IL38439A - 8-benzofurylmethyl-1,3,8-triazaspiro(4,5)decanes,their manufacture and pharmaceutical preparations containing them - Google Patents

Description

(5«4)n»3DRTK*nB-8,3,1-?»nD,? Tisi t aa-8 o' 'aan mnpn »-i»t£ m oms»* to»ap*T οηικ 8-Benzo urylmethyl-l, ,8-triazasplro (4.5)<¾©canes9 their manufacture and pharmaceutical preparations containing them s 36545 The present invention concerns the manufactur new 8-(2,3-dihydro-2-benzofurylraethyl) -1, 3, 8-triazaspir (4,5)decanes of the general formula I in which R^ is hydrogen, lower alkoxy, halo, lower a-hydroxy- alkyl or lower alkanoyl, each of R2> ^ and R6 represents hydrogen or lower alkyl, ^ is hydrogen, cyclohexyl or phenyl, and R^ represents two hydrogen atoms or oxo. °r salts thereof .

The substituent R^ is lower alkoxy, halo, lower a-hydroxyalkyl or lower alkanoyl, e.g. methoxy, ethoxy, n- or i-propoxy or -butoxy; fluoro, chloro or bromo; 1-hydroxy- ethyl or l-hydroxy-2-methyl-propyl; acetyl, propionyl or butyryl.

The term "lower", referred to above or hereinafter in connection with organic radicals or compounds respectively, defines such with up to 7, preferably up to 4, carbon atoms.

Each of the radicals R , R and R, represents preferably hydrogen, but also lower alkyl, e.g. ethyl, n- or i-propyl or -butyl, especially methyl.

Salts of the compounds of formula I are preferably therapeutically acceptable acid addition salts derived, for example, from the inorganic or organic acids listed below.

The compounds of the invention exhibit valuable pharmacological properties, especially central nervous system depressant and analgetic effects. This can be demonstra-ted in animal tests, using advantageously mammals, such as rats, mice, rabbits, cats, dogs and especially monkeys, as test objects. The compounds of the invention can be applied enterally or parenterally, e.g. orally, subcutaneously, intraperitoneally or intravenously, for example, within gelatin capsules, mixed with corn starch or in the form of aqueous solutions or suspensions respectively. Said compounds produce, for example, a quieting effect in mice, as demonstrated in the jiggle-cage or light-box test, where a reduction of their spontaneous motor activity is recorded after oral or subcutaneous doses. They antagonize the stimulating effects of amphetamine in rats, working (bar-pressing) in an operant electric shock avoidance situation. Analogously, they decrease the leverpressing avoidance responses of squirrel monkeys, i.e. the number of electric' shocks taken b the animals increases with the dose applied (Sidman procedure). Accordingly, the compounds of the invention are useful neuroleptics and analgetics, for example, in the treatment or management of agitation, aggression or anxiety in warm-blooded animals, preferably mammals. They are also valu-able intermediates of other preparations, preferably pharmacologi -p^ f v.o l n m ni 1 nri i n vi nw m f h a i τ r\p-nr>n p n a a-nalgetic activity are those of .formula Ή—in which Ph in un Particularly valuable are those compounds of the formula I, in which R^ is hydrogen, lower alkoxy or halo, each of and R^ is hydrogen or methyl, R^ is cyclohexyl or phenyl, R^ is hydrogen or methyl, and R^ represents two hydrogen atoms, or therapeutically acceptable acid addition salts thereof.

Especially valuable are the compounds of formula I, in which R^ is hydrogen, methoxy , fluoro, chloro, 1-hydroxy-ethyl or acetyl, each of R^> R^ and R^ is hydrogen or methyl, R^ is phenyl, and R^ represents two hydrogen atoms, and of these especially the l-phenyl-4-oxo-8- [5-methoxy- or 5-(l-hydroxyethyl)-2,3-dihydro-2-benzofurylmethyl]-l,3,e-tri-azaspiro(4,5)decane, or a therapeutically acceptable acid addition salt thereof, more particularly the optically levoro-tatory forms thereof, which exhibit outstanding effects in the above-described test systems, especially the Sidman procedure.

The compounds of the invention are prepared by condensing compounds of the general formulae II and III in which X is a reactive esterified hydroxy group, and, if desired, reducing a resulting compound having a lower alkanoyl substituent in the 1 , 2-phenylene radical to the corresponding (ot-hydroxy-lower alkyl) -1 , 2-phenylene compound with sodium borhydride, and/or, if desired, converting a resultin verting a resulting salt into the free compound, and/or, if desired, resolving a mixture of isomers or racemates obtained into the single isomers or racemates, and/or, if desired, resolving a racemate obtained into the optical antipodes.

A reactive functionally converted hydroxy group in the above starting materials is preferably a hydroxy group esterified with a strong* mineral >r sulfonic acid, e,g sulfuric, methane-, ethane-, benzene-, p-toluene- or camphorsul-fonic acid, but preferabl that of a hydrohalic acid, e.g. hydrochloric or hydrobromic acid.

The chemical process of the present invention is carried out according to standard methods, e.g. in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of condensing agents, and/or 38439/2 inert atmospheres, at low temperatures, room temperature or elevated temperatures, at atmospheric or superatmospheric pressure. Condensing agents are basic agents, for example, alkali or alkaline earth carbonates, hydroxides or lower alkoxides, such as sodium, potassium or calcium carbonate, sodium or potassium hydroxide, methoxide or ethoxide, but also organic nitrogen bases, such as aliphatic or aromatic tertiary amines, such as tri-lower alkylamines, e.g. triethylamine; pyridine or collidine.

The compounds of the invention so obtained and having a lower alkanoyl substituent in the 1,2-phenylene residue, can be reduced to the corresponding e-hydroxyalkyl-1,2-phenylene compounds, for example, with the use of complex light metal hydrides, e.g. sodium borohydride.

The compounds of the invention are obtained in the free form or in the form of their salts, depending on the conditions under which the above process is carried out. A resulting free base can be converted into a corresponding acid addition salt, for example by reacting it with an inorganic or organic acid, preferably a therapeutically useful acid, or with a corresponding anion exchange preparation, and isolating the desired salt. An acid addition salt may be converted into the free compound by treatment with a base, e.g. a metal hydroxide, ammonia or a hydroxyl ion exchange preparation. Therapeutically useful acids are, for example, inorganic acids, such as strong metalloidic acids, for example, hydrohalic, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric, nitric or perchloric acid, or organic acids, such as carboxylic or sulfonic acids, e.g. formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyroracemic, phenylacetic, benzoic, ½-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, aminosalicylic, embonic, nicotinic, methanesulfonic , ethanesulfonic, hydroxyethanesulfonic, ethylenesul onic, halo-g«*ibenzenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic and cyclohexylsulfamic acid; methioni^, tryptophan! lysine and argiriine.

. These or other salts, for example, the picrates, can also be used for purification of the resulting free com-, pounds, which are converted into salts, the salts separated and the free compounds liberated from the salts .

In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

• The invention also comprises any modification of the above process, wherein a compound resulting as an intermediate at any stage of the process is used as starting material and any remaining steps are carried out, or in which the starting materials are formed under the reaction conditions, or in which the reaction components are used in the form of their salts.

Mainly, those starting materials should be used in the process of the invention that lead to the formation of those compounds indicated above as being specially valuable.

The starting material used is known, or if new, may be prepared according to the methods illustrated by the examples herein or the literature cited. The 1- (2, 5-dihydro-2-benzofuryl)-alkanol derivatives, as well as the 1, 3, 8-triaza-spiro( , 5)decanes are described in the U.S. Patents Nos. , 59,860; 5, 70,185 and 3,258,216, Starting materials or final products that are mixtures of isomers can be separated into the single isomers by methods in themselves known, e.g. by fractional distillation, crystallization and/or chromatography. Racemic products can likewise be resolved into the optical antipodes, for example by separation of diastereomeric salts or esters thereof, e.g. by the fractional crystallization of d- or 1-tartrates, -maleates, -rnandelates, -N-acetylphenylalani- nates or -camphorsulfonates, and reconverting the diastereo- meric salts or esters into the free antipodes, or using said esterintermediates direct in the reaction.

The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions containing an effective amount thereof in conjunction or admixture with inorganic or organic, solid or liquid excipients suitable for either enteral or parenteral appli^ cation. Preferred are tablets and gelatin capsules comprising the active ingredient together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, and lubricants, e.g. silica, talcum, · stearic acid or salts thereof, such as, magnesium or calcium salts thereof, and/or polyethyleneglycol; tablets also contain binders, e.g. magnesium aluminium silicate, starches, e.g. corn, wheat or rice starch or arrow root, gelatin, tragacanth, methylcellu-lose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and if desired, disintegrants, e.g. starches, agar, alginic acid or a salt, such as sodium salt thereof, and/or effervescent mixtures and adsorbents, colorants, flavors and/or sweeteners. Injectable compositions are preferably aqueous isotonic solutions or suspensions and suppositories advantageously fatty emulsions or suspensions. They may be sterilized and/or contain auxiliary substances, such as preserving, stabilizing, wetting or emulsifying agents, solu-bilizers, salts for regulating the osmotic pressure and/or buffers. The pharmaceutical preparations which in addition may include other therapeutically valuable substances are prepared according to known methods, e.g. conventional mixing, granulating or coating methods .

Preferred compositions for veterinary use are the parenterally, e.g. intravenously or intramuscularly, applicable solutions or suspensions.

The following examples are intended to illustrate t the invention and are not to be construed as being limj/ations thereon. Temperatures are given in degrees Centigrade.

Example 1 The mixture of 3· 7 S of 2-bromomethyl-5-methoxy-2, j5-dihydrobenzofuran, $ ~ . 6 g of l-phenyl-4-oxo-l, J>, 8-triazaspiro-( , 5) -decane, 6 g of anhydrous sodium carbonate and 50 ml of 2-propanol is refluxed for three days. The mixture is filtered and the filtrate evaporated under reduced pressure. The residue is crystallized by agitating vigorously with a mixture of 50 ml of diethyl ether and 0 ml of water. The product is re-crystallized twice from ethanol to afford the l-phenyl- -oxo- 8- (5-methoxy-2,;5-dihydro-2-benzofurylmethyl)-1,3,8-1riaza- spiro(4,5)decane of the formula melting at 191-192°.

The hydrochloride salt thereof is prepared by adding 6N ethanolic hydrogen chloride to an acetone solution of the above free base. The hydrochloride crystallizes out and melts at 29O0 with decomposition.

Example 2 In an analogous manner to example 1, 2.8 g of 2-bromomethyl-2, 3-dihydrobenzofuran, ·0 g of l-phenyl-4-oxo-l,j5,8-triazaspiro(4,5)decane and 6 g of anhydrous sodium carbonate in 40 ml of 2-propanol are refluxed for three days vihich affords on recrystallization from acetone-ethanol the l-phenyl-4-oxo-8- (2, 3-dihydro-2-benzofurylmethyl )-l, , 8-tri-azaspiro(4,5)decane, melting at 202-205°· Example 3 2.7 g of 2-bromomethyl-5-fluoro-2, 3-dihydrobenzo-furan, 2.7 g of l-phenyl-4-oxo-l, i8-triazaspiro(4J5)decane and 5 S o anhydrous sodium carbonate in 45 ml of 2-propanol are treated as previously described in Example 1 to give the l-phenyl-4-oxo-8- (5- luoro-2,3-dihydro-2-benzofurylmethyl)-l,3,8-triazaspiro(4,5)decane, -melting at 188-191° on recrys- tallization from ethanol.

The starting 2-bromomethyl-5-fluoro-2,3-dihydro- benzofuran is prepared as follows: The mixture of 125 g of -fluorophenol, 00 ml of acetone, l60 g of potassium carbonate and 135 g of allyl bromide is refluxed for 8 hours and allowed to stand overnight. The mixture is diluted with 600 ml of water and the resulting layers separated. The aqueous layer is extracted with 2 x 0 ml of methylene chloride. The combined organic extracts are washed with 225 nil of 10$ aqueous sodium hydroxide, dried, filtered and the filtrate evaporated to give the l-allyloxy-4-fluorobenzene . 60 g of l-allyloxy-4-fluorobenzene are heated under a nitrogen atmosphere to an internal temperature of 220° for 2 1/2 hours. On cooling, there is afforded the 2-allyl-4-fluorophenol .

The mixture of 60 g of 2-allyl- -fluorophenol and 102 g of acetic anhydride is refluxed for 3 hours. The acetic acid formed is removed under reduced pressure and the residue is distilled to afford the l-acetoxy-2-allyl-4-fluoro-benzene, boiling at 118-121°/3A mm Hg.

The solution of 42 g of bromine ih 120 ml of carbon tetrachloride is added dropwise to the solution of 1 S of l-acetoxy-2-allyl- -fluorobenzene in 150 ml of carbon tetrachloride. The reaction mixture is stirred for 1 1/2 hours after the addition and then treated with 60 ml of saturated aqueous s.odium carbonate and 100 ml of water. The organic layer on separation is dried, filtered and evaporated under reduced pressure to give the 1, 2-dibromo- - (2-acetoxy-5- luoro- phenyl)-propane .

The solution of 15 g of sodium methoxide in 250 ml of ethanol is added dropwise to the solution of 90 g of 1, 2- dibromo-3- (2-acetoxy-5-fluorophenyl) -propane in 125 ml of ethanol. The reaction mixture is refluxed for 2 hours, filtered and the filtrate evaporated under reduced pressure. The residue.' is diluted with water and extracted -with methylene chloride.

The methylene chloride extract is dried and filtered; the filtrate is evaporated. The residue is distilled to afford the 2-bromomethyl-5-fluoro-2, 3-dihydrobenzofuran, boiling at 135-139°/15 mm Hg.

Example The mixture of 1 . 1 g of 2-bromomethyl-5-methoxy-1, 2-dihydrobenzofuran, 1 . 1 g of l-cyclohexyl- -oxo-l, 3> 8-tri-azaspiro( 4, 5)decane, } g of sodium carbonate and 2 ml of 2-propanol is refluxed for 3 days. The salts are filtered off and the filtrate evaporated under reduced pressure. The residue is treated with a mixture of 50 ml of diethyl ether and 50 ml of water. The ether layer is separated and extracted with aqueous citric acid. The combined acid fractions are made basic with ammonium hydroxide and extracted with diethyl ether'. The ether extracts are dried and evaporated. The residue is recrys-tallized from ethanol to give the l-cyclohexyl- -oxo-8- ( 5-methoxy-2 , 3-dihydro-2-benzofurylmethyl)-l, 3, 8-triazaspiro( 5 ) -decane, melting at 155- 156° .

Example - 5 To the solution of 5 g of d,-£-l-phenyl- -oxo-8- (5-methoxy-2, 3-dihydro-2-benzo rylmethyl) -1, 3, 8-triazaspiro- (4,5)decane (obtained according to example 1) in l800 ml of acetone, the solution of 26.4 g of N-acetyl- -phenylalanine in 350 ml of acetone is added while stirring and the mixture concentrated to abou 1500 ml. It is allowed to stand overnight in the refrigerator, and the precipitate formed filtered off, to yield the salt A, m.p. 103-105° (dec). The mother liquor is further concentrated to about 800 ml, and the precipitate formed in the cold filtered off, to yield the salt B, m.p. 90-105°. 31 g of the salt A is recrystallized from 32 ml of ethanol . containing 6 ml of water, 26 g of the recovered material recrystallized from 325 ml of ethanol containing .4 ml of water and 24.5 g of the recovered material recrystallized from 450 ml of ethanol. The purified salt is taken up in water, the mixture made basic with aqueous ammonia and extracted with chloroform. The extract is dried and evaporated, to yield the <-l-phenyl-4-oxo-8- (5-methoxy-2, 3-dihydro-2-benzofurylmethyl )-l,3j8-triazaspiro(4,5)decane, melting at 185-188°, ία]^ = -12.4° (chloroform).

The salt B is taken up in water, the mixture made basic with aqueous ammonia and extracted with chloroform. The extract is dried and evaporated. l8.1 g of the residue are taken up in 450 ml of acetone and the solution combined with that of 9· 5 g of N-acetyl-d-phenylalanine in l80 ml of acetone. The mixture is concentrated to about 500 ml and 21 g of the precipitate formed in the cold recrystallized first from 400 ml of ethar.ol containing 2 ml of water. 17 g of the re- covered material is recrystallized from 300 ml of ethanol and the resulting salt converted into the free base as shown above, to yield the d-l-phenyl- 4-oxo-8- (5-methoxy-2 , j5-dihydro-2-benzofurylmethyl)-l, 3, 8-triazaspiro( 4, 5)decane, melting at 18^-186° , [aJD = +12 Λ0 (chloroform).

Example 6 To the solution of g of either the d, - or the Ai-phenyl- -oxo-8- ( 5-methoxy-2 , 3-dihydro-2-benzofurylmethyl) - 1 , 3J 8-triazaspiro( , 5)decane in 100 ml of acetone and 30 ml of ethanol, 0 . 8 ml of methanesul onic acid are added, followed by 20 ml of water and 200 ml of diethyl ether while stirring. The precipitate formed is filtered off and recrystallized from water, to yield either the d, - or the /-l-phenyl- 4-oxo-8- (5-methoxy-2 , j5-dihydro-2-benzofurylmethyl)-l, 3, 8-triazaspiro-( , 5)decane methanesulfonate hemihydrate, both melting at 188-190° .

Example 7 The mixture of 6 . 6 g of 2-bromomethyl-7-methoxy-2 , 3-dihydrobenzofuran, 6 . S of l-phenyl-4-oxo-l, j5, 8-triazaspiro-( , 5)decane, 12 g of sodium carbonate and 100 ml of 2-propanol is refluxed for 3 days while stirring. After cooling, it is filtered, the filtrate evaporated under reduced pressure and the residue taken up in diethyl ether. The solution is shaken with 5^ hydrochloric acid, the suspension formed filtered, the precipitate suspended in water and the mixture made basic with aqueous ammonia. It is extracted with chloroform, the extract dried, filtered, evaporated and the residue recrystallized from ethanol, to yield the l-phenyl-4-oxo-8- (7-methoxy-2,3- dihydro-2-benzofurylmethyl)-l,3,8-triazaspiro(4, 5)decane, melting at 170°.

Example 8 The mixture of 12.5 g of a 2:1 composition of 2-' bromomethyl-4- or -6-methoxy-2, 3-dihydrobenzofuran, 12 g of l-phenyl~4-oxo-l,3,8-triazaspiro(4,5)decane, 25 g of sodium carbonate and 200 ml of 2-propanol is refluxed for 3 days while stirring. After cooling, it is filtered, the filtrate evaporated and the residue taken up in diethyl ether. The solution is shaken with hydrochloric acid, the aqueous solution made basic with ammonia and extracted with diethyl ether. The extract is dried, evaporated and the residue chromatographed on silica gel. The column is eluted with benzene-methanol (9:l)> to yield a first eluate containing the l-phenyl-4-oxo-8- (4-methoxy-2, -dihydro-2-benzofurylmethyl)-l, , 8-triazaspiro(4, 5)-decane, showing in the I.R. spectrum bands at 3193* 169 * 1590, 1195, 8θ4, 7 9 and 69Ο cm"1, followed by the l-phenyl-4-oxo-8- (6-methoxy-2,3-dihydro-2-benzofurylmethyl)-l,3, 8-triaza-spiro(4,5)decane, having a similar I.R. spectrum, but the band at 8θ4 cm-1 is missing, whereas a new band at 78 cm"1 appears. Both isomers have in the thin layer chromatogram on silica gel with the same eluent a R = cm 6.0 and 7·0 respectively.

The starting material is prepared as follows: the mixture of 100 g of 3-rnethoxyphenol, 70 ml of allyl bromide, 120 g of potassium carbonate and 200 ml of acetone is refluxed for 8 hours while stirring. It is diluted with water and extracted with OO ml of diethyl ether. The extract is washed with $ aqueous sodium hydroxide and water, dried and evaporated, to yield the 3-allyloxy-anisole .

It is taken up in 200 ml of Ν,Ν-dimethylaniline and • the mixture refluxed for 2 hours. After cooling, the mixture is poured onto crushed ice and acidified with hydrochloric acid. It is extracted with diethyl ether, the extract washed with water and shaken with 5 aqueous sodium hydroxide. The aqueous layer is acidified with hydrochloric acid and extracted with diethyl ether. The extract is dried, evaporated and the residue refluxed with 125 ml of acetic anhydride for 2 hours. The mixture is evaporated under reduced pressure, the residue distilled and the fraction boiling at Ι5β-153°/15 mmHg collected, to yield a 2:1 mixture of 3-acetoxy-4-allyl- anisole and >-acetoxy-2-allylanisole .

To the solution of 5 g of a 2:1 mixture of ^-acetoxy- -allylanisole and 3-acetoxy-2-allylanisole in 150 ml of carbon tetrachloride, l g of bromine in 5 ml of carbon tetrachloride are added dropwise during 1 hour while stirring and keeping the temperature below 25°· The mixture is washed with aqueous sodium bicarbonate, dried and evaporated. The residue is taken up in 75 ml of ethanol and to the solution that of l .5 g of sodium methoxide in 0 ml of ethanol is added during 1/2 hour while stirring. The mixture is refluxed for 1 hour, cooled, filtered, and the filtrate concentrated under reduced pressure. The concentrate is diluted with water, extracted with chloroform, the extract dried and evaporated, to yield a 2:1 mixture of the 2-brornornethyl-4- or 6-methoxy-2, 3-dihydrobenr.ofuran, which is'' used as such without further purification.

Example 9 The mixture of 3-1 g of 2-bromomethyl-2-methyl-5- methoxy-2, -dihydrobenzofuran, 2.9 g of l-phenyl-½-oxo-l, 3* 3- triazaspiroC2!, 5)decane, 6 g of sodium carbonate and 50 mi of -methyl-2-pentanone is refluxed for 1 week while stirring. It is cooled, filtered, and the filtrate washed with water and £ hydrochloric acid. The combined aqueous solutions are made basic with ammonia and extracted with chloroform. The extract is dried, evaporated under reduced pressure, and the residue chromatographed on silica gel. The column is eluted with chloro form-diethylamine 9:1> to yield the l-phenyl- -oxo-8- (5-me-thoxy-2-methyl-2, 3-dihydro-2-benzofurylmethyl) -1, , 8-triaza-spiro( , 5) • The starting material is prepared as follows: The mixture of 100 g of -rnethoxyphenol, 73 g of 3-chloro-2-me-thyl-propene, 117 g of potassium carbonate and 200 ml of acetone is refluxed for 12 hours while stirring. After cooling, It. is diluted with water and extracted with diethyl ether. The extract is washed with 5 aqueous sodium hydroxide, dried and evaporated under reduced pressure, to yield the -methallyloxy-anisole.

It is diluted with an equal volume of N, N-dirnethyl-aniline and the mixture refluxed for 6. hours. After cooling, it is poured onto ice and the mixture acidified with hydro- chloric acid. It is extracted with diethyl ether, the extract washed with water, dried and evaporated under reduced pressure The residue is taken up in petroleum ether and the mixture extracted with a solution prepared from 35 S of potassium hydroxide, 25 ml of water and 100 ml of methanol. The aqueous phase is diluted -with water, acidified with hydrochloric acid, extracted with diethyl ether, the extract dried and evaporated to yield the 2-methallyl-4-methoxyphenol. 66 g of 2-methallyl-4-methoxyphenol are added to the solution of 122 g of mercuric chloride in lJOO ml of water, and the mixture stirred at room temperature overnight. It is filtered and the residue recrystallized from ethanol, to yield the 5-methoxy-2-methyl-2,3-dihydro-2-"benzofurylmethyl-mercuric chloride, melting at 70° < To the suspension of 4.5 g thereof in 150 ml carbon tetrachloride, the solution of 5· 75 ml of bromine in 0 ml of carbon tetrachloride is added dropwise while stirring at 0-5°· After 6 hours, the mixture is filtered and the filtrate evaporated, to yield the 2-bromomethyl-2-methyl-5-methoxy-2, 3-dihydrobenzofuran.

Example 1Q The mixture of 15-5 g of 2-bromomethyl-5-methoxy-2,3-dihydrobenzofuran, 10 g of 4-oxo-l,3, 8-triazaspiro(4,5)-decane, 20 g of sodium carbonate and 100 ml of isopropanol is refluxed for J days while stirring. It is cooled, filtered and the filtrate evaporated under reduced pressure. The residue is taken up in methylene chloride and the solution extracted with methane sulfonic acid. The aqueous phase is made basic with ammonia and extracted with chloroform. The extract is dried and evaporated, to yield the 4-oxo-8-(5-methoxy-2,3-dihydro- 2-benzofurylmethyl)-l, 3* 8-triazaspiro(4, 5)decane, shov/ing in the I.R. spectrum bands at 158, 1700, l600 and 1204 cm-1.

The starting material is prepared as follows: To the mixture of 8 g of l-benzyl-4-piperidone, 15-5 g of ammonium acetate and 120 ml of acetic acid, the solution of 14.3 S of potassium cyanide in 40 ml of water is added while stirring at 45°. After stirring for 24 hours at room temperature, the mixture is poured onto 200 g of ice and 2β0 ml of saturated aqueous ammonia. It is extracted with chloroform, the extract dried and evaporated, to yield the 4-amino-l-benzyl-hexa.hydro-isonicotinonitrile .

The mixture of 10 g of 4-amino-l-benzyl-hexahydro-isonicotinonitrile and 100 ml of 8θ?ό sulfuric acid is heated to 70° for 10 minutes while stirring. It is cooled, made basic with ammonia and extracted with chloroform. The extract is dried and evaporated, to yield the 4-amino-l-benzyl-hexahydro-isonicotinamide .

The mixture of 20 g of 4-amino-l-benzyl-hexahydro-is©nicotinamide and 60 ml of formamide is heated to 170° for 12 hours while stirring. After cooling, it is poured into 3OO ml of water and the mixture extracted with. chloroform.

The extract is dried and evaporated, to yield the 8-benzyl-4-oxo-1, 3, 8-triazaspiro(4, 5)decane. g of 8-benzyl-4-oxo-l, 3 8-triazaspiro(4, 5)decane are dissolved in 200 ml of acetic acid and the solution hydrogenated at 55° over 5 g of 10% palladium on chareoal It is filtered, the filtrate evaporated and the residue taken ' up in 0 ml of water. The solution is made basic with ammonia, extracted with chloroform, the extract dried and evaporated, to yield the 4-oxo-l,3,9-triazaspiro(4,5)decane.

Example 11 To the solution of 0.668 g of £-2.- (tosyloxymethyl)- 5-methoxy-2,3-dihydrobenzofuran in ml of dimethylformamide, . Ο. 75 g of l-phenyl-4-oxo-l, 3, 8-triazaspiro(4, )decane and O.I5 g of sodium carbonate are added and the mixture stirred for six hours at 110°. It is cooled, diluted with water and filtered two hours thereafter, the residue dried and recrys-tallized from benzene, to yield the (5-methoxy-2, 3-dihydro-2-benzofurylmethyl)-l, J, 8-triazaspiro- ( ,5)decane melting at 188-1900, f JD = -11.9° (chloroform); it is identical with that obtained according to example 5· The starting material is prepared as follows: To the solution of 0.97 g of d, -5-methoxy-2, 3-dihydro-2-benzo-furancarboxylic acid in 50 ml of diethyl ether, 0.7 g of - -amphetamine are added while stirring. The precipitate formed is filtered off and washed with diethyl ether, to yield the corresponding salt melting at 134-1 2°. It is taken up in.

I25 ml of hot acetone and the solution allowed to cool to room temperature during 2 1/2 hours. The precipitate formed is filtered off, washed with acetone and again dissolved in 60 ml of hot acetone. The precipitate formed after three hours cooling is again filtered off, to yield the corresponding d-salt melting at 153-162°.

All the mother liquors obtained are concentrated to a volume of 60 ml and the solution allowed to cool to room temperature for three hours. The precipitate formed is filtered off and recrystallized once from acetone, to yield the corresponding salt melting at 150- 165 · Both salts obtained are taken up in the minimum amount of 6 hydrochloric acid' and the solution obtained extracted with diethyl ether. The extract is washed with water and saturated aqueous sodium chloride, dried and evaporated, to yield the: (a) d-5-methoxy-2 , 5-dihydro- 2-benzofurancarboxylic acid, [aJD = +57° (chloroform) (b) the ^-antipode thereof, [aj^ = -38° (chloroform).

To the solution of 0 . 68 g of d-5-methoxy-2 , j5-di-hydrb-2-benzofurancarboxylic acid in 25 ml- of tetrahydrofuran, O . I5 g of lithium aluminum hydride is added and the mixture refluxed for one hour. After cooling 0. 15 ml of water, O.J ml of 12 aqueous sodium hydroxide and 0.45 ml of water are added,- the mixture filtered and the filtrate evaporated under reduced pressure. The residue is taken up in benzene, the solution filtered and the filtrate evaporated under reduced pressure, to yield the 2-hydroxymethyl- 5-methoxy- 2 , -di-hydrobenzofuran, [oc]-^ = - 9° (chloroform).

Analogously, the id is reduced to yield the corresponding d-alcohol, [aJ-^ - + 5° (chloroform).

To the solution of 0 . 5 g of > -2-hydroxymethyl-5-methoxy- 2, -dihydrobenzo uran in 5 ml of pyridine, 0 . 75 g of p-toluenesulfonyl chloride are added and the mixture stirred overnight at room temperature. Thereupon ml of water are added and the mixture stirred for 10 minutes. It is further diluted with water, extracted with benzene, the extract washed with 5N hydrochloric acid, water and saturated aqueous sodium chloride, dried, evaporated under reduced pressure and the residue triturated with diethyl ether, to yield the -Z-2- (tosyl- oxymethyl)-5-methoxy-2, 3-dihydrobenzofuran melting at 80-31°.

Example 12 The mixture of 1J>.2 g of 2-bromomethyl-5-methoxy- 2, -dihydrobenzofuran, 10 g of 3-methyl-2, 4-dioxo-l, 3, 8-tri-azaspiro(4,5)decane, 20 g of sodium carbonate and 200 ml of isopropanol is refluxed for three days while stirring. It is filtered hot, the filtrate evaporated and the residue taken up in methylene chloride. The solution is shaken with 5 methanesulfonic acid, the aqueous phase made basic with ammonia and extracted with chloroform. The extract is dried and evaporated, to yield the j5-methyl-2, 4-dioxo-8- (5-methoxy-2, dihydro-2-benzofurylmethyl)-l, 8-triazaspiro(4, 5)decane, which melts at l8 l87°.

The starting material is prepared as follows: The solution of 20 g of 8-benzyl-^-methyl-2, -dioxo-l, >, 8-tri-azaspiro(4,5)decane [II Pharmaco, 25, 68l (1970)] in 200 ml of 9 aqueous acetic acid is hydrogenated over 5 g of 10% palladium on charcoal at 55°* until the theoretical amount of hydrogen has been absorbed. It is filtered, the filtrate concentrated, the concentrate diluted with water and made basic with ammonia. The mixture is extracted with chloroform, the extract dried and evaporated, to yield the 3-methyl-2, 4- dioxo-1, , 8-triazaspiro(4, 5)decane .

Example 13 .Preparation of 10,000 tablets each containing 1.0 mg of the active ingredient: Formula : l-phenyl-4-oxo-8- (5-methoxy-2,3-dihydro-2-benzofurylmethyl)-l,5~, 8-triazaspiro (4, )decane 10.00 g Lactose 828.00 Corn starch 50.00 g Polyethylene glycol 6,000 50.00 g Talcum powder 50.00 g Magnesium stearate 12.00 g Purified water q.s.

Procedure : All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance, lactose, talcum, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in ml of water and the suspension added to the boiling solution of the polyethylene glycol in 100 ml of water. The paste formed is added to the powders which are granulated, if necessary, with an additional amount of water. The granulate is dried overnight at 35°* broken on a screen with 1.2 mm openings and compressed into tablets using flat punches with Example 14 Preparation of 10, 000 tablets each containing 25.0 mg of the active ingredient: Formula : ^-l-phenyl-4-oxo-8- (5-methoxy-2, -dihydro- 2-benzofurylmet yl)-l, 5j 8-triazaspiro- (4, 5)decane methanesulfonate hemihydrate 250. 00 g Lactose 1, 956. 00 g Corn starch 90.00 g Polyethylene glycol 6, 000 90.00 g Talcum powder 90.00 g Magnesium stearate 24.00 g Purified water q. s .

Procedure : All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance, lactose, talcum, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half, of the starch is suspended in 5 ml of water and the suspension added to the boiling solution of the polyethylene glycol in l80 ml of water. The paste formed is added to the powders which are granulated, if necessary, with an additional amount of water. The granulate is dried overnight at 35°> broken on a screen with 1.2 mm openings and compressed into tablets using concave punches with 7. 1 mm diameter, uppers bisected.

Example 15- The solution of 5 g of 2-bromomethyl-5-acetyl-2, 3-dihydrobenzofuran in 40 ml of 4-methyl-2-pentanone is added dropwise to the mixture of .5 g of l-phenyl-4-oxo-l, 3, 8-triazaspiro(4, 5)decane, 7.4 g of sodium carbonate, 1 crystal o potassium iodide and 200 ml of 4-methyl-2-pentanone while stirring. The mixture is refluxed days, cooled and filtered. The precipitate is washed with 4-methyl-2-pentanone and water, the filtrate extracted with 5 hydrochloric acid and the aqueous solution made basic with ammonia. It is extracted with chloroform, the extract washed with water, dried, evaporated' and the residue recrystallized from acetone, to yield the l-phenyl-4-oxo-8- (5-acetyl-2, 3-dihydro-2-benzofurylme- hyl)-l,3,8-triazaspiro(4, )decane, melting at 166-168°. · The starting material is prepared as follows: The mixture of 50 g of 4-hydroxyacetophenone, 44.5 g of allyl-bromide, 1· 5 g of potassium carbonate and 80 ml of acetone is refluxed for 8 hours while stirring. After standing overnight at room temperature, it is diluted with 500 ml of water and extracted with diethyl ether. The extract is washed with water, dried, evaporated, the residue distilled and the fraction boiling at 110-115°/0.7 mmHg collected, to yield the 4-allyloxyacetophenone . 57 g thereof are heated under nitrogen to 230° for 90 minutes, cooled and diluted with 80 ml of aceti anhydride. The mixture is refluxed for 3 hours, evaporated, the residue distilled and the fraction boiling at 122-12.3°/ 0.2 mmHg collected, to yield the 4-acetyl-3-al3-ylacetophenone .

To the solution of 52.5 S of -acetyl- -allylaeeto- phenone in l80 ml of carbon disulfide, 38 g of bromine are added dropwise during J hours while stirring at -5 to 0°, and the mixture evaporated under reduced pressure, to yield the l,2-dibromo-3-(2-acetoxy-5-acetylphenyl)-propane.

To the mixture of 100 g of 1, 2-dibromo-^- (2-acetoxy-5-acetylphenyl) -propane and 250 ml of diethyl ether, the solution of 0 g of sodium methoxide in 500 ml of diethyl ether is slowly added while stirring and the mixture refluxed for 2 hours. It is cooled, filtered and the filtrate evaporated under reduced pressure. The residue is taken up in water, the mixture extracted with methylene chloride, the extract washed with water, dried, evaporated, the residue distilled and the fraction boiling at 155-157°/0.07 mmHg collected, to yield the 2-bromomethyl-5-acetyl-2, 3-dihydrobenzof ran.

Example l6 To the solution of 1.8 g of l-phenyl-4-oxo-8- (5-acetyl-2, 3-dihydro-2-benzofurylmethyl)-l, 3, 8-triazaspiro (½, 5)-decane in 500 rnl of ethanoi, 0. g of sodium borohydride are added portionwise while stirring at 50°C. The mixture is slowly evaporated under reduced pressure, the residue triturated with water, filtered, washed with water and recrystalli-zed from ethanoi, to yield the l-phenyl- -oxo-8- [5- (l-hydroxy-ethyl)-2, 3-dihydro-2-benzofurylmethyl] -1, 3, S-triazaspiro^, 5)-decane of the formula melting at 196-200°.

Example 17 .

Preparation of 10,000 capsules each containing 10 mg of the active ingredient: Formula : l-phenyl-4-oxo-8- [5- (1-hydroxyethyl)-. 2, 3-dihydro-2-benzofurylmethylJ -1, 8-triazaspiro( ,5)decane 100.0 g Lactose 1,800.0 g Talcum powder 100.0 g Procedure : All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance is placed in a suitable mixer and mixed first with the talcum, then with the lactose until homogenous. No. 3 capsules are filled with 200 mg, using a capsule filling machine.

• . Example 18 The mixture of 1.97 g of ^- - (d-10-camphorsulfonyloxy-methyl)-5-methoxy-2,3-dihydrobenzofuran, 20 ml of dimethyl-formamide, 1.15 g of l-phenyl- -oxo-l,5~, 8-triazaspiro( , )-decane, 1.37 g of potassium carbonate and 3 crystals of potassium iodide is refluxed for 15 minutes while stirring. It is eva orated under reduced ressure, the residue is taken up in 100 ml of chloroform, the mixture washed twice with 50 ml of water, dried and evaporated. The residue is recrys- tallized from 25 ml of hot ethanol, and the precipitate formed after cooling is washed with 10 ml of cold ethanol, to yield the ^l-phenyl-4-oxo-8- (5-methoxy-2, 3-dihydro-2- benzofurylmethyl)-l, 3, 8-triazaspiro(4, 5)decane, . melting at 188-190°; it is identical with that obtained according to examples 5 or 11.

The starting material is prepared as follows: To the solution of 206.5 S of d, ^-2-bromomethyl-5-methoxy-2, 3-di- hydrobenzofuran and 105 g of benzoic acid in 300 ml of dimethylformamide, the suspension of 138.2 g of potassium carbonate in 500 ml of dimethylformamide is added during 14 minutes while stirring. After 12 minutes, the mixture is cooled, filtered and the residue washed twice with 100 ml of dimethylformamide . The filtrate is concentrated, 500 g of ice are added, whereupon crystallization occurs. The precipitate formed is filtered off, washed with water, taken up in 2000 ml of diethyl ether, the solution washed with 100 ml each of water, aqueous sodium bicarbonate and water, dried and evaporated. The residue is recrystallized from SOO.rnl of isopropanol and washed with 400 ml ice cold isopropanol, to yield the d, -2-benzoyloxymethyl-5-methoxy-2, 3-dihydrobenzo-: furan, melting at 67-68° . 1 0 g of d, ^-2-benzoyloxymethyl-5-methoxy-2, 3-dihydro- benzofuran are added to the solution of .8 g of potassium hydroxide in ^ ml of anhydrous ethanol and the mixture is water are added to keep it homogeneous. It is evaporated under reduced pressure, the residue taken up in 200 ml of water, the mixture concentrated under reduced pressure and the concentrate extracted times with 300 ml of diethyl ether. The extract is dried, evaporated, the residue distilled and the fraction boiling at 108-110°/0.1 mmHg collected, to yield the d, -2-hydroxymethyI-5-rcethoxy-2,3-dihydrobenzo-furan, melting at 2- °.

To the solution of 39.08 g of d, -2-hydroxymethyl-5-methoxy-2, 3-dihydrobenzofuran in 350 ml of pyridine, 56.13 g of .d-10-camphorsulfonylchloride are added during 15 minutes while stirring and keeping the temperature between 18 and 20°. The mixture is allowed. to stand overnight at room temperature and is evaporated under reduced pressure. The residue is distributed between 60.0 ml of methylene chloride and I37O ml of h ice cold hydrochloric acid. The organic phase is separated, washed with water, dried, filtered and evaporated. The residue is recrystallized from 875 ml of methanol and washed twice with 125 ml of methanol. It is again recrystallized from 600 ml boiling methanol, the precipitate formed at room temperature filtered off and washed twice with 125 nil of methanol, to yield the C-2.- (d-10-camphorsulfonyloxymethyl)-5-methoxy-2, 3-dihydrobenzofuran, melting at 111-112°, [α]ρ = -20.5° (chloroform).

Example ,.19' The mixture of 5 g of 2-bromomethyl-3-methyl-5-methoxy-2 , 3-dihydrobenzofuran, 4.5 g of l-phenyl-4-oxo-l , 3, 8-triazaspiro- (4,5)decane, 8 g of anhydrous sodium carbonate, 0.1 g sodium iodide and 100 ml of 4-methyl-2-pentanone is refluxed for three days while stirred. It is filtered hot, the residue washed with acetone and the comined filtrate evaporated under reduced pressure. The residue is dissolved in 200 ml of diethyl ether and the solution extracted with 200 ml of N-hydrochloric acid. The extract is cooled and the precipitate formed collected, to yield the 1-phenyl-4-OXO-8- (3-methyl-5-methoxy-2 , 3-dihydro-2-benzofurylmethyl) -1,3,8-triazaspiro (4, 5)decane melting at 295°.

It is suspende'd in 100 ml of methylene chloride and the suspension shaken with aqueous ammonia until the solid phase disappears. The organic solution is separated, evaporated under reduced pressure and the residue recrystallized from ethanol, to yield the corresponding free base melting at 200-205°.

The starting material is prepared as follows: The mixture of 92 g of 4-methoxyphenol , 100 g of crotyl bromide, 100 g of potassium carbonate and 300 ml of acetone is refluxed for six hours while stirring.

It is filtered, the residue washed with acetone and the combined filtrate evaporated under reduced pressure. The residue is taken up in diethyl ether, the solution washed with N-aqueous sodium hydroxide and water, dried and evaporated to yield the 4-crotyloxyanisole.

The 4-crot lox -anisole obtained is taken up in 300 ml After cooling, it is poured into 3 -hydrochloric acid and the ^ mixture extracted with diethyl ether. The extract is washed with water, dried and evaporated; the residue is taken up in petroleum ether and the mixture extracted with a solution prepared from g of potassium hydroxide, 25 ml of water and 100 ml of methanol. The aqueous phase is diluted with water, acidified with hydrochloric acid, extracted with diethyl ether, the extract dried and evaporated, to yield the 2 - (2-but-3-enyl) -4-methoxyphenol.

The mixture of 130 g of 2 - (2 -but -3-enyl) -4-methoxyphenol and 220 ml of acetic anhydride is refluxed for three hours and evaporated under reduced pressure, to yield the corresponding phenol-acetate.

The solution of 30. 2 g thereof in 80 ml of carbon tetrachloride, the solution of 22. 2 g of bromine in 80 ml of carbon tetrachloride is added dropwise while stirring at 25° . After two hours the mixture is washed with aqueous sodium bicarbonate, dried and evaporated, to yield the 4-acetoxy-3- (3, -dibromo-2 -butyl) -anisole.

The 4-acetoxy-3- (3 , 4-dibromo-2-butyl) -anisole is dissolved, in 75 ml of ethanol and the solution combined with that of 7. 6 g of sodium methoxide in 180 ml of ethanol. After stirring for two hours at room temperature the mixture is filtered and the filtrate concentrated under reduced pressure. The concentrate is diluted with water and extracted with diethyl ether. The extract is dried, evaporated, the residue distilled and the fraction boiling at 115-118° /0. 1 mm Hg collected, to yield the 2-bromomethyl-3 -methyl-5-methoxy-2 , 3-dihydrobenzofuran.

Claims (48)

38439-2 What we claim is:

1. An 8-(2,3-dihydro-2-benzofurylmethyl) triazaspiro(4,5)decane of the general formula I in which R-^ i-s hydrogen, lower alkoxy, halo, lower a-hydrox alkyl or lower alkanoyl, each of R0, R„ and R represents £. 3 0 hydrogen or lower alkyl, R^ is hydrogen, cyclohexyl or phenyl, and R^ represents two hydrogen atoms or oxo.

2. A compound of the formula I shown in claim I, in which R^ is hydrogen, lower alkoxy or halo, each of R2> R^ and R^ represents hydrogen or lower alkyl, is cyclohexyl or phenyl, and R^ represents two hydrogen atoms.

3. A compound of the formula I shown in claim 1, in which R^ is hydrogen, lower alkoxy, halo or lower alkanoyl, each of R > R^ and R^ represents hydrogen or lower alkyl, R^ is hydrogen, cyclohexyl or phenyl, and R^ represents two hydrogen atoms or oxo.

4. A compound of the formula I shown in claim 1, in which R^ is hydrogen, lower alkoxy or halo, each of ^ aVi& ^ is hydrogen or methyl, R^ is cyclohexyl or phenyl, R^ is hydrogen or methyl and R,- represents tx^o hydrogen atoms.

5. A compound of the formula I shown in claim 1, in which R^ is hydrogen, methoxy, fluoro, chloro, 1-hydroxy- ethyl or acetyl, each of R2> and is hydrogen or methyl, R^ is phenyl, and represents two hydrogen atoms.

6. A compound of the formula I shown in claim 1, in which R^ is hydrogen, methoxy, fluoro or chloro, each of R£> R^ and R^ is hydrogen, R^ is phenyl and R<. represents two hydrogen atoms.

7. l-Phenyl-4-oxo-8-(5-methoxy-2 , 3-dihydro-2-benzo-furylmethyl) -1,3, 8-triazaspiro (4, 5) decane.

8. 1-Phenyl -4-oxo-8-(2, 3-dihydro-2-benzofuryl-methyl) - I, 3, 8-triazaspiro (4, 5) decane,

9. l-Phenyl-4-oxo-8-(5-fluoro-2, 3-dihydro-2-benzo-furylmethyl) -1, 3, 8-triazaspiro(4, 5) decane.

10. l-Cyclohexyl-4-oxo-8-(5-methoxy-2, 3-dihydro-2-benzofurylmethyl) -1, 3, 8-triazaspiro(4, 5) decane.

11. II.. ' l-Phenyl-4-oxo-8-(7-methoxy-2, 3-dihydro-2-benzo-furylmethyl) -1, 3, 8-triazaspiro(4,-5) decane.

12. l-Phenyl-4-oxo-8-(4-methoxy-2, 3-dihydro-2-benzo-furylmeth l) -1, 3, 8-triazaspiro(4, 5) decane.

13. l-Phenyl-4-oxo-8-(6-methoxy-2, 3-dihydro-2-benzo-furylmethyl) -1, 3, 8- riazaspiro(4, 5) decane.

14. l-Phenyl-4-oxo-8-(5-methoxy-2-methyl-2, 3-dihydro-2-benzofurylmethyl) -1, 3, 8-triazaspiro(4, 5) decane.

15. 4-Oxo-8-(5-methoxy-2, 3-dihydro-2-benzofurylmethyl) -1, 3, 8-triazaspiro(4, 5) decane.

16. l-Phenyl-4-oxo-8-(5-acetyl-2, 3-dihydro-2-benzofuryl- 38439-2

17. r 3-Methyl-2,4-dioxo-8-(5-methoxy-2,3-dihydro-2-benzo-furylmethyl) -1, 3, 8- triazaspiro(4, 5) decane.

18. l-Phenyl-4-oxo-8-[5-(l-hydroxyethyl) -2, 3-dihydro-2-benzofurylmethyl] -l,3,8-triazaspiro(4,5)decane.

19. A compound as claimed in any one of claims 2, 4 and^ 1 i 6 . to 10, in the optically levorotatory form. u

20. . A compound as claimed in any one of claims 3 ' and li to 17, in the optically levorotatory form.

21. A compound as claimed in any one of claims 1, 5 and 18, in the optically levorotatory form.

22. A compound as claimed in any one of claims 2, 4, 6 to 10 and 19 in the form of an acid addition salt.

23. A compound as claimed in any one of claims 2, 4, 6 to 10 and 19 in the form of a therapeutically acceptable acid addition salt.

24. A compound as claimed in any one of claims 3, 11 to 17 and 20 in the form of an acid addtition salt.

25. A compound as claimed in any one of claims 3, 11 to 17 and 20 in the form of a therapeutically acceptable acid addition salt.

26. A compound as claimed in any one of claims 1, 5, 18 and 21 in the form of an acid addition salt.

27. A compound as claimed in any one of claims 1, 5, 18 and 21 in the form of a therapeutically acceptable acid addition salt.

28. A pharmaceutical preparation containing a compound

29. A pharmaceutical preparation containing a compoLvwcr claimed in any one of claims 3, 11 to 17, 20 and 25.

30. A pharmaceutical preparation containing a compound claimed in any one of claims 1, 5, 18, 21 and 27.

31. A new compound claimed in claim 2 and described in any one of Examples 1 to 4.

32. A new compound claimed in claim 3 and described in any one of Examples 5 to 12 and 15.

33. A new compound claimed in claim 1 and described in any one of Examples 16 and 18.

34. Process for the manufacture of new 8- (2 , 3-dihydro-2-benzofurylmethyl) -1 , 3, 8-triazaspiro(4, 5) decanes of the general formula I — - in which is hydrogen, lower alkoxy, halo, lower a-hydroxy- alkyl or lower alkanoyl, each of R2, R^ and R, represents hydrogen or lower alkyl, R^ is hydrogen, cyclohexyl or phenyl, and R,. represents two hydrogen atoms or oxo. or salts thereof, which consists in condensing compounds of the general formulae II and III in which X is a reactive esterified hydroxy group, and, if desired, reducing a resulting compound having a lower alkanoyl substituent in the 1 , 2-phenylene radical to the corresponding (a-hydroxy-lower alkyl) -1 , 2-phenylene compound with sodium borohydride, and/or, if desired, converting a resulting compound into a salt,and/or, if desired, converting a resulting salt into the free compound, and/or, if desired, resolving a mixture of isomers or racemates obtained into the single isomers or racemates, and/or, if desired, resolving a racemate obtained into the optical antipodes.

35. A process as claimed in claim 34, wherein X is a hydroxy group esterified with a hydrohalic acid, sulfuric acid, methane-, ethane-, benzene-, p-toluene sulfonic or camphorsulfonic acid.

36. A process as claimed in either of claims 34 and 35, wherein the reaction is carried out in the presence of an alkali or alkaline earth metal carbonate, hydroxide or lower alkoxide or of an aliphatic tertiary amine.

37. Process for the manufacture of new 8- (2 , 3-dihydro-benzofurylmethyl) -1,3, 8-triazaspiro(4, ) decanes of the general formula I shown in claim 34, in which formula the symbols R^ to R, have the meanings given in claim 2, or salts thereof, o which consists in condensing compounds of the general formulae reactive esterified hydroxy group, and, if desired, conve !.^ a resulting compound into a salt, and/or, if desired, converting a resulting salt into the free compound, and/or, if desired, resolving a mixture of isomers obtained into the single isomers, and/or, if desired, resolving a racemate obtained into the optical antipodes.

38. -A process as claimed in claim 37, wherein X is a hydroxy group esterified with a hydrohalic acid, sulfuric acid, methane-, ethane-, benzene- or p-toluene sulfonic acid.

39. process as claimed in either of claims 37 and 38> wherein the reaction is carried out in the presence of an alkali or alkaline earth metal carbonate, hydroxide or lower alkoxide or of an aliphatic tertiary amine.

40. Process for the manufacture of new 8- (2 , 3-dihydro- benzofurylmethyl)-l,3,8-triazaspiro(4,5)decanes of the general formula I shown in claim 34, in which formula the symbols to have the meanings given in claim 3, or salts thereof, which consists in condensing compounds of the general formulae II and III shown in claim 34, in which formulae the symbols to have the meanings given in claim 3, and X is a reactive esterified hydroxy group, and/ or, if desired, converting a resulting compound into a salt, and/or, if desired, converting a resulting salt into the free compound, and/or, if desired, resolving a mixture of isomers or racemates obtained into the single isomers or racemates, and/or, if desired, resolving a racemate obtained into the optical antipodes.

41. A process as claimed in claim 40, wherein X is a acid, methane-, ethane-, benzene- or p-toluene sulfonic ~* acid.

42. process as claimed in either of claims 40 and 41, wherein the reaction is carried out in the presence of an alkali or alkaline earth metal carbonate, hydroxide or lower alkoxide or of an aliphatic thertiary amine.

43. _ The process described in any one of Examples 1 to 4 herein.

44. The process described in any one of Examples 5 to 12 and 15 herein.

45. " The process described in any one of Examples 16 and 18 herein.

46. A compound whenever obtained by the process claimed in any one of claims 37 to 39 and 43.

47. A compound whenever obtained by the process claimed in any one of claims 40 to 42 and 44.

48. A compound whenever obtained by the process claimed in any one of claims 34 to 36 and 45.