JPS58135880A - Manufacture of antiallergic tricyclic compounds - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for synthesizing a novel tricyclic compound useful as a medicine.

The tricyclic compound represented by the formula 1 shown below and its salts are active in mammals, and are effective when administered internally to the mammary proboscis, for example, as inhibitors against human-related allergic reactions; The effect was found to be due to K in inhibiting the release of the hypersensitivity mediator: where 21 is a substituent in the 3-position, which represents a 5-tetrazolyl group, and z2 is a substituent in the 7-position. is a substituent and represents halogen, alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms.

The inhibitory effect of the compound of formula 1 is demonstrated by the following three test methods.

(IL) Test using positive skin hypersensitivity reaction (P
The skin reaction that occurs as a result of the interaction between a special antigen injected intravenously and a cell-fixed rare antibody previously injected into the skin of an animal is measured in the Om test (7-
Ovary NiFe1n.

Proa, m, 8oa, @Xp, Biol,
2i, 94 (1965) 几mast oolls)
After antigen administration (after antig@n0hall
Measure the amount of histamine released into @ng・) (1
: Mueta Pharmacol, et Toxiao
l.

2 wholesale-1 supp, 1 (1971), 2: Tho
rax, 27/1.5B (1972)).

(0) Homologous anti
g@n) to measure histamine released from human lung tissue sections sensitized in vivo with rarein antibodies upon administration (Br, M@d, J, 5.272
(1968)).

In this specification, the activity of the acid represented by Formula 1 is shown using a cation solution.

Pharmaceutically acceptable salts of compounds of formula I include ammonium salts, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. magnesium and calcium salts), and salts of organic bases ( Examples include amine salts derived from mono-, di- or tri-lower atom, canolamines such as triethanolamine and diethylamine, and salts with heterocyclic amines such as pipericine, pyricine, piperazine and morpholine. be able to.

Of particular value for intravenous and respiratory administration are water-soluble salts, most preferably those having a solubility in water of at least 1 w/m. Since the pharmacological activity of the salt is due to the anion, the base can be a pharmacologically acceptable cation.

A formula that shows very high anti-allergy activity when administered orally■
The compounds include 3-(5-tetrasilik)-7-methylthioxanthone, 5-C3-tetrazolyl)-7-nitylthioxanthone, and salts of these compounds, especially the alkali metal salts, including the sodium and potassium salts. .

Compounds of formula (2) that exhibit very high antiallergic activity upon intravenous administration include 3-(5-tetrazolyl)-thioxanthone, 3-(5-tetrazolyl)-7-methylthioxanthone, and 3-(5-tetrazolyl). -7-nitylthioxanthone, 3-(5-tetrazolyl)-7-medoxythioxanthone and their salts, % alkali metal salts including sodium and potassium salts.

Compounds of formula I can be produced by chemical methods known per se. Generally, this includes cyclization accomplished by ring closure, hydrolysis, oxidation or reduction of precursors with both zl and z2 groups by a variety of methods. Examples of the preparation of compounds of formula (1) by these methods are described at the end of the specification. These general synthetic methods can also be applied to the production of intermediates.

Compounds of formula 1 are substituted diphenyl sulfides of the formula where zl and z8 are as defined in formula 1 and R1 represents a carboxyl group or a derivative thereof such as a nitrile, amide, aldehyde or acid chloride. It can be produced by reacting with acid or protonic acid. Preferred proton removers are phosphoric acid (tetralin and sulfuric acid).

Aluminum trichloride and 37) as suitable Lewis acids
There is boron oxide. This reaction is preferably carried out at a temperature of 50 to 500"Y3.

The pharmacologically acceptable salt of the tetrazole compound of formula 1 can be prepared by conventional methods, for example, by neutralizing the desired tetrazole compound with a suitable Pronsted base;
Alternatively, the tetrazole of formula I may be double resolved or salted to produce the desired salt of a suitable pharmaceutically acceptable cation. Suitable Solnsted bases include organic bases (eg ethanolamine), ammonium-containing bases, alkali metal cations and alkaline earth metal cations.

The K that isolates the Takenatsu base may be harvested from the reaction medium by any conventional method of harvesting the salt from its solution in a polar medium.

The pharmaceutical compositions of the present invention include a compound of Formula 1 as the active ingredient and may also contain a pharmacologically acceptable carrier and other suitable therapeutic ingredients. This composition can be used orally, rectally, and optically.
c), pulmonary, nasal
l) There are compositions suitable for dermal application, topical or parenteral (including subcutaneous, intramuscular and intravenous administration), although the most appropriate route in a given case will depend on the nature and severity of the condition being treated. It also depends on the nature of the active ingredient. The compositions can be prepared in unit dosage form by methods known in the art of formulation.
).

The pharmacological compositions of the invention suitable for oral administration may be presented in discrete unit doses, each containing a predetermined amount of the active ingredient, e.g. as capsules, cachets or tablets. Aqueous or non-aqueous solutions or dispersions, oil-in-water emulsions, or water-in-oil/II
It may also be provided as a liquid emulsion of I. Such compositions may be made by any method of formulation, which includes the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.

Preferably, each unit quantity separated contains from 50 to 500 mg of active ingredient. Useful forms of the pharmacological compositions of the present invention for use in the treatment of allergic asthma are those suitable for administration to the lungs through the oral cavity. Preferably, when the composition containing the active ingredient is administered to the lungs of a patient, the particles of the composition have a diameter of 0.5-7μ,
Most preferably it is 1-6μ. Such compositions are generally administered in a powder inhaler device or self-propelled powder dispenser (5
slf-propelling powder-d
is in the form of a dry powder for dispensing from ISP@nsing containers), preferably the powder has at least 98% by weight of the particles containing the active ingredient larger than 0.5μ in diameter and at least 95 microns in diameter. is 7μ in diameter
It is made up of smaller particles. Most preferably, at least 95 by weight of the particles are larger than 1 micron in diameter and at least 90 by weight are smaller than 6 microns in diameter.

The composition in dry powder form includes a finely divided solid diluent and generally has a puncturing force! Preferably, it is administered as a capsule made of cells, such as r-latin.

The self-spray compositions of the present invention may be either powder formulation compositions or compositions dispensing the active ingredient in droplets of solution or dispersion. The self-spraying composition contains a liquid propellant having a boiling point of 65"P or less at atmospheric pressure. Generally, the propellant is 50 to 99.9 mm (W/W) of the composition.
), the active ingredient of which accounts for 0.1 to 20% of the composition.
9G (W/W), for example about 2% (W/W). The carrier for such compositions includes the other components,
In particular, it may contain nonionic liquid or cationic solid surfactants, or solid diluents (preferably having a particle size on the order of the particles of the active ingredient), or both. This surfactant accounts for 20% of the composition (
W/W), but 1% of the composition
(W/W) or less is preferable.

Self-propelling compositions in which the active ingredient is present in solution consist of the active ingredient, a propellant, a co-solvent, and preferably an antioxidant stabilizer. Co-solvent is 5-40% (W/W) of the composition
However, less than 2°1 (Vl/Vl) of the composition is preferred.

The compositions of the present invention may also be prepared by using an aqueous or dilute alcoholic solution of the active ingredient, preferably undiluted, for use in a nebulizer.
It may be an iIm liquid.

Compositions of the invention suitable for parenteral administration generally consist of a sterile aqueous solution of the active ingredient, which solution is desirably isotonic with the blood of the patient being treated.

Pharmaceutical compositions of the invention suitable for topical therapy include compositions suitable for administration to the skin, eyes, nose and mouth. Compositions for administration to the skin include p-jones and creams consisting of liquid or semisolid emulsions (which may be either oil-in-water or water-in-oil emulsions) and ointments, preferably containing 0. 2 to 5 mi (W/V). Preferably, creams and ointments should contain a preservative, such as methyl hydroxybenzoate.

Compositions for administration are eye drops and ointments containing the active ingredient in an aqueous or oily solution, preferably containing 0.2-5% (W/V) of the active ingredient.

This eye drop is bacteriostatic (fuxhgistat
io anl baotsriostatia)
It is desirable that the preparation be carried out under aseptic conditions.

Compositions suitable for nasal administration are similar to those already described for compositions suitable for pulmonary administration, but with a somewhat larger particle size of 10 to 20 cm when applied. powder, self-spraying and atomizing compositions. Other compositions suitable for nasal administration include coarse powders of particle size 20 to 500 microns that are administered by snorting, i.e., by rapid inhalation through the nasal passages from a container of powder placed close to the nose. do. Another composition suitable for nasal administration contains 0.2 of the active ingredient in an aqueous or oily solution.
Nasal drops containing ~5% (W/V) (na@a: L dro
ps).

Compositions suitable for topical administration in the oral cavity include tablets containing from 10 to 100 of the active ingredient in a flavored paste, usually sucrose and acacim or gum tragacanth (1oli@ng.), and inert. Tablets (pa
still・g).

Bronchodilators, such as iso! Renarin, adrenaline, orciplenary 7 (
oralprena11n*), inetanin and physiologically acceptable acid addition salts thereof, especially imprenalen sulfate. Bronchodilators generally contain 0.1 to 501 (W/WE') of the active ingredient present.
) quantity exists.

Compounds of Formula 1 are useful in the treatment or prevention of allergic conditions in mammals (eg, allergic asthma) and other allergic chest conditions, hay fever (allergic rhinitis), conjunctivitis, urticaria, and dermatitis. In particular, these include reaction-mediated hypersensitivity asthma ('extrinsiaasthma') and so-called 'intrinsic asthma', which cannot show sensitivity to exogenous antigens (1ntrins1a asthma).
hma).

The dosage of a Formula 1 compound when used prophylactically or therapeutically will, of course, vary depending on the nature of the severity of the allergic reaction involved and on the particular Formula 1 compound and route of administration. Generally, the dosage is 2 per hour of animal weight.
It is within the range of 0 to 100 mg.

In the case of allergic conditions as defined herein, such as atherosclerotic asthma, suitable dosages are:
20 μg to 0.5 μg of a compound of formula 1 per kliF of patient body weight during treatment when using the pulmonary dosing methods described herein.
mg, for example about 0.1 to 0.5 da.

When the composition is administered intravenously, suitable dosages range from 0.2 to 109 (preferably 1 to 5 da) of the compound per kilogram of the patient's body; for oral administration, a suitable The dosage is 1 to 5 of the compound of formula 1 per patient's body weight.
0 mg, preferably in the range of 10 to 40119/yu.

When administering the composition to the nose and eyes, for example in the treatment of allergic rhinitis, a suitable dosage is from 0.5 to 25 Da of the compound of formula 1 for the patient.

The following special forms are also included within the scope of the present invention, but are not limited thereto.

(1) Novel compounds of formula 1 as described herein.

(2) Synthesis by any method known in the art for producing compounds of formula I and compounds of similar chemical structure as described in the Honcho Specification.

(3) A pharmaceutical composition comprising a compound of formula (1) as described herein in combination with a pharmaceutically capable carrier thereof.

(4) Preparation of a pharmaceutical composition comprising a compound of formula 1 as described herein as the active ingredient, including mixing the components by known methods.

(5) A therapeutic or prophylactic method comprising administering a therapeutic or prophylactic dosage, respectively, of a compound of Formula 1 as described herein.

The method of making the compounds according to the invention, as well as the compositions of the invention, are illustrated in the examples and hereinafter. In each □1 example, all temperatures are the Celsius temperature ('O). If the compound of formula (II) does not exhibit a melting point, it decomposes at 1 degree below its melting point and/or its melting point is above a temperature that can be easily determined by conventional methods. In these examples, the number of substituents of the Sandan nucleus used is not as important as that used in Equation 1, but [Ring Index], (R1ng1Hd
・X) Volume 2, 1960 (American Chemical Society), which is the standard number for each Sanyang-type nuclear. This standard number also applies to the names of each of the compounds described herein.

Example 1 7-chloro-6-(5-tetrazolyl)thioxanthone(mu)2-(p-chlorophenylthio)-4-(5-tetrazolyl)benzonitrile p-chlorophenylthioterephthalonitrile (5,28
g), sodium azide (0,78II), ammonium chloride (0,65Ii) and dimethylformand (
Combine 3Q+a/) and heat on a hot water bath for 16 hours.

The mixture is cooled and poured into dilute hydrochloric acid. The precipitated and slowly solidified oil is dissolved in sodium t-podate solution and the solution is extracted with chloroform to remove unreacted starting material. Oxidation of the aqueous solution precipitated 2-(p-chlorophenylthio)-4-(5-tetrazolyl)benzonitrile (decomposition point 222°C).

(B) 2-(p-chlorophenylthio)-4-(5-tetrazolyl)benzoic acid 2-(p-chlorophenylthio)-4-(5-tetrazolyl)benzonitrile (5,24Ii) 0.5M hydroxide ) Dissolve in IJum bath solution (150117) and boil for 16 hours under reflux. The warm solution was acidified with hydrochloric acid to precipitate 2-(p-chlorophenylthio)-
4-(5-Tetrazolyl)-benzoic acid was filtered, washed with water and dried (decomposition point: 245°C).

(0) 7-chloro-6-(5-tetrazolyl)thioxanthone 2-(p-chlorophenylthio)-4-(5-tetrazolyl)benzoic acid (3,419) was added to polyphosphoric acid (70,9
) on a hot water bath for 1 hour. This reaction 1 compound was heated with water to decompose it, and the product was filtered and washed with water.
Recrystallized from dimethyl formand at 156°C under reduced pressure.
When dried, 7-chloro-6-(5-tetrazolyl)
Thioxanthone (decomposes without melting) was changed.

Elemental analysis value 20 53.75-1H2,27 rumor, N
17.9596 Calculated value as 0.4H, 01N, 08: 0 53.42 Arrogance, H2, 24s, N
17.80 Example 2 7-Methyl-3-(5-tetrazolyl)thioxanthone (A14-(5-tetrazolyl)-2-(p-),
Lylthio)benzoic acid 2-(p-)lylthio)terephthalonitrile (20,0
g)', sodium azide (5,20II), ammonium chloride (4,28&) and dimethylformand (10011/) are heated together at 125 DEG C. for 4 hours.

Cool the mixture and pour it onto ice and hydrochloric acid. The precipitated oil solidifies, is filtered off, and recrystallized from a sodium hydroxide solution after removing insoluble alkaline substances by filtration, yielding crude 4-(5-tetrazolyl)-2-
(p-Tolylthio)benzonitrile, melting point 215-21
7 degrees Celsius can be seen. Add this nitrile compound to 601 aqueous sulfur #
(20011/) and acetic acid (20011117) by boiling for 8 hours,
Upon cooling, 4-(5-tetrazolyl)-2-(p-tolylthio)benzoic acid crystallized out; it was filtered off, washed with water and dried. Melting point 245-247°C (decomposed).

(I31 7-Methyl-6-(5-tetrazolyl)thioxanthone 4-(5-tetrazolyl)-2-(p-tolylthio)benzoic acid (2,0, @ ) is heated with polyphosphoric acid (411) for 1.5 hours You will get a clear orange syrup.
This was cooled, decomposed with water, the solid precipitate was collected by filtration, washed with water, and crystallized from dimethylformamide P at 156°C/2.
Drying at 0 wHg gave 7-methyl-6-(5-tetrazolyl)thioxanthone, melting point 560°C.

Elemental analysis value: 0 61.1O-1f (3,491G, N
19.021G 0□l5H1゜N408 [calculated value: 0 61.24%, H5,421G, M
19.04 Analogously to Bun Examples 1 and 2, the following compounds are prepared: a) 7-Nithyl-5-(5-tetrazolyl)thioxanthone, melting point 247°C (decomposition); Elemental analysis: 01. Calculated value as iii, N, 08:
062.52%: it 5.92 arrogance: N 18
．． 171G actual value: 061.92 *: H4,0
511: N 18.1811b) 7-t-butyl-3
-(5-tetrazolyl)thioxant/, melting point 277°C
(Decomposition); Elemental analysis 200, H1, Calculated value as N40B: 064.27 Excellent: H4,801i: Pi
16.66 Actual value: CJ 64.55%: H
5,1111: N 16.689IO) 7-medoxy 3-(5-tetrazolyl)thioxanthone, melting point>6
50℃: Elemental analysis: Oza"x. Calculated value 20 as N40-
58.0611 ; ) I 3.25 * : M 1
8.06 *Actual value: 057.70%: l(5,5
9 pieces: N 17.9796゜Example Powder capsule for inhalation 6-(5-tetrazolyl)-7-nitylthioxanthone sodium salt (0.5-7.0μ powder)
4ay lactose (50-9071!L powder)
46. These powders are mixed until homogeneous and 50 wl9 of this mixture per capsule is filled into suitably sized hard 7' Latin capsules.

Example B Injection 6-(5-tetrazolyl)7-nitylthioxanthone sodium salt 50II
Q British Pharmacopoeia Water for Injection 5. Dissolve this sodium salt in 9591 of water until low, then add the remaining water and sterilize by filtering. Aseptically divide the resulting solution into ampoules.

Example O Aerosol menthol for inhalation 2ag trichlorofluoromethane 4.5.9 dichlorodifluoromethane IQ,Qm
Dissolve sorbitan trioleate and menthol in trichlorofluoromethane. After dispersing the saccharin sodium and tet-)furyl compound in the mixture, it is transferred to a suitable aerosol container and dichlorofluoromethane is injected through the pulp system. This composition contains eII2a! in each 100 sL dosage. provide i.

Example D Suppository 6-(5-tetrazolyl)-7-methylthioxanthone 250 da suppository base 1.8 g finely powdered tetraf
The IJL compound is dispersed in a small volume of suppository paste melted at 50°C. Mix the dispersion with the bulk of the base at the same temperature, cool to 42-45°C, pour into a suitable suppository mold,
Leave at 15-20°C. The suppository base is Massa 1cst@rinum O.
and WittenH8uppository Com
pound) Example l Capsules 6-(5-tetrazolyl)-7-methylthioxanthone 250■Lactose 100■Corn starch 1001111F Stearin Sakamagnesium 10■Each component was mixed together to homogenize and 460'mg of the resulting mixture was added to each Example: Tablet 6-(5-tetrazolyl)-7-methylthioxanthone 500 ■ Corn starch 1009 Microcrystalline cellulose 75 mg Stearin fII & Magnesium 10 ■ 509 g (W/V) Polyvinyl t in aqueous ethanol Lolidon 1096 (W/V
) and make it into granules.

The tetrazolyl compound, corn starch and microcrystalline cellulose are mixed together and granulated with the alcoholic I-lybirrolidone.

The resulting granules are dried and compressed into tablets, each tablet having a weight of approximately 690 Da.

Example G Lotion Sorbitan Monolaurate 0.6 II for Topical Treatment
Polysolvay) 20 0.6.
9-k) Stearyl alcohol 1.29
Glycerin 6. OI Hydroxybenzoic 1 Methyl 0.2g British Pharmacopoeia Purified Water 1QQ, Dissolve methyl hydroxybenzoate and glycerin to Qm in water 70114 at 75°C. melting sorbitan monolaurate, polysorbate 20 and cetostearyl alcohol together at 75°C;
Add this to the aqueous solution. The resulting emulsion is homogenized, cooled with continuous stirring, and the sodium salt is added to the remaining water to dissolve. Stir everything to make it homogeneous.

Example H Nasal Drop Ell/Chlorbutol
0.511 British Pharmacopoeia Purified Water 10
Each component is dissolved in 95aj of purified water at room temperature to a concentration of 0.01117. The resulting mixture was made 100114 with purified water,
Filter and make clear.

Example Eye drops 6-(5-tetrazolyl)-7-methylthioxanthone sodium salt 2.0 g Methyl hydroxybenzoate 0.10 g Hydroxybenzoic acid 11f Lobil 0.04 & British Pharmacopoeia Purified water 100.01111j Up to hydroxybenzoic acid Methyl and! After dissolving the p-bil in purified water at 75°C, the resulting solution was mixed with a pore size of 0.2
Filter to sterilize using a 2 μm membrane filter, and pack aseptically into a suitable sterile container.

Agent Akira Asamura 2 people outside

Claims (1)

[Claims] Formula (1) (in the formula, zl is a substituent at the 5-position, and represents a 5-tetrazolyl group, and zll is a substituent at the 7-position, and represents a hapden group) , 1-4
111 carbon atoms or alkoxy having 1 to 4 carbon atoms); As defined above, R1 represents a carzaxyl group or a derivative thereof) is cyclized in the presence of a Lewis acid or a protonic acid, and optionally the compound of formula 1 thus obtained is cyclized. A method characterized in that it is converted into a pharmaceutically acceptable salt.