FI56831C - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ANIMAL PRODUCTS PYRROLIDYLIDEN- PIPERIDYLIDEN- OCH HEXAHYDROAZEPINYLIDEN-URINAEMNEN - Google Patents

Description

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Patent * OCh registerstyrelsan '' AiwBkan utlagd och utl. * Krlft «n publtcarad 31 * 12.79 (32) (33) (31) Privilege claimed —Begird prlorltet 17 * 03 * 72 26.02.73 USA (US) 235816, 3358 ^ 5 Proven-Styrkt (71) McNeil Laboratories Incorporated, Camp Hill Road, Port Washington, Pennsylvania, USA (72) Chris Royce Rasmussen, Ambler, Penn., Joseph Francis Gardocki,

Doylestown, Penn., James Nelson Plampin, Roslyn, Penn., USA (US) (7 ^) Oy Kolster Ab (5I +) Method for the preparation of therapeutically useful pyrrolidylidene, piperidylidene and hexahydroazepinylidene ureas -Förfarande för framställ therapeutically active pyrrolidylidene, piperidylidene and hexahydroazepinylidene urinary tract

The present invention relates to pyrrolidylidene, piperidylidene and hexahydroazepinylidene ureas which have a central nervous system retarding effect. The closest prior art comprises Swiss Patent Application No. 11853/68 and U.S. Patent No. 3,566U,010, which describe pyrrole-dylidene ureas having two cyclic substituents at the 3-position of the pyrrolidine ring and in which the ring has a nitrogen atom. is unsubstituted. In contrast, the pyrrolidylidene ureas of the application have no substituents at the 3-position of the pyrrolidine ring, but the ring nitrogen atom is substituted with either lower alkyl or benzyl.

2 56831

The invention relates to a process for the preparation of therapeutically useful pyrrolidylidene, piperidylidene and hexahydroazepinylidene ureas of the formula: <CH2> n-10

fl-k „^ M-C-K-Ar I

1, 2 and 3, wherein n is an integer of 1, 2 or 3, R is hydrogen or lower alkyl, R 1 is lower alkyl or benzyl, R 2 is hydrogen or methyl, and Ar is phenyl, naphthyl, mono-, di- or tri-halophenyl, mono-, di- or tri-lower alkylphenyl, mono-, di- or tri-loweralkoxyphenyl, mono- or di-trifluoromethylphenyl, nitrophenyl, cyanophenyl, methylthiophenyl, acetylphenyl , benzyloxyphenyl, lower alkylhalophenyl, lower alkoxy-halophenyl, benzyloxy-halophenyl, trifluoromethylhalophenyl or nitrohalophenyl, provided that when n is 2 or 3 then R is hydrogen and R is methyl.

The process according to the invention is characterized in that a) the compound of the formula ICH 2> n -RL 2 R 2 is reacted with a compound of the formula 0 = C = N-Ar, preferably in a non-hydroxylated solvent, to prepare a compound of the formula I, wherein R 2 is hydrogen; or 3,56831 b) reacting a compound of formula II with a compound of formula 0 I »(halide) -C-N-Ar» R2, preferably in a non-polar solvent; and, if desired, forming a therapeutically active acid addition salt of the product obtained in steps a) or b).

As used herein, the terms "lower alkyl" and "lower alkoxy" mean a straight or branched group having about 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, and the like alkyl, methoxy, ethoxy, etc., respectively. The term "halogen" means bromine, fluorine, iodine and chlorine.

The pyrrolidylidene, piperidylidene and hexahydroazepinylidene ureas of formula (I) containing hydrogen are readily obtained by administering 2-imino-pyrrolidine, 2-imino-piperidine or 2-imino-hexahydroazepine of formula (II) and which are also known as 2-imino- (tetra-, penta- and hexa-) -methyleneimines, to react with a phenyl or naphthyl isocyanate of the formula (IIi), preferably using equimolar amounts, in a non-hydroxyl solvent, e.g. in a hydrocarbon such as benzene, toluene or xylene, in an ether such as dioxane, diethyl ether, tetrahydrofuran, or in a halogenated hydrocarbon such as methylene chloride or chloroform. Generally, no external heating is required to effect the reaction. The reaction can be described as follows: 56831 tCVn__ (CH 2> n-1 °.

R-L X == NH + O®C = N-Ar - m, R-1 J = N-C-NH-Ar

K K

<-> (III> «X-.,

Compounds of formula (I) wherein R 2 is lower alkyl may be prepared by acylation of a compound of formula (II) with a carbamoyl halide of formula (IV), preferably using two molar equivalents of the former for one equivalent of the latter. One of the molar equivalents of compound (II) acts as an HCl-receiving agent, while the other forms the desired urea product. Preferably, a non-polar solvent such as the above-mentioned solvents are used so that the insoluble salt formed by the HCl-receiving agent and the HCl separates, and is easily removed by filtration. The desired urea product (I), which usually remains in solution, is then recovered by known techniques, e.g. by evaporating the solvent and then recrystallizing from conventional solvents. The acylation reaction can be described as follows: Vn-S (CH) 0 I. 2? - 1 R— + C1'C-rAr M J = N-C-N-Ar I R | I r2 i r2

Rl Rx (II) (IV) (I)

2-Imino- (tetra-, penta- and hexa-) -methyleneimines of formula (II) have for the most part been described in the literature. If not described, they are obtained by modifying the corresponding acid addition salt: <CH2> n_R_1 - NH · HX (V) R1 56831 wherein HX is a typical acid such as HCl HBr, HBF4 and the like. A typical process for the preparation of salts of formula (V) is described below. The base is easily converted to a base 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 10-30? NaOH is preferred in an aprotic solvent such as benzene, ether and the like. In general, as little water as possible is also used. The free base (II) obtained remains in solution in an aprotic solvent and the organic solution is used as such in the reactions described previously. However, before use, the solution is treated with a desiccant, e.g. potassium carbonate, to remove residual water, which may interfere with the subsequent reaction with isocyanates (III).

_ with: Q

HgO + 20 0-C »N-Ar -> Ar-NH-C-NH-Ar + CO2 (III)

Several phenyl isocyanates of formula (III) are known and, if not known, can be prepared according to methods described in the literature, such as those described by K. Inukai and Y. Mäki, Kogyo Kagaku Zasshi, 67 (3). ) »807-9 (196U) and Kogyo Kagaku Zasshi, 70 (H), U91-U (1967), or JG Lombardino and CF Gerber in J. Med. Chem., 7, 101 (1961 *). According to such methods, phenyl isocyanates such as 2,6-dibram (m.p. 68-70 ° C), 3,5-dichloro- (m.p. 81-88 ° C), 2,6- dimethoxy (m.p. 32-35 ° C), 3'-dimethoxy, 3,5,5-trimethoxy, 3-trifluoromethyl and the like phenyls of formula (III). isocyanate derivatives.

Carbamoyl chlorides of formula (IV) can be prepared according to the method described by J.A. Aeschlimann in U.S. Patent No. 2, U1 + 9.1 * U0. According to this method, the appropriate aniline of formula: HN-Ar R 2 wherein Ar is as defined above and R 9 is lower alkyl is treated with excess Cl 2 CO to give the carbamoyl chloride of formula (IV):

CloCO0 (excess) + HN-Ar -> Cl-CO-N-Ar + HCl 2 1 R2 R2 (IV) 6 56831

The compounds of formula (I) have been found to have useful pharmacological properties which have been found in one or more of the following experiments showing CNS depressant activity in laboratory experiments on animals.

Test A; An analgesia test is described by I. Geller in Psychosomatic Medicine, eds. JH Nadine and JH Moyer (Lea and Febiger, Phila), pp. 267 (1962), and modified by DL Margules and L. Stein in Psychopharmacologia (Berl.) 13, 7-80 (1968). The analgesic effect of the test compound is studied daily in rats for 5 days after i.p. using the compound at doses ranging from 10 to 25 mg / kg body weight and the effect of the compound is determined by how many times the animal presses against the rod in an attempt to obtain food. The method determines the effect of a test compound on untreated and disciplined reactions. Hungry rats are taught to squeeze the rod for food: a cup full of milk is brought close to the rat on average every two minutes (variable time scale - V.I. II). Twelve minutes after this treatment, a sound is turned on for 3 minutes, which sounds a signal of credit and simultaneous discipline for each bar press (a bowl full of milk is drenched and each bar press is followed by an electric shock conducted through the mesh-Tian). The electric shock lasts 0.2 milliseconds and has an intensity of 0.5-3.5 milli-amps. Each rat receives U-6 alternating pairs of non-disciplined episodes when milk alone is present and disciplined episodes when milk and electric shock are present. Control reactions are obtained from each rat after daily injections for 5 days i.p. saline solution. Each rat is graded simultaneously daily and in the same experimental chamber.

Reactions are recorded and nutrition (milk) and discipline (electric shock) are provided by a suitable automatic device.

Experiment B: A muscle tension-triggering experiment determines the effect of a test compound on a strychnine-induced disease attack as described by M. J. Orloff et al., Proc. Soc. Exp. Biol. and Med. 70, 25h (19-9) and modified by G. Chen and B. Bohner, J. Pharmacol, and Expt. Therap. 117, 1 ^ 2 (1956). Inhibition of strychnine activity is monitored in mice by oral administration of about 25-5ΟΟ mg / kg body weight in an amount equal to the effect of the compound on the strychnine-induced disease seizure threshold.

Experiment C: The anticonvulsant assay is a supramaximal electroshock-disease assay described by E. A. Svinyard et al., J. Pharmacol. Expt. Therap.

106, 319 (1952). In this experiment, the test compound is administered orally to a mouse at a dose in the range of 25-5ΟΟ mg / kg body weight, and the inhibitory effect of the compound on 7,56831 extensor muscle spasm is determined after administering a supra to the animal.

Experiment D: A mouse behavioral experiment has been described by S. Irvin, Gordon Research Conference on Medicinal Chemistry, 1959 »Ρ · 133. In this experiment, symptoms such as fumbling, decreased motor activity, and lack of performance reflex are observed after administration i.p. mouse test compound at a dose of 10-300 mg / kg body weight.

The following table describes the effect of several test compounds on the central nervous system, as illustrated by their relative positive reactions in one or more of the above experiments. It is to be understood that said compounds do not limit the present invention in any way, but merely demonstrate the useful properties of all compounds of formula I.

Compound Active Compound described in experiments (S) described Active in Example No. Example No. in Experiments (S) "'1" - —— "·.

1 A 3; e B&D

2 D 3. f B&D

2.8 B&D 3.g C

\ k 9 B&D

3.a B&D 9.a B&D

2.b A 9.b. ‘L&D

2, c D 9.c q

2.d B&D 9. c C

2. c. a 8 C

3. b · B&D 3.h rad

2-f B&D 3.i B&D

3.a C 3.j B&D

2-S. C 3.k A

2. h B&D 3.1 C

3. c B&D 10 ^

2 * i A 3.m A

2.j * B&D 11 r

2.k B&D 12 C

2.1 B&D *, 13 B&D

2. tn C - ik C

3. d D 15 D

5 C 2 »n q

^. A 3.n B&D

7 C 16. B & D

1Ö B&D

22.a; C

22.c C

/ 8 56831

The compounds of formula (I) in base form may be converted into the corresponding pharmaceutically acceptable therapeutically active acid addition salts by reacting them with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and the like, e.g. organic acid, or organic acid. , with glycolic acid, lactic acid, oxalic acid, malonic acid, tartaric acid, citric acid, suifamic acid, ascorbic acid and the like. On the other hand, acid addition salts can be converted to the free base by treatment with a suitable alkali.

Typical examples of compounds of formula (i) wherein n is 1, R is hydrogen and R 1 is methyl and which may be prepared according to the invention are the following:

L J = N-CO-NH-Ar N

We

Ar Form Melting point (° C) o-Me-Ph base 91 ** 93 mI-Ph base lUU-93 2-Et-6-Me-Ph HgSO 4 salt 2U3-2U5 o-IsoPr-Ph HCl salt 163- 165 U-EtO-Ph base 1U7-1U8 2-EtO-Ph base 108-110 k-Cl-2-CF3Ph base 13 ^ -135.5 2, U-di-Cl-Ph base 153-155 5-Cl- 2-MeO-Ph base 161-163 5-Cl-2-MeO-Ph base

The following examples illustrate the invention. Unless otherwise indicated, all parts are by weight.

Preparation of the starting material This example illustrates a general process for the preparation of acid addition salts of formula (V). First, fluoroborate is prepared, from which other acid addition salts can be easily obtained.

Triethyloxinium fluoroborate is prepared on a 0.6 mole scale from 113.55 g (0.80 moles) of boron trifluoride etherate and 55-52 g (0.60 moles) of epichlorohydrin in anhydrous ether according to the method described by Meervein et al., Ann. 6Ui, 1 (1961). After washing the oily crystals by decantation with fresh anhydrous ether, 0.60 mol of 66831 of the appropriate 2-pyrrolidone or 2-piperidone of the formula: <-2> R-J-0

R 1 wherein n, R and R 2 are as defined above, in an anhydrous methylene chloride solution of the oxonium salt. After stirring for about 2 to 17 hours, depending on the reaction rate, anhydrous ammonia is introduced into the reaction mixture at such a rate that reflux is maintained (due to the heat of reaction caused by the addition of ammonia). After the initial reaction has subsided, ammonia is further added, which cools the reaction mixture, which is then stirred at ambient temperature until the reaction is complete. Both the excess ammonia and the solvent are then removed in vacuo to give the corresponding 2-iminopyrrolidine or 2-iminopiperidine fluoroborate salt as a residue, which is then recovered and purified by standard crystallization from the appropriate solvents. The fluoroborate salts are converted to the corresponding free bases by treatment with a strong alkali, e.g. 10-50%: 11 & 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 according to known methods. .

~ Θ «Vn-1 (CH2> n_,

kj_ Meerwein reaction Q

TS '' ° ~ -> R-BFh CH9C1_ f Et_0 BF, i ether h --2-> I 3 h xs HH_

Rl Rl 3 -i iCtz \ -1 <CH2> n -f -fr »__ I Lbh.hx I benzene j ^ ^ R R i (fluoroborate salt) 1 B1 10 56831

According to the above procedure, the following typical salts of formula (V) are obtained: MR R 2 HX Sp. (° C) 1H Me HBF ^ 109-111

1 H Me HCl 186-189X

1 H Et HCl 181-185 1 H n-Bu HO SHH 110-111, 5

1 H Bz HBF ^ 112-111

1 H Bz HC1 203-20UX

1 Me Me HBF ^ 100-102 2 H Me HCl xx x described by R. Kwok et al., J. Org. Chem., 32, 738 (1967) · xx described by J. Renault, Ann. Chim. (Paris) 10, 135 (1955) ·

Example 1 1- (1-Methyl-2-pyrrolidylidene) -3-phenyl-urea:

After dissolving U, 9 g (0.05 moles) of 2-imino-1-methylpyrrolidine in anhydrous benzene are added dropwise with stirring 5.96 g (0.055 moles) of phenyl isocyanate (heat evolved). The reaction mixture is stirred for 1/2 hour. The solid product formed 1- (1-methyl-2-pyrrolidylidene) -3-phenyl-56831 urea (m.p. 10-1H1 ° C) is collected, recrystallized from methanol to give the pure product, m.p. LU6-lU7 »5 ° C.

Example 2 1- (1-Methyl-2-pyrrolidylidene) -3- (3-dimethoxyphenyl) urea:

After dissolving 5 g (0.055 mol) of 2-imino-1-methylpyrrolidine in dry benzene, 9.85 g (0.055 mol) of 3'-dimethoxyphenyl isocyanate (prepared according to the method described by JG Lombardino) are added dropwise to the solution. and CT Gerber, J. Med. Chem., 7, Jan. 196U, p. 101) - dissolved in dry benzene. The reaction mixture is stirred at room temperature overnight (about 16 hours). The solvent is evaporated off under vacuum and, on cooling, the solidified residue is mixed with anhydrous methanol. Recrystallization from methanol gives the pure product, 1- (1-methyl-2-pyrrolidylidene) -3- (3,1-dimethoxyphenyl) urea, m.p. 118-120 ° C.

By repeating the procedure of Example 2 and substituting an equivalent amount of the appropriate phenyl isocyanates of formula III for 3, N-dimethoxyphenyl isocyanate, the compounds of formula I listed in the following table are obtained.

ch3

Compound Q

marking Sp. C

2, a p-Cl 1U2-1U

2, b m-Cl 137-138 2, c p-Br I36-I38 2, e p-CF3 130-132 2, f 1 * -C1, 3-CF3 175 2, g 3,5 di-CF3 165- 166.5 2h 2.6 di-CH3 119-120 2.1 m-CH3 1U9-151 2, j m-OCH_ 128-129-5 2, k 2-Cl, o-CH- 103-105-5 2.1 m- CF J 155-156-5 2, m UO-OT.-CrH-lU0-lU2 2, n 0-CH * °> 91-93 12 66831

Example 3 1- (1-Methyl-2-pyrrolidylidene) -3-p-nitrophenyl urea:

To a suspension of 6.73 g (0.05 mol) of 1-methyl-2-iminopyrrolidine hydrochloride in 100 ml of benzene is added 2 ml of water followed by 5 ml of 50 l of NaOH. After stirring for 5 minutes, the Bent fungal layer is decanted into excess anhydrous potassium carbamate. The treatment is repeated twice using 75 ml portions of fresh benzene. The combined extracts are filtered quickly from the desiccant (dicalite layer and suction). 8.21 g (0.05 mol) of p-nitrophenyl isocyanate are added in one portion to the filtrate with stirring as a solution in benzene (isocyanate solution filtered before use). After stirring for 1 hour, 1- (1-methyl-2-pyrrolidylidene) -3-p-nitrophenyl urea is collected and dried, m.p. 180-182 ° C. Recrystallization from acetane / methanol gives the pure product, m.p. L82-L83 ° C.

By repeating the procedure of Example 3 and substituting the equivalent of p-nitrophenyl isocyanate for the appropriate amount of phenyl isocyanate of formula III, the compounds of formula I shown in the table are obtained; ! ^ / 3

I I.r — .M — C — UK

k 13 «rfiste- R 56831

marking Sp. C

3. a p-CH 2 136-137 3.b 2.6 di-Cl 134-136 3.c 2.5 di-Cl 148-150-5 3.d p-SCH3 141-144 3.e 2, 6-di C2H5 71-73 3.f 2,6-di-Br 115-117 3.g 2.6 di-OCH3 114-117 3.h 3.5 di-Cl 157-159 3.1 2,4.6 tri-Br 165-167-5 3.j 2,4,6 tri-Cl 160-162 3.k 3-Br 138-140 3.1 2,4,6 tri Ch, 121-123 3.m mF 142-143 3.n 3,4 di-Cl 16 ~ ~ 16l - 3.o m-CN 145-147

Example 4 1-Methyl-3- (1-methyl-2-pyrrolidylidene) -1-phenylurea: 13.46 g (0.1 mol) of the hydrochloride salt of 2-imino-1-methylpyrrolidine are converted to the free base by adding 10 ml of 50 l from NaOH and extraction into Bent. After drying over potassium carbonate, the benzene layer is stirred at room temperature and 8.46 g (0.05 mol) of N-methylphenylcarbamoyl chloride (prepared according to the method described in U.S. Patent No. 2,449,440) dissolved in anhydrous benzene are added dropwise to this solution. A precipitate forms and a solid precipitates out of solution. The mixture is stirred at room temperature overnight and then filtered. The filtrate is evaporated in vacuo to an oily residue which is dissolved in hot hexane and filtered hot. Upon cooling and stirring, crystals are obtained which are collected and recrystallized from hexane to give the pure product 1-methyl-3- (1-methyl-2-pyrrolidylidene) -1-phenyl urea, m.p. 27 "5" at 30 ° C.

Example 5 1- (1-n-Butyl-2-pyrrolidylidene) -3- (2,6-dimethylphenyl) urea; 15 to 97 g (0.05 mol) of the cyclohexylsulphamic acid salt of 1-n-butyl-2-iminopyrrolidine are converted into the free base (7 to 01 g; 0.05 mol) in the usual manner. After drying over potassium carbonate, the benzene solution is filtered through diatomaceous earth and 7 * 36 g (0.05 mol) of 2,6-dimethylphenyl isocyanate are added. The reaction mixture is stirred at room temperature for 3 1/2 hours and then evaporated to dryness in vacuo to give an oily residue which crystallizes on cooling. Recrystallization from ethyl acetate gives the pure product £> 6831

AND

1- (1-n-butyl-2-pyrrolidylidene) -3- (2,6-dimethylphenyl) urea, m.p.

93-95 ° C.

Example 6 1- (1-n-butyl-2-pyrrolidylidene) -3- (m-chlorophenyl) urea; 15.97 g (0.05 mol) of the cyclohexylsulphamic acid salt of 1-n-butyl-2-iminopyrrolidine are converted into the free base (7> 01 g; 0.05 mol) in the usual manner. After drying over potassium carbonate, the benzene solution is filtered through diatomaceous earth and 7.68 g (0.05 mol) of m-chlorophenyl isocyanate are added. The reaction mixture is stirred at room temperature for 2 1/2 hours and then - evaporated to dryness in vacuo to leave a solid residue which is 1- (1n-butyl-2-pyrrolidylidene-3- (m-chlorophenyl) urea.) Recrystallization from ethyl acetate gives a pure solid. product, mp 9-96 ° C. -

Example 7 1- (1-n-Butyl-2-pyrrolidylidene) -3- (2-chloro-5-trifluoromethylphenyl) urea hydrochloride; 7.99 g (0.025 mol) of the cyclohexylsulphamic acid salt of 1-n-butyl-2-iminopyrrolidine are converted into the free base (3.5 g> 0.025 mol) in the usual manner. After drying over potassium carbonate, the benzene solution is filtered through diatomaceous earth and 5.5 * g (0.025 mol) of 2-chloro-5-trifluoromethylphenyl isocyanate are added. The reaction mixture is stirred at room temperature for 3 hours and then evaporated to dryness in vacuo to leave an oily residue which crystallizes on cooling to give 1- (1-butyl-2-pyrrolidylidene) -3- (2-chloro-5-trifluoromethylphenyl) urea, m.p. UO-U5 ° C. Conversion to the hydrochloride salt gives a white substance, m.p. 178-L80 ° C. Recrystallization from methanol gives the pure HCl salt, m.p. 177 DEG-179 DEG C. ~

Example 8 1- (1-n-Butyl-2-pyrrolidylidene) -3- (3-chloro-2-methylphenyl) urea hydrochloride hydrate: 7 * 99 g (0.025 moles) of 1-n-butyl The cyclohexylsulfamic acid salt of 2-iminopyrrolidine is converted to the free base (3.5 g / 0.025 mol) by adding 2.5 ml of 50 2 NaOH to the aqueous slurry of the salt and extracting with benzene. After drying over potassium carbonate, the benzene solution is filtered through diatomaceous earth and U, 19 g (0.025 mol) of 3-chloro-2-methylphenyl isocyanate are added. The reaction mixture is stirred at room temperature for 3 hours and then evaporated to dryness in vacuo to give an oily residue of 1- (1-butyl-2-pyrrolidylidene) -3- (3-chloro-2-methylphenyl) urea which is dissolved in ether and converted to the hydrochloride salt. Crystallization from methanol / ether gives the product, 1- (1-n-butyl-2-pyrrolidylidene) -3 '(3-chloro-2-methylphenyl) urea HCl hydrate, m.p. 126-128 ° C.

Example 9 1- (1-Benzyl-2-pyrrolidylidene) -3- (m-chlorophenyl) urea; 6.55 g (0.025 moles) of the fluoroborate salt of 1-benzyl-2-iminopyrrolidine are converted to the free base (U, 36 g; 0.025 moles of 100% conversion) by adding 5 ml of 50% NaOH to an aqueous slurry of the salt and extracting with benzene .

After drying over potassium carbonate, the benzene solution is filtered through diatomaceous earth and 3.81 * g (0.025 mol) of m-chlorophenyl isocyanate dissolved in anhydrous benzene are added. The reaction mixture is stirred at room temperature for 2 hours and then evaporated to dryness in vacuo to give an oily residue which may crystallize. Recrystallization from acetone / petroleum ether gives the pure product 1- (1-benzyl-2-pyrrolidylidene) -3- (m-chlorophenyl) urea, m.p. 91 'at 93 ° C.

Following the procedure described in Example 9 and substituting an equivalent amount of the appropriate phenyl isocyanate for m-chlorophenyl isoocyanate, the following pyrrolidylidene ureas of formula I are obtained: 1- (1-benzyl-2-pyrrolidylidene) -3- (3- chloro-U-fluorophenyl) urea, m.p. 131 DEG-132 DEG C. (Compound 9 (a)) 1- (1-benzyl-2-pyrrolidylidene) -3- (U-methylthiophenyl) urea, m.p. 113-115 ° C (compound 9 »b); 1- (1-benzyl-2-pyrrolidylidene) -3 '(m-trifluoromethylphenyl) urea hydrochloride, m.p. 16U-165 ° C (compound 9, c); 1- (1-benzyl-2-pyrrolidylidene) -3 ”(2,6-dimethylphenyl) urea HCl, m.p. 185-195 ° C (comp. 9 »d).

Example 10 1-Chlorophenyl-3- (1-ethyl-2-pyrrolidylidene) urea: 7.13 g (0.05 mol) of the hydrochloride salt of 1-ethyl-2-iminopyrrolidine is converted into the free base (5 * 6 g; .05 moles) by adding 7 ml of 50 l of NaOH to the aqueous salt slurry (as little water as possible and extracting with benzene. After drying over potassium carbonate, the benzene solution is stirred at room temperature and 7 * 68 g (0.05 moles) of m chlorophenyl isocyanate dissolved in anhydrous benzene The reaction mixture is stirred for 1 3/1 * hour and then the solvent is evaporated off under vacuum to leave a solid residue.

16 5683 1 which is 1-m-chlorophenyl-3- (1-ethyl-2-pyrrolidylidene) urea. Recrystallization from ethyl acetate gives the pure product, m.p. 122 ° C ~ 12b.

Example 11 1- (2,6-Dimethylphenyl) -3- (1-ethyl-2-pyrrolidylidene) urea: 7.3 g (0.05 mol) of 1-ethyl-2-iminopyrrolidine hydrochloride is converted to the free base ( 5.6 g, 0.05 mol) in benzene in the usual manner. 7.35 g (0.05 mol) of 2,6-dimethylphenyl isocyanate dissolved in anhydrous benzene are then added. The reaction mixture is stirred at room temperature for 1 3 / U hour and then the solvent is evaporated off under vacuum, leaving an oily residue. Upon mixing with ethyl acetate and cooling, 1- (2,6-dimethylphenyl) -3- (1-ethyl-2-pyrrolidylidene) urea is obtained as a solid, m.p. 120-122 ° C. Recrystallization from acetone gives the pure product, m.p. 121-123 ° C.

Example 12 1- (2,6-Dimethylphenyl) -3- (1,5-diaethyl-2-pyrrolidylidene) urea: 6.75 g (0.0337 moles) of 1,5-dimethyl-2-iminopyrrolidine HBF the salt is converted to the free base in benzene in the usual manner. Then, 96.9 g (0.0337 moles) of 2,6-dimethylphenyl isocyanate dissolved in anhydrous benzene are added. The reaction mixture is stirred for 2 hours and then the solvent is evaporated off under vacuum, leaving an oily residue which may crystallize. Recrystallization from ethyl acetate gives 1- (2,6-dimethylphenyl) -3- (1,5-dimethyl-2-pyrrolidylidene) urea as product, m.p. 120-122 ° C.

Example 13 1-m-Chlorophenyl-3- (1,5-dimethyl-2-pyrrolidylidene) urea: 6.75 g (0.0337 moles) of the HBF salt of 1,5-dimethyl-2-iminopyrrolidine are converted to the free base in benzene in the usual manner. 5.16 g (0.0337 mol) of m-chlorophenyl isocyanate dissolved in anhydrous benzene are then added. The reaction mixture is stirred for 2 hours and then the solvent is evaporated off in vacuo to leave 1-m-chlorophenyl-3- (1,5-dimethyl-2-pyrrolidylidene) urine as a solid residue, m.p. 129 "to 130 ° C. When crystallizing. Again, ethyl acetate still retains its melting point at 129 ° C to 130 ° C.

IT

S6631

Example ΐΛ 1-Phenyl-3- (1-methyl-2-piperidylidene) urea: 7.1 + 3 g (0.05 moles) of the hydrochloride salt of 2-imino-1-methylpiperidine are converted to the free base by adding 5 ml of 50 # NaOH to the aqueous salt slurry (using as little water as possible) and then extracting with benzene. After drying over potassium carbonate, the benzene solution is stirred at room temperature and 5 to 96 g (0.05 mol) of phenyl isocyanate dissolved in anhydrous benzene are added dropwise. Turbidity forms and a solid may precipitate from solution. The reaction mixture is stirred at room temperature overnight (about 17 hours). The substance is recovered, m.p. 1U5-I580 C. The filtrate is evaporated to dryness in vacuo to give an additional solid. Recrystallization of the combined substances from methanol gives 1-phenyl-3- (1-methyl-2-piperidylidene) urea as a pure product, m.p. 160-116 ° C.

Example 15

Following the procedure described in Example ik and using an equivalent amount of the appropriate phenyl isocyanate, the following corresponding piperidylidene urea of formula (i) is obtained: 1- (1-methyl-2-piperidylidene) -3- (U-trifluoromethylphenyl) urea , mp 15U-155 ° C (compound lU.2).

Example 16 1- (1 + -Benzyloxy-3-chlorophenyl) -3- (1-methyl-2-pyrrolidinylidene) urea: 32.0 g (0.11 moles) of ethyl 1 + -benzyloxy-3-chlorobenzoate [ cf, Jones & Robinson, J.Chem. Soc. 3UU5 (1955)] »25 ml of methanol and 20 ml of 95 # hydrazine are stirred at reflux for 8 hours and cooled to room temperature. The mixture is filtered and the resulting material is dried in vacuo to give 29.0 g of 1-benzyloxy-3-chlorobenzoic acid hydrazide (yield 96.7 $ 5), m.p. l68-171 ° C.

27.6 g (0.1 mol) of 1 + -benzyloxy-3-chlorobenzoic acid hydrazide are 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 1 ml of water is added at such a rate that the temperature remains below 5 ° C. The mixture is stirred at 5 ° C for 3A hours, filtered and the precipitate is dried in vacuo to give 27.8 g (96.8% yield) of 18,66831 1'-benzyloxy-3-chlorobenzoyl azide.

2.87 g (0.01 mol) of 1-benzyloxy-3-chlorobenzoyl teide (vigorously dried in vacuo at room temperature) are heated under reflux in 25 ml of dry (molecular sieve) toluene. After one hour, the mixture is homogeneous and the solution has a strong band in the infrared spectrum at 2300 cm due to U-benzyloxy-3-chlorophenyl isocyanate, which tends to separate from the solution upon cooling. The heated toluene solution can be used as such in the next step.

A benzene solution of 2-imino-1-methylpyrrolidine (obtained from 8.8 g, 0.055 mol of carbonate salt) is dried over potassium carbonate and filtered. Add the above warm toluene solution of 1 * benzyloxy-3'-chlorophenyl isocyanate.

The mixture is stirred for 1 / U hour, the solvent is removed in vacuo and the residue is crystallized by adding ether. Recrystallization from ethanol / ether gives a total of 12.6 g (70.3% yield) of 1- (1H-benzyloxy-3-chlorophenyl) -3- (1-methyl-2-pyrrolidinylidene) urea, m.p. 115-117 ° C.

Example 17 1- (m-Acetylphenyl) -3- (1-methyl-2-pyrrolidinylidene) urea: 13.5 g (0.1 mol) of m-aminoacetophenone are 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 to reflux while continuously passing phosgene for 1 * hour. The monoglyme is removed in vacuo and the residue is dissolved in dry benzene, filtered through a filter aid and the resulting benzene solution of m-acetylphenyl isocyanate is used in the next step without purification.

A solution of 2-imino-1-methylpyrrolidine (obtained from 10.09 g, 0.075 mol, hydrochloride salt) in benzene is dried over anhydrous potassium carbonate and filtered into a flask equipped with a thermometer. A solution of the above m-acetylphenyl isocyanate in benzene is added to the flask. The mixture is warmed from 21 ° C to 1.3 ° C and stirred at room temperature. The resulting precipitate is removed by filtration and crystallized several times from acetone to give pure product 1- (m-acetylphenyl) -3- (1-methyl) -2-pyrrolidinylidene) urea as a white solid, m.p. 15 ^ -155.5 ° C.

Example 18 1- (1-Methyl-2-pyrrolidinylidene) -3- (1-naphthyl) urea: Solution of 2-imino-1-methylpyrrolidine (obtained from 6.91 g, 0.051 mol, hydrochloride salt) in benzene dried over potassium carbonate and filtered. A solution of 8.5 g (0.05 mol) of 1-naphthyl isocyanate in benzene is added. The mixture is stirred for 1 1/2 hours at room temperature and the precipitate is filtered off. Recrystallization from acetone gives 1- (1-methyl-2-pyrrolidinylidene) -3- (1-naphthyl) urea as product, m.p. * II-8 lU9 ° C.

Example 19 1- (1-Methyl-2-pyrrolidinylidene) -3- [m- (methylthiophenyl) urea; 27-8 g (0.2 moles) of m-aminothioanisole in 100 ml of dry dimethoxyethane are added to a saturated solution of phosgene 200 Phosgene is passed to the refluxing mixture for a further U hours and then "the mixture is heated under nitrogen for 21 hours. The solvent is removed in vacuo to give m-methylthiophenyl ieocyanate as an amber oil which is dissolved in benzene for use in the next step.

A solution of β-imino-1-methylpyrrolidine (obtained from 26.9 g, 0.2 mol, 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 and the mixture is warmed from 21 ° C to 2 ° C. After stirring for 1 hour, the mixture is filtered and the solvent is removed in vacuo. The residue is recrystallized from acetone to give the product 1- (1-methyl-2-pyrrolidinylidene) -3H- (methylthiophenyl) urea, mp 110-111 ° C. Recrystallization from the same solvent gives a melting point of 11-117 ° C: a.

Example 20

Hexahydro-2-imino-l-methyl-lH-azepine-cyclohexanesulfamate; 12.5 g (0.1 mol) of epichlorohydrin are added rapidly to a stirred solution of 25.7 g (0.18 mol) of boron trifluoride etherate in 90 ml of anhydrous ether. After the reaction was initially vigorously exothermic, the mixture was stirred at reflux for 3 hours. The ether is removed as a filter and the solid residue is washed twice with anhydrous ether. 60 ml of dry methylene chloride are added to triethyloxonium fluoroborate and 17 g (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. Additional methylene chloride is added and ammonia is bubbled into the solution. The mixture becomes exothermic and after 1/2 hour it cools.

After 3 hours, the addition of amen is stopped and more methylene chloride is added and the mixture is stirred overnight at room temperature. The inorganic material is filtered off and the filtrate is evaporated to give 26 g of an oily residue which is washed with benzene to remove the starting lactam. Benzene 56831 20 is decanted off and the residual oil is dried in vacuo to give 22.5 g of the fluoroborate salt as a waxy substance.

The fluoroborate salt is converted to the free base in benzene using 50 # NaOH (7 mL). The benzene layer is decanted, filtered and dried (K2CO3). Evaporation gives 11.5 g of an oil which is dissolved in acetone (20 ml) and treated with a solution of cyclohexanesulphamic acid (16.4 g) in warm acetone (150 ml). The resulting mixture was rapidly heated on a steam bath and then cooled and filtered to give the product hexahydro-2-imino-1-methyl-1H-azepine-cyclohexanesulfamate, m.p. LK2-LKK ° C. After recrystallization from ethanol / ether, the melting point is 10-3 ° C.

Example 21 1- [2- (Hexahydro-1-methylazepinylidene)] - 3-phenylurea:

To a mixture of 1.25 g (0.00 μmol) of hexahydro-2-imino-1-methyl-1H-azepine-cyclohexanesulfamate in 20 ml of benzene is added an excess of 50 # of sodium hydroxide. The mixture is stirred and the benzene layer is decanted.

The base layer is washed several times with benzene. The combined benzene extracts are dried over potassium carbonate and evaporated to give 0.3 U g (0.0027 mol; 66%) of the free base, which is dissolved in dry benzene (2 ml) and treated with 0.32 g (0.0027 mol) of phenyl isocyanate. . After 10 minutes, the reaction solution is stirred gently to precipitate a solid. The reaction mixture is then cooled and filtered to give the product 1- [5- (hexahydro-1-methylazepinylidene] -β-phenylurea, mp 135-136 ° C. After recrystallization from ethyl acetate, the melting point is 136-137 ° C.

Example 22

Following the procedure used in Example 21 and using an equivalent amount of the appropriate aryl isocyanate which is reacted with hexahydro-2-imino-1-methyl-1H-atheepine, the following 1-aryl-3-hexahydroazepinylidene urines of formula (I) are obtained: substances: 1- (hexahydro-1-methyl-2-azepinylidene) -3- (2,6-xylyl) urea, ep.

132-133 ° C (comp. 22.a); 1-m-chlorophenyl-3 '(hexahydro-1-methyl-2-azepinylidene) urea, m.p. 119-121 ° C (comp. 22.b); 1- (2,6-dichlorophenyl) -3- (hexahydro-1-methyl-2-azepinylidene) urea, m.p. IU3-1M ° C (compound 22.c); 21 56831

Example 23 1-m-Chlorophenyl-3- (1-methyl-2-pyrrolidylidene) urea:

Calculated on the basis of a change of 100 and 2kkk (0.03 mol) of 2-imino-1-methylpyrrolidine is liberated from its HCl salt using a calculated amount of 50% NaOH (2.0 U, 0.03 mol) and by extraction into benzene. The benzene solution is dried over potassium carbonate. To this solution is added 1.6 g (0.03 mol) of m-chlorophenyl isocyanate dissolved in anhydrous benzene and added dropwise with stirring. A solid formed and the mixture was stirred at room temperature overnight. 1-m-chlorophenyl-3- (1-methyl-2-pyrrolidylidene) urea is recovered, m.p. - 135 ~ 136 ° C. The second crop is recovered from the mother liquor by evaporation to dryness, mixing with hot CHCl 3 and filtration of the insoluble material. Both yields are combined and recrystallized from methanol / ether to give the pure product, m.p. 137 "13o ° C.

Example 2k 1- (2,6-Dimethylphenyl) -3- (1-methyl-2-pyrrolidinylidene) urea: To a stirred solution of 6.73 g (0.05 mol) of 1-methyl-2-imino- pyrrolidine hydrochloride in about 2 ml of water, about 50 ml of benzene are added, followed by 10 ml of 50% NaOH. After stirring for 1 minute, the benzene layer is decanted into anhydrous potassium carbonate. The extraction is repeated twice. The combined benzene extracts are filtered off from the desiccant (dicalite layer) and rinsed with very dry benzene. 7 * 36 g (0.05 mol) of 2,6-dimethylphenyl isocyanate are added to the filtrate in one portion with stirring. The reaction mixture is stirred overnight. The solvent is removed and the residue is recrystallized from ethyl acetate / ether to give 1- (2,6-dimethylphenyl) -3- (1-methyl-2-pyrrolidylidene) urea as white crystals, mp 19-120 ° C. .

Claims (3)

56831 22 Claim: A process for the preparation of therapeutically useful pyrrolidylidene, piperidylidene and hexahydroazepinylidene ureas having the formula: “Vn 2 R —k x1— N-C-N-Ar I ^ N, and their therapeutically active acid addition salts, wherein n has an integer of 1, 2 or 3, R is hydrogen or lower alkyl, is lower alkyl or benzyl, Rg is hydrogen or methyl, and Ar is phenyl, naphthyl, mono-, di- or tri-halophenyl, mono-, di- or tri-lower alkylphenyl, mono-, di- or tri-lower alkoxyphenyl, mono- or di-trifluoromethylphenyl, nitrophenyl, cyanophenyl, methylthiophenyl, acetylphenyl, benzyloxyphenyl, lower alkylhalophenyl, lower alkoxyhalophenyl, trifluoroalkoxyphenyl, benzyloxyhalogenophenyl, benzyloxyhalogenophenyl that when n is 2 or 3 then R is hydrogen and R 1 is methyl, characterized in that a) a compound of formula 'A-] R-V 11 R 1 is reacted with a compound of formula 0 = C = N-Ar, preferably in a non-hydroxylated solvent, to prepare a compound of formula I wherein E 1 is hydrogen; or b) reacting a compound of formula II with a compound of formula 0 (f) (halide) -C-N-Ar! R 2 is preferably in a non-polar solvent; and, if desired, forming a therapeutically active acid addition salt of the product obtained in steps a) or b).