CA1068708A

CA1068708A - 1,3-dihydrospiro (isobenzofuran-1,4'-piperidine)s and methods for preparing them

Info

Publication number: CA1068708A
Application number: CA320,142A
Authority: CA
Inventors: Victor J. Bauer; Solomon S. Klioze
Original assignee: Hoechst AG
Current assignee: Hoechst AG
Priority date: 1975-04-30
Filing date: 1979-01-23
Publication date: 1979-12-25

Abstract

Abstract of the Disclosure This application is directed to the preparation of a compound of the formula I

I

wherein R represents alkyl of from 1 to 4 carbon atoms or phenalkyl of from 7 to 9 carbon atoms, R1 represents hydrogen, alkoxy of from 1 to 3 carbon atoms or trifluoromethyl; R2 represents hydrogen, alkoxy of from 1 to 3 carbon atoms, Br, Cl or F and the pharmaceutically acceptable acid addition salts thereof, in which a piperidine of the formula II

II

Description

~0687~8 HOE 75/F 170 This invention relates to novel 1,3-dihydrospiro[iso-benzofuran-l,4'-piperidine]s which are useful as analgetics and to intermediates therefor, to their pharmaceutically acceptable salts, to methods of preparing the same, to methods of treatment with pharmaceutically effective amounts thereof, and to pharma-ceutical compositions containing such compounds as essential ingredients. Additionally, compounds of the invention are useful as anticonvulsants and antidepressants.
To the best of our knowledge, the compounds of this invention have not heretofore been described or suggested. Spiro [phthalan-piperidine]s of the formula lR2 in which Rl is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, R2 is hydrogen or benzyl, and Z is -CH2- or -CO-, described by W. J. Houhlihan et al. in U.S. Patent 3,686,186, are outside the scope of the invention. The same applies to the natural product of the formula ~ - CH3 o O
described by Y. Inushubi et al. [Chem, and Pharm. sull. (Japan), 12, 749 (1964)].
Also outside the scope of this invention are the teachings of V. J. Bauer et al. in Canadian Applications Serial Numbers 215,785 and 215,786, both filed on December 11, 1974.
28 The compounds of this invention have substantial dif-

- 2 -~06~708 HOE 75/F 170 ferences from the compounds of the prior art and exhibit unanti-cipated pharmacological activity and low toxicity levels.
This invention relates to novel substituted 1,3-dihydro-spiro[isobenzofuran-1~4'-piperidine]s of the formulae X R O

Rl ~ R~ C ~

wherein R is alkyl of from 1 to 4 carbon atoms or phenalkyl of from 7 to 9 carbon atoms, X is nitroso, amino, alkylamino of from 1 to 5 carbon atoms, hydroxy or benzoyloxy; Rl is hydrogen alkoxy of 1 to 3 carbon atoms or trifluoromethyl; and R2 is hydrogen, alkoxy of 1 to 3 carbon atoms, bromine, fluorine or chlorine, and to the pharmaceutically acceptable addition salts thereof. The preferred compounds are those wherein X is hydroxy.
Acids useful for preparing the pharmaceutically accept-able acid addition salts of the invention include inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and perchloric acids, as well as organic acids such as tartaric, citric, acetic, succinic, maleic, and fumaric acids.
The compounds of the present invention are prepared by one of the three methods described below from starting piperi-dines such as those described in United States Patent Application Serial No. 424,117. While some compounds of the invention are more active pharmaceutically than others, the less active com-29 pounds are nevertheless useful as intermediates for the prepara-10687~8 HOE 75/F 170 tion of the more active compounds.
METHOD A
1. A piperidine of the formula H
S ~.

Rlt~k~
H ~ R2 is N-nitrosated by a method known to the art to produce the corresponding nitroso compound of the invention. One prefer-red method of carrying out the N-nitrosation involves the use of aqueous acetic acid as a solvent and sodium nitrite as a nitrosating salt at a reaction temperature of from about 0 to about 5C.
2. The above nitroso compound is converted to the corresponding amino compound by a reducing agent, such as elemental zinc, at a temperature of from about 0 to about 110C.
(in a solvent such as aqueous acetic acid) for from 5 minutes to two hours.

3. The above amino compound is reductively alkylated for a few minutes to 24 hours at a temperature bf from about 15 to about 100C., with a suitable alkylating and reducing agent in the presence or absence of an organic solvent to produce the corresponding secondary amine, likewise a compound of the inven-tion. One such method involves the use of a carbonyl compound such as a ketone or an aldehyde as the alkylating agent, sodium cyanoborohydride as the reducing agent, and acetonitrile as the 29 solvent.

1~68708 HOE 75/F 170 METHOD B
1. To a cooled solution of benzoylperoxide in a suitable organic solvent such as benzene is added the piperi-dine, as defined in Method A, step 1, and the mixture is then allowed to react for from a few minutes to twelve hours at about 60C. to the corresponding N benzoyloxy compound of the invention of the formula / ii Rl~

. H ~ R2 2. The above N-benzoyloxy compound is converted to the corresponding N-hydroxy compound of the invention, preferably by cleaving the benzoyloxy sroup by treatment with aqueous potassium hydroxide and ethanol and permitting the mixture to react at reflux for from a few minutes to two hours.
METHOD C

A piperidine of the formula ~,N~
~J

~ R2 _ 5 _ wherein R is alkyl or phenalkyl is oxidized to the correspond- !
ing N-oxide of the invention having the formula R - ~ O

~R2 preferably with hydrogen peroxide as the oxidizing agent and an organic solvent at a reaction temperature of about 100C. for from a few minutes to two hours.
It will be readily appreciated by those skilled in the art that the time and temperature necessary to complete the reaction in the steps of the above methods are interrelated and dependent upon the structures and compositions of the reaction components and the solvent.
The compounds of the invention are useful as analgetic, anticonvulsant and antidepressant agents; the daily dosage unit ranges from 0.1 to 50 mg/kg.
Illustrative examples of compounds of the invention are:
5-methoxy-1'-nitroso-1,3-dihydro-3-phenylspiro[isobenzo-furan-1,4'-piperidine];
1,3-dihydro-1'-methyl-6-~rifluoromethyl-3-phenylspiro-28 [isobenzofuran-1,4'-piperidine]-1'-oxide;

~068708 l'-(l-propylamine)-1,3-dihydro-3-phenylspiro[isobenzo-furan-1,4'-piperidine];
l'-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];
l-butyl-1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine]-l'-oxide;
1,3-dihydro-1'-phenethyl-3-phenylspiro[isobenzofuran-1,4'-piperidine]-1'-oxide; and l'-hydroxy-1,3-dihydro-3-(4-fluorophenyl)-5-methoxy-spiro[isobenzofuran-1,4'-piperidine~;
l'-benzoyloxy-1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine];
1'-amino-1,3-dihydro-3-phenyl-spiro[isobenzofuran-1,4'-piperidine]; l'-hydroxy-1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine]; 1'-benzyl-1,3-dihydro-3-phenylspiro[isobenzo-furan-1,4'-piperidine]-1'-oxide, and 1'-(isopropylamino)-1,3-dihydro-3-phenylspiro-[isobenzofuran-1,4'-piperidine];
1'-hydroxy-1,3-dihydro-3-(4-methoxy-phenyl)spiro[isobenzofuran-1,4'-piperidine];
l'-hydroxy-1,3-dihydro-6-methoxy-3-phenylspiro[isobenzofuran-1,4'-piperidinel~;
l'-hydroxy-1,3-dihydro-3-(4-fluoro-phenyl)spiro[isobenzofuran-1,4;-piperidine];
1,3-dihydro-1'-methyl-3-phenylspiro[isobenzofuran-1,4'piperidine]-l'-oxide.
28 Effective quantities of the compounds of the invention may be administered to a patient by any one of various methods, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intraveneously in the form of sterile solutions. The free base final products, while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable addition salts for purposes of stability, convenience of crystal-lization, increased solubility and the like.
The active compounds of the present invention may be orally administered, for example, with an inert diluent or with an edible carrier, or they may be enclosed in gelatin capsules, or they may be compressed into tablets. For the purpose of oral therapeutic administration, the active compounds of the invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum and the like. These preparations should contain at least 0.5% of active compound, but may be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit. The amount of active compound in such compositions is such that a suitable dosage will be obtained.
Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between 1.0-300 milligrams of active compound.
The tablets, pills, capsules, troches, and the like may also contain the following ingredients: a binder such as micro-crystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, corn starch and the like; a lubricant such as 29 magnesium stearate or Sterotex; a glidant such as colloidal 106870~3 1 silicon dioxide; and a sweetening agent such as sucrose or saccharin may be added or a flavouring agent such as peppermint, methyl salicylate, or orange flavouring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills may be coated with sugar, shel-lac, or other enteric coating agents.~ A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings, and flavors.
Materials used in preparing these various compositions should be pharmaceutically puré and non-toxic in the amounts used.
For the purpose of parenteral therapeutic administration, the active compounds of the invention may be incorporated into solutions or suspensions. These preparations should contain at least 0.1~ of active compound, but this may be varied to be be-tween 0.5 and about 30% of the weight thereof. The amount of active compound in such compositions is such that an effective dosage will be obtained. Preferred compositions and prepara-tions according to the present invention are prepared so that parenteral dosage units contain between 0.5 to 100 milligrams of active compound.
The solutions or suspensions may also include the following components: sterile diluents such as water for in-jection, saline solutions, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; anti-bacterial agents such as benzyl alcohol or methyl parabens;
antioxidants sùch as ascorbic acid or sodium bisulfite; chelat-ing agents such as ethylenediaminetetraacetic acid; bufferssuch as acetates, citrates or phosphates and agents for the adjustment of tonicity such as~sodium chloride or dextrose.
The parenteral preparations can be enclosed in ampules, dispos-able syringes or multiple dose vials made of glass or plastic.
The invention is further illustrated by the following examples, given for illustrative purposes.

A solution of 2.1 g of sodium nitrate }n 9 ml of water is added dropwise to a stirring solution of 4.0g of 1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine] in 15 ml of~
glacial acetic acid and 6 ml of water at 0C. while maintaining the reaction temperature between 0 and 5C. Upon completion of the addition, the reaction mixture is allowed to stand for one hour 2~ ambient temperature. Then the reaction mixture is dilut-ed with water, filtered, and the white precipitate is collected, washed with water and cold ethanol and dried. The dried precipi-tate is recrystallized from ethanol to give very slightly yellow leaflets, mp 159-161C., of l'-nitroso-1,3-dihydro-3-phenylspiro [isobenzofuran - 1,4'-piperidine].
Analysis:
Calculated for C18H18N2O2 Found: 73.20%C; 6.11%H; 9.37%N.

A solution of 7.1 g of 1'-nitroso-1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'piperidine], Example l, in 75 mlof glacial acetic is added to a stirring suspension of 7.1 g of zinc dust in 50 ml of glacial acetic acid and 50 ml of water while maintaining the reaction temperature between 10 and 20C.
The reaction mixture is stirred for 15 minutes at ambient S temperature and then at 80C. for S minutes; an additional 4.7 g of zinc dust are introduced and stirring is continued for an additional 10 minutes. The heated mixture is filtered, the precipitate is washed with hot lN hydrochloric acid and the combined filtrate and washings are basified and extracted with chloroform. The organic solution is dried and the solvent is removed, leaving a white crystalline solid, l'-amino-1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine], which is recrystal-lized from ethanol to give the pure product, mp 143-145C.
Analysis:

Found: 77.04%C; 7.13%H; 9.69%N.

0.24 g of sodium cyanoborohydride are added to a mixture of 1.4 g of 1'-amino-1,3-dihydro-3-phenyl-spiro[isobenzo-furan-1,4'-piperidine], Example 2, 25 ml of acetonitrile and 2.5 ml of acetone. Five drops of glacial acetic acid are added and the mixture is warmed briefly and stirred at am~ient temperature under nitrogen for five hours while maintaining the pH between 6 and 8. The reaction mixture is then diluted with 250 ml of chloroform, washed with 2N hydrochloric acid and 10%
aqueous sodium hydroxide solution and dried. The solvent is removed, leaving a pale yellow oil which upon trituration with 28 an ether-petroleum ether mixture gives a white crystalline solid.

106870~1 The solid is recrystallized from ethanol to give fine white crystals, mp 110-]12C., of l'-l:isopropylamino)-1,3'-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine].
Analysis:
Calculated for C21H26N2O: 78.22~C; 8.13%H; 8.69%N.
Found: 78.03%C; 8.18%H; 8.73%N.

5.3 g of 1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine] are added portionwise to an ice bath cooled solution of 2.4 g of benzoyl peroxide in 75 ml of benzene. The mixture is allowed to react at 60C. under nitrogen for two hours and the solvent is removed leaving a semi-crystalline residue which is recrystallized from ethanol to give nearly colorless needles,mp 161-164C., of l'-benzoyloxy-1,3-dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine].
Analysis:
Calculated for C25H23NO3: 77.90%C; 6.01%H; 3.63%N.
Found: 77.94~C; 6.08%H; 3.64%N.

By following the manipulati~e procedure described above in Example 4, 1,3 dihydro-3-(4-methoxyphenyl)spiro[isobenzo-furan-1,4'-piperidine], 1,3-dihydro-6-methoxy-3-phenyl-spiro[is~-benzofuran-1,4'-piperidine], and 1,3-dihydro-3-(4-fluorophenyl) spiro[isobenzofuran-1,4'-piperidine] are treated respectively to give the corresponding l'-benzoyloxy compounds tabulated below in Table II.

10~708 HOE 75/F 170 TABLE II

Analysis Empirical mp Calculated Found E Formula C. %C %H %N %F %C %H %N %F- - - _ C26H25NO4 164-166 75.16 6.06 3.37 - 75.14 6.22 3.34 6C26H25NO4 163-167 75.16 6.06 3.37 - 75.11 6.17 3.36 7 C25H22NO3F 163-166 74.42 5.50 3.47 4.71 74.58 5.65 3.51 4.85 A mixture of 2.1 g of 1'-benzoyloxy-1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine], Example 4, 24 ml of ethanol and 16 ml of a 10% aqueous sodium hydroxide solution is heated at reflux under nitrogen for 20 minutes. Most of the ethanol is removed in vacuo and the residue is diluted with 40 ml of water and the pH is adjusted to 6 by the dropwise addition of 2N hydrochloric acid. The aqueous solution is extracted with chloroform, the combined chloroform extracts are dried, and the chloroform is removed, leaving a pale yellow oil which upon trituration with an ether-petroleum ether mixture gives a white solid. The solid is recrystallized from ethanol to give fine white crystals, mp 184-187~C. of l'-hydroxy-1,3-dihydro-3-phenyl-spiro[isobenzofuran-1,4'-piperidine].
Analysis:
Calculated for C18HlgNO2: 76.84%C; 6.81%H; 4.98%N.
Found: 76.63%C; 6.85%H; 4.80%N.

A mixture of l.99g of 1'-benzoyloxy-1,3-dihydro-3-(4-methoxyphenyl) spiro [isobenzofuran-1,4'-piperidine]. Example 5, 24 ml of ethanol and 16 ml of a 10% aqueous sodium hydroxide solution is heated at reflux under nitrogen for 25 minutes. Most 29 of the ethanol is removed ln vacuo, the residue is diluted with 10687~8 40 ml of water and the pH is adjusted to 9 by addition of 2N
hydrochloric acid. The aqueous solution is extracted with chloroform, the combined chloroform extracts are dried, and the chloroform is removed, leaving a pale beige solid which upon trituration with an ether-petroleum ether mixture leaves a nearly colorless crystalline solid. The solid is recrystallized from ethanol to give fine white crystals, mp 183-185C., of l'-hydroxy-1,3-dihydro-3-(4-methoxyphenyl)spiro[isobenzofuran-1,4'-piperi-dine].
Analysis:
Calculated for ClgH21NO3: 73.2g%C; 6-80%H; 4-50%N-Found: 73.18~C; 6.82%~; 4.48%N.

A mixture of 1.3 g of 1'-benzoyloxy-1,3-dihydro-6-methoxy-3-phenylspirolisobenzofuran-1,4'-piperidine], 18 ml of ethanol and 12 ml of 10% aqueous sodium hydroxide solution is heated at reflux under nitrogen for 20 minutes. Most of the ethanol is removed in vacuo, the residue is diluted with 30 ml of water, and the pH adjusted to 8 by addition of 2N hydrochloric acid. The aqueous solution is extracted with chloroform, the combined chloroform extracts are dried, and the chloroform is removed to give a yellow crystallinc solid which upon tritura-tion with an ether-petroleum ether mixture leaves a pale yellow crystalline solid. The solid is recrystallized from ethanol to give fluffy white crystals, mp 186-188C., of l'-hydroxy-1,3-dihydro-6-methoxy-3-phenylspiro[isobenzofuran-1,4'-piperidine].
Analysis:
Calculated for ClgH21NO3: 73.29%C; 6.80%H; 4-50~N-Found: 73,41%C; 6.84%H; 4.46%N.

~ 687~8 By following the manipulative procedure described above in Example 10, the treatment of a mixture of 1.5g of ll-benzoyloxy-l~3-dihydro-3-(4-fiuorophenyl)spiro[isobenzo-furan-1,4'-piperidine], Example 7, 18 ml of absolute ethanol, and 12 ml of a 10% aqueous sodium hydroxide solution produces fine white crystals, mp 182-185C., of l'-hydroxy-1,3-dihydro-3-(4-~luorophenyl)spiro[isobenzofuran-1,4'-piperidine].
Analysis:
Calculated for C18H18NO2F: 72.22~C; 6.06%H; 4.68%N; 6.35~F.
Found: 72.20~C; 6.09%H; 4.72%N; 6.15%F.

A solution of 2.8 g of 1,3-dihydro-1'-methyl-3-phenyl-spiro[isobenzofuran-1,4'-piperidine], 50 ml of acetic acid and

4 ml of 30% hydrogen peroxide is heated on a steam bath for one hour, diluted with 200 ml of water, concentrated to a total volume of 50 ml, again diluted with 200 ml of water and concen-trated ~o an oil. The oil is dissolved in chloroform, the chloroform solution is washed consecutively with an aqueous sodium bicarbonate solution and water, dried, and the chloroform is removed, leaving an oil which upon trituration with ether gives a solid. The solid is recrystallized from acetonitrile to give colorless crystals, mp 166-167C., of 1,3-dihydro-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidine]-1'-oxide.
Analysis:
Calculated for Cl9H21N2 H2 72.82%C; 7.40%H; 4.41%N.
Found: 72.00%C; 7.44%H; 4.39%N.
By the following the manipulative procedure outlined 28 above, 1,3-dihydro-1'-methyl-6-trifluoromethyl-3-phenylspiro 10687()8 [isobenzofuran -1,4'-piperidine] is converted to 1,3-dihydro-1'-methyl-6-trifluoromethyl-3-phenylspiro~isobenzofuran-1,4'-piperi-dine]-l'-oxide.

A solution of 2.0 g of 85% 3-chloroperbenzoic acid in 25 ml of chloroform is added dropwise to a stirring solution, chilled to 0C. under nitrogen, of 3.6g of 1'-benzyl-1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine] in 15 ml of chloro-form. After total addition the resulting solution is stirred for three hours at ambient temperature, diluted with 50 ml of chloroform, washed with a saturated aqueous sodium bicarbonate solution and the chloroform is removed in vacuo, leaving a very pale yellow oil. The oil is triturated with an ether-petroleum ether mixture to give a white crystalline solid which is recrystallized from acetonitrile to give a somewhat hygroscopic white crystalline solid, mp 147-150C., of l'-benzyl-1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine]-1'-oxide.
Analysis:
Calculated for C25H25NO2: 80.83%C; 6.78%H; 3.77%N.
Found: 80.65%C; 6.84%H; 3.73%N.
This application is a division of Canadian Application Serial No. 251,487, filed April 29, 1976.

~ 16 -

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of the formula I

I

wherein R represents alkyl of from 1 to 4 carbon atoms or phenalkyl of from 7 to 9 carbon atoms, R1 represents hydrogen, alkoxy of from 1 to 3 carbon atoms or tri-fluoromethyl; R2 represents hydrogen, alkoxy of from 1 to 3 carbon atoms, bromine, fluorine or chlorine; and the pharmaceutically acceptable acid addition salts thereof, in which a piperidine of the formula II

II

wherein R, R1 and R2 are as defined above, is oxidized;
and to produce salts, the compounds may be reacted with a pharmaceutically acceptable acid.

2. A compound of the formula I as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, whenever obtained according to a process as claimed in claim 1 or by an obvious chemical equivalent thereof.

3. A process for the preparation of a compound of the formula I as defined in claim 1 in which piperidine of the formula II as defined in claim 1 is oxidized in an organic solvent at a temperature of about 100°C for a period of from a few minutes to 24 hours.

4. A process as claimed in claim 2 in which the oxidi-zing agent is 4-chloroperbenzoic acid and the solvent is chloroform.

5. A process as claimed in claim 2 in which the oxi-dizing agent is hydrogen peroxide and the solvent is glacial acetic acid.

6. A compound of the formula I, whenever obtained according to a process as claimed in claim 3, claim 4 or claim 5 or by an obvious chemical equivalent thereof.

7. A process as claimed in claim 1 for the prepara-tion of 1,3-dihydro-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidine]-1'-oxide in which 1,3-dihydro-1'-methyl-3-phenyl-spiro[isobenzofuran-1,4'-piperidine] is oxidized in glacial acetic acid solvent using hydrogen peroxide as an oxidizing agent at a temperature of about 100°C and the product is sub-seguently isolated.

8. 1,3-Dihydro-l'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidine]-1'-oxide, whenever obtained according to a process as claimed in claim 7 or by an obvious chemical eguivalent thereof.