JPS6363533B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula

[expression] or

Among the spiro compounds represented by the formula, 1'-methyl-spiro[isochroman-3,4'-piperidine],
1'-benzyl-spiro[2H-3,4-dihydrobenzo-1,3-thiazine-2,4'-piperidin]-4-one or 1'-benzyl-spiro[phthalane-3,4'-piperidine] The present invention relates to an antiallergic drug containing -1-one or a salt thereof as an active ingredient. These compounds are designated as compounds No. 1, 19 and 26, respectively, in the following description. The present invention relates to an antiallergic drug containing an acid addition salt thereof as an active ingredient. In addition, each symbol in the formula has the following meaning. W: CH or N X: O, CH ₂ or CO Y: O, NH or (CH ₂ ) n (n is 0 or 1) Z: O, S, NH, (CH ₂ ) n (n is 0 or 1) )
or CHCOO-alkyl R ₁ : H, alkyl, allyl, aryl, aralkyl, cycloalkyl or cycloaralkyl R ₂ R ₃ }: H, alkoxy or hydroxyalkyl The compound is a known or new compound, and is disclosed in Japanese Patent Publication No. 48-31114 and U.S. Patent No. 3686186.
No., Il Farmaco-Ed. Sc. 32 212-219 (1977) or J. Med. Chem. 19 1315-1324 (1976). An example is shown below. Example 1 1'-cyclohexylmethyl-spiro[isochroman-3,4'-piperidin]-1-one (formula: W=N, X=CO, Y=O, Z=CH ₂ , R ₁
= cyclohexylmethyl, R ₂ = R ₃ = H): 2 g of N-methyl-O-toluamide was dissolved in 70 ml of anhydrous tetrahydrofuran, and in a nitrogen gas stream,
22 ml of 15% n-butyllithium-hexane solution was gradually added dropwise under ice cooling, and the mixture was stirred at room temperature for 40 minutes. A solution of 2.4 g of 1-cyclohexylmethyl-4-piperidone dissolved in 50 ml of anhydrous ether was added dropwise to this mixture under ice-cooling, and after stirring for 2 hours, 10% hydrochloric acid was added to the reaction solution to form a basic substance. was extracted. The aqueous layer was separated, the pH was adjusted to 10 with 20% sodium hydroxide, extracted with ethyl acetate, the ethyl acetate was distilled off, and the residue was poured into 8 ml of concentrated sulfuric acid and 32 ml of a 50% aqueous acetic acid solution for 2 hours. Heated. After reaction, 20
The pH was adjusted to 10 with % sodium hydroxide, extracted with ether, and the ether was distilled off. The residue was recrystallized from cyclohexane to obtain 1.1 g of needle-like crystals with a melting point of 112-113°C. Example 2 1'-benzyl-spiro[isochroman-3,
4′-cyclohexane]-1-one (formula: W=
Preparation of CH, X=CO, Y=O, Z= _CH2 , _R1 =benzyl, _R2 = _R3 =H): 9.
Using 4-benzylcyclohexanone (g), the reaction was carried out with n-butyllithium in the same manner as in Example 1. As a result, crystals of 4-benzyl-1-(2-methylcarbamoylbenzyl)cyclohexanol (melting point
180-181.5°C) 3.0g was obtained. After heating 2.5 g of this compound in 30 ml of tetralin at 180 to 200°C for 6 hours, the tetralin was distilled off under reduced pressure, and the residue was separated and purified by elution chromatography using silica gel. 1.52 g of crystal was obtained. Example 3 4-ethoxycarbonyl-1'-benzyl-spiro[isochroman-3,4'-piperidine]-1
-on (formula: W=N, X=CO, Y=O, Z
= CHCOOC ₂ H ₅ , R ₁ = benzyl, R ₂ = R ₃ =
Preparation of H): 3.1 g of 1-benzyl-4-piperidone and 5.1 g
homophthalic acid diethyl ester is dissolved in 50 ml of anhydrous benzene, and a solution of 0.5 g of 50% sodium hydride dissolved in 50 ml of anhydrous benzene is gradually added dropwise to the solution. After stirring at room temperature for 3 hours, benzene was distilled off under reduced pressure, and the residue was separated and purified using ion exchange resin IR-120. As a result, 1-benzyl-4-(α-ethoxycarbonyl-2-carboxy)benzyl-3-piperidene
4.42g was obtained. Mix this with 20 ml of acetic anhydride, 10 ml of acetic acid, and 1 g of sodium acetate anhydride.
After heating under reflux for a period of time, the pH of the reaction solution was adjusted to 10 with 20% sodium hydroxide, extracted with ethyl acetate, and the residue obtained by distilling off the ethyl acetate was an oil. After thorough drying, it was dissolved in anhydrous benzene and passed through dry hydrogen chloride gas to form hydrochloride crystals, and then recrystallized from a mixed solvent of ethanol and acetone. Yield 1.1g,
Melting point 195-197°C (decomposition). Example 4 1'-phenethyl-spiro[(2H)-3,4-dihydrobenzo-1,3-oxazine-2,4'-
piperidin]-4-one (formula: W=N, X=
CO, Y=NH, Z=OR ₁ = phenethyl, R ₂ =
Production of R ₃ =H): 3 g of salicylamide and 3.7 g of 1-phenethyl-4-piperidone were placed in a Soxhlet apparatus and dissolved in 100 ml of chloroform, and 5.1 g of toluenesulfonic acid was added thereto and heated to reflux. Anhydrous magnesium sulfate was added to the thimble filter, and the mixture was reacted for 5 hours while absorbing water, and then chloroform was distilled off under reduced pressure. Add 10% sodium hydroxide to the residue to make it alkaline, extract with ethyl acetate, wash the ethyl acetate layer with water, dry it, ethyl acetate is distilled off, and the residue is recrystallized from a benzene petroleum ether mixture to give a melting point of 153-154°C. 4 g of crystals were obtained. Example 5 1'-benzyl-spiro[chroman-2,4'-piperidin]-4-one (formula: W=N, X=
CO, Y= _CH2 , Z=O, _R1 =benzyl, _R2 =
Preparation of R ₃ =H): 5 g of ortho-hydroxyacetophenone and
6.9 g of 1-benzyl-4-piperidone was dissolved in 50 ml of anhydrous methanol, 2.62 g of pyrrolidine was added thereto, and the mixture was heated under reflux in a nitrogen stream for 8 hours. After concentrating the reaction solution, the residue was recrystallized from a benzene-cyclohexane mixture to obtain 9.25 g of 1'-benzyl-spiro[chroman-2,4'-piperidin]-4-one with a melting point of 91-93°C. Ta. Example 6 1'-benzyl-spiro[isochroman-4,
4′-piperidine] (formula: W=N, X=CH ₂ ,
Y=O, Z= _CH2 , _R1 =benzyl, _R2 = _R3 =
Production of H): 5.5 g of 4-cyano-4-phenyl-1-benzylpiperidine, 12 g of methanol and 6 g of concentrated sulfuric acid.
was added and heated at 140°C for 25 hours in a sealed tube. After the reaction,
Add water and 20% sodium hydroxide solution to PH 10
and extracted with ether. When the ether is distilled off, methyl-1-benzyl-4 with a melting point of 94-95℃ is obtained.
-Phenylpiperidine-4-carboxylate
3.3g was obtained. When this product is reduced with lithium aluminum hydride in ether by a conventional method, 1
-Benzyl-4-hydroxymethyl-4-phenylpiperidine was obtained almost quantitatively. 10 ml of anhydrous dioxane was added to 4 g of this product and dissolved, 5 g of paraformaldehyde was added, and the mixture was heated under reflux for 5 hours while passing dry hydrogen chloride gas.
After the reaction, the pH was adjusted to 10 with 20% sodium hydroxide and extracted with ether. The ether residue was dissolved in anhydrous benzene, and then passed through dry hydrogen chloride to crystallize it as a hydrochloride. Target product with melting point 285-299℃ (decomposition)
2.1g was obtained. Example 7 1'-benzyl-spiro [isochroman-4,
4′-piperidin]-1-one (formula: W=N,
X=CO, Y=O, Z= _CH2 , _R1 =benzyl,
Preparation of R ₂ = R ₃ = H): 1'-benzyl-spiro [isochroman-4,
3.2 g of 4'-piperidine was dissolved in 30 ml of acetic acid and added dropwise at 30 to 35°C into a solution of 4.4 g of chromic anhydride dissolved in 50 ml of acetic acid and 10 ml of water. After stirring for 2 hours, isopropyl alcohol was added dropwise to consume excess chromic acid, and the solvent was distilled off under reduced pressure. Add 20% sodium hydroxide to the residue to adjust the pH.
10, extracted with ethyl acetate, and distilled off the ethyl acetate. The residue was converted into a hydrochloride by passing dry hydrogen in anhydrous benzene. 1.2 g of the target product with a melting point of 265-285°C (decomposed) was obtained. Example 8 7-Hydroxymethyl-6-methoxy-1'-phenethyl-spiro[isochroman-4,4'-piperidine (formula, W=N, X= _CH2 , Y=O,
Production of Z=CH ₂ , R ₁ = phenethyl, R ₂ = 6-methoxy, R ₃ = 7-hydroxymethyl): Add 32 g of sodium amide and 88.0 g of 2-chloroethyl vinyl ether to 400 ml of dry benzene and cool on ice. While stirring, 55.0 g of benzyl 3-methoxycyanide was gradually added dropwise. After the dropwise addition, the mixture was heated under reflux for 3 hours. After cooling, the reaction solution is extracted with benzene, and then the benzene is distilled off, resulting in a boiling point of 190-202℃ (0.18℃).
86.0 g of oily 3-methoxy-α,α-bis(β-vinyloxyethyl)phenylacetonitrile was obtained. 85.0g of this stuff is 1.5
% hydrochloric acid and heated for 30 minutes. After the reaction, extraction with ethyl acetate was carried out. Ethyl acetate was distilled off, and the residue was recrystallized from dichloromethane to give α,α-bis( β-hydroxyethyl)-3-methoxyphenylacetonitrile
39.7g was obtained. 79.0 g of diethylaniline was added to 39.0 g of this product, and 79.0 g of thionyl chloride was added dropwise while stirring while cooling. After dropping, it was heated to 80℃ for 30 minutes, then extracted with ether, and the ether was distilled off.The resulting residue was distilled under reduced pressure to obtain a boiling point of 195-198
The fraction at 0.12 mmHg was collected. This product is crystallized from methanol and α, α with a melting point of 33 to 35°C
38.6 g of -bis-(β-chloroethyl)-3-methoxyphenylacetonitrile was obtained. Add 32.0g of phenethylamine to 18.0g of this material and heat to 140℃.
Heat for 1.5 hours. Water is added to the reaction solution, and the aqueous layer is washed with ether to remove the ether-soluble portion. The aqueous layer is then made basic by adding 20% sodium hydroxide solution and extracted with ether. After distilling off the ether, the residue was recrystallized from methanol, with a melting point of 53.5~
12.1 g of 4-cyano-4-(3-methoxyphenyl)-1-phenethylpiperidine as crystals at 55°C
was gotten. 12.0g of this stuff with anhydrous methanol
Add 24.0g and 12.0g of concentrated sulfuric acid, and heat at 140℃ in a sealed tube for 25 minutes.
Allow time to react. After cooling, extraction with ether and distillation of the ether yielded 4-(3-methoxyphenyl)-1-phenethylpiperidine-4 with a melting point of 46-48°C.
-7.8 g of carboxylic acid methyl ester were obtained. 6.1 g of this product was dissolved in 100 ml of anhydrous ether, and added dropwise under cooling to a solution of 1.0 g of lithium aluminum hydride dissolved in 60 ml of anhydrous ether. Then, after reacting at room temperature for 1.5 hours, excess lithium aluminum hydride was decomposed with water, and 10
% sodium hydroxide and extracted with ether. When the residue obtained by distilling off the ether was recrystallized from cyclohexane, 4.4 g of 4-hydroxymethyl-4-(3-methoxyphenyl)-1-phenethylpiperidine was obtained as crystals with a melting point of 106-107°C. Ta. Add 3.0g of this to 20% of anhydrous tetrahydrofuran.
ml, add 2g of paraformaldehyde,
Dry hydrogen chloride gas was passed through the mixture for 9 hours while stirring under ice cooling. Furthermore, 1.5 g of paraformaldehyde was added, and after reacting for 4 hours, 20% sodium hydroxide was added to make the mixture basic, and the mixture was extracted with ether. After distilling off the ether, the residue was converted into a hydrochloride salt using a conventional method, and recrystallized from acetone-ethanol, with a melting point of 264-268.
1.5 g of the target product was obtained as crystals at ℃ (decomposition). Table 1 shows compounds produced in the same manner and their melting points.

【table】

[Table] The present inventors have discovered that a compound with the above-mentioned spiro-bond and characteristic structure is effective in promoting chemical messengers (histamine, serotonin, SRS-A, etc.) from mast cells or basophils during allergies. It has been found that the release of anti-allergenic substances is inhibited and anti-allergic effects are exhibited. Disodium chromoglycate (DSCG), which has a chromone skeleton, is a compound that suppresses the release of chemical mediators, but such an effect is not known at all for compounds with spiro bonds, and some It is only known to have a pain-relieving effect. Antiallergic drugs that suppress the release of chemical mediators are useful for the prevention and treatment of immediate or type allergies, such as bronchial asthma and allergic rhinitis. The antiallergic effect of the present invention will be described in detail below along with the test method and effects. In other words, the inhibitory effect on histamine release from mast cells (in vitro) and the inhibitory effect on passive cutaneous anaphylaxis (PCA) (in vivo) are considered to be important for the pharmacological evaluation of chemical mediator release inhibitors. In addition, the Schultz-Dale reaction inhibitory effect was also investigated. (1) Inhibition of histamine release Suppression of histamine release from isolated rat mast cells: Wistar rats weighing 200 to 350 g were hit on the head to cause them to faint, then bled to death from the common carotid artery, and exposed to 95% O ₂ +5 Inject 15 ml of physiological saline solution (hereinafter referred to as PS solution) into the abdominal cavity with % CO ₂ bubbled in.
The abdominal wall was gently massaged for 2 minutes. Then, a small incision was made in the abdominal wall to collect the ascites, and the temperature was increased to 4°C.
The mixture was centrifuged at 500 rpm for 5 minutes. PS with ice-cooled sediment
It was suspended in a solution and centrifuged under the same conditions. The mast cells in the sediment were suspended in an appropriate amount of PS solution and used for the experiment. PS with suspended mast cells (1-2 x 10 ⁵ cells)
1.9 ml of each solution was placed in a centrifuge tube and pre-incubated for 5 minutes in a constant temperature bath at 37°C. after that,
Divide into two groups, one group will be treated as a control, and the mast cell suspension in the other group will be treated with a compound.
48/80 (Wellcome Reagents Ltd., Brit.J.
Pharmacol. (1951), 6, 499; 0.5-5μg/ml)
0.1 ml was added and further incubated at 37°C for 15 minutes. As a control, 0.1 ml of PS solution was added and incubated in the same manner. Thereafter, the centrifuge tube was ice-cooled to stop the reaction, centrifuged at 1500 rpm at 4°C for 10 minutes to separate the supernatant, and 2 ml of fresh PS solution was added to the precipitate to suspend the cells. 0.05 ml of 1N hydrochloric acid was added to both the supernatant and cell suspension, and the samples were immersed in a boiling water bath for 5 minutes.
In an experiment to investigate the inhibitory effect of the test drug Compound 48/80 on histamine release, various concentrations of the test drug were added to the PS solution after pre-incubation and allowed to act for 15 minutes.
Thereafter, Compound 48/80 was applied in the same manner as before to examine its effect. For the control group, Compound 48/80 was not applied, and other operations were performed in exactly the same manner to prepare samples for measuring the amount of histamine contained in the supernatant and sediment. Histamine was determined using Shore's fluorescence assay method (J.
Pharmac.exp.Ther. 127 182-186 (1959)). That is, 0.4 ml of 1N sodium hydroxide solution and 0.1 ml of 1% O-phthalaldehyde solution were added to 2 ml of the test solution, stirred, and
After reacting for a minute, 0.2 ml of 2M citric acid was added to stop the reaction, and the excitation wavelength was 360 nm and the fluorescence wavelength was
The fluorescence intensity was measured at 440 nm, and the histamine concentration of the sample was determined from a separately prepared calibration curve. A calibration curve was created each time histamine was quantified. The histamine release rate was calculated using the following formula. Histamine release rate=Hr/Hr+Hp×100 Hr: amount of histamine released in the supernatant Hp: amount of histamine remaining in the sediment The rate of inhibition of histamine release when the test drug was applied was calculated using the following formula. Inhibition rate = AB/A x 100 A: Histamine release rate when compound 48/80 acts alone B: Histamine release rate when the test drug is pretreated and compound 48/80 acts. Tables 2 and 3 show the histamine release inhibitory effects obtained.

【table】

【table】

[Table] (2) PCA inhibitory effect: Z.Ovary's method (Progr.Allergy 5 459
(1958) was used as the basis. That is, 1 mg of ovalbumin was added to B. pertussis.
The suspension was suspended in 1 ml of a suspension (2×10 ¹⁰ /ml) and injected intraperitoneally into guinea pigs (Hartley strain) to sensitize them. Antiserum is collected from the guinea pigs two weeks after injection and stored frozen. Furthermore, it was epidemiologically confirmed that this antiserum contained reagin-like antibodies. Next, 0.1ml of the frozen antiserum
After thawing, administer intradermally to rats (Wister strain),
After a further 4 hours and 30 minutes, ovalbumin and Evans Blue were administered intravenously (1% ovalbumin 0.25 ml/100 g body weight and 2% Evans Blue 0.25 ml/100 g body weight). Further, 30 minutes later, the rats were bled to death, and the Evans blue leaked into the skin was extracted by immersion in a 0.05% Na ₂ SO ₄ -acetone (3:7 V/V) mixture for 24 hours.
It was quantified spectroscopically (620 nm). To examine the inhibitory effect of a test compound, administer 5 mg/Kg (dissolved in saline) of the test compound intravenously to Larats 30 minutes before administering the antigen (ovalbumin), quantify the amount of dye leaked, and compare it with a control. (rats administered only saline), and the inhibition rate was determined. The results are shown in Table 4.

[Table] (3) Schulz-Dail reaction inhibitory effect (J.
Pharmacol.Exptl.Therap., 1 549 (1910)
ibid., 4 167 (1913): 1 mg of ovalbumin was added to Bordetella pertussis suspension (2×
10 ¹⁰ /cc) and injected intraperitoneally into guinea pigs to sensitize them. Two weeks after the injection, the guinea pigs were bled to death, their intestines were removed, suspended in a Magnus device, and treated with the test compound (No. 1,
No. 19, No. 24), then add the antigen and record the contraction of the intestinal tract. When compared with antigen-induced intestinal contraction in the case where no test compound was added (control), each compound completely inhibited contraction. We also investigated the effect of adding the test compound at the point when the intestinal tract contracted to its maximum due to antigen addition, but the intestinal contraction rapidly relaxed. The spiro compound of the present invention has excellent antiallergic activity but low toxicity, with acute toxicity value (LD ₅₀ )
For example, compound No. 19 was administered intraperitoneally to mice at 320
mg/Kg or more, compound No. 1 is 120.5mg/Kg, compound
No. 24 was 190.3 mg/Kg. In order to prevent or treat so-called immediate-type or type allergies, such as bronchial asthma or allergic rhinitis, using spiro compounds according to the present invention, the appropriate dosage range is 10 mg/day to 5 g/day. 50-2000mg/day 1-
It is considered sufficient to administer the drug in four doses. Intravenous administration is also possible, in which case a smaller amount may be required, but prophylactic oral administration is suitable in order to effectively utilize the antiallergic effect by suppressing the release of chemical mediators. As for the dosage form, it can be mixed with fillers, excipients, binders, and other commonly used pharmaceutical fillers, excipients, binders, etc., as appropriate, and used in the form of powders, tablets, capsules, syrups, etc. In addition, as a special administration method, inhalation as a powder, solution, or suspension may be considered.

Claims (1)

[Claims] 1 1'-Methyl-spiro[isochroman-3,
4'-piperidine], 1'-benzyl-spiro[2H-
3,4-dihydrobenzo-1,3-thiazine-
An antiallergic drug containing 2,4'-piperidin]-4-one, 1'-benzyl-spiro[phthalan-3,4'-piperidin]-1-one, or a salt thereof as an active ingredient.