NO140136B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE N- (2-AZACYCLOALKYLIDENE) -N`-ARYLURIN SUBSTANCES - Google Patents

Description

Analogy method for the production of therapeutic

tically active N-(2-azacycloalkylidene)-N'-aryl-

urine substances.

The present invention relates to methods for the production of pyrrolidylidene, piperidylidene and hexahydro-azepinylidene ureas which show SNS suppressive action. In the state of the art, in the U.S. patent no. 3,564,010 described pyrrolidylideneureas which have two cyclic substituents in the 3-position in the pyrrolidine ring and in which ring the nitrogen atom is unsubstituted. In contrast to this, the present pyrrolidylidene ureas do not have any substituents in the 3-position of the pyrrolidine ring and furthermore the ring nitrogen atom is substituted either with a lower alkyl group or a benzyl group.

The new pyrrolidylidene, piperidylidene and hexahydroazepinylidene ureas according to the invention can be structurally described with the formula:

where: n is the whole number 1, 2 or 3;

R is selected from hydrogen and lower alkyl, preferably methyl;

R-1 is selected from lower alkyl and benzyl;

R 2 is selected from hydrogen and lower alkyl, preferably methyl; and

Ar is selected from phenyl, naphthyl, mono-, di- and tri-halophenyl, mono-, di- and tri-lower alkylphenyl, mono-, di- and tri-lower alkoxyphenyl, mono- or

di-trifluoromethylphenyl, nitrophenyl, cyanophenyl, methylthiophenyl, lower alkylcarbonylphenyl, benzyloxyphenyl, lower alkylhalophenyl, lower alkoxyhalophenyl, benzyloxyhalophenyl, trifluoromethylhalophenyl and

nitrogen phenyl;

provided that said R is hydrogen and said R is lower alkyl when n is 2 or 3.

The therapeutically active acid addition salts of the preceding compounds (I) are also within the scope of the present invention.

As used herein, the terms "lower alkyl" and "lower alkoxy" mean a straight or branched chain of from 1 to about 5 carbon atoms such as e.g. methyl, ethyl, propyl, isopropyl, butyl, pentyl and similar alkyls and further the respective corresponding alkoxy compounds such as methoxy, ethoxy etc. The term "halogen" means bromine, fluorine, iodine and chlorine.

The pyrrolidylidene, piperidylidene and hexahydroazepinylidene ureas of the formula I, where R 2 is hydrogen, are readily obtained by reaction of a suitable 2-iminopyrrolidine, 2-imino-piperidine or 2-iminohexahydroazepine (II), also known as 2-imino-( tetra-, penta- and hexa-)-methylene imines with a suitable phenyl or naphthyl isocyanate (III), preferably using equimolar amounts in a non-hydroxyl solvent, e.g. an aromatic hydrocarbon such as benzene, toluene, xylene and the like, ethers such as dioxane, diethyl ether, tetrahydrofuran and the like, and halogenated hydrocarbons such as methylene chloride, chloroform and the like. Usually, no external heating is necessary to increase the reaction rate. The above-mentioned reaction can be schematically illustrated as follows:

The present compounds (I) where R2 is lower alkyl, can be prepared by acylation of (II) with a suitable carbamoyl halide of the formula (IV), preferably by using two molar equivalents of the former per molar equivalent of the latter. One of the molar equivalents of (II) acts as an HCl scavenger while the other forms the desired urea product. A non-polar solvent as mentioned above is preferably used so that the HCl salt with the HCT remover, which is insoluble, is separated and can be easily removed by filtration. The desired urea product (I) which usually remains in solution is then recovered by conventional techniques such as evaporation of the solvent followed by recrystallization from conventional solvents. The acylation reaction can be illustrated schematically as follows: The 2-imino-(tetra-, penta- and hexa-)methylene imines of the formula (II) are for the most part described in the literature. To the extent that they are not described, they are obtained by conversion of the corresponding acid addition salt:

where HX denotes typical acids such as HC1, HBr, HBF^ and the like.

A characteristic method for the preparation of the salts

with the formula (V) will be found in the examples. The salt-to-base conversion is readily accomplished by treatment with a suitable alkali such as alkali metal or alkaline earth metal hydroxides, carbonates and the like, although a strong alkali such as 10-50% NaOH is preferred in an aprotic solvent such as benzene, ether and such. Usually a minimal amount of water is also used. The resulting free base (II) remains in the up-

solution in the aprotic solvent and the organic solution is used as in the reaction method described above. Before use, however, the solution is treated with a desiccant, e.g. potassium carbonate, to remove residual water that can affect the subsequent reaction with the isocyanates

(III):

Many of the phenyl isocyanates with the formula (III) are known and, to the extent that they are not known, they can be prepared by methods that have previously been described in the literature, such as e.g. by K. Inukai and Y. Maki in "Kogyo Kagaku Zasshi", 67 (5), 807 - 9 (1964) and in "Kogyo Kagaku Zasshi", 70 (4), 491 - 4 (1967) or by J.G. Lombardino and CF. Gerber in "J. Med. Chem.", 7, 101 (1964). E.g. can according to such methods such phenyl isocyanates as 2,6-dibromo- (melting point 68 - 70°C); 3,5-di-chloro- (melting point 84 - 88°C); 2,6-di-methoxy- (melting point 32 - 35°C); 3,4-di-methoxy-; 3,4,5-tri-methoxy; 3-trifluoromethyl-; and similar derivatives of phenyl isocyanates which are encompassed by the formula (III) are obtained. The carbamoyl chlorides of the formula (IV) can be prepared by the method described by J.A. Aeschlimann in the U.S. Patent No. 2,449,440. According to this method, a suitable aniline is treated with the formula NH-Ar, in which Ar is such as be-<R>2 written above and R2 is a lower alkyl with an excess of ClgCO to obtain the corresponding carbamoyl chlorides of formula (IV):

The present compounds of formula (i) have been found to have useful pharmacological properties as shown in one or more of the following tests of SNS depressant effect on laboratory animals.

Test A: This is an anti-anxiety test as indicated by I. Geiler in "Psychosomatic Medicine", (J.H. Nadine and J.H. Moyer) (Lea and Febiger, Phila.), p. 267, 1962, modified

by D.L. Margules and L. Stein in "Psychopharmacologia" (Berlin) 13, 74 - 80, 1968. The anxiolytic effect of the compound to be tested is studied in rats daily for 5 days after i.p. injection of the compound in doses usually in the range of 10 - 25 mg/kg body weight and the effect of the compound is noted in the animal's degree of pushing against an obstacle while working to obtain food. The method consists in determining the effect of a test compound on non-punished and punished animals. Hungry rats are trained to push an obstacle to obtain nourishment: a scoop full of milk is given to the rat on average once every two minutes (variable interval schedule V, I, II). After following this plan for 12 minutes, a tone is given for 3 minutes that signals reward and simultaneous punishment for each push against the obstacle (one scoop full of milk is given and this is accompanied by a shock given through the grid floor for each push of the obstacle). The shock given has a duration of 0.2 milliseconds and is in intensity in the range from 0.5 to 3.5 milliamperes. Each rat is presented with 4 to 6 alternating pairs of non-punishment periods when only milk is given and punishment periods when milk and shock are given. Checks are made for each rat after intraperitoneal injection of saline solution daily for 5 days. Each rat is assessed at the same time of day and in the same test chamber. The reactions are recorded and the food (milk) and the punishment (shock) are given using appropriate automated equipment.

Test B: This is a test of the muscle relaxant effect, judged by the effect of the compound to be tested on strychnine-induced seizures as described by M.J. Orloff et al. in "Proe. Soc. Exp. Biol. and Med.", 70, 254, 1949, modified by G. Chen and B. Bonner in "J. Pharmacol. and Expt. Therap.' 117, 142, 1956. The antistrychnine effect is observed in mice at oral doses of about 25-500 mg/kg body weight by determining the effect of the compound on the number induced by strychnine.

Sample C: This is a sample of the anticonvulsant effect induced by supramaximal electroshock convulsions as described by E.A. Swinyard et al. in "J. Pharmacol. Expt. Therap.", 106, 319, 1952. In this test, the compound to be tested is administered orally to mice in doses usually in the range of 25 - 500 mg/kg body weight and the blocking effect of the compound on the tonic convulsion that follows after the supramaximal current is applied to the animals is noted.

Sample D: This is a sample of mouse behavior as described by S. Irwin, "Gordon Reserach Conference on Medicinal Chemistry", 1959, p. 133. In this sample, symptoms such as ataxia, reduction in motor activity are observed and loss of stability reflexes after intraperitoneal administration in mice of the compound to be tested in doses ranging from 10 - 300 mg/kg body weight.

In the following table, the SNS profile for various of the present compounds is indicated, shown by their relative positive response to one or more of the aforementioned samples.

The present compounds with the formula (I) in base form can be converted into the corresponding pharmaceutically acceptable, therapeutically active acid addition salts by reaction with a suitable inorganic acid such as e.g. hydrochloric, hydrobromic, hydroiodic, sulfuric and similar acids; or with a suitable organic acid such as e.g. acetic acid, propionic acid, glycolic acid, lactic acid, oxalic acid, malonic acid, tartaric acid, citric acid, sulfamic acid, ascorbic acid and similar acids. Conversely, the acid addition salt can be converted to the free base by known treatment with a suitable alkali.

Typical examples of compounds with the formula (1) in which n is 1, R is hydrogen and R-^ is methyl, and which can be prepared according to the present invention are the following:

Below is described a general method for producing the acid addition salts with the formula V. The fluorine borates are initially prepared and from these other acid addition salts are easily obtained.

Triethyloxonium fluoroborate is prepared on a 0.6 mole scale from 113.55 g or 0.80 mol of boron trifluoride etherate and 55.52 g or 0.60 mol of epichlorohydrin in anhydrous ether according to the procedure described by Meerwein et al., "Ann. ", 641, 1

(1961). After the oily crystals have been washed with fresh anhydrous ether by decantation, 0.60 mol of the suitable 2-pyrrolidone or 2-piperidone with the formula is added:

wherein n, R and R-^ are as described previously, to an aqueous methylene chloride solution of the oxonium salt. After stirring for periods of 2 - 17 hours, depending on the individual reaction rate, anhydrous ammonia is bubbled into the reaction mixture at such a rate that reflux is achieved (due to the heat of reaction when adding ammonia). After the initial reaction has occurred, the reaction mixture is quenched with additional ammonia and the mixture is then stirred at ambient temperatures until the reaction is complete. Subsequent removal of both the excess ammonia and the solvent in vacuo yields a residue of the respective 2-iminopyrrolidine or 2-iminopiperidine fluoroborate salt which is then recovered and purified in the usual manner for recrystallization from

suitable solvents. The fluoroborate salts are converted into the corresponding free bases by treatment with strong alkali, e.g.

10 - 50 percent NaOH, and extracted into organic solvents, e.g. ether, benzene, methylene chloride and the like, from which other mineral or organic acid salts are obtained by standard techniques.

According to the above-mentioned method, below are examples of typical salts of the formula V which are obtained:

<+> described by R. Kwok et al. in "J. Org. Chem.", 32, 738 (1967). <++> described by J. Renault, "Ann. Chim.", (Paris) 10, 135 (1955).

The following examples are given to further illustrate the invention. Unless otherwise stated, all parts are given as parts by weight.

Example 1

1-(1-methyl-2-pyrrolidylidene)-3-phenylurea:

After dissolving 4.9 g or 0.05 mol of 2-imino-1-methylpyrrolidine in anhydrous benzene, 5.96 g or 0.05 mol of phenyl isocyanate is added dropwise while stirring (heat is developed). The reaction mixture is stirred for half an hour. The solid product that forms, l-(l-methyl-2-pyrrolidylidene)-3-phenylurea, is collected (melting point 140 - 144°C), recrystallized from methanol and the pure product with a melting point of 146 - 147.5 is obtained °C. Example 2 1-(1-methyl-2-pyrrolidylidene)-3-(3,4-dimethoxyphenyl)-urea: After dissolving 5.4 g or 0.055 mol of 2-imino-1-methylpyrrolidine in dry benzene, add 9.85 g or 0.055 mol of 3,4-dimethoxyphenyl isocyanate (prepared according to the method described by J.G. Lambardino and C.T. Gerber in "J. Med. Ch<?m.", 7, January 1964, p. 101), dissolved in dry benzene , to the solution. The reaction mixture is stirred at room temperature overnight (about 16 hours). The solvent is evaporated in vacuum and the residue which becomes solid on cooling is triturated with anhydrous methanol. Repeated recrystallizations from methanol give the pure product, 1-(1-methyl-2-pyrrolidylidene)-3-(3,4-dimethoxyphenyl)urea with a melting point of 118 - 120°C.

By repeating the procedure indicated in Example

2 and by replacing 3,4-dimethoxyphenyl isocyanate with an equivalent amount of a suitable phenyl isocyanate of the formula III, the compounds of the formula I which are indicated in the following table are obtained.

Example 3

1-( 1- methyl- 2- pyrrolidylidene)- 3- P- nitrophenyl- urea:

To a suspension of 6.73 g or 0.05 mol of 1-methyl-2-iminopyrrolidine hydrochloride in 100 ml of benzene, 2 ml of water are added followed by 5 ml of 50% NaOH. After stirring for 5 minutes, the benzene layer is decanted to excess anhydrous potassium carbonate. This is repeated twice with 75 ml portions of fresh benzene. The combined extracts are quickly filtered from the absorbent ("dicalite pad" and suction). 8.21 g or 0.05 ml of p-nitrophenyl isocyanate as a solution in benzene is added to the filtrate in one portion with stirring (the isocyanate solution is filtered before use). After stirring for one hour, the solid, 1-(1-methyl-2-pyrrolidylidene)-3-p-nitrophenylurea is collected, and this is used and has a melting point of 180 - 182°C. Recrystallization from acetone-methanol gives the pure product with a melting point of 182 - 183°C.

By repeating the general procedure in the example

3 and by replacing p-nitrophenyl isocyanate with an equivalent amount of a suitable phenyl isocyanate with the formula III is obtained for-

Example 4 1-methyl-3-(1-methyl-2-pyrrolidylidene)-1-phenylurea:

The hydrochloride salt of 2-imino-l-methylpyrrolidine i

a quantity of 13.46 g or 0.1 mol is converted to free base by adding 10 ml of 50% NaOH and extraction into benzene. After evaporation over K^CO-^, the benzene layer is stirred at room temperature and 8.48 g or 0.05 mol of N-methyl-phenylcarbamoyl chloride (prepared according to the method in U.S. patent no. 2,449,440), dissolved in anhydrous benzene, is added dropwise to this solutionc Cloudiness sets in and then the solid precipitates out from the reading. The mixture is stirred at room temperature overnight and then filtered. The filtrate is evaporated to dryness in vacuum to an oily residue which is then dissolved in hot hexane and filtered hot. Cooling and scraping produce crystals that are collected and recrystallized from

hexane and one obtains the pure product, l-methyl-3-(l-methyl-2-pyrrolidylidene)-l-phenylurea with a melting point of 27.5 - 30°C.

Example 5

1-(l-n-butyl-2-pyrrolidylidene)-3-(2,6-dimethylphenyl)-urea: 15.97 g or 0.05 mol of the cyclohexylsulfamic acid salt of l-n-butyl-2-iminopyrrolidine is converted to 7 .01 g or 0.05 mol free base in the usual way. After evaporation over ^CO^, the benzene solution is filtered through diatomaceous earth and 7.36 g or 0.05 mol of 2,6-dimethylphenyl isocyanate is added. The reaction mixture is stirred at room temperature for 3.5 hours and is then evaporated to dryness in vacuum and an oily residue is obtained which crystallizes out on cooling. Recrystallization from ethyl acetate gives the pure product, 1-(1-n-butyl-2-pyrrolidylidene)-3-(2,6-dimethylphenyl)urea with a melting point of 93 - 95°C

Example 6

1(l-n-butyl-2-pyrrolidylidene)-3-(m-chlorophenyl)urea:

15.97 g or 0.05 mol of the cyclohexylsulfamic acid salt of 1-n-butyl-2-iminopyrrolidine is converted to 7.01 g or 0.05 mol of the free base in the usual way. After evaporation over I^CO-^, the benzene solution is filtered through diatomaceous earth and 7.68 g or 0.05 mol of m-chlorophenyl isocyanate is added. The reaction mixture is stirred at room temperature for 2.5 hours and is then evaporated to dryness in vacuum and a solid residue is obtained, l-(l-n-butyl-2-pyrrolidylidene)-3-(m-chlorophenyl)urea. Recrystallization from ethyl acetate gives the pure product with a melting point of 94 - 96°C. Example 7 1-(1-n-Butyl-2-pyrrolidylidene)-3-(2-chloro-5-trifluoromethylphenyl)-urea hydrochloride: 7.99 g or 0.025 mol of the cyclohexylsulfamic acid salt of 1-n-butyl-2- iminopyrrolidine is converted to 3.5 g or 0.25 mol of free base in the usual way. After evaporation over K2C0^, the benzene solution is filtered through diatomaceous earth and 5.54 g or 0.025 mol of 2-chloro-5-trifluoromethylphenyl isocyanate is added. The reaction mixture is stirred at room temperature for 3 hours and is then evaporated to dryness under vacuum and man

obtains an oily residue which crystallizes out on cooling to 1-(1-n-butyl-2-pyrrolidylidene)-3-(2-chloro-5-trifluoromethylphenyl)urea with a melting point of 40 - 45°C. The conversion to the hydrochloride salt gives a white solid with a melting point of 178 - 180°C. Recrystallization from methanol gives the pure HCl salt with a melting point of 177 - 179°C

Example 8

l-(l-n-butyl-2-pyrrolidylidene)-3-(3-chloro-2-methylphenyl)urea hydrochloride hydrate: 7.99 g or 0.025 mol of the cyclohexylsulfamic acid salt of l-n-butyl-2-iminopyrrolidine is converted to 3.5 g or 0.025 mol of free base by adding 2.5 ml of 509g NaOH to an aqueous slurry of the salt and subsequent benzene extraction. After evaporation over ^CO^, the benzene solution is filtered through diatomaceous earth and 4.19 g or 0.025 mol of 3-chloro-2-methylphenyl isocyanate is added. The reaction mixture is stirred at room temperature for 3 hours and is then brought to a dry state in vacuum and an oily residue is obtained, 1-(1-n-butyl-2-pyrrolidylidene)-3-(3-chloro-2-methylphenyl)urea, which is dissolved in ether and is converted to the hydrochloride. Recrystallization from methanol-ether gives the product, 1-(1-n-butyl-2-pyrrolidylidene)-3-(3-chloro-2-methylphenyl)-urea-NCl hydrate with a melting point of 126-128°C.

Example 9

1-( 1- benzyl- 2- pyrrolidylidene)- 3-( m- chlorophenyl) urea:

6.55 g or 0.025 mol of the fluoroborate salt of 1-benzyl-2-iminopyrrolidine is converted to 4.36 g or 0.025 mol (assuming 100 percent conversion) of the free base by adding 5 mL of 50% NaOH to an aqueous slurry of the salt with subsequent benzene extract ion. After concentration over K^CO-^, the benzene solution is filtered through diatomaceous earth and 3.84 g or 0.025 mol of m-chlorophenyl isocyanate, dissolved in anhydrous benzene, is added. The reaction mixture is stirred at room temperature for 2 hours and is then brought to a dry state in vacuum and an oily residue is obtained which eventually crystallizes out. The recrystallization from acetone-petroleum ether gives a pure product, 1-(1-benzyl-2-pyrrolidylidene)-3-(m-chlorophenyl)urea with a melting point of 91-93°C.

By following the general procedure in example 9

and by replacing m-chlorophenyl isocyanate with an equivalent amount of

of a suitable phenyl isocyanate, the following pyrrolidylidene ureas are obtained with the formula I: 1-(1-benzyl-2-pyrrolidylidene)-3-(3-chloro-4-fluorophenyl)urea melting point 131 - 132°C (Compound 9.a) l -(1-Benyl-2-pyrrolidylidene)-3-(4-methylthiophenyl)urea

melting point 113 - 115°C (Compound 9.b) 1-(1-benzyl-2-pyrrolidylidene]-3-(m-trifluoromethylphenyl)urea hydrochloride melting point 164 - 165°C (Compound 9.c) 1-(1 -benzyl-2-pyrrolidylidene)-3-(2,6-dimethylphenyl)urea-

HC1 melting point 185 - 195°C (Compound 9.d) Example 10

l- m- chlorophenyl- 3-( l- ethyl- 2- pyrrolidylidene) urea:

7.43 g or 0.05 mol of the hydrochloride salt of l-ethyl-2-iminopyrrolidine is converted to 5.6 g or 0.05 mol of the free base by adding 7 ml of 50% NaOH to an aqueous slurry (minimum amount of water) of the salt and subsequent benzene extraction. After evaporation over K^CO^, the benzene solution is stirred at room temperature and 7.68 g or 0.05 mol of m-chlorophenyl isocyanate, dissolved in anhydrous benzene, is added. The reaction mixture is stirred for 1 3/4 hours and the solvent is then evaporated in vacuo and a solid residue is obtained, 1-m-chlorophenyl-3-(1-ethyl-2-pyrrolidylidene)urea. Recrystallization from ethyl acetate gives the pure product with a melting point of 122 - 124°C.

Example 11

1-(2,6-Dimethylphenyl)-3-(1-Ethyl-2-pyrrolidylidene)urea:

7.43 g or 0.05 mol of the hydrochloride salt of l-ethyl-2-iminopyrrolidine is converted to 5.6 g or 0.05 mol of the free base in benzene in the usual way. 7.35 g or 0.05 mol of 2,6-dimethylphenyl isocyanate, dissolved in anhydrous benzene, is then added. The reaction mixture is stirred at room temperature for 1 3/4 hours and the solvent is then evaporated to dryness in vacuum and an oily residue is obtained. Trituration with ethyl acetate and cooling gives a solid product, 1-(2,6-dimethylphenyl)-3-(1-ethyl-2-pyrrolidylidene)urea with a melting point of 120 - 122°C. Recrystallization from acetone gives the pure product with a melting point of 121 - 123°C Example 12 1-(2-,6-dimethylphenyl)-3-(1.5-dimethyl-2-pyrrolidylidene)urea f;

6.75 g or 0.0337 mol of the HBF^ salt of 1,5-dimethyl-2-iminopyrrolidine is converted to the free base in benzene in the usual manner. 4.96 g or 0.0337 mol of 2,6-dimethylphenyl isocyanate, dissolved in anhydrous benzene, is then added. The reaction mixture is stirred for 2 hours and then the solvent is evaporated in vacuo and an oily residue is obtained which eventually crystallizes out. Recrystallization from ethyl acetate gives the product , 1-(2,6-dimethylphenyl)-3-(1,5-dimethyl-2-pyrrolidylidene)-urea f, with a melting point of 120 - 122-°-CU

Example 15

l- m- chlorophenyl- 3-( 1. 5- dimethyl- 2- pyrrolidylidene) urea:

6.75 g or 0.0337 mol HBF^ salt of 1,5-dimethyl-2-iminopyrrolidine is converted to the free base in benzene in the usual way. 5.16 g or 0.0337 mol of m-chlorophenyl isocyanate, dissolved in anhydrous benzene, is then added. The reaction mixture is stirred for 2 hours and then the solvent is evaporated in vacuo and a solid residue of 1-m-chlorophenyl-3-(1,5-dimethyl-2-pyrrolidylidene)urea with a melting point of 129 - 130°C is obtained. After recrystallization from ethyl acetate, the melting point is still 129 - 130°C.

Example 14

l- phenyl- 3-( 1- methyl- 2- piperidylidene) urea:

7.43 g or 0.05 mol of the hydrochloride salt of 2-imino-1-methylpiperidine is converted to the free base by adding 5 ml of 50% NaOH to an aqueous slurry (using a minimal amount of water) of the salt and then by extraction with benzene. After evaporation over K^CO-^, the benzene solution is stirred at room temperature and 5.96 g or 0.05 mol of phenyl isocyanate dissolved in anhydrous benzene is added dropwise. It appears unclear hot and possibly separate solids from the solution. The reaction mixture is stirred at room temperature overnight (about 17 hours). The solid collects and has a melting point on it

145 - 158°C. The filtrate is brought to a dry state in vacuum and further solid is obtained. Repeated recrystallizations of the combined solids from methanol give the pure product, 1-phenyl-3-(1-methyl-2-piperidylidene)urea with a melting point of 160 - 161°C.

Example 15

By following the procedure in example 14, except that an equivalent amount of a suitable phenyl isocyanate is used, the following piperidylideneurea with formula I is obtained: 1-(1-methyl-2-piperidylidene)-3-(4-trifluoromethylphenyl)urea,

melting point 154 - 155°C (Compound 15.a) Example 16

l- methyl- 3-( 1- methyl- 2- piperidylidene)- l- phenylurea:

14.8 g or 0.1 mol of the hydrochloride salt of 2-imino-1-methylpiperidine is converted to the free base by the addition of 10 ml of 50% NaOH and extraction into benzene. After extraction over K^CO-j, the benzene layer is stirred at room temperature and 8.84 g or 0.05 mol of N-methyl-phenylcarbamoyl chloride (prepared according to U.S. Patent No. 2,449,440), dissolved in anhydrous benzene, is added dropwise to this solution. The mixture is stirred at room temperature overnight (about 17 hours) and then filtered. The filtrate is brought to a dry state in vacuum and the residue is dissolved in and recrystallized from hexane to obtain the product, 1-methyl-3-(1-methyl-2-piperidylidene)-1-frenylurea. Example 17 1-(4-benzyloxy-5-chlorophenyl)-3-(1-methyl-2-pyrrolidinylidene)-urea: 32.0 g or 0.11 mol ethyl 4-benzyloxy-3-chloro-benzoate (cf. Jones & Robinson, "J. Chem. Soc." 3845 (1955), 25 ml of ethanol and 20 ml of 95% hydrazine are stirred under reflux for 8 hours and cooled to room temperature. The mixture is filtered and the resulting solid is dried in vacuo and obtains 29.4 g of 4-benzyloxy-3-chlorobenzoic acid hydrazide in a yield of 96.7%, with a melting point of 168 - 171°C.

27.6 g or 0.1 mol of 4-benzyloxy-3-chlorobenzoic acid hydrazide is suspended in 500 ml of 1N hydrochloric acid and the mixture is cooled to about 0°C. A solution of 7.0 g of sodium nitrite in 40 ml of water is added at such a rate that the temperature is kept below 5°C. The mixture is stirred at 5°C for 3/4 hour, filtered and the precipitate is dried in vacuo and 27.8 g of 4-benzyloxy-3-chlorobenzoyl azide is obtained in a yield of 96.8%.

2.87 g or 0.01 mol of 4-benzyloxy-3-chlorobenzoyl azide (thoroughly dried in vacuo at room temperature) is heated to reflux in 25 ml of tbr (molecular sieve) toluene. After an hour, the mixture is homogeneous and the solution has a strong signal in it

infrared region at 2300 cm~^ due to the 4-benzyloxy-3-chloro-phenyl isocyanate which tends to separate out of the solution on cooling. The toluene solution in a heated state can be used as such in the next step.

A benzene solution of 2-imino-1-methylpyrrolidine (obtained from 8.8 g or 0.055 mol of the carbonate salt) is washed over potassium carbonate and filtered. The above-mentioned hot toluene solution of 4-benzyloxy-3-chlorophenyl isocyanate is added by filtration. The mixture is stirred for 1/4 hour and the solvent is removed in vacuo, after which the residue is crystallized out by adding ether. Recrystallization from ethanol-ether gives a total of 12.6 g or 70.3% yield of 1-(4-benzyloxy-3-chlorophenyl)-3-(1-methyl-2-pyrrolidinylidene)urea with a melting point of 115 - 117°C

Example 18 1-(m-acetylphenyl)-3-(1-methyl-2-pyrrolidinylidene)urea:

13.5 g or 0.1 mol m-aminoacetophenone is dissolved in

50 ml of dry monoglyme and the solution is added to a saturated solution of phosgene in 100 ml of dry monoglyme. The mixture is heated at reflux and with continued passage of the phosgene for 4 hours. Monoglyme is removed under vacuum and the residue is dissolved in dry benzene, filtered through a filter and the thus obtained benzene solution of m-acetylphenyl isocyanate is used in the next step without further purification.

A solution of 2-imino-1-methylpyrrolidine (obtained from 10.09 g or 0.075 mole of the hydrochloride salt) in benzene is diluted over anhydrous potassium carbonate and filtered into a flask equipped with a thermometer. The above solution of m-acetylphenyl isocyanate in benzene is filtered into the flask. The temperature in the mixture rises due to the heat of reaction from 24 to 43°C and it is stirred until it has cooled to room temperature. The resulting precipitate is removed by filtration and recrystallized several times from acetone and 1-(m-acetylphenyl)-3-(1-methyl-2-pyrrolidinylidene)urea is obtained as a whitish solid with a melting point of 154 - 155.5° C. Example 19

1-(1-methyl-2-pyrrolidinyldene)-3-(1-naphthyl)urea:

A solution of 2-imino-1-methylpyrrolidine (obtained from 6.91 g or 0.051 mol hydrochloride salt) in benzene is washed over potassium carbonate and filtered. A solution of 8.45 g or 0.05 mol of 1-naphthyl isocyanate in benzene is added by filtration. The mixture is stirred for 1.5 hours at room temperature and the precipitate is separated by filtration. Recrystallization from acetone gives the product, 1-(1-methyl-2-pyrrolidinylidene)-3-(1-naphthyl)-urea with a melting point of 148-149°C.

Example 20

1-(1-methyl-2-pyrrolidinylidene)-3-(m-(methylthiophenyl)7-urea:

27.8 g or 0.2 mol of m-aminothioanisole in 100 ml of dry dimethoxyethane is added to a saturated solution of phosgene in 200 ml of dry dimethoxyethane. Phosgene is passed through the reflux mixture for an additional 4 hours and then the mixture is heated under nitrogen for 21 hours. Solvent is removed in vacuo and m-methylthiophenyl isocyanate is obtained as an amber-coloured oil which is dissolved in benzene for use in the next step. A solution of 2-imino-1-methylpyrrolidine (obtained from 26.9 g or 0.2 mole of the hydrochloride salt) in benzene is dried over anhydrous potassium carbonate and filtered into a flask equipped with a thermometer. A benzene solution of the previously prepared m-methylthiophenyl isocyanate is added by filtration and due to the exothermic nature of the reaction the temperature rises from 21 to 42°C. After stirring for 1 hour, the mixture is filtered and the solvent is removed in vacuo. The residue is recrystallized from acetone and one obtains the product, 1-(1-methyl-2-pyrrolidinylidene)-3.-/5-(methylthiophenyl}7urea, with a melting point of 110 - 111° C. Recrystallizations from the same solvent raise the melting point to 116 - 117° C. Example 21 a) Hexahydro-2-imino-1-methyl-1H-azepine-cyclohexanesulfamate: 12.5 g or 0.14 mol epichlorohydrin is added quickly

to a stirred solution of 25.7 g or 0.18 mol of boron trifluoride etherate in 90 ml of anhydrous ether. After the first intense development of heat, the mixture is boiled under reflux for 3 hours. The ether is removed by filtration and the solid residue is washed twice with anhydrous ether. Next, 60 ml of dry methylene chloride are added to the triethyloxonium fluoroborate and 17 g or 0.13 mol of hexahydro-1-methyl-1H-azepin-2-one in 20 ml of methylene chloride are added. The resulting solution is stirred overnight (about 15 hours)

at room temperature. More methylene chloride is added and ammonia is bubbled into the solution. The mixture is exothermically heated and after 1/2 hour it settles again. After 3 hours, the ammonia supply is stopped, more methylene chloride is added and the mixture is stirred overnight at room temperature. The inorganic substance is filtered off <p>g of the filtrate is evaporated and 26 g of a residual oil is obtained which is washed with benzene to remove the starting lactam. The benzene is decanted and the residual oil is dried under vacuum, and 22.5 g of fluoropyratate salt is obtained as a wax-like solid.

The fluoroborate salt is converted to a free base using

7 ml of 50% NaOH. The benzene layer is decanted, filtered and dried over K 2 CO 2 . Evaporation yields 11.5 g of the oil, which is dissolved in 20 ml of acetone and treated with a solution of 16.4 g of cyclohexanesulfamic acid in 150 ml of hot acetone. The resulting

mixture is heated briefly on a steam bath and then cooled and filtered and the product, hexahydro-2-imino-1-methyl-1H-azepine-cyclohexanesulfamate with a melting point of 142 - 144°C is obtained. After recrystallization from ethanol-ether, the melting point is 143 - 145°C.

b) 1-/2-hexahydro-l-methylazepinylidene)7-5-phenylurea: To a mixture of 1.25 g or 0.0041 mol of hexahydro-2-imino-l-methyl-1H-azepine-dichlorohexanesulfamate in 20 ml benzene, an excess of 50% sodium hydroxide is added. The mixture is shaken and the benzene layer is decanted. The basic layer is washed with several additional portions of benzene. The combined benzene extracts are dried over K2C0^ and evaporated and 0.34 g (0.0027 mol or 66%) of free base is obtained, which is dissolved in 2 ml of dry benzene and treated with 0.32 g or 0.0027 mol of phenyl isocyanate. After 15 minutes, the reaction solution is lightly scraped and a solid precipitates out. The reaction mixture is then cooled and filtered and the product, 1-(hexahydro-1-methylazepinylidene}7-3-phenylurea) is obtained with a melting point of 135 - 136° C. After recrystallization from ethyl acetate, the melting point is 136 - 137° C

Example 22

By following the procedure in example 21, except that an equivalent amount of a suitable aryl isocyanate is used for reaction with hexahydro-2-imino-1-methyl-1H-azepine, 1-aryl-3-hexahydroazepinylidene ureas of the formula I can be obtained, f .ex. 1-(hexahydro-1-methyl-2-azepinylidene)-3-(2,6-xylyl)urea,

melting point 132 - 133°C (Compound 22.a) 1-m-chlorophenyl-3-(hexahydro-1-methyl-2-azepinylidene)urea,

melting point 119 - 121°C (Compound 22.b) 1-(2,6-dichlorophenyl)-3-(hexahydro-1-methyl-2-azepinylidene)-urea melting point 143 - 144°C (Compound 22.c) Example 23

1- m- chlorophenyl- 3-( l- methyl- 2- pyrrolidylidene) urea:

Assuming a 100-percent conversion is released

2.94 g or 0.03 mol of 2-imino-1-methylpyrrolidine from the HCl salt using the calculated amount of 2.4 g or 0.03 mol of 50% NaOH and by extraction into benzene. The benzene solution is evaporated over K2C0^. To this solution, 4.6 g or 0.03 mol of m-chlorophenyl isocyanate, dissolved in anhydrous benzene, is added dropwise with stirring. A solid forms and the mixture is stirred at room temperature overnight. The solid, 1-m-chlorophenyl-3-(1-methyl-2-pyrrolidylidene)urea, is collected and has a melting point of 135-136°C. A second fraction is collected from the mother liquors after evaporating them to a pure state, trituration with hot CHCl^ and filtering off the insoluble matter. The two fractions are combined and recrystallized from methanol-ether and the pure product with a melting point of 137 - 138°C is obtained. Example 24

1-(2.6-dimethylphenyl)-3-(1-methyl-2-pyrrolidylidene)urea:

To a stirred solution of 6.73 g or 0.05 mol of 1-methyl-2-iminopyrrolidine hydrochloride in about 2 ml of water, add about 50 ml of benzene followed by 10 ml of 50% NaOH. After stirring for 1 minute, the benzene layer is decanted onto anhydrous potassium carbonate. The extraction is repeated twice. The combined benzene extracts are filtered from a dicalite pad and rinsed well with dry benzene. 7.36 g or 0.05 mol of 2,6-dimethylphenyl isocyanate is added to the filtrate in one portion while stirring. The reaction mixture is stirred overnight. Solvent removal and recrystallization from ethyl acetate ether gives the product, 1-(2,6-dimethylphenyl}-3-(1-methyl-2-pyrrolidylidene)-urea as white crystals with a melting point of 119-120°C.

Claims (1)

Analogous process for the preparation of N-(2-aza-cycloalkylidene)-N'-arylureas with the formula: and their therapeutically active acid addition salts, where n is the whole number 1, 2 or 3; R is hydrogen or lower alkyl; R"L is lower alkyl or benzyl; R2 is hydrogen or lower alkyl; and Ar is phenyl, naphthyl, mono-, di- or trihalo-phenyl, mono-, di- or tri-lower alkylphenyl, mono-, di- and tri-lower alkoxyphenyl, mono- or di-trifluoromethylphenyl, nitrophenyl, cyanophenyl, methylthiophenyl, lower alkylcarbonylphenyl, benzyloxyphenyl, lower alkylhalophenyl, lower alkoxyhalophenyl, benzyloxyhalophenyl, trifluoromethylhalophenyl and nitrohalophenyl; provided that R is hydrogen and R-^ is lower alkyl when n is 2 or 3, whereby lower alkyl and lower alkoxy denote groups of 1-5 carbon atoms, characterized by) to react a compound with the formula where R and R-^ are as indicated above, with a compound of the formula 0=C=N-Ar where Ar is as indicated above, preferably in a non-hydroxyl solvent to prepare a compound of formula I wherein R 1 is hydrogen; or b) reacting a compound of formula II with a compound else with the formula where Ar is as indicated above and R~ is hydrogen or lower alkyl, preferably in a non-polar solvent; and if desired • to prepare a therapeutically active acid addition salt of the products from steps a) or b).