Versions of method of producing derivatives of 2-pyridine-thiol or acid-additive salts thereof

专利摘要:
The invention relates to derivatives of 2-pyridsh1-thiol (PT), in particular the preparation of compounds of the general formula N-CRi -CH CH-K-CH C-S- (CH) 2NR2 3 where R, is H or C, C is alkyl; alkyl; K - group C (0) Z; Z is non- or substituted with one or more alkyl or halogen; R and R, are independent - H, alkyl, C alkylphenyl or group R, -C (o) -; The K group is in the 3 or 4 position of the pyridine ring, provided that if Rj and R are CH and Z is 4-chlorophenyl, then R cannot be hydrogen, or their acid addition salts, which have a gastro-cytoprotective effect. and can be used in medicine. The goal is to create active substances in a wide spectrum of action of the indicated class. FP synthesis is carried out either from a 2-halogen-substituted pyridine derivative and thioamine (a), and if necessary (if R, H), the resulting product is acylated with a necessary agent or compound R, where R is not hydrogen, in the presence of a reducing agent, or from a 2-thiol-pyridinosubstituted compound and a halogenamine or its acid addition salt (b), moreover, if necessary (with the value of R and Rg H), the treatment is carried out as indicated in variant a. The allocation of the target product is carried out in a free form or in the form of an acid additive salt. Newer PT has an effect on the suppression of acid secretion of the stomach caused by indomethacin, antral and intestinal ulcers of the small intestine and stomach ulcers caused by aspirin. 2 sp.f-ly. 5 tab. CO 00 4 CR Q nCik u sn
公开号:SU1346042A3
申请号:SU853959903
申请日:1985-10-04
公开日:1987-10-15
发明作者:Эзер Элемер；Харшаньи Кальман；Викар Хайналка；Матуз Юдит；Спорни Ласло；Шолноки Эстер；Кути Чаба；Тришлер Ференц；Хегедюш Бела；Каполнаш Марта；Каллаи Анна
申请人:Рихтер Гедеон Ведьесети Дьяр Рт (Инопредприятие)；
IPC主号:

专利说明:

The invention relates to the chemistry of the preparation of new 2-pyridyl-thiol derivatives of the general formula 1
g
Bx
.0
RI
S-CH2-CH2-N:
.2
 T.
where R (is hydrogen or C, - C, -aLksh1; Z is phenyl, which may be substituted by one or more alkyl C, - With groups or halogen atoms;
R and R are independently of each other hydrogen, C, - C4 alkyl;
C, - C, | - alkylphenyl or group
°
The general formula: where, R, has the indicated meanings;
ABOUT
AND
The -C-Z group is in the 3 or 4 position of the pyridine ring, provided that if R and R are methyl, Z is 4-chlorophenyl, then R is not hydrogen; or their acid additive salts with gastrocyto protective action.
The purpose of the invention is to search for a series of 2-pyridine-thiol derivatives of a research institute with gastroprotective action.
PRI me R 1. 2- (2-Amino-ethyl) thio-3-benzoylpyridine HC1,
In a hot solution prepared with 100.0 cm of this solution, 10.88 g (0.05 mol) of 3-benzoyl-2-chloropyridine and 8.51 g (0.075 mol) of HS-CH-CH - NHj-HCl ( cysteamine HC1) ethanol prepared with 50.0 cm and a solution of 9.88 g (0.15 mol) of a 85.0% hydroxide, potassium oxide, was added dropwise within 30 minutes. The reaction mixture is boiled for another 30 minutes, neutralized with concentrated hydrochloric acid, the inorganic salt is filtered off and the solution is evaporated. The residue is dissolved in water, first extracted at pH 4, then at pH 11 with 1,2-dichloroethane, after which the last extract is washed with water and decanted. A salt is formed from the oily residue after distillation with hydrochloric acid ethanol, which is then recrystallized from ethanol. 9.90 g (67.2%) 2- (2
25
 thirty
amino ethyl ethyl-thio-3-benzoylpyridine HC1, mp. 190-192 ° C.
If the reaction between 3-benzoyl 2-5 chloropyridine and cysteamine-hydrochloride is carried out in a concentrated aqueous solution of hydrochloric acid, 2- (2-aminoethyl) -til-3-benzoylpyridine 10 "HC1 is also obtained, m.p. 190-19 c.
1.60 g (o, 04 mol) of sodium hydroxide was diluted in 25. O ml of water, then 4.31 g (0.02 mol) of 3-benzoyl-1,2-dihydro-15 pyridine-2 was added thereto. -thion and 2.32 g (0.02 mol) of 2-chloroethylamine IS1 and the reaction mixture is boiled for 40 minutes.
After cooling, the mixture is extracted at pH-4, then at pH-1I with 20 using 1,2-dichloroethane, after which the last dichloroethane phase is extracted with aqueous hydrochloric acid. The aqueous phase is evaporated and the crystalline crude product is recrystallized from ethanol.
-2- (2-amino-1 yl) -thioZ-3-benzoylpyridine HC1 is obtained, m.p. 190-191 C.
Calculated,%: C 57.04; H 5.13; C1 12.02; N 9.50; S 10.88.
C, q H, N OS-HC 1 (pn weight molecules 294.80).
Found,%: C 56.94; H 5.22; C1 11, 57; N 9.67; S 10.72. IR spectrum (KVg): 1648 cm (); 1284 cM -. (- S-CH -); 1598, 788 ,, 758, 701 cm (-AG); 3200-2300 cm- (-MH).
NMR spectrum (flMCOoig), ppm; 3.13,
40 multiplet (-SCH ,, -); 3.37, multiplet (-N-CH; j-); 7., 1, double doublet (pyridine 4,5-n); 7.2-7.7, multiplet (phenyl ring); 8.11, in; 8.4, double doublet (pyridine 6-H).
45 Example2. 3-Benzoyl-2- 2- (N, M-diacetylamino) ethyl-thio-pyridine.
16.54 g (0.056 mol) 2- (2-amino-ethyl) -thio-3-benzoylpyridine HC1
50 is dissolved in water. The solution is alkalinized, the base is extracted with ethyl acetate, then ground. 50 cm (54.1 g) (0.53 mol) of acetic anhydride are added to the residue, and
55 The reaction mixture is boiled for 30 minutes. After that, the excess anhydride is removed with 50 cm of water and the solution is evaporated. The crystalline residue is triturated with water, filtered, then recrystallized from ethanol. Get 3-benzoyl-2- 2- (M, M-diacetylamino) ethyl thioZ pyridine with so pl. 104-105 0.
The results of the analysis:
Calculated,%: C 63.14; H 5.30; N 8.18; S 9.36.
C, gH, in OjS (molecular weight 342.41).
Found,%: C 63.21; H 5.56; N 8.16; S 9.21.
IR spectrum (KBG): 1704, 1692 amide /; 1642 (, ketone), 1598, 787, 753, 708 (-Ag-). NMR spectrum (CDC1,), ppm: 2.5, singlet (-As-C H,); 3.4, multiplet (-N-CHj); 4.0, multiplet (-N-CH); 7.2, double doublet (pyridine, 4,5-H7 .6, multiplet (phenyl ring);
8.7, multiplet (pyridine, 6-H). Example 2- {C2-Aminoethyl
(thio) -3-p-chlorobenzoyl-pyridine ,. .
In a solution prepared with 30 cm of ethanol, 16.2 g (0.05 mol) of 2-chloro-3- (p-chlorobenzoyl) -pyridine and 8.52 g (0.075 mol) of cysteamine HC) are dropped at room temperature for 30 minutes prepared with 35 cm of ethanol solution of 9.9 g (o, 15 mol) of 85% potassium hydroxide. The suspension is stirred for 23 hours, then neutralized with a concentrated aqueous hydrochloric acid solution. The inorganic salt is filtered off and the ethanol solution is evaporated. The solid residue is dissolved in water, alkalinized to pH 10 and extracted with ethyl acetate. The ethyl acetate phase is blended, and the salt is obtained from the residual oily residue with isopropanol with hydrochloric acid, the salt is obtained, filtered, dried, and then recrystallized from nitromethane. The melting point of the resulting aminoethyl (thio) -3-p-chlorobenzoyl | -pyridine HC} is 171-173 ° C.
Calculated,%: C 51.07; H 4.29; N 8.51; S 9.74.
C ,, H ,, xHC1 (molecular weight 329.24).
Found,%: C 50.94; H 4.17; N 8.70; S 9.46.
J-spectrum (KVg): 3250-2300 (-NH); 1655 cm- (); 1088 cm
-one
(Ar-Cl); 1590, 842, 815, 765
(-AG-).
NMR spectrum (CDCl1 + flMCOtii, M.d .: 3.4, multiplet (-S-CH - and -N-CH -), 7.5, multiplet (pyridine, 4,5-H and phenyl ring); 8.7, double doublet (pyridine, 6-H).
Example 4. 2- 2-Amino.til- (-thio) -3-2,5-dimethylbenzosh1} -pyridine HC 1.
In a hot solution prepared with 200 cm of ethanol, 24.6 g (0.1 mol) of 3- (2,5-dimethylbenzoyl) -2-chloropyridine and 17.04 g (0.15 mol) of cysteamine HC1 for 30 The prepared 100 ml of ethanol solution of 19.8 g of 0.3 mol of 85% potassium hydroxide is added in a minute and the mixture is boiled for 20 minutes and then diluted with 450 cm of water. The pH of the solution is adjusted to 2 and extracted with di-isopropyl ether, after which it is adjusted to pH 1I and extracted with ethyl acetate. The ethyl acetate phase is extruded, the salt is obtained from the oily residue with hydrochloric acid isopropyl, the salt is obtained, filtered, then recrystallized from isopropanol. 16.07 g (49.7%) of 2-2-aminoethyl (-thio) -3-1 2,5-dimethylbenzoyl} -pyridine-HC 1, m.p. 208-21О S.
Calculated,%: C 59.53; H 5.93; N 8.68; S 9.93.
C, gH, B HCl (molecular weight, 322.85).
Found,%: C 59.70; H 6.10; N 8.74; S 9.77.
IR spectrum (KVg): 1660 cm (C "0); 3250-2400 cm- (); 1580, 810, 770 cm (-AG-).
NMR spectrum (CDCl,), ppm: 2.3, singlet (-Ag-CH,); 3.6, singlet (-S-CHj, -, and -N-CHj-); 7.3, multiplet (pyridine, 4,5-H and phenyl, 3.4-6-H); 7.8, double doublet pyridine 6-H; 8.9, X b ... (g N H,).
PRI me R 5. 2 - (- Aminoetht) thio- 2-benzoyl-6-propylpyridin-NS 1.
In cooked with 60 cm ethano-. La hot solution of 23.37 g (0.09 mol) of 4-benzoyl-2-chloro-6-propylpyridine and 20.43 g (0.18 mol) of HS-CH-CH--NH HCI (cysteamine-HC 1) A solution of 22.4 g (0.34 mol) of 85% potassium hydroxide prepared with 90 cm is added, the suspension is boiled for 4.5 hours, then diluted with 500 cm of water. The solution is acidified to pH-1 with concentrated hydrochloric acid, extracted with diisopropyl ether, then the aqueous phase is alkalinized to pH 10 and extracted with ethyl acetate. The ethyl acetate phase is quenched, a salt is obtained from the remaining oily base, and then recrystallized from n-butanol. The resulting 2- (2-amino ethyl) -thio-4-benzoyl-6-propylpyridine HC1 melts at 185 ° C,
Calculated,%: C 54.69; H 5.94; N 7.50; C1 18.99.
C, 7H, 2HCl (molecular weight 373.33).
Found,%: C 54.65; H 5.78; N 7.58; C1 18.58.
J-spectrum (KVg): 3200-2100
($); 1665 cm- ().
NMR spectrum (), ppm: 1.3, triplet (Pr-CH); 2.0, quadruplet (CHz-CH -CHj); 8.2, triplet (Ar-); 3.9, multiplet (-З-СНг- и-N-CH); 8.0, multiplet (AH-H).
EXAMPLE 6 N- (1-phenyl-2-propyl) -2- (2-c1Minoethyl-thio-3-benzoylpyridine.
1.32 g (o, 02 mol) of 85% potassium hydroxide is dissolved in 8 cm of methanol, and a solution of 5.9 g (0.02 mol) of 2- ((2 -aminoethyl) -thio-3-benzoylpyridine hydrochloride and 2.64 cm of benzylmethyl ketone. Then, at 40 ° C for 1 h, O, 19 g (0.0005 mol) of sodium borohydride is added in small portions to the mixture. the mixture is stirred for another 10 hours, then after evaporation and extraction with chloroform, evaporation is carried out again in ether. The weight of the substance dissolved in the ether is 3.41 g, in nitromethane After about becomes crystalline perekris;. polucha- metallization occurs from acetonitrile dissolved 0.7 g of the compound m.p. 92 ° C.
Calculated,%: C, 72.97; H 6.92; N 7.40; S 8.47.
 S (molecular weight 378.53).
Found,%: C 72.90; H 7.00; N 7.25; S 8.90.
346042 6
IR spectrum (KVg): 3300-2200 (OH 4-NH); 1082 (C-OH); 1591, 1570 cm (skeleton aromatic); 5,783, 748, 700 (ArN H Def).
NMR spectrum (SOS1), ppm: 1.1, doublet (-CH); 2,, 4, multiplet (Ar-CHj; S-CHj; N-CH ,,; N-CH) 6.0, singlet (0-CH); 6.8-8.3, multiplet (AH-H). 10 The pharmacological effect of the compounds was investigated in the following tests.
Investigation of gastric damage caused by acid ethanol and cyto-15 protective action).
For the studies, female RG-Wistar rats weighing 120-150 g were used. The animals were forcibly starved for 2 hours, while they received 20 water. To irritate the stomach, a mixture of 1 ml of concentrated hydrochloric acid and 50 ml of absolute ethanol at a dose of 0.5 ml / g of body weight is orally administered. The compounds under study were also orally administered, 30 minutes before the acid treatment with ethanol, and the animals after 1 h were put to sleep by anesthesia with ether. The stomach is removed, then vspryshayut. 30 After cleaning, the wet weight of the stomach is determined, then to determine the swelling of the stomach, the difference between the raw weight and the raw weight of the stomach of untreated 35 (control) animals is calculated. After that, the stomachs are drained and the damage to the stomach is visually examined. The size of the damage indicated in mm is the average 40 length of damage to the stomach. Static evaluation of the results was carried out with the help of a student sample.
The results of the experiment in comparison with 45 of the especially active, known compound cimetidine are shown in Table 1.
and 2. :
Research compounds: 50 A 2- (2-amnnoethnp) -thio-3-benzoylpyridine HC1.
B 3-benzoyl-2 - 2- (N, M-diacetsch1amino.) -Ethyl-thio-pyridine.
C 2-} 2-aminoethyl (-thio) -3-p-chloro-55 benzosht-pyridine HC1.
D 2-p-aminoethyl (-thio) -3- 2.5-.
dimethylbenzoyl-pyridine NS 1.
E 2- (2-aminoethyl) -thio-4-benzoyl 6-propylpyridine -2 HC1,
7 -1
Caused in Shay-rats, reducing the secretion of gastric acid acid.
H-Wistar rats weighing 120-150 g themselves are forced to fast for 24 hours while the animals receive water. Under a weak ethereal anesthesia, the pylorus is transferred. The test compounds are administered, during the intervention, partially orally, partially intraperitoneally. After 4 hours, the rats are euthanized by ether anesthesia, after removal of the stomach, the volume and pH of the stomach contents are measured and the amount of acid is determined by titration. The results of the experiment are presented in table.3.
Suppression of indomethacin-induced antral and intestinal infections.
Female RG-Wistar rats weighing 120-150 g are forced to fast for 24 hours while they receive water. The animals are then allowed to approach the food for 1 hour, 30 minutes after the treatment with the test compound, they are treated orally with indomethacin at a dose of 15 mg / kg. Twenty-four hours after indomethation treatment, the rats are put to sleep by ether anesthesia. After the removal of the stomach and the whole small intestine, the stomach is spiked, then the sum of the ul areas (ulcer index) is determined.
mm
}.
To assess small intestinal intestines, the so-called swollen method is used. The tensile strength at stretching of the small intestine (PPTA), indicated in mm Hg, is well measurable, with progressive formation of ul. Static evaluation of results is performed using a student sample.
The results are presented in table 4.
Suppression of aspirin-induced stomach ulcers.
Female H-Wistar rats weighing 120-, 150 g are forced to fast for 24 hours while they receive water. On the part of the gastric gland by oral dacha prepared with a twin-80 suspension of aspirin at a dose of 100 mg / kg results in formation
1 ulcer of the stomach. The test substance is administered to the animals at the same time as ac460428
pyrin, also oral. After 24 hours, the animals are euthanized, and the brown-red erosions located on the part of the gastric gland are calculated. When estimating, the number of ulcers produced on the stomach is indicated, respectively, their ratio, related to the number of control ulcers found in the stomachs (suppression of ulcers).
The results are presented in table.5.
AU jg is determined based on dose / mortality curves.
LD "g of the proposed compounds is in the range of 300-500 mg / ml p.o.j
As can be seen from the experimental data, the proposed method allows to obtain compounds with gastrocytoprotective effect. 20 Formula of the invention
1. A method of obtaining 2-pyridine-thiol derivatives of the general formula 1

.0
R
"1 N
B.
where R, is hydrogen or C, - C alkyl; Z is phenyl, which may be substituted by one or more alkyl groups or halogen atoms;
R and R, - independently of each other hydrogen. C, - C-alkyl, C, - C ,, -alkylphenyl or a group of the general formula
/
RI-C
where R, has the indicated meanings;
 ABOUT
the group is in position
3 or 4 pyridine rings, provided that if Ri and R are methyl groups, and Z is 4-chlorophenyl, then R, not hydrogen,
their acid addition salts, characterized in that the feed pyridine of the general form 11 0
WITH
hh -v
N x
RI
S

where X is halogen,
K | And Z have the indicated values; they are reacted with a compound of the general formula III
.2. HS-CH -CHr N
Ra
where R j and R, have the indicated meanings, or its acid addition salt, or, if necessary, the obtained compound I, where R and R, are hydrogen, act with an acylating agent or a compound of the general formula.

D. /
where R and R, have the indicated values, with the exception of hydrogen,
in the presence of a reducing agent, followed by separation in free form or in the form of an acid addition salt.
2. A process for the preparation of 2-pyridine-thiol derivatives of general formula I
with
Well
1 N
R (
2
R,
hydrogen or C, -C-alk1; phenyl, which may be substituted by one or more alkyl C, - C4 - groups or halogen atoms J independently of one another hydrogen. C, - C4-alkyl, C ,, -alkylphenyl or a group of the general formula
"ABOUT
where R, has the indicated meanings; ABOUT
IL
group-C-Z is in position

3 or 4 pyridine rings, provided that if Rj and R are methyl groups and Z is 4-chlorophenyl, then R (not hydrogen, or their acid addition salts, characterized in that
pyridine-2-thiol derivative of general formula
0
five
where is r,
one
and
xqt
e
about
N z
have the indicated meanings
subjected to interaction with the compound of the formula V
g X-CH2-CH2-N
R
where X is halogen;
 R, have the indicated meanings, 0 or its acid addition salt, or, if necessary, the obtained compound I, where R and R are hydrogen, act with an acylating agent or a compound of the general formula
35
.
Where
RI and Rj
have the indicated meanings, with the exception of hydrogen,
in the presence of a reducing agent, followed by isolation in a free form of ipi in the form of an acid additive salt.
k) p 0.05 compared with the control group where it is used
only acid-ethanol; kk) p 0.01.
Table I
Table 2
scary
ten
12 intraperitoneally 200130
5 25 intraperitoneally
x) p, 01 compared with the control group mg / kg.
Table4
Indomethacin € p-iO.Ol compared with the treated indometatsion control group.
505t29
eleven
)
65
100
15
Control with asc) U „2.1 mg / kg
1346042
16 T a b i c a 5

权利要求:
Claims (1)
[1]
Claim
1. Method of obtaining derivatives
2-pyridine-thiol of General formula 1
25
35
40
30 where K, is hydrogen or C, is C ₄ -alkyl;
Ζ - phenyl, which may be substituted by one or more alkyl C <- C ₄ groups or halogen atoms;
and K, - independently of each other, hydrogen, C, - C ₄ -alkyl,
C, - C „-alkylphenyl or a group of the general formula Ό
B, C
where K,
45
50
has the indicated meanings;
ABOUT
the group is in position 3 or 4 of the pyridine ring, provided that if K ₂ and K are methyl groups, and Ζ is 4-chlorophenyl, then K is not hydrogen,
or their acid additive salts, characterized in that the pyridine derivative of General formula II
55
N ^x
9
1346042
1 o
where X is halogen,
k, and Ζ have the indicated meanings, are reacted with a compound of general formula III
nz-cng-cng-te
Cs
where and K, have the indicated values or its acid addition salt, or, if necessary, the obtained compound I, where and K, hydrogen, is acted with an acylating agent or a compound of the general formula.
W = 0
to/
where K _g and have the indicated values, with the exception of hydrogen,
in the presence of a reducing agent, followed by isolation in free form or in the form of an acid additive salt.
2. The method of obtaining derivatives
2-pyridine-thiol of General formula I
£
Well
Well
^H 1 5 N-CH ₂ CH ₂ -g <
where K,
hydrogen or C, -C ^ -alkyl; phenyl, which may be substituted by one or more alkylC, - C4 groups or halogen atoms; independently of each other hydrogen, C, - C ₄ -alkyl, C ₇ - C _{) (} -alkylphenyl or a group of the general formula
K _G C
where K has the indicated meanings;
ten
15
20
25
thirty
35
0
group - (5} —Ζ is in position!
3 or 4 pyridine rings, provided that if K _g and I are methyl groups, and 2 is 4-chlorophenyl, then K ₍ not hydrogen,
or their acid additive salts, characterized in that
pyridine-2-thiol derivative of general formula IV
with '°
ΌΊ
Ι N
where K,
δ have the specified values
subjected to interaction with the compound of the formula V
x-cngsng-Νζ ⁴
where X is halogen;
K ^ IR, have the indicated values, or its acid addition salt, or, if necessary, the obtained compound I, where K ₂ and is hydrogen, is acted by an acylating agent or a compound of the general formula
'2 , Ζ
c = o
40
45
where I _g and K ₃ have the indicated values, with the exception of hydrogen,
in the presence of a reducing agent, followed by isolation in free form or in the form of an acid additive salt.
, 0
eleven
1 346042
12
Table 1
Preliminarytreatment NumberexperiencesN Dose,mg-kgoral Edema mg Suppression of edema7o Humorrhagicdamage mm Suppression of hemorrhagic damage, 7 Controlacid ethanol 25 379 + 34 85 + 15 BUT eight 0.05 307 + 42 nineteen 48 + 19 45 BUT ten 0.1 209 + 51 45 * ’ 38 + 18 56 ⁴⁾ BUT 12 1.0 72 + 28 82 * ⁴⁾5 + 1.5 96 ** ^ BUT 12 10.0 22 + 12 ' 95 "’ 6 ± 3 94 ’” Cimetidine eight 25 441 + 82 - 82 + 21 2 Cimetidine eight 100 301 + 42 21 42 + 13 46
x) p <0.05 compared with the control group, only acid-ethanol;
xx) p <0.01.
where used
Table 2
Investigatedcompound Suppression of gastric edema ED _5o mg / kg oralvno Suppression of hemorrhagic damage ED ₅₀ , mg / kg orally BUT 0.2 0.1 AT 1.0 2.0 WITH 10.0 15.0 d 10.0 10.0 E 20.0 25.0
13
1346042
14
T a b l and c a 3 Treatment NumberexperiencesN Dose, mg / kg Selection HC1 / 1 OOg Suppression of HC1 better, Ζ in 4 hoursweights MKMOLbody) Control ten - 564 + 42 - BUT five 5 oral 357 + 35 37 BUT 15 10 orally 350 * 38 38 BUT 15 20 orally 372140 34 BUT five 40 orally 124 * 27 70 * ’ BUT five 6 intraperitoneum scary 505129 eleven BUT ten 12 intraperitoneal tonally 200 + 30 65 * BUT five 25 intraperitoneal neally 0 100 •
x) p + 0.01 compared with the control group ED is _about 50 mg / kg.
Table4
Treatment NumberexperiencesN Dose, mg / kg Enteric ulcer Antral ulcer PPTK after 24 h after treatment with indomethacin,mmHg. Index ulcers, mm / stomach Rats withoutulcers Indomethacin Control 50 15 + material 147 + 11 14.8 15 Indomethacin ++ A ten carrier15 + 5 162 + 14 18.9 3 Indomethacin ++ A 20 25 198 + 9 * ^ 4.0 * ’ *)12 ' Indomethacin ++ pyrenzipin 20 15 + 25 152 + 8 12.0 five Indomethacin *"Cimetidine ten 15 + 50 161 + 8 14.7 2
χ'ι p <0.01 compared with treated indometacion
control group.
15 1346042 16
Table5
- --- _,Treatment Numberexperiences ^N Dose, mg-kg orally Ulcer / stomach Suppression Control with aspirin thirty 100 + carrier material 15.0 + 3.1 - Aspirin + A 20 100 + 1 9.4 + 4.1 38 Aspirin + A ten 100 + 2 8.0 + 3.0 47 *> Aspirin + A ten 100 + 10 3.7 + 4.5 76 * ’
a) AU ₅₀ "2.1 mg / kg

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JPH06135925A|1994-05-17|Intermediate for substituted 3,4-diamino-1,2,5-thiadiazole having activity of antagonizing histamine h2-receptor

同族专利:

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公开号 | 公开日

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YU158385A|1988-04-30|

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HU192875B|1987-07-28|

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ZA857676B|1986-06-25|

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PT81255B|1987-03-23|

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US4713388A|1987-12-15|

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DK455285D0|1985-10-04|

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EP0177907B1|1988-06-01|

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PH21435A|1987-10-15|

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FI853866L|1986-04-06|

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EP0177907A1|1986-04-16|

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CN85107284A|1986-06-10|

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DD238384A5|1986-08-20|

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HUT38907A|1986-07-28|

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NO853935L|1986-04-07|

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JPS6191172A|1986-05-09|

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ES8704460A1|1987-04-01|

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PT81255A|1985-11-01|

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GR852409B|1986-02-04|

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ES547604A0|1987-04-01|

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PL255643A1|1987-01-12|

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FI853866A0|1985-10-04|

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PL146371B1|1989-01-31|

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KR860003212A|1986-05-21|

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AU579665B2|1988-12-01|

---

IL76577D0|1986-02-28|

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DK455285A|1986-04-06|

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AU4832885A|1986-04-10|

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IN162570B|1988-06-11|

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DE3563048D1|1988-07-07|

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AT34739T|1988-06-15|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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AT238200B|1962-03-27|1965-01-25|Degussa|Process for the preparation of new pyridine derivatives|

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JPS5746022B2|1978-06-23|1982-09-30|

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US4304781A|1978-11-30|1981-12-08|John Wyeth & Brother Limited|Treatment of ulcers and hypertension|

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HU194830B|1984-10-05|1988-03-28|Richter Gedeon Vegyeszet|Process for the production of derivatives of piridine|CA1339423C|1988-09-14|1997-09-02|Yuji Ono|Pyridine compounds and pharmaceutical use thereof|

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DE69209576T4|1991-05-10|1997-01-30|Takeda Chemical Industries Ltd|Pyridine derivatives, their production and use|

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AR029289A1|2000-07-05|2003-06-18|Ishihara Sangyo Kaisha|DERIVED FROM BENZOILPIRIDINE OR ITS SALT, FUNGICIDE THAT CONTAINS IT AS AN ACTIVE INGREDIENT, ITS PRODUCTION AND INTERMEDIARY PROCESS TO PRODUCE IT|

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TWI329105B|2002-02-01|2010-08-21|Rigel Pharmaceuticals Inc|2,4-pyrimidinediamine compounds and their uses|

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PL1656372T3|2003-07-30|2013-08-30|Rigel Pharmaceuticals Inc|2,4-pyrimidinediamine compounds for use in the treatment or prevention of autoimmune diseases|

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JP2008518967A|2004-10-29|2008-06-05|ライジェルファーマシューティカルズ，インコーポレイテッド|Substituted pyridine having activity against Syk kinase|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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HU843775A|HU192875B|1984-10-05|1984-10-05|Process for preparing 2-pyridinethiol derivatives|

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