FI62091B - FRUIT PROCESSING FOR THERAPEUTIC USE OF THERAPEUTIC ANALYTICAL PRODUCTS 1,3-DIHYDROSPIRO (ISOBENTSOFURAN-1,4'-PIPERIDINE) E OCH -1,3'-PYRROLIDINE) ER - Google Patents

Description

RSC ^ I Γβΐ rt1 ^ ANNOUNCEMENT PUBLICATION, θηθ1 yggr · w <11> utlaggningsskmft 6 / uyi C (45) Patent cyhntictty 10 11 1932 (5,) K.jjZcP 7 ° 07 ^ ^ 17107 ENGLISH I - FI N LAN D (21) ) Puenttlhikemu · - PatanttnaBkninf 801703 (22) HakamitpUvt —Anteknlnstdif 27-05.80 (FI) (23) Alkuptlvt — GlW | h «tt4 ·! 10.12.7 ^ + (41) Tullut Julklsalul— BHvlt offumtij 27. 05.80

Fatanttl · ·) · registry administrator · (44) Nlhtivik * lp «non ji audit.

Patent and ocean registration Amttkan uti * fd ech uti. »Krift * n pubiicand 30.07.82 (32) (33) (31) Pyydetty tcuoltai * - Begird prlorlut 12.12.73 03-09-7 ^ USA (US) U2U117, 502650 (71) Hoechst Aktiengesellschaft, 6230 Frankfurt / Main 80, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (72) Victor John Bauer, Somerville, New Jersey, Raymond Walter Kosley, Jr., Convent, New Jersey, USA (US) (7 * 0 0y Kolster Ah (5 ^) Process for the preparation of therapeutically useful substituted 1,3-dihydro-spiro [ibenzofuran-1, k'-piperidinines and -1,3'-pyrrolidines - For the preparation of therapeutic alternatives to 1,3-dihydrospiro / isobenzofuran-1,3'-piperidines and -1,3'-pyrrolidiners (62) Divided by application 355 This invention relates to novel processes for the preparation of substituted 1,3-dihydrospiro (isobenzofurans. 1,3-dihydrospiro [isobenzofur] prepared according to the invention. aneja] can be used as antidepressant, sedative and analgesic agents.

To the best of our knowledge, the compounds of this invention have not previously been described or suggested for use in this art. purposes. Spiroephthalene-piperidine of formula 2,62091 r / N'Ssi

R 1 is 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- described in U.S. Patent No. 3,686,186 to WJHoulihan et al. within the scope of this invention. The same applies to a natural product with the formula N-CH-,

Xx Π) o described by Y.Inubushi et al. Fchem. and Pharm.Bull. (Japan), 12,749 (1964) J.

The present invention relates to a process for the preparation of therapeutically useful substituted 1,3-dihydrospiro (isobenzofuran-1,4'-piperidines and -1,3-pyrrolidines of formula I).

? 1 / N \ <CH-i> n <PH2> n · ^ -03 h 'i * 2 3 62091 wherein R is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethyl or halogen, is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkylalkyl of 4 to 8 carbon atoms, phenylalkyl of the formula (CH 2) x -PhrR ", wherein R" is halogen; R 2 is alkyl of 1 to 6 carbon atoms, or phenyl of the formula PhR ", wherein R" 1 is hydrogen, lower alkyl, lower alkoxy or halogen; Ph is phenyl; m is an integer from 1 to 3, n is an integer from 1 or 2; n 'is an integer 2; x is an integer from 1 to 4. The method according to the invention is characterized in that

a) o-halobenzoyl chloride is reacted with alkylated or unsubstituted 2-amino-1-ethanol to form the corresponding o-halo-N- (1-hydroxy-2-ethyl) -benzamide of formula II

- ^ 'SsN— hai

Rm I R3

CONHC-CH2OH II

R3

wherein R 3 is hydrogen or lower alkyl, the benzamide is cyclized by treatment with a dehydrating agent to the corresponding o-halophenyl oxazoline of formula III

o J

oxazoline is converted to a Grignard reagent by reaction with magnesium, the Grignard reagent is reacted with a cycloazaalkanone of formula IV

(CH2 ^ n IV

No. 4 62091

for the preparation of the corresponding hydroxy-o-oxazolinyl-phenyl-cycloazaalkane of formula V

? 1

OF

v

the azaalkane is reacted with an acid to give the corresponding 1,3-dihydrospiro- [isobenzofuran-cycloaza-alkan] -S-one of formula VI

? 1 Λ <CH2> „<CH2> n '0

VI

aza-alkanone is reacted with an organometallic reagent to give a 3-substituted 1,3-dihydro-3-hydroxyspiro (isobenzofuran-cycloaza-alkane) of formula VII

B

OF

<CH2> ^ (CH2> n · * Ly

HO R2 VII

5,62091

hydroxyazaalkane is reduced to o-hydroxyalkylphenyl-cycloazaalkanol of formula VIII

? 1

OF

/ \, (CH2 »n lCH2> n '

VIII

Rr4- I OH

mV \

CHOH

R2

VIII

and azaalkanol is cyclized with an acid to the corresponding 3-substituted 1,3-dihydrospiro (isobenzofuran-cycloazaalkane) of formula I, and b) if desired, hydrogenating such a 3-substituted N-benzyl-1,3- dihydrospiro (isobenzofuran cycloazaalkane) with CH 2 PhR "to a compound of formula I wherein R 1 is hydrogen, and c) if desired, converting N- and 3-disubstituted-1,3-dihydrospiro (isobenzofuran cycloaza) alkane) to react with chloroformate to prepare substituted N-oxycarbonyl-1,3-dihydrospiro (isobenzofuran cycloazaalkane) which is then treated with a base or acid to give the corresponding N-unsubstituted 1,3-dihydrospiro (isobenzofuran cycloaza-alkane) alkane ) optionally alkylating or acylating a 3-substituted 1,3-dihydrospiro (isobenzofuran cycloazaalkane) of formula I to the corresponding N-alkylated or N-acylated derivative and reducing the N-acylated 1,3-dihydrogen of formula I ospiro (isobenzofuran cycloazaalkane) to the corresponding N-alkylated derivative.

Preferred are compounds wherein R is hydrogen, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, fluorine, chlorine or trifluoromethyl ·, R 1 is hydrogen, alkyl of 1 to 6 carbon atoms. atom, cycloalkylalkyl of 4 to 5 carbon atoms, phenylalkyl of the formula - (CH 2) -PhR "; R 2 is alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms or halogen.

Acids which can be used to prepare pharmaceutically acceptable acid addition salts of the compounds of formula I include inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as well as organic acids such as tartaric acid, citric acid, acetic acid, acetic acid and , maleic acid, fumaric acid and oxalic acid.

Some compounds within the scope of this invention are more pharmaceutically active than others. However, the latter compounds are also preferred as intermediates in the preparation of more active compounds.

Method A

o-Halobenzoic acid is converted to the corresponding benzoyl chloride by treatment with a halogenating agent such as thionyl chloride, phosphorus pentachloride or oxalyl chloride at 0-120 ° C for 0.25-24 hours without a catalyst or in the presence of a catalyst in the presence of a catalyst, e.g. dimethylformamide. a solvent such as ether, toluene or dichloromethane. The benzoyl chloride is then reacted with 2-aminoethanol, which may be substituted in the 2-position by lower alkyl, at a temperature between -20 ° C and 35 ° C without an acid neutralizing agent or using an acid neutralizing agent, e.g. sodium hydrogen carbonate in a solvent, e.g. in the presence of dichloromethane or benzene to give o-halo-N- (1-hydroxy-2-methyl-2-propyl) -benzamide II. It will be apparent to those skilled in the art that the times and temperatures required to complete the reactions in this and the following steps will depend on each other and on the structures of the reaction components and the solvent.

o-Halogen-N- (1-hydroxy-2-methyl-2-propyl) -benzamide II is cyclized to o-halophenyloxazoline III by treatment with a dehydrating agent such as thionyl chloride, phosphene, or phosphorus oxychloride at -20 to + 40 ° C without solvent or solvent. , such as toluene, pyridine, Tao in the presence of chloroform for 0.5 to 24 hours.

7 62091 o-Halophenyloxazoline III is converted to Grignard reagents under standard conditions, i. by reacting the compound with magnesium at about 25-100 ° C in a solvent, e.g. ether or tetrahydrofuran, suitably for 0.25-24 hours, optionally using an initiator, e.g. iodine or 1,2-dibromoethane. Reaction of the Grignard reagent with cycloazalkanone IV at -60 to + 100 ° C for 0.25-24 hours gives oxazolinylphenyl-cycloazalkanol V.

Oxazolinylphenylcycloazalkanol V is treated with an acid such as aqueous hydrochloric acid or sulfuric acid at 25-125 ° C for 10 minutes to 24 hours without solvent or with a solvent such as water, ethanol or acetic acid to give 1,3-dihydro-spiro / isobenzofuran-cycloaza-alkan-3-one (VI). It is reacted with an organometallic reagent such as an alkyl or arylmagnesium halide or an alkyl or aryllithium under normal conditions, e.g. -60 ° to + 100 ° C in the presence of a solvent, e.g. hexane, toluene, ether or tetrahydrofuran, for 10 minutes - 24 hours to give 1,3-dihydro-3-hydroxy-1-spiro / isobenzofuran-cycloazaalkane / VII.

1,3-Dihydro-3-hydroxyspiro [isobenzofuran-cycloaza-alkane] III is converted with a reducing agent such as lithium aluminum hydride or sodium bis (2-methoxyethoxy) aluminum hydride at a temperature of 0-110 ° in a solvent such as toluene, ether or in tetrahydrofuran for 10 minutes to 24 hours to o-hydroxyalkylphenylcycloazaalkanol VIII.

o-Hydroxyalkylphenylcycloazaalkanol VIII is treated with an acid, e.g. hydrochloric acid, formic acid or p-toluenesulphonic acid without a solvent or in the presence of a solvent such as toluene or acetic acid at a temperature of 25-150 ° C, preferably 25-110 ° C 5 minutes to 24 hours, preferably 5 minutes to 3 hours, to give 1,3'-dihydrospiro [isobenzofuran-cycloazaalkane '.

Method B

The N-benzyl-1,3-dihydrospiro [isobenzofuran-cycloazaalkane] of the formula I with C 1 -C 4 is hydrogenated at a pressure of 1-15 atm with a catalyst, e.g. palladium carbon, in a solvent, 62091 δ e.g. in ethanol, acetic acid or in water in the presence of an acid, e.g. hydrochloric acid or perchloric acid, at a temperature of 25-100 ° until hydrogen bonding ceases to give the corresponding 1,3-dihydrospiro [isobenzofuran cycloazaalkane of formula I] wherein R 1 is hydrogen.

Method C

The hydrogen-containing 1,3-dihydrospiro / isobenzofuran-cyclohexaalkane of formula I can be prepared by treating the N-substituted 1,3-dihydrospiro / isobenzofuran-cycloaza-alkane 7 with chloroformate, e.g. alkyl or phenyl chloroformate. At 0.25 to 24 hours in a solvent, e.g. toluene or benzene, to give the corresponding N-alkoxycarbonyl or N-phenyloxycarbonyl-1,3-dihydrospiro / isobenzofuran-cycloazaalkane7, which then treated with a base, e.g. sodium or potassium hydroxide in a solvent, e.g. water or ethanol, or an acid, e.g. hydrogen bromide in acetic acid for 0.25 to 24 hours at 25-125 ° C.

Method D

The N-unsubstituted 1,3-dihydrospiro [iso] benzofuran cycloazaalkane of formula I prepared by Method B or C can be reacted with an alkanoyl chloride or anhydride, an alkyl halide, a cycloalkanoyl halide, an aralkyl halide to give the corresponding N-alkyl The N, alk-alkyl, N-cycloalkanoyl or N-aralkyl derivative, the N-alkanoyl, N-cycloalkanoyl-1,3-dihydrospiro [isobenzofuran-cycloaza-alkanes] can be reduced, for example, with a reagent such as lithium aluminum hydride - or N-cycloalkylalkyl-1,3-dihydrospiro [isobenzofuran-cycloazaalkanes]

A reaction scheme illustrating Methods A-D is shown on page 9.

The compounds of formula I are useful in the treatment of depressive disorders in mammals, as demonstrated by their ability to prevent tetrabenzazine-induced depressive disorder in mice / international Journal of Neuropharmacoloby, 8, 73 (1969) .7, a standard test used to determine antidepressant properties of drugs. Thus, for example, the ED 1 values observed for the following compounds that prevent tetrabenzazine-induced depression in mice are: α 62091 y

-C

xj \ J g

/ T

- ΓΟ ΓΟ _C I & &., <5 / a $ 1, · ~% j; .

1 t-c \ J

0 -.c L

3 = f “ε

«/ S \ B I

2 “<<> = 0 - i \! Ϊ, -» 0 ·

ΰ · Mj7 J

O) Ph 1 t g

(OF

m e m

r — H Z

3 ö j? O

ö a Λ 5 8

O

«E ίο 62091 ED 50 mg / kg 1,3-dihydro-3-phenylspiro / isobenzofuran-1,4'-piperidine / 0,5 1,3-dihydro-1'-methyl-3-phenylspiro / isobenzofuran-1,4'-piperidine7 1,0 1,3-Dihydro-1'-ethyl-3-phenylspiro [isobenzofuran-1,41-piperidine] 5,0 1,3-Dihydro-11-methyl-3- (4-methoxyphenyl) -spiro- / isobenzofuran-1 , 4'-piperidine7 2,5 1,3-dihydro-11-methyl-3-phenylspiro / isobenzofuran-1,31-pyrrolidine7 1,6 1,3-dihydro-11-butyl-3-phenylspiro / isobenzofuran-1,4'-piperidine7 10.0 1,3-Dihydro-3-p-fluorophenylspiro [isobenzofuran-1,4'-piperidine] 0.5 1,3-Dihydro-1'-cyclopropylmethyl-3-phenylspiro [isobenzofuran-1,4'-piperidine] 2.5 1,3-dihydro-3-phenylspiro [isobenzofuran-1,3'-pyrrolidine] 0,7 1,3'-cyclopropylmethyl-1H-dihydro-β-phenylspiro [isobenzofuran-1,31-pyrrolidine] hydrobromide 0,7 3-p-tolylspiro [isobenzofuran-1,4'-piperidine] 7,8 1,3-dihydro-6-fluoro-3H-fluorophenylspiro [isobenzofuran-1,4'-piperidine] 0.8 k, 3-dihydro-6-methoxy-3-phenylspiro / isobenzofuran-1,4'-piperidine / 0.3 1,3-dihydro-3-p-fluorophenyl-1'-methylspiro [isobebzofuran-1,4 ' -piperidine / 1,4 1,3-dihydro-3-p-methoxyphenylspiro / isobenzofuran-1,4'-piperidine / 2,0 1,3-dihydro-11,3-dimethyl-3-phenylspiro / isobenzofuran-1,4'-piperidine / hydrobromide 9.5 The compounds of this invention may further be used as sedatives due to their crippling effect on the central nervous system of mammals. This activity is demonstrated by an experimental method in mice commonly used for the testing of central nervous system depressants / Psychopharmacologia, 9, 259 (196627 · Thus, for example, an effective dose of (ED 2) 1,3-dihydro-1 '- (2-phenylethyl) -3-phenyl - 11 62091 spiro (Isobenzofuran-1,4'-piperidine), which has a significant effect on behavior and reflex borrowing as well as muscle relaxation, is 20 mg / kg The corresponding EDj-q values for the other compounds are:

ED5C

pgAg 1,3-dihydro-1 ', 3-dimethylspiro / isobenzofuran-1,4'-piperidine / 25.0 1H-dihydro-1'-benzyl-3,5-dimethoxy-3-phenylspiro [isobenzofuran-1,4 '-piperidine / 20,0' N-dihydro-1'-cyclopropylmethyl-3-phenylspiro [isobenzofuran-1,4'-piperidine] / 2,5 1,3-dihydro-1'-propyl-3-phenylspiro / isobenzofuran-1, 4'-Piperidine / 25.0 1β-dihydro-1'-benzyl-3- (4-fluorophenyl) spiro / isobenzofuran-1,41-piperidine / 25.0 The utility of the compounds of this invention as sedatives is also demonstrated by their ability to to prevent shock - induced vibration of the feet in mice.

Int.Pharmacodynam. et de Therap., 142, 30 (19632 / 3a anti-amphetamine toxicity in accumulation situations. / J.Pharmacol. Exp.Therap., 87, 214 (1946/7 · Thus 1,3-dihydro-1'-methyl-3- phenylspiro (isobenzofuran-1,4'-piperidine) and 1,3-dihydro-3-phenylspiro (isobenzofuran-1,41-piperidine) at doses of 3 and 10 mg / kg, respectively, 50% of mice received at doses of 27 and 1.0 mg / kg 1,3-dihydro-11-methyl-3-phenylspiro (isobenzofuran-1,4'-piperidine) and 1,3-dihydro-1,3-dihydro-11'-piperidine, respectively. The anti-toxicity effect of -1 '- (2-phenethyl) -3-phenylspiro / isobenzofuran-1,4'-piperidine / amphetamine is observed in 50% of mice. / are useful sedatives in mammals at doses ranging from 0.1 to 50 mg / kg / day.

The compounds of formula I are also useful analgesic agents due to their ability to relieve pain in mammals. Their analgesic utility can be demonstrated by a phenyl-o-quinone torsion test performed in mice, which is used as a standard method for determining analgesia. /Proc.Soc.Exptl.Biol.Med., 95, 729 (1957 // Thus, e.g.

Approximately 50% of the anti-torsional effect is obtained with 1,3-dihydro-1'-methyl-3-phenylspiro [isobenzofuran-1,4-piperidine] at a dose of 8.4 mg / kg. An equally effective effect is obtained at a dose containing 14.5 mg / kg of 1,3-dihydro-3-phenylspiro (isobenzofuran-1,4'-piperidine). Doses of 50 mg / kg 1,3-dihydro-11-ethyl-3-phenylspiro (isobenzofuran-1,4'-piperidine), 1,3-dihydro-1 ', 3-dimethyl-3-hydroxyspiro / isobenzofuran-1 , 4'-piperidine], 1,3-dihydro-3-hydroxy-1 '- (2-phenylethyl) -3-phenylspiro [isobenzofuran-1,41-piperidine], 1,3-dihydro-1', 3- dimethylspiro (isobenzofuran-1,4'-piperidine), 1,3-dihydro-3- (4-methoxyphenyl) -1'-methylspiro (isobenzofuran-1,4'-piperidine), and 1,3-dihydro -1'-ethoxycarbonyl-3-phenylspiro (isobenzofuran-1,41-piperidine), the corresponding percentages of anti-torsion are 79%, 51%, 56%, 57%, 47% and 52%. By comparison, aspirin and propoxyphene hydrochloride, which are known analgesics, have a contraceptive effect of 34% and 50% at doses of 60 mg / kg and 28 mg / kg, respectively. These values indicate that the 1,3-dihydrospiro (isobenzofurans) of this invention are useful for relieving pain in mammals when administered at doses of 1 to about 50 mg / kg / day.

The compounds of this invention may be administered to a patient by any conventional route, such as orally, intramuscularly, intravenously, subcutaneously, or intraperitoneally. The preferred route is oral, e.g. with a neutral diluent or ingestible carrier, or as gelatin capsules or tablets.

For oral administration, the active compounds of this invention may be mixed with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums 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 7% to about 70% of the weight of the unit. The amount of active compound contained in such mixtures is so large that a suitable dosage will be obtained. The primary compositions and preparations of this invention are prepared so that an oral dosage unit of 13,62091 contains from 10 to 200 mg of active compound.

Tablets, pills, capsules, troches, and the like can also contain the following ingredients: a binder such as gum tragacanth or gelatin; an additive such as starch or lactose, a disintegrating agent such as alginic acid, potato starch and the like; a bone solid such as magnesium stearate; and, if desired, a sweetening agent such as sucrose or saccharin may be added or flavoring agents such as peppermint, methyl salicylate or orange flavoring may be added. A dosage unit form in the form of a capsule 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 agents which modify the physical form of the dosage unit. coatings. Thus tablets or pills may be coated with sugar, shellac, or both. The syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. The substances used in the preparation of these various mixtures must be pharmaceutically pure and non-toxic in the amounts in which they are used. The invention is further illustrated by the following examples. Temperatures are given in degrees Celsius.

Example 1 1,3-Dihydro-1'-methyl-3-phenylspiro [isobenzofuran-1,4'-piperidine? (a) A mixture of 400 g of o-bromobenzoic acid, 230 g of thionyl chloride and 1 ml of dimethylformamide is brought to a slow boil and boiled. Then for one hour at reflux. The excess thiacyl chloride is distilled off in vacuo and the residue is dissolved in 1 liter of dichloromethane. The resulting solution is added dropwise with stirring to a solution (0 °) of 520 g of 2-amino-2-methylpropanol in 1 liter of dichloromethane and the mixture is stirred for 2 hours at 0 °, then the mixture is filtered. The solid is air dried, stirred for 1 hour in 2 L of warm water, filtered, washed with copious amounts of water and air dried to give an off-white solid, 2-bromo-N- (1-hydroxy-2-methyl-2-propyl) -benzamidia, m.p. 142-145 °.

b) 254 g of 2-bromo-N- (1-hydroxy-2-methyl-2-propyl) benzamide are added to 200 ml of cold (0 °), stirred thionyl chloride over a period of 15 minutes. The solution is stirred at 0 ° for 1/2 hour and at room temperature for 12 hours T and then poured into 1.5 l of ether. The separated solid is collected, washed with ether, dried and then added to 0 ° 20% aqueous sodium hydroxide solution (1 L). The mixture is extracted with ether, and the ether solution is dried over potassium carbonate and concentrated to an oil. Crystallization from hexane gives 2- (2-bromo-phenyl) -4,4-dimethyl-2-oxazoline as colorless crystals, m.p. 39-40 °.

c) Prepare by adding dropwise a solution of 53.3 g of 2- (2-bromophenyl) -4,4-dimethyl-2-oxazoline and 500 ml of dry tetrahydrofuran to a boiling stirred mixture of 6.2 g of Grignard reagent. magnesium turnings and 100 ml of tetrahydrofuran. The lunar entry of the reaction sometimes requires the addition of iodine crystals. After the addition, the mixture is heated to reflux for 2 hours. A solution of 25 ml of 1-methyl-4-piperidone in 25 ml of tetrahydrofuran is then added dropwise, the solution is heated under reflux for 2 hours and then allowed to cool to room temperature. Approximately 25 mL of saturated aqueous ammonium chloride is added, the mixture is filtered and the solid is washed with benzene. The combined organic solution is washed with water and saturated aqueous sodium chloride solution, dried over potassium carbonate and concentrated to an oil. Crystallization from ethanol gives colorless crystals, m.p. 162-163 °, 4- [2- (4,4-dimethyl-2-oxazol-2-yl) -phenyl] -4-hydroxy-1-methylpiperidine.

d) A solution of 6.0 g of 4- (2- (4,4-dimethyl-2-oxazolin-2-yl) -phenyl) -4-hydroxy-1-methylperidine and 70 ml of 3-hydrochloric acid is heated to reflux. 3 hours, the solution is cooled to 0 ° and basified with sodium hydroxide, extracted with chloroform and the chloroform solution is dried over potassium carbonate and evaporated to dryness. Recrystallization from benzene gives colorless crystals, m.p. 147-148 °, 1,3-dihydro-1'-methylspiro [isobenzofuran-1,4'-pLperidin] -3-one · e) Solution containing 2.20 μl of 3-dihydro-1'-methylspiro [ iso-benzofuran-1,4'-piperidin-3-one in 60 ml of dry tetrahydrofuran is added dropwise over 15 minutes to 12 ml of a cold, stirred 2 molar solution of phenyllithium in benzene-ether. The solution is stirred at 0 ° for 1 hour and at room temperature for 1 hour 62091, the solution is diluted with water and extracted with benzene. The benzene solution is dried over anhydrous potassium carbonate and concentrated to an oil. Trituration with ether and then recrystallization from ethanol gives 1,3-dihydro-3-hydroxy-1'-methyl-3-phenylspiro [isobenzofuran-1,41-piperidine_7] as colorless crystals, m.p. 182-183 °.

Analysis: Calculated for c 19 H 21 NO 2: c 77.72%; H 7.17%; N 4.74% found: C 77.45%; H 7.34%; N 4.84%. The following 3-hydroxy compounds are prepared in a similar manner:

Table I

R m hai, £ ϋΐ, R2 Sp. ° C

H - Br CH2Ph 2 2 Ph 87-90 H - Br CH2CH2Ph 2 2 Ph 146-150 5-CH30 1 Br CH3 2 2 Ph 208-10 H - Br CH3 2 2 Ph-pOCH3 123-4 H - Br CH2Ph 2 2 Ph-pF 60- * HCl, 178 oil 5-CH30 1 Br CH2Ph 2 2 Ph-pF 70 H - Br CH3 2 2 CH3 157-8 H - Br CH2Ph 2 2 CH3 126-27 H - Br CH2Ph 3 1 Ph oil f) A solution of 8.5 μl of 3-dihydro-3-hydroxy-1'-methyl-3-phenylspiro / isobenzofuran-1,4'-piperidine7 in 150 ml of tetrahydrofuran is added dropwise over 30 minutes to the stirred mixture. to a suspension of 2.0 g of lithium aluminum hydride in 150 ml of dry tetrahydrofuran. The mixture is stirred at room temperature for 30 minutes and at 50 ° C for 1 hour, cooled, carefully diluted with water and extracted with chloroform. The chloroform solution is dried over potassium carbonate and concentrated to a solid. Recrystallization from benzene gives colorless crystals, m.p. 190-191 °, 4-hydroxy-4- (α-hydroxy-α-phenyl-2-tolyl) -1-methylpiperidine.

g) A solution of 4.4 g of 4-hydroxy- (N, N-hydroxy-N-phenyl-2-tolyl) -1-methylpiperidine, 30 ml of glacial acetic acid and 7.5 ml of concentrated hydrochloric acid is heated under reflux for 10 minutes. 16620 91 it is cooled to 0 °, diluted with water, basified with sodium hydroxide and extracted with chloroform. The chloroform solution is dried over potassium carbonate and evaporated. Recrystallization from hexane gives colorless crystals, m.p. 123-124 ° C, 1,3-dihydro-11-methyl-3-phenylspiro [isobenzofuran-1,4'-piperidine] 7, (hydrochloride salt mp 255 °).

Analysis: Calculated for C 19 H 11 NO: C 81.68%; H 7.58%; N 5.01%; Found: C, 81.73%; H 7.65%; N 5.02

In a similar manner, the following compounds of formula I are prepared using the 3-hydroxy compounds of e) as starting materials. Table II

R m hai R ^ n n_ | _ Sp. ° C

H - Br CH2Ph 2 2 Ph 135-7 H - Br CH2CH2Ph 2 2 Ph 257-61 5-CH30 1 Br CH3 2 2 Ph 78-30 H - Br CH3 2 2 Ph-pOCH3 127-8 oil H - Br CH2Ph 2 2 Ph-pF -HCl, 235-7 5-CH30 1 Br CH2Ph 2 2 Ph-pF oil oxalate H - Br CH3 2 2 CH3 165-6 H - Br CH2Ph 2 2 CH3 74-6 H - Br CH2Ph 3 1 Ph 82-4

Example 2 1,3-Dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine] A. A solution of 7.7 g of 1'-benzyl-1,3-dihydro-3-phenyl-spiro / isobenzofuran-1 , 4J-piperidine / (Table II), 40 ml of benzene and 2.5 ml of ethyl chloroformate are refluxed for 18 hours and then evaporated to dryness. Recrystallization from cyclohexane gives 1,3-dihydro-1'-ethoxycarbonyl-3-phenylspiro / isobenzofuran-1,4'-piperidine / as colorless crystals, m.p. 115-119 °.

Analysis: Calculated for C 21 H 23 NO 3: C 74.75%, H 6.87%, N 4.15% Found: C 74.55%, H 7.00%, N 4.06%.

In a similar manner, the compounds listed in the table below are prepared.

17 62091

Table HI

\ H n_j_n_ | · SP. ° c H CH3 C00C2H5 2.2 68-70 H Ph-pF COOC2H5 2.2 104-106 H Ph COOPh 2.2 179-183 H Ph COOC2H5 2.1 P1 ^ H Ph COOC2H5 3.1 115-118 H Ph -pCH30 COOC2H5 2.2 113-115 H- Ph COOC2H5 3.2 oil.

6-F Ph COOC2H5 2.2 6-CH30 Ph COOC2H5 -2.2 178-180 5-CH30 Ph COOC6H5 2.2 181-185 5- CH30 Ph-pF COOC2H5 2.2 oil H Ph-pCH3 COOC2H5 2 , 2 106-108 6- CH30 Ph-pF COOC2H5 2.2 168-170 6-F Ph-pF C00C2H5 2.2 123-126 H Ph-m, p COOPh 2.2 170-172 <ch3o) 2 62091 18

A solution of 6.3 μl of 3-dihydro-1'-ethoxycarbonyl-3-phenylspiro [isobenzofuran-1,41-piperidine] / 300 ml of ethanol and 240 ml of 20% aqueous potassium hydroxide solution are refluxed for 9 hours, cooled , concentrated to 250 ml, diluted with water and extracted with chloroform. The chloroform solution is dried over potassium carbonate and concentrated. The residue is recrystallized from cyclohexane to give 1'-benzyl-1,3-dihydro-3'-phenylspiro [isobenzofuran-1,4'-piperidine] as colorless crystals, m.p. 119-123 °.

Analysis: Calculated for C 18 H 28 N 2 O: C 81.48%; H 7.22%; N 5.28%; Found: C, 81.55%; H 7.56%; N 5.12%.

The hydrochloride salt m.p. 262 °.

B. A mixture of 2.9 g of 1'-benzyl-1,5-dihydro-5-phenyl-spiro / isobenzofuran-1,4'-piperidine $ 7, 0/4 g of 10% palladium on carbon, ml of 95% ethanol and 2 ml of concentrated hydrochloric acid are hydrogenated at a pressure of 345 kPa and a temperature of 50 °. After hydrogen uptake is complete, the mixture is filtered and the filtrate is concentrated. Recrystallization of the residue from cyclohexane gives the title compound as colorless crystals, m.p. 119-123 °.

In a similar manner, the compounds of formula I listed in Table IV are prepared.

19 62091

Table lv \ n, n * sp> ° c H CH3 L, L 183_184 H Ph-pF 2.2 98-100 H Ph 2.1 90-95 H Ph 3.1 106-110 H Ph-pCH30 2.2 101-103 H Ph 3.2.HCl> 250 6-F Ph 2.2 6-CH30 Ph 2.2 204-212 5-CH30 Ph 2.2 265-268 5-CH30 Ph-pF 2,2-HCl , 275 H Ph-pCH3 2.2 116-117 6-F Ph-pF 2.2 111-112 • HCl, H \ Ph-m, p 2.2 212-216 (ch3o) 2

Example 3 1,3-Dihydro-1'-ethyl-3-phenylspiro [isobenzofuran-1,4'-piperidine? A. To a cold, stirred solution of 6.0 g of 3-dihydro-3-phenyl-spiro-isobenzofuran-1,4'-piperidine / 2.4 g of triethylamine and 50 ml of chloroform is added dropwise a solution containing is 2.0 g of acetyl chloride in 50 ml of chloroform. The mixture is stirred for 2 hours at room temperature, washed with water, dried over sodium sulfate and concentrated. The residue is recrystallized from chloroform to give 1'-acetyl-1,3-dihydro-3-phenyl-spiro (isobenzofuran-1,4'-piperidine) as colorless crystals, m.p. 128-130 °.

20 62091

Analysis: Calculated for C 20 H 21 NO 2: C 77.89%, H 6.90%, N 4.55% Found: C 78.06%, H 6.99%, N 4.43%.

In a similar manner, the compounds listed in the table below are prepared.

Table V

Rm n, n1 SP »° c H Ph COC2H5 2.2 116-119 H Ph COC3117 2.2 110-112 H Ph COCH2 Ph 2.2 174-176 H Ph. C0PhCH3 2.2 172-175 H Ph C0 <] 2.2 133-135 H Ph-pF CO-0 2.2 149-152 H Ph C0 ^> 2.2 127-130 H Ph C0- <3 3, 2 oil B. To a stirred suspension of 0.53 g of lithium aluminum hydride in 50 ml of tetrahydrofuran is added dropwise a solution of 2.20 g of 1'-acetyl-1,3-dihydro-3-phenylspiro [isobenzofuran-1,4 ' -piperidine7 in 50 ml of tetrahydrofuran. The mixture is refluxed for 2 hours, cooled, carefully added with water and extracted with ether. The ether solution is dried over sodium sulfate and evaporated. Recrystallization from chloroform gives the title compound as colorless crystals, m.p. 113-115 °. Analysis: Calculated for C 20 H 23 NO: C 81.87%, H 7.91%, N 4.77%, Found: C 81.76%, H 8.10%, N 4.62%

In a similar manner, the compounds of formula I listed in Table VI are prepared.

21 62091

Table VI

η, η * H Ph C3H7 2.2 98-100 H Ph C4H9 2.2 102-103 H Ph CH2 <] .2.2 97-99 H Ph-pF CH2- <] 2 »2 233-235.

H Ph ch2O 2.2 119'121 HCl H Ph CH2 <] 3.2 203-206 H Ph-pCH3 Cll3 2.2 135-136 H Ph CH3 3.2 88-89 „„ * HHr, 6-CH30 Ph -pF CH3 2.2 235 h-aj.

Example 4 {-) - 1,3-Dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine]

To a stirred solution of 0.80 g of 3-dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine] [(Example 2) and 3 ml of methanol is added a solution of 1.16 g of di- ( p-toluyl) -d-tartaric acid in 6 ml of methanol. The solution is concentrated to dryness and the residue is recrystallized three times from methanol-water to give colorless crystals. The crystals are dissolved in methanol and the solution is treated with an excess of aqueous sodium hydroxide solution. The mixture is extracted with ether and the ether solution is dried over sodium sulfate and concentrated to an oily solid. Recrystallization from cyclohexane gives the title compound as off-white crystals, mp, 99-107 °, = 126.0 ° (0 = 1.35, MeOH).

Example 5 (+) - 1,3-dihydro-3-phenylspiro [isobenzofuran-1,4'-piperidine.7

The compound, colorless crystals, m.p. 104-112 °, / <λ / 25 ° = + 134.4 ° (c = 1.35, MeOH), prepared from 1,3-dihydro-3-phenylspiro 22,62091-isobenzofuran-1,4'-piperidine7 # ( Example 2), and di- (p-toluoyl) -1-tartaric acid as described in Example 4, or alternatively recovered from the water / methanol base liquid of Example 4.

Example 6 1'-Cyclopropylmethyl-1,3-dihydro-3-phenylspiro [isobenzofuran-1,3'-pyrrolidine]

Reaction of 1,3-dihydro-3-phenylspiroisobenzofuran-1,31-pyrrolidine with cyclopropylcarbonyl chloride using the procedure of Example 3, followed by reduction with lithium aluminum hydride by the method of the latter part of Example 3, affords the amine. The amine is converted to its hydrobromide salt, m.p. 187-190 ° crystallized from acetone-ethyl acetate.

Analysis: Calculated for .HBr: C 65.28%, H 6.26%, N 3.62%, Found: C 65.08%, H 6.36%, N 3.45%.

Claims (1)

23 62091 Claim: A process for the preparation of therapeutically useful substituted 1,3-dihydrospiro / isobenzofuran-1,4'-piperidines and -1,3'-pyrrolidines of formula I? 1 / N \ (CH2in < S 2 is n hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethyl or halogen is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkylalkyl, wherein is 4 to 8 carbon atoms, phenylalkyl of the formula (CH2) x-PhR ', wherein R "is halogen; R2 is alkyl of 1 to 6 carbon atoms, or phenyl of the formula PhR"', wherein R "1 is hydrogen, lower alkyl, lower alkoxy or halogen; Ph is phenyl; m is an integer from 1 to 3; n is an integer from 1 or 2; n 'is an integer from 2; x is an integer from 1 to 4, characterized in that a) o-Halobenzoyl chloride is reacted with alkylated or unsubstituted 2-amino-1-ethanol to form the corresponding o-halo-N- (1-hydroxy-2-ethyl) -benzamide of formula II —- shark Rm - I II —conhc-ch2oh R3 wherein R1 is hydrogen or lower alkyl, the benzamide is cyclized by treatment with a dehydrating agent to give the corresponding o-halophenyl oxazoline of formula III 24 62091 "3 0 - 'R' 3 III oxazoline is converted to a Grignard reagent by reaction with magnesium, the Grignard reagent is reacted with a cycloazaalkanone of formula IV <cH2) n Γω2) „. iv V IV to prepare the corresponding hydroxy-o-oxazolinyl-phenyl-cycloazaalkane of formula V h N (C 20-20 C 2 V R'3 v azaalkane is reacted with an acid of the corresponding 1,3-dihydrospiro / to prepare an isobenzofuran-cycloaza-alkan-7-one-one of formula VI 25 62091? 1 Λ <ch2 »„ <CH2> n · 0 VI aza-alkanone is reacted with an organometallic reagent to give a 3-substituted 1,3-dihydro 3-Hydroxyspiro (isobenzofuran-cycloazaalkane) of formula VII? 1 N <CH2> n (CH2> n · HO R2 VII hydroxyazaalkane) is reduced to o-hydroxyalkylphenylcycloazaalkanol of formula VIII 62091 of N (CH2) / (CH2) n, N CHOH R2 VIII and azaalkanol are cyclized with acid to the corresponding 3-substituted 1,3-dihydrospiro (isobenzofuran-cycloazaalkane) of formula I T and b) if desired, hydrogenated a 3-substituted N-benzyl-1,3-dihydrospiro (isobenzofuran-cycloaza-alkane) of the formula I Cl 2 PhR ", a compound of formula I with hydrogen, and c) if desired, reacting an N- and 3-disubstituted-1,3-dihydrospiro (isobenzofuran cycloazaalkane) of formula I with a chloroformate-substituted N-oxycarbonyl-1 To prepare 3-dihydrospiro (isobenzofuran cycloazaalkane), which is then treated with a base or acid to give the corresponding N-unsubstituted 1,3-dihydrospiro (isobenzofuran cycloazaalkane), and d) if desired, alkylated or acylated 1,3-dihydrospiro (isobenzofuran cycloazaalkane) to the corresponding N-alkylated or N-acylated derivative and reduced to the corresponding N-alkylated derivative of the N-acylated 1,3-dihydrospiro (iso-benzofurancycloazaalkane) of formula I. 62091 27 For the preparation of a therapeutically active substituent, 1,3-dihydrospiro (isobenzofuran-1,4'-piperidine) and och-1,3'-pyrrolidine are obtained with the formula I:? N / \ (C !! A < RV · er <R-- 0 H color R är derivative, alkyl med 1-6 cholatomer, alkoxy med 1-6 cholatomer, trifluoromethyl or halogen, R ^ är derivative, alkyl med 1-6 cholatomer, cycloalkyl gloss1 4-6 cholatomer , phenylalkyl of formula (CH2-x-PhR ", with R" is halogen; R2 is alkyl of 1-6 cholaters with phenyl of formula PhR "1, with R" 'is hydrogen, alkyl, with alkoxy or halogen; Ph är fenyi; m är ett helt tai 1-3; n är ett helt tai 1 eller 2; n 'är et helt tai 2; x är ett helt tai 1-4, känne-t ecknat därav, att man a) omsätter en o-halobenzoyl chloride with alkyl or substituted 2-amino-1-ethanol to give a mixture of o-halo-N- (1-hydroxy-2-ethyl) benzamide with formula II: R Γ / ^^ ΪΓ hal * 3 11 IL CONHC-CH 2 o H r3 is R ^ betecknar väte eller lägre alkyl, cyclic benzariden account motsvar and o-halophenloxazoline with formula III::. 62091 28 f 4 III of the genome with a dehydrating agent, with oxazoline accounts for the Grignard reagent genome with magnesium, with a Grignard reagent with a cycloaza alkane of formula IV: R1 I '<CH2> n ^ CH2> n · IV V IV for the preparation of hydroxy-o-oxazolinylphenylcycloaza-Alkane with the formula V: h N% 0CH2> "'X„ V | 0H ^, 3 of the aza-alkane with Sura The mixture for the preparation of 1,3-dihydrospiro / isobenzofuran-cycloaza -alkane / -3-one with the formula VI: 29 62091? 1 Λ CH2> n (CH2> n · * 'VI 0 VI is an aza-alkanone with an organometallic reagent to the image-and a 3-substituent 1,3- dihydro-3-hydroxyspiro (isobenzofuran-cycloazalalkane) of formula VII:? 1 N (C »2)„ <CH2) n, ^ Cy ° HO R2 VII reducer of hydroxyazaalkanes to o-hydroxyalkylphenylcycloazaalkanol of formula VIII: