JPH02311479A - Quinoline derivative - Google Patents

Abstract

NEW MATERIAL:A quinoline derivative shown by formula I (Ar is phenyl or 5 or 6-membered heterocyclic containing N, O and/or S; R<1> and R<2> are H or alkyl or both are bonded to form alkylene; W is O or S; X is H, nitro, halogen or alkoxy; Y is ethylene or vinylene; (n) is 1 to 3 and broken line shown existence or absence of bond). EXAMPLE:2,2-Dimethyl-2H-5-(4-hydroxystyryl)pyrano[3,2-C]quinoline. USE:A drug for treating or preventing transient ischemic disease such as coronary blood vessel infarct or cerebral infarct and arteriosclerosis. PREPARATION:A compound shown by formula II is condensed with a compound shown by formula III to give a compound shown by formula I.

Description

[Detailed Description of the Invention] l! Part 1 of the present invention relates to a novel quinoline derivative, and more specifically,
The present invention relates to styrylpyrano[3,2-c]quinoline and thiopyrano[3,2-c]quinoline derivatives having at least one of antioxidant action and platelet aggregation inhibiting action.

(Left below) Tomoma UL Tun JP-A-63-208576 discloses styrylquinoline derivatives as leukotriene D4 antagonists.

Japanese Patent Application Laid-open No. 64-40485 describes pyranoquinoline derivatives having platelet aggregation inhibiting action;
discloses tetrahydroquinoline derivatives having antioxidant effects.

However, no reports have been found regarding the styrylpyrano[3,2-C]quinoline and thiopyrano[3,2-cl quinoline derivatives provided by the present invention, which have antioxidant effects and platelet aggregation inhibiting effects.

It is now known that reactive oxygen species and organic radical species play an extremely important role in the damage to living tissues, especially those following ischemia-reperfusion in the heart, brain, kidneys, lungs, and gastrointestinal system. It is being In addition, due to platelet aggregation,
It is known that bodily tissue disorders such as blood clots, stroke, myocardial infarction, angina pectoris, and brain plasticity occur. However, effective therapeutic agents for these have not yet been developed.

In view of the above points, the inventors of the present invention have conducted extensive studies, and have found that
The following formula (■): [In the formula, Ar is phenyl which may have a substituent, or a 5- or 6-membered phenyl group containing one or more nitrogen atoms, oxygen atoms and/or sulfur atoms which may have a substituent. member heterocycle;
R1 and R2 are the same as each other or are hydrogen, C
, -C, alkyl or together C3-C, alkylene; W is an oxygen atom or a sulfur atom; X is hydrogen, nitro, halogen or C3-C, alkoxy; Y is ethylene or vinylene; n is 1-3 an integer; and a broken line represents the presence or absence of a bond.] The quinoline derivative or its pharmaceutically acceptable salt has excellent antioxidant activity and/or platelet aggregation inhibiting activity; The present invention was completed based on the discovery that the present invention is effective in treating or preventing various thrombotic diseases, such as transient ischemic diseases such as coronary artery urinary tract and cerebral infarction; and arteriosclerosis.

The compound of the present invention has the formula (If): A r -(Y'L-I CHO(n) [wherein A
r and n have the same meanings as above, Y' represents vinylene,
] Compound and formula (■): [wherein R1, R2,
WlX and the broken line have the same meanings as above] are condensed, and if desired, further subjected to a reduction reaction.

In the present invention, phenyl which may have an r substituent means unsubstituted phenyl or halogen such as hydroxy, fluoro, chloro, bromo, C such as methyl, ethyl, propyl, n-butyl, tart-butyl, etc. , -C, alkoxy, such as -C, alkyl, methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy,
Substituted nitro, carboxy, carboxyethynyl and unsubstituted amines, 5- or 6-membered cyclic amino or mono- or di-C1-C4 alkylamino, acylamino, phenylsulfonylamino, N, N-C, ~C, alkylphenylamino, etc. It means phenyl substituted with one or more groups such as amino which may have a group.

15- or 6-membered cyclic amino means a 5- or 6-membered cyclic amine that may contain a hetero atom such as an oxygen atom, and specifically includes pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, Mention may be made of pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl or morpholinyl.

"Acylamino" means C, NC, alkylcarbonylamino, where "C1-C, alkyl" has the same meaning as above.

In the term "5- or 6-membered heterocycle containing one or more nitrogen atoms, oxygen atoms and/or sulfur atoms which may have one or more substituents", "one or more nitrogen atoms, oxygen atoms and/or a 5- or 6-membered heterocycle containing a sulfur atom r" specifically includes chenyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, inthiazolyl, isoxasilyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, or furazanyl, etc. It is. Examples of substituents include halogens such as hydroxy, fluoro, chloro, and bromo, 01-C4 alkyl, C1-C, alkoxy, nitro, and the above-mentioned optionally substituted amino and carboxy. Any of the above may be substituted on the ring.

"rC1-C, alkyl" refers to straight-chain or branched 01
~C, means alkyl, specifically methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,
5ee-butyl, tart-butyl, n-pentyl, impentyl, neopentyl, tart-pendel, n-
Examples include hexyl, isohexyl, neohexyl, tart-hexyl and the like.

1C! ~C, alkylene” specifically refers to ethylene,
Means propylene, butylene, bemprene, hexylene.

-r C3~C,alkoxy" means a linear or branched 01~C,alkyloxy, where 'C+~
"C, alkyl" has the same meaning as above.

Preferred Ar includes, for example, hydroxy:fluoro,
Halogens such as chloro or bromo: C, -C, alkyl such as ethyl or ta'rt-butyl;methoxy;nitro;carboxy; carboxyethynyl and amino, piperidyl, morpholinyl, isopropylamine, dimethylamino, acetylamino, butyrylamino or phenyl Examples include phenyl, chenyl, pyridyl, imidazolyl, imidazolyl, 5-pyrimidinyl or inoxasilyl, which may be substituted with one or more of amino which may have a substituent of sulfonylamino e, and more Preferably unsubstituted phenyl or hydroxy: hydroxy and two methyl; hydroxy and two tart-butyl; hydroxy and methoxy; hydroxy and two methoxy; hydroxy, methoxy and halogen; hydroxy, methoxy and nido; Hydroxy and halogen; Hydroxy and carboxyl; Carboxy; Carboxyethynyl;
phenyl or dimethylamino optionally substituted chenyl, pyridyl, imidazolyl substituted with 3 methoxy; amino; , 5-pyrimidinyl or inoxasilyl.

Preferred examples of R1 and R2 include methyl respectively or pentamethylene taken together.

Preferred examples of X include hydrogen, methoxy, and nitro.

Preferred n is 1 or 2.

(The following is a blank space) The following compound can be mentioned as a representative example of the 3,4-dihydro-2H-penzopyran derivative represented by the general formula (1).

<1> 2.2-dimethyl-21-5-(4-hydroxystyryl) pyrano[3,2-c]quinoline <2> 2.2-dimethyl-28-5-(3-hydroxystyryl) pyrano[3 ,2-c]quinoline (3) 2.2-dimethyl-2H-5-(2-hydroxystyryl)pyrano[3,2-c]quinoline (4) 2.2-dimethyl-2H-5-(5- Chloro
2-Hydroxysteryl)pyrano[3,2-cl quinoline (5) 2.2-dimethyl-2H-5-(3-methoxy-4-hydroxy-5-iodostyryl)pyrano[3
,2-c]quinoline (6) 2.2-dimethyl-2H-
5-(3-methoxy-4-hydroxy/-5-promoszolyl)pyrano[3,2-c]quinoline (7) 2.2-
Dimethoxy-2H-5-(3-methoxy-4-hydroxystyryl)pyrano[3,2-c]quinoline (8) 2
．． 2-dimethoxy-2H-5-(3-methoxy-5-nitro-4-hydroxystyryl)pyrano[3,2-c]
Quinoline (9) 2,2-dimethyl-28-5-(3,
5-dimethoxy-4-hydroxystyryl) pyrano[3
,2-c]quinoline (10) 2,2-dimethyl-2H
-5-(4,5-dimethoxy-3-hydroxysteryl)pyrano[3,2-c coquinoline (11) 2,2-dimethyl-2H-5-(2,4-dimethoxy-6-hydrochinstyryl) Pyrano[3,2-cl quinoline (12>
2.2-methyl-2H-5-(3,5-dimethyl-
4-hydroxystyryl) pyrano[3,2-c]quinoline (13) 2,2-tmethyl-2H-5-(3,5-
dimethoxy-4-hydroxysteryl)-9-methoxypyrano C3,2-cl quinoline (14) 2,2-dimethyl-2H-5-(3,5-dimethoxy-4-hydroxystyryl)-9-nitropyrano[3, 2-cl quinoline (15) 5-(3,5-dimethoxy-4-hydroxystyryl)-2H-pyrano[3,2-c]quinoline-2
-spiro-1-cyclohexane (16) 2,2-dimethyl-2H-5-(4-dimethylaminostyryl)pyrano[3,2-clquinoline (17) 2,2-dimethyl-2H-5-(2 -chloro-4-dimethylaminostyryl)pyrano[3,2-c]
Quinoline (1 g) 1-(2,2-dimethyl-2H-pyrano[3,2-cl quinolin-5-yl)-4-(4-
dimethylaminophenyl)-1,3-butadiene (19) 2,2-dimethyl-2H-5-(4-dimethylaminostyryl)-9-methoxypyrano[3,2-c
]Quinoline (20) 2,2-dimethyl-28-5-(
3-carboxy-4-hydroxystyryl) pyrano[3
,2-c]quinoline (21) 2,2-dimethyl-28
-5-(4-carboxystyryl)pyrano[3,2-c
]Quinoline (22) 4-[2-(2,2-dimethyl-2H-pyrano[3,2-c]quinolin-5-yl)vinylcocinnamic amide (23) 2,2-dimethyl-28-5-
(3,4,5-trimethoxysderyl)pyrano[3,2
-c] Quinoline (24) 3.4-dihydro-5-(3
,5-dimethoxy-4-hydrocinstyryl)-2,2
-dimethyl-2H-pyrano[3,2-c]quinoline (25) 3,4-dihydro-5-(3,5-dimethoxy-4-hydroquinstyryl)-2,2-dimethyl-2
H-9-methoxypyrano[3,2-c]quinoline<26) 3.4-dihydro-5-(3,5-dimethoxy-4-hydroquinostyryl)-2H-pyrano[3,2
-〇] Quinoline-2-spiro 1-cyclohexane (27) 1-(3,5-di-2,2-dimethylethyl-4-hydroxyphenyl)-4-(3,4-dihydro-2,2-dimethyl- 2H-pyrano[3,2-c]quinolin-5-yl)-1,3-butadiene (28) 2.
2-dimethyl-28-5-(3,5-dimethoxy-4-
hydroquinstyryl) thiopyrano[3,2-c]quinoline (29) 2,2-dimethyl-2H-5-(4-dimethylaminostyryl)pyrano[3,2-clquinoline (30) 5-<3.5 -dimethoxy-4-hydroxystyryl)-2H-thiopyrano[3,2-c]quinoline-2-spiro-1-cyclohexane (31) 2,2-dimethyl-2H-5-[(2-pyridine-3- yl) vinylcopyrano[3,2-c]quinoline (32) 2,2-dimethyl-28-5-(imidazol-2-yl)pyrano[3,2-c]quinoline (33) 2,2-dimethyl-2 )1-5-[2-(2
,4,6-trimethoxypyrimidin-5-yl)vinyl]pyrano[3,2-c]quinoline (34) 3.4-dihydro-5-(3,5-dimethoxy-4-hydroquinphenethyl)-2 ,2-dimethyl-
2H-pyrano[3,2-c]quinoline The compound represented by the general formula (1) can be converted into an acid addition salt by treatment using a known method.

Pharmaceutically acceptable salts of the compound represented by the general formula (I) include salts with hydrohalic acids such as hydrochloric acid and 1 g of hydrobromic acid, or salts with dicarboxylic acids such as oxalic acid, malonic acid, and succinic acid. salt.

(Left below) Compound (1) of the present invention can be obtained by condensing a compound represented by formula (I[) and a compound represented by formula (Ill), and further subjecting it to a reduction reaction, if desired. The condensation reaction can be carried out using alcohol solvents such as methanol, ethanol, and isopropanol, aromatic hydrogen ashing solvents such as benzene, toluene, and xylene, ether solvents such as noedel ether, tetrahydrofuran, dioxane, glyme, and diglyme, and dichloromethane. , chloroform,
halogenated hydrocarbon solvents such as dichloroethane and carbon tetrachloride, ester solvents such as ethyl acetate, or am;
at a temperature in the range of about 1 to 150°C in the presence or absence of a solvent such as dimethylformamide or pyridine,
This can be carried out by reacting for several hours to several days. or optionally as an acid catalyst, for example an inorganic acid such as sulfuric acid, hydrochloric acid, phosphoric acid or an organic acid such as para-toluenesulfonic acid, acetic acid, formic acid, or as a base catalyst such as triethylamine, pyridine, pyrrolidine, piperidine, etc. Organic bases such as these may also be used.

The reduction reaction is palladium-carbon, rhodium-alumina,
This can be carried out according to the conventional method of catalytic reduction using a catalyst such as platinum.

The starting material of the compound (1) of the present invention represented by the general formula (Ill) can be produced as follows.

(VI) (V) ↓ [In the formula, R1, R2, W, ,・H Henion (G.

H, Henn1on), Journal of the American Chemical Society (J, A, C, 5),
Vol. 72, p. 3542, (1950), the ether compound (IV) is obtained by subjecting it to a phase transfer reaction, and without further purification (by subjecting it to a thermal rearrangement reaction, the general formula (I) is obtained. Among the compounds represented by , those in which the broken line indicates the presence of a bond can be obtained. Those in which the broken line does not indicate the presence of a bond can be obtained by reducing the previously obtained compound according to a conventional method.

The compound (I) of the present invention has excellent antioxidant effects and platelet aggregation inhibitory effects as shown below, and has anti-thrombotic, cardiac, and anti-inflammatory effects.
It is expected to have preventive and therapeutic effects on ischemic diseases of arterial smooth muscle in the lungs, brain, and kidneys, i.e., myocardial chamber, cerebral infarction, arteriosclerosis, and is useful for preventing circulatory system dysfunction. Or it is a compound that can be used as a therapeutic agent. Furthermore, since the compound (1) of the present invention exhibits useful cholesterol-lowering or antioxidant activity, it can be expected to have lipoxygenase inhibitory activity, and is expected to be a therapeutic agent for diseases caused by lipoxygenase. There is.

(The following is a blank space.) Test Example 1 [Suppressive effect on lipid peroxide production in rat brain homogenate] After sacrificing SD rats (weighing about 200 g), the entire thickness was immediately removed. After homogenizing with 4 times the amount of 0.05M phosphate-sodium chloride buffer (pH 7.4), the supernatant after centrifugation at 1000g for 10 minutes was stored at -80°C until use. This homogenate serum was diluted with twice the volume of the same phosphate-sodium chloride buffer,
30 μl of vehicle (di, ethyl sulfoxide) or test compound was added to 0.45 ml of this solution and incubated at 37° C. for 30 minutes.

20 μm of 0.1x butylated hydroxytoluene solution and 125 μm of 25% metaphosphoric acid! was added to stop the reaction, and the lipid peroxides in the supernatant after defaminization were collected by Ohkava et al. [Analytical Biochemistry (Anal.

Biochem, ), Volume 95, Page 351, 1979
The amount of lipid peroxide produced was measured by the thiobarbic acid (TBA) method according to the description in [2013]. The inhibitory effect on lipid peroxide production was expressed as a % inhibition rate relative to the amount produced in the group to which dimethyl sulfoxide was added.

The results are shown in Table 1.

Test Example 2 [Platelet aggregation inhibitory effect] ACD (85mM sodium citrate, 70mM citric acid, 110mM glucose) 1 from the abdominal artery of male rats (Spragua-Dowley, 8 weeks old)
．． 5ml and prostaglandin E, (20μg)
10 ml of blood was collected using a plastic ring containing a ring. The blood was placed in a plastic test tube, mixed by gentle inversion, and then centrifuged at 160 g for 10 minutes.
h plasma) was collected. After adding avirase (25 μs/m+) to the obtained PRP, it is layered on 40% bovine serum albumin and centrifuged at 1200×g for 25 minutes. Platelet pellets were added to a small amount of buffer (137mM
Mail, 2.7mM KCI, 1. omMMI
CL, 3.8 mM NaHmPOa, 3.8 m
M Hepes, 5.6 mM glucose, 0.0
35% bovine serum albumin, pH 7.35) and a column of 5epharose 2B (10 ml).
Washed platelets were obtained by overlaying the platelets on the plate and eluting them with a buffer solution.

Platelet aggregation reaction was measured using an alibometer (NKKHEMA).
It was measured using TRACERIMODEL PAT-6A/6M, Nikko Biosciences). In other words, the platelet count is 5XIO'/μ! Washed platelets 2 adjusted to
Put 45 μl into a measurement cuvette, set it in an aggregometer, stir at 37°C (looorpm), and add 0.1 MCaC.
After adding 1, 3, and 8μl for λ1.1 minutes, the test compound solution (dimethyl sulfoxide solution) is 0.5μ! was added, and after 2 minutes, fullergen [CollagenreC] was added as an aggregation-inducing substance.
olla Worm” (HORMON-C) IEMI
1 μl (final concentration: 4 μg/ml)] was added, and changes in light transmittance caused by aggregation were recorded over time.

The aggregation rate of platelets was determined by setting the translucency of washed platelets and buffer solution to 0% and 100%, respectively, and adding an aggregation-inducing substance to 3.
It was measured as the light transmittance after minutes.

The activity of the test compound was expressed as the ID, ie, the dose required to inhibit platelet aggregation by 50%.

The results are shown in Table 1.

(Left below) Table 1 Control 1 Probufur: Control 2 Aspirin The compound of the present invention, a quinoline derivative, can be administered using any conventional formulation method. ! can do. Therefore, the present invention contains at least one quinoline derivative (I). Such compositions may be prepared by conventional means using any required pharmaceutical carriers, excipients and other pharmaceutically acceptable excipients! 14! I can get angry.

When the composition is an oral preparation, it is desirable that the preparation be provided in a form suitable for absorption from the gastrointestinal tract.
Tablets and capsules for oral administration are in unit dosage form and contain binders such as syrup, arabicum, gelatin, sorbitol, tracanth, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxymethylpropylmethylcellulose, macrogol, potato, etc. Starch, disintegrants such as carboxymethyl cereulose calcium, excipients such as lactose, corn starch, calcium phosphate, sorbitol, glycine, lubricants such as magnesium stearate, talc, polyethylene glyfur, silica, lauryl sulfate. ff1 such as sodium
The tablets may be coated by a known method, and the oral liquid preparations may be aqueous or oil-based suspensions, solutions, syrups, elixirs, etc. Alternatively, it may be a dry product that is redissolved in a suitable vehicle, such as water or water, before use; such liquid formulations may contain commonly used additives, such as sorbitol, methyl cellulose, gluten / Suspending agents such as sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, lecithin,
Emulsifiers such as sorbitan monooleate, gum arabic, almond oil, fractionated coconut oil, oily esters, propylene glyfur, non-aqueous vehicles such as ethyl alcohol, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid, etc. A preservative may be added as appropriate.

In addition, when manufacturing parenteral preparations such as injections, tonicity agents such as glucose, D-sorbitol, D-mannitol, and sodium chloride, benzyl alcohol, chlorobutanol, methyl paraoxybenzoate, and propyl paraoxybenzoate are used. By adding appropriate preservatives, buffers such as phosphate buffer, sodium acetate buffer, etc., it can be made into a skin, intramuscular, or intravenous injection by a conventional method.

(The following is a blank space) The compound (1) of the present invention can be made into an injection, an oral preparation, a drug substance, etc. together with various pharmacologically acceptable carriers known per se. Since the dosage varies depending on the target therapeutic effect, administration method, age, body weight, etc., it cannot be generally specified, but the daily dose is usually about 0.01 mg parenterally per kg of body weight. - about 20 mg, more preferably about 0.05 mg - about 2 mg, orally about 0.1 mg - about 200 mg, more preferably about 0.5 mg
mg to about 20 mg, which may be administered in 1 to 5 divided doses.

The present invention will be explained in more detail with reference to Examples and Reference Examples below, but these are not intended to limit the present invention in the same way.

Song”■Li 1 2.2-〉Production of methyl-28-5-(4-hydroquinosteryl)pyrano[3,2-c]quinoline (■1) p-hydroxybenzaldehyde (I[1) 159 mg
(1,3 mmol) and 2,2,5-trimethyl-2H-
Pyranoquinoline (I [[1) 226 mg (1 mmol)
was dissolved in 1 ml of toluene, 0.1 ml of acetic acid and 0.1 ml of piperidine were added as catalysts, and the solution was heated at 110°C for 3.
Time reacts. The diameter was reduced under reduced pressure and subjected to glue-gel-lamb chromatography.
:l) Obtain 26Qmg of the title compound (Il) from the outflow. This product was converted into a hydrochloride with ethereal hydrochloric acid and recrystallized from ethanol to yield 266mg of orange prismatic crystals with a melting point of 250-252°C (yield 729%) get.

Elemental analysis (C, *H,, CI No, closed) Calculated value (
X): C, 72, 22; H, 5, 51; N, 3
．． 83 Experimental value (X): C, 71,97; H, 5,
65i N, 3.85LR: VNuJ0' 3100
．． 1630.1235.1163 cm-'ax NMR: S DMSO-" 1.65 (3Hx
2. s), 6.17(l)l, d).

pffi 7.78 (21, d), 7.18 (LH, d), 7
．． 78 (2H, d), 7.70-8.51 (6H, m
).

(Left below) X1! [In the formula, R1, R'', Ar, n, , W, X, Y, Y' and the broken line have the same meanings as above] Compound (I[) and compound (I[[)] dissolved in
The reaction is carried out under a nitrogen stream at room temperature or under heating. After concentration under reduced pressure, the residue is crystallized with ether or subjected to silica gel column chromatography to obtain the target compound (I). Purify this product by recrystallizing it if necessary.

Details of the reaction conditions for producing the target compounds of the present invention listed in Table 2 below by the above method are listed in Table 3. Furthermore, the recrystallization solvent, appearance (crystal form, color), molecular formula, and elemental analysis values of each product or its acid addition salt are listed in Table 4.
The JR and NMR spectrum data are listed in Table 5.

(The following is a blank space) Example 34 3.4-'; Hydro-5-(3,5-dimethoxy-4
-Hydroquinphenethyl)-2,2-dimethyl-2H-
Preparation of pyrano[3,2-C]quinoline (I34) 2.2-dimethyl-2H-5-(3,5-dimethyan-4-hydroxystyryl)pyrano[3,2-C]quinoline (I9) (Example 9) 0.4 g (1
, 03 mmol) and 02 g of 5% rhodium-alumina were added to 10 ml of methanol and subjected to hydrogen reduction. After filtration, methanol was distilled off and the residue was subjected to silica gel column chromatography, and the title compound (
038 g of I34) are obtained. Compound (I34) was recrystallized from acetone as a hydrochloride, melting point 215-220.
0.4 g of yellow needles showing °C (91.7% yield)
get.

Elemental analysis (as C*4HtsCINO1) Calculated value m
: C, 67,05; H, 6,57; N, 3.26
Experimental value C'1. '): C, 66, 74; H, 6, 5
3; N, 3.141R Niji Nu"13275.120
6.1115 cm-'ax CDCI.

NMR: l; 1.4 (3Hx2.s),
1.85 (2H, t).

pm 2.65 (2H, t), 3.1 (4H, m), 3.
77 (3Hx2.s), 6.4 (2H,s), 7
．． 34.2 (4H, a+).

Below, 2,2-dimethyl-2H-5-(3,5-'.

Metquin-4-hydroxystyryl) pyrano[3,2-
c] A formulation example containing quinoline (112) (compound completely produced in Example 12) as an active ingredient is shown.

Composition (powder) Compound (I!2) 100
+ng lactose 300ff1g corn starch 100 whole
Amount 50
0rI@ or more, mix these according to a conventional method to form a compound (
112) was prepared.

(Tablet) Compound (II2) 100
mg lactose 200■ corn starch 1100II
I Carboquine Methylcellulose Calcium 100n@
Microcrystalline cellulose 350rr @ polyvinylpyrrolidone 50ff @ talc 100 total amount
iooomg Tablets of compound (112) were prepared by mixing these in accordance with the conventional method.

Lλ■U2 H-2,2,5-) Limethylpyrano[3,2-C Production of coquinoline (■1) H 4-Hydroxyquinaldine (VII) 39.16 g
(0246 mol), 35.3 g (0,344 mol) of 3-chloro-3-methyl-1-butyne (1/1), 180 mL of 9° 4% sodium hydroxide solution) 45 g of Lydone B was added to 200 ml of tetrahydrofuran, The reaction mixture was stirred for 3 days at 30 °C. The reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate, and after filtration, ethyl acetate was distilled off. 700 ml of n-decane was added to the residue (■1), and the mixture was extracted at 180 °C. Heat for 15 minutes. Purification was performed by silica gel column chromatography, and the outflow of ethyl acetate was subjected to distillation.
Obtain 40-b.

Elemental analysis (as C+sH+aNO) Obtained value (X): C, 79,97; H, 6,71i
N, 6.22 Experimental value (X): C, 79, 89;
H, 6,76; N, 6.09IR: V"jo" 1
636.1125 am-'.

ax 5.68 (II (, d), 6.60 (IH, d),
7.4-8.08 (4H, m).

(Left below) l (41 Main 2H-2,2,5-1-rifthyl-9-methoxypyrano[3,2-c]quinoline <■2) Production 0) I (Vl2) (Vl) 4-Hydroxy- 6-Medoxyquinaldine (Vl2)1
8.9 g (0, t mol) and (Vl) 14.4 g (0,1
4 mol) was treated in the same manner as in Reference Example 1 to obtain an oily (■2
) was obtained (8.5 g (yield 33.3%)). (Il[2)1
70-175°C/0, 2 mmHg*CDC1°NMR: S 1.54 (3) 1x2. s
), 2.64 (3H, s).

29m 3.93 (38, s), 5.67 (IH, d),
6.58 (LH, d), 7.25-7.79 (3
H, m).

Vine λ堡1 2H-2,2,5-trimethyl-6-nitrovira z[3
, 2-c coquinoline (■3) production H (IVI) (1[3)4-hydroxy-6-nitroquinaldine (■2) 20.5 g (0
, 1 mol) and 20 g (0,195 mol) of (Ml) were treated in the same manner as in Reference Example 1 to obtain 10 g (yield 3
7.0%). (I [3) mp 194-195
°C, yellow needles (isopropyl ether) Elemental analysis (as CIaH,, N, O,) Calculated value (X
): C, 66, 65i H, 5, 22; N, 10
．． 37 fruit IIH1i (X): C, 66, 32; H,
5, 33: N, 10.30LR: Li"jo" 1
640. 1336. 1127 cm-'ax NMR: l; CD"" 1.60 (3H x 2.s
), 2.72 (3H, s).

29m 5.77 (IH, d), 6.59 (LH, d), 7
．． 97-9.03 (38, m>.

(Left below) ``j'' ± 2H-5-methylpyrano[3,2-c]quinoline-2-
Preparation of spiro-1-cyclohexane (I [[4 H (VII) (V2) compound (Vll) 15.9 g C0.1 mol) and 1-nibnyl-1-chlorocyclohexane (V2) 19°9 g
(0.14 mol) was treated in the same manner as in Reference Example 1, and (■
16 g (yield 63.7%) of 4) is obtained.

(3H, s), 5.67 (IH, d), 6.5
9 (IH, d), 7.37-8.15 (4H, m)
.

Yutaka 211 Production of 3,4-dihydro-28-2,2,5-trimethylpyrano[3,2-C]quinoline (■5) 2H-2,2
,5-trimethylpyrano[3,2-C]quinoline (II
[1] Add 2.25 g (10 mmol) and 0.3 g of 10% vanadium-carbon to 40 ml of tetrahydrofuran and reduce with hydrogen. After filtration, the residue is purified by silica gel column chromatography, and an oily mixture is extracted from the ethyl acetate outflow. 22g (yield 969%) of (■5) was obtained.

NMR: S CpCl” 1.45 (3) 1x2.
s), '1.96 (28, t).

99m 2.64 (38, s), 2.78 (2H, t), 7
．． 38-8.14 (4H, m).

Reference example 6 3.4-dihydro-2H-2,2,5-trimethyl-6
-Production of methylpyrano[3,2-c coquinoline <■6) 2 H-2,2,5-1-rifthyl-6-methoxybira/[3,2-C]quinoline (I[[2) 5.1 g (
20 mmol) was treated in the same manner as the reference inversion (I[[6
) 5g (yield 9B%) is obtained.

(II[6) mp 92-93°C. Colorless needle crystals (hexane) Elemental analysis (C, H, NO, closed) Calculated value (X)
: C, 74,68; H, 7,44; N, 5.4
4 Experimental value (X): C, 74,55; o, 7.4i
; N, 5.46IR Niji""11602.1226.
1159 cm-1aX DCII NMR: 8 1.45 (3Hx2.s), 1
．． 94(2)1. t).

99m 2.58(3)1. s), 2.76(2)! , t
), 7.25-7.82 (38, m).

Fsu[3,4-dihydro-2H-5-methylpyrano[3,2-
clquinoline-2-spiro-1-cyclohexane (1
! I7) Production (If[4) (I[[7)2H-
5-methylpyrano[3,2-c]quinoli/-2=spiro-1-cyclohexane (III4) 531 g (20
mmol) was treated in the same manner as in Reference Example i to obtain (I[[7]
Obtain 4.76 K (yield 89.6%). ([[17)
mp 144-145℃, colorless needle crystals (\xane) Elemental analysis (as C,, Hl, NO) Calculated value (X)
: C, 80, 86: H, 7, 92: N, 5.24 Experimental value (X): C, 80, 71; H, 7, 87;
N, 5.02T, R: V Nu"' 1598.11
12 cm-'ax NMR: l; CD" 1.30-2.16 (IOH
, m), 1.93 (2H.

99m t), 2.61 (3H, s), 2.76 (2H, t
>, 7.38-8.17 (4H.

m).

(Left below) 20 vines 2 H-2,2,5-trimethyl-thiopyrano[3,2
-c] Production of quinoline (■8> R (Vl3) (Vl)
4-Hydrothioquinaldine (Vl3) 1.625 g
(9,27 mmol) and 3-chloro-3-methyl-1-
Butyn (Ml) 1.31 g (12,77 mmol)
was treated in the same manner as in Reference Example 1 to obtain oily (Il[8) 1°O
g (yield 448%).

CDC1°NMR: S 1.45 (3HX2.s
), 2.76 (3H, s).

99m 5.89 (LH, d), 6.76 (LH, d),
7.44-8.08 (4H, m).

Reference Example 9 2H-5-methylthiopyrano[3,2-c]quinoline-
Production of 2-spiro-1-cyclohexane (■9) H (■3) (V 2) (IV6) (]I[9)4-P drothioquinaldine (V!3)! , 1 g (5 furimmol) and 1-ethynyl-1-chlorocyclohexane (
V2) 1.13 g (7,'92 mmol) was treated in the same manner as in Reference Example 1 to obtain 05 g (yield 30.6%) of oily (I[9).

NMR: l; CDCl' 1.35-2.34 (IO
H, m), 2.74 (3) 1°99 m 9), 5.95 (IH, d>, 6.76 (1) 1.
d), 7.32-8.16 (4B.

m).

Patent applicant: Shionogi & Co., Ltd. Representative: Yu Shiota, patent attorney

Claims (6)

[Claims] (1) Formula: ▲ Numerical formulas, chemical formulas, tables, etc. or a 5- or 6-membered heterocycle containing a sulfur atom;
R^1 and R^2 are the same or different from each other and represent hydrogen, C_1~C_6 alkyl, or together C_2~
C_6 alkylene; W is an oxygen atom or a sulfur atom; X is hydrogen, nitro, halogen, or C_1 to C_6 alkoxy; Y is ethylene or vinylene;
and dashed lines represent the presence or absence of a bond. ] A quinoline derivative or a pharmaceutically acceptable salt thereof. (2) Formula: Ar-(Y')_a_-_1CHO [wherein Ar and n have the same meanings as above, and Y' represents vinylene. ] Compounds and formulas: ▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼ Condensate the compound represented by [In the formula, R^1, R^2, W, Featured formulas: ▲Mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, Ar, R^1, R^2, W, X, Y, n, and the broken line have the same meanings as above. ] A method for producing a quinoline derivative. (3) A pharmaceutical composition comprising an effective amount of at least one compound according to claim 1 and a pharmaceutically acceptable additive. (4) The pharmaceutical composition according to claim 3, which is a therapeutic or ameliorating agent for diseases caused by oxidation or platelet aggregation. (5) The pharmaceutical composition according to claim 3, which is a therapeutic or ameliorating agent for diseases caused by dysfunction of the heart, brain, lungs, or kidneys. (6) The pharmaceutical composition according to claim 3, which is intended for improving circulatory system function.