JPH0449555B2 - - Google Patents

Description

[Detailed description of the invention]

FIELD OF THE INVENTION The present invention relates to novel imidazoquinoline derivatives having heterocyclic groups. More specifically, the present invention includes:
The present invention relates to novel imidazoquinoline derivatives useful for the treatment of ulcers or hypersecretion in mammals, methods for their preparation, and pharmaceutical compositions containing the novel compounds. BACKGROUND OF THE INVENTION GB Patent Specification No. 2069492A by the present inventors discloses phenylsulfinyl alkylpyridines which are useful, inter alia, for the treatment of ulcers or gastric acid hypersecretion in mammals. However, the inventors have now modified the compound by substituting its phenyl group with an imidazoquinoline group, resulting in anti-ulcer activity, anti-secretory activity or H ⁺ /
It has been found that new compounds are obtained which have one or more of the following K ⁺ _ATPase inhibitory activities. Summary of the invention The present invention is based on the formula (1): and pharmaceutically acceptable salts thereof. In the formula, A is a linear or branched alkylene chain having 1 to 4 carbon atoms which may be saturated or unsaturated, B is a linear alkylene chain having 3 carbon atoms which may be saturated or unsaturated, R ¹ and R ² is the same or different, hydrogen, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, hydroxy, halogen, nitro, carboxy, carboxyester, carbamoyl, carbamoyloxy, acylamino, lower alkanoylamino such as acetamino, cyano, Acyl or trifluoromethyl, Het is a heterocyclic group selected from thiazolyl, quinolyl or pyridyl, substituted or unsubstituted with one or more alkyl or aryl, and X means 0 or 1. Detailed Description of the Invention Examples of A include CH ₂ , CH(CH ₃ ), CH(CH ₃ )CH ₂ ,
CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ , CH=CH and CH=
_CHCH2 , preferably A is _CH2 . B is _CH2CH2CH2 or _{CH = CHCH2} . The Het group may be mono- or polysubstituted, but
Preferably it is mono- or di-substituted. The Het group is preferably attached at its 2-position, but may be attached at other positions, such as in 4-thiazolyl. In the present specification, the alkyl group is preferably lower alkyl, that is, alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t
- means butyl, n-pentyl or n-hexyl. The alkoxy group is preferably a lower alkoxy group whose alkyl portion is the same as the lower alkyl group described above. When the term lower alkyl or lower alkoxy is used herein as part of another group, e.g. Contains carbon atoms. The aralkyl group is preferably
Aryl lower alkyl, for example benzyl, phenethyl or phenpropyl. The aryl moiety in an aryl group or other group such as an aralkyl group may be substituted, for example, by any of the substituents described above for the Het group. Preferably, the aryl group is phenyl and the aralkyl group is phenylalkyl having 7 to 12 carbon atoms. A particularly preferred group of compounds within the formula range is Het
is pyridyl, for example 2-pyridyl, which group may be substituted with any of the substituents described above for Het, but where aryl and substituted aryl, such as phenyl or substituted phenyl, When it is 0, it is a particularly preferred substituent. Lower alkyl substituents are also important. These compounds have very interesting antisecretory activity as assessed by their ability to inhibit the highly specific proton transport enzyme H ⁺ /K ⁺ _ATPase . A particularly preferred group of compounds is formula (a): [In the formula, A, R ¹ and R ² are the same as in the above formula, R ³ and R ⁴ are the same or different, and hydrogen,
lower alkyl or aryl unsubstituted or substituted with any of the substituents described above for Het, with the proviso that one of R ³ and R ⁴ is other than hydrogen] and pharmaceutically acceptable salts thereof; can. Aryl is preferably phenyl or substituted phenyl. Pharmaceutically acceptable salts are preferably acid addition salts. Acid addition salts of compounds of formula or a include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid,
Sulfuric acid, nitric acid, citric acid, acetic acid, formic acid, fumaric acid,
maleic acid, tartaric acid, embonic acid
acid (permoic acid), malonic acid, alkylsulfonic acid (e.g. methanesulfonic acid) or arylsulfonic acid (e.g. p-toluenesulfonic acid)
It may be a salt with any pharmaceutically acceptable organic or inorganic acid such as. The present invention includes methods for making compounds of formula. Compounds of formula where X is 1, i.e. sulfinyl compounds, can be prepared by oxidizing the corresponding compound of formula where X is 0 or a pharmaceutically acceptable salt thereof, optionally converting the product into an acid addition salt. It may be manufactured by Oxidation may be by any suitable means of forming sulfoxides from thioethers (Kharasch Organic Sulfur Compounds).
Pergamon Press, New York, 1961, Volume
1, pages 157-159)], for example, with peracids or peroxides. Examples of peracids are perbenzoic acid, m-chloroperbenzoic acid or peracetic acid. Hydrogen peroxide may also be used. To prevent or minimize attack on the pyridine nitrogen by oxidizing agents, it is preferred to use acid addition salts of the compounds. A compound of the formula where X is 0 is represented by the formula (): Het-A-Hal () [wherein Het and A are the same as above, and Hal means a halogen atom, especially chlorine, bromine or iodine] The compound represented by the formula (): [In the formula, B, R ¹ and R ² are the same as above] It may be produced by reacting with a thiol represented by the following or an alkali metal salt thereof. As an alternative method, a compound represented by the formula (a): Het-A-SH (a) [Het and A are the same as above] or an alkali metal salt thereof can be used as a compound represented by the formula (a): [In the formula, R ¹ , R ² , B and Hal are the same as above] It may be reacted with a halide represented by the following. The starting compounds of formula and formula a are known compounds or can be prepared by methods known for analogous compounds. The starting compounds of formula or a are known compounds (e.g., Journal of Organic Chemistry (J.Org.Chem) 1960
25, p. 1138 or 1963, vol. 28, p. 2581), or similar compounds can also be produced by known methods. In the above reactions, the compound of formula () may be isolated in free base form or as an acid addition salt. Furthermore, as a method for producing a compound of the formula, the formula (): [In the formula, R ¹ , R ² , A, B and X are the same as above,
M means sodium, potassium or lithium] A compound represented by the formula (): Het-Q () [where Het is the same as above, Q is a reactive esterified hydroxy group or an elimination group such as a halogen. It also includes reacting with a compound represented by [meaning a group]. Compounds of formula and are known compounds or can be prepared by methods known for similar compounds. The reactive esterified hydroxy group is preferably a hydroxy group esterified with an organic sulfonic acid, such as benzenesulfonic acid or p-toluenesulfonic acid. The compounds of formula and their pharmaceutically acceptable salts have anti-ulcer activity and/or anti-secretory activity as assessed by standard test methods and, therefore, have anti-ulcer and/or anti-secretory activity in mammals. Useful in treating overabundance. A compound of formula where X is 0, or a pharmaceutically acceptable salt thereof, is also an intermediate for the corresponding compound where X is 1. Antiulcer activity has been shown in Senay and Levin [(Senay
and Levine), Brothedings of the
Society for Experiments in Biology and Medicine (Proc.Soc.Exp.Biol.Med., 124, 1221-3
(1967)]'s stress-induced erosion test. Antisecretory activity was reported by Beattie et al., Journal of Medical Chemistry (J.
Med. Chem. 20, 714 (1977)] H. Shay, D. Sun and H.
H.Gruenstein, Gastroenterology,
Judgment was made by the method of 1959, 26 , 903-13). Compounds of formula were also tested for anti-secretory activity by their ability to inhibit the highly specific proton transport enzyme H ⁺ /K ⁺ _ATPase . Effective H ⁺ /K ⁺ _ATPase inhibitors are evaluated by techniques that include measuring aminopyrine accumulation in isolated gastric glands of rabbits. Aminopyrine is a weak base and accumulates in gastric acid-secreting cells. That is, aminopyrine uptake is increased by secretagogues, and gastric acid secretion inhibitors reduce said response to one or more secretagogues, depending on their site of action. Compounds that attenuate the response to dibutyryl cyclic adenosine monophosphate (DBcAMP) stimulation are thought to have an intracellular site of action, and also include the highly specific proton transport enzyme H ⁺ /K ⁺ _ATPase , DBcAMP
Compounds that decrease their response both to high potassium ion concentrations (K ⁺ ) and to high potassium ion concentrations (K + ) are thought to have an intracellular site of action on the secretory surface of lateral wall cells. The test method is as follows. Berglind T. and Obrink K.
(Berglindh T., Obrink KJ, Acta Fuisiior Scandinavia)
Gastric glands are excised from the gastric mucosa of the rabbit's stomach by the method described by Physiol. Determination of aminopyrine consumption was performed by Belglindh T., Helllander H.F. and Obrink K.G.
KJ) supra, Vol. 97, pp. 401-414, 1976)]. The compounds were tested for their ability to inhibit ¹⁴ C-aminopyrine uptake in gastric glands stimulated by DBcAMP and high K ⁺ , respectively, initially at 10 ⁻⁴ M concentrations, and optionally from lower concentrations. Results are expressed as % inhibition of the maximal response to secretagogues elicited by the test compound. H ⁺ /
K ⁺ _ATPase inhibitors are thought to reduce the response to both secretagogues. The present invention also provides a pharmaceutical composition comprising a compound of the above formula, where X is 0 or 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Pharmaceutical formulations include solid or liquid. Any suitable carrier known in the art can be used in preparing the pharmaceutical compositions. In such compositions, the carrier is generally a solid or a liquid, or a mixture of solids and liquids. Solid form compositions include powders, granules, tablets and capsules (eg, hard and soft gelatin capsules). The solid carrier may contain one or more additives which may also act as, for example, flavoring agents, lubricants, solubilizers, suspending agents, fillers, lubricants, tableting aids, binders, effervescent agents or tablet disintegrants. It may be a substance, or it may be an encapsulating substance. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active component. In tablets, the active ingredient is mixed in appropriate proportions with a carrier having the necessary tableting properties and compressed into the desired shape and size. Powders and tablets preferably contain up to 99%, e.g. 10
Contains ~80% active ingredient, preferably 25-75%. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sucrose, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone,
Included are low melting point waxes and ion exchange resins. As used herein, the term "composition" includes a dosage form of the active ingredient forming a capsule with a capsule as a carrier, in which the active ingredient is present (with or without further carriers). surrounded by and associated with the carrier. Also included are casier agents. Liquid form compositions include, for example, suspensions, emulsions, syrups and elixirs. Active ingredients include, for example, water, organic solvents,
It can be suspended in a mixture of the two or in a pharmaceutically acceptable liquid carrier such as a pharmaceutically acceptable oil or fat. The liquid carrier may contain other agents such as solubilizing agents, emulsifying agents, buffering agents, preservatives, sweetening agents, flavoring agents, suspending agents, thickening agents, colorants, viscosity modifiers, stabilizers or osmotic pressure modifiers. It may contain suitable formulation additives. Suitable examples of liquid carriers for oral administration include water (including, inter alia, excipients such as those mentioned above, such as cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (monohydric and polyhydric alcohols). (including, for example, glycerol and glycols) and their derivatives, and oils (eg, fractionated coconut oil and peanut oil). Preferably, the pharmaceutical composition is in unit dosage form,
For example, it can be a tablet or a capsule. In such form, the composition is subdivided into unit doses containing appropriate quantities of the active component;
The unit dosage form can be a packaged composition, eg, a packaged powder. The unit dosage form can be, for example, a capsule or tablet itself, or it can be in the form of a package of the appropriate number of any such compositions. The amount of active ingredient in a unit dose of the composition varies from less than 10 mg to 500 mg, depending on individual needs.
It may be varied and adjusted in various ways up to mg or more. The anti-ulcer compositions of the present invention can be administered orally in either liquid or solid composition form. Compositions of the invention may include one or more antacids, such as aluminum hydroxide, magnesium hydroxide, bismuth carbonate, aluminum glycinate, calcium carbonate, as described in British Patent Specification No. 1284394; It may also contain magnesium trisilicate, sodium bicarbonate or alumina gel. In another aspect of the present invention, the above-mentioned compound in which X is 0 or 1 or a pharmaceutically acceptable salt thereof is provided as a medicament, for example, an anti-ulcer agent. The present invention also provides treatment for ulcers or hypersecretion in a mammal in need thereof comprising administering to the mammal an effective and non-toxic amount of a compound of formula or a pharmaceutically acceptable salt thereof. Provide treatment methods. Dosage is 0.1-30mg/
You can change it within the Kg range. Examples Next, the present invention will be explained in more detail with reference to examples. Example 1 5,6-dihydro-2-(2-pyridylmethylthio)-4H-imidazo[4,5,1-i,j]
Quinoline 5,6-dihydro-2-mercapto-4H-imidazo[4,5,1-i,j] in 30 ml of ethanol
A solution of 1.9 g of quinoline is heated to reflux, treated with 2.5 g of 2-picolyl chloride hydrochloride, and the solution is heated to reflux for 6 hours. Take the solid formed by cooling,
After drying, the title compound is obtained as the dihydrochloride salt (2.8 g).
Melting point 215℃ (decomposition). Elemental analysis value, as C ₁₆ H ₁₆ N ₃ S・2HCl Theoretical value (%): C, 54.1; H, 5.1; N, 11.8 Actual value (%): C, 54.5; H, 5.0; N, 12.1 Example 2 2-(2-pyridylmethylsulfinyl)-5,
6-dihydro-4H-imidazo[4,5,1-
i, j] Quinoline In 10 ml of water, 5,6-dihydro-2-(2-pyridylmethylthio)-4H-imidazo[4,5,1-
i, j] A solution of 4.0 g of quinoline hydrochloride is made alkaline with sodium carbonate solution and extracted with chloroform. The extract is dried ( _MgSO4 ) and evaporated, the residue is dissolved in 50 ml of methylene chloride and cooled to -50<0>C. Add 2 g of 3-chloroperoxybenzoic acid with stirring and heat the solution to -20°C, at which point add more 3-chloroperoxybenzoic acid.
Add 0.5g and keep the solution at 6°C for 16 hours. The solution was then washed with Na ₂ CO ₃ solution and brine, dried (MgSO ₄ ) and evaporated to give an oil, which was chromatographed on alumina using ethyl acetate as eluent. Crystallization from diisopropyl ether gives the title compound as 0.25 hydrate, 2.1 g. Melting point 100~102
℃. Elemental analysis value, as _C16H15N3OS・_0.25H2O , _Theoretical value (%): C, 63.7; H, 5.2; N, 13.9 Actual _value (%): C, 63.9; H, 5.1; N , 14.0 Example 3 5,6-dihydro-2-(2-(3-methylpyridyl)methylthio)-4[H]-imidazo[4,
5,1-i,j]quinoline 5,6-dihydro-2-mercapto-[4H]-imidazo[4,5,1-i,
j] A stirred suspension of 3.8 g of quinoline is treated under reflux with 3.6 g of 3-methylpicolyl chloride hydrochloride and the mixture is heated for 4 hours. The solvent is removed by evaporation and the residue is dissolved in water, made alkaline with 2N NaOH and extracted with EtOAc. The extract was dried (MgSO ₄ ) and evaporated to give a solid which was recrystallized from cyclohexane to give 4.5 g (75
%). Melting point 106-108℃. Elemental analysis value, C ₁₇ H ₁₇ N ₃ S Theoretical value (%): C, 69.1; H, 5.8; N, 14.2 Actual value (%): C, 69.3; H, 5.9; N, 13.9 Example 4 2-(2-pyridylmethylthio)-4[H]-imidazo[4,5,1-i,j]quinoline 0.8 g (0.005 mol) of 2-picolyl chloride hydrochloride was added to 2-mercapto-[4H] in 17 ml of ethanol. -Imidazo[4,5,1-i,j]quinoline 0.83g
(0.004 mol) to a stirred refluxing solution. The mixture is heated to reflux for 4 hours and evaporated. The residue is dissolved in water, made alkaline (2NNaOH) and extracted with ethyl acetate. The extract is washed (0.1 N NaOH), dried (MgSO ₄ ), evaporated and the residue is recrystallized from cyclohexane to yield 0.8 g (65%) of the title compound. Melting point 109-110℃. Elemental analysis value, C ₁₆ H ₁₃ N ₃ S, theoretical value (%): C, 68.8; H, 4.7; N, 15.05 Actual value (%): C, 68.95; H, 4.7; N, 14.8 Example 5 5,6 _- dihydro-2-(2-(3-methylpyridyl)methylsulfinyl)-[4H]-imidazo[4,5,1-i,j]quinoline in 50 ml of _CH2Cl2 , 5,6 -dihydro-2-(2-
(3-Methylpyridyl)methylthio)-4[H]-imidazo[4,5,1-i,j]quinoline 1 g
(0.0034 mol) of 80% m-chloroperoxybenzoic acid is added at 0° C. with stirring. After stirring the solution for 1 hour
Since TLC (SiO ₂ /Et ₂ O or EtOAc) showed the presence of starting material, an additional 0.1 g of m-chloroperoxybenzoic acid is added. The solution is stirred at 0° C. for 0.5 h, warmed to room temperature, washed with saturated sodium carbonate solution, water and brine, dried (MgSO ₄ ) and evaporated. The residue is purified by chromatography on silica gel using ethyl acetate as eluent and then tritiated with ethyl acetate to give 0.6 g (57%) of the title compound. Melting point 172-173℃. Elemental analysis value, C ₁₇ H ₁₇ N ₃ OS: Theoretical value (%): C, 65.6; H, 5.5; N, 13.5 Actual value (%): C, 65.7; H, 5.6; N, 13.2 Example 6 5,6-dihydro-2-(2-(6-phenylpyridyl)methylthio)-[4H]-imidazo[4,
5,1-i,j]quinoline 5,6-dihydro-2-mercapto-[4H]-
Imidazo[4,5,1-i,j]quinoline 1.8g
was suspended in 25 ml of ethanol, and 0.8 NaOH in 5 ml of water.
Add solution of g. The resulting solution is treated with 2.4 g of 6-phenylpicolyl chloride hydrochloride and the mixture is heated to reflux for 1 hour. The reaction mixture is filtered and evaporated to give an oil which is dissolved in ethyl acetate. The solution is briefly dried (MgSO ₄ ) and filtered to precipitate crystals. The crystals are collected and dried to obtain 2.2 g (62%) of the title compound. Melting point 121~123
℃. Elemental analysis value, C ₂₂ H ₁₉ N ₃ S Theoretical value (%): C, 73.9; H, 5.4; N, 11.8 Actual value (%): C, 74.0; H, 5.5; N, 11.8 Example 7 5,6-dihydro-2-(2-(3,5-dimethylpyridyl)methylthio)-[4H]-imidazo[4,5,1-i,j]quinoline in 30 ml of ethanol, 5 ml of water and 0.4 g of NaOH,
A solution of 1.9 g of 5,6-dihydro-2-mercapto-[4H]-imidazo[4,5,1-i,j]quinoline was diluted with 3,5-chloride at room temperature for 24 hours and then at 60°C for 24 hours. Treat with 1.9 g of dimethylpicolyl hydrochloride. If the solution is filtered and left to stand, crystals will form,
Take this, dry it, and convert the indicated compound into hydrochloride 1.2
g (35%). Melting point 195-199℃. Elemental analysis value, C ₁₈ H ₁₉ N ₃ S・HCl, Theoretical value (%): C, 62.5; H, 5.8; N, 12.15 Actual value (%): C, 62.0; H, 5.9; N, 11.9 Example 8 5,6-dihydro-2-(2-(3,5-dimethylpyridyl)methylsulfinyl-4H-imidazo[4,5,1-i,j]quinoline in 20 ml of CH ₂ Cl ₂ ) 6-dihydro-2-(2-
(3,5-dimethylpyridyl)methylthio)-
1.25 g of [4H]-imidazo[4,5,1-i,j]quinoline (free base) is treated with 0.9 g of m-chloroperoxybenzoic acid at 0 DEG C. for 1 hour. The solution was washed (Na ₂ CO ₃ ), dried (MgSO ₄ ) and the product was separated by chromatography on silica using ethyl acetate as eluent, then
Recrystallization from EtOAc-MeCN- _CHCl3 gives 2.6 g (20%) of the title compound. Melting point 164-165℃. Elemental analysis value, C ₁₈ H ₁₉ N ₃ OS: Theoretical value (%): C, 66.4; H, 5.9; N, 12.9 Actual value (%): C, 66.2; H, 6.0; N, 12.9 Example 9 5,6-dihydro-2-[(2-phenylthiazol-4-yl)methylthio]-4H-imidazo[4,5,1-i,j]quinoline 10.7 ml of 1N sodium hydroxide and ethanol
In 10 ml, 5,6-dihydro-2-mercapto[4H]imidazo[4,5,1-i,j]quinoline
A solution of 2.04 g (10.7 mmol) is treated with 2.25 g (10.7 mmol) of 4-chloromethyl-2-phenylthiazole and the resulting solution is heated to reflux for 5 minutes. The mixture is concentrated under vacuum and the aqueous mixture is extracted twice with 50 ml of ethyl acetate. The extract was dried (MgSO ₄ ) and evaporated under vacuum to give a yellow oil;
This is crystallized by trituration with 50 ml of diethyl ether to give 3.62 g (93%) of the title compound. Melting point 116-118℃. Elemental analysis value, C ₂₀ H ₁₇ N ₃ S ₂ Theoretical value (%): C, 66.1; H, 4.7; N, 11.6 Actual value (%): C, 66.4; H, 5.0; N, 11.3 Example 10 (A) 5,6-dihydro-8-methoxy-4H-imidazo[4,5,1-i,j]quinoline-2
[1H]-thione A suspension of 20 g (98 mmol) of 6-methoxy-8-nitroquinoline in 200 ml of methanol
Hydrogenate over 0.5 g of PtO ₂ at 50 p.si for 2.5 hours. Add the solution to 11.5 ml (200 mmol) of acetic acid and
Treat with 0.5 g PtO ₂ and hydrogenate at 50 p.si for 18 hours. The catalyst is removed and the solution is evaporated under vacuum to give an oil. Pour the residue into 1N sodium hydroxide
It is made alkaline with 200 ml and the aqueous mixture is extracted twice with 200 ml of diethyl ether. The extract was dried (MgSO ₄ ) and evaporated under vacuum to give the crude 8
-amino-1,2,3,4-tetrahydro-6
-Methoxyquinoline is obtained as a red oil. This oil was dissolved in 100 ml of methanol and the solution was treated with 10 ml (167 mmol) of CS ₂ and 18
Heat to reflux for an hour, cool to room temperature and evaporate under vacuum to give a brown solid. The solid is dissolved in 100 ml of hot 1N sodium hydroxide and the cooled solution is washed twice with 200 ml of diisopropyl ether. Add ethereal washing solution to 0.1N sodium hydroxide
Extract with 100ml. Combine the aqueous liquid and extract;
Heat in a steam bath, decolorize with activated carbon, filter, and remove
Cool to °C and neutralize with 10 ml of acetic acid while stirring. The precipitate was filtered, washed with copious amounts of water, and dried under vacuum to give light brown crystals of 5,6-dihydro-
8-Methoxy-4H-imidazo[4,5,1-
i,j]Quinoline-2[1H]-thione 18.2g
(84%). Melting point 188-192℃. Elemental analysis value, C ₁₁ H ₁₂ N ₂ OS Theoretical value (%): C, 60.0; H, 5.5; N, 12.7 Actual value (%): C, 59.8; H, 5.5; N, 12.4 (B) 5,6-dihydro-8-methoxy-2-[(6
-phenylpyridin-2-yl)methylthio]
-4H-imidazo[4,5,1-i,j]quinoline 1.942 g (8.1 mmol) of 2-chloromethyl-6-phenylpyridine hydrochloride was added to 16 ml of ethanol.
and 5,6- in 16.2 ml of 1N sodium hydroxide.
dihydro-8-methoxy-4H-imidazo [4,
5,1-i,j]quinoline 2[1H]-thione
Add 1.78 g (8.1 mmol) to the solution. The mixture is heated to reflux for 15 seconds and cooled to room temperature.
The ethanol is evaporated off under vacuum and the aqueous mixture is extracted twice with 150 ml of dichloromethane.
The extract was dried (MgSO ₄ ) and evaporated under vacuum to give a brown solid, which was recrystallized from MeOH to yield 2.77 g (88%) of the title compound as 0.25 hydrate.
get as. Melting point 134-135℃. Elemental analysis value, as _C23H21N3OS・_0.25H2O , _Theoretical value (%): C, 70.5; H, 5.5; N, 10.7 Actual _value (%): C, 70.5; H, 5.8; N , 10.4 Example 11 5,6-dihydro-2-(quinolin-2-ylmethylthio)-4H-imidazo[4,5,1-
i, j] Quinoline in 25 ml of ethanol and 1N sodium hydroxide,
5,6-dihydro-4H-imidazo[4,5,1
-i,j]quinoline-2(1H)-thione 2.02g
(11.6 mmol) was treated with 2.48 g (11.6 mmol) of 2-(chloromethyl)quinoline hydrochloride,
After heating to reflux and cooling to room temperature, the ethanol is evaporated off under vacuum. strain the aqueous mixture;
The precipitate was washed 5 times with 50 ml of water, dried under vacuum,
Recrystallization from cyclohexane-EtOAc gave yellow crystals of 5,6-dihydro-2-(quinoline-2-
ylmethylthio)-4H-imidazo[4,5,1-
i, j] 2.13 g (55%) of quinoline are obtained. melting point
125-126℃. Elemental analysis value, C ₂₀ H ₁₇ N ₃ S Theoretical value (%): C, 72.5; H, 5.2; N, 12.7 Actual value (%): C, 72.8; H, 5.3; N, 12.4 Example 12 5,6-dihydro-2-(3-pyridylmethylthio)-4H-imidazo[4,5,1-i,j]
Quinoline In 30 ml of ethanol according to the method of Example 1,
Treatment of 1.9 g of 5,6-dihydro-2-mercapto-4H-imidazo[4,5,1-i,j]quinoline with 2.5 g of 3-picolyl chloride hydrochloride gives the title compound as the dihydrochloride. Example 13 5,6-dihydro-2-(4-pyridylmethylthio-4H-imidazo[4,5,1-i,j]
Quinoline In 30 ml of ethanol according to the method of Example 1,
Treatment of 1.9 g of 5,6-dihydro-2-mercapto-4H-imidazo[4,5,1-i,j]quinoline with 2.5 g of 4-picolyl chloride hydrochloride gives the title compound as the hydrochloride. Free base melting point 105-107°C. Example 14 According to the method of Example 1, the following compounds were produced. (a) R ¹ and R ² = H (b) R ¹ = H, R ² = Cl (c) R ¹ = CN, R ² = H (d) R ¹ = NO ₂ , R ² = H (e) R ¹ =Cl, R ² =H Example 15 According to the method of Example 2, the sulfinyl compound shown below was produced. (a) R ¹ = MeO, R ² = H (b) R ¹ = CN, R ² = H (c) R ¹ = H, R ² = MeO (d) R ¹ = CN, R ² = MeO Next The results of the pharmacological tests are shown in Table 1 below.

[Table] When the compounds subjected to these pharmacological tests were tested for toxicity at concentrations up to 100 mg/Kg using the method of Senai and Levin, none of the compounds showed any toxicity. Example 16 5,6-dihydro-8-methoxy-2-(quinolin-2-ylmethylthio)-4H-imidazo[4,5,1-i,j]quinoline 2-chloromethylquinoline hydrochloride 0.845 g (4.0
5 mmol) in 8 ml of 1N NaOH and 8 ml of EtOH,
Add to 0.871 g (4.0 mmol) of 6-dihydro-8-methoxy-4H-imidazo[4,5,1-i,j]quinoline-2(1H)-thione. The mixture is heated to reflux, cooled to room temperature, cooled in vacuo and the aqueous residue is extracted with 50 ml of CH ₂ Cl ₂ . The extract was mixed with 1N NaOH (2 x 30 ml) and saline (20 ml).
Wash with water, dry (MgSO ₄ ) and evaporate in vacuo to give an oil. This was purified by chromatography (SiO ₂ , Et ₂ O) and tritiated with Et ₂ O-petroleum ether to yield 0.885 g of the title compound.
(62%) was obtained as yellow crystals. Melting point 89-91℃. Elemental analysis value, C ₂₁ H ₁₉ N ₃ OS: Theoretical value (%): C, 69.8; H, 5.3; N, 11.6 Actual value (%): C, 70.1; H, 5.4; N, 11.4 Example 17 5,6-dihydro-8-methoxy-2-(4-
Pyridylmethylthio-4H-imidazo [4,5,
1-i,j]Quinoline 5,6-dihydro-8-methoxy-2-mercapto-4H-imidazo[4,5,1
-i,j] 4-picolyl chloride hydrochloride (1.68 g) was added to quinoline (2.2 g), and the mixture was heated at room temperature for 16
Stir under reflux for 2 hours. The solvent is removed by evaporation and the residue is dissolved in water. The solution was diluted with EtOAc
and then make it alkaline (water-based).
NaOH), extracted with _CHCl3 . After short column chromatography (SiO ₂ /CHCl ₃ ), the residue was crystallized from EtOAc to give 1.45 g (43
%). Melting point 99-101℃. Elemental analysis value, C ₁₇ H ₁₇ N ₃ OS: Theoretical value (%): C, 65.6; H, 5.5; N, 13.5 Actual value (%): C, 65.55; H, 5.6; N, 13.8

Claims (1)

[Claims] 1 Formula: [In the formula, A has 1 to 1 carbon atoms, which may be saturated or unsaturated.
4 straight or branched alkylene chain, B is a straight chain alkylene chain having 3 carbon atoms which may be saturated or unsaturated, R ¹ and R ² are the same or different and are hydrogen, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, hydroxy, halogen, nitro, carboxy, carboxyester, carbamoyl, carbamoyloxy, cyano, acyl, acylamino or trifluoromethyl; Het is a heterocycle selected from thiazolyl, quinolyl or pyridyl substituted or unsubstituted with alkyl or aryl; group, and x means 0 or 1] or a pharmaceutically acceptable salt thereof. 2 Formula for effective and non-toxic amount: [In the formula, A has 1 to 1 carbon atoms, which may be saturated or unsaturated.
4 straight or branched alkylene chain, B is a straight chain alkylene chain having 3 carbon atoms which may be saturated or unsaturated, R ¹ and R ² are the same or different and are hydrogen, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, hydroxy, halogen, nitro, carboxy, carboxyester, carbamoyl, carbamoyloxy, cyano, acyl, acylamino or trifluoromethyl; Het is a heterocycle selected from thiazolyl, quinolyl or pyridyl substituted or unsubstituted with alkyl or aryl; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.