KR830001838B1 - Process for preparing phenyl quinolizicines - Google Patents

Abstract

Title compds., I≮X=H, F, Cl, C1-4 alkoxy, C1-4 alky1, CF3; A"=formula IV(R5,R6=H, Me, F, Cl, MeO, CF3)≉ were prepd. by cyclizing phenylene-diamine(II) with cyclizing agent (III; Rb,Rc=halogen, amino, l-imidazolyl) at the temp. between 00C and b.p. of the mixt. in the inert org. solvent. Thus, rac-(9a H)-7β-(O-fluoropehnyl)-octahydro-2-(α1,α1,α1-trifluoro-2- amino -p-toluidino)-2H-quinolidine dissolved in methylene chloride was stirred with N,N1-carbonyldiimidazole to give crystalline rac-1≮(aβH)-7β-(O-fluoropheny1)octahydro-2H-quinolidin-2α-yl≉-5-(trifluoro methyl)-2-benzimidazolinone(yield 83.5%)

Description

Method of Preparation of Phenyl-Quinolizidine

The present invention relates to a process for the preparation of the novel phenyl-quinolizidine of the general formula (III-4) which is pharmacologically active.

Wherein X represents hydrogen, fluorine, chlorine C _1-4 -alkoxy, C _1-4 -alkyl or trifluoromethyl at the 0-, m- or p-position; A "represents a group of the following general formula.

[Wherein R ₅ and R ₆ each independently represent hydrogen, fluorine, chlorine, methoxy or trifluoro methyl or together represent-(CH) 4-]

The compounds of the general formula (III-4) according to the present invention may exist in the form of free base and acid addition salts as well as racemates or enantiomers.

As specified in general formula (III-4) and several general formulas below, hydrogen atoms in the 7- and 9a-positions exist in trans relationship with each other, and hydrogen atoms in the 9a-position of the structural formula And the hydrogen atom in the 7-position thus represents the α-position. However, the phenyl-quinolizidines and corresponding intermediates and starting materials provided by the present invention are not limited to this absolute configuration, and compounds having hydrogen atoms in the corresponding enantiomer types, i.e., 9aα- and 7β-positions. As well as the racemates of these two enantiomer types. The same applies to the 2-position coordination of phenyl-quinol zidinedine. If the hydrogen atoms in the 2- and 9a-positions represent the β-position and the hydrogen atoms in the 7-position represent the α-position, then the relative coordination is fixed at these three asymmetric centers (9aH vs. 7H: trans; 9aH vs. 2H: cis), but not limited to expression for one enantiomer.

The C 1-4 -alkyl and C 1-4 -alkoxy groups mentioned herein are alkyl and alkoxy groups each containing 1 to 4 carbon atoms, which contains 3 or more carbon atoms, straight or branched.

Acid addition salts of phenyl-quinolizidines according to the present invention include pharmaceutically acceptable salts with organic and inorganic acids which are commonly used for salt formation. Examples of such acids are inorganic acids (e.g. sulfuric acid, nitric acid, phosphoric acid and hydrochloric acid such as hydrochloric acid and hydrobromic acid) and organic acids (e.g. tartaric acid, citric acid, aliphatic or aromatic sulfonic acid, maleic acid, mandelic acid, etc.). Salt formation can be carried out by methods known per se.

The compounds of general formula (III-4) described above have excellent neuroroleptic actvity. X is hydrogen, O-fluoro or O-chloro, R ₅ represents fluorine, chlorine or trifluoromethyl, and R ₆ represents hydrogen, chlorine or fluorine Zolinone derivatives are preferred. Particularly preferred among the compounds of the general formula (III-4) is as follows.

(a) X = O-Cl; R ₅ , R ₆ + H,

(b) X = O-Cl; R ₅ , R ₆ = CH ₃ ,

(c) X═O—Cl; R ₅ , R ₆ = Cl,

(d) X = O-Cl; R ₆ = H; R ₅ = CF ₃ ,

(e) X = O-Cl; R ₆ = H; R ₅ = Cl,

(f) X = O-Cl; R ₅ and R ₆ together =-(CH ₂ ) _4- ,

(g) X = OF; R ₅ , R ₆ = CH ₃ ,

(h) X = OF; R ₅ , R ₅ = Cl,

(i) X = OF; R ₅ and R ₆ together =-(CH2) 4-,

(j) X = OF; R ₆ = H; R ₅ = CF ₃ ,

(k) X = OF; R ₆ = H; R ₆ = Cl.

According to the process of the present invention, the above-described phenyl-quinol ridged group is prepared by the following phenylene-diamine of the general formula (X) in the inert organic solvent at a temperature between about 0 ° C. and the boiling point of the reaction compound. It is prepared by the condensation with a condensation agent of.

Wherein X, R ₅ and R ₆ have the same meanings as described above, and R ^b and R ^c represent halogen, amino or 1-imidazolyl.

The reaction of the above-described process can be carried out according to a known method. For example, phosgene, carbonyl diimidazole, or urea may be used as the ring closure agent in the reaction.

If the intermediate or starting material compound described below is not a known compound, it can be prepared by a known method itself as in Example 1.

Phenyl-quinolizidine prepared by the process of the present invention has useful pharmacological properties. Since they exhibit neuro-relaxation, central nervous suppression, calmness and / or anti-causing action, they can be used as antipsychotics or anti-cause agents in the treatment of psychosis and neurological diseases or nausea.

The neuroleptic action of the compounds of the present invention is measured numerically using the test method described below.

"Pole Climbing" test (rat)

For each dose, ten trained to climb up a pole vertically in an experimental cage, avoiding an electric shock (unconditional stimulus) applied through the grid floor immediately after giving an auditory signal (conditional stimulus). Use rats as a group. Inhibition of conditioned response in 50% of rats during the 6-hour observation period is defined as parameter ED 50 BCR, and inhibition of unconditional response is defined as parameter ED 10 BUR.

Spiroperides-Binding Test (In Vitro)

In in vitro experiments, calf striatum (Creese et al., Life sci, 17, 993 (1975)) is used as the receptor and described in Fields et al., Brain Research 136, 578r1977. Incubate with [ ³ H] spirophiles in a similar manner to the previous method. Using a computer program, the IC ₅₀ is used to determine the concentration of the test substance, ₅₀ , which separates the specific binding of [ ³ H] spirophiles on the receptor by 4 different concentrations in a three step process.

The results of the test are summarized in Table A below.

Phenyl-quinolizidine provided by the present invention can be used as a medicament, for example in the form of a pharmaceutical formulation. Such pharmaceutical preparations may be administered orally (eg in the form of tablets, coated tablets, dragees, hard and soft capsules, solutions, emulsions or suspensions). However, they can also be rectally (eg in the form of suppositories), topically or percutaneously (eg in the form of ointments, creams, gels or solutions) or parenterally (eg in the form of injectable solutions). Can also be administered.

For the preparation of tablets, coated tablets, dragees and hard gelatine capsules, the phenyl-quinolizidines of the invention can be formulated with pharmaceutically inert, inorganic or organic excipients. Examples of excipients that can be used in tablets, dragees and hard gelatine capsules are lactose. Corn starch or derivatives thereof, talc, stearic acid or salts thereof. Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols. However, in the case of soft gelatin capsules, excipients are generally not necessary depending on the nature of the active ingredient. Suitable excipients for the preparation of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose and the like. Suitable excipients for injectable solutions are, for example, water, alcohols, polyols, glycerin, vegetable oils and the like. Suitable excipients for suppositories or topical or transdermal formulations are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols.

The pharmaceutical preparations may also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, salts for controlling osmotic pressure, buffers, skinning agents or antioxidants. Such formulations may also contain substances useful for other therapeutic purposes.

In the pharmaceutical formulations described above, the dosage may range from approximately 0.5 to 1000 mg. In the case of oral administration, the dose of the active ingredient is about 0.05 mg / kg to about 10 mg / kg per day, and for parenteral administration, 0.01 mg / kg to 1 mg / kg of active ingredient is used per day.

Example 1

(a) 93% N of a solution of rac- (9αβH) -7β- (0-fluorophenyl) -octahydro-2α- (α ', α'α'-trifluoro-2-amide in 180 ml of methylene chloride , N'-carbonyldiimidazole and 4.59 g of the mixture, the mixture is stirred overnight at room temperature After 20 hours, the separated product is filtered and washed three times with 100 ml of methylene chloride to continue drying. Crystalline rac- (9αβH) -7β- (0-fluorophenyl) -octahydro-2H-quinolizine-2α-yl-5- (trifluoromethyl) -2-benzimidazolinone 6.45 ° C. g (83.5%) is obtained.

In the above process, rac- (9α / H) -7β- (0-fluorophenyl) octahydro-2α- (α ', α' α'-trifluoro-2-amino-P-toluidino)- Instead of 2H-quinolizine the corresponding substituted phenylene-diamine is reacted with N, N'-carbonyldiimidazole to afford the following compounds.

TABLE 1

rac- (0αβH) -7β- (Ra) -octahydro-2H-quinolizine-2α-yl]-(B) -2-benz-imidazolinone:

(b) rac- (9αβH) -7β- (0-fluoro-phenyl) -octa-hydro-2α- (α ', α', α'-trifluoro used as starting material in paragraph (a) above 2-Amino-P-toluidino) -2H-quinolizine can be prepared by the following method:

rac- (9αβH) -7β- (0-fluoro-phenyl) octahydro-2α- (α ', α', α'-tri-fluoro-2-nitro-P-toluidino) -2H-qui 25.7 g of tealzin are hydrogenated with 13 g of Ranikel for 20 hours at room temperature and atmospheric pressure in 0.91 of tetrahydrofuran and 0.91 of metalol. Thereafter, suction filtration removes the catalyst and the filtrate is evaporated. Thus, crystalline rac- (9αβH) -7β- (0-fluorophenyl) octahydro-2α- (α ', α' α'-trifluoro-2-amino-P-toluidino) -2H 23.6 g (99%) of quinolyzine are obtained, which may optionally be recrystallized from alcohol / ethyl acetate;

Melting point 133 ° to 138 ° C.

Rac- (9αβH) -7β- (0-fluorophenyl) octahydro-2α- (α ', α', α'-trifluoro-2-nitro-P-toluidino) -2H- in the process When the corresponding substituted nitro compound is reacted in place of quinolyzine, the following compound is reacted to obtain the next compound;

TABLE 2

rac- (9αβH) -7β- (Ra) octahydro-2α- (B) -2H-quinolizine:

(c) rac- (9αβH) -7β- (0-fluoro-phenyl) -octa-hydro-2α- (α ', α' α'-trifluoro- used as starting material in paragraph (b) above 2-nitro-P-toluidino) -2H-quinolizine can be prepared by the following method:

20.0 g of rac- (9αβH) -7β- (0-fluoro-phenyl) -2α- (amino) -octahydro-2H-quinolizine was dissolved in 300 ml of cyclohexane with a purity of 99% or higher and anhydrous sodium carbonate 8.62 g Heat to 160 ° C. At this temperature, a solution of 20.0 g of 4-chloro-3-nitro-benzo trifluoride dissolved in 200 ml of cyclohexane having a purity of 99% or more was added dropwise over 3 hours. The solution is then held further at 160 ° C. for 4 hours. After cooling to room temperature, the inorganic solid is filtered off and the filtrate is evaporated in vacuo. The residue is dissolved in 500 ml of hot ethyl acetate and 5 g of activated carbon is added to the solution and the mixture is boiled under reflux for 5 minutes. The mixture is then filtered hot through a Hoflo Super Cel and the filtrate is concentrated to 200 ml and 100 ml of n-hexane added. Thus, rac- (9αβH) -7β- (0-fluorophenyl) -octahydro-2α- (α ', α', α'-tri-fluoro-2-nitro-P at a melting point of 163 ° to 165 ° C 22.3 g of toluidino) -2H-quinolizine is crystallized. The mother liquor was chromatographed on 250 g of silica gel with n-hexane / ethyl acetate (4: 1) to afford an additional 5.45 g of product. The total yield is 78.8%.

In this process, instead of rac- (9αβH) -7β- (0-fluorophenyl) -2α- (amino) octahydro-2H-quinolizine, the corresponding substituted amino-quinolizine is replaced with the corresponding substituted O Reaction with -chloro-nitrobenzene gives the following compounds:

TABLE 3

rac- (9αβH) -7β- (Ra) octahydro-2α- (B) -2H-quinolizine:

(d) ac- (aβH) -7β- (0-fluorophenyl) -2α- (amino) octahydro) -2H-quinolizine used as starting material in (c) above may be prepared as follows. Can be:

rac- (9αβH) -7β- (0 = fluoro-phenyl) octahydro-2H-quinolizine-2-1.5 kg in 1700 ml of methanol with 47.4 g of hydroxylamine hydrochloride and 94.3 g of anhydrous potassium carbonate for 1.5 hours Heated to reflux. The methanol is then distilled off and the residue is partitioned between 750 ml of water, 600 ml of chloroform and 150 ml of isopropanol. The aqueous phase is back extracted twice with 250 ml of a mixture of 200 ml of chloroform and 50 ml of isopropanol, the combined organic phases are dried over magnesium sulfate and then evaporated. 85.3 g of oxime thus obtained are dissolved in 1.51 tetrahydrofuran 0.51 alcohol and 1 l of 5% (g / g) ammonia in alcohol and hydrogenated to 45 g Raney-Nickel for 30 hours at room temperature and atmospheric pressure. The catalyst is then filtered off and the filtrate is evaporated. Dissolve in 400 ml of the residue alcohol, and add 130 ml of 5N hydrochloric acid in alcohol and add rac- (9αβH) -7β- (0-fluorophenyl) -2α- (amino) octahydro-2H-quinolin at a melting point of 299 ° to 302 ° C. 53.5 g of dihydrochloride can be crystallized. The diastereoisomer rac- (9αβH) -7β- (0-fluorophenyl) -2α- (amino) octahydro-2H-quinolizine is dissolved in the mother liquor as dihydrochloride.

In the above process, rac- (9αβH) -7β- (0-fluorophenyl) -octahydro-2H-quinolizine-2- instead amination of the corresponding substituted quolizidinone to give the following compounds do :

TABLE 4

rac- (9αβH) -7β- (R _a ) -2α- (amino) -octahydro-2H-quinolizine:

(e) The rac- (9αβH) -7β- (0-fluorophenyl) -octahydro-2H-quinolinzin-2-one used as starting material can be prepared as follows:

Dissolve in 1.2 l of methyl rac- (1αH, 9αβH) -7β- (0-chlorophenyl) -octahydro-2-oxo-2H-quinolizine-1-carboxylate 76.2g 6N hydrochloric acid, and reflux for 3 hours. Boil. The cooled solution is then poured over ice and made alkaline by the addition of concentrated sodium hydroxide. Extract three times with 500 ml of methylene chloride to evaporate the organic phase and dry over magnesium sulfate to give 68 g of crude product. 50.4 g of rac- (9αβH) -7β- (0-chlorophenyl) octahydro-2H-quinolizin-2-one can be crystallized with ether / hexane; Melting point 80 ° to 82 ° C (81%)

Equivalent amount of corresponding substituted β-keto- in place of methylrac- (1αH 9αβH) -7β- (0-chlorophenyl) octahydro-2-oxo-2H-quinolizine-1-carboxylate Decarboxylation of the ester affords the following products:

TABLE 5

rac- (9αβH) -7β- (R _a ) octahydro-2H-quinolinzin-2-one:

(f) In addition, the octahydro-carboxylates used as starting materials in (e) can be prepared from the corresponding hexahydro-carboxylates as follows:

Monoglyme (dimethoxyethane) 180 g of methyl rac-7- (0-chlorophenyl) -3,4,6,7,8,9-hexahydro-2-oxo-2H-quinolizine-1-carboxylate Suspend to 3.6 l, add 1.33 l of DIBAH (diisobutylaluminum hydride, 20% solution in toluene) with cooling to -30 ° C and stirring. Subsequently, the mixture is stirred at -20 ° C to -30 ° C for 1 hour, and then hydrolyzed with 1.72 l of 2N sodium hydroxide at this temperature. In the completion step, the mixture is partitioned between 25 l of water and 20 l of chloroform and the organic acid is washed twice with 5 l of water, dried over magnesium sulfate and evaporated to afford 185.2 g of crude product. 109 g of product can be crystallized from ether / hexane. The mother liquor was chromatographed on silica gel 1 gg acid with ethyl acetate to afford 37 g of product. Methyl rac- (1αH 9αβH) -7β- (0-chlorophenyl) -octahydro-2-oxo-2H-quinolizine-1-carboxylate and the total yield is 136 g (81%): Melting point 122 ° C to 124 ℃.

Equivalent molar equivalent of methyl rac-7- (0-chloro-phenyl) 3,4,6,7,8,9-hexahydro-2-oxo-2H-quinolizine-1-carboxylate in the above process The substituted compound is reduced to DIBAH to obtain the following compounds:

TABLE 6

Methyl rac- (1αH, 9αβH) -7β- (R _a ) -octahydro-2-oxo-2H-quinolizine-1-carboxylate:

(g) Hexahydro-carboxylate costed as starting material in paragraph (f) can be prepared as follows:

150 g of 5- (0-chlorophenyl) -2-piperidone are dissolved in 2 l of methylene chloride and added dropwise to 410 g of triethyloxonium tetrafluoroborate (Meerwein salt) in 1 l of methylene chloride over 60 minutes with stirring at room temperature. . Subsequently, the mixture is boiled under reflux for 4 hours and left for another 15 hours at room temperature. 372 g of potassium charcoal in 370 ml of water is then added dropwise to the solution cooled to 0 ° C. and the mixture is vigorously stirred. The mixture is stirred for an additional 2 hours at room temperature to decant the methylene chloride phase and the residue is extracted twice with 500 ml of methylene chloride. The dried methylene chloride phase over potassium carbonate is concentrated to give an oily, partially crystalline residue which is boiled in 1 l of hexane and filtered on hot. After evaporation of hexane from the filtrate, oily lactim ether, i.e. 3- (0-chlorophenyl) -6-ethoxy-2,3,4,5-retrahydropyridine [IR (film): 1684 cm ^-1 ] 151.4 To obtain.

The resulting lactim ester (151.4 g) was dissolved in 1.4 l of methanol, to which 1.3 g of anhydrous P-toluenesulfonic acid was added and 85 g of 3-oxo-5-pentenoic acid methyl ester (Nazarow reagent, 85 g) was added over 60 minutes. After 20 hours at room temperature, the easily volatile components are removed in vacuo and the residue is subsequently dissolved in methylene chloride and washed with 500 ml of saturated sodium carbonate solution The methylene chloride phase dried over magnesium sulfate is concentrated and the residue is ethyl acetate / Crystallize from 800 ml of ether (4: 1), thus methyl rac-7- (0-chlorophenyl) -3,4,6,7,8,9-hexahydro-2-, having a melting point of 145 ° to 147 ° C. 123.7 g (54%) of oxo-2H-quinolizine-1-carboxylate are obtained.

In this process, equimolar amounts of the corresponding substituted piperidones in place of 5- (0-chlorophenyl) -2-piperidone are used to afford the following compounds.

TABLE 7

Methyl rac-7- (R _a ) -3,4,6,7,8,9-hexahydro-2-oxo-2H-quinolizine-1-carboxylate

In the same manner as in Example 1 (a), the following compounds can be obtained:

Rac-1-[(9αβH) -7β- (0-chlorophenyl) -octahydro-2H-quinolizine-2α-yl] -5,6-dimethyl-2-benzimidazolinone hydrochloride at melting point 310 ° C ; The melting point of the base is between 268 and 272 ° C.

TABLE 8

rac-1-[(9αβH) -7β- (R _a ) -octahydro-2H-quinolizine-2α-yl]-(B) -2-benzimidazolinone:

The following example illustrates a pharmaceutical formulation containing phenyl-quinolizidine prepared by the present invention.

Example A

The active ingredient, lactose, corn starch and gelatinized corn starch are mixed thoroughly with each other. The mixture is passed through a mill and wetted with water to form a concentrated paste. Pass the wet mass through a sieve. The wet granules are dried at 45 ° C. and the dried granules are thoroughly mixed with calcium stearate. The granules are compressed to have a tablet weight of 200 mg and a diameter of about 8 mm.

Example B

The active ingredient, lactose and corn starch are thoroughly mixed with each other and passed through a grinder. The mixture is thoroughly mixed with talc and filled into hard gelatin capsules.

Example C

Parenteral dosage form (0.2 mg) per each ampoule;

2.04 g of active ingredient is treated with 400 mg of leucose, dissolved in water for injection, and the volume of the injection is added to make a volume of 10,000 ml. The solution is sterilized by filtration to fill the colorless ampoule and filled with nitrogen gas to seal, or to the colorless ampoule to fill with nitrogen gas and sealed and sterilized with steam for 30 minutes or autoclaved at 120 ° C.

Example 2

The following compounds can be prepared in the same manner as described in Example 1 (a): melting point 158 to 162 ° C. rac- (9αβH) -7β- (0-chlorophenyl) octahydro-2α- (2-amino Rac-1-[(9αβH) -7β- (0-chlorophenyl) octahydro-2H-qui, having a melting point of 248 to 256 ° C. in 74% yield with -5-anilino) -2H-quinolizine as starting material Nolizin-2α-yl] -6-chloro-2-benzimidazolinone bromide hydrochloride was prepared; Melting point 116-118 ° C. with rac- (9αβH) 7β- (0-chlorophenyl) octahydro-2α- (2-amino-5-fluoroanilino-2H-quinolizine as starting material in 68% yield Prepared rac-1-[(9αβH) -7β- (0-chlorophenyl) octahydro-2H-quinolizine-2α-yl] 5-fluoro-2-benzimidazolinone at a melting point of 268 to 272 ° C. do.

Example 3

Rac-1-[(9αβH) -7β- (0-chlorophenyl) -2H-quinolizine-2α-yl] -5- (trifluoromethyl) -2-benzimine dissolved in 250 ml of methanol and 500 ml of chloroform A solution of 14.0 g of dazolinone is treated with a solution of 7.0 g of (+)-2,2 '-(1,1'-binafthyl) -phosphate dissolved in 100 ml of methanol and 100 ml of methylene chloride. Subsequent evaporation of the mixture to a volume of 500 ml precipitates crystals of (+)-phosphate at 20 ° C .: 11.0 g. After two recrystallizations from chloroform: methanol: acetonitrile (4: 2: 1), it is possible to liberate the (-)-base using ammonia from 5.5 g of the remaining (+)-phosphate: [(-) (2S , 7S, 9aS) -1-[(0-fluorophenyl) octahydro-2H-quinolinzin-2-yl] -5- (trifluoromethyl) -2-benzimidazolinone: 2.75 g ( 39%), chloroform: crystallized with methanol (2: 1) to give a (-)-base having a melting point of 297 to 300 ° C. and a [α] ₂₀ ^D = -10.5。 (C = 1, chloroform: methanol = 2: 1). To obtain.

The mother liquor obtained by crystallization of (+)-phosphate is made basic by addition of concentrated ammonia and extracted with ethyl acetate / ether (1: 1). The organic phase is washed with water to neutral, dried over magnesium sulfate and evaporated to give 10.6 g of base. The base was made up to 250 ml of methanol and 500 ml of chloroform and 5.0 g of (-)-2,2 '-(1, ('-binafthyl) -phosphate in 100 ml of methanol and 100 ml of methylene chloride were added. The mixture was concentrated to 500 ml, and 9.5 g of (-)-phosphate precipitated as crystals was recrystallized twice from chloroform: methanol: acetonitrile (4: 2: 1) using ammonia from 5.3 g of remaining (-)-phosphate. Base (+)-(2R, 7R, 9aR) -1- [0-fluoro-phenyl) -octahydro-2H-quinolizin-2-yl] -5- (trifluoromethyl) -2- Benz imidazolinone (2.8 g, 40%) is liberated. Chloroform: crystallized with methanol (2: 1) to give a (+)-base having a melting point of 297 to 300 DEG C and having a [alpha] ₂₀ ^D = + 10.6 ° (C = 1, chloroform: methanol = 2: 1).

Claims (1)

The phenylene-diamine of the following general formula (X) is condensed with the ring-cloning agent of the following general formula (XI) in an inert organic solvent at a temperature between about 0 ° C. and the boiling point of the reaction mixture, A process for preparing 2-substituted phenylquinolizidines of the general formula (III-4) in the form of enantiomers, or acid addition salts thereof.

Wherein X represents hydrogen, fluorine, chlorine, C _1-14 -alkyl or trifluoromethyl in the O-, m- or P-position: A '' represents a group in the following general formula,

R ⁵ and R ⁶ each independently represent hydrogen, methyl, fluorine, chlorine, methoxy or trifluoro methyl or together represent-(CH ₂ )-and R ^b and R ^c are halogen, amino or 1-imide It represents jolyl.