NO753594L - - Google Patents

Description

Procedure for the production of azacyclic compounds

The present invention relates to new pharmaceutical active azacyclic compounds and therapeutically acceptable salts thereof, methods for their production and compositions containing such compounds or salts. Also included are certain intermediates which are useful for the production of the new compounds.

The compounds according to the invention are pharmaceutically active benzhydryl azacyclic compounds suitable for the treatment of severe obesity in mammals and which have general formula I:

where n is an integer from 1 to 5, R and R1 independently represent a hydrogen atom or a lower alkyl group, X is a hydrogen atom, a hydroxy, lower alkoxy, aralkyl or acyloxy group or an unsubstituted or mono- or di-substituted amino group, wherein the substituents are lower alkyl, aralkyl or acyl, and Y, Y' and Y" are independently a hydrogen atom, a hydroxyl group, a lower alkoxy group, a halogen atom or a trifluoromethyl group, and therapeutically acceptable salts of

such connections. This definition naturally includes all isomeric forms of the above-mentioned compounds.

The terms "lower alkyl" and "lower alkoxy" as used here represent all alkyl or alkoxy groups with 4 carbon atoms and include, among other things, methyl, ethyl, iso-propyl, t-butyl, methoxy, ethoxy, isopropoxy and t-butyloxy.

The aralkyl groups to which reference is made above are phenyl-lower alkyl groups whose phenyl ring may optionally be substituted with any of the Y-substituents specified above. The lower alkyl part comprises groups with 1-4 carbon atoms. The preferred phenyl-lower alkyl group is benzyl..

The preferred acyl groups are those of the formula:

where R3 represents a lower alkyl group with 1-4 carbon atoms, a phenyl group or a lower alkylphenyl group.

The term halogen covers fluorine, chlorine and bromine.

The compounds in which Y, Yr and Y" represent hydrogen are preferred. It is likewise preferred that R represents a hydrogen atom and R' represents a hydrogen atom or methyl. Within this subgroup, X is as indicated above, however, the groups of compounds in which X represents a hydrogen atom, a hydroxy, methoxy or amino group or the grouping NHCB^CgH^, preferably a hydroxy or, amino group, particularly valuable. Azetidine (n=1) is the preferred azacyclic ring although pyrrolidines, piperidines, azepines and azosines also are very active.

Preferred compounds within the scope of formula I include the following compounds and their isomers: 1-benzhydryl-2-(α-hydroxybenzyl)-azetidine, 1-benzhydryl-2-(α-aminobenzyl)-azetidine, 1-benzhydryl-2-benzylazetidine, l-benzhydryl-2- [ (α_-hydroxy-ct-methyl)benzyl]-axetidine-, l-benzhydryl-2-[α-(N-acetamido)benzyl]-azetidine, l-benzhydryl-2-[α- (N-benzylamino)benzyl]-azetidine, 1-[a-chlorophenyl)-p-bromobenzyl]-2-(a-hydroxybenzyl)-azetidine, 1-[a-(m-fluorophenyl)-benzyl]-2-( (α-hydroxy-m-trifluoromethyl-benzyl)-azetidine, 1-[α-(p-methoxyphenyl)-p-hydroxybenzyl]-2-(α-hydroxy-p-chloro-benzyl)-azetidine, 1-[α-methylbenzhydryl]-2-(α-hydroxybenzyl)-azetidine, 1-[α-ethylbenzhydryl]-2-(α-.(.N-acetamido)-benzyl]-azetidine, l-benzhydryl-2- (a-hydroxy-m-trifluoromethylbenzy1)-azetidine, l-benzhydryl-2 - (a-amino-m-trifluoromethylbenzy1)'-azetidine, l-benzhydryl-2-(a-methoxybenzyl)-azetidine, l- benzhydryl-2-(a-amino-p-chlorobenzyl)-azetidine, 1-benzhydryl-a-(a-hydroxy-o-bromobenzyl)-azetidine, l-benzhydryl-2-[a-(N-ethylamino)-benzyl ]-azetidine, 1-[a-(o-chlorophenyl)-benzyl]-2-(a-hydroxybenzyl)-azetidine, 1-[a-(p-bromophenyl)-p-bromobenzyl]-2-(a- aminobenzyl)-azetidine, 1-[α-(m-trifluoromethyl)-benzyl]-2-(α-hydroxybenzyl)-azetidine, l-benzhydryl-2-[α-(N-methanesulfonylamino)-benzyl]-azetidine, l -benzhydryl-2-[α-(N-tosylamino)-benzyl]-azetidine, l-benzhydryl-2-(α-hydroxybenzyl)-pyrrolidine, l-benzhydryl-2-(α-aminobenzyl)-piperidine, l-benzhydryl -2-(α-hydroxybenzyl)-piperidine, l-benzhydryl-2-(α-aminobenzyl)-pyrrolidine, l-benzhydryl-2-benzyl-pyrrolidine, l-benzhydryl-2-benzyl-piperidine,

l-benzhydryl-2-benzyl-azepine,

1- benzhydry1-2-benzyl-azocine

The most preferred compound is threo-1-benzhydryl-2-(α-hydroxybenzyl)-azetidine.

The preferred acid addition salts are those formed with maleic acid, phthalic acid, succinic acid, tartaric acid, citric acid, malic acid, cinnamic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid or nitric acid.

The compounds according to the invention can be prepared by standard methods well known in the art.

Hereafter is the benzhydryl azacyclic part of the molecule

sometimes characterized by A and the phenyl ring by B so as to indicate the simplified formula •I x for the compounds of formula I (a) A method for the preparation of the compound of formula I comprises reacting a compound of general formula with a compound of general formula in which the formulas n, R, R', X, Y, Y' and Y" are as previously indicated, with the exception that any primary amino group represented by X may be protected with a protecting group which is then removed. The reaction is carried out according to known methods. Preferably, the azacyclic compound (II) is dissolved in acetonitrile or other suitable solvent. Potassium bicarbonate is added and the diphenyl methyl halide III (e.g. bromide) is added to the resulting suspension. The mixture is boiled under reflux (e.g. for about 3 hours). and processed in a known manner.<>>(b) The compounds of formula I where X represents OH, respectively NH2 and R' is H are suitably prepared by reduction of the corresponding compounds r of general formula IV

where A and B are as previously stated and Z represents a grouping that can be reduced to X as previously stated, by standard reduction methods.

The compounds where X represents hydroxyl are preferably prepared by reduction of corresponding carbonyl compounds and for the preparation of compounds in which X represents NH2 and Z preferably =NH, =N-CH2 or =N-OH:

The reduction of the carbonyl compounds is preferably carried out using sodium borohydride in methanol, ethanol or iso-propanol at temperatures varying from 0 to 30° C. The reduction of the imine is preferably carried out using LiAlH^ in ether at temperatures between 0° C and room temperature. Of course, however, a number of other reducing agents and solvents can be used in the above/indicated reactions, such as LiAlH^ in ether, tetrahydrofuran (-70° C to reflux temperature), diglyme (-70° C to +80° C) or 1, 2-dimethoxyethane (-70° C to +80° C), LiAlH4/AlCl3 in the same solvent as above, LiBH^ in tetrahydrofuran (approx. 0° C to +40° C), diglyme .

(about 0° C to +50° C) or ether, NaAlH2(OCH2CH2OCH3)2in benzene (+10° C to reflux temperature), toluene (-70 to +80° C) or xylene (-70 to +80° C) , LiAIH(OC2^5^ 3 or LiAlH[OC(CH3)3<]>3 in tetrahydrofuran or diglyme, as well as other metal hydrides, e.g. BH3, NaAlH^, NaCNBH3 etc. The preferred temperature range is from +10 to +25° C.

Also other reduction methods such as the so-called "dissolving metal reduction" [e.g. sodium amalgam in ethanol (50 - 80° C), zinc in ethanol (60 - 80° C), lithium metal in liquid ammonia (-33° C)] or electrochemical or catalytic reduction can also be used.

c) The compounds of formula I in which X represents OH, or unsubstituted or mono-substituted amino and R<1> is lower

alkyl. can conveniently be prepared by reacting the respective organometallic compound with a compound of general formula

where R 2 Q is oxygen or NR 21 where R 21 is hydrogen, lower alkyl, aralkyl or acyl, followed by hydrolysis of the organometallic complex thus obtained.

The preferred organometallic compound is alkyllithium, although Grignard reagents such as R<1>MgBr or R'Mgl (in ether or tetrahydrofuran at room temperature) or A1(R')3 (in benzene) can also be used. (d) The compounds of formula I where X represents a mono- or di-substituted amino group can be prepared by alkylation, aralkylation or acylation of the corresponding amino compound. The reaction is carried out according to standard alkylation and acylation methods, e.g.

(e) Compounds of formula I where X represents NH 2 can also be prepared from the corresponding compound with the amino group protected with one or two protecting groups by removal of the protecting groups. The protecting groups can be any group suitable for this purpose. Preferably, the amino group is protected by an acyl group such as trifluoroacetyl, e.g. (f). The compounds of formula I where X represents alkoxy or aralkyl can conveniently be prepared from the corresponding hydroxy compound by standard etherification reactions: (g) Compounds of formula I where X represents hydroxyl and R' represents lower alkyl can be prepared according to standard reactions from the corresponding alkylidene compound by addi- tion of the elements in water to the double bond:

The addition reaction is preferably carried out by treating the compound (IX) with Hg(0Ac) 2 in a mixture of tetrahydrofuran and water. R" obviously represents a lower alkylidene group.

(h) Compounds of formula I where X represents hydroxyl and R" is hydrogen can also be prepared by the following reaction:

Standard reaction conditions for the condensation of an amine with one dibromide can be used.

(i) Compounds of formula I where R represents H can be prepared by the following reaction:

This reaction can also be carried out according to methods well known in the art. Preferably, the reaction is carried out in the presence of a reducing agent such as NaCNBH-^.

(j) The compounds of formula I where X represents hydrogen can be prepared by reduction of the corresponding derived hydroxy compound or ketone according to standard methods:

wherein formula XIV R 2 q is a derived hydroxyl group such as -OSO 2 -CH 3 or

or together with R<1>en of-

led keto group such as a hydrazone. In the latter case, R' in the final compound is hydrogen. Preferably, the reaction is carried out using a reducing agent such as those described in method (b).

The starting compound for the various methods (a) to (i) are either well-known compounds or can be prepared by standard methods in the field. Some of the end compounds are also starting compounds for the production of other end compounds.

1. Preparation of the starting compound (IVb) used in method (b):

Compounds XIII and IVb are new compounds which form part of the present invention.

2. Preparation of the starting compound (IVa) used in method (b): 3. Preparation of the starting compound (IVb) used in method (b): Reaction 3 (a) is preferably carried out by heating the carbonyl compound (IVa) with NH- jNH^ to reflux temperature in n-butanol and reaction 3(b) by heating (IVa) with NI^OH.HCl to reflux temperature in ethanol in the presence of either NaOH or Na2<C0>3. 4. The starting compounds of formula II [method (a)] can be obtained by the following methods 5. The starting compounds of formula VII [method (e)] in which R<1> represents lower alkyl can be prepared according to the following reaction sequence:

In this example, the amino blocking group is trifluoroacetyl, but other hydrolyzable blocking groups could also be suitable.

6. Compounds IX used in method (g) can be prepared by a Wittig reaction as follows:

(R" represents either H or C-^ to C-. lower alkyl)

The reaction is preferably carried out in ether at reflux temperature. The Wittig reagent is preferably prepared in a known manner:

7. The starting compound X in reaction (h) can also be prepared by standard reactions:

The compounds of formula I and their salts induce a weight loss in mammals. It is well known that amphetamines and other sympathomimetics have both anorexigenic activity and CNS activity

(central nervous system). The latter, i.e. the CNS effects include nervousness, over-irritability, insomnia, well-being and habituation. Amphetamine can also cause CV (cardiovascular) effects such as palpitations, tachycardia and increased blood pressure. Furthermore, it is well known that sympathomimetics, when administered continuously with a given daily dose, induce a less anorexic effect over time.

The compounds according to the invention are suitable for the treatment of severe obesity in mammals by reducing the consumption of carbohydrate for fat synthesis in order to thereby reduce excess body fat and increased body weight. In addition, many of the compounds according to the invention can induce an anoretic effect without the serious side effects of amphetamines and other sympathomimetics.

Compositions containing as active ingredients compounds according to the present invention exhibit an anti-lipogenic activity. Many have anorexic activity with little or no CNS side effects, e.g. insomnia, over-irritability, well-being and habituation. Based on laboratory tests and laboratory procedures, the assumed effective dose ED,-q of the active ingredient according to the invention is to be within the range from 0.2 to 20 mg/kg p.p. per body weight mammal per day. Thus, the dose can vary from 15 to 1400 mg per 70 kg per day.

A minimum effective dose for threo-1-benzhydryl-2-(α-hydroxybenzyl)-azetidine is 0.5 - 3 mg/kg, whereby the LD3 rn 0 for the compound in mice is 2350 mg/kg. The daily dose is preferably administered in divided doses at or around meals. The exact dose to be administered will depend on the particular type of drug within the range indicated above, as well as on the dosage form, age and weight of the mammal to be treated.

The compositions according to the invention can be administered alone or combined with other drugs. The compositions are administered orally. In any case, a suitable pharmaceutical carrier is used, the carrier being selected according to the physical properties of the compound in the pharmaceutical composition. The carrier shall. do not react chemically with the compound to be administered. Preparations containing them. active ingredients can be in the form of tablets, capsules, syrups, elixirs, suspensions and the like, including formulations which provide a prolonged release of the active ingredient.

Production of starting materials

a) 2, 4-dibromobutyramide

Cooled to -55° a two-phase system consisting of 650 ml

concentrated ammonium hydroxide and 750 ml of ether. Add to the stirred mixture 30"0 g of 2,4-dibromobutyryl bromide, (G. Bischoff, Chemical Abstracts 4_4 P2,549d) while maintaining the temperature between -55 and -35° C. After completion of the addition of the acid bromide, allow the stirred mixture to warm to 0° C and add sufficient ether to dissolve any suspended solids. Separate the layers and extract the aqueous phase twice with ether. Wash the combined ether phases in order: 'with water and brine (saturated aqueous sodium chloride), and dry the solution

over anhydrous sodium sulfate. Remove the bulk of the solution. the agent in vacuo to a thick suspension. Add hexane to this suspension and triturate thoroughly. Filter to form the analytically pure title amide with melting point 80.5 - 81.5° C.

b) 2, 4-dibromobutyronitrile

Prepare a mixture of 100 g of 2,4-dibromobutyramide and

76.5 g phosphorus pentoxide. Place the solid mixture under vacuum of 0.02 - 0.10 Torr, heat to 200° C and collect distillate until a peak temperature of 120° C is reached. Dissolve this impure distillate in ether and wash successively with 10% HCl, aqueous sodium bicarbonate, water and brine. Dry the ether solution over anhydrous magnesium sulfate and remove the solvent in vacuo. Vacuum distill the residual oil through a fractionation column and collect

the analytically pure title compound at 66 - 67° C. at 0.05 Torr.O

c) 1-benzhydryl-2-cyanoazetidine

Boil under reflux for 18 hours a stirred mixture of

10 g of 2,4-dibromobutyronitrile, 7.35 g of benzhydrylamine and 7.41 g

sodium bicarbonate in 100 ml of acetonitrile. Filter from the solids and remove the acetonitrile in vacuo. Treat the residue with ether and filter out insoluble solids. Wash the ether solution first with water, then with a solution of 5.40 g of oxalic acid in 200 ml of water and finally with salt water (saturated aqueous NaCl solution). Dry the solution over anhydrous magnesium sulfate and remove the solvent in vacuo. Crystallize the solid residue from methylene dichloride-hexane to give the analytically pure title compound with melting point 103.5 - 105°C

d) 1-benzhydryl-2- benzimidoylaxetidine

Suspend phenylmagnesium bromide in ether by adding

under gentle reflux, a solution of 189.2 g of bromobenzene in 500 ml of ether to a stirred suspension of 24.4 g of magnesium shavings in 1000 ml of dry ether. After the addition is complete, reflux for an additional 30 minutes and then allow the mixture to cool for 15 minutes to room temperature. Add 110.6 g of 1-benzhydryl-2-cyanoazetidine in portions over the course of 3-4 minutes. Stir the mixture for 18 hours at room temperature, cool to 0° C and stop the reaction by adding 750 ml of water, 250 ml of ether and 400 ml of methylene chloride. Filter the mixture. Remove the aqueous layer of the filtrate. Wash the organic phase with water and dry over anhydrous sodium sulfate. Remove the solvent in vacuo. Triturate the solid residue with 500 ml of isopropyl ether and filter to form the analytically pure title product with m.p. 123.5 - 126.5° C.

ej 1-benzhydryl-2-benzoylazetidine

Add 68 ml of 3.6N aqueous sulfuric acid to a stirred solution of 40.0 g of 1-benzhydryl-2-benzimidoylazwtidine in 800 ml of methanol. Stir under a nitrogen atmosphere for 1.5 hours at room temperature. Pour the mixture slowly with continuous stirring into 234 ml of a 1.1N aqueous sodium bicarbonate solution. Filter the resulting solid and extract the filter cake with methylene chloride. Combine the methylene chloride extracts with the methanolic filtrate and remove all solvent in vacuo. Dissolve the solid residue in ether, wash with water and dry over anhydrous sodium sulphate. Remove the desiccant, concentrate the solution in vacuo to a volume of 350 ml and triturate the solid material that precipitates. Filter to form the analytically pure product with m.p. 114 - 115° C.

Example 1

Threo-(-)-1-benzhydryl-2-(α-hydroxybenzyl)-axetidine

Add 9.3 g of sodium borohydride to a stirred ice-cold suspension of 40 g of 1-benzhydryl-2-behzoyloxetidine in 1600 ml of methanol. When the foaming subsides allow the reaction mixture to warm to room temperature. Stir for 16 hours and then remove solvent in vacuo. Dissolve the remaining solid material and the oil in a mixture of ether and water. Separate: the layers and extract the aqueous phase with ether. Wash the combined ether extracts successively with water and saturated sodium chloride solution and dry over anhydrous sodium sulfate.

Add 40 mL of a 4N ethereal HCl solution to it. stirred ether solution (800 ml). Decant, add 800 ml of fresh ether and triturate the gummy precipitate to a powdery solid. Recrystallize the impure salt from methanol-ethyl acetate to form the analytically pure hydrochloride salt of the title compound, with sm. p. 175 - 176° C (decomposition). This crystalline salt corresponds to the molecular formula NOC23H23.<H>CI and is a mixture of a predominant amount of threo isomer with a very small amount of erythro isomer. For the preparation of a free base, stir a suspension of 60 g of the hydrochloride salt in a mixture consisting of 220 ml of 1.0 N aq.

sodium bicarbonate, 500 ml ether and 75 ml methylene dichloride. Separate the layers, wash the organic phase successively with water and brine, then dry over anhydrous sodium sulfate. Remove the solvent in vacuo and triturate the solid residue in ether to form the analytically pure, free base in the form of the title compound with melting point 87.5 - 88.5° C.

Example 2

Optical resolution of threo-(-)-1-benzhydryl-2-(α-hydroxy-benzyl)-axetidine

Dissolve 3.50 g of racemic threo-1-benzhydryl-2-(α-hydroxy-benzyl)-axetidine and 3/03 g of N-tosyl-L-leucine in 30 ml of boiling acetonitrile. Allow the solution to cool to room temperature. Filter the solid and recrystallize from acetonitrile to give the analytically pure diastereomer salt: m.p. 154 -

155° C, [α]^<6>- 39.40° (1%, DMF). The mother liquor will be used to obtain more soluble diastereomers. ■

Prepare the free base in the form of the pure diastereomeric salt in a known manner by treatment with aqueous sodium carbonate and ether. Recrystallize the thus obtained solid material from isopropyl ether to form an analytically pure enantiomer

o 2 6 free base form of the title compound: sm.p. 72-73 C, [α]D 54.80° (1%, EtOH). To obtain the hydrochloride, dissolve the pure free base in ether, treat with ethereal hydrogen chloride, and filter the precipitate. Triturate the solid material with ethyl acetate to form the analytically pure dextrorotatory hydro-

o 2 fi chloride salt of the title compound: m.p. 149 - 152 C, [alD + 91.1° (1%, DMF).

Prepare by treatment with sodium carbonate and ether the free base from the mother liquor derived from the formation and recrystallization of the N-tosyl-L-leucine salt, as described above. Dissolve 2.0 g of this free base and 1.73 g of N-tosy1-D-leucine in 30 ml of boiling acetonitrile. Allow the solution to cool to room temperature. Filter the solid material and recrystallize from acetonitrile to form the analytically pure diastomeric salt m.p. 155 - 156° C, [α]^<6>= +40.20° (1%, DMF). Prepare the free base of this salt by treatment with aqueous sodium carbonate and ether. Recrystallize the resulting solid from isopropyl ether to give the analytically pure dextro-enantiomeric free base form of the title compound: m.p. 72 - 72°C, [α]D + 55.30° (1%, EtOH). Dissolve the pure free base in ether, treat with ethereal hydrogen chloride and filter the precipitate. Triturate the solid with ethyl acetate to form the analytically pure levo enantiomeric hydrochloride salt of the product according to this example: m.p. 150 - 151° C,' [ a.]^ 6 - 92.1°, (1%, DMF). Other salts can be prepared by treating the free base with an acid in a known manner to form pharmaceutically acceptable acid addition salts.

Example 3

Erythro-1-benzhydryl-2-(α-hydroxybenzyl)-azetidine

Add 75.0 g of 1-benzhydry1-2-benzoylaxetidine in several portions to a stirred solution of 10.0 g of lithium borohydride in 3 liters of ether. Allow the resulting solution to stand overnight at room temperature. Add 1 liter of water and sufficient methylene chloride to dissolve any insoluble organic material. Separate the layers and wash the organic phase with water. Dry over anhydrous sodium sulfate. Remove the solvent in vacuo, then redissolve the solid residue in 2 liters of dry ether. Add 85 ml of 3.5N ethereal hydrogen chloride. Filter the solid and recrystallize from methanol-ethyl acetate to form the analytically pure hydrochloride salt of the title compound, m.p. b. 182.5 - 184° C.

To prepare the free base, stir a suspension of 50 g of the hydrochloride salt in a mixture of 175 ml of 1.1N aqueous sodium bicarbonate, 400 ml of ether and 50 ml of methylene chloride. Separate the layers and wash the organic phase successively with water and salt water. Dry over anhydrous sodium sulfate. Remove the solvent and triturate the solid residue in ether to form the analytically pure base form of the title compound, m.p. 130.5 - 131° C. Other salts can be prepared in a known manner by treating the free base with an acid while forming the . pharmaceutically acceptable acid addition salts.

Example 4

1-benzhydryl-2-(α-aminobenzyl)-azetidine

Add 5.0 g of 1-benzhydryl-2-benzimidoyl azetidine to an ice-cold suspension of 1.16 g of lithium aluminum hydride in 135 ml of dry ether. Stir the mixture at 0° C. for 15 minutes, then allow the mixture to warm to room temperature and continue stirring for 18 hours. Cool the suspension to 0°C and carefully suspend by successive addition of 1.25 ml of water, 1.75 ml of 10% aqueous sodium hydroxide and 3.5 ml of water. Stir,. filter and wash the precipitate with ether. Combine the ether washes with the original filtrate and wash the resulting solution successively with water and brine. Dry over anhydrous sodium sulfate and remove ether. in vacuum.

The erythro isomer:

Recrystallize the solid residue from isopropyl ether to give the analytically pure erythro isomer of the title compound, m.p. 112.5 - 113° C. (Retain the mother liquor for isolation of the threo-isomer).

To prepare the dihydrochloride salt" of the erythro-isomer, dissolve 3.5 g of the pure free base in 80 ml of ether. Add 5 ml of 5N ethereal hydrogen chloride. Filter the precipitate and wash with ether to form the analytically pure dihydrochloride salt, containing 0, 5 mol of crystal water The melting point shows a wide cleavage region around 190° C.

The threo isomer:

Remove in vacuo the isopropyl ether from the mother liquor from the crystallization of the erythro-isomeric free base. Chromatograph the residual oil on silica gel, eluting with 1/5 (v/v) ethyl acetate-hexane to form the analytically pure free base form of the threoisomer of the title compound with m.p. 101 - 102° C.

To prepare the dihydrochloride salt of the threo isomer, dissolve 4.5 g of the pure free base in 110 ml of ether and add 6.5 ml of 5N ethereal hydrogen chloride. Filter the precipitate and triturate in ether to give the analytically pure dihydrochloride salt containing 1 mole of water of crystallization, m.p.: cleavage over a wide range starting at 14 2°C.

Optical resolution of erythro-(-)-1-benzhydryl-2-(α-amino-benzyl)-axetidine

a. Dissolve 9.84 g of racemic erythro-1-benzhydryl-2-(α-aminobenzyl)-axetidine and 11.58 g of di-p-toluyl-1-tartaric acid in 200 ml of boiling acetonitrile. Allow the solution to cool to room temperature and decant from the fine powdery material present. Recrystallize from acetonitrile the large dense crystals that remain to form the analytically pure diastomeric salt: m.p. 126 - 128°C [α]^<6>+ 17.1° (1% EtOH).

Dissolve the pure free base in ether and treat the solution with ethereal hydrogen chloride. Filter and wash the precipitate with cold acetonitrile to form the analytically pure enantiomeric hydrochloride salt according to this example: m.p. 190 - 192° C, [a]^<6>+

8.2° (1% H 2 O).

b. Dissolve 9.84 g of racemic erythro-1-benzhydryl-2-(α*-aminobenzyl)-azetidine and 11.58 g of d-p-toluoyl-d-tartaric acid in 200 ml of boiling acetonitrile. Allow the solution to cool to room temperature and decant from the fine powdery solids present. Recrystallize from acetonitrile the large compact crystals which remain behind to form the analytically pure diastomer salt: m.p.; 125-128°C, [α]^<7>-17.4°

(1% DMF). Prepare the free base from this salt by treatment with aqueous sodium hydroxide and ether. Triturate the solid material thus isolated with petroleum ether to form the analytically pure enantiomeric free base form of the title compound: m.p. 090 - 92°C [α]^<6>-118.6° (1% EtOH). Dissolve the pure free base in ether and add ethereal hydrogen chloride to the solution. Filter and wash the precipitate with cold acetonitrile to form the analytically pure enantiomeric hydrochloride salt according to this example: m.p. 191 - 192° C [ a]* 6 -8.5 (1% H 2 O).

Example 5

A: 1-benzhydryl-2-(m-trifluoromethylbenzimidoyl)-azetidine

Suspend m-trifluoromethylphenylmagnesium bromide in ether by adding a solution of 18 g of m-bromobenzotrifluoride in 30 ml of ether to a stirred suspension of 1.94 g of magnesium shavings in 20 ml of dry ether. After the addition is complete, allow the reaction mixture to cool to room temperature and add 7.95 g of 1-benzhydry1-2-cyanoazetidine.

Stir the mixture for 18 hours at room temperature, cool to 0° C or below and quench by dropwise addition of 50 ml of water. Add 15 ml of ether and 25 ml of methylene chloride and filter the mixture through a pad of diatomaceous earth such as commercially available Celite. Remove the aqueous layer of the filtrate. Wash the organic phase with water and dry over anhydrous sodium sulfate. Remove the solvent in vacuo to give the title compound as an oil. By suitable substitution, analogues can

halogen compounds are produced.

B: 1-benzhydryl-2-(m-trifluoromethylbenzoyl)-azetidine

Stir at room temperature for 45 minutes a solution of 1.0 g of 1-benzhydryl-2-(m-trifluoromethyl)-benzimidoylasetidine from step A and 3.6 N aqueous sulfuric acid in 20 ml of methanol. Add 5 mL of 1.1N aqueous sodium bicarbonate to the reaction mixture and remove methanol in vacuo to give the title compound as an oil.

C: 1-benzhydryl-2-(α-hydroxy-m-trifluoromethylbenzyl)-azetidine

Add 910 mg of sodium borohydride to a solution of 4.75 g of 1-benzhydryl-2-(m-trifluoromethyl)-benzoylazetidine obtained in reaction B in 15 ml of methanol and stir the resulting mixture at room temperature for 3.5 hours. Remove methanol in vacuo. Dissolve the residue in ether and water, separate into layers and wash the ether phase successively with water and salt water. Dry over anhydrous magnesium sulfate. Remove the solvent in vacuo and chromatograph the residual oil on 85 g silica gel using 1/14 (v/v) ethyl acetate-hexane as eluent, forming the free base forms of erythro and threoisomers of the title compound. Crystallize from ether, the oil corresponding to the first eluted chromatographic fraction to give the free base form of the erythro isomer of the title compound, m.p. 145.0 - 145.5° £.

Dissolve in 60 ml of ether the oil corresponding to the second chromatographic fraction and treat the solution with 2.5 ml of 5N ethereal hydrogen chloride. Triturate the precipitate. Filter and recrystallize the solid from methanol-ethyl acetate to give the analytically pure hydrochloride salt of the threo-isomer according to this example: m.p. 144 - 146° C (decomposition).

Example 6

1-benzhydryl-2-(α-amino-m-trifluoromethylbenzyl)-azetidine

Add 4.75 g of 1-benzhydryl-2-(m-trifluoromethylbenzimidoyl)-azetidine to a stirred, ice-cooled suspension of 695 mg of lithium aluminum hydride in 85 ml of dry ether. When the addition is complete, remove the cooling bath and stir the mixture at room temperature for 5 hours. Cool the suspension to 0° C and neutralize excess metal hydride by careful successive addition of 0.9 ml of water, 1.4 ml of 10% aqueous sodium hydroxide and 2.8 ml of water. Filter and wash the precipitate with ether. Combine these washes with the original filtrate and wash the resulting solution successively with water and saline. Dry over anhydrous magnesium sulfate. Remove the ether in vacuo and chromatograph the residual oil on

105 g of silica gel and elute with 1/8 (v/v) ethylacetate-hexane to form purified oils of the free base forms of the erythro- and threo-isomers of the title compound (characterized by NMR spectra). Under the above conditions, the erythro form is the more mobile of the two isomers.

Di-HCl salt of the erythroisomer:

Dissolve the free base form of the erythro isomer obtained

from the above chromatography in 50 ml of ether and treat the solution with 2 ml of 5N ethereal hydrogen chloride. Filter the resulting solid and recrystallize it from methanol-acetonitrile to give the analytically pure dihydrochloride salt of the erythroisomer of the title compound, m.p.: darkens and softens to a gum at 176°C and then decomposes over a wide temperature range varying with the rate of heating .

The dihydrochloride salt of the threoisomer:

Dissolve the free base form of the threoisomer obtained from the above chromatography in 5 ml of ether and treat the solution with 1 ml of 5N ethereal hydrogen chloride. Filter the resulting solid and crystallize it from methanol-ethyl acetate to give the analytically pure dihydrochloride salt of the threoisomer of the title compound, m.p. 173.5 -

175.5° C (decomposition).

Example 7

1-benzhydryl-2-benzylazetidine

To a solution of 6.0 g of threo-1-benzhydryl-2-(α-hydroxybenzyl)-azetidine and 1.84 g of triethylamine in 100 ml of dry benzene kept below 10° C., add 2.08 g of methanesulfonyl chloride. Allow the stirred solution to stand at 6 - 10° C for 2 hours. Add to the mixture 150 ml of dry dimethylsulfoxide and 3.40 g of sodium borohydride. Stir at room temperature for 85 hours. Add ether and water, separate the resulting layers and re-extract the aqueous layer with additional ether. Wash the combined organic phases successively with water and brine, dry over anhydrous sodium sulfate and remove the solvent in vacuo. Chromatograph the resulting oil on 275 g of silica gel, eluting with 1/20 (v/v) ethyl acetate-hexane to give the analytically pure product according to this example, m.p. 87.5 - 89.5° C.

Example 8

Brythro-1-benzhydryl-2-[α-(N-acetamido)-benzyl]-azetidine

Dissolve 500 mg of erythro-1-benzhydryl-2-(α-aminobenzyl)-azetidine in 6 ml of dry ether and to the stirred solution add 1 ml of acetic anhydride. Stir at room temperature for 5 minutes. Dissolve the resulting precipitate in 3/1 (v/v) ether-methylene chloride and wash the solution successively with 10% aqueous sodium bicarbonate, water and saturated aqueous sodium chloride solution. Dry over anhydrous sodium sulfate and remove the solvent in vacuo. Triturate the resulting solid with ether to give the analytically pure title compound, m.p. 183 - 187° C.

. Example 9

A.. 1-Benzhydryl-2-[d-(N-trifluoroacetylimino)-benzyl]-azetidine

Dissolve 100 mg of l-benzhydryl-2-benzimidoylazetidine in

3.5 ml of benzene, add an equivalent of triethylamine and cool the solution to approx. 5° C. Add one equivalent of trifluoroacetic anhydride and maintain the reaction solution at 5° C. for 30 minutes. Treat the solution with ether and sufficient aqueous sodium bicarbonate to make the resulting mixture slightly alkaline. Separate the layers and wash the organic phase successively with water and saturated aqueous sodium chloride solution. Dry over anhydrous sodium sulfate and remove the solvent in vacuo. The resulting oil is used directly without further purification in the preparation of 1-benzhydryl-2-[α-(N-trifluoroacetamido)-benzyl]-azetidine.

B-1-Benzhydryl-2-[α-(N-trifluoroacetamido)-benzyl]-azetidine

Cool to 0°C a solution of 1.0 g of 1-benzhydryl-2-[α-(N-trifluoroacetylimino)-benzyl]-azetidine (from step A) in 25 mL of ether. Add to this solution 1.3 ml of a 2 molar ethereal solution of methyllithium. Maintain the reaction mixture at 0° C. for 1 hour, then allow it to stand at room temperature for 2 hours. Cool the mixture in an ice bath and quench by careful dropwise addition of 4-5 ml saturated aqueous ammonium chloride solution. Dilute the mixture with additional ether and water, separate the layers and wash the organic phase successively with water and saturated aqueous sodium chloride solution. Dry over anhydrous sodium sulfate and remove the solvent in vacuo to give the title compound.

C: 1-benzhydryl-2-[(α-methyl-α-amino)-benzyl]-azetidine

Dissolve 1.0 g of 1-benzhydryl-2-[α-methyl-α-(N-trifluoro-azetamido)-benzyl]-azetidine. (from step B) in 15 ml of a 1N solution of potassium hydroxide in methanol. Add 0.5 ml of water and reflux under nitrogen for 65 hours. Cool to room temperature, treat the reaction mixture with ether and water and separate the resulting layers. Wash the organic phase thoroughly with water, then with saturated aqueous sodium chloride solution and dry over anhydrous sodium sulfate. Remove the solvent in vacuo to form the product of this example.

Example 10

Threol-1-benzhydryl-2-(α-methoxybenzy1)-azetidine

Cool to 0 - 5°C a solution of 4.0 g of threo-1-benzhydryl-2-(α-hydroxybenzyl)-azetidine in 40 ml of dry dimethylformamide. Add to this solution 640 mg of a 55% (by weight) dispersion of sodium hydride and stir at ice bath temperature for 30 minutes. Add 2.25 g of methyl iodide and stir at room temperature for 2.5 hours. Quench the reaction mixture with water, add ether and separate the layers. Wash the organic phase successively with water and saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate and remove the solvent in vacuo. Chromatograph the residual oil over silica gel, eluting with 1/2.5 (v/v) ethyl acetate-hexane. Low temperature crystallization from hexane of the first eluted fraction gives the analytically pure title compound, m.p. 51- - 56° C.

Example 11

l- benzhydryl- 2-[ a- methyl- a- hydroxy)- benzyl]- azetidine-

By treating 1-benzhydryl-2-benzoylazetidine obtained according to preparation (e) with methyllithium in a known manner, the title compound is obtained with a melting point for the HCl salt of

152 - 153.5° C.

Example 12

Threol-1-benzhydryl-2-(α-hydroxybenzyl)-azetidine

Dissolve 1.63 g of threo-2-(α-hydroxybenzyl)-azetidine in 45 ml of acetonitrile. Add 1.0 g of potassium bicarbonate and to the resulting suspension, with stirring, add a solution of 2.57 g of benzhydryl bromide (bromodiphenylmethane) in 15 ml of acetonitrile. Heat the stirred mixture to reflux temperature and maintain boiling under reflux and nitrogen atmosphere for 3 hours. Allow the reaction mixture to cool, dilute with ether and filter out solids. Remove the solvent in vacuo from the filtrate. Dissolve the residue in ether, wash the solution with water and salt water and dry over anhydrous sodium sulphate. Add to the dried ether solution 5 ml of 2M ethereal hydrogen chloride. Filter the resulting solid and recrystallize it from methanol-ethyl acetate to give the analytically pure hydrochloride salt of threo-1-benzhydryl-2-(α-hydroxybenzyl)-azetidine, m.p. 175 - 176° C (decomposition).

Example 13

1-benzhydryl-2-(α-hydroxy-α-methylbenzyl)-azetidine

Add to a stirred solution of 3.19 g mercuric acetate

in a medium consisting of 10 ml of water and 15 ml of tetrahydrofuran slowly a solution of 3.39 g of 1-benzhydryl-2-(a-methylenebenzyl)-azetidine in approx. 60 ml tetrahydrofuran. When the addition is complete, stir the reaction mixture for 30 minutes at room temperature. Add 10 ml of 3M aqueous solution of sodium hydroxide followed by 10 ml of a 0.5M solution of sodium borohydride in 3M sodium hydroxide and stir for 30 minutes. Dilute the reaction mixture with sufficient ether to give a biphasic system. Separate the organic layer, dry over anhydrous sodium sulfate and remove the solvent in vacuo to form a mixture of erythro-

and, threoisomers of 1-benzhydryl-2-(α-hydroxy-α-methylbenzyl)-azetidine. Dissolve this product in 100 ml of ether and add 6 ml of 2M ethereal hydrogen chloride. Recrystallize the impure salt to form the analytically pure hydrochloride salt of an isomer (the relative stereochemistry has not been definitely determined) of the title compound, m.p. 182 - 184° C. Further crystallization of the mother liquor gives the hydrochloride salt of the second isomer with m.p. 152 - 153.5° C.

Example 14

1-benzhydryl-2-(α-methylaminobenzyl)-azetidine

o

To a stirred solution of 2.50 g of 1-benzhydryl-2-(α-aminobenzyl)-azetidine in 25 ml of N,N-dimethylformamide, add 365 mg of a 55% dispersion of sodium hydride. Stir the mixture under a nitrogen atmosphere and when the foaming subsides, heat and maintain the stirred mixture at 40°C for 20 minutes. Cool the mixture to -25°C and add 1.20 g of methyljpdid. Remove the reaction mixture from the cooling bath and allow it to warm to room temperature. After approx. 15 minutes at room temperature, keep the contents of the reaction flask in a stirred mixture of 100 ml water and 25 ml ether. Separate the layers and reextract the aqueous phase with ether. Combine all ether extracts, wash successively with water and brine, dry over anhydrous sodium sulfate and evaporate solvent in vacuo. Crystallize the solid residue from ether to form the analytically pure title compound containing 1/4 mol of crystal water and with a melting point of 111 - 113°C.

Example 15

1-benzhydryl-2-(α-hydroxybenzyl)-azetidine

To a mixture of 5.0 g of 1-phenyl-2,4-dibromo-butanol (mixture of diastereomers) and 3.25 g of potassium bicarbonate in 30 ml of acetonitrile, add 2.70 g of benzhydrylamine. Reflux the stirred mixture under a nitrogen atmosphere for 18 hours. Filter the solid material and wash it thoroughly with ether. Combine the washings with the filtrate and remove the solvent in vacuo from the resulting solution. Dissolve the residue in ether and wash successively with a 1:1 mixture of saline and water, then only with saline. Dry over anhydrous sodium sulfate and remove the solvent in vacuo. Chromatograph the residue on silica gel using 1/15 (v/v) ethyl acetate-hexane as eluent to form the erythroisomer (analytically pure sample has m.p. 131.0 - 131.5°C) and the threoisomer (analytically pure sample has m.p. 87.5 - 88.5° C) of 1-benzhydryl-2-(α-hydroxy-benzyl)-azetidine.

Example 16

1-benzhydryl-2-(α-acetoxybenzyl)-azetidine

Cool in an ice bath a solution of 1.5 g of threo-1-benzhydryl-2-(α-hydroxybenzyl)-azetidine and 1.22 g of triethylamine in 15 ml of dry benzene. Add to the stirred solution 865 g of acetyl chloride. Stir the resulting reaction mixture in an ice bath for 10 minutes, then at room temperature for 1.5 hours. Pour the reaction mixture into a stirred mixture of 50 ml of ether and 50

ml of water. Separate the layers, reextract the aqueous phase with fresh ether and combine the ether phases. Wash the resulting ether solution successively with water and brine, dry over anhydrous sodium sulfate and remove the solvent in vacuo. Crystallize the residue from ether to give analytically pure 1-benzhydryl-2-(α-acetoxybenzyl)-azetidine, m.p. 128 - 131° C.

Example 17

Threol-1-benzhydryl-2-(α-hydroxybenzyl)-azetidine

Dissolve 500 mg of threo-2-(α-hydroxybenzyl)-azetidine in

12.5 ml of methanol. Add to the solution 1/60 ml of 1.9 M ethereal hydrogen chloride, then 560 mg of benzophenone and 193 mg of sodium cyanoborohydride. Add an amount of Type 3A molecular sieve and allow the resulting mixture to stir under a nitrogen atmosphere at room temperature until the reaction is complete as indicated by thin layer chromatography. Filter out the solid materials and wash thoroughly with methylene chloride. Combine the methylene chloride washes with the filtrate and pour the resulting solution into a stirred mixture of 50 ml saturated aqueous sodium bicarbonate solution and 35 ml ether. Separate the phases and reextract the organic layers with ether. Wash the combined organic phases successively with water and brine and dry over anhydrous sodium sulfate. Filter the desiccant, remove the solvent

vacuum and redissolve the residue for approx. 10 ml of ether. Add to this ethereal solution 1.75 ml of 2M ethereal hydrogen chloride. Filter the resulting solid and recrystallize it from methanol-ethyl acetate to give the analytically pure hydrochloride salt of threo-1-benzhydryl-2-(α-hydroxybenzyl)-azetidine, m.p. 175 - 176°C (decomposition).

Procedure:

Mix the threo-1-benzhydry1-2-a-(hydroxybenzyl)-azetidine hydrochloride with the lactose, dicalcium phosphate and sodium lauryl sulfate. Sieve the above mixture through a No. 60 sieve and granulate with an aqueous solution containing polyvinylpyrrolidone. Add additional water if necessary to bring powders to a paste-like mass. Add cornstarch and continue mixing until uniform granules are formed.- Thoroughly pass the mass through a sieve No. 10 (US standard), spread out the mass and dry in an oven at 100° C for 12 - 14 hours. Reduce the dried granulated mass through a No. 16 sieve, add sodium lauryl sulfate and magnesium sulfate, mix and press into the desired shape on a tablet machine.

Coating:

Treat the above cores with a varnish and sprinkle with talcum powder to prevent moisture absorption. Add substrate to round out the core. Apply a sufficient number of layers of varnish to make the core "gut-fit". Apply additional undercoat and smooth, the layers to completely round and smooth tablets. Add color coating until the desired shape is obtained. After drying, they polish the coated tablets to give the tablets a uniform shine.

Procedure:

Mix together erythro-1-benzhydryl-2-(α-aminobenzyl)-azetidine, propionic acid, lauryl sulfate and lactose. Pass the mass through a No. 80 sieve. Add magnesium stearate, mix and encapsulate in the appropriate two-part gelatin capsule.

Claims (1)

1. Pharmaceutically active compounds of general formula I: where n is an integer from 1 to 5, R and R' independently represent a hydrogen atom or a lower alkyl group, X is a hydrogen atom, a hydroxy, lower alkoxy, aralkyl or acyloxy group or an unsubstituted or mono- or di- substituted amino group, wherein the substituents are lower alkyl, aralkyl or acyl group, and Y, Y <*> and Y" independently represent a hydrogen atom, a hydroxyl group, a lower alkoxy group, a halogen atom or a trifluoromethyl group, and therapeutically acceptable salts of such compounds.; 2. Compounds according to claim 1, characterized in that Y' and Y" both represent hydrogen.;3. Compounds according to claim 1 or 2, characterized in that R represents hydrogen.;4. Compounds according to any one of claims 1-3, characterized in that Y represents hydroxyl, lower alkoxy, halogen or trifluoromethyl in the meta or para position.;5. Compounds according to any one of claims 1-3, characterized in that Y is hydrogen.; 6. Compounds according to any one of claims 1-5, characterized in that R' is methyl.; 7. Compounds according to any one of claims 1-5, v characterized in that R1 is hydrogen.;8. Compounds according to any one of claims 1-7, characterized in that X represents a hydrogen atom, a hydroxy, lower alkoxy, amino, phenyl-lower alkyl-amino or acyl-amino groupi.;9. Compounds according to any one of claims 1-8, characterized in that X represents a hydrogen atom, a hydroxy, methoxy or amino group or the grouping -NHCH2 CgH5 .;10. Compounds according to any one of claims 1-9, characterized in that X represents a hydroxy or amino group.; 11. Compounds according to any one of claims 1-10, characterized in that n denotes the whole number 1.; 12. Compounds according to any one of claims 1-10, characterized in that n denotes the whole number 2.; 13. Compounds according to any of claims 1-10, characterized in that n denotes the whole number 3,;4 or 5.;14. Threq-1-benzhydryl-2-(α-hydroxybenzyl)-azetidine.; 15. * Erythro-1-benzhydryl-2-(α-hydroxybenzyl)-azetidine. 16. Threo-(+)-1-benzhydryl-2-(α-hydroxybenzyl)-azetidine. 17. Threo-(-)-1-benzhydryl-2-(α-hydroxybenzyl)-azetidine. 18. Erythro-1-benzhydryl-2-(α-aminobenzyl)-azetidine. 19. Threo-1-benzhydryl-2-(α-aminobenzyl)-azetidine. 20. Threo-(+)-1-benzhydryl-2-(α-aminobenzyl)-azetidine. 21. Threo-(-)-1-benzhydryl-2-(α-aminobenzyl)-azetidine. 22. Erythro-1-benzhydryl-2-(α-hydroxybenzyl)-pyrrolidine. 23. Threo-1-benzhydryl-2-(α-hydroxybenzyl)-pyrrolidine. 24 . Erythro-1-benzhydryl-2-(α-hydroxybenzyl).-piperidine. 25. Threo-1-benzhydryl-2-(α-hydroxybenzyl)-piperidine. 26. 1-[a-phenyl-(p-chlorobenzyl)]-(a-hydroxybenzyl)-azetidine, 1-benzhydryl-2-benzyl-azepine and 1-benzhydryl-2-benzyl-azocine. 27. The hydrochloride salts of the compounds according to any one of claims 1-26. 28. Process for the production of pharmaceutically active compounds of general formula I where n is an integer from 1 - 5, R and R1 independently represent a hydrogen atom or a lower alkyl group, X is a hydrogen atom, a hydroxy, lower alkoxy, aralkyloxy or acyloxy group or one unsubstituted or mono- or di-substituted amino group, wherein the substituents are a lower alkyl, aralkyl or acyl group, and Y, Y<1> and Y" independently represent a hydrogen atom, a hydroxy group, a lower alkoxy group, a halogen atom or a trifluoromethyl group, and therapeutically acceptable salts of such compounds, characterized by ata) .a compound of general formula II is reacted with a compound of general formula in which the formulas n, R, Y, Y <1> and Y" have the meanings given above, or except that any primary amino group represented by X may be protected with a protecting group, which is then removed, b) for the preparation of the compounds of formula In which X represents a hydroxy or amino group and R<1> represents hydrogen, that a compound of general formula: where n, R, Y, R<1> and Y" have the meanings given above and Z represents a group which is reducible to a hydroxy-respectively amino group, the group Z,c) is subjected to a reduction for the preparation of compounds of formula I wherein X is a hydroxy group or an unsubstituted or mono-substituted amino group and R' is a lower alkyl group, that a compound of general formula: where n, R, Y<1> , Y" and Y have the meanings given above and R2Q represents oxygen or the grouping NR^^ where R2^ is hydrogen, or a lower alkyl, aralkyl or acyl group, reacted with the respective. R 1 -organo-metallic compound, followed by hydrolysis of the organometallic complex thus obtained, d) for the preparation of compounds of formula I where X represents a mono- or di-substituted amino group, that the corresponding compound of formula I where X represents a. amino group is subjected to an alkylation, aralkylation or acylation reaction, e) for the preparation of compounds of formula I where X represents an amino group, that the corresponding compound of formula I where X represents an amino group protected by a protecting group is subjected to a removal of the protecting group, f) for the preparation of compounds of formula I where X represents a lower alkoxy or aralkyl group, that the corresponding compound of formula I where X represents a hydroxy group is subjected to an etherification reaction, g) for the preparation of compounds of formula I where X represents a hydroxy group and R<1> represents lower alkyl,' that a compound of general formula where n, R, Y, Y' and Y" have the previously stated meanings and R" represents a lower alkylidene group, is subjected to an addition reaction whereby water is added to the double bond, h) for the preparation of compounds of formula I where X represents a hydroxy group and R<1> represents hydrogen, that a compound of general formula is reacted with a compound of the formula in which formulas n, R, Y, Y' and Y" have the previously indicated meanings, i) for the preparation of compounds of formula I where R represents hydrogen, that a compound of general formula is reacted with a compound of general formula in which formulas n, R', X, Y, Y' and Y" . have the previously indicated meanings, j) for the preparation of compounds of formula I where both X and R' represent hydrogen, that a compound of general formula where n, R, R', Y, Y1 and Y" have the previously indicated meanings and R^q represents a derived ketp group, is subjected to a reduction of the group R-^q to hydrogen, k) for the preparation of compounds of formula I. where X represents hydrogen, that a compound of general formula where n, R, R <1> , Y, Y <1> and Y" have the previously indicated meanings and R, -, represents. a derived hydroxy group, subject to a reduction of the grouping R-^ to hydrogen, and that if desired , any compound obtained according to methods a) to k) is transferred to a salt. 29. Method according to claim 28 b), characterized in that the grouping Z represents oxygen respectively NH, N-NH2 or N-OH. 30. Method according to claim 28 c), characterized in that the organometallic compound used is R'Li, R1 MgBr or R'-Mgl., where R1 is a lower alkyl group. 31. Method According to claim 28 j), characterized in that the derived keto group R1Q is NNHTs where Ts denotes a tosyl group. 32. Method according to claim 28 k), characterized in that the derived hydroxy group R-^ is 33. Method according to any one of claims 28 - 32. characterized by n being 1. 34. Method according to any one of claims 28 - 32, characterized in that n is 2. 35. Method according to any one of claims 28 - 32/characterized in that n is 3.4. or 5. 36. Pharmaceutical compositions comprising as active ingredient a compound according to any one of claims 1 - 27. 37. Pharmaceutical compositions as described in claim 36 and mainly as described here. 38. Method for producing a pharmaceutical composition, characterized in that a compound according to any one of claims 1-27 is brought into a form suitable for therapeutic administration. 39. Method according to claim 38, characterized in that the active ingredient is mixed with a suitable carrier. 40.. Pharmaceutical composition prepared by a method according to claim 38 or claim 39. 41. Pharmaceutical composition according to any one of claims 36, 37 and 40 in the form of a dosage unit. 42. Pharmaceutically active compound of formula I according to claim 1, prepared by a method according to any one of claims 28-35. 43. Method according to any one of claims 28 - 35, 38 and 39 and mainly as described and exemplified here. 44. 1-Benzhydryl-2-cyanoazetidine. 45. l-Benzhydryl-r2b enzymIdo <y> l- aze <t> idin <.>