FI65249C - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ANALYTICAL PRODUCTS 1-ENYL-8-BENZIMIDAZOLE-1-YLPROPYL-1,3,8-TRIAZASPIRO (4,5) DEKA N - ONDERIVAT - Google Patents

Description

65249

Process for the preparation of therapeutically useful 1-phenyl-8-benzimidazol-1-ylpropyl-1,3,3-triazaspiro [4,5] decan-4-one derivatives By partitioned from application 762 086 -

Patent No: 62667

The invention relates to a process for the preparation of novel 1-phenyl-8-benzimidazol-1-ylpropyl-1,3,8-triazaspiro [1,5] decan-10 4-one derivatives and their pharmaceutically acceptable acid addition salts. The formula for the new compounds is K x 20 * Wr6 1 2

wherein R and R represent hydrogen, halogen, C 1-4 alkyl or trifluoromethyl, B is divalent radio-O

C 1 -C 6 -CH- or -NL-C-, wherein L is hydrogen, C 1-4 alkyl or C 2-5 alkenyl and the divalent radical is attached to the benzene ring via a heteroatom, R 1 is hydrogen or C 1-6 alkyl and R 1 and R 2 represent hydrogen, halogen, C 1-6 alkyl or trifluoromethyl. These compounds have an antiemetic effect.

Compounds of formula I and their acid addition salts may be prepared by reacting a compound of formula 2 65249 Β N-CH2-CH2-CH2-X (II) 5 R1 ^ = ^ R2 1 2 wherein R, R and B are as defined above. and X is a reactive ester group derived from the corresponding alcohol to react with a compound of formula ---- V yA-N-R4

v_XJ

Λ

20 R

wherein R 4, R 2 and R 2 are as defined above, in a suitable organic solvent; and optionally converting the resulting compound of formula I to a pharmaceutically acceptable acid addition salt.

Several benzazolylalkyl- and indolylalkyl-substituted piperidine derivatives and several aminoalkyl-substituted benzazoles are known, some of which have pharmacological, e.g. antidepressant, anticonvulsant, antihistamine or antispasmodic activity.

The compounds of the formula I differ from these known compounds e.g. chemical structure. The above-mentioned known compounds have been described e.g. in the following publications; 35 3 65249

Int. Pharmacopsychiat. 1968 (1), pp. 214; C.A., 64, 2093 b (1966); C.A., 72, 111466 (1970); C.A., 81, 120632 b (1974); 5 FR Patent Publication 2,042,321 (Derw.Fr.Week S16,

Pharm. p. 12); and BE Patent 753,472.

The term "C 1-6 alkyl" means a straight or branched chain alkyl having 1 to 5 carbon atoms, such as 10 methyl, ethyl, propyl, 1-methylethyl, butyl or pentyl. "C 2-6 alkenyl" means a straight or branched chain an alkenyl radical having 2 to 5 carbon atoms, such as 1-methylethenyl, 2-propenyl, 2-butenyl, 3-butenyl or 2-pentenyl, and "halogen" means halogen having an atomic weight of less than 127, i.e. . fluorine, chlorine, bromine and iodine.

The condensation reaction to prepare compounds of formula I is preferably carried out in a suitable organic solvent such as a lower alkanol, e.g. methanol, ethanol, propanol or butanol, or an aromatic hydrocarbon, e.g. benzene, methylbenzene or dimethylbenzene, or ketone, e.g. In 4-methyl-2-pentanone or ether, e.g. 1,4-dioxane or 1,1'-oxybisethane, or Ν, Ν-dimethylformamide or nitrobenzene. A suitable base such as an alkali metal or alkaline earth metal carbonate or bicarbonate may be added to scavenge the acid liberated during the reaction. A small amount of metal iodide, e.g. sodium or potassium iodide, may be added to initiate the reaction, especially when the reactive ester of formula (II) is chloride. Somewhat elevated temperatures are appropriate to improve the reaction rate, and the reaction is preferably carried out at the reflux temperature of the reaction mixture. The reaction products are separated from the medium and, if necessary, purified in a manner known per se.

4 65249

Reactive esters of formula (II) wherein B is -NH-CO- (L = H) or -N = CH- can be prepared by reacting an appropriately substituted 2-chloronitrobenzene of formula (VIII) with the appropriate aminoalkanol (IX). by heating the reaction components under reflux in an inert organic solvent such as a lower alkanol, e.g. ethanol, 2-propanol or butanol, followed by reduction of the resulting N - (2-nitrophenyl) amino-C7-10 alkanol of formula X to convert the nitro group to an amino group, e.g. The (12-aminophenyl) amino (alkanyl) alkanol of formula XI thus obtained is then reacted with a suitable cyclizing agent and the alcohol of formula XII thus obtained is then converted into the desired reactive ester of formula II-a in a manner known per se.

The halides are conveniently prepared by reacting a compound of formula XII with a suitable halogenating agent such as, for example, sulfinyl chloride, sulfuryl chloride, phosphorus pentachloride, phosphorus pentabromide or phosphoryl chloride. When the reactive ester is iodide, it is preferably obtained from chloride or bromine, respectively, by replacing this halogen with iodine. Other reactive esters such as methanesulfonates and 4-methylbenzenesulfonates are obtained by reacting the alcohol with a suitable sulfonyl halide such as methanesulfonyl chloride and 4-methylbenzenesulfonyl chloride.

The above reactions can be described by the following reaction scheme: o2n Cl V. \ + H2N-CH2-CH2-CH2-OH -> 35 R1 r2 (IX) (VIII) 1; 5 65249

0oN NH-CHo-CH_-CHo-OH

^ \ / Δ Z Z

ζ \ H2 / RaNi R1 p2 5 (X)

H2N NH-CH2-CH2-CH2-OH

Ring Closure 10 -> ΪΤ R2 (XI) Isli-CH, -CH, -CH, -OH Reactive Barrier Formation {A (II-Al)

R1X2R2 RR (XII) compounds of the formula II in which B is -N (L) -CO- (L = H) 2 O or -N = CH- can be prepared by coupling a reactive ester side chain in a manner known per se to a compound of the formula is

B

rK == ^ r \ 2

R R

(XIII) For example, a hydroxyalkyl chain can be attached by N-alkylating a compound (XIII) with a haloalkanol of formula (XIV) to give an alcohol of formula (XV), the hydroxyl group of which is then converted to a reactive ester group in a manner known per se. Instead of the halo-35 alcohol of formula (XIV), its tetrahydro-2H-pyran-2-yl ether derivative can also be used to give the corresponding ether derivative, the ether group of which is opened by acidic hydrolysis, e.g. by stirring and heating the ether compound in dilute hydrochloric acid.

When the reactive ester of formula ΙΙ-b is a halide, (II-b-1), it may alternatively be prepared by reacting a compound of formula XIII with an equivalent of a suitable dihaloalkane of formula XVI in the presence of a strong base such as sodium methanolate or following the Mackosza method. using an aqueous alkali and quaternary ammonium catalyst, e.g. Ν, Ν, Ν-10 triethylbenzenemethanamine ammonium chloride.

The above process can be described as follows: N-alkylation (XIII) + halo-CH 2 -CH 2 -CH 2 -OH - (XIV) 15 s - "v formation of reactive barrier B - N-CH 2 -CH 2 -CH 2 -OH (/ S <XV) r1A = Z-r2 (XIII) ♦ hal-CH2 -CH., - CH, - hal base 2 2 2 -> · 25 z '- \ B N-CH0-CHo-CHo-hal

B

R1 '^ == S3'nr2 (II-b-1) starting materials of formula II wherein B is -NH-CO- (L = H) can be prepared by attaching a reactive ester side chain to a compound of formula I.

7 65249 Λ Ρ-Ν ΝΗ R1 R2 wherein Ρ is a protecting group, and thereafter deprotecting the compound of formula XIV thus obtained in a manner known per se. The coupling of the reactive ester side chain can be performed in the same manner as described above for the coupling of the side chain to the starting materials of formula (XIII). For example, a hydroxyalkyl chain may be first attached, after which the hydroxyl group of the intermediate of formula XVIII thus obtained is converted to a reactive ester group to give a compound of formula XIV, or when the reactive ester is a halide of formula XIV-a, said halide may be obtained directly by administering a compound of formula XVII. 20 react with a dihaloalkane. When the protecting group P is to be subjected to alkaline hydrolysis, e.g. being lower alkylxycarbonyl, methanesulphonyl or 4-methylbenzenesulphonyl, the N-alkylation reaction to attach the corresponding hydroxyalkyl or haloalkyl chain to a suitable sodium hydroxide is carried out under suitable conditions, e.g. in an organic solvent such as N, N-dimethylformamide, Ν, Ν-dimethylacetamide or hexamethylphosphoric triamide. The reactions described above can be represented by the following reaction scheme: 8 65249 o N-alkyl 11

(XVII) + (XIV),. Ρ-ΓΓ ^ N-CH 2 -CH 2 -CH 2 -OH

-> \ / 2 2 2 r1 ^ = As, r2 (XVIII) + (XVI) formation of reactive ester j l

Ρ-ΪΓ TJ-CH2-CH2-CH2-hal P-N ^ N> I-CH2-CH2-CH2-X

r1 ^ r2 r '^^ r2 (XIX-a) (XIX) Removal of P Removal of P 0 / c \ HN N-CH0 ~ CH0-CH2-hal (II-c)

M

1 ^ x 2

R R

(II-c-1) i 9 65249 starting materials of formula II wherein B is -N (L) -CO- wherein L is C 1-6 alkyl or C 2-5 alkenyl in which the unsaturation is N, S or position can be prepared as follows.

The compound of formula (II-c) is treated with sodium metal in absolute ethanol to form a cyclic ether of formula (XX). It is then reacted with a reactive ester LX of formula XXI, e.g. by heating the reaction components under reflux in an organic solvent such as 2-propanone to give the desired intermediate (II-d).

15 -CH -CH X Jg -> ΎΥ ΤΙ r2 r (II-c) (XX) 20 -—-> (II-d) (XXI) 25 The starting materials of formula (III) can be prepared as described in U.S. Patent 3,238,216. way.

The compounds of formula (I) may be converted into therapeutically useful acid addition salts by treatment with a suitable acid such as an inorganic acid, e.g. a hydrohalic acid such as hydrochloric, hydrobromic or the like acid; or sulfuric acid, nitric acid, phosphoric acid or the like? or an organic acid such as acetic, propanone, hydroxyacetic, 2-hydroxypropanone, 2-oxopropanone, propanedione, butane-35-dione, (Z) -2-butenedione, (E) -2- butenedione, 2-hydroxy-butanedione, 2,3-dihydroxybutanedione, 2-hydroxy-1,2,3-propanetricarbon, benzo, 3-phenyl-2-propenone, N-hydroxybenzeneacetic , methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexane-sulfamine, 2-hydroxybenzoic-4-amino-2-hydroxybenzoic or the like acid The salt form may also be converted into the free base form by treatment with the free base form.

The compounds of formula (I) and their therapeutically active acid addition salts have a potent antiemetic (antiemetic) effect, as demonstrated by their ability to inhibit apomorphine-induced emesis in dogs. The research method used has been previously described by P.A.J. Janssen and C.J.E. Niemegreers in Arzneim. Forsch. (Drug Res.), 9, 765-767 (1959).

The compounds were administered subcutaneously to beagle dogs at various doses and the animals were administered a standard dose of 0.31 mg / kg (subcutaneously) apomor-15in 1 hour thereafter. In addition, an antidopamine experiment was performed in rats using the method described in Arch.Int.Pharm. Ther., 227, 238 (1977). The values obtained in the experiment indicate the intensity of the effect on the central nervous system.

The results obtained in the anti-apomorphine and antidopamine experiments (ED50 apo dog and ED ^ q apo rat) are shown in Tables I-a and I-b. Table II shows the corresponding values for some known compounds. The results show that the compounds of formula I have a much more specific antiemetic effect than the known compounds.

25 TABLE I-a p4

30 L-N N-CH0-CH0-CH - N Y

w 2 2 2 w \ J

No,

35 R

11 65249 1 4 5 Ε ° 50 Ε ° 50 L R R R apo-dog apo-rat _____mgAg s.c. Rog / kg HHHH 0.03> 40 H 5 -Cl HH 0.05> 40 H 5 "CH 3 hh 0.06> 40 CH 3 HHH 0.08 10 'CH 2 = CH-CH 2 HHH 0.25> 10 HHH 4- F 0.04> 40 H 5-Cl H 4-F 0.015> 10 HHH 3-CF 3 0.025> 10 HH CH 3 H 0.015 10 TABLE Ib

Compound H> 5q mgAg s.c. <T> 50 mgAg apo-dog apo-rat 0 H- (CH2) 3-N Y 0.25> 10 N— N— ό ----- - τ ~.

12 65249

TABLE II

I p5 ^ ED50

Compound jul- mg / kg 50 mgAg release apo-dog apo-rat ___ o _

, / T ^ \ 11 / \ / NH FI

F-γ \) - C-CH -CH.-CHY

\ - / 2 2 2 N Λν_Ι 46967 0.00026 0.016

SPIPERONE JL

o Q v

/ \ / \ / —NH FI

S N-CH -CH -CH, -N Y

Ö2 2 2 \ / \ N 53820 <2.5 0.04 ό q r

) \ / - \ $ —NH FI

s 53020 1 f25 0 25 3 ό CF3 o

/ \ / - \ f ~ NH FI

\ _ ^ N_CH2 "CH2" CH2 ~ N \ _ / (HC1 53820 0.31 $ 0.08 0

Cl / r \ \ - / 0

/ \ / - \ / NH FI

S \ __ I 53 820 1, 25 0.30

Q ό f I

TABLE II

65249 ED50 ED50

Compound μl mg / kg 50 mg / kg I guess apo-dog apo rat \ __ / 0

/ \ / - \] h ~ NH FI

S) »CH-CH, -CH -N X I HCl \ _ / 2 2 \ _Λν — 1 53820 0.63 0.63 Ö o

§ / \ f — NH FI

CH-CH2-CH2-N \ _Xn_ 53820 2.5 0.015 «i

rv nrp FI

53820 10 0.015

® 6 [I I

- Π 14 65249

The compounds of formula I may be formulated into various pharmaceutical forms for administration. To prepare the pharmaceutical compositions, an antiemetic effective amount of the compound, in the form of either a base or acid addition salt, is combined with a pharmaceutically acceptable carrier, the choice of which depends on the formulation desired for administration. These pharmaceutical compositions are preferably in unit dosage form suitable for oral, rectal or parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as water, glycols, oil, or alcohols. Such oral liquid preparations include, for example, suspensions, syrups, elixirs and solutions. Useful solid carriers are, for example, starches, sugars, kaolin and lubricants. In addition, binders, disintegrants, and the like can be used with powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at which point the carrier may be saline, Gluosol, or a mixture of saline and glucose. Injectable suspensions may also be prepared in which case liquid carriers, suspending agents and the like, acid addition salts of the compounds due to their greater water solubility over the base form are obviously more suitable in the preparation of aqueous compositions.

It is preferable to formulate the aforementioned pharmaceutical compositions in unit dosage form for simplification and uniformity of dosage. Dosage unit form means physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient to produce the desired therapeutic effect in association with the pharmaceutical carrier. Examples of such dosage unit forms are tablets, capsules, pills, powder packets, injectable solutions or suspensions, and the like.

15 65249

The amount of active ingredient per dosage unit is about 0.25 to 100 mg, and preferably about 1 to 50 mg.

The following examples illustrate the invention. All parts are by weight unless otherwise indicated.

5

Preparation of starting materials EXAMPLE I

• 3 - ((2-nitro-4- (trifluoromethyl) phenyl / amino) -1-propanol.

A mixture of 100 parts of 1-chloro-2-nitro-4- (trifluoromethyl) benzene, 90 parts of 3-amino-1-propanol and 200 parts of butanol is stirred and heated to reflux. Stirring is continued overnight. The reaction mixture is cooled and evaporated. Water is added to the residue and acidified with hydrochloric acid solution. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The solid residue is crystallized from petroleum ether. The product is filtered off and dried, yielding 141 parts (100%) of 3- (2-nitro-4-2q (trifluoromethyl) phenyl) amino) -1-propanol.

As described above, using equivalent amounts of the corresponding starting materials, the following is prepared: 3 - [(4-methyl-2-nitrophenyl) amino] -7-propanol as a residue; 3- / ¾, 5-dichloro-2-nitro-phenyl) aminq7-1-propanol, mp. 97 ° C, and 2 g of 3 - [(2-chloro-6-nitrophenyl) amino] -1-propanol as a residue.

EXAMPLE II

3 - [(2-amino-4-methylphenyl) amino] -1-propanol as a residue.

A mixture of 70 parts of 3- (13-methyl-2-nitrophenyl) amino (-1-propanol) and 400 parts of methanol is hydrogenated under normal pressure at room temperature using 10 parts of palladium on carbon (10%). After the calculated amount of hydrogen has elapsed, the catalyst is filtered off and the filtrate is evaporated. 54 parts (91%) of 3- (12-amino-4-methyl-phenyl) amino] -1-propanol are obtained as a residue.

EXAMPLE III

16 65249 3 - ([2-amino-4- (trifluoromethyl) phenyl] amino) -1-propanol.

A mixture of 141 parts of 3- (p-nitro-4- (trifluoromethyl-5-yl) phenylamino) -1-propanol and 1200 parts of methanol is hydrogenated at normal pressure and room temperature using 15 parts of Raney nickel catalyst. After the calculated amount of hydrogen has been consumed, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from 2,2'-oxybispropane to give 110 parts (100%) of 3 - ([2-amino-4- (trifluoromethyl) phenylamino) -1-propanol.

As described above and using equivalent amounts of the corresponding starting materials, the following are prepared: 3 - [(2-amino-4,5-dichlorophenyl) amino] -1-propanol-hydrochloride, m.p. -185 ° C; 3 - / * (2-amino-6-chlorophenyl) amino] -1-propanol as a residue, and 3- (12-amino-4-chlorophenyl) amino] -1-propanol as an oily residue.

EXAMPLE IV

1,3-Dihydro-1- (3-hydroxypropyl) -5-methyl-2H-benzimidazol-2-one.

To a stirred and cooled solution of 54 parts of 3 - ['(2-amino-4-methylphenyl) amino] -1-propanol in 30 parts of 25 hydrochloric acid solution (10%) and 200 parts of water is added dropwise a solution of 28 parts of potassium cyanate in 50 parts of water, at a temperature below 10 ° C. After the addition is complete, stirring is continued first for 1 hour at room temperature and then for 24 hours at reflux temperature. After cooling to room temperature, the product is extracted with trichloromethane. The extract is washed with hydrochloric acid solution (5%), dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone to give 19.5 parts (31%) of 1,3-dihydro-1- (3-hydroxypropyl) -5-methyl-2H-benzimidat-35-sol-2-one, m.p. . 114.1 ° C.

As described above and using equivalent amounts of the corresponding starting materials, the following are prepared: 17 65249 1,3-dihydro-1- (3-hydroxypropyl) -5- (trifluoromethyl) -2H-benzimidazol-2-one; 5,6-dichloro-1,3-dihydro-1- (3-hydroxypropyl) -2Hbentsimi-indazole-2-one; mp. 174.7 ° C; 4-chloro-1,3-dihydro-3- (3-hydroxypropyl) -2H-benzimidazol-2-one; and 5-chloro-1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazol-2-one; mp. 148.8 ° C.

10 EXAMPLE V

1,3-Dihydro-1- (3-hydroxypropyl) -5-methyl-2H-benzimidazol-2-one methanesulfonate.

To a stirred solution of 18.5 parts of 13-dihydro-1- (3-hydroxypropyl) -5-methyl-2H-benzimidazol-2-one in 325 parts of dichloromethane is added 11.9 parts of Ν, Ν-diethylethanamine. . 11.5 parts of methanesulfonyl chloride are added dropwise (slowly). After the addition is complete, stirring is continued for 1 hour at reflux temperature. After cooling, the reaction mixture is washed with water, dried, filtered and evaporated. The solid residue is crystallized from 4-methyl-2-pentanone to give 15 parts (58%) of 1,3-dihydro-1- (3-hydroxypropyl) -5-methyl-2H-benzimidazol-2-one methanesulfonate, m.p. 125 ° C.

Using equivalent amounts of the corresponding starting materials as described above, prepare: 3- (5,6-dichloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -propyl methanesulfonate as an oily residue; 3- (7-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -propylmethanesulfonate; and 3- (5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -propyl + methyl methanesulfonate; mp. - 140 C.

EXAMPLE VI

1- (3-chloropropyl) -1,3-dihydro-5- (trifluoromethyl) -2H-benzimidazole-1-one.

35, β 65249

To a stirred mixture of 23 parts of 1,3-dihydro-1- (3-hydroxypropyl) -5- (trifluoromethyl) -2H-benzimidazol-2-one in 150 parts of trichloromethane is added dropwise 32 parts of sulfinyl chloride. At the end of the addition, the mixture is heated under reflux and stirring is continued for 1 hour at reflux temperature. After cooling, the reaction mixture is evaporated and the residue is crystallized from 2,2'-oxybispropane to give 14 parts (56%) of 1- (3-chloropropyl) -1,3-dihydro-5- (trifluoromethyl) -2H-benzimidazole-2- one.

Using the equivalent amount of the corresponding hydroxy compound as a starting material, the following chlorides are prepared as described above: 5-chloro-1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazol-2-one; 6-chloro-1- (3-chloropropyl) 1,3-dihydro-2H-benzimidazol-2-one; mp. 122 ° C.

EXAMPLE VII

(3-chloropropyl) -1,3-dihydro-3- (1-methylethenyl) -2H-benzimidazol-2-one.

To a stirred solution of 8.5 parts of 1,3-dihydro-1- (1-methylethenyl) -2H-benzimidazol-2-one in 45 parts of N, N-dimethylformamide is added portionwise 1.7 parts of sodium hydride dispersion (78 parts). % strength). After stirring for 1 hour at room temperature, cool to 0-5 ° C and 7.65 parts of 1-bromo-3-chloropropane are added dropwise (slowly). After the addition is complete, stirring is continued for 3 hours at room temperature. The reaction mixture is poured into crushed ice and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from 2-propanol to give 5.5 parts (44%) of 1- (3-chloropropyl) -1,3-dihydro-3- (1-methylethenyl) -2H-benzimidazol-2-one, m.p. 115 ° C.

I; 19 65249

EXAMPLE VIII

1- (3-chloropropyl) -1,3-dihydro-5,6-dimethyl-3- (1-methyl-2-phenylethenyl) -2H-benzimidazol-2-one

To a stirred and hot (55 ° C) mixture of 22.2 parts of 1,3-dihydro-5,6-dimethyl-3- (1-methyl-2-phenylethenyl) -2H-benzimidazol-2-one, 3 parts of , Ν, Ν-triethylbenzenemethanaminium chloride and 112.5 parts of sodium hydroxide solution (60%) are added dropwise 15.8 parts of 1-bromo-3-chloropropane (slightly exothermic reaction). After the addition is complete, stirring is continued for 5 hours at 55 ° C. After cooling, water is added and the oily product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane to give, after drying, 25 parts (8.5%) of 1- (3-chloropropyl) -1,3- [4-dihydro-5,6-dimethyl-3- (1-methyl- 2-phenylethenyl) -2H-Benzimidazol-2-one, m.p. 98 ° C.

Using equivalent amounts of the corresponding starting materials as described above, 1- (3-chloroperopyl) -1,3-dihydro-3- (2-propenyl) -2H-benzimidazol-2-one is prepared as an ice-2q.

EXAMPLE IX

1- (3-Chloropropyl) -1,3-dihydro-2H-benzimidazol-2-one 25-part solution of 1- (3-chloropropyl) -1,3-dihydro-3- (1-methylethenyl) ) -2H-Benzimidazol-2-one in 6 parts of hydrochloric acid solution and 40 parts of ethanol are stirred for 2 hours at room temperature. The reaction mixture is evaporated and the solid residue is crystallized from 2-propanol to give 9.5 parts (90%) of 1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazol-2-one, m.p. 115 ° C.

EXAMPLE X

65249 20 1- (3-chloropropyl) -1,3-dihydro-5,6-dimethyl-2H-benzimidazol-2-one 5 A mixture of 25 parts of 1- (3-chloropropyl) -1,3- dihydro-5,6-dimethyl-3- (1-methyl-2-phenylethenyl) -2H-benzimidazol-2-one, 165 parts of 6N hydrochloric acid solution and 160 parts of ethanol are stirred and refluxed for 6 hours. The reaction mixture is evaporated and the residue is dissolved in trichloromethane. The solution is dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane and 2-propanol to give, after drying, 16 parts (94.7%) of 1- (3-chloropropyl) -1,3-dihydro-5,6-dimethyl-2H-benzimidazole -2-one, m.p. 140 ° C.

15

EXAMPLE XI

1,3-dihydro-1- (3-iodopropyl) -3-methyl-2H-benzimidazol-2-one 20

A solution of 180 parts of 3 - [(2-nitrophenyl) -amino] -1-propanol in 200 parts of methanol and 100 parts of 10N hydrochloric acid solution is hydrogenated at 50 ° C under normal pressure in the presence of 5 parts of palladium on carbon (10%).

After the calculated amount of hydrogen (3 moles) has elapsed, the hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. The residue (mainly 3 - [(2-aminophenyl) amino] -1-propanol hydrochloride) is dissolved in 500 parts of water. To this solution is added a solution of 88.8 parts of potassium isocyanate in 150 parts of water and stirred and refluxed for 15 hours. The reaction mixture is cooled and the product is extracted with trichloromethane. The extract is dried and evaporated. The residue is dissolved in 250 parts of boiling water, treated with activated carbon and crystallized at room temperature. The precipitate-35 nucleus is filtered and recrystallized from 400 parts of water followed by ethyl acetate to give 58 parts of 1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazol-2-one hydrate, m.p. 48-65 ° C.

I: 21 65249

To a solution of 52.5 parts of 1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazol-2-one hydrate in 200 parts of pyridine is added dropwise 63 parts of methanesulfonyl chloride. The mixture is stirred and cooled in air for 2 hours.

5 The pyridine is evaporated. 500 parts of water are added to the residue and the precipitate formed is filtered off. It is dissolved in 350 parts of trichloromethane. The resulting solution is dried over magnesium sulfate and evaporated. The residue is crystallized from 40 parts of methylbenzene to give 25.5 parts of 1,3-dihydro-1- (3-hydroxy-10-propyl) -2H-benzimidazol-2-one methanesulfonate, m.p. 118-120 ° C.

To a solution of 0.5 parts of sodium in 40 parts of absolute ethanol in the cold is added 5.4 parts of 1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazol-2-one methanesulfonate. Stir until all solids are dissolved. The solution is further stirred and refluxed for 2 hours. After cooling, the reaction mixture is filtered off with small amounts of inorganic matter and the filtrate is evaporated. The residue is dissolved in 80 parts of methylbenzene, boiled with activated carbon, cold methylbenzene and crystallized from 16 parts of methylbenzene to give 2.6 parts of 3,4-dohydro-2H- [1,3,3-oxazino] -3,2-α-7-benzimidazole, m.p. 116.5 to 118.5 ° C.

To a solution of 5.7 parts of 3,4-dihydro-2H- [1,37-oxo-25 Sino] -3,2-a7benzimidazole in 80 parts of 2-propanone is added 5.7 parts of iodomethane and stirred and refluxed for 2 hours 50 minutes. A second portion of 5.7 parts of iodomethane is added and the mixture is further stirred and refluxed for 2 hours and 50 minutes. The solvent is evaporated to give 1,3-dihydro-1- (3-iodopropyl) -3-methyl-2H-benzimidazol-2-one as an oily residue.

22 AS 9 4- 9 PREPARATION OF FINISHED PRODUCTS U 3 n 7 EXAMPLE 1 8- [3- (1,3-Dihydro-2-oxo-2H-benzimidazol-1-yl) propyl] -1H- (4-fluorophenyl) -1 , 3,8-triazaspiro / 4,57dekaanl-4-one

Mixture of 4.6 parts of 1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazol-2-one, 5 parts of 1- (p-fluorophenyl) -1,3,8-triazaspiro / 4 , 5 / decan-4-one, 10 parts of sodium carbonate, 0.2 parts of potassium iodide and 80 parts of 4-methyl-2-pentanone are stirred and refluxed overnight. After cooling, the precipitated product is filtered off and stirred twice, first in a boiling mixture of 4-methyl-2-pentanone and 2-propanol and then in boiling methanol. .j t- Refilter and recrystallize from a mixture of N, N-dimethylformamide and water to give 4.5 parts of 8- [3- (1,3-dihydro-2-oxo-2H-benzimidazol-1-yl) propyl] -1- (4-fluorophenyl) -1,3,8-triazaspiro [4.57] decan-4-one; mp. 215.4 ° C.

As described above, using equivalent amounts of the corresponding starting materials, the following compounds are prepared: 8- [3- (6-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -propyl] -1- (4-fluorophenyl ) -1,3,8-triazaspiro [4.5] decan-4-one hemihydrate; mp. 233 ° C; 1- (4-fluorophenyl) -8- [3- (2,3-dihydro-5,6-dimethyl-2-oxo-25H-benzimidazol-1-yl) propyl] -1,3,8-triazaspiro [4 , 57-decan-4-one; mp. 245.2 ° C; 8- (3- / 2,3-dihydro-2-oxo-3- (2-propenyl) -1H-benzimidazol-1-yl) -7-propyl) -1-phenyl-1,3,8-triazaspiro [4.5-7] decane -4-one; mp. 114 ° C; 8- [5- (2,3-Dihydro-2-oxo-1H-benzimidazol-1-yl) -propyl] -4- 1- [3- (trifluoromethyl) phenyl] -1,3,8-triazaspiro / 4,5_7dekaa-ni-4-one; mp. 198.2 ° C; 8- / 3- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl / -1-phenyl-1,3,8-triazaspiro / 4 ^ lekaani-4-one; mp. 228 ° C; 35 8- [3- (5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -1- (4-fluorophenyl) -1,3,8-triazaspiro [4 , 5 / decan-4-one; mp. 171.7 ° C; 23 65249 8- [3- (6-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -propyl] -1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one; mp. 255-256 ° C; 1- (4-fluorophenyl) -8- (3- [1,3-dihydro-2-oxo-5- (trifluoro-5-methyl) -1H-benzimidazol-1-yl] propyl) -1,3,8 triazine-spiro / 4,5 / decan-4-one; mp. 259.7 ° C; 8- [3- (2,3-Dihydro-2-oxo-1H-benzimidazol-1-yl) -propyl] -3-methyl-1-phenyl-1,3,8-triaza-spiro / 4,57-decane-4- one; mp. 186 ° C; 1- (4-chloro-3-methylphenyl) -8- [3- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -1,3,8-triazaspiro [4], 5 / dekaa-ni-4-one; mp. 208.6 ° C; 8- [3- (1H-benzimidazol-1-yl) propyl] -1-1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one; mp. 191 ° C; 8- [3- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -1- (3-fluorophenyl) -1,3,8-triazaspiro [4.57] decane-4- one; mp. 237-244 ° C? 8- [3- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -1- (3-fluoro-3-methylphenyl) -1,3,8-triazaspiro [4.5] decane-20 4-one monohydrate, m.p. 167.6 ° C; 8- [3- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -1- (3,4-dimethylphenyl) -1,3,8-triazaspiro [57] decane-4- oni hemihydrate, m.p. 185.9 ° C; and 1- (4-bromophenyl) -8- [3 '(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -1,3,8-triazaspiro [4.5] decane -4-one monohydrate, m.p. 197.4 ° C.

EXAMPLE 2 8- [3- (7H-ol-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl) -30-propyl] -1-phenyl-1,3,8-triaza-spiro / 4.5 / decane-4-one

A mixture of 4.2 parts of 4-chloro-1,3-dihydro-3- (3-hydroxypropyl) -2H-benzimidazol-2-one methanesulfonate, 2.5 parts of 1-phenyl-1,3, 8-Triazaspiro [4.5] decan-4-one, 10 parts of sodium carbonate and 80 parts of 4-methyl-2-pentanone are stirred and refluxed overnight. The reaction mixture is cooled and water is added. The precipitated product is filtered off and crystallized twice from a mixture of Ν, Ν-dimethylformamide and water to give 0.8 part (17%) of 8- [3- [7-chloro-1,3, -dihydro-2-oxo-2H- benzimidazol-1-yl) propyl] -1-phenyl-1,3,4-8,8-triazaspiro [4.5] decan-4-one; mp. 258.4 ° C.

65249 24

As described above and by carrying out the reaction in N, N-dimethylformamide, the following compounds are prepared from the corresponding starting materials: 8- [3- (5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -5-propyl] -1 -phenyl-1,5-triazaspiro [1,5-decan-4-one; mp. 233.7 ° C; and 8- [3- (2,3-dihydro-5-methyl-2-oxo-1H-benzimidazol-1-yl) -propyl] -1-phenyl-1,3,8-triazaspiro [57] decane-4- one; mp. 255.5 ° C.

EXAMPLE 3 8- [3- (1,3-Dihydro-3-methyl-2-oxo-2H-benzimidazol-1-yl) -propyl] -N-phenyl-1,3,8-triaza-spiro / * 4,57dekaani-4-one

A mixture of 5 parts of 1,3-dihydro-1- (3-iodopropyl) -15-3-methyl-2H-benzimidazol-2-one, 3.4 parts of 1-phenyl-1,3,8-triaza-pyro [ 4.5 / decan-4-one, 2.65 parts of sodium carbonate and 22.5 parts of Ν, Ν-dimethylformamide are stirred and heated at 70 ° C for 2 hours. The reaction mixture is cooled and poured into water to form an oily precipitate.

2q The supernatant aqueous phase is decanted off and the residual oil is dissolved in trichloromethane. The solution is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using trichloromethane containing 5% methanol as eluent. The pure fractions were collected and the eluent was evaporated, yielding 1 part of 8- [(1,3-dihydro-3-methyl-2-oxo-2H-benzimidazol-1-yl) propyl] -1-phenyl-1,3, 8-triazaspiro / 4,57dekaani-4-one; mp. 164.4 ° C.

EXAMPLE 4 30- 8- [3- (5,6-Dichloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl) propyl] -1-phenyl-1,3,8 -triazaspiro [4.5] decan-4-one

A mixture of 8 parts of 5,6-dichloro-1,3-dihydro-1- (3-hydroxypropyl) -2H-benzimidazol-2-one methanesulfonate, 9.2 parts of 1-phenyl-1,3, 8-Triazaspiro [4.5] decan-4-one 35 and 90 parts of Ν, Ν-dimethylformamide are stirred and heated at 60 ° C for 1 hour. The reaction mixture is evaporated and water is added to the residue. It is basified with ammonium hydroxide and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column chromatography on silica gel using 10% methanol in trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is stirred in 4-methyl-2-pentanone. The product is filtered off and dried, yielding 2 parts of 8- [3- (5,6-dichloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl) propyl] -1-phenyl- 1,3,8-triazaspiro / 4,57dekaani-4-one; mp. 275.2 ° C.

Claims (2)

26 65249 A process for the preparation of therapeutically useful 1-phenyl-8-benzimidazolylprop-5-yl-1,3,8-triazaspiro [4,5] decan-4-one derivatives of the formula I and their pharmaceutically acceptable acid addition salts. n-R4 BN -CH_-CH0-CH0-N \ / -. R R 6 1 2 wherein R and R represent hydrogen, halogen, alkyl or trifluoromethyl, B is a divalent O · «radical -N = CH- or -NL-C-, where L is hydrogen. C 1-5 alkyl or C 2-8 alkenyl and the divalent radical is attached to the benzene ring via a heteroatom, 25. is hydrogen or C 1-6 alkyl and R and R represent hydrogen, halogen, C 1-6 alkyl or trifluoromethyl, characterized in that a compound of the formula ^ -CH0-CH0-CH ~ -X (II) 30 \ ✓ 2 2 2 Ä. 1 2 wherein R, R and B are as defined above and X is a reactive ester group derived from the corresponding alcohol is reacted with a compound of formula 65249 27 HN V Λ (III) rJxxIr6 10 4 5 6 30 in R, R 3a R is as defined above in a suitable organic solvent; and optionally converting the resulting compound of formula I to a pharmaceutically acceptable acid addition salt. Process according to Claim 1, 8- [3- (1,5-dihydro-4-oxo-1H-benzimidazol-1-yl] propyl] '' - (4-fluorophenyl) -1,3,8- for the preparation of triazaspiro [4.5,5] decan-4-one and its pharmaceutically acceptable acid addition salt, characterized in that 1 2 a compound of formula II in which R and R represent 20 hydrogen, B is -NH-CO- and X represents the same as above, is reacted with a compound of formula III wherein R and R are hydrogen and R is 4-fluoro, and if desired the compound obtained is converted into a pharmaceutically acceptable acid addition salt.