HU191702B - New process for preparing 1-aryl-5 h-2,3-benzodiazepines - Google Patents

Abstract

Process for the preparation of 5H-2,3-benzodiazepine derivatives of general formula (I) and of their pharmaceutically acceptable acid addition salts, <IMAGE> from one mole of a 1,5-diketone represented by the general formula (II) below: <IMAGE> Application: treatment of the central nervous system.

Description

(57) ABSTRACT

The present invention relates to novel novel central nervous system 5H-2,3-benzodiazepine derivatives of the formula (I) wherein R is an unsubstituted or substituted phenyl group having 1 to 3 identical or different substituents independently selected from halo, hydroxy, (C1-C5) alkyl, (C1-C5) alkoxy, trifluoromethyl or nitro, and naphthyl, furyl or thienyl,

R 1 is hydrogen or C 1-4 alkyl,

R 2 and R 1 are the same or different and are C 1 -C 8 alkyl or

R2 and R1 may also be taken together to form a methylene group for the preparation of pharmaceutically acceptable acid addition salts thereof comprising 3 to 7 moles of hydrazine per mole of a compound of formula II wherein R, R, R2 and R are as defined above. with a hydrate at -20 to ΠΙΟθΟ in an organic solvent, and converting the resulting base into an acid addition salt, if desired, with a pharmaceutically acceptable acid, then liberating the resulting base and optionally forming an acid addition salt with another acid.

The present invention relates to a novel process for the preparation of 4H-2,3-benzodiazepine derivatives of the formula I in which

R is unsubstituted or substituted phenyl which may have from 1 to 3 identical or different substituents independently selected from halogen, hydroxy, C 1-5 alkyl, C 1-5 alkoxy, trifluoromethyl, or nitro; naphthyl, furyl or thienyl,

R | is hydrogen or C1-C4 alkyl,

R 2 and R 1 are the same or different and are C 1 -C 8 alkyl or

R 2 and R 2 taken together may also be methyl and pharmaceutically acceptable acid addition salts thereof.

In the compounds of the present invention, the alkyl and alkoxy groups are straight or branched and the halogen atoms may be fluorine, chlorine or bromine. As mentioned above, R in the formula (I) is, for example, phenyl, 3-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 3,5-dichlorophenyl, 3-methylphenyl. , 4-t-butylphenyl, 2-chloro-4-diethylphenyl,

3-trifluoromethylphenyl, 3-methoxyphenyl, 3,4-dimethoxyphenyl, 3-methoxy-4-isopropoxyphenyl, 2-, 3- or

4-nitrophenyl, 3-nitro4-chlorophenyl, 3-nitro4-methylphenyl, 3-nitro4-methoxyphenyl, 2-hydroxy-3-methoxyphenyl, 2-nitro 4,5 -dimethoxyphenyl, 1 or 2-naphthyl, 2-furyl or 2-thienyl. R1 can be methyl, ethyl, η-propyl, isopropyl or butyl, R2 and R are, for example, methyl, ethyl, propyl, butyl or octyl.

The compounds of formula (I) obtained by the process of the invention are partly known and partly novel. Among the 5H-2,3-benzodiazepines of formula (I), compounds wherein R is unsubstituted or substituted with 2 or halogen atoms or 1 or 2 hydroxy, C 1-3 alkyl, C 14 alkoxy are known. phenyl substituted with trifluoromethyl or nitro; and naphthyl, furyl or thienyl; R 1 is hydrogen or C 14 alkyl; R 2 and R 1 are C 1 -C 5 alkyl or together are methylene 179 018 Hungarian registration number 879 404 Belgian patents).

There are several processes known in the literature for the preparation of compounds of the formula I:

1. Hungarian registration No 155 572 and registration number 179 018, application No 3 736 315; U.S. Pat. Nos. 1,202,579 and 1,334,271. Great British Patents and Chem. 107, 3883 (1074), is prepared from the corresponding diketone of formula (I) with hydrazine hydrate at 60-120 ° C, followed by ring closure with hydrochloric alcohol and releasing the base from the hydrochloric salt. The first two steps of this process can be combined by reacting the compounds of formula II with hydrazine monohydrochloride to liberate the compound of formula I from the crude hydrochloric acid salt (Chem. Bér. 107,3883 / 1974).

2. According to another method described in Hungarian Patent Application No. 179,018, 2-benzopyrilium salts which can also be prepared from diketones of the general formula II are reacted with excess hldrazine hydrate (Swiss Patent No. 585,714, British Patent No. 3,736,315). U.S. Patent Nos. 107, 3883 (1974).

3. Another known route for the preparation of 5H-2,3-benzodiazepines consists in the preparation of tosylhydrazones from 2-allyl, 2-alkanoyl, 2-aroylstyrenes or stilbenes by thermal decomposition of the sodium compounds of the shells. O-alkenylaryl / diazoalkanes are formed which are converted to 1H-2,3-benzodiazepines by 1,7-electrocyclic ring closure. The latter can be rearranged with sodium ethylate to form 5H-2,3-benzodiazepines (J. Chem. Soc. Chem. Comm. 1972, 823, J. Chem. Soc. Perkin I 1973, 2543 1080, 1718, 1984, 849). Benzodlazepine prepared in this way contains a hydrogen atom or an aryl group at the 4-position, unlike the compounds obtained by the process we require.

The disadvantages of the above procedures are summarized below:

a.) The 5H-2,3-benzodiazepines having the 1-position aryl substituent of formula (I) are as defined in claims 1-2. They are generally not directly synthesized by synthesis but only by at least a two-step reaction (rnonohydrazone preparation + ring closure or 2-benzopyrilium salt preparation · ring closure). These steps always require strong acid and special technical equipment (eg acid-proof device). The production achieved by these processes is max. 60%.

b) Another disadvantage of Process 1 is that the bases can only be accessed via the acid addition salts. However, bases are preferred for pharmaceutical formulations because benzodiazepines, being weak bases, only form salts with strong acids which are highly acidic.

c) Process 3 is of limited practical importance as the starting 2-acylstyrene derivatives themselves can only be prepared by a multi-step reaction, and the tosylhydrazone preparation and the sodium ethylate reaction increase the number of steps and greatly reduce the yield.

SUMMARY OF THE INVENTION It is an object of the present invention to overcome the disadvantages of the above known processes by providing a simpler, industrially feasible process which results in a high purity final product.

The present invention is based on the discovery that the diketones of formula II, wherein the substituents have the meanings given above, can be prepared directly in one step without the presence of an acid in hydrazine hydrate, under mild conditions, in good yield and purity. 2,3-benzodiazepines.

This discovery is surprising because, according to the state of the art, only 5H-2,3-benzodiazepines of the formula (I) which have a hydrogen atom or an alkyl group at the 1-position can be prepared from 1,5-diketones in one step with the hydrazine hydrate. They contain. Further, according to the above literature data (Chem. Bér. 107, 3883 (1974), 155, 172, United States Patent Nos. 3,202,579 and 1,334,271), such 1,5- diketones containing an aliphatic and an aromatic keto group - such as the starting compounds of formula II according to the invention

191,702 also - with oxo reagents e.g. with hydrazine hydrate so that only the more reactive aliphatic keto group is reacted and converted, e.g. monohydrate. The low reactivity of aromatic keto groups is also evidenced by the fact that compounds containing only aromatic keto groups, such as benzophenone and benzophenone derivatives, give Schiff bases in good yield only under very strong conditions. Thus, benzophenone is reacted in a bomb-tube with hydrazine hydrate at 150 ° C for 6 hours to form benzophenone hydrazone (J. Prak. Chem. (2) 44. 194 (1891)) or, for example, 2-amino-5- The preparation of the oxime of chlorobenzophenone in hot ethanol requires 22 hours c (J. Am. Chem. Soc., 82, 475, 1960).

In contrast to the literature, it has been found that the asymmetric diketones of formula (II) form a benzodiazepine ring in good yield in one step with hydrazine hydrate.

Thus, the invention is based on overcoming technical prejudice 20. Namely, the starting diketones are diketones tensed by IR and * NM-NMR spectroscopy, and even ring traces are not detectable by spectroscopic methods.

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of a compound of formula (I) wherein ® ^s ^ 3 are as defined above - 5H-2,3-benzodiazepines ^do k and pharmaceutically usable acid addition salts thereof, which comprises the formula (II) • 1.5 mole of diketone 1 - wherein R, R · Ro and Ro is reacted with the above-3-7 mol hydrazine hydrate in a solvent at a temperature of -20 ° C to + 110 ° C and the base thus obtained is optionally converted into the acid addition salt with a pharmaceutically acceptable acid and optionally liberated from the resulting salt and optionally forming a acid addition salt with another acid.

Suitable solvents are polar or non-polar solvents, preferably C 1-5 alcohol, dioxane, tetrahydrofuran, dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide, pyridine or mixtures thereof. 40

In a preferred embodiment of the process according to the invention, the diketone 11 is suspended in a C 1 -C 5 alcohol and stirred with 98-100% hydrazine hydrate at -20 to + 30 ° C, preferably at room temperature. -96 hours. Most of the excess hydrazine hydrate 45 is then neutralized with acetic acid and the precipitated product is isolated by filtration after cooling. If desired, the product thus obtained is recrystallized.

In another preferred embodiment of the process according to the invention, the dike ions of formula II are reacted with 98-100% hydrazine hydrate at high temperature, for example 78-100 ° C, for a short time, for example 10 minutes to 1 hour. . In this case, the crude product of good yield has to be recrystallized. The recrystallization is preferably carried out from alcohol, dimethylformamide, acetone, water or a mixture thereof.

The yield of the process according to the invention is 80-85%.

The compounds of formula (II) used as starting materials in the process of the invention are partly known and partly novel. They may be prepared as described in Acta Chim. Acad. Sci. Hung. 40, 295 (1964), 41, 451 (1964), 52 (1067), 57, 181 (1968), Zh. Organ. Khim. 2, 1492 (1955) C. A. 66, 46286 p (1967), 2, 1499 (1966), C. A. 66, 46287q (1967), Doc. Lags. Nauk 166, 359 (1966), Khim. Geterotskl. Soedin. 1970, 1003, 1308, 1971, 730, CA 74, 12946d, 76293w (1971), 76, 25035x (1972), 1976, 1484, CA 86, 10630t (1977), 1981, 1608, CA96,142656z (1982). .

In the process of the present invention, the compounds of formula I are obtained in the form of the base. The salts of the compounds of formula (I) may conveniently be prepared by dissolving the base in a suitable solvent such as methanol, isopropanol or diethyl ether and then adding the appropriate acid or a solution thereof in a suitable solvent. The salts are isolated by direct filtration or optionally by distillation of the solvent.

Some crude bases cannot be purified by direct recrystallization, so it is convenient to liberate the base from the pure acid addition salt prepared as described above.

The bases of formula (I) are liberated from their salts by, for example, water. dissolved in methanol, ethanol or a mixture thereof, the solution is made basic with an organic base such as triethylamine or pyridine or an inorganic base such as aqueous sodium hydroxide or ammonium hydroxide, and the free base is isolated by filtration. From the pure base obtained in this manner, another acid addition salt may be prepared, if desired, with a pharmaceutically acceptable acid, as described above.

The novel compounds of formula (I) obtained by the process of the present invention have valuable central nervous system (CNS) effects as known. The anti-aggressive effect was assayed by the "Fighting behavior" test (J. Pharm. Exp. Ther. 25, 28 (1959)). The results of the studies are summarized in Table 1. The reference was the commercially available Grandaxin (tofisopam, i.e. 1- (3,4-dimethoxyphenyl / 4-methyl-5-ethyl-7,8-dimethoxy-5H-1,3-benzodiazepine). From the data in the table it can be seen that many compounds in this test are superior to Grandaxin.

Some of the compounds of formula I have significant anesthetic effects. The most effective of these is the compound of Example 24, 1- (3-chlorophenyl) 4-methyl-7,8-diethoxy-5H-2,3-benzodiazepine, which is equivalent to the known 1,4-benzodiazepine derivative in rodents. nitrazepam (7-nitro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one).

191,702

Examination of Compound Anti-Aggressive (Fighting Behavior) in Mouse

Εθ50 mg / kg bw. relative strength' $. 4i 1.4 16th 45 1.4 25th 36 1.8 29th 12 5.3 31st 40 1.6 32nd 30 2.1 33rd 16 4.0 34th 40 1.6 35th 40 1.6 36th 40 1.6 38 15 4.3 49th 50 1.3 50th 30 2.1 51st 22 2.9 53rd 35 1.8 Grandaxin (Tofisopam) 64 Shoot

* with respect to Grandaxin, ED is the dose that eliminates aggression in half of the fighting pairs.

The invention is illustrated by the following non-limiting examples.

Example 1 1- (3-Chloro-phenyl) -4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine

2.0 g (6 mmol) of 2-acetonyl-3'-chloro-4,5-dinethoxyl-benzophenone is suspended in 7 ml of isopropanol, 1.86 g (36 mmol) of 100% hydrazine hydrate is added and stirred until ca. 5-6 minutes) and then allowed to stand at 25 ° C for 82 hours. To the reaction mixture was added water (7 mL) and glacial acetic acid (1.8 g, 30 mmol) while cooling with ice water. A white, crystalline precipitate is formed from the light yellow solution. After cooling for 10-15 hours at 5 ° C, the final product is filtered, washed 3 times with 1 ml 50% isopropane and dried at 60-80 ° C. Weight: 1.67 g (84.8%) m.p. 166-168 ° C. The crude product was recrystallized from 17 ml of isopropanol. Cooled to 10 to 15 hours at 5 ^° C, filtered, washed with 3x1 ml of isopropanol and dried at 60-80 ° C. Yield: 015 g (80.7%), colorless, luminous crystals. op .:

167-169θ0. The hydrochloride salt of the compound of the example decomposes at 135-187 ° C and the hydrochloric acid salt at 198200 ° C.

In order to prepare the compound of Example 1, Table 2 shows some of our experiments in which the molar ratio of benzophenone derivative to hydrazine hydrate was varied by temperature, reaction time, and medium (solvent):

Table 2

benzophenone tem- reaction Yield derivatives solvents ture tion % -hidrazinhidrát (Molar ratio) agent C hour 80.2 1: 5 iPrOH 25 48 1: 5, iPrOH 25 72 84.2 1: 5 iPrOH 25 168 83.7 1; 6 iPrOH 25 168 84.8 1: 6 MeOH 25 72 82.8 1: 6 DMF 100 1 80.2 1: 5 ^- dioxane 25 72 82.2

2-23. examples

Using the procedure described in Example 1 for further diketones of formula II, the following compounds of formula I are prepared, which are characterized in Table 3 by their melting point and the solvent or solvent mixture used for recrystallization (abbreviations 3 to 5). : Me: methanol, DMF: dimethylformamide, EtOAc: ethyl acetate),

Example R Spreadsheet. R - R _o Op (° C) (Recrystallization agent) (Ethanol) '- Second 4-chlorophenyl H ¹ Me ² measuring Third 3,4-dimethoxyphenyl H Me Me 157-159 (absolute ethanol) 4th 3-chlorophenyl Me Me Me 162-164 (isopropanol) 5th 2-chlorophenyl et Me Me 150-152 (zopropanol) 6th phenylalanine H Me Me 151-152 (isopropanol) 7th 2-chlorophenyl H Me Me 137-139 (isopropanol) 8th 3-fluorophenyl et Me Me 122-124 (ethanol-water) 9th 1 naphthyl H Me Me 178-180 (ethanol-water) 10th 2-naphthyl H Me Me 198-200 (isopropanol) 11th 3-trifluoromethylphenyl H Me Me 133-135 (ethanol-water) 12th 2-nitrophenyl H Me Me 158-160 (absolute ethanol) 13th 2-furyl H Me Me 156-158 (DMF water) 14./HO/ 2-thienyl H Me Me 189-191 b. (Ethanol-acetone) 15th 4-nitrophenyl H Me Me 238-240b (DMF) 16th 4-isopropoxyphenyl H Me Me 157-159 (isopropanol) 17th 3-nitrophenyl H Me Me 196-198 b. (DMF) 18th 3-methoxy-4-isopropoxyphenyl H Me - Me . 141-143 (isopropanol ether) 19th 3-methoxy-4-nitrophenyl H Me Me 202-204b (ethanol) 20th 3-nitrophenyl H et et 178-180 (absolute ethanol) 21st 3-nitro-4-chlorophenyl H Me Me 212-214b (DMF) 22nd 3-methyl-4-nitrophenyl H Me Me 196-198 (DMF-ethanol) 23rd 3-nitro 4-methylphenyl H Me Me 212-213 (DMF-ethanol)

191,732

Example 24 (3-Chloro-phenyl) -4-methyl-7,8-diethoxy-5H-2,3-benzodiazepine

1.3 g (3.6 mmol) of 2-acetonyl-3'-chloro-4,5-diethoxybenzophenone in 15 ml of abs. To a suspension of ethanol was added 0.9 ml (18 mmol) of 98% hydrazine hydrate and the reaction mixture was refluxed for 1 hour. The reddish solution was then clarified with activated charcoal, and the resulting pale yellow solution was concentrated in vacuo and the residue was recrystallized from 15 mL of 50% ethanol. Yield: 1.04 g (81.25%) of a white crystalline powder, m.p. 119-120 ° C.

The hydrochloride salt decomposes at 172-173 ° C.

25-45. examples

Using the procedure described in Example 24 for other 1,5-diketones of formula (II), additional compounds of formula (I) were prepared as described in Table 4:

J 1 Box ^R 1 Example

R

Rf Op. (° C) (Recrystallizer)

25th 2-methoxyphenyl H Me Me 119-121 (isonroDano!) 26th 4-nitrophenyl H -CHY 230-232 b. (DMF) 27th 2-nitro-5-chlorophenyl H Me ^z Me 225-227 (DMF) 28 3-fluorophenyl 11 Me Me 142-144 (isopropanol) 29th 3-methoxyphenyl H Me Me 157-159 (isopropanol) 30th 3-methoxy-4-hydroxyphenyl H Me Me 219-221 b (DMF water) 31st 3-ethoxyphenyl H Me Me 133-135 (isopropanol-water) 32nd 3-methylphenyl H Me Me 184-186 (ethanol) 33rd 3-isopropyl-4-methoxyphenyl H Me Me 142-144 (ethanol-water) 34th 3-propyl-4-methoxyphenyl H Me Me 140-142 (isopropanol) 35th 3- (3-pentyl) 4-methoxyphenyl H Me Me 130-132 (isopropanol-hexane) 36th 3-n-butyl-4-methoxyphenyl H Me Me 105-107 (isopropanol-water) 37th 3-chlorophenyl H CH, 219-221 (DMF-isopropanol) 38th 2-hydroxy-3-methoxyphenyl H Me ² Me 176-178 (DMF water) 39th 3-isopropyl-4-methoxyphenyl U CH, 169-171 (isopropanol) 40th 3-chlorophenyl H Me 'No 152-154 (isopropanol) 41st 4-nitrophenyl H et et 188-190 b. (Ethanol) 42nd 2-chloro-5-nitrophenyl H Me Me 197-199 (ethanol) 43rd 3-chloro-4-nitrophenyl H Me Me 218-220 (DMF) 44th 2-chloro-3-nitrophenyl H Me Me 169-170 (isopropanol) 45th 2-hydroxy-3-methoxy-phenyl H -ch ₂ - 206-207 (DMF)

Example 46 1-Phenyl-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine

2-Acetonyl-4,5-methylenedioxybenzophenone (0.255 g, 0.9 mmol) in isopropanol (16 mL) was heated with 100% hydrazine hydrate (0.225 mL, 4.5 mmol) for 10 min. To the cooled solution was added glacial acetic acid (0.27 mL) followed by water (1.8 mL) and the reaction mixture was allowed to stand under ice-cooling for 2 hours.

The precipitated crystals are filtered off, washed several times with water and dried. The 0.131 g of a cream-colored crude product of melting point 215-218 ^o C. This was applied to a silica gel column and eluted with benzene-cyclohexane-ethanol (5: 4: 1). Yield: 0.112 g of colorless crystals. Mp 222-224 ° C.

47-67. examples

By following the procedure described in Example 46, additional compounds of formula (I) were prepared as shown in Table 5:

191,702

Table 5 Example R Rj Rj Rj Op. (° C) (Recrystallizer)

47th (HCl) 3-chlorophenyl H (N) -Bu (N) -Bu '135-138 (CHCl _r EtOAc) 205-207 b (DMF) 48th 2,3-dihydroxyphenyl H Me Me 49th 3,4-dimethylphenyl H Me Me 184-186 fethanol benzene) 50th 3,4-di-n-butoxyphenyl H Me Me 98-100 (ethanol-water) 51st 3-ethyl-4-methoxyphenyl H Me Me 144-145 (isopropanol-hexane) 52nd (HO) 3-chlorophenyl H nC _Q H 1 * 7 Me ^{8 17} n-Cn-H »-7 Me ^{8 17} 140-142 (CHCl3-EtOAc) 130-132 (isopropanol-hexane) 53rd 3-chair .b util 4-methoxy-phenyl H 54th 2-nitrophenyl H -CHY 194-196 (DMF water) 55th 3-nitrophenyl H -CHjEt ^Z 215-217 b. (DMF-water) 56th phenyl H et 58-60 (Benzene Cyclohexane) 57th 4-t-butylphenyl H Me Me 180-182 (diethyl ether) 58th 3-methoxyphenyl H -ch ₉ - 161-162 (methanol) 59th 4 _(1; 1-Ethyl -diene methyl) phenyl H Me Me 114-116 (isopropanol-water) 60th 3-methyl 4-methoxy-phenyl H et et 146-J48 (Benzene Cyclohexane) 61st 62nd 3 hours 4-methoxyphenyl 3,4-diethoxyphenyl H H et et et et * 161-163 (isopropanol-hexane) 111-113 (isopropanol) 63rd Íluor4-3-methoxyphenyl H -CH _? - 231-232 (Benzene Cyclohexane) 64th 2-methylphenyl H -CH ~ - 177-179 (ethanol) 65th 4-fluorophenyl H Me ^z Me 165-167 (isopropanol) 213-215 (isopropanol) 66th 4-bromophenyl H Me Mc 67th 2-nitro4,5-dimethoxyphenyl H Me Me 238-240 b. (absolute ethanol)

Example 68

PHARMACEUTICAL FORM Preparation Tablets containing 50 mg of 1- (3-isopropyl-4-methoxyphenyl) 4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine (compound of Example 33) were prepared in the usual manner. 1 tablet composition:

Active ingredient 50.0 mg

Potato starch 30.0 mg

Lactose 100.0 mg

PVP (aqueous) 5% 0.2 mg

Mg stearate 1.0 mg

Stearin 1.0 mg

Talcum 2.0 mg

184.2 mg

PATENT CLAIMS

Claims (5)

A process for the preparation of 5H-2,3-benzodiazepines of formula I wherein: R is unsubstituted or substituted phenyl, which may have from 1 to 3 identical or different substituents independently selected from halogen, hydroxy, C1-5 alkyl, C1-5 alkoxy, trifluoromethyl, or nitro. and naphthyl, furyl or thienyl. R 1 is hydrogen or C 14 alkyl, R 2 and R 1 are the same or different and are C 1 -C 8 alkyl or R 1 and R ₃ may also be taken together to form a methylene group, and pharmaceutically acceptable acid addition salts thereof, wherein one mole of a diketone of formula II wherein R, R 1, R 1 and R 1 are as defined above is 3-7 moles. reaction with hydrazine hydrate at -20 to + 110 ° C in an organic solvent and converting the resulting base into an acid addition salt, if desired, with a pharmaceutically acceptable acid, then liberating the base from the resulting salt and optionally forming an acid addition salt with another acid. . 2. A process according to claim 1 wherein the solvent is selected from the group consisting of C 1-5 alcohol, dioxane, tetrahydrofuran, dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide, pyridine and mixtures thereof. Process according to claim 1 or 2, characterized in that the diketones of the formula (II) are reacted with 4-6 moles of hydrazine hydrate. 4. Process according to any one of claims 1 to 3, characterized in that the reaction is carried out at a temperature of -20 to <30 ° C. A process for the preparation of a medicament having a central nervous system action, comprising the step of forming a compound of formula (I) or a pharmaceutically acceptable acid produced by the process of claim 1; a salt thereof - wherein R, R 1, R 1 and R 3 are as defined in claim 1, with the proviso that when R is unsubstituted phenyl or with 1 to 2 or 3 halogens or 1 or 2hydrocq xyl, C 1 -C 3 alkyl- , Phenyl substituted with C14 alkoxy, trifluoromethyl or nitro, and naphthyl, furyl or thienyl; group The compounds of the invention may be formulated into a pharmaceutical composition either alone or in combination with other pharmaceutically active compounds which do not show synergism with the compounds of formula (I) and by the use of excipients used in the preparation of medicaments.