KR810000335B1 - Methods for preparing 1,3 dihydro spiro(isobenaofuran-1,4'-piperidines) - Google Patents

Abstract

Analgesic title compds. (I; X = nitroso, amino, C1-5alkyl amino, benzoyloxy, OH; R1 = H, C1-3 alkoxy, CF3; R2 = H, C1-3 alkoxy, Br, F, Cl) were prepd. by several method. Thus, II was converted to nitroso compd. at 0-5≰C, reduced to corresponding amino compd. and alkylated to corresponding alkylamino compd., or II was reacted with benzoylperoxide at 0-80≰C, 12 hr to give benzoyloxy compd. (III) and benzoyloxy group of III was eleminated to give corresponding hydroxy compd.

Description

Method for producing 1,3-dihydrospiro [isobenzofuran-1,4-piperidine]

The present invention provides the preparation of 1,3-dihydrospiro [isobenzofuran-1,4'-piperidine] of the following structural formula (I) useful as analgesics, anticonvulsants and antidepressants, and pharmaceutically toxic acid addition salts thereof. It is about a method.

In the above structural formula,

X is nitroso, amino, alkylamino, hydroxy, or benzoyloxy of 1 to 5 carbon atoms,

R ₁ is hydrogen, an alkoxy having 1 to 3 carbon atoms, or a trifluoromethyl group,

R ₂ is hydrogen, alkoxy having 1 to 3 carbon atoms, bromine, fluorine or chlorine.

Among the above choices are compounds in which X is hydroxy.

As we know well, the compounds of the present invention have not been described or presented so far. Spiro [phthalan-piperidine] of the following structural formula is described in US Pat. No. 3,686,186 to W.T. Hohlihan et al. And is not within the scope of the present invention,

In addition, compounds of the following structural formulae are described in Y. Inushubi et al. [Chem. and Pharm. Bull (Japan) 12,794 (1964).

The prior art described in U. S. Patent Nos. 424,080 and 424,117, filed on December 12, 1973, is also outside the scope of the present invention.

The compounds of the present invention are substantially different from the compounds of the prior art and have unexpected pharmaceutical activity and low toxicity.

Acids useful for making the pharmaceutically toxic acid addition salts of the present invention include inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid and perchloric acid, and tartaric acid, citric acid, acetic acid, succinic acid, maleic acid and furaric acid. There is an organic acid.

Compounds of the present invention are prepared by the following method using as a starting material piperidine described in US Patent Application No. 424,117. Some of the compounds of the present invention are pharmacologically more active than others, and less active materials are useful as intermediates to prepare more active materials.

The compound of formula (II) is then N-nitrated at about 0 to 5 ° C. using acetic acid as solvent and sodium nitrite as nitrosulfate salt to produce the corresponding nitroso compound, or the resulting nitroso compound Is converted to the corresponding amino compound by reaction with a reducing agent such as zinc in a solvent such as aqueous acetic acid at about 0 ° to 110 ° C. for 5 minutes to 2 hours, or the amino compound obtained above is subjected to moisture at about 15 to 100 ° C. Reducing alkylation with a suitable alkylating agent and reducing agent in the presence or absence of an organic solvent for 24 hours yields a corresponding secondary amine, a kind of a compound of the invention (in this process, a carbonyl compound such as a ketone or an aldehyde as an alkylating agent, sodium as a reducing agent). Cyano borohydride, and acetonitrile may be used as the solvent), The compound of formula (II) as defined above was added to a cooled solution of benzoyl peroxide dissolved in a suitable organic solvent such as benzene, and the mixture was reacted for 12 hours at 60 ° C. to give the corresponding N-benzoyloxy of formula (III). To prepare a compound,

The resulting N-benzoyloxy compound is treated with aqueous potassium hydroxide and ethanol, and the mixture is refluxed to react for a few minutes to remove benjongoxy group to obtain the corresponding N-hydroxy compound.

The analgesic effect of the representative compounds of the present invention can be seen in the mouse twist test induced by 2-phenyl-1,4-quinone, which is a standard test method of analgesics. [Reference: proc. Soc. Exptl. Biol Med., Vol 45,729 (1975). As a result of this experiment, 1'-benzoyloxy-1,3-dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine] was 54% twisted when orally administered 50 mg / kg body weight. 1'-amino-1,3-dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine], 1'-hydroxy-1,3-dihydro-3- Phenylspiro [isobenzofuran-1,4'-piperidine] and 1 '-(isopropylamino) -1,3-dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine Or 50 mg / kg body weight, respectively, exhibits a distortion inhibitory effect of 53%, 53% and 27%. The above data shows that the compound of the present invention is effective in alleviating pain in mammals when about 1 to 50 mg / kg body weight per day is administered.

, 73 (1969)〕, 다음표(Ⅰ)에 나타낸 바와 같이 표준 시험에서 알수있는 바와 같이 유용한 항우울제 특성을 가지고 있다.The antidepressant action of the compounds of the present invention in mammals can be seen as an inhibitory effect of tetrabenzazine-induced depression in mice [see International Journal of Nearophamacology, vol.

, 73 (1969)], as shown in the following table (I), which has useful antidepressant properties, as can be seen in standard trials.

The results are expressed as ED ₅₀ (50% effect when intraperitoneally administered the compound to mice suffering from tetrabenzazin-induced depression), the dose is mg per kg body weight, and according to Table (I), the compound of the present invention is less toxic. It can be seen. Toxicity is ALD ₅₀ (50% acute lethality when intraperitoneally administered mg per body weight).

This data is determined by administering four groups of mice at multiple doses and counting the number of mice killed.

TABLE I

These data show that the compound of the present invention is effective in the treatment of depression when intraperitoneally injected into a mammal in an amount of 0.1 to 50 mg / kg per day.

Compounds according to the invention are described by Woodbury, I.A and Davenport, V.D [Arch. Int. Pharmacodynam, Vol. 92, pp 97-107] shows that it is also useful as an anticonvulsant in mammals. For example, when 1'-amino-1,3-dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine] was administered intraperitoneally, about 5 mg / kg body weight, a strong electric shock 50% of the effect was protected. These data indicate that the compound of the present invention is effective for the treatment of convulsions when 0.1 to 50 mg / kg body weight per day is administered.

Examples of the compound of the present invention are as follows.

5-methoxy-1'-nitroso-1,3-dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine];

1 '-(1-propylamino) -1,3-dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine];

1'-ethylamino-1,3-dihydro-6-methoxy-3-phenylspiro [isobenzofuran-1,4'-piperidine];

1'-amylamino-1,3-dihydro-6-methoxy-3- (4-methoxyphenyl) -spiro [isobenzofuran-1,4'-piperidine];

1'-hydroxy-1,3-dihydro-3- (4-fluorophenyl) -5-methoxy-spiro [isobenzofuran-1,4'-piperidine]

An effective amount of the compound of the present invention may be administered orally in capsule or tablet form, or parenterally in sterile liquid or suspension, or in some cases by intravenous injection of a sterile solvent. The final product of the free base is effective on its own and can be formulated and administered in the form of their pharmaceutically harmless salts for the purpose of increasing stability, ease of crystallization and solubility.

The active compounds of the present invention may be administered orally together with an inert diluent or an edible carrier, or may be administered in a gelatin capsule or tablet form. For the purpose of oral treatment, the active compounds of the present invention may be administered in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers and chewing gums in combination with excipients. The formulation should contain at least 0.5% of the active compound but may contain from about 4% to 70% by weight, depending on the dosage form. The amount of the active compound in such a composition preferably contains 1.0 to 300 mg in an appropriate one, for example oral administration.

Tablets, pills, capsules, troches and the like may contain the following components. Binders such as microcrystalline cellulose, tragacanth gum or gelatin; Excipients such as starch or lactose; Disintegrants such as alginic acid primogel, corn starch and the like; Lubricants such as magnesium stearate or sterotex; Lubricants, such as clad silicon dioxide; Sweeteners such as sucrose, saccharin and the like; Or fragrances such as peppermint, matyl salicylate or orange flavor. When the unit dosage form is a capsule, in addition to the above substances, it may contain a liquid carrier such as fatty oil. Other dosage forms may contain other substances that convert the physical form of the dosage unit (eg, coating). Thus tablets or pills may be coated with sucrose, shellac or enteric coating. Syrups may contain sucrose and preservatives, colorants and fragrances as sweeteners in addition to the active compounds. The materials used to prepare these various compositions should be pharmaceutically pure and non-toxic in use.

For parenteral administration purposes, the active compound of the present invention is added to a liquid or suspending agent. The formulation should contain at least 0.1% active compound and can vary from 0.5 to about 30%. The amount of the active compound in such a composition should be contained in an effective dose, for example, it is preferable to contain 0.5 to 100 mg of the active compound for parenteral administration.

Solutions or suspensions may contain the following components; Distilled water for injection, saline, nonvolatile oil, polyethylene glycol; Sterile diluents such as glycerin, propylene glycol or other synthetic solvents; Antibacterial agents such as benzyl alcohol or methylparabens; Antioxidants such as ascorbic acid or sodium bisulfite; Chelating agents such as ethylenediamine tetraacetic acid; Buffers such as acetate, citrate or phosphate; And enteric regulators such as sodium chloride or dextrose. Parenteral dosing agents may be sealed in ampoules, disposable syringes or multiple vials made of glass or plastic.

The following examples are provided to further illustrate the present invention.

Example 1

A solution of 2.1 g of sodium nitrite dissolved in 9 ml of water was dissolved in 15 ml of glacial acetic acid and 6 ml of water at 0 ° C. and stirred. 1,3-dihydro-3-phenylspiro [isobenzofuran-1,4′-piperi Dean] was added dropwise to the solution of 4.0 g while maintaining the reaction temperature at 0 to 5 ℃. After the addition is complete, the reaction mixture is diluted with water, filtered and the white precipitate is collected, washed with water and cold ethanol and dried. The dried precipitate is recrystallized with ethanol to obtain 1'-nitroso-1,3-dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine], which is a pale yellow leaf crystal. Melting Point: 159 ~ 161 ℃

Analysis: C ₁₈ H ₁₈ N ₂ O ₂

Theoretic: C73.45, H6.16, N9.52

Found: 73.20, 6.11, 9.37

Example 2

A solution obtained by dissolving 7.1 g of 1'-nitroso-1,3-dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine] obtained in Example (1) in 75 ml of glacial acetic acid, Dissolve 7.1 g of zinc powder in 50 ml of glacial acetic acid and 50 ml of water, and add the mixture to the stirred suspension while maintaining the reaction temperature at 10 to 20 ° C.

The reaction mixture is stirred at ambient temperature for 15 minutes, stirred at 80 ° C. for 5 minutes, 4.7 g of zinc powder is added, and further stirred for 10 minutes. After filtering the heated mixture, the precipitate was washed with hot 1N hydrochloric acid, combined with the filtrate and the washing solution to make it cheap, and then extracted with chloroform. The organic solution was dehydrated and the solvent was removed to give 1'-amino-1,3-dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine] as a white crystalline solid, which was ethanol. Recrystallize. Melting Point: 143 ~ 145 ℃

Analysis: C ₁₈ H ₂₀ N ₂ O

Theoretic: C77.11, H7.19, N9.99

Found: 77.04, 7.13, 9.69

Example 3

0.24 g of sodium cyanoborohydride and 1.4 g of 1'-amino-1,3-dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine] obtained in Example (2); To a mixture of 25 ml acetonitrile and 2.5 ml acetone is added. Five drops of glacial acetic acid are added and the mixture is simply warmed and stirred at pH 6-8 at ambient temperature in the presence of nitrogen and stirred for 5 hours. The reaction mixture is then diluted with 250 ml of chloroform, washed with 2N hydrochloric acid and 10% aqueous sodium hydroxide solution and dehydrated. The solvent was removed and the pale yellow oil obtained was treated with an ether-mixture to obtain a white crystalline solid, which was recrystallized from ethanol to give 1 '-(isopropylamino-1,3'-dihydro-3- at a melting point of 110 to 112 ° C. Phenylspiro [isobenzofuran-1,4'-piperidine] is obtained.

Analysis: C ₂₁ H ₂₆ N ₂ O

Theoretic: C78.22, H8.13, N8.69

Found: 78.03, 8.18, 8.73

Example 4

5.3 g of 1,3-dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine] is added to a solution of 2.4 g of benzoyl peroxide dissolved in 75 ml of benzene and cooled in an ice bath. The mixture was reacted for 2 hours at 60 ° C. in the presence of nitrogen, and the solvent was removed to obtain a semicrystalline residue, which was recrystallized from ethanol to give a nearly colorless acicular crystal, 1'-benzoyloxy-1,3'-dihydro-3-phenylspiro. [Isobenzofuran-1,4'-piperidine] is prepared.

Melting Point: 161-164 ℃

Analysis: C ₂₅ H ₂₃ NO ₃

Theoretic: C77.90, H6.01, N3.63

Found: 77.94, 6.08, 3.64

Example 5-7

1,3-dihydro-3- (4-methoxyphenyl) -spiro [isobenzofuram-1,4'-piperidine], 1,3-dihydro- by the method described in Example (4) 6-methoxy-3-phenylspiro [isobenzofuram-1,4'-piperidine] and 1,3-dihydro-3- (4-fluorophenyl) spiro [isobenzofuran-1,4 ' -Piperidine] is treated respectively to prepare the corresponding 1'-benzoyloxy compound of the following table (II).

TABLE II

Example 8

2.1 g of 1'-benzoyloxy-1,3'-dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine] obtained in Example (4), 24 ml of ethanol and 10% sodium hydroxide The mixture of 16 ml of aqueous solution is heated at reflux for 20 minutes in the presence of nitrogen. Most of the ethanol is removed in vacuo and the residue is diluted with 40 ml of water and adjusted to pH 6 by dropwise addition of 2N hydrochloric acid. The aqueous solution is extracted with chloroform, the combined chloroform extracts are dehydrated, and the chloroform is removed to obtain a pale yellow oil, which is treated with an ether-petroleum ether mixture to give a white solid. This was recrystallized from ethanol to obtain fine white crystals of 1'-hydroxy-1,3'-dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine] having a melting point of 184 to 187 캜. Get

Analysis: C ₁₈ H ₁₉ NO ₂

Theoretic: C76.84, H6.81, N4.98

Found: 76.63, 6.85, 4.80

Example 9

1.99 g of 1'-benzoyloxy-1,3'-dihydro-3- (4-methoxyphenyl) spiro [isobenzofuran-1,4'-piperidine] obtained in Example (5), ethanol 24 A mixture of mL and 16 mL of 10% aqueous sodium hydroxide solution is heated under reflux for 25 minutes in the presence of nitrogen. Most of the ethanol is removed in vacuo and the residue is diluted with 40 ml of water and then adjusted to pH 9 by dropwise addition of 2N hydrochloric acid. The aqueous solution was extracted with chloroform, the chloroform extract was dehydrated and the chloroform was removed to give a pale beige solid which was treated with an ether-petroleum ether mixture to give a nearly colorless crystalline solid which was recrystallized from ethanol to give a melting point of 183 to 185 ° C. 1'-hydroxy-1,3-dihydro-3- (4-methoxyphenyl) spiro [isobenzofuran-1,4'-piperidine] as white crystals was prepared.

Analysis: C ₁₉ H ₂₁ NO ₃

Theoretic: C73.29, H6.80, N4.50

Found: 73.18, 6.82, 4.48

Example 10

1.3 g of 1'-benzoyloxy-1,3'-dihydro-6-methoxy-3-phenylspiro [isobenzofuran-1,4'-piperidine] with 18 ml of ethanol and 10% aqueous sodium hydroxide solution 12 The ml mixture is heated at reflux for 20 minutes in the presence of nitrogen.

Most of the ethanol is removed in vacuo and the residue is diluted with 30 ml of water and the pH is adjusted to 8 by addition of 2N hydrochloric acid. The aqueous solution was extracted with chloroform, the combined chloroform extracts were dehydrated and the solvent was removed to obtain a yellow crystalline solid, which was treated with ether-petroleum ether to give a pale yellow crystalline solid, which was then recrystallized from ethanol to have a melting point of 186 to 188. 1'-hydroxy-1,3-dihydro-6-methoxy-3-phenylspiro [isobenzofuran-1,4'-piperidine], which is a fluffy white solid at ° C, is obtained.

Analysis: C ₁₉ H ₂₁ NO ₃

Theoretic: C73.29, H6.80, N4.50

Found: 73.41, 6.84, 4.46

Example 11

By the method described in Example (10) above, 1'-benzoyloxy-1,3'-dihydro-3- (4- pullophenyl) spiro [isobenzofuran-1,4'-piperidine A mixture of 1.5 g and 18 ml of anhydrous ethanol and 12 ml of 10% aqueous sodium hydroxide solution was reacted with fine white crystals of 1'-hydroxy-1,3-dihydro-3- (4-fluoro) having a melting point of 182 to 185 ° C. Rophenyl) spiro [isobenzofuran-1,4'-piperidine] is obtained.

Analysis: C ₁₈ H ₁₈ NO ₂ F

Theoretic: C72.22, H6.06, N4.68, F6.35

Found: 72.20, 6.09, 4.72, 6.15

Claims (1)

The compound of formula (II) is then nitrated with a nitro extinguishing agent at 0-5 ° C. to obtain the corresponding nitro-compound or the resulting nitro-compound is reduced to the corresponding amino compound, or the resulting amino compound is reduced Alkylation yields the corresponding alkylamino compound, or the compound of formula (II) is dissolved in an organic solvent and added to a cooled solution, and then the mixture is reacted at 0 to 80 ° C. for 12 to 12 hours to give the corresponding benzoyloxy. Obtaining a compound or removing the benzoyloxy group from the resulting benzoyloxy compound to obtain the corresponding hydroxy compound, thereby preparing a compound of formula (I) and a pharmaceutically toxic acid addition salt thereof.

In the above structural formula X is nitroso, amino, alkylamino having 1 to 5 carbon atoms, benzoyloxy or hydroxy R ₁ is hydrogen, alkoxy having 1 to 3 carbon atoms, or trifluomethyl R ₂ is hydrogen, alkoxy having 1 to 3 carbon atoms, bromine, fluorine or chlorine.