KR810000892B1 - Process for preparing 1,3-dihydrospiro (isobenzofuran-1,4-piperidine)s - Google Patents

Abstract

The title compds. (I; R = C1-4 alkyl or C7-9 phenalkyl; R1 = H, C1-3 alkoxy or trifluoromethyl; R2 = H, C1-3 alkoxy, Br, F or Cl) useful as analgesics, anticonvulsants, and antidepressants were manufd. by oxidation of piperidine(II) with org. or inorg. peroxide in the presence of org. solvent. Thus, 1-nitroso-1,3-dihydro-3-phenylspiro(isobenzofuran-1,4'-piperidine) was mixed with glacial acetic acid and extracted to give 1'-amino-1,3-dihydro-3-phenylspiro(isobenzofuran-1,4'-piperidine), which was reacted with sodium cyanoborohydride to give 1'-(isopropylamino)1,3'-dihydro-3-phenylspiro(isobenzofuran-1,4'-piperidine.

Description

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

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

Wherein R is alkyl having 1 to 4 carbon atoms or phenalkyl having 7 to 9 carbon atoms, R ₁ is hydrogen, alkoxy having 1 to 3 carbon atoms, or trifluoro methyl and R ₂ is hydrogen, alkoxy having 1 to 3 carbon atoms, Bromine, fluorine or chlorine.

As we are well aware, the compounds of the present invention have not been described or presented so far. Spiro [phthalan-piperidine] in the following structural formula is W.J. Described in U.S. Patent No. 3,686,186 to Honlihan et al. And is not within the scope of the present invention.

Wherein R ₁ is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, R ₂ is hydrogen or benzyl and Z is —CH ₂ — or —CO—.

In addition, compounds of the following structural formulae are described in Y. Inushnbi et al. [Chem and Parm. Bull (Japan) 12,749 (164).

The prior art described in U. S. Patent Nos. 424,080 and 424,117, filed December 12, 1973 (V. J. Bauer et al.) 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 organic acids such as tartaric acid, citric acid, acetic acid, succinic acid, maleic acid and fumaric acid. There is this.

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

The piperidine of formula (II) is then oxidized with an organic or inorganic peroxide such as hydrogen peroxide or 3-chloroperbenzoic acid (preferably hydrogen peroxide) at a temperature of about 100 ° C. for about 2 hours in the presence of an inert organic solvent such as chloroform. To prepare a compound of).

R is alkyl or phenalkyl.

The time and temperature required to complete the reaction in the above reaction are correlated with the structure of the compound, the composition of the reactive components and the solvent.

The analgesic effect of the representative compounds of the present invention can be seen in the 2-phenyl-1,4-quinone induced mouse warpage test, which is a standard test for analgesics. [Reference: Proc. Soc. Exptl. Biol Med, Vol 45, 729 (1957). As a result of this experiment, 1'-benzoyloxy-1,3-dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine] was warped by 54% when 50 mg / kg body weight was orally administered. 1'-amino-1,3-dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine], 1'-hydroxy-1,3-dihydro-3- Phenylspiro [isobenzofuran-1,4'-piperidine], 1'-benzyl-1,3-dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine] -1 ' 50 mg / kg body weight of -oxide and 1 '-(isopropylamino) -1,3-dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine] 53%, 48% and 27% of the warp inhibitory effect. The above data shows that the compound of the present invention is effective in alleviating pain in mammals when about 1-50 mg / kg body weight per day is administered.

The antidepressant action of the compounds of the present invention in mammals can be seen in their ability to inhibit tetrabenzazine-induced depression in mice. See International Journal of Neurophrmacology, Vol. 8,73 (1969)].

As shown in Table 1, it has useful antidepressant properties as can be seen in the standard test.

The results are expressed as ED ₅₀ (50% effect when intraperitoneally administered the compound to mice with tetrabenzazine induced depression) and the dose is mg / kg body weight and Table 1 shows that the compound of the present invention is less toxic. Toxicity is expressed as 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 1

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 in Woodbury, I. A and Davenport. Method of V.D [Reference: Arch Int. Pharmacodynam, Vol 92, pp 97-107] shows that it is also useful as an anticonvulsant in mammals. For example, when an intraperitoneal injection of 1'-amino-1,3-dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine] is administered at about 5 mg / kg body weight, 50% was protected from the effects of electric shock. 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]; 1,3-dihydro-1'-methyl-6-trifluoromethyl-3-phenylspiro- [isobenzofuran-1,4'-piperidine] -1'-oxide; 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'-butyl-1,3-dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine] -1'-oxide; 1,3-dihydro-1'-phenethyl-3-phenylspiro [isobenzofuran-1,4'-piperidine] -1'-oxide; And 1'-hydroxy-1,3-dihydro-3- (4-fluorophenyl) -5-methoxyspiro [isobenzofuran-1,4'-piperidine].

An effective amount of a 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 safety, ease of crystallization and increased solubility.

The active compounds of the present invention can be administered orally with an inert diluent or edible carrier, or can 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 and the like. The amount of the active compound in such a composition preferably contains 1.0 to 300 mg in a suitable one, for example oral administration.

Tablets, pills, capsules, troches and the like may contain the following components. Binders such as microcrystalline cellulose rosetracanth 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 steerotex; Lubricants, such as colloidal silicon dioxide; Sweeteners such as sucrose, saccharin and the like; Or fragrances, such as peppermint, methylsalicylate or orange flavor. When the unit dosage form is a capsule, in addition to the substance, it may contain a liquid carrier such as fatty oil. Other dosage forms may contain other materials that convert the physical form of the dosage unit (eg, coating). Thus tablets or pills may be coated with sucrose, shellac or other enteric coatings. 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. This formulation should contain at least 0.1% of the 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; Sterile diluents such as distilled water for injection, saline, nonvolatile oil, polyethylene glycol, 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 parenteral administration agents, such as enteric control agents such as sodium chloride or dextrose, or may be sealed in plastic ampoules, disposable syringes or multiple vials.

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] is added dropwise to the solution of 4.0g while maintaining the reaction rate at 0-5 ℃. After the addition is complete, the reaction mixture is left for 1 hour at ambient temperature. The reaction mixture is then diluted with water, filtered and white precipitates are 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 to 161 ° C

Analysis: C ₁₈ H ₁₈ N ₂ O ₂

Theoretic: C 73.45, H 6.16, N 9.52%

Found: 73.20, 6.11, 9.37

Example 2

Glacial acetic acid 50 A solution of 7.1 g of 1'-nitroso-1,3-dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine] obtained in Example 1 was dissolved in 75 ml of glacial acetic acid. 7.1 g of zinc powder was dissolved in 50 ml of water and 50 ml of water and added 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, the filtrate and the wash were combined, made basic and 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 ° C

Analysis: C ₁₈ H ₂₀ N ₂ O

Theoretic: C 77.11, H 7.19, N 9.99%

Found: 77.84, 7.13, 9.69

Example 3

0.24 g of sodium cyanoborohydride, 1.4 g of 1'-amino-1,3-dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine] obtained in Example 2 and acetonitrile To a mixture of 25 ml and 2.5 ml of acetone. 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-petroleum ether mixture to obtain a white crystalline solid, which was recrystallized from ethanol to 1 '-(isopropylamino) -1,3'-dihydro with a melting point of 110 to 112 ° C. -3-phenylspiro [isobenzofuran-1,4'-piperidine] is obtained.

Analysis: C ₂₁ H ₂₆ N ₂ O

Theoretic: C 78.22, H 8.13, N 8.69%

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].

Melting point 161 to 164 ° C

Analysis: C ₂₅ N ₂₃ NO ₃

Theoretic: C 77.90, H 6.01, N 3.63%

Found: 77.94, 6.08, 3.64

Example 5-7

1,3-dihydro-3- (4-methoxyphenyl) spiro [isobenzofuran-1,4'-piperidine], 1,3-dihydro-6-meth as described in Example 4 Oxy-3-phenylspiro [isobenzofuran-1,4'-piperidine] and 1,3-dihydro-4- (4-fluorophenyl) spiro [isobenzofuran-1,4'-piperi Din] is treated separately to produce the corresponding 1'-benzoyloxy compound in Table 2 below.

TABLE 2

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 16 ml of 10% aqueous sodium hydroxide solution Is heated for 20 minutes under reflux 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 and the combined chloroform extracts are combined and dehydrated to remove chloroform to give a pale yellow oil, which is treated with an ether-petroleum ether mixture to give a white solid. This is recrystallized with 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.

Analysis: C ₁₈ H ₁₉ NO ₂

Theoretic: C 76.84, H 6.81, N 4.98%

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, 24 ml of ethanol and 10 The mixture of 16 ml of% 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 adjusted to pH 9 by addition of 2N hydrochloric acid. The aqueous solution was extracted with chloroform and the combined chloroform extracts were dehydrated and the chloroform 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] is prepared as white crystals.

Analysis: C ₁₉ H ₂₁ NO ₃

Theoretic: C 73.29, H 6.810, N 4.50%

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] and 18 ml of ethanol and 12 ml of 10% aqueous sodium hydroxide solution Is heated for 20 minutes under reflux 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 ° C. 1'-hydroxy-1,3-dihydro-6-methoxy-3-phenylspiro [isobenzofuran-1,4'-piperidine] is obtained as a fluffy white solid.

Analysis: C ₁₉ H ₂₁ NO ₃

Theoretic value: C 73.29, H 6.80, N 4.50%

Found: 73.41, 6.84, 4.46

Example 11

In the method described in Example 10 above, 1.5 g of 1'-benzoyloxy-1,3-dihydro-3- (4-fluorophenyl) spiro [isobenzofuran-1,4'-piperidine] A mixture of 18 ml of anhydrous ethanol and 12 ml of 10% aqueous sodium hydroxide solution was reacted to form 1'-hydroxy-1,3-dihydro-3- (4-fluorophenyl) spiro, which is a fine white crystal having a melting point of 182 to 185 캜. [Isobenzofuran-1,4'-piperidine] is obtained.

Analysis: C ₁₈ H ₁₈ NO ₂ F

Theoretic: C 72.22, H 6.06, N 4.68, H 6.35%

Found: 72.20, 6.09, 4.72, 6.15

Example 12

A solution of 2.8 g of 1,3-dihydro-1'-methyl-3-phenylspiro [isobenzofuran-1,4'-piperidine], 50 ml of acetic acid and 4 ml of 30% hydrogen peroxide in a steam bath for 1 hour Heat, dilute with 200 mL of water, concentrate to 50 mL of volume, add 200 mL of water and concentrate to give an oil. The oil was dissolved in chloroform and the chloroform solution was washed with aqueous sodium bicarbonate solution and water, then dehydrated and chloroform was removed to obtain an oil which was treated with ether to give a solid, which was then recrystallized from acetonitrile to give 1,3 as colorless crystals. -Dihydro-1'-methyl-3-phenylspiro [isobenzofuran-1,4'-piperidine] -1'-oxide is obtained.

Assay: C ₁₉ H ₂₁ NO ₂ H ₂ O

Theoretic: C 72.82, H 7.40, N 4.41%

Found: 72.00, 7.44, 4.39

By the above method, 1,3-dihydro-1'-methyl-6-trifluoro methyl-3-phenylspiro [isobenzofuran-1,4'-piperidine] is converted to 1,3-di Hydro-1'-methyl-6-trifluoromethyl-3-phenylspiro [isobenzofuran-1,4'-piperidine] -1'-oxide is obtained.

Example 13

A solution obtained by dissolving 2.0 g of 85% 3-chloroperbenzoic acid in 25 ml of chloroform was cooled to 0 ° C. in the presence of nitrogen, and then cooled to 0 ° C. with 1'-benzyl-1,3-dihydro-3-phenylspiro [isobenzofuran-1. , 4'-piperidine] is dissolved in 15 ml of chloroform and added dropwise to the stirred solution. The resulting solution was then stirred for 3 more hours at ambient temperature, washed with saturated aqueous sodium bicarbonate solution and chloroform removed in vacuo to yield a pale yellow oil. This oil was treated with an ether-petroleum ether mixture to give a white crystalline solid which was recrystallized from acetonitrile to give 1'-benzyl-1,3-dihydro-3-phenylspiro [isobenzofuran- having a melting point of 147 to 150 ° C. 1,4'-piperidine] -1'-oxide is obtained as a white crystalline solid containing some moisture.

Analysis: C ₂₆ H ₂₅ NO ₂

Theoretic: C 80.83, H 6.78, N 3.77%

Found: 80.65, 6.84, 3.73

Claims (1)

A process for preparing a compound of formula (I) and acid addition salts thereof by oxidizing piperidine of formula (II) with an organic or inorganic peroxide in the presence of an organic solvent.

Wherein R is alkyl having 1 to 4 carbon atoms or phenalkyl having 7 to 9 carbon atoms, R ₁ is hydrogen, alkoxy having 1 to 3 carbon atoms, or trifluoromethyl and R ₂ is hydrogen, alkoxy having 1 to 3 carbon atoms, Bromine, fluorine or chlorine.