KR820000097B1 - Process for preparing pyrido (2,1-b)quinazoline derivatives - Google Patents

Abstract

Title compds. (I; R1, R2, R3 = H, lower alkyl, lower alkoxy, lower alkylthio, halogen, cyclopropyl, cyclobutyl, hydroxy; R4 = hydroxy-lower alkyl), useful as anti-allergics were prepd. by the hydrolysis of II(R7 = acyloxy-lower alkyl). Thus, 5 g 5-methoxyanthranylic acid, 3.9 g 6-chloro-3-pyridine-methanolbenzoate and N-oxide were suspended in 9 ml triethylene glycol dimethylether, then heated to 120≰C overnight to give 1.75 g 8-hydroxymethy1-2-methoxy-11H-pyrido[2,1-b -quinazolin-11-one benzoate.

Description

Method for preparing pyrido [2,1-b] quinazoline derivatives

The present invention relates to a pyrido [2,1-b] quinazoline derivative of the general formula (I) useful as an anti-allergic agent and a method for preparing a pharmaceutically toxic acid addition salt thereof.

Wherein R ₁ , R ₂ and R ₃ are each hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen, cyclopropyl, cyclobutyl, or hydroxy, and R ₄ is hydroxy-lower alkyl, At least one of R ₁ , R ₂ and R ₃ is not hydrogen

As used herein, "lower alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 7 carbon atoms as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, neopentyl, pentyl, heptyl and the like. "Lower alkoxy" refers to an alkoxy group such as lower alkyl group, for example methoxy, ethoxy, propoxy, pentoxy and the like, and "halogen" refers to beton, chlorine, fluorine, iodine.

"Acyloxy" is an "alkanoyloxy" group derived from an aliphatic carbaxyl acid having 1 to 7 carbon atoms, and refers to formyloxy, formyloxy, acetoxy, propionyloxy, and the like. "Aroyloxy" groups such as benzoyloxy and the like are also included.

Examples of the "acyloxy-lower alkyl" group include formyloxymethyl, acetyloxymethyl, propionyloxymethyl, benzoyloxymethyl and the like.

Particularly preferred compounds of the present invention are compounds of the following general formula (I ').

R ₁ ′, R ₂ ′ and R ₃ ′ in the general formula are hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen or hydroxy, respectively, and R ₄ is as described above.

More preferred compounds are those of the general formula (I ') wherein at least one of R ₁ ′, R ₂ ′ and R ₃ ′ is lower alkylthio.

In addition, preferred compounds of the present invention also include compounds of formula (I) wherein at least one of R ₁ , R ₂ and R ₃ is cyclopropyl or cyclobutyl.

In a more preferred aspect, the compound of the present invention the R _1, R _2, and R is ₃ at least one is lower alkyl, lower alkoxy or lower alkyl of the alkylthio, R ₄ is a compound and R ₂ in the formula (Ⅰ) in the 8-position Hydrogen, R ₁ and / or R ₃ are not hydrogen and R ₄ is a compound of the general formula (I) located at 8 position, more preferably R ₂ is hydrogen, R ₁ and / or R ₃ are each A lower alkyl, lower alkoxy or lower alkylthio compound of formula (I).

Examples of compounds of formula (I) are as follows:

8-hydroxymethyl-2-isopropyl-11H-pyrido [2,1-b] quinazolin-11-one;

8-hydroxymethyl-2-isopropoxy-11H-pyrido [2,1-b] quinazolin-11-one;

8-hydroxymethyl-2-methylthio-11H-pyrido [2,1-b] quinazolin-11-one;

8-hydroxymethyl-2-isopropylthio-11H-pyrido [2,1-b] quinazoline-11-one etc. (including the later mentioned compound).

The compound of formula (I) of the present invention and its pharmaceutically toxic acid addition salt are prepared by hydrolyzing the compound of formula (II) and converting the compound obtained into a pharmaceutically toxic salt if necessary.

In the general formula, R, R ₂ and R ₃ are as described above, and R ₇ is acyloxy-lower alkyl.

In this reaction, the compound of general formula (II) is hydrolyzed by treatment with an inorganic acid such as concentrated hydrochloric acid in the presence of a solvent such as, for example, alkanol (e.g. ethanol), and the desired final product is recovered by recrystallization with methanolic hydrogen chloride.

Compounds of formula (II) used as starting materials may be prepared by reacting the compounds of formula (III) with halopyridine derivatives of the following formula (IV) or their corresponding N-oxides.

Wherein R is hydrogen or lower alkyl, R ₁ , R ₂ and R ₃ are as described above, R ₄ ′ is acyloxy-lower alkyl and X is halogen.

In the above reaction, the anthranilic acid or ester of formula (III), which is a known compound or can be prepared by a known method, is also known compound or halopyridine of formula (IV), which can be produced by a known method. Or a corresponding N-oxide thereof in the presence or absence of a solvent at about 100 ° to 200 ° C., the reaction being carried out in the presence of a catalytic amount of alkali metal iodide (eg, sodium iodide, potassium iodide, cesium iodide, etc.). Perform.

As a solvent, a high boiling point solvent such as acetic acid, diglyme, triglyme, and the like is used, and the reaction is usually carried out at atmospheric pressure, and the reaction product can be recovered by conventional methods (eg, crystallization).

Compounds of formula (I) react with acids to form pharmaceutically toxic salts, and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, bromic acid and sulfuric acid are used.

Compounds of formula (I) and their pharmaceutically harmless salts have inhibitory effects on skin hypersensitivity in rats and are therefore useful for the prevention of allergic reactions, for example for the treatment of bronchial asthma. The anti-hypersensitivity effect can be seen through the passive skin hypersensitivity test (PCA test) in rats. The experiment also included a passive local sensitivity test in mice by antiserum intradermal injection. After 24 hours of incubation, intraperitoneal injection of the experimental compound pyrido [2,1-b] quinazoline is given 5 minutes after intravenous injection of antigen and Evans blue dye. Local antigen-antibody reactions are measured by the size of the lesion formed on the skin. The activity of the test compound is determined by comparing the size of the lesion with the control.

In addition, the anti-allergic activity of the compound of general formula (I) was demonstrated in the actively sensitized Mormoto (IgC). In this experiment, morphot is sensitized with horse serum for one day and intravenous administration of antigen (horse serum) for 11 to 14 days induces hypersensitivity reactions (bronchial side, IHR bronchospaspasm). Intravenous injection of an anti-allergic compound prior to administration of the antigen inhibited IHR and inhibited bronchial contraction.

Anti-allergic activity has also been demonstrated in passively sensitized rats (IgE). In this experiment, IHR was induced by intravenous administration of antigen (egg albumin) in mice and administration of antiserum 18 hours ago. Intravenous injection of an anti-allergic compound prior to administration of the antigen inhibited IHR and prevented bronchial contraction.

The compounds of formula (I) and their pharmaceutically harmless salts can be administered orally or parenterally as anti-allergic agents, for example, for the treatment of bronchial asthma (with varying doses from individual to individual).

They may be administered orally or parenterally in therapeutic doses by suitable preparations, such as tablets, capsens, elixirs, suspensions, solvents, and the like.

These may be administered in admixture with suitable pharmaceutical carriers or excipients such as corn starch, calcium stearate, magnesium carbonate, calcium silicate, dicalcium phosphate, talc, lactose and the like. In addition, buffers, isotonic agents, and the like may be added thereto, sterilized if necessary, and may also contain other therapeutically valuable substances.

The amount of active agent varies, but it is preferable to contain 10 to 20 mg of the base of general formula (I), or an equivalent molar amount of a pharmaceutically toxic salt thereof, in the case of capsene or tablet.

The frequency of administration of the agent depends on the amount of active agent, the needs and requirements of the patient. Typically, however, about 20 mg / kg of the compound is administered several times a day. However, this is merely an example, which does not limit the scope and implementation of the present invention.

The following examples illustrate the invention in detail, with all temperatures in degrees Celsius.

Example 1

6-chloro-3-pyridinmethanol benzoate

24.41 g of 2-chloro-5-hydroxymethyl-pyridine is dissolved in 250 ml of anhydrous methylene chloride and 27.0 ml of anhydrous triethylamine, and 23.0 ml of benzoyl chloride is added dropwise to an ice-cooled solution. The resulting mixture is stirred at 0 ° C. for 1 hour and at room temperature for 2 hours, then diluted with 500 ml of methylene chloride and washed with 100 ml of water, saturated sodium bicarbonate and saturated sodium chloride. Then dried over potassium carbonate and evaporated to give 45.4 g of a yellow semisolid material which was distilled through a short distillation to yield 41.51 g (98%) of crude 6-chloro-3-pyridinemethinol benzoate having a boiling point of 150 to 160 °. do.

The insoluble material was filtered off and then recrystallized from ether-ligroin to give 32.42 g (79%) of material having a melting point of 58 to 60 °. Analytical samples are obtained by recrystallization from ether-hexane with a melting point of 59 to 62 °.

Example 2

6-chloro-3-pyridine methanolbenzoate, N-oxide

33.42 g of 6-chloro-3-pyridinemethanolbenzoate and 75 g of N-chloroperbenzoic acid were dissolved in 1800 ml of methylene chloride and stirred at room temperature for 5 days, followed by 500 ml of 2 times with 500 ml of 1N sodium hydroxide solution. Washed twice with water and once with 500 mL of brine, dried over potassium carbonate and evaporated to give a yellow solid which was crystallized from ethyl acetate-hexane to give 6-chloro-3-3 having a melting point of 116 ° to 121 °. 25.87 g (73%) of pyridine-methanol benzoate, N-oxide are obtained. Analytical samples are obtained by recrystallization from ethyl acetate. Analytical samples are obtained by recrystallization from ethyl acetate.

Melting Point: 120 ~ 123 °

Example 3

8-hydroxymethyl-2-methoxy-11H-pyrido [2,1-b] quinazolin-11-one benzoate.

5.00 g of 5-methoxyanthranilic acid, 3.90 g of 6-chloro-3-pyridine-methanolbenzoate and N-oxide are suspended in 9 ml of triglyme and heated to 120 ° overnight.

After cooling, the reaction mixture was treated with 15 ml of ethanol and filtered to afford 3.79 g (71%) of crude 8-hydroxymethyl-2-methoxy-11H-pyrido [2,1-b] quinazolin-11-. On benzoate (melting point: 206 to 219 °) is obtained. Treatment with boiling methanol yields 1.75 g (33%) of material having a melting point of 226 to 229 and recrystallized twice with aqueous acetic acid to give a sample having a melting point of 228 to 230 °.

Example 4

8-hydroxymethyl-2-methoxy-11H-pyrido [2,1-b] quinazolin-11-one-hydrochloride

1.75 g of 8-hydroxymethyl-2-methoxy-11H-pyrido [2,1-b] quinazolin-11- is dissolved in 10 ml of concentrated hydrochloric acid and 7 ml of ethanol and refluxed overnight. 8-hydroxymethyl-2-methoxy-11H-pyrido [2,1-b] quinazolin-11- with a melting point of 248 ° to 251 ° (decomposition) to obtain 0.60 g of hydrochloride, An additional 0.72 g (51%) of material having a melting point of 244 to 248 ° is obtained from the filtrate. Analytical samples are obtained from methanolic hydrochloric acid ether. Melting point 253 to 255 °

Example 5

8-hydroxymethyl-2-isopropoxy-11H-pyrido [2,1-b] quinazolin-11-one-benzoate

1.0 g of 5-isopropoxycyranylic acid, 1.1 g of 6-chloro-3-pyridinmethanol benzoate and 0.01 g of potassium iodide are suspended in 10 ml of triglyme and heated to 150 ° under an argon stream overnight. After cooling, the reaction mixture is dissolved in hot methanol, filtered and evaporated to give an orange oil. This was separated by chromatography and recrystallized with hexane-dichloromethane to give 8-hydroxymethyl-2-isopropoxy-11H-pyrido [2,1-b] quinazolin-11-silver having a melting point of 123 to 126 °. Yield is obtained.

Example 6

[Capsules preparation]

[Way]

The active ingredients of formula (I), lactose and corn starch are mixed in a suitable mixer, ground through a grinder and then mixed with magnesium stearate and talc and filled into capsules.

Example 7

[Capsules preparation]

[Way]

The active ingredient of formula (I), lactose, microcrystalline cellulose, modified starch and corn starch are mixed for 1 to 15 minutes in a suitable mixer, magnesium stearate is added and mixed for 5 minutes.

Example 8

[Wet Granule Tablet Formulation]

[Way]

The active ingredient of formula (I), lactose and gelatinized starch are mixed in a suitable mixer, ground in a grinder, mixed with modified starch and magnesium stearate and tableted.

Claims (1)

A process for preparing the compound of formula (I) and acid addition salts thereof, characterized in that the compound of formula (II) is hydrolyzed.

R ₁ , R ₂ and R ₃ are each hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen, cyclopropyl, cyclobutyl, or hydroxy, R ₄ is hydroxy-lower alkyl, R ₇ Is an acyloxy-lower alkyl provided that at least one of R ₁ , R ₂ and R ₃ is not hydrogen.