Description:
OBJECTS OF THE INVENTION
An object of the present invention is the preparation of new esters of 2-alkyl thiazole 5-carboxylic acid of formula I: ##SPC3##
wherein n represents the whole numbers 0,1,2,3,4 or 5, n' represents the whole numbers 1,2,3,4 or 5, m represents the whole numbers 0,1,2,3,4 or 5 and R represents a substituted or unsubstituted phenyl radical of general formula: ##SPC4##
X 1 and X 2 , identical or different, representing hydrogen, a chlorine, bromine or iodine atom, an alkyl radical containing from 1 to 6 carbon atoms, an alkyloxy radical containing from 1 to 6 carbon atoms or a trihalogenomethyl group, or R represents a heterocycle containing a maximum of 6 links and capable of bearing 1 or more heteroatoms, and of salts of these compounds with a mineral or organic acid.
Another object of the present invention is the development of a process for the preparation of new esters of 2-alkyl thiazole 5-carboxylic acid of formula I and of salts of these compounds with a mineral or organic acid.
A further object of the present invention is to provide therapeutic compositions and methods of combatting hypertension utilizing the compounds of formula I and salts thereof with a mineral or organic acid.
These and other objects of the present invention will become more apparent as the description thereof proceeds.
DESCRIPTION OF THE INVENTION
The present invention is directed to new esters of 2-alkyl thiazole 5-carboxylic acid of formula I: ##SPC5##
wherein n represents the whole numbers 0,1,2,3,4 or 5, n' represents the whole numbers 1,2,3,4 or 5, m represents the whole numbers 0,1,2,3,4 or 5 and R represents a substituted or unsubstituted phenyl radical of general formula: ##SPC6##
X 1 and X 2 , identical or different, representing hydrogen, a chlorine, bromine or iodine atom, an alkyl radical containing from 1 to 6 carbon atoms, an alkyloxy radical containing from 1 to 6 carbon atoms or a trihalogenomethyl group, or R represents a heterocycle containing a maximum of 6 links and capable of bearing 1 or more heteroatoms, as well as the salts of these compounds with a mineral or organic acid.
In the compounds of formula I, the X 1 and X 2 groupings represent more particularly an alkyl such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl radical, or an alkyloxy radical such as a methoxy, othoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, diethylaminoethoxy or trifluoroethoxy radical. The heterocyclic radical R can be more particularly a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, thiapyranyl, oxazinyl or thiophene radical, the value of the m factor is preferably 0,1 or 2.
As compounds according to the invention, one will cite more particularly:
ω[4'-(O-methoxy phenyl) 1'-piperazino] butyl 2-propyl thiazole 5-carboxylate and its dihydrochloride,
β-[4'-(O,O'-dimethyl phenyl) 1'-pyperazino] ethyl-2-propyl thiazole 5-carboxylate and its monohydrochloride,
β- (4'-benzyl 1'-piperazine) ethyl 2-propyl thiazole 5-carboxylate and its dihydrochloride,
β-(4'-p-tolyl 1'-piperazine) ethyl 2-propyl thiazole 5-carboxylate and its dihydrochloride,
β-(4'-o-tolyl 1'-piperazine) ethyl 2-propyl thiazole 5-carboxylate and its hydrochloride,
β-[4'-(p-methoxy phenyl) 1'-piperazino] ethyl 2-propyl thiazole 5-carboxylate and its dihydrochloride,
β-[4'-(o-methoxy phenyl) 1'-piperazino] ethyl 2-propyl thiazole 5-carboxylate, its maleate and its dihydrochloride,
β-(4'-α-pyridyl 1'-piperazino) ethyl 2-propyl thiazole 5-carboxylate and its maleate,
β-(4'-phenyl 1'-piperazine) ethyl 2-propyl thiazole 5-carboxylate and its dihydrochloride,
β-[4'-(o-chloro phenyl) 1'-piperazine] ethyl 2-propyl thiazole 5-carboxylate and its monohydrochloride,
β-[4'-(m-trifluoro methyl phenyl) 1'-piperazine] ethyl 2-propyl thiazole 5-carboxylate and its monohydrochloride,
β-[4'-(o-ethoxy phenyl) 1'-piperazino] ethyl 2-propyl thiazole 5-carboxylate and its maleate,
β-[4'-(o-methoxy phenyl) 1'-piperazino] ethyl 2-methyl thiazole 5-carboxylate and its maleate,
β-[4'-(o-methoxy phenyl) piperazine] ethyl 2-butyl thiazole 5-carboxylate and its oxalate.
The compounds of the invention are endowed with interesting physiological properties. They possess more particularly an adrenolytic and peripheral vasodilatory activity which makes them suitable for therapeutical use - in treating hypertension, in improving cerebral circulation and in treating migraine. They can be used by buccal, perlingual, transcutaneous or rectal route.
They can take the form of injectable solutions or suspensions dispensed in ampoules, in multi-dose phials, of plain or coated tablets, of sublingual tablets and of suppositories.
The useful dose can range for example between 10 and 100 mg. per day for the adult using the parenteral route, and between 100 and 500 mg. using the buccal or rectal route.
The pharmaceutical forms such as injectable solutions or suspensions, plain or coated tablets, sublingual tablets and suppositories are prepared according to the usual methods.
The invention also includes a process for preparing compounds of formula I, as well as the salts of these compounds with a mineral or organic acid, characterized mainly in that one reacts the 2-alkyl thiazole 5-carboxylic acid of general formula II: ##SPC7##
wherein m has the aforesaid meaning, or a functional derivative of this acid with an alcohol of general formula III: ##SPC8##
wherein n', n and R have the aforesaid meanings, then optionally salifies according to the usual methods, the resulting ester of general formula I: ##SPC9##
with a mineral or organic acid.
To esterify alcohol III, one can use 2-alkyl thiazole 5-carboxylic acid II. One operates in such a case in the presence of an acid catalyst, such as paratoluene sulphonic acid of hydrochloric acid and removes the water formed.
One can also use the chloride or the anhydride of acid II, preferably operating in the presence of a tertiary base, such as triethylamine or pyridine.
The anhydride of 2-alkyl thiazole 5-carboxylic acid II can be conveniently obtained by reacting acid II with dicyclohexyl carbodiimido. To carry out esterification one can also use a mixed anhydride of acid II. To prepare this anhydride, one reacts a tertiary base with acid II, then subjects the resulting salt to the action of a lower alkyl chloroformate, to obtain the mixed anhyydride of general formula IV: ##SPC10##
which one reacts with alcohol III.
The tertiary base which one reacts with acid II is preferably triethylamine or pyridine.
Salification of acid II by the tertiary amine is carried out in an organic solvent such as acetone.
The lower alkyl chloroformate which one reacts with the salt is more particularly methyl or ethyl chloroformate. This condensation is carried out preferably in an acetonic medium. Condensation of the mixed anhydride of formula IV with alcohol of formula III, is preferably carried out in an acetonic medium. Conjointly with the desired ester I, it tends to form a lower alkyl hemicarbonate, which is immediately decomposed into carbon dioxide and the corresponding alcohol.
The esterification can also be carried out by reacting the acid or one of its functional derivatives with an alcoholate of formula: ##SPC11##
wherein M represents an alkali-metal atom.
Optional salification of the amino functions of the ester I piperazine ring, - can more particularly be realized by the action of a suitable acid with ester of formula I. This salification is carried out in an organic solvent such as methanol, ethanol, isopropanol, acetone or ether.
The piperazine alkanols used are described in general in the literature. -- 4-benzyl piperazine ethanol can be obtained according to the process described in NATURWISSENSCHAFTEN 53 (16) 405 (1966). --4-α-pyridyl piperazine ethanol can be obtained according to the process described in -- U.S. Pat. No. 2,562,036. --4-o-tolyl piperazine ethanol is described by C. B. POLLARD and T. H. WICKER J. Am. Chem. Soc. 76 1853 (1954). --4-(p-methoxy phenyl) piperazine ethanol is described in British Pat. No. 889,223.
--4-(o-methoxy phenyl) piperazine butanol is described in -- U.S. Pat. No. 2,922,788.
--4-p-tolyl piperazine ethanol is described by C.B. POLLARD and T.H. WICKER J. Am. Chem. Sec. 76 1853 (1954), as well as 4-(o-chlorophenyl) piperazine ethanol. 4-(o-ethoxy phenyl) piperazine ethanol, 4-(2',5'-dimethyl phenyl)piperazine ethanol, and 4-(3-trifluoro methyl phenyl) piperazine ethanol can be prepared by the action of ethylene oxide on the corresponding substituted piperazines. The preparations for these 3compounds which are not described in the literature, are given in the experimental section.
The other alcohols of general formula V can be prepared by the known methods, more particularly, by those described in the references quoted above.
2-alkyl thiazole 5-carboxylic acids are obtained by the process described in French Pat. No. 2,047,876.
The following examples illustrate the invention without limiting it.
Preparations:
A. 4-(0,0'-dimethyl phenyl) piperazine ethanol:
One adds at -15°C,43 c.c. of a methanolic solution of ethylene oxide titrating; 200g./litre, to a solution of 14,3 g. of N-(2,6-dimethyl phenyl) piperazine in 38 c.c. of methanol, leaves in contact for 90 hours, removes the solvent by distillation under reduced pressure, rectifies the residue and obtains 14.67 g. of 4-(0,0'-dimethyl phenyl) piperazine ethanol, b.p. = 146°C under 0.05 mm. of mercury.
B. 4-(m-trifluoro methyl phenyl) piperazine ethanol:
In a similar way to that of the preceding example, starting with 17.3 g. of N-(m-trifluoro methyl phenyl) piperazine., one obtains 15.8 g. of 4-(m-trifluoromethyl phenyl) piperazine ethanol b.p.= 143°C, under 0.1mm. of mercury.
C. 4-(o-ethoxy phenyl) piperazine ethanol:
In a similar way to that in example A), starting with 10.3 g. of N-(o-ethoxy phenyl) piperazine, one obtains 7.9 g. of 4-(o-ethoxy phenyl) piperazine ethanol b.p. = 148°C, under 0.1 mm. of mercury.
Example I: β-(4'-phenyl 1'-piperazine) ethyl 2-propyl thiazole 5-carboxylate dihydrochloride,
One puts 10.27 g. of 2-propyl thiazole 5-carboxylic acid into suspension in 70 c.c. of acetone, adds a solution of 9.10 g. of triethylamine in 20 c.c. of acetone, then in 20 minutes and maintaining the temperature between +6° and +8°C adds a solution of 8.14 g. of ethyl chloroformate in 30 c.c. of acetone; one lets the reaction mixture come back to ambient temperature, suction-filters and washes the precipitate with acetone; one cools the combined filtrates to +8°C, adds a solution of 12.37 g. of 4-phenyl 1'-piperazine ethanol (obtained according to the process described in J. Med. Chem. 6 133-135, 1963) in 30 c.c. of acetone, leaves in contact for one night and evaporates off the acetone; one takes the oily residue up with 150 c.c. of ether and 10 c.c. of water, washes the ethereal phase with an aqueous solution containing 20% of potassium carbonate, to bring to pH 10, decants the organic phase and reextracts the aqueous phases with ether; one washes the combined ethereal phases with water, dries on magnesium sulphate, treats with active charcoal, filters and evaporates off the solvent; one obtains 17.5 g. of β-(4'-phenyl 1'-piperazine) ethyl 2-propyl thiazole 5-carboxylate; one dissolves 17.24 g. of the base obtained above in 30 c.c. of ethanol, adds the stoichiometric quantity of a 4.29 N solution of hydrochloric acid in ethanol, suction-filters and dries the precipitate. One purifies the product by recrystallization from isopropanol and obtains 10 g. of β-(4'-phenyl 1'-piperazine) ethyl 2-propyl thiazole 5-carboxylate dihydrochloride, in the form of colourless crystals, soluble in chloroform, fairly soluble in water and methanol, slightly soluble in ethanol, insoluble in ether, acetone and benzene, melting at 160°C.
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__________________ Analysis : C 19 H 25 N 3 O 2 S,2HCl = 432.41 Calculated : C% 52.77 H% 6.29 Cl% 16.4 N% 9.72 S% 7.41 Found : 52.5 6.1 16.3 9.5 7.6 ____________________________________________________________
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U.v. spectrum ethanol:
Max. at 245 nm E 1cm 1 % = 502
I.r. spectrum -KBr:
Peaks at 3,000, 2,960, 2,400, 1,720, 1,600 and 1,500cm - 1
Example II : β-[4'-(o-methoxy phenyl) 1'-piperazine] ethyl 2-propyl thiazole 5-carboxylate dihydrochloride:
One puts 10.3 g. of 2-propyl thiazole 5-carboxylic acid into suspension in 70 c.c. of acetone, adds a solution of 9.1 g. of triethylamine in 20 c.c. of acetone, cools to +6°C and adds a solution of 8.1 g. of ethyl chloroformate in 35 c.c. of acetone under agitation and maintaining the temperature at +6°C; one lets come back to ambient temperature and continues agitation for 30 minutes; one filters washes the precipitate with acetone; one cools the combined acetonic phases to +8°C, adds a solution of 14.2 g. of 4-(o-methoxy phenyl) piperazine ethanol (obtained according to the process described in Chem. Abstr., 1958, 52 p.20216c) in 70 c.c. of acetone under agitation and maintaining the temperature at +8°C; one lets the solution come back to ambient temperature, leaves in contact for 48 hours; then evaporates to dryness; one takes up the oily residue with 150 c.c. of ether, washes the ethereal phase with water, then with an aqueous solution containing 20% potassium carbonate and finally with water till the washing waters are neutral; one dries on magnesium sulphate, treats with active charcoal, filters and evaporates to dryness; one obtains 16.9 g. of β- 4'-(o-methoxy phenyl) 1'-piperazine ethyl 2-propyl thiazole 5-carboxylate.
One dissolves the 16.9 g. of base in 170 c.c. of ethanol, adds 20 c.c. of a 4.3 N solution of hydrochloric acid in ethanol, filters, washes the precipitate with ethanol and dries; by recrystallization from ethanol one obtains 9.1 g. of β-[4'-(o-methoxy phenyl) 1'-piperazine] ethyl 2-propyl thiazole 5-carboxylate dihydrochloride, in the form of colourless crystals, soluble in water and methanol, insoluble in ether, benzene and acetone, melting at 170°C.
______________________________________ Analysis: C 20 H 29 Cl 2 N 3 O 3 S = 462.43 Calculated N% 9.08 S% 6.93 Cl% 15.33 Found 8.62-8.63 6.58-6.61 15.01-14.94 ______________________________________
I.r. spectrum -KBr :
Bands at 3,000, 2,400, 1,700, 1,600, 1,420, 1,280, 1,100, 1,010, 750 and 630cm - 1
M.v. spectrum ethanol:
Max. at 247 nm E 1cm 1 % = 350
Obtaining the maleate:
To 1.19 g. of maleic acid in solution in 150 c.c. of ether, one adds 4 g. of β-[4'(o-methoxy phenyl) 1'-piperazino] ethyl 2-propyl thiazole 5-carboxylate in solution in 50 c.c. of other, leaves in contact for 2 hours 30 minutes, isolates the precipitate formed by suction filtering, washes it with ether, crystallizes it in ethyl acetate and obtains 4.4 g. of β-[4'-(o-methoxy phenyl) 1'-piperazine] ethyl 2-propyl thiazole 5-carboxylate maleate, m.p. = 133°C.
______________________________________ Analysis: C 24 H 31 N 3 O 7 S = 505.595 Calculated C% 57.02 H% 6.18 N% 8.31 S% 6.34 Found 56.8 6.0 8.0 6.4 ______________________________________
Example III: β-[4'-(o-chlorophenyl) 1'-piperazine] ethyl 2-propyl thiazole 5-carboxylate hydrochloride:
One adds a solution of 7.9 g. of triethylamine in 25 c.c. of acetone to a suspension of 8.9 g. of 2-propyl thiazole 5-carboxylic acid in 60 c.c. of acetone; one cools to +6°C, in 20 minutes adds a solution of 6.8 g. of ethyl chloroformate in 25 c.c. of acetone under agitation and maintaining the temperature between +6° and +8°C; one lets the reaction mixture come back to ambient temperature, filters and washes the precipitate with acetone; one cools the combined filtrates to +8°C, adds a solution of 9.6 g. of 4'-(o-chloro phenyl) piperazine ethanol in 40 c.c. of acetone, under agitation and maintaining the temperature between 8° and 10°C; one lets the solution come back to ambient temperature, agitates for 3 hours and leaves in contact for 12 hours; one evaporates off the acetone, takes up the residue with 50 c.c. of ether and 10 c.c. of water, washes the ethereal phase with an aqueous solution containing 10% potassium carbonate till the washing waters are neutral, then with water and dries on magnesium sulphate; one treats -- with active charcoal, filters and evaporates to dryness; one obtains 14.6 g. of β-[4'-(o-chloro phenyl) 1'-piperazine] ethyl 2-propyl thiazole 5-carboxylate.
One dissolves the 14.6 g. of base obtained above in 250 c.c. of ether and adds 8.60 c.c. of a 4.29 N ethanolic solution of hydrochloric acid; one filters, washes the precipitate with ether and dries; one obtains 13.8 g. β-[4'-(o-chlorophenyl) 1'-piperazine] ethyl 2-propyl thiazole 5-carboxylate hydrochloride.
For the anaylsis one recrystallizes the compound from isopropanol; the melting point remains unchanged.
The product takes the form of colourless crystals, soluble in water, methanol and ethanol, insoluble in ether, melting at 145°C.
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__________________ Analysis: C 19 H 25 Cl 2 N 3 O 2 S = 430.39 Calculated C% 53.02 H% 5.85 Cl% 16.48 N% 9.76 S% 7.45 Found 52.8 5.8 16.5 9.6 7.4 ____________________________________________________________
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U.v. spectrum ethanol:
Max. at 250 nm E 1cm 1 % = 400
I.r. spectrum -KBr:
Bands at 3,080, 2,960, 2,920, 2,880, 2,840, 2,680, 2,500, 1,700, 1,580, 1,440, 1,280, 1,100, 1,010 and 750cm - 1
Example IV: β-(4'-p-tolyl 1'-piperazine) ethyl 2-propyl thiazole 5-carboxylate dihydrochloride:
One puts 9.8 g. of 2-propyl thiazole 5-carboxylic acid into suspension in 70 c.c. of acetone, adds a solution of 6.4 g. of triethylamine in 20 c.c. of cetone and cools to 6°C; one adds a solution of 6.5 g. of ethyl chloroformate in 30 c.c. of acetone under agitation and maintaining the temperature between 6° and 8°C; one brings back to ambient temperature, agitates for 40 minutes, filters and rinses the filter with acetone; one cools the combine filtrates to 8°C, adds a solution of 11 g. of 4-p-tolyl piperazine ethanol (obtained according to the process described in J. Am. Chem. Soc. 76, 1854, 1954) in 40 c.c. of acetone, maintaining the temperature between 8° and 10°C and leaves in contact for 48 hours; one evaporates off the acetone, takes up the residue with 200 c.c. of ether and 20 c.c. of water, washes the ethereal phase with an aqueous solution containing 20% potassium carbonate, then with water till pH is neutral, dries on magnesium sulphate, treats with active charcoal, filters and evaporates off the ether; one takes up the residue with 5 c.c. of petroleum ether, recrystallizes the precipitate from isopropyl ether and obtains 7.8 g. of β-(4'-p-tolyl 1'-piperazine) ethyl 2-propyl thiazole 5-carboxylate, in the form of colourless crystals, melting at 50°C.
______________________________________ Analysis: C 20 H 27 N 3 SO 2 = 373.50 Calculated N% 11.23 S% 8.58 Found 11.11-11.03 8.67-8.67 ______________________________________
One dissolves the 7.8 g of compound obtained above in 80 c.c. of ethanol, adds 9.8 c.c. of a 4.29 N solution of hydrochloric acid in ethanol, filters and recrystallizes the precipitate from ethanol; one obtains 7.3 g. of β-(4'-p -tolyl 1'-piperazine) ethyl 2-propyl thiazole 5-carboxylate dihydrochloride, in the form of colourless crystals, soluble in water, ethanol, methanol and chloroform, insoluble in benzene and ether, melting at 183°C.
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__________________ Analysis: C 20 H 27 N 3 SO 2 2HCl = 446.43 Calculated C% 53.80 H% 6.55 Cl% 15.89 N% 9.41 S% 7.18 Found 53.5 6.5 16.0 9.6 6.8 ____________________________________________________________
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U.v. spectrum ethanol:
Max. at 247 nm E 1cm 1 % = 488
I.r. spectrum -KBr:
Presence of N + at 2,440 cm - 1 , of C=O at 1,720cm - 1 , and of C=O atomatic ester at 1,100cm - 1
Example V: β-(4'-benzyl 1'-piperazine) ethyl 2-propyl thiazole 5-carboxylate dihydrochloride:
One puts 8.9 g. of 2-propyl thiazole 5-carboxylic acid into suspension in 60 c.c. of acetone, adds a solution of 7.9 g. of triethylamine in 25 c.c. of acetone and cools to 6°C; one adds a solution of 6.8 g. of ethyl chloroformate in 25 c.c. of acetone under agitation and maintaining the temperature between 6° and 8°C; one brings back to ambient temperature, agitates for 40 minutes, filters and rinses the filter with acetone; one adds to the combined filtrates a solution of 8.8 g. of 4-benzyl piperazine ethanol (obtained according to the process described in Chem. Abstr. 65, 16970f, 1966) in 25 c.c. of acetone, maintaining the temperature between 8° and 10°C and leaves in contact for 18 hours; one evaporates off the acetone, takes up the residue with 100 c.c. of ether and 10 c.c. of water, washes the ethereal phase with an aqueous solution containing 10% potassium carbonate, then with water, dries on magnesium sulphate, treats with active charcoal, filters and evaporates off the ether. After reprecipitation from an acetone-water mixture and washing the crystals with ethanol containing 10% water, one obtains 6.4 g. of β-(4'-benzyl 1'-piperazine) ethyl 2-propyl thiazole 5-carboxylate, melting at 48°C.
______________________________________ Analysis: C 20 H 27 N 3 SO 2 = 373.50 Calculated S% 8.58 Found 8.57-8.54 ______________________________________
One dissolves the 6.4 g. of the compound obtained above in 35 c.c. of ethanol, adds 8 c.c. of a 4.29 N solution of hydrochloric acid in ethanol -- and filters; by recrystallization from ethanol, one obtains 5.3 g. of β-(4'-benzyl 1'-piperazine) ethyl 2-propyl thiazole 5-carboxylate dihydrochloride, in the form of colourless crystals, soluble in water, slightly soluble in chloroform, insoluble in ether and benzene, melting at 208°C.
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__________________ Analysis: C 20 H 27 N 3 SO 2 2HCl = 446.43 Calculated C% 53.80 H% 6.55 Cl% 15.89 N% 9.41 S% 7.18 Found 53.8 6.3 15.8 9.3 6.9 ____________________________________________________________
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U.v. spectrum ethanol:
Max. at 256 nm E 1cm 1 % = 261
I.r. spectrum:
Presence of N + carbonyl at 1,715cm - 1 , of mono-substituted aromatic structure at 750 and 699 cm - 1 and of thiazole at 1,673 and 1,653 cm - 1
Example VI: ω-[4'-(o-methoxy phenyl) 1'-piperazine] butyl 2-propyl thiazole 5-carboxylate dihydrochloride:
One puts 6.9 g. of 2-propyl thiazole 5-carboxylic acid into suspension in 60 c.c. of acetone, adds a solution of 4.5 g. of triethylamine in 20 c.c. of acetone, cools to +6°C and adds a solution of 4.6 g. of ethyl chloroformate in 25 c.c. of acetone under agitation and maintaining the temperature between +6° and +8°C; one brings back to ambient temperature, agitates for 1 hour, filters and rinses the filter with acetone; one cools the combined filtrates +8°C, adds a solution of 9.3 g. of 4-(o-methoxy phenyl) piperazino butanol (prepared according to the process described in--U.S. Pat. No. 2,922,788) in 30 c.c. of acetone, maintaining the temperature between +8° and +10° C and leaves in contact for 48 hours; one evaporates to dryness, takes up the residue with 200 c.c. of ether and 20 c.c. of water, separates the ethereal phase, washes it with an aqueous solution containing 20% potassium carbonate, then with water, treats with active charcoal, filters, dries on magnesium sulphate and evaporates to dryness; one obtains 11.3 g. of ω-[4'-(o-methoxy phenyl) 1'-piperazino] butyl 2-propyl thiazole 5-carboxylate.
One dissolves the 11.3 g. of base in 14 c.c. of ethanol, adds 12.6 c.c. of a 4.29 N ethanolic solution of hydrochloric acid and filters; one recrystallizes the precipitate from ethanol and obtains 6.6 g. of ω-[4'-(o-methoxy phenyl) 1'-piperazine] butyl 2-propyl thiazole 5-carboxylate dihydrochloride in the form of colourless crystals, soluble in water, methanol, ethanol and chloroform, insoluble in ether and benzene, melting at 160°C.
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__________________ Analysis: C 22 H 31 N 3 O 3 S2HCl = 490.49 Calculated C% 53.86 H% 6.78 Cl% 14.46 N% 8.57 S% 6.54 Found 54.1 6.8 14.2 8.4 6.2 ____________________________________________________________
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U.v. spectrum ethanol:
Max. at 243 nm E 1cm 1 % = 340
I.r. spectrum -KBr:
Presence of N + at 2,380cm - 1 , of C=O at 1,700cm - 1 and of C=N - thiazole at 1,600cm - 1 .
Example VII: β-[4'-(0,0'-dimethyl phenyl) 1'-piperazino] ethyl 2-propyl thiazole 5-carboxylate hydrochloride:
One puts 9.85 g. of 2-propyl thiazole 5-carboxylic acid into suspension in 70 c.c. of acetone, adds a solution of 6.4 g. of triethylamine in 20 c.c of acetone, cools to +6°C and adds a solution of 6.55 g. of ethyl chloroformate in 30 c.c. of acetone under agitation and maintaining the temperature between +6° and +8°C; one allows to come back to ambient temperature, agitates for 1 hour, filters and washes the filter with acetone; one cools the combined filtrates to +6°, +8°C, adds a solution of 11.75g. of 4'-(0,0'-dimethyl phenyl) piperazino ethanol (obtained according to the process described in part A of the preparations) in 30c.c. of acetone under agitation, agitates for 30 minutes and leaves in contact for 84 hours; one evaporates to dryness under vacuum, takes up the residue with 200 c.c. of ether and 20c.c. of water, separates the ethereal phase, washes it with an aqueous solution containing 10% potassium carbonate, then with water, treats with active charcoal, filters, dries on magnesium sulphate, filters and evaporates to dryness under vacuum; one obtains 19.17g. of β-[4'-(0,0'-dimethyl phenyl)1'-piperazino] ethyl 2-propyl thiazole 5-carboxylate.
One triturates 19g. of base with 103 c.c. of N hydrochloric acid, suction-filters makes the residue into a paste with ether, suction-filters, washes the residue with acetone and crystallizes it in water; on obtains 6.53g. of β-[4'-(0,0'-dimethyl phenyl)1'-piperazino] ethyl 2-propyl thiazole 5-carboxylate hydrochloride in the form of colourless crystals soluble in methanol, ethanol, chloroform and water, insoluble in benzene and ether, melting at 195°C.
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__________________ Analysis: C 21 H 30 ClN 3 O 2 S = 424.00 Calculated C% 59.48 H% 7.13 Cl% 8.36 N% 9.91 S% 7.56 Found 59.6 7.1 8.5 9.6 7.7 ____________________________________________________________
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Ir spectrum -KBr:
Presence of CH at 2,940cm - 1 , of N + at 2,540cm - 1 , of C=O ester at 1,700cm - 1 and of C--O at 1,290 at 1,100cm - 1 .
Example VIII: β-[4'-(m-trifluoro methyl phenyl) 1'-piperazino] ethyl 2-propyl thiazole 6-carboxylate hydrochloride:
Operating as in example VII, starting with 9.85g. of 2-propyl thiazole 5-carboxylic acid, 6.4g. of triethylamine, 6.55g. of ethyl chloroformate and 13.72g. of 4'-(m-trifluoro methyl phenyl) piperazino ethanol (obtained according to the process described in part B of the preparations), one obtains 21.45g. of β-[4'-(m-trifluoro methyl phenyl)1'-piperazino] ethyl 2-propyl thiazole 5-carboxylate. By reacting 104 c.c. of N-hydrochloric acid with 21.2 g. of base, one obtains 6.7g. of β-[4'-(m-trifluoromethyl phenyl)1'-piperazino] ethyl 2-propylthiazole 5-carboxylate hydrochloride.
The compound takes the form of colourless crystals, soluble in water, methanol and ethanol, insoluble in ether and benzene, melting at 202°C.
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__________________ Analysis: C 20 H 25 ClF 3 N 3 O 2 S = 463.95 Calculated C%51.77 H%5.43 Cl%7.64 F%12.28 N%9.06 S%6.91 Found 52.0 5.5 7.7 12.1 8.9 6.8 ____________________________________________________________
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I.r. spectrum-KBr:
Presence of CH at 2,940 and 2,900cm - 1 , of N + at 2,570cm - 1 , of C=O ester at 1,710cm - 1 , of C=N-thiazole at 1,600cm - 1 , of CF 3 at 1,310, 1,160 and 750cm - 1 , of C--O ester at 1,280 and 1,110cm - 1 .
Example IX: β-4'-(o-tolyl 1'-piperazino)ethyl 2-propyl thiazole 5 carboxylate hydrochloride:
Operating as in example VII, starting with 8.8g. of 2-propyl thiazole 5-carboxylic acid, 5.8g. of triethylamine, 5.9g. of ethyl chloroformate and 9.9g of 4-(o-tolyl)piperazino ethanol, one obtains 15.5g of β-(4'-o-tolyl 1'-piperazino) ethyl 2-propyl thiazole 5-carboxylate. Reacting 83c.c. of N-hydrochloric acid with the 15.5g. of base, one obtains 9.9g. of β-(4'-o-tolyl 1'-piperazino)ethyl 2-propyl thiazole 5-carboxylate hydrochloride, in the form of colourless crystals soluble in methanol, ethanol and chloroform, slightly soluble in water, insoluble in ether and benzene, melting at 198°C.
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__________________ Analysis: C 20 H 27 N 3 O 2 S,HCl = 409.97 Calculated C% 58.59 H% 6.88 Cl% 8.65 N% 10.25 S% 7.82 Found 58.8 6.5 8.9 10.4 7.7 ____________________________________________________________
______________
U.v. spectrum ethanol:
Max. at 247 nm E 1cm 1 % = 338
I.r. spectrum -KBr:
Presence of N + at 2,560cm - 1 , of C=O ester at 1,720cm - 1 and of C=N-thiazole at 1,600cm - 1 .
The 4-(o-tolyl) piperazino ethanol is obtained according to the process described by POLLARD et al, J.Am.Chem.Soc. 76, 1853-5, 1954.
Example X: β-[4'-(p-methoxy phenyl) 1'-piperazino] ethyl 2-propyl thiazole 5-carboxylate and its dihydrochloride:
Operating as in example VII, starting with 8.8 g. of 2-propyl thiazole 5-carboxylic acid, 5.8 g. of triethylamino, 5.9 g. of ethyl chloroformate and 10.6 g. of 4-(p-methoxy phenyl) piperazino ethanol, one obtains 11.4g of β-[4'-(p-methoxy phenyl) 1'-piperazino] ethyl 2-propyl thiazole 5-carboxylate in the form of colourless crystals, soluble in methanol, ether, benzene, acetone and chloroform, insoluble in water, melting at 77°C.
______________________________________ Analysis: C 20 H 27 N 3 O 3 S = 389.50 Calculated S% 8.23 N% 10.78 Found 7.91-7.89 10.65-10.62 ______________________________________
The 4-(p-methoxy phenyl) piperazine ethanol is obtained according to the process described in British Pat. No. 889,223 (C.A., 1962,57,13778a)
By reacting 15 c.c. of a 3.15 N ethanolic solution of hydrochloric acid with 9.2 of base, one obtains 5.9 g. of β-[4'-(p-methoxy phenyl) 1'piperazino] ethyl 2-propyl thiazole 5-carboxylate dihydrochloride, in the form of colourless crystals, soluble in water, methanol and chloroform, slightly soluble in ethanol, insoluble in ether and benzene, melting at 168°C.
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__________________ Analysis: C 20 H 27 N 3 O 3 S, 2HCl = 462.43 Calculated C% 51.94 H% 6.32 Cl% 15.33 N% 9.08 S% 6.93 Found 52.0 6.0 15.3 9.3 6.6 ____________________________________________________________
______________ U.V. Spectrum ethanol:
Max. at 242 nm E 1cm 1 % = 465
I.r. spectrum -KBr:
Presence of N + at 2,400cm - 1 , of C=O ester at 1,720cm - 1 and of C=N-thiazole at 1,620cm - 1 .
Example XI: β-(4'-pyridyl 1'-piperazino) ethyl 2-propyl thiazole 5-carboxylate and its maleate:
Operating as in example VII, starting with 9.8g. of 2-propyl thiazole 5-carboxylic acid, 6.4g. of triethylamine, 6.5g. of ethyl chloroformate and 10.2 g. of 4-(α'-pyridyl) piperazino ethanol, one obtains 5.4 g. of β-(4'-α-pyridyl 1'-piperazino) ethyl 2-propyl thiazole 5-carboxylate, in the form of colourless crystals soluble in ether, ethanol, benzene and acetone, insoluble in water, melting at 56°C.
______________________________________ Analysis: C 18 H 24 N 4 O 2 S = 360.47 Calculated C% 59.97 H% 6.71 N% 15.54 S% 8.90 Found 59.7 6.6 15.5 8.7 ______________________________________
The 4-(α'-pyridyl) piperazino ethanol is obtained according to the process described in U.S. pat. No. 2,562,036.
By reacting a solution of 1.45 g. of maleic acid in 100 c.c. of ether, with a solution of 4.5 g. of β-(4'α-pyridyl 1'-piperazino) ethyl 2-propyl thiazole 5-carboxylate in 50 c.c. of ether, one obtains 4 g. of maleate in the form of colourless crystals, soluble in methanol, slightly soluble in water and ethanol, insoluble in ether, melting at 154°C.
______________________________________ Analysis: C 22 H 28 N 4 O 6 S = 476.54 Calculated C% 55.45 H% 5.92 N% 11.76 S% 6.73 Found 55.4 5.8 11.5 6.4 ______________________________________
I.r. spectrum -KBr:
Presence of C=O ester at 1,720cm - 1 and of C=N thiazole at 1,600cm - 1
Example XII: β-[4'-(o-methoxy phenyl) 1'-piperazino] ethyl 2-methyl thiazole 5-carboxylate and its maleate:
To the suspension of 8.59g. of 2-methyl thiazole 5-carboxylic acid (compound described by RUBLEW Ann. 259, 271) in 60 c.c. of acetone, one adds 7.28g. of triethylamine in 30 c.c. of acetone, then one adds 7.16g. of ethyl chloroformate in solution in 30 c.c. of acetone in 30 minutes at +5°C, agitates for 1 hour at ambient temperature, removes, by filtering, the triethylamine hydrochloride formed, adds 14.1g. of 4-(o-methoxy phenyl) piperazino ethanol to the filtrate in 15 minutes, leaves in contact for 40 hours, removes the acetone by distillation under reduced pressure, dissolves the residue in ether, washes the ethereal solution with potassium carbonate, with water, dries, removes the solvent by distillation, crystallizes the residue in hexane, prepares the dihydrochloride using an ethanolic solution of hydrochloric acid, crystallizes the dihydrochloride in ethanol, isolates the base by adding potassium carbonate and obtains 7.15 g. of β-[4'-(o-methoxy phenyl) 1'-piperazino] ethyl 2-methyl thiazole 5 -carboxylate m.p. = 73°C.
______________________________________ Analysis: C 18 H 23 N 3 O 3 S = 361.46 Calculated C% 59.81 H% 6.41 N% 11.62 S% 8.87 Found 60.1 6.3 11.6 8.7 ______________________________________
One adds, 1.27 g. of maleic acid in solution in 200c.c. of ether to 4 g. of β-[4'-(o-methoxy phenyl) 1'-piperazino] ethyl 2-methyl thiazole 5-carboxylate in solution in 145c.c. of dry ether, isolates the precipitate formed by suction-filtering, crystallizes it in water and obtains 5 g. of β-[4'-(o-methoxy phenyl) 1'-piperazino] ethyl 2-methyl thiazole 5-carboxy maleate, m.p. = 108°-109°C.
______________________________________ Analysis: C 22 H 27 M 3 O 7 S = 477.53 Calculated C% 55.33 H% 5.70 N% 8.80 S% 6.71 Found 55.1 5.8 8.7 6.5 ______________________________________
Example XIII: β-[4'-(o-ethoxy phenyl) 1'-piperazino] ethyl 2-propyl thiazole 5-carboxylate maleate:
In a similar way to that of example VII, starting with 5.5 g. of 2-propyl thiazole 5-carboxylic acid, with 7 g. of 4-(o-ethoxy phenyl) piperazino ethanol (obtained according to the process described in part C of the preparations), with 3.6 g. of triethylamine and 3.7 g. of ethyl chloroformate; one obtains 4.8g of β-[4'-(o-ethoxy phenyl) 1'-piperazino] ethyl 2-propyl thiazole 5-carboxylate melting at 42°C.
______________________________________ Analysis: C 21 H 29 N 3 O 3 S = 403.53 Calculated C% 62.50 H% 7.24 N% 10.41 S% 7.95 Found 62.7 7.3 10.7 7.8 ______________________________________
One adds 4.35g. of β-[4'-(o-ethoxy phenyl)1'-piperazino] ethyl 2-propyl thiazole 5-carboxylate in solution in 20c.c. of ether to a solution of 125g. of maleic acid in 80c.c. of ether, isolates the crystals formed by suction-filtering, crystallizes them in isopropanol and obtains 5.2g. of β-[4'-(o-ethoxy-phenyl) 1'-piperazino] ethyl 2-propyl thiazole 5-carboxylate maleate m.p. = 77°C.
______________________________________ Analysis: C 25 H 33 N 3 O 7 S = 519.60 Calculated C% 57.78 H% 6.40 N% 8.09 S% 6.17 Found 57.5 6.3 8.2 5.9 ______________________________________
Example XIV: β-[4'-(o-methoxy phenyl) 1'-piperazino] ethyl 2-propyl thiazole 5-carboxylate dihydrochloride:
a. 2-propyl thiazole 5-carboxylic acid anhydride;
One introduces a solution of 573.6 g. of dicyclohexyl carbodiimide in 4.5 litres of tetrahydrofuran into a solution of 950.76g. of 2-propyl thiazole 5-carboxylic acid in 6 litres of tetrahydrofuran, in 1 hour, agitates for 3 hours and removes the dicyclohexylurea formed by filtering.
b. esterification:
One adds 655g. of 4-(o-methoxy phenyl) piperazino ethanol in solution in 2.2 litres of tetrahydrofuran to the filtrate previously in 40 minutes obtained, leaves the reaction mixture on one side for 2 days, concentrates to dryness by distillation under reduced pressure, adds ether to the residue, removes a slight insoluble matter by filtering, washes the ethereal solution with an aqueous solution of potassium carbonate, extracts the alkaline washing waters with ether, combines the ethereal solutions, washes them with water, dries them, adds active charcoal, agitates, removes the actived charcoal by filtering, concentrates to dryness by distillation under reduced pressure, dissolves the residue in ether, removes a slight insoluble matter by filtering, concentrates to dryness by distillation under reduced pressure, dissolves the residue in ether, removes the insoluble matter again by filtering, concentrates almost to dryness by distillation under reduced pressure isolates the crystals formed by suction-filtering, washes them with petroleum ether (b.p.= 65°-75°C), dries them and obtains 692g. of β-[4'-(o-methoxy phenyl) 1'-piperazino] ethyl 2-propyl thiazole 5-carboxylate m.p. = 59°C.
Beginning with the ethereal filtrate and the petroleum ether, one recovers a second yield of 72g. of β-[4'-(o-methoxy phenyl)1'-piperazino] ethyl 2-propyl thiazole 5-carboxylate.
c. dihydrochloride:
671g. of β-[4'-(o-methoxy phenyl)1'-piperazino] ethyl 2-propyl thiazole 5-carboxylate previously obtained are dissolved in 6 litres of ethanol, one adds to this 937 c.c. of 3.67mol/litre alcohol solution of hydrochloric acid leaves the reaction mixture on one side for 15 hours at 0°C, isolates the crystals formed by suction-filtering, washes them with ether, crystallizes them in ethanol while treating them with active charcoal, and obtains 642g. of β-[4'-(o-methoxy phenyl)1'-piperazino] ethyl 2-propyl thiazole 5-carboxylate dihydrochloride m.p. = 190°C.
______________________________________ Analysis: C 20 H 29 N 3 O 3 SO1 2 = 462.43 Calculated Cl% 15.33 S% 6.92 N% 9.08 Found 15.51 7.06 9.15 ______________________________________
This compound is identical to that obtained by the process of example II.
Example XV: β-[4'-(o-methoxy phenyl) 1'-piperazino] ethyl 2-butyl thiazole 5-carboxylate oxalate:
One mixes 10.66g. of ethyl 2-butyl thiazole 5-carboxylate and 11.82g. of 4-(o-methoxy phenyl)piperazino ethanol under an atmosphere of nitrogen, adds 10.6g. of sodium methylate, heats the mixture to 140°C, maintains it there for 3 hours 30 minutes, cools, adds ether, leaves in contact for 1 hour, decants, suction-filters the combined ethereal phases, washes the filtrate with water, dries on magnesium sulphate, filters, evaporates to dryness under reduced pressure to obtain an oil which one chromatographs on silica gel, eluting with a (2:1) chloroform-acetone mixture.
One thus isolates 9.9g. of β-[4'-(o-methoxy phenyl)1'-piperazino] ethyl 2-butyl thiazole 5-carboxylate.
Oxalate:
One dissolves 7.7g. of the base obtained above in 15c.c. of ethanol, adds a solution of 2.41g. of oxalic acid in 15c.c. of ethanol, brings the mixture to boiling point, cools, suction-filters, washes the filter with ethanol, then with ether, recrystallizes the residue from ethanol and obtains 5.17g. of β-[4'-(o-methoxy phenyl)1'-piperazino] ethyl 2-butyl thiazole 5-carboxylate oxalate, in the form of a solid ochrecoloured product, soluble in acetic acid, slightly soluble in ethanol, benzene and acetone, and insoluble in ether and water, m.p. = 138°C.
______________________________________ Analysis: C 23 H 31 N 3 O 7 S = 493.57 Calculated C% 55.96 H% 6.33 N%8.51 S% 6.49 Found 56.0 6.5 8.5 6.3 ______________________________________