylaminomethyl-2-furl) methyl ethyl ethyl J ethanediimidamide,
A suspension of 1-oxide of 3-amino-4- | 2- (3-dimethylaminomethyl-2-furyl) -methyl tis ethylamino -1,2,5-thiadiazl (6.59 g of 20.0 mmol) in 200 ml of methane is slightly heated to achieve a polystyrene dissolution, then treated with 13.3 ml of concentrated HC1. After stirring at ambient temperature for 2.5 hours, the solution is concentrated and the residue is triturated with 70 ml of absolute ethanol. The crystals are collected by filtration and dried under vacuum to give 4.3 g (52%) of the title compound, m.p. 1b6-169 ° C (decomposition).
Calculated,%: C 35.08; H 6.38; N 17.05; S 7.80.
C, gig, N50S-3HC1 H O.
Found,%: C 34.85; H 6.24; N 17.45; S 7.97.
B. 3-Amino-4- | 2- (3-dimethylamino-methyl-2-furyl) methylthio eti.pamino {- 1,2,5-thiadiazole.
To a stirred suspension of trihydrochloride hydrate (5-dimethyl-aminomethyl-2-furyl) methylthio ethyl ethanediimidamide (12.3 g, 30.0) prepared in stage A, 7.2 ml of sulfuric chloride (12.1 g) are added to 150 ml of DMF g, 90 mmol). After stirring for 4 hours at ambient temperature, approximately half of the DMF is removed under reduced pressure. The remaining black solution was poured into 1 liter of water, alkalized with potassium carbonate and extracted first with ethyl acetate and then with chloroform. After drying over magnesium sulphate, filtration and concentration, 9.0 g of a black resin containing the product are obtained. This product is purified by preparative high pressure liquid chromatography on silica using a mobile phase with -1y of ethyl acetate (100: 2) propanol (10): Hydroxy C-1MMS1HII (0.5). Soot
but
, ten
15
20
25
thirty
35
40
45
50
18
Veterinary fractions yield 1.24 g of the title compound as a gum.
Treatment of a portion of this product with an equivalent amount of 2N PS in methanol gives the hydrochloride salt of the target compound.
Calculated,%: C 41.18; H 5.76; N 20.02; S 18.33.
C, H, N5.S O-HC1.
Found (corrected for 1.65%),%: C 40.54; H 5.70; N 19.39; S 18.44.
Treatment of the product with an equivalent amount of cyclohexyl sulfamic acid in acetone gives the cyclohexyl sulfamate salt of the target compound, m.p. 93-95 ° C.
Calculated,%: C, 43.88; H 6.55; N 17.06; S 19.53.
C, H ,,
CbH, NO; jS.
N
Found,%: C 43.77; H 6.17; 17.21; S 19.58.
Example 3. 3-Amino-4- | 2- (5-dimethylaminomethyl-4-methyl-2-thienyl) methylthio ethyl-amino -1,2,5-thiadiazl.
A. Trihydrochloride (5-dimethylaminomethyl-4-methyl-2-thienyl) -methylthioethylI ethanediimide.
A stirred solution of 1-oxide of 3-amino-4- 2-; (5-dimethylaminomethyl-4-methyl-2-thienyl) methylthio ethylamino-1,2,5-thiadiazole (17.9 g, 50.0 mmol) prepared According to the method described above, in 500 ml of methanol, 33.3 mm of concentrated HC1 is discarded. After stirring for 3 hours, the reaction mixture was concentrated and the excess water was removed by azeotropic concentration with absolute ethanol, to give an almost colorless crystalline residue. The residue is triturated with 200 ml of absolute ethanol at 0 ° C, filtered and dried to give 16.9 g (80%) of the title compound, m.p. 206- (decomposition;). Recrystallization from a 50% mixture of methanol and ethyl acetate gives a product having a mp. 210-222 ° C (decomposition).
Calculated,%: C 36.92; H 6.20; 16.56; S 15.17.
N
C ,, H, NjS ,,. 3HCl.
Found,%: C 36.76; H N 16.97; S 15.54.
B. 3-Amino-4- 2- (5-dimethylamino-methyl-4-methyl-2-thienyl) methyl ethylamino | -1,2,5-thiadiazole.
To a stirred suspension of trihydrochloride (5-dimethylaminomethyl51
4-methyl-2-thienyl) methylthio ethyl ethanediimidamide (6.34 g, 15.0 mmol) prepared in step A, 6.1 g (45.0 mmol) of sulfur monochloride are added to 60 ml of DMF. After stirring for 4 hours at ambient temperature, the reaction mixture is poured into 800 ml of water, made basic with potassium carbonate and extracted several times with 100 ml portions of methylene chloride. The extracts are dried over magnesium sulfate, filtered, and concentrated to give 3.4 g of a black gum containing the product. The product is purified by preparative high pressure liquid chromatography on silica using methylene chloride (100: 2-propanol (10): ammonium hydroxide (0.5) as the mobile phase. Further purification is achieved by additional liquid chromatography at high pressure on silica using methylene chloride (100): methanol (2.5): ammonium hydroxide (0.5) as the mobile phase. Relevant fractions give the target compound (purity about 98%). Treatment of the product with an equivalent amount by 2 NHH, gives the hydrochloride salt of the target compound.
Calculated,%: C 41.09; H 5.84; N 18.43; S 25,32.
C, H, NjS.-HCl.
Found (adjusted for 0.51% H,),%: C 40.78; H 5.63; N 18.31; S 25.44.
EXAMPLE 4. 3-Amino-4- 3- (3-pyrrolidinomethylphenoxy) propylamino - 1,2,5-thiadiazole.
A. Trihydrochloride (3-pyrrolidinometiAphenoxy) prepil ethane-diimide-amide.
A suspension of 1-oxide, Z-amino-4-3- (Z-pyrrolidine-methylphenoxy) propyl-amino-1,2,5-thiadiazole (13.4 g, 38.3 mmol), prepared by a known method, in 350 ml of methanol - 25.5 ml of concentrated HC1 are used. The resulting solution was stirred for 3 hours at ambient temperature. Concentration of the solution followed by azeotropic removal of water with absolute ethanol gave the product. The crystalline residue is triturated with 150 ml of absolute ethanol, filtered and dried.
186
giving 10.8 g of the title compound,
m.p. 195-203 s (decomp.).
Calculated,%: C 46.55; H 6.84; N 16.97.
СН-15 50-ЗНС1.
Found,%: C 46.55; H 6.93; N 16.93.
B. H-Amino-4- 3- (3-pyropolydine-methyl-phenoxy) propylamino -1,2,5-thiadiazole.
A stirred suspension of trihydrochloride (3-propanolidinomethyl-phenoxy) propyl ethylene imide (8.25 g of 20.0 mmol) obtained in stage A in 80 ml is treated with sulfur monochloride (5.4 g of 40.0 mmol and stirred in nitrogen atmosphere for 3 hours. Concentrating the reaction mixture gives a dark gum, which is suspended in 500 ml of water, made basic with potassium carbonate and extracted with three 100 ml portions of methylene chloride. The extracts are dried over magnesium sulfate, filtered and concentrated to give 7.5 g of dark gum, containing product. The product is cleaned. using preparative high pressure liquid chromatography on silica using methypenchloride (100): 2-propanol (5): ammonium hydroxide (0.5) as the mobile phase. The fractions containing the desired product are combined and concentrated, yielding l, 64 g (24.4%) of the purified desired product. Treatment of the product in absolute ethanol with an equivalent amount of 2 H.HCl gives the hydrochloride salt of the target compound (1.13 g): mp. 138-140 C.
Calculated,%: C, 51.95; H 6.54; N 18.93; S 8.67.
C gHjjNjOS-HCl.
Found,%: C, 51.97; H, 6.36; N 18.63; S 8.76.
PRI me R 5. Z-Amino-4- 3- (3-piperidinomethylphenoxy) propylamino) - 1,2,5-thiadiazole.
This example is a variation of Example 1, Stage B, in which less sulfur monochloride and a shorter reaction time are used.
To a stirred suspension of N-3- (3-piperidino 1-methylphenoxy) propyl trihydrochloride Zetanedimidamide (12.08 g 28.3 mmol) in sulfuric acid are added sulfur monochloride (7.64 g.
7
56.6 mmol) and the mixture is stirred under nitrogen for 3 hours. The DOP is removed under reduced pressure, leaving a black gum, which is suspended in water, made basic with potassium carbonate and extracted with 3x100 ml of methylene chloride. The combined extracts are dried over magnesium sulphate, filtered and concentrated to a black gum. This resin is purified by preparative liquid chromatography at lIC under pressure on silica using a mixture of methylene chloride (100): 2-propanol (5): ammonium hydroxide (0.5) as the mobile phase. The appropriate fractions give 3.1 g of the desired product as a dark oil, which gives with fumaric acid in n-propanol 2.66 g (23.2%) of the target compound as a crystalline fumarate salt, m.p. 186-186.5 C. HPLC indicates 99% purity.
Calculated,%: C 56.27; And 6.71; N 17.27; S 7.90.
(WITH,, ), .
Found,%: C 56.27; H 6.96; N 17.31; S 7.98.
Example 6. 3-Amino-4- 3- (3-piperidinomethylphenoxy) propylamino-1,2,5-thia Diazole.
In Example 1, Stage B, sulfur dichloride is used instead of sulfur monochloride.
To a stirred suspension of N-L3- (3-pyridinomethylphenoxy) rohydride trihydride ethanediimidamide (854 mg,
2 mmol) in 6 ml of TMP in the atmosphere of azo- I
dichloric sulfur (206 mg, 2 mmol) in 2 ml of D11F was added in an ice bath. The reaction mixture is stirred at ambient temperature and the desired compound is obtained.
PRI me R 7. 3-Methylamino-4- 3- (3-piperidinomethylphenoxy) propyl-, 2,5-thiadiazole.
A. N-Methyl-S (3-piperidine-methylphenoxy) -propyl-ethanediimidamide trihydrochloride.
A suspension of 1-oxide, 3-methylamino-4- 3- (3-piperidinomethylphenoxy) -propyl amino, 2,5-thiadiazole (4.13 g of 10.9 mmol) in 95 ml of methanol is treated with 7.2 ml of concentrated HC. After stirring and at ambient temperatures for 3 hours the solution is concentrated and the residue grows 188
It is treated with acetone, filtered and dried, yielding 4.35 g (90.4%) of the product. The sample is recrystallized from isopropyl alcohol to give the title compound, m.p. 207-225 ° C (decomp.).
Calculated 1: o,%: C 49.03; H 7.33; N 15.89.
c:, 8Hj, N50-3HCl.
Found (corrected, for 0.94%. H.0),%: C 49.37; H 7.35; N 15.71.
B. 3-Methylamino-4- 3- (3-piperidino-methylphenoxy) propylamino -1,2,5-thiaiazole.
S-N-MeTHJi-N-3- (3-piperidinomethylphoxy) -propyl ethanediimidamide trihydrochloride sms (3.74 g, 8.47 mmol) obtained in stage A, 34 ml of methylene chloride and 3.5 ml of triethylamine are treated with N, N-thioisobthalimide (; T. Solvate) (3.36 g, 8.46 mmol) and stirred for 1 hour. The mixture was washed with 30 ml of 10% hydroxide
potassium, dried with magnesium sulfate, filtered, diluted with toluene, and concentrated to give 3.6 g of product. The product is purified by flash chromatography on 90 g.
silica gel (230-400 mesh) using a mixture of ethyl acetate and methanol (95: 5) as the eshoent, yielding 1.9 g (62%) of the desired compound. Processing product equivalent amount
aqueous IS1 in 1-propanol gives the hydrochloride salt of the target compound, m.p. 163.5-164.5 C.
Calculated,%: C 54.32; H 7.04; N 17.60; S 8.06; Cl 8.91.
C, gH2, N50S HCl.
Found,%: C 54.35; H 7.07; N 17.64; S 8.36; Cl 8.86.
PRI me R 8. 3-Benzylamino-4- 3- (3-piperidinomethylphenoxy) propyl HoJ-1, 2,5-thiadiazole.
A. Trihydrochloride K-benzyl-K-CH3- (3-piperidinomethylphenoxy) propyl2-ethanediimidamide.
A suspension of 1-oxide of 3-benzylamino-4 3- (3-piperidinomethylphenoxy) -propylamino} -1,2,5-thiadiazole (5.14 g, 11.3 mmol), prepared according to a known method, in 100 ml of methanol
7.55 tisi is treated with concentrated HC1. After stirring at ambient temperature for 3 hours, the solution is concentrated, and the residue is triturated with acetone, filter
914
Route and dry to give 5.16 g (88%) of the title compound, m.p. 187-205 C (decomposition).
Calculated,%: C 55.75; H 7.03; N 13.55; C1 20.57.
Cj4H ,, N50-3HCl.
Found,%: C 5A, 88; H 6.75; N 13.33; C1 20.20.
B. 3-Benzylamino-4-3- (3-piperidinomethylphenoxy) propnlamino -1,2,5-thiadiazole.
The mixture of M-benzyl-N-3- (3-piperidinomethylphenoxy) -propyl ethanediimidamide trihydrochloride (4.73 g, 9.16 mmol) obtained in stage A, 45 ml of methylene chloride and 3.8 ml of triethylamine is treated with N, N -thiobisphthalimide (DMF solvate) (3.64 g, 9.16 mmol) and stirred for 1 hour. The mixture was washed with 44 ml of 10% KOH, dried with magnesium sulfate, filtered, diluted with toluene and concentrated. The residue is chromatographed on flash chromatography on 110 g of silica gel (230-400 mesh) using ethyl acetate as eluant to give 3.1 g (77%) of the desired compound. Treatment of the product with an equivalent amount of aqueous HC1 in 2-propanol gives the hydrochloride salt of the target compound, m.p. 138-141 C.
Calculated,%: C 60.80; H 6.80; N 14.77; S 6.76; C1 7.48.
C ,, N505-НС1.
Found,%: C 60.53; H 6.64; N 14.99; S 6.91; C1 7.47.
PRI me R 9. 3-Amino-4- 3- (3-piperidinomethylphenoxy) propylaminoJ - 1,2,5-thiadiazole.
In Example 1, Stage B, N, N -thiobisphthalimide is used instead of sulfur monochloride.
A mixture of trihydrochloride. (3-Piperidinomethylphenoxy) propyl-ethanediimidamide (27.3 g, 64.0 mmol) obtained in Example 1, in Step A, 250 ml of methylene chloride and 26.6 ml (192.0 mmol) of triethylamine were treated in portions mi N, N-thiobisphthalimide (DMF solvate) (25.4 g, 64.0 mmol). After stirring at ambient temperature for 1 h, the mixture is washed with 120 ml of 20% KOH, dried. T-magnesium sulfate, filtered and concentrated, then it is taken in 1-propanol and 10.7 ml of 6H.NS1, treated bleaching carbon and filter through celite. The
1810
the solution is concentrated to 100 ml of the volume, diluted with 175 ml of dry 1-propanol and stored at, giving 20.2 g (82.1%) of the crystalline hydrochloride salt of the target compound, m.p. 137-138 ° C.
Calculated,%: C 53.18; H 6.83; N 18.24; S 8.35. With „H j yOS-HCl.
Found,%: C 52.78; H 6.74; N 18.52; S 8.66.
Example 10. 3-Amino-4- 3- (3-pyrrolidinomethylphenoxy) propylamino-1,2,5-thiadiazole.
In Example 4, Stage B, N, N -thiobisphthalimide is used instead of sulfur monochloride.
The mixture of L-HZ- (3-pyrrolidinomethylphenoxy) trihydrochloride) promolpJ-ethanediimidamide (22.0 g, 53.0 mmol) obtained in Example 4 in Step L, 200 ml of methylene chloride and 22 ml of triethylamine are treated with N, N-thiol-phyphthalimide house (DMF solvate) (21.2 g, 53.0 mmol). After stirring at ambient temperature for 1 hour, the mixture is washed with 100 ml of 20% KOH, dried with magnesium sulfate, filtered, diluted with 100 ml of toluene and concentrated. The product is treated with one equivalent of aqueous HC1 in 1-propanol, giving 13.2 g (67%) of the hydrochloride salt of the target compound, m.p. 135-137 ° C. Calculated,%: C 51.95; H 6.54; N 18.93; S 8.67.
CteHz NjOS-HCl.
Found %: C, 51.92; H 6.55; N 19.30; S 9.06.
Example 11. 3-Amino-4- {2-C (5-dimethylaminomethyl-3-thienyl) methylthio ethylamino -1,2,5-thiadiazole.
A. Trihydrochloride (5-dimethylaminomethyl-3-thienyl) methylthio) ethyl 1-ethanediimidamide.
A suspension of 1-oxide of 3-amino-4- 2- (5-dimethylaminomethyl-3-thienyl) methylthio ethylamino -1,2,5-thiadiazole (7.8 g, 22.6 mmol), prepared according to i.e. According to the known method, 15.0 ml of concentrated hydrochloric acid is treated in 150 ml of methanol. After stirring at ambient temperature for 3 hours, the solution is concentrated and the residue is triturated with 1-
propanol, filtered and dried,
giving 7.38 g (80%) of the product. A sample of the product is recrystallized from a mixture of methanol and acetone, yielding 11 o.
left connection, so pl. 190-205 ° C (decomp.)
Calculated,%: C 35.25; And 5.92; N 17.13.
C, H, ZNS1.
Found,%: C 35.03; H 5.93; N 17.39.
B. 3-Amino-4- 2- (5-dimethylamino-methyl-3-thienyl) methylthio ethylamino-1,2,5-thiadiazole.
A mixture of dimethylaminomethyl-3-thienyl) -methyl-thio-1 ethyl-ethidiimidamide trihydrochloride (6.13 g, l5.0 mmol) obtained in stage A is treated with 60 ml of methylene chloride and 6.3 ml of triethylamine with N, N-thiobis and phthalimide ( D11F solvate) (5.96 g, 15.0 mmol) and stirred for 1 hour. The mixture was washed with 100 ml of 10% KOH, dried over magnesium sulfate, filtered, diluted with toluene and concentrated to give 5.1 product . Treatment of the product with a 0.5 molar equivalent of fumaric acid in 1-propanol gives the fumaric acid salt of the indicated compound, m.p. 141-143 s. The 11R spectrum in flllCO-dg shows the presence of about 0.12 mol of 1-propanol.
Calculated,%: C 43.68; H 5.61; N 17.75; S 24.38.
(,, N, S) -C4H404 0.12 CjH50.
Found,%: C 43.4 1; H 5.53; N 17.54; S 24.24.
EXAMPLE 12 3-Lmino-4- 2- (5-piperidinomethyl-3-thienyl) methylthio ethylamino -1,2,5-thiadiazole.
A. N- | 2- (5-piperi dinomethyl-3-thienyl) methyl hydroxyethylthiadiimide, trihydrochloride.
A suspension of 1-oxide of 3-amino-4- (2- (5-piperidinomethyl-3-thienyl) methylthio ethyl amine o | -1,2,5-thiadiazole (6.1 g, 15.8 mmol), 10.5 ml of concentrated HCl is processed in Wb ml of methanol.After stirring at ambient temperature for 3 hours, the solution is concentrated, the residue is triturated with 50 ml of 1-propanol, filtered and dried, yielding 5.86 g ( 83%) of the product. The sample recrystallized from a mixture of methanol and acetone to give the title compound, mp 201-214 ° C (decomp.).
Calculated,%: C 40.13; 1 6.29; N 15.60; S 1A, 29.
C, 5Hj5f rS, .ЗНС1.
19518 2
in,,: C 39,97; H 6.47;
about d. With 1 l. J
N 15.28; s l4,63.
B. 3-Amino-4- {2- (5-Pigleridino-methyl-3-thienyl) methylthio ethylamino-1,2,5-thiadiazole.
A mixture of trihydrochloride (5-piperidinomethyl-3-thienyl) methyl-thio ethyl 1-ethanediimidamide (5.17 g,
11.5 mmol) obtained in Stage A, 48 ml of methylene chloride and 4.8 ml of triethylamine are treated with H, n-thioisobfthalimide (DMF solvate) (4.57 g
5 (11.5 mmol) and stirred for. The mixture is washed with 90 ml of 10% KOH, dried over magnesium sulphate, filtered, diluted with toluene and concentrated to give
0 4.5 g of product. Treatment of the product with one equivalent of cyclohexylsulfonic acid; toads in methciol gives the cyclohexyl sulfamate salt of the target compound, m.p. 142-143 C.
5 Calculated,%: C 45.96; H 6.61; N 15.31; S ,. 23.38.
C, jHj5N5Sj-C6H, 5NOjS. Found,%: With 45.61; H 6.41; N 15.46; S 23.48.
0 Example13. 3-Amino-4- 3- (6-piperidinomethyl-2-p1: ridyloxy) propyl-amino -1,2,5-thiadiazole.
A. 3-Amino-4- 3- (6-piperidinomethyl-2-pyrid1Shoxy) propylamino) -1,2,5-thiadiazole 1-oxide.
A solution of 3- (6-piperidinomethyl-2-pyridyloxy) propylamine (4.65 g
18.6 mmol), obtained according to the known method, in 50 ml of methanol
d is reacted with 3-am1sho-4-methoxy-1,2,5-thiadiazole 1-oxide (2.74 g, 18.6 mmol), giving a solution containing 3-amino-4-3- (6 -piperidinomethyl- 2-pyridyloxy) propylamino -1, 2,5-thiadiazole 1-oxide. The purified sample is melted at 145-147 C.
B. Trihydrochloride (6-piperidinomethyl-2-pyridyloxy) propyl-ethanediimide.
The methanol solution of the product obtained in step A is diluted to 100 ml and 12.4 ml of concentrated HCl is added. The solution is stirred at ambient temperature for 18 hours, concentrated, the residue is dissolved in 80 ml of BORN, and extracted twice with methylene chloride. The aqueous layer is concentrated, treated with n-propanol and concentrated 5
0
with a high vacuum, giving the title compound as a foam.
C. 3-Amino-4- 3- (6-piperidinometi 2-pyridyloxy) propylamine -1,2,5-thiadiazole.
A mixture of the crude product obtained in stage B in 80 ml of methylene chloride containing 7.69 ml of triethyl amine is treated with M, S-thiobis-phthalimide (DIF solvate) (7.35 g, 18.5 mol). After stirring at ambient temperature for 1 hour, the mixture is washed with 50 ml of 4N. The sodium hydroxide, with water, is saturated with an aqueous solution of sodium chloride, dried over sodium sulfate, filtered and evaporated under reduced pressure, to give a crude product. The product is purified by flash chromatography on 100 g of silica gel (230-400 mesh) using ethyl acetate-methanol (95: 5) as eluent. Dawa 3.63 g of the title compound as a viscous oil. Treatment of the product with one equivalent of cyclohexyl sulphamic acid in acetone gives the cyclohexyl sulphamate salt of the target compound, m.p. 125.5-131 C.
Calculated,%: C 50.07; H 7.07; N 18.58; S 12.15.
CibHj NgOS-CeH NO S.
Found,%: C 50.01; H 7.03; N 18.54; S 12.14.
EXAMPLE 14. 3-Lmino-4- 3- (6-dimethylaminomethyl-2-pyridyloxy) propylamino -1,2,5-thiadiazole.
A methanol solution of 3- (6-dimethylaminomethyl-2-pyridyloxy) propylamine prepared according to a known method is reacted with 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide according to according to the general procedure, the resulting 3-amino-4- 3- (6-piperidino-mets-1-2-pyridyloxy) propylamino-1,2,5-thiadiazole 1-oxide is subsequently introduced into the reaction in example 1, step A or in example 1 Step B, or in Example 10, the target compound is obtained.
Example 15. 3-Lmino-4- | 2- (6-dimethylaminomethyl-2-pyridyl) methyl thioethylamino-1,2,5-thiadiazole.
Suspension of 3-amino-4- (6-dimethyl aminomethyl-2-pyridyl) methylthioP ethyl 1
Amino -1,2,5-thiadiazole 1-oxide is subsequently introduced into the reaction according to example 1, stage a or example 1
Step B, or in Example 10, the target compound is obtained.
Example 16. 3-Amino-4- 3- (4-piperidinomethyl-2-pyridyloxy) propyl-amino 3-1,2,5-thiadiazole.
A.3- (4-Piperidinomethyl-2-pyridyloxy) propylamine.
3- (6-Piperidinomethyl-2-pyridyloxy) propylamine is obtained by a known method, except that 2-chloro-6-methylpyridine, replaced by 2-bromo-4-methylpyridine, gives the title compound as an oil.
Calculated,%: C, 67.44; H 9.30; N 16.85.
С „Н„ Н, 0.
Found,%: C 67.54; H 8.98; N 16.55.
B. H-amino-4- 3- (4-piperidino-methyl-2-pyridyloxy) propylamino-1,2,5-thiadiazole 1-oxide.
A solution of the product of stage A (6.5 g, 26.0 mmol) in 90 ml of methanol reacts with 3-amino-4-methoxy-1,2, 5-thiadiazole 1-oxide (3.84 g, 26 , 0. Mmol), get 6,33 g of the product. Recrystallization from a mixture of methanol and acetonitrile gives the target compound, so pl. 154-158 C.
Calculated,%: C, 52.73; H 6.64; N 23.06; S 8.80.
.
Found 7: C 52.72; H 6.30; N 23.32; S 8.74.
B. Trihydrochloride (4-piperidinomethyl-2-pyridyloxy) propyl-zthanediimidamide.
The product of stage B (5.0 g, 13.7 mmol) is dissolved in 80 ml of methanol and treated with 9.1 ml of concentrated HCl. After stirring at ambient temperature for 4.5 hours, the solution is evaporated to dryness under reduced pressure, to give the desired compound.
G. 3-amino-4- 3- (4-piperidinomethyl-2-pyridyloxy) propylamino -1,2,5-thiadiazole.
A mixture of the product obtained in Stage B in 50 ml of methylene chloride and 5.7 ml of triztilamine is treated with S, M-thioisphthalmicide (DMF solvate)
55
5.44 g, 13.7 mmol). After stirring at ambient temperature for 1 hour, the mixture is washed with 40 ml of 4N. NaOH, water, saturated NaCl aqueous solution, dried over sodium sulfate, filtered.
Ib
and evaporated under reduced pressure to give the crude product. Debate
The product is purified by flash chromatography on 90 g of silica gel (230-400 mesh) using a mixture of ethane ketone and methanol (96: 4) as eluent, to give 3.44 g of the title compound as a viscous oil. equivalent to cyclohexyl sulfamic acid in acetone gives the cyclohexyl sulfamate of the target compound, m.p. 124.5.
Calculated,%: C 50.07; H 7.07; N 18.58; S 12.15.
CiGH ,,, NO, S.
Found,%: C 30.47; H 7.12; M 18.33; S 11.87.
PRI me R 17. Z-Lmino-4- 3- 3.- (1,2,3,6-tetrahydro-1-pyridyl) methyl phenoxy-propanolamo -1,2,5-thiadiazo
In Example 15, with the exception that the 3-6-piperid nomethyl-2-pyridyloxy) propylamino used in it is replaced by an equivalent amount of (1, 2, 3,6-tetrahydro-1-pyridyl) methylphenoxy propylamine, 2.31 g of product are obtained . Crystallization from toluene gives the desired compound, so pl. .99.5-104 ° C.
Calculated,%: C 59.10; H 6.71; N 20.27; S 9,28.
WITH,.
Found (corrected for 2.1),%: C 58.78; And 6.71; N 19.90; S 9,26.
Determination of gastric antisecretory activity in rat gastric fistle.
Male Long Eva rats weighing about 240-260 g are used during cannula implantation. The construction and implantation of stainless steel cannula into the inner stack of the anterior complex stomach is carried out according to a known method. The components of the fistula are constructed and procedural procedure is carried out. After the operation, animals are individually housed with sawdust cells, they are given food and water on demand. in the te-jetnie of the entire recovery period. For at least 15 days after the procedure, animals are not used for the purpose of the experiment.
The animals are kept hungry, but yes they need water for

0
five
0
five
0
five
0
five
0
five
1816
20 hours before the test procedure begins. Immediately prior to collection, the cannula is opened and the stomach is gently rinsed with 30-40 ml of warm physiotherapy solution or distilled water to remove any residual content. The catheter is then screwed into the cannula in place of the closing cap and the rats are placed in a transparent plastic rectangular cage, 40 cm long, 15 cm wide and 13 cm high. The bottom of the cage has a slit approximately 1.5 cm wide and 25 cm long, running down to the center, to accommodate a catheter that is attached through it. TaKiiM, the rat is not constrained by 3 actions and can move freely around the cage during the collection periods. The rest of the analysis is carried out in a manner known per se.
Gastric discharges collected during the first hour after gastric lavage are discarded, as they may be contaminated. To evaluate oral administration, the catheter is then removed from the cannula and replaced with a screw-in stopper. Water (2 ml / kg) is orally administered via gastric intubation, and the animal is returned to the cage for 45 minutes. After this period of time, the screw cap is removed and replaced with a catheter, to which a small plastic tube is connected to collect gastric secretions. A 2 hour sample is collected (this is a control secretion), the catheter is removed and replaced with a screw cap. Now, the drug is orally administered in a volume of 2 ml / kg by gastric intubation. After 45 minutes, the plug was removed again, replaced with a catheter connected to a small plastic tube, and another 2-hour sample was collected. The excretions in the second sample are compared with the excretions of the control sample in order to determine the effect of the test drug.
For parenteral evaluation, 111x compounds were injected intraperitoneally or subcutaneously into the animal with a vehicle of the test compound in a volume of 2 ml / kg immediately after discarding the initial 60-minute collection. Collect two hours on the sample (control secretion) and the animal
Injected or intraperitoneally or subcutaneously tested compound in a volume of 2 ml / kg. An additional 2-hour sample is collected, and its excretions are compared with those of the control period to determine the effect of the drug.
Samples are centrifuged and placed in a graduated centrifuge tube to determine the volume. The titratable acidity is measured by titration of a one-milliliter sample to a pH of 7.0 0.02 n. sodium hydroxide using Autobiuret and Electrometric pH-meter (radiometer). The yield of titratable acid is calculated in microequivalents by multiplying the volume in milliliters by the acid concentration in milliequivalents per liter.
Results are expressed as percent inhibition compared to control data. The response dose curves are plotted and the values are calculated using regression analyzes. At least three rats are used for each dose level, and at least three dosage levels are used to determine the response dose curve.
The table shows the gastric antisecretory activity in the gastric fistula of rats.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining derivatives of 1,2, 5-thiadiazole of the general formula
{CH2) m-z-lCH2) n-NHv NHBt
NV
R, is hydrogen, C-C-alkyl, benzyl;
O or 1; 2 or 3; oxygen, sulfur, methylene;
m p
Z
,BUT
- groups
Vpz
N-cH2-n | -;
,-ABOUT-,
where Rj and R - C-Cj-alkyl or
together with nitrogen, they form a piperidine, pyrrolidine or tetrahydropyridyl ring; or their non-toxic pharmaceutically acceptable salts, hydrates or solvates, characterized in that the compound of the general formula
Zimethadin
In example 1
3,481,0
(1.68-5.75)
0.094 37
(0.043-0, .0)
0.774.5
(0.45-1.4)
: 35 A- (CH2) w- - (CH2ln-NH.NHR,
Igl
five
where R, ra, n, z and A have the indicated values;
subjected to interaction with a strong mineral acid in an inert solvent at room temperature with the Subsequent interaction of the obtained compound of General formula
NHR,
45
A- (CH2) ni-Z- (CH2) n-NH-C -C - divariously imterpons.
A- (CH2) ni-Z- (CH2) n-NH-C-C NH NH
where R |, ra, n, z and A have the indicated meanings;
with monochloride or sulfur dichloride, or JJ, N -thio-bisphthalimide at a molar ratio of 1: 1-3 in
inert solvent at a temperature from 0 ° C to room temperature, followed by isolation of the desired product in its free form or in the form of a salt, hydrate or solvate.

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引用文献:

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GB1595291A|1976-09-21|1981-08-12|Smith Kline French Lab|Pyrimidone and thiopyrimidone derivatives|

FI76795C|1979-09-04|1988-12-12|Bristol Myers Co|Process for the preparation of novel, therapeutically useful 3,4-disubstituted 1,2,5-thiadiazole-1-oxides and -1,1-dioxides and novel intermediates|

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AU2222083A|1982-12-14|1984-06-21|Smith Kline & French Laboratories Limited|Pyridine derivatives|AU2222083A|1982-12-14|1984-06-21|Smith Kline & French Laboratories Limited|Pyridine derivatives|

US4593039A|1984-04-02|1986-06-03|Merck & Co., Inc.|1-aryloxy-3--2-propanols|

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WO2022034121A1|2020-08-11|2022-02-17|Université De Strasbourg|H2 blockers targeting liver macrophages for the prevention and treatment of liver disease and cancer|

法律状态:

优先权:

申请号 | 申请日 | 专利标题

US36320782A| true| 1982-03-29|1982-03-29|

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