JPS62175474A - 2-guanidinothiazole derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A 2[2-(guanidino)-thiazol-4-ylmethylthio]-ethylamine derivative expressed by formula I (R is phenyl, furyl, thienyl, pyridyl, naphthyl or cyclohexyl; p is 0, 1 or 2) and salt thereof. EXAMPLE:A compound expressed by formula II. USE:An antipeptic ulcer agent having powerful histamine H2 receptor antagonistic action and inhibitory action on gastric acid secretion and further protective action on gastric mucosa. PREPARATION:A compound expressed by formula III (X is halogen) is reacted with an [(substituted thio)acetamid]ethyl disulfide expressed by formula IV to afford the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a compound having anti-peptic ulcer activity and a method for synthesizing the same.

[Conventional technology]

The biggest cause of ulcers in the stomach or duodenum is said to be excessive secretion of gastric acid, and to deal with this, compounds with anticholinergic effects or compounds that neutralize gastric acid are used as anti-ulcer agents. Proposed. It is also known that gastric acid secretion is caused by stimulation of histamine H2 receptors, and it is also known that some substituted phenoxypropylamide derivatives have histamine H2 receptor antagonistic effects and suppress gastric acid secretion. (Japanese Patent Application Laid-open No. 1983-149936, Japanese Patent Application Laid-open No. 55-1309)
No. 47, JP-A-56-7760, JP-A-Sho 56
-8352, JP-A-56-115750, etc.). In addition to the substituted phenoxyglopyramide derivatives, the following general formulas are also available.

[In the formula, 2 is N-+O- or C-NH-A-B group (
A represents CO or SO□ group, B represents an alkyl group having 1 to 6 carbon atoms, or phenyl, pyridyl, pyridyl 1-
oxide, pyrazinyl or chenyl group) is known to have a histamine H2 receptor antagonistic effect (%
Publication No. 0).

[Problems to be solved by the invention] Drugs consisting of compounds with anticholinergic effects are undesirable because they have strong side effects, and drugs for neutralizing gastric acid have poor sustainability, and there is a desire to improve this. .

Compared to conventional compounds that have an antagonistic effect on histamine H2 receptors, this effect is stronger, the suppressive effect on gastric acid secretion is enhanced, and the anti-digestive effect is long-lasting and protects the gastric mucosa. It was hoped that a drug for treating sexual ulcers would emerge.

[Means for solving problems]

The present invention has been made to achieve such an object.

2(2-(guanidino)) having the general formula (1) (wherein R represents a phenyl group, a furyl group, a chenyl group, a pyridyl group, a naphthyl group, or a cyclohexyl group, and p represents an integer of 0 or 1 to 2). -thiazol-4-ylmethylthio)-ethylamine derivative has this desired effect, and this compound (I).

General formula (Ill (In the formula, X represents a halogen atom.) and a compound having.

This was accomplished by discovering that it could be efficiently obtained by reacting with ((substituted thio)acetamido)ethyl disulfide having the general formula (III) (wherein R and p are as defined above).

The furyl group may be either a 2-furyl group or a 3-furyl group, and the chenyl group is also a 2-chenyl group.

It may be any 3-chenyl group. The pyridyl group may be any of 2-pyridyl, 3-pyridyl, and 4-pyridyl, and the naphthyl group may be either α-naphthyl or β-naphthyl.

Such a compound (1) can be synthesized by reacting the starting compound (Ill) with the starting compound (1).

The raw material compound (If) is, for example, disclosed in JP-A-53-14706.
It can be synthesized by the method of Example 1 of No. 9.

Starting compound (III) can be synthesized, for example, by either method A or B below.

(Synthesis Corporation) (In the formula, R represents a phenyl group, a furyl group, a chenyl group, a pyridyl group, a 7-tyl group, a cyclohexyl group 1&:p represents an integer of 0 or 1 to 2, and Y represents a hydroxyl group.) Raw materials Although the reaction between compound (If/) and starting compound (V-1) can be carried out without a solvent, it is generally carried out using an inert organic solvent, such as a halogenated hydrocarbon such as dichloromethane or chloroform, benzene, toluene, Preferably, aromatic hydrocarbons such as xylene, ethers such as tetrahydrodioxane, amides such as dimethylformamide and trimethylacetamide, acetonitrile, dimethyl sulfoxide, etc. are used. Reaction temperature 1 The reaction pressure may be varied depending on the raw material compounds used. 1 It is usually advantageous to select the reaction pressure within the range of 0° C. to reflux temperature under normal pressure. The reaction can be carried out in the presence of a condensing agent, if necessary,
The condensing agent may be appropriately selected from among those commonly used. Examples of the condensing agent include dicyclohexylcardiimide and 1-ethyl-3,3-(dimethylaminopropyl)caldiimide hydrochloride.

(Synthesis method B) (In the formula, R and p are the same as above, and Y represents a).logon atom. ) In the reaction between raw material compound (IV) and (V-2), it is desirable to use the same inert solvent or water as mentioned above alone or in combination as necessary. Reaction temperature 1 The reaction pressure may be changed depending on the raw material compounds used 1 Usually, it is advantageous to select the reaction temperature in the range of 0° C. to reflux temperature under normal pressure.

The reaction is carried out in the presence of an inorganic base or an organic base, and examples of the inorganic base include sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate, and the organic bases include pyridine and triethylamine.

Although the reaction between the starting compound (It) and the starting compound (2) can be carried out without a solvent, it is generally carried out using an inert organic solvent such as a halogenated hydrocarbon such as dichloromethane or chloroform, benzene, toluene, xylene, etc. aromatic hydrocarbon, tetrahydrofuran.

It is desirable to use ethers such as nooxane, amides such as dimethylformamide and dimethylacetamide, acetonitrile, dimethylsulfoxide, and the like. Reaction temperature 1 The reaction pressure may be changed depending on the raw material compound used. 1 It is usually advantageous to select the reaction pressure within the range of 0° C. to reflux temperature under normal pressure. The reaction can be carried out in the presence of a condensing agent, if necessary, and the condensing agent may be appropriately selected from commonly used condensing agents. Examples of condensing agents include dicyclohexylcarbodiimide, 1-ethyl-3
, 3-(dimethylaminopropyl)cardiimide hydrochloride and the like.

To isolate the target compound of the present invention from the reaction solution.

Commonly used means 2, such as liquid-liquid extraction, ion exchange chromatography, column chromatography, thin layer chromatography, and recrystallization, may be used alone or in combination.

The compound of general formula (1) of the present invention can be converted into a corresponding acid addition salt if necessary. Inorganic acid 1 as a salt
Examples include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, etc., and adducts of organic acids such as acetic acid, f-lobionic acid, lactic acid, citric acid, oxalic acid, maleic acid, etc. These salts can be easily prepared by methods known per se.

[For production]

The compound represented by formula (1) of the present invention and its salt are:
Both have a strong histamine H2 receptor antagonistic effect and a strong gastric secretion suppressing effect, and also have a gastric mucosal protective effect.
It can be used as an anti-digestive anti-inflammatory agent. In addition to oral administration, these compounds may be administered intravenously, subcutaneously, or intramuscularly.

Therefore, these compounds are available in a variety of dosage forms.

For example, it can be used in the form of tablets, capsules, liquids or herbal medicines.

〔Example〕

Example 1 2-guanidino-4-chloromethylthiazole 0.49
, the above nosulfide 0.5011 and potassium iodide 0.36IIi dry dimethylformamide (DMF')
After dissolving in 20 ff1j, the mixture was cooled to -15 to -18°C, and 0.13 I of 60% sodium hydride was added under a nitrogen stream. This reaction bath liquid was stirred at -15 to -18°C for 10 hours, and further stirred at 60°C for 1 hour.

DMF was removed under reduced pressure, and the residue was subjected to silica column chromatography to obtain 0.58 g (70%
)Obtained.

MR CDCLs e δ 2.63 (2H,t, J=7.0Hz), 3.
15 (2H-), 3.41 (2Ht, J=7.0
Hz), 3.43 (2H, s), 3.74 (2H, s)
.

3.66 (5H, brs), 6.82 (IH, s), 6
-40 (LH, brs).

7.3 'I-'1.40 (2H, m)IR(w-
', ν) 1603 film
(Ma 8 m C+ s
H19N502 S Calculated value as s 385.0
701 Actual value 385.0714 Examples 2 to 7 The following compounds were synthesized in the same manner as in Example 1.

(Example 2) MR CDCl2. δ 2.64 (2H, t, J=6.5Hz), 3
．． 13(2H,s), 3.37(2H,dt,J
=6.5, 6.5Hz), 3.67 (2H, s), 3.
74 (2Hss), 5.93 (4H, brs), 6.4
7 (IH, a).

6.97-7.07 (IH, m), 7.24-7.37
(5H, m)IR(tMK, ν) 16
50 (C=O)Br Ma I m C, b Calculated value as H21Ns O8s 395.0908 Actual value 395.0919 Example 3) MR cDct, , δ 2.62 (2H, t, J=6.57) 3.20 (
2H,s), 3.37(2H.

s), 3・43 (2H, t, J=6.5Hz), 3.7
5 (2H,s).

4.04 (5H, brs), 6.86 (IH, s
), 6.90-7.00 (2H, m), 7.34
(LH, dd, J=5.0.1.0Hz)IR(m
, ν) 1685.1615Br Calculated value as MaslIC74H1, N50S4 4
01.0473 Actual value 401.0473 (Example 4) MR cDct3. δ 0.87-1.88 (11H, m), 2.45 (2
H, d, J = 7.0Hz).

2.66 (21(, t, J=6.5Hz), 3.2
0(2H,s).

3.46 (2H, t, J = 6.5Hz), 3.74
(2H, s), 3.59 (5H, brs), 6.79 (
IH, 5) IR (α, ν) 1690, 1618B
r Mass C, 6H, Calculated value as N50S3 4
01.1377 Actual value 401.1356 (Example 5) MR coct3. δ 2.54 (2H, t, J=7.0Hz), 3.
27 (2H,t, J = 7.0Hz).

3.11 (2H, s), 3.74 (2H, s), 3.9
6 (2H, s).

4.84 (5H, brs), 6.91 (IH, s), 7
．． 43-7.56 (3H.

m), 7.72-7.90 (4H, m) IR (prepared)
, ν) Calculated value as 1615 Br Mass C2oH23N50S3
445.1064 Actual value 445.1043 (Example 6) MR cDct3. δ 2.64 (2H, t, J=6.5Hz), 3.15 (2
H,s), 3.38 (2H,t, J=6.5Hz)
, 3.80 (2H, s), 3.92 (2H.

s), 4.85 (5H, brs), 7.05 (IH, m
) 7.31 (IH.

d d d IJ=7.5 e 5-0-1.0Hz
) −7,47 (I H, d −J=7.5Hz), 7
．． 80 (IH, ddd, J=7.5e, 7.5.15H
z), 8.47 (IH.

d d , J=5.0, 1.5Hz)IR(m-
' + ν) 1650 (C=O)Br Calculated value as MassIC75H2oN60S 39
6.0861 Actual value 396.0866 (Example 7) MR CDC13, δ 2.66 (2H, t, J = 6.50), 3.21 (2
H, a), 3.39 (2H.

dt, J=6.50, 6.50), 3.67 (2H, s
), 3.76 (2H, s).

1-64 (4H, b r s ), 6.21 (I
H, d, J = 3.0 Hz) e 6.30 (
dd, J = 3.0, 2.0Hz), 6.46 (IH, S
), 6.98-7.07 (IH, m), 7.36 (IH
, d, J=2.0Hz) IR(m-' m ν) 1
650 (C=O) film Na5s C, 4H,, calculated value as N50□S3
385.0701 Actual value 385.0710 (Raw material synthesis example) Synthetic corporation cystamine dihydrochloride 2.371 (0,0105 mol)
was dissolved in 70 m/DMF. While cooling with water, 1.0111 (0,0253 mol) of 60% sodium hydride was added and the mixture was returned to room temperature.

Stirred for 30 minutes. After cooling on ice again, 3.631 (0,021 mol) of 2-(3-furylmethylthio)acetic acid was added to DM.
Solution dissolved in F30- and 1-ethyl-3,3-(dimethylaminozolobyl)cardediimide hydrochloride 4,841
(0,025 mol) was added and stirred for 18 hours.

Extraction was carried out with 200 M of reaction water and 200 d of benzene, the benzene layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain white crystals.

Yield 1.821! mp, 81.6-83.0℃, coct3. δ 2.82 (6H,t, J=6.5Hz), 3.17 (
4H, a).

3.58 (4H, dt, J = 6.5Hz,
6.5Hz) 3.61 (4H, s), 6.39 (2H
, s), 7.15 (2H, brs) 7.35-7.4 (
4H, m) The following compound was synthesized according to the synthesis corporation @mp82.
8. -83.9℃ NMR, CDC2, δ 2.80 (6H, t, J=6.5Hz), 3.28 (
4H,s).

3.54 (4H, dt, J=6.5Hz, 6
．． 5Hz).

3.78 (4H,s), 6.28(2H,d,
J = 3.0Hz)6.32 (2H, dd, J
=3.0Hz, J=2.0Hz)7.15(2H
,brs) ,7.39(2H,d,J =2.0Hz
).

NMR, CDC1, δ 2.85 (6H, t, J=6.5Hz), 3.14 (4
H,s).

3.60 (4H, dt, J=6.5Hz +6.5H
r-).

3.89 (4H, s), 7.2-7.35 (4H, m)
.

7.65-7.75 (2H, m), 7.98 (2H, b
rs).

8.5-8.6 (2H, m) Synthesis method B Cystamine dihydrochloride 2.8111 (0,0125mol
) in 1001 nl of water, add 6,9 liters of potassium carbonate to this
9 g (0,0506 mol) was added. While vigorously stirring under water cooling, 2-(benzylthio)acetyl chloride 5,10 and Sl (0,0253 mol) were added to ooform at 50 mA! A solution dissolved in was added dropwise. After stirring as it was for 1.5 hours, 50% of chloroform was added for extraction.

The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. Methanol the obtained yellow crystals:
Separation was performed by silica gluchromatography using dichloromethane = 3:97 as a developing solvent.

White crystals were obtained.

Yield 432g mp 87.9-89.0°C NMR, CDCt, , δ 2.76 (6H,t, J=6.5Hz), 3.1
5 (4H, s).

3.52 (4H, dt, J=6.5Hz,
6.5Hz).

3.75 (4H, s), 7.10 (2H, brs)
.

7.2-7.4 (10H, m).

The following compound was synthesized according to Synthesis Method B.

mp 64.9-65.5℃ Orchid, cDct, , δ 2.79 (6H, t, J=6.5Hz), 3.22
(4H, s), 3.55 (4H.

dt, J = 6.5Hz, 6.5Hz), 3.99
(4H,s), 6.9-7.0 (4H.

m), 7.11 (2H, brs), 7.2-7
．． 3 (2H, m) NMR, CDC1,, δ 0.9-1.9 (22H, m).

2.44 (4H, d, J=7.0Hz).

2.85 (4H, t, J=6.5Hz).

3.22 (4H, s), 3.64 (4H, dt, J=
6.5Hz.

6.5Hz), 7.36 (2H, b r s )m
p 77.6-79.0℃ Todorokan, coct3. δ 2.61 (6H, t, J=6.5Hz), 3.15 (4
H,s).

&43(4H, dt, J=6.5Hz, 6.5Hz
).

3.90 (4H-s), 7.05 (2H*bra)e
7.4-7.85 (14H, m) - mp 155.1-157.3°C [Histamine H2 receptor antagonism test] Hartley type Sorumotto (male: 300-3501) was beaten on the head and exsanguinated. , Shinzo was removed. Mixed gas (029596: CO2
The right atrium was dissected in Krebs-Henseleit solution to which Krebs-Henseleit solution was aerated with >5%, and suspended in a Magnus tube (30 t/) filled with Krebs-Henseleit solution maintained at 32°C, and the mixed gas was aerated into the Magnus tube. The rest tension was set to 19. Atrial contractions are recorded by a force fist displacement transducer, and a heart rate monitor is linked to measure heart rate 1 (
Ill decide 9.

Histamine (used in the form of dihydrochloride; the same applies hereinafter) was administered at doses of I x 10"M to 3
A dose-response curve of histamine was obtained by cumulatively adding 0 M1 degree into the Magnus tube. After washing the inside of the Magnus tube several times, a test compound (IXIO-'?1xlOM) was added into the Magnus tube, and 10 minutes later, a dose-response curve of histamine in the presence of the compound was obtained.

From the initial histamine dose-effect curve and the dose-effect curve of histamine in the presence of test compound, J, M.

Van Rossum's method (Arch, int@
Pharmacodyn*Th@r, e 143-29
9.1963), the pAz value of each compound was determined.

The results are shown below.

Test Compound pA2 Example 16.7 #2 7.1 #3 6.7 #4 6.1 #6 7.6 #7 7.1 Cimetidine was used for comparison and its pA2 was determined by the same procedure as above. However, the value was 6.5.

[Gastromucosal protective effect test]

Male Tonryu rats (150Ii-
250g) was used. The experiment was conducted using the test drug (10m 97kg)
, p, o, ) 30 minutes after administration, necrotic material (0,4N-
HCL+ 50 cm (Etoa) 5 RVkll was orally administered. One hour after administration of the necrotic material, the stomach was removed and fixed in formalin. The area of the ulcer was measured and compared with the control group to determine the inhibition rate. The inhibition rates of the compounds of Examples are shown below.

Test compound Inhibition rate (related) Example 1 50.6 #4 52.3 #5 51.2 [Effects of the invention] The product of the present invention exhibits strong histamine receptor antagonism and strong cyanide secretion inhibiting action. Furthermore, since it has a gastric mucosal protective effect, it can be an excellent drug for treating gastric or duodenal ulcers. The method of the present invention allows synthesis with high yield and also allows for large-scale failure.

Claims (2)

[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼……(I) (In the formula, R is a phenyl group, furyl group, thienyl group, pyridyl group, naphthyl group, or cyclohexyl group, and p is a 2{2-(guanidino)-thiazol-4-ylmethylthio}-ethylamine derivative and its salt (2) General formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼……(II) (In the formula, X represents a halogen atom.) Compounds having the general formula (III) ▲Mathematical formulas, chemical formulas, tables, etc. etc.▼......(III) (wherein R represents a phenyl group, furyl group, thienyl group, pyridyl group, naphthyl group, or cyclohexyl group, and p represents 0 or an integer from 1 to 2) { (Substituted thio)acetamide}ethyl disulfide. 2{2-(guanidino)-thiazol-4-yl having the general formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼......(I) (In the formula, R and p have the same meanings as above.) Method for producing methylthio}-ethylamine derivative