US3853875A - Esters of 2-alkyl thiazole 5-carboxylic acid - Google Patents

Esters of 2-alkyl thiazole 5-carboxylic acid Download PDF

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US3853875A
US3853875A US00262785A US26278572A US3853875A US 3853875 A US3853875 A US 3853875A US 00262785 A US00262785 A US 00262785A US 26278572 A US26278572 A US 26278572A US 3853875 A US3853875 A US 3853875A
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ethyl
carboxylate
thiazole
piperazino
phenyl
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F Clemence
Martret O Le
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Sanofi Aventis France
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms

Definitions

  • n represents the whole numbers 0, l, 2, 3, 4 or 5
  • n' represents the whole numbers 1, 2, 3, 4 or 5
  • m represents the whole numbers 0, l, 2, 3, 4 or 5
  • R represents a substituted or unsubstituted phenyl radical of general formula:
  • An object of the present invention is the preparation of new esters of 2-alkyl thiazole S-carboxylic acid of formula I:
  • n represents the whole numbers 0,1 ,2,3,4 or 5
  • n represents the whole numbers l,2,3,4 or 5
  • m represents the whole numbers 0,1,2,3,4 or 5
  • R represents a substituted or unsubstituted phenyl radical of general formula:
  • X and X identical or different, representing hydrogen, a chlorine, bromine or iodine atom, an alkyl radical containing from l to 6 carbon atoms, an alkyloxy radical containing from I 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 S-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.
  • the present invention is directed to new esters of 2- alkyl thiazole S-carboxylic acid of formula I:
  • X and X identical or different, representing hydrogen, a chlorine, bromine or iodine atom, an alkyl radi cal containing from l 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.
  • the X and X 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, secbutoxy, tert-butoxy, diethylaminoethoxy or trifluoroethoxy radical.
  • an alkyl such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl radical
  • an alkyloxy radical such as a methoxy, othoxy, propoxy, isopropoxy, n-butoxy, secbutoxy, 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,] or 2.
  • the compounds of the invention are endowed with interesting physiological properties. They possess more particularly an adrenolytic and peripheral vasodilatory route, and between 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 11:
  • n and R have the aforesaid meanings, then optionally salifies according to the usual methods, the resulting ester of general formula I;
  • 2-alkyl thiazole S-carboxylic acid ll To esterify alcohol 111, one can use 2-alkyl thiazole S-carboxylic acid ll. 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.
  • an acid catalyst such as paratoluene sulphonic acid of hydrochloric acid
  • a tertiary base such as triethylamine or pyridine.
  • the anhydride of 2-alkyl thiazole S-carboxylic acid [I can be conveniently obtained by reacting acid 11 with dicyclohexyl carbodiimido. To carry out esterification one can also use a mixed anhydride of acid 11. To prepare this anhydride, one reacts a tertiary base with acid 11, then subjects the resulting salt to the action of a lower alkyl chloroformate, to obtain the mixed anhyydride of general formula IV:
  • the tertiary base which one reacts with acid 11 is preferably triethylamine or pyridine.
  • Salification of acid 11 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 111, is preferably carried out in an acetonic medium. Conjointly with the desired ester 1, it tends to form a lower alkyl hemicarbonate, which is immediately decomposed into carbon dioxide and the corresponding alcohol.
  • esterification can also be carried out by reacting the acid or one of its functional derivatives with an alcoholate of formula:
  • M represents an alkali-metal atom
  • Optional salification of the amino functions of the ester 1 piperazine ring can more particularly be realized by the action of a suitable acid with ester of for mula I.
  • This salification is carried out in an organic solvent such as methanol, ethanol, isopropanol. acetone or ether.
  • 4-benzyl piperazine ethanol can be obtained according to the process described in NATURWISSENSCHAFTEN 53 (16) 405 (1966).
  • 4-a-pyridyl piperazine ethanol can be obtained according to the process described in US. Pat. No. 2,562,036.
  • 4-o-to1yl 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-p-tolyl piperazine ethanol is described by C8. POLLARD and T.H. WlCKER J. Am. Chem. Sec. 76 1853 (1954), as well as 4-(0-ch1orophenyl) piperazine ethanol.
  • 4- (2',5-dimethyl pheny1)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.
  • Z-alkyl thiazole 5carboxylic acids are obtained by the process described in French Pat. No. 2,047.876.
  • Example I B-(4-phenyl 1-piperazine) ethyl 2-propy1 thiazole 5-carboxylate dihydrochloride
  • One taining the maleatel purifies the product by recrystallization from isopropa- T0 g-Df flleiC ac d n Solution in 150 0.6.
  • 10 g. of ,8-(4'-phenyl 1-piperazine) ether one adds 4 g. of B-[4(o-methoxy phenyl) 1'- ethyl 2-propyl thiazole S-carboxylate dihydrochloride, piperazino] ethyl 2-propyl thiazole S-carboxylate in soin the form of colourless crystals, soluble in chloro- 25 lution in 50 c.c.
  • the product takes the form of colourless crystals, soluble in water, methanol and ethanol, insoluble in ether, melting at 145C.
  • Example 1V B-(4-p-tolyl l'-piperazine) ethyl 2-propyl thiazole S-carboxylate dihydrochloride:
  • the compound takes the form of colourless crystals, soluble in water, methanol and ethanol, insoluble in ether and benzene, melting at 202C.
  • the 4-(o-tolyl) piperazine ethanol is obtained according to the process described by POLLARD et a1, .l.Am.Chem.Soc. 76, 1853-5, 1954.
  • the 4-(p-methoxy phenyl) piperazine ethanol is obtained according to the process described in British Pat. No. 889,223 (C.A., 1962,57,l3778a) 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 B- ⁇ 4'-(p-methoxy phenyl) l'piperazino] ethyl 2- propyl thiazole S-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 168C.
  • Example XIV B-[4'-(o-methoxy phenyl) l'- piperazino] ethyl 2-propyl thiazole S-carboxylate dihydrochloride: a. 2-propyl thiazole 5-carboxylic acid anhydride;
  • Example XV B-[4'-(o-methoxy phenyl) l'-piperazino] ethyl 2-butyl thiazole 5-carboxylate oxalate:
  • n represents the whole numbers 0, l, 2, 3, 4, 5, n represents the whole numbers 1, 2, 3, 4, 5, m represents the whole numbers 0, l, 2, 3, 4, 5, and R is a member of the group consisting of a phenyl of the formula wherein X and X identical or different, represent a member of the group consisting of a hydrogen atom, a chlorine atom, a bromine atom, an iodine atom, an alkyl containing from 1 to 6 carbon atoms. an alkyloxy containing from 1 to 6 carbon atoms, trifluoro methyl and pyridyl; and their non-toxic, pharmaceutically ac ceptable acid addition salts.
  • the compound of claim 1 being B-(4'-phenyl 1'- piperazino) ethyl 2-propyl thiazole S-carboxylate and its dihydrochloride.
  • the compound of claim 1 being B-[4-(ochlorophenyl) l'-piperazinp] ethyl Z-propyl thiazole S-carboxylate and its hydrochloride.
  • the compound of claim 1 being m[4-(o-methoxy phenyl)l-piperazino]butyl 2-propyl thiazole 5- carboxylate and its dihydrochloride.
  • the compound of claim 1 being B-[4-(0, 0-- dimethyl phenyllllpiperazino ⁇ ethyl Z-propyl thiazole 5-ca r bo x late and its monohydrochloride.
  • the compound of claim 1 being B-(4'-benzyl lpiperazino) ethyl 2-propyl thiazole S-carboxylate and its dihydrochloride.
  • the compound of claim 1 being B(4'-p-tolyl lpiperazino) ethyl 2-propyl thiazole S-carboxylate and its dihydrochloride.
  • the compound of claim 1 being B-(4-o-tolyl lpiperazino) ethyl 2-propyl thiazole S-carboxylate and its hydrochloride.
  • the compound of claim 1 being B-[4'(pmethoxy phenyl) l-piperazino] ethyl 2-propyl thiazole S-carboxylate and its dihydrochloride.
  • the compound of claim 1 being B-(4-a-pyridyl l-piperazino) ethyl Z-propyl thiazole i-carboxylate and its maleate.
  • the compound of claim 1 being B-[4-(mtrifluoro methyl phenyl) l-piperazino ⁇ ethyl 2-propyl thiazole S-carboxylate and its monohydrochloride.
  • the compound of claim 13 being B-[4-(o-ethoxy phenyl) l-piperazino ⁇ ethyl 2-propyl thiazole 5- carboxylate and its maleate.
  • the compound of claim 1 being B-[4'-(omethoxy phenyl) l-piperazino] ethyl 2-methyl thiazole S-carboxylate and its maleate.
  • the compound of claim 1 being ,8-[4-(omethoxy phenyl) piperazino ⁇ ethyl 2-butyl thiazole 5- carboxylate and its oxalate.

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Abstract

X1 and X2, 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 tribalogenomethyl 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, and the process of preparation. These compounds have an adrenolytic and peripheral vasodilatatory activity.

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:

New esters of 2-alkyl thiazole 5-carboxylic acid of formula I:

Description

United States Patent [191 Clemence et a1.
[ ESTERS OF 2-ALKYL THIAZOLE S-CARBOXYLIC ACID [75] Inventors: Francois Clemence,
Rosny-Sous-Bois; Odile Le Martret, 7
Paris, both of France [73] Assignee: Roussel-UCLAF, Paris, France [22] Filed: June 14, 1972 [21] Appl. No.: 262,785
[30] Foreign Application Priority Data June 14, 1971 France 71.21466 [52] US. CL... 260/268 PH, 260/268 H, 260/302 R,
424/250 [51] Int. Cl C07d 91/32 [58] Field of Search... 260/268 PH, 268 H, 306.8 R
[56] References Cited UNITED STATES PATENTS 3/1966 Krapcho ..260/247.2 8/1973 Philippe ..260/295R Primary ExaminerG. Thomas Todd Attorney, Agent, or Firml-Iammond & Littell [57] ABSTRACT I New esters of 2-a1kyl thiazole S-carboxylic acid of for- [451 Dec. 10,1974
mula I:
wherein n represents the whole numbers 0, l, 2, 3, 4 or 5, n' represents the whole numbers 1, 2, 3, 4 or 5, m represents the whole numbers 0, l, 2, 3, 4 or 5 and R represents a substituted or unsubstituted phenyl radical of general formula:
15 Claims, N0 Drawings E S TERS OF Z-ALKYL THIAZOLE S-CARBOXYLIC ACID OBJECTS OF THE INVENTION An object of the present invention is the preparation of new esters of 2-alkyl thiazole S-carboxylic acid of formula I:
wherein n represents the whole numbers 0,1 ,2,3,4 or 5, n represents the whole numbers l,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:
X and X identical or different, representing hydrogen, a chlorine, bromine or iodine atom, an alkyl radical containing from l to 6 carbon atoms, an alkyloxy radical containing from I 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 S-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 S-carboxylic acid of formula I:
X and X identical or different, representing hydrogen, a chlorine, bromine or iodine atom, an alkyl radi cal containing from l 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 and X 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, secbutoxy, 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,] or 2.
As compounds according to the invention, one will cite more particularly:
w[4'-(O-methoxy phenyl) l'-piperazino] butyl 2- propyl thiazole S-carboxylate and its dihydrochloride,
B-[4-(0,0'-dimethyl phenyl) l'-pyperazino] ethyl- 2-propyl thiazole S-carboxylate and its monohydrochloride,
3- (4-benzyl l'-piperazine) ethyl 2-propyl thiazole S-carboxylate and its dihydrochloride,
B-(4'-p-tolyl l-piperazine) ethyl 2-propyl thiazole S-carboxylate and its dihydrochloride,
B-(4'-o-tolyl l'-piperazine) ethyl 2-propyl thiazole S-carboxylate and its hydrochloride,
B-[4'-(p-methoxy phenyl) l'-piperazino] ethyl 2- propyl thiazole S-carboxylate and its dihydrochloride,
B-[4'-(o-methox y phenyl) l'-piperazino] ethyl 2- propyl thiazole S-carboxylate, its maleate and its dihydrochloride,
B-(4-a-pyridyl l-piperazin0) ethyl 2propyl thiazole S-carboxylate and its maleate,
B-(4'-phenyl l-piperazine) ethyl 2-propyl thiazole 5-carboxylate and its dihydrochloride,
B-[4-(o-chloro phenyl) l-piperazine] ethyl 2- propyl thiazole S-carboxylate and its monohydrochloride,
B-[4-(m-trifluoro methyl phenyl) l-piperazine] ethyl 2-propyl thiazole S-carboxylate and its monohydrochloride,
B-[4-(o-ethoxy phenyl) l'-piperazino] ethyl 2- propyl thiazole S-carboxylate and its maleate,
B-[4-(o-methoxy phenyl) I'-piperazino] ethyl 2- methyl thiazole S-carboxylate and its maleate,
B-[4'-(o-methoxy phenyl) piperazine] ethyl 2-butyl thiazole S-carboxylate and its oxalate.
The compounds of the invention are endowed with interesting physiological properties. They possess more particularly an adrenolytic and peripheral vasodilatory route, and between 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 11:
11 CH .{CH mi 0 0 OH 3 I 2 s 7 1r wherein m has the aforesaid meaning, or a functional derivative of this acid with an alcohol of general formula Ill:
wherein it, n and R have the aforesaid meanings, then optionally salifies according to the usual methods, the resulting ester of general formula I;
with a mineral or organic acid.
To esterify alcohol 111, one can use 2-alkyl thiazole S-carboxylic acid ll. 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 ll, preferably operating in the presence of a tertiary base, such as triethylamine or pyridine.
The anhydride of 2-alkyl thiazole S-carboxylic acid [I can be conveniently obtained by reacting acid 11 with dicyclohexyl carbodiimido. To carry out esterification one can also use a mixed anhydride of acid 11. To prepare this anhydride, one reacts a tertiary base with acid 11, then subjects the resulting salt to the action of a lower alkyl chloroformate, to obtain the mixed anhyydride of general formula IV:
which one reacts with alcohol 111.
The tertiary base which one reacts with acid 11 is preferably triethylamine or pyridine.
Salification of acid 11 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 111, is preferably carried out in an acetonic medium. Conjointly with the desired ester 1, 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:
wherein M represents an alkali-metal atom.
Optional salification of the amino functions of the ester 1 piperazine ring, can more particularly be realized by the action of a suitable acid with ester of for mula 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-a-pyridyl piperazine ethanol can be obtained according to the process described in US. Pat. No. 2,562,036. 4-o-to1yl 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 US. Pat. No. 2,922,788.
4-p-tolyl piperazine ethanol is described by C8. POLLARD and T.H. WlCKER J. Am. Chem. Sec. 76 1853 (1954), as well as 4-(0-ch1orophenyl) piperazine ethanol. 4-(o-ethoxy phenyl) piperazine ethanol. 4- (2',5-dimethyl pheny1)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.
Z-alkyl thiazole 5carboxylic 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 -l5C,43 c.c. of a methanolic solution of ethylene oxide titrating; ZOOg/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. 146C under 0.05 mm. of mercury.
B. 4-(mtriflu0ro 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.= 143C, 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. 148C, under 0.1 mm. of mercury.
Example I: B-(4-phenyl 1-piperazine) ethyl 2-propy1 thiazole 5-carboxylate dihydrochloride,
One puts 10.27 g. of 2-propyl thiazole S-carboxylic acid into suspension in 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 +8C 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 +8C, adds a solu acid in ethanol, filters, washes the precipitate with ethanol and dries; by recrystallization from ethanol one obtains 9.1 g. of B-[4-(o-methoxy phenyl) 1'- piperazine] ethyl 2-propyl thiazole S-carboxylate dition of 12.37 g. of 4-phenyl l-piperazine ethanol (ob- 5 hydrochloride, in the form of colourless crystals, solutained according to the process described in J. Med. ble in water and methanol, insoluble in ether, benzene Chem. 6 133-135, 1963) in 30 c.c. of acetone, leaves and acetone, melting at 170C. 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 10 aqueous solution containing of potassium carbon- Analysis: C .,H ,Cl,N,0,S 462.43 ate, to bring to pH 10, decants the organic phase and ggh g $3252 31; 2 311 23 reextracts the aqueous phases with ether; one washes the combined ethereal phases with water, dries on magnesium sulphate, treats with active charcoal, filters and i5 evaporates off the solvent; one obtains 17.5 g. of B-(4'- l-R- Spectrum -KBr I phenyl 1'-piperazine) ethyl 2-propyl thiazole 5- Bands at carboxylate; one dissolves 17.24 g. ofthe base obtained 750 and 630cm" above in 30 c.c. of ethanol, adds the stoichiometric M- Spec rum ethanol: quantity of a 4.29 N solution of hydrochloric acid in 20 Max. at 247 nm E 350 ethanol, suction-filters and dries the precipitate. One taining the maleatel purifies the product by recrystallization from isopropa- T0 g-Df flleiC ac d n Solution in 150 0.6. Of nol and obtains 10 g. of ,8-(4'-phenyl 1-piperazine) ether, one adds 4 g. of B-[4(o-methoxy phenyl) 1'- ethyl 2-propyl thiazole S-carboxylate dihydrochloride, piperazino] ethyl 2-propyl thiazole S-carboxylate in soin the form of colourless crystals, soluble in chloro- 25 lution in 50 c.c. Of other, leaves in contact for 2 hours form, fairly soluble in water and methanol, slightly solminutes, isolates the precipitate formed by suction uble in ethanol, insoluble in ether, acetone and benfiltering, washes it with ether, crystallizes it in ethyl aczene, melting at 160C, etate and obtains 4.4 g. of B-[4-(0-methoxy phenyl) Analysis C,,,H,,N,,0,s,2HCl 432.41 Calculated C% 5277 H7: 629 (31% 16.4 We 9.72 5% 7.41 Found 52.5 6.1 16.3 9.5 7.6
U.V. Spectrum ethanol: l'-piperazine] ethyl 2-propyl thiazole S-carboxylate Max. at 245 nm E 502 35 maleate, m.p. 133C. l.R. Spectrum -KBr:
Peaks at 3,000, 2,960. 2,400, 1,720, 1,600 and 1.500cm Example 11 B-[4'-(o-methoxy phenyl) l'- Analysis: CaIHMNaOYS 505,595 r piperazinelethyl 2-propyl thiazole S-carboxylate dihyd- 40 E35? C70 21,12 H b 216 if s/(i 2:3 rochloride:
One puts 10.3 g. of 2-propyl thiazole 5-carboxylic acid into suspension in 70 c.c. of acetone, adds a solu Example 'P "Y tion of 9.1 g. of triethylamine in 20 c.c. of acetone, Piperazinelethyl z'propyl thiazole s'carboxylate cools to +6C and adds a solution of 8.1 g. of ethyl drochlorlde: chloroformate in 35 c.c. of acetone under agitation and one adds a solution of of trieihylamine in 25 maintaining the temperature at +6C; one lets come of acetone to a Suspension of of 'p py b k to ambient temperature and continues agitation azole 5-carboxylic acid in 60 c.c. of acetone; one cools for 30 minutes; one filters washes the precipitate with to i in 20 minutes adds a Solution of of ethyl acetone; one cools the combined acetonic phases to chloroformate in 25 c.c. of acetone under agitation and +3C, dd a l i f 142 of 4 maintaining the temperature between +6 and +8C; l) piperazine h l (obtained according to the one lets the reaction mixture come back to ambient cess described in Chem. Abstr., 1958, 52 P202160) in temperature, filters and washes the precipitate with a 70 c.c. of acetone under agitation and maintaining the 55 eIOrie; One 00018 t e Co b ned fil rates to +8C, adds temperature at +8C; one lets the solution come back a Solution of gof p y p p n to ambient temperature, leaves in contact for 48 hours; h n l n 40 f ne. un r gi n n mainthen evaporates to dryness; one takes up the oily resimining e temperature between and One lets due with 150 c.c. of ether, washes the ethereal phase e o ut o Come back o b ent temperature, agiwith water, then with an aqueous solution containi tates for 3 hours and leaves in contact for 12 hours; one 20% potassium carbonate and finally with water till the evaporates off the acetone, takes up the residue with 50 washing waters are neutral; one dries on magnesium c.c. of ether and 10 c.c. of water, washes the ethereal sulphate, treats with active charcoal, filters and evapophase with an aqueous solution containing 10% potasrates to dryness; one obtains 16.9 g. of B- 4-(osium carbonate till the washingwaters are neutral, then methoxy phenyl) 1'-piperazine ethyl 2-propyl thiazole with water and dries on magnesium sulphate; one treats 5-carboxylate.
One dissolves the 16.9 g. of base in c.c. of ethanol, adds 20 c.c. of a 4.3 N solution of hydrochloric with active charcoal, filters and evaporates to dryness; one obtains 14.6 g. of B-[4'-(o-chloro phenyl) lpiperazinelethyl 2-propyl thiazole S-carboxylate.
One dissolves the 7.8 g of compound obtained above in 80 c.c. of ethanol, adds 98 c.c. ofa 4.29 N solution of hydrochloric acid in ethanol, filters and recrystallizes the precipitate from ethanol; one obtains 7.3 g, of ,8-(4-p -tolyl l-piperazine) ethyl 2-propyl thiazole carboxylate dihydrochloride, in the form of colourless crystals, soluble in water, ethanol, methanol and chloroform, insoluble in benzene and ether, melting at 183C.
Analysis:
Calculated Found Cl7r 15.89
N /r 9.41 S'/( 7.18
The product takes the form of colourless crystals, soluble in water, methanol and ethanol, insoluble in ether, melting at 145C.
U.V. Spectrum ethanol:
Max. at 247 nm E 488 IR. Spectrum -KBr:
Analysis: C H Cl N O S 430.39
Calculated C% 53.02 H7r 5.85 (31% 16.48 N?! 9.76 5% 7.45
Found 52.8 5.8 16.5 9.6 7.4
U.V. Spectrum ethanol: Presence of N at 2,440,,,,, of C=O at l,720cm Max. at 250 nm 400 and of C=O atomatic ester at 1,1O0cm' l.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 Example 1V: B-(4-p-tolyl l'-piperazine) ethyl 2-propyl thiazole S-carboxylate dihydrochloride:
One puts 9.8 g. of 2-propyl thiazole S-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 6C; one adds a solution of 6.5 g. of ethyl chloroformate in c.c. of acetone under agitation and maintaining the temperature between 6 and 8C; one brings back to ambient temperature, agitates for 40 minutes, filters and rinses the filter with acetone; one cools the combine filtrates to 8C, adds a solution of l l g. of 4-ptolyl piperazine ethanol (obtained according to the process described in .1. Am. Chem. Soc. 76, 1854, 1954) in 40 c.c. of acetone, maintaining the temperature between 8 and 10C 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 B-(4-p-tolyl 1'-piperazine) ethyl 2-propyl thiazolc S-carboxylate, in the form of colourless crystals,
melting at 50C.
Analysis: C ,H, N;,SO, 373.50 Calculated N9? 11.23 S; 8.58 Found l1.11l1.03 8.67-8.67
Analysis: Calculated Found Example V: B-(4'-benzyl l'-piperazine) ethyl 2-propyl thiazole 5-carboxylate dihydrochloride:
One puts 8.9 g. of 2-propyl thiazole S-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 6C; 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 8C; 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. ot4-benzyl piperazine ethanol (obtained according to the process described in Chem. Abstr. 65, l6970f, 1966) in 25 c.c. of acetone, maintaining the temperature between 8 and 10C and leaves in contact for 18 hours; one evaporates off the acetone, takes up the residue with 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 B44- benzyl l-piperazine) ethyl 2-propyl thiazole 5- carboxylate, melting at 48C.
Analysis: Calculated Found One dissolves the 6.4 g. of the compound obtained above in 35 c.c. of ethanol, adds 8 c.c. ofa 4.29 N solution of hydrochloric acid in ethanol and filters; by recrystallization from ethanol, one obtains 5.3 g. of B-(4'-benzyl l'-piperazine) ethyl Z-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 208C.
Nft 9.41
One puts 6.9 g. of 2-propyl thiazole S-carboxylic acid into suspension in 60 c.c. of acetone, adds a solution of 4.5 g. of triethylamine in c.c. of acetone, cools to +6C and adds a solution of 4.6 g. of ethyl chloroformate in c.c. of acetone under agitation and maintaining the temperature between +6 and +8C; one brings back to ambient temperature, agitates for 1 hour, filters and rinses the filter with acetone; one cools the combined filtrates +8C, adds a solution of 9.3 g. of 4-(o-methoxy phenyl) piperazino butanol (prepared according to the process described inU.S. Pat. No. 2,922,788) in 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 cools to +6C 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 +8C; 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, +8C, adds a solution of l 1.75g. 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 B-[4'-(0,0'-dimethyl phenyl)l piperazino] ethyl 2-propyl thiazole 5-carboxy1ate.
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 653g. of B-[4'-(0,0-dimethyl phenyl)1'-piperazino] ethyl 2-propyl thiazole S-carboxylate hydrochloride in the form of colourless crystals soluble in methanol, ethanol, chloroform and water, insoluble in benzene and ether, melting at 195C.
Analysis: cziuanclNaogs 424.00 Calculated C)? 59.48 H% 7.13 Cl% 8.36 N 7! 991 57: 7.56 Found 59.6 7.1 8.5 9.6 7.7
IR Spectrum -KBr:
Presence of CH at 2,940cm", of N at 2,540cm, of C=O ester at 1,700cm and of C0 at 1,290 at 1,100cm.
Example Vlll: B-[4'-(m-trifluoro methyl phenyl) lpiperazino] ethyl 2-propyl thiazole 6-carboxylate hydrochloride:
Operating as in example .3711, starting with 9.85g. of 2-propyl thiazole S-carboxylic acid, 6.4g. of triethylamine, 6.55g. of ethyl chloroformate and 13.72g. of 4- (m-trifluoro methyl phenyl) piperazino ethanol (ob- Analysis: C,,H,,N,0,$2HC1 490.49 Calculated C% 5386 H7: 6.78 Found 54.1 6.8
U.V. Spectrum ethanol:
Max. at 243 nm E 340 LR. Spectrum -1(Br:
Presence of N at 2,380cm", of C=O at 1,700cm' and of C=N thiazole at 1,600cm". Example Vll: B-[4'-(0,0-dimethyl phenyl) 1- piperazino] ethyl 2-propyl thiazole 5-carboxylate hydrochloride:
One puts 9.85 g. of 2-propyl thiazole S-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,
tained according to the process described in part B of the preparations), one obtains 21.45g. of B-[4'-(mtrifluoro methyl phenyl)l-piperazino] ethyl 2-propy1 thiazole 5-carboxylate. By reacting 104 c.c. of N- hydrochloric acid with 21.2 g. of base, one obtains 6.7g. of B-[4'-(m-trifluoromethyl phenyl)1 piperazino] ethyl 2-propylthiazole S-carboxylate hydrochloride.
The compound takes the form of colourless crystals, soluble in water, methanol and ethanol, insoluble in ether and benzene, melting at 202C.
Analysis:
Calculated Found LR. Spectrum-KBr:
Presence of CH at 2,940 and 2,900cm, of N at 2,570cm' of C=O ester at 1,710cm", of C=N- thiazole at 1,600cm, of CF at 1,310, 1,160 and 750c1n",ofC-O ester at 1,280 and 1,1 10cm". Example 1X: B-4'-(o-tolyl l'-piperazino)ethyl 2-propyl thiazole carboxylate hydrochloride:
Operating as in example Vll, starting with 8.8g. of 2- propyl thiazole S-carboxylic acid, 5.8g. of triethylamine, 5.9g. of ethyl chloroformate and 9.9g of 4-(0- tolyl)piperazino ethanol, one obtains 155g of {3-(4'-otolyl 1-pipera7.ino) ethyl 2-propyl thiazole 5- carhoxylate. Reacting 83cc of N-hydrochloric acid with the 15.5g. of base, one obtains 9.9g. of B-(4'-o- U.V. Spectrum ethanol:
Max. at 242 nm E 465 IR. Spectrum -KBr:
Presence of N at 2,400cm, of C=O ester at 1,720cm and of C=N-thiazole at 1,620cm". Example XI: B-(4-pyridyl 1'-piperazino) ethyl 2- propyl thiazole 5'carboxylate and its maleate:
Operating as in example Vll, 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-(o1- pyridyl) piperazine ethanol, one obtains 5.4 g. of ,8-(4'- rx-pyridyl l'-piperazino) ethyl 2-propyl thiazole 5- carboxylate, in the form of colourless crystals soluble in ether, ethanol, benzene and acetone, insoluble in watolyl l'-piperazino)ethyl Z-propyl thiazole 5- 15 ter, melting at 56C. carboxylate hydrochloride, in the form of colourless crystals soluble in methanol, ethanol and chloroform, Analysis: C,KHNN4O,S 360,47
(alculated C92 59.97 14% 0.71 N'z 15.54 5% s so slightly soluble in water, msoluble in ether and ben Found 59,7 66 5.5 8.7 zene, meltmg at 198 C.
Analysis: C,,,H,,N,O,S,HC1 409.97 Calculated C; 58.59 11% 6.88 C? 8.65 N'7r 10.25 5% 7.82 Found 58.8 6.5 8.9 10.4 7.7
U.V. Spectrum ethanol:
Max. at 247 nm E 338 IR. Spectrum -KBr:
Presence of N at 2,560cm, of C=O ester at 1,720cm and of C=N-thiazole at 1,600cm.
The 4-(o-tolyl) piperazine ethanol is obtained according to the process described by POLLARD et a1, .l.Am.Chem.Soc. 76, 1853-5, 1954.
Example X: B[4'-(p-methoxy phenyl) l'-piperazino] ethyl Z-propyl thiazole S-carboxylate and its dihydrochloride:
Operating as in example Vll, starting with 8.8 g. of Z-propyl thiazole S-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 1 1.4g ofB-[4'-(p-methoxy phenyl) l'-piperazino] ethyl 2-propyl thiazole S-carboxylate in the form of colourless crystals, soluble in methanol, ether, benzene, acetone and chloroform, insoluble in water, melting at 775C Analysis: C H N O S 389.50 Calculated 5% 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,l3778a) 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 B-{4'-(p-methoxy phenyl) l'piperazino] ethyl 2- propyl thiazole S-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 168C.
The 4-(a'-pyridyl) piperazine 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 c.c. of ether, with a solution of 4.5 g. of B-(4a-pyridyl l'-piperazino) ethyl 2-propyl thiazole S-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 154C.
Analysis: c,,H,,N.o,s 476.54 Calculated c r 55.45 11% 5.92 N71 11.76 5% 6.73 Found 55.4 5.8 11.5 6.4
[.R. Spectrum -KBr:
Presence of C==O ester at 1,72Ocm and of C=N thi azole at 1,600cm Example Xll: B-{4'-(o-methoxy phenyl) l'-piperazino] ethyl 2-methyl thiazole S-carboxylate and its maleate:
To the suspension of 859g. of Z-methyl thiazole 5- carboxylic acid (compound described by RUBLEW Ann. 259, 271) in 60 c.c. of acetone, one adds 728g. 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 +5C, agitates for 1 hour at ambient temperature, removes, by filtering, the triethylamine hydrochloride formed, adds 14.1g. of 4-(0- methoxy phenyl) piperazine ethanol to the filtrate in 15 minutes, leaves in contact for 40 hours, removes the ac etone by distillation under reduced pressure, dissolves Analysis: C t- 14 0 5, 2HC1 462.43 Calculated C'7: 51.94 11% 6.32 C17r 15.33 N7r 9.08 Found 52.0 6.0 15.3 9.3
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 B-[4-(omethoxy phenyl) l-piperazino] ethyl 2-methyl thiazole -carboxylate m.p. 73C.
was; iQHi .=!N-3Q% Calculated C% 59.81 H% 6.41 N% 11.62 8% 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 l3-[4'-(o-methoxy phenyl) 1'- piperazino] ethyl 2-methyl thiazole 5 carboxylate in solution in l45c.c. of dry ether, isolates the precipitate formed by suction-filtering, crystallizes it in water and obtains 5 g. of B[4'-(o-methoxy phenyl) l'- piperazino] ethyl 2-methyl thiazole S-carboxy maleate, m.p. lO8-l09C.
Analysis: c,,11,,M,o,s 477.53 Calculated C% 55.33 H% 5.70 N% 8.80 8% 6.7l Found 55.l 5.8 8.7 6.5
Analysis: C, H,,N,O,S 403.53 Calculated ("1' 62.50 H7r 7.24 N% IOAI 8% 7.95 Found 62.7 7.3 10.7 7.8
One adds 4.35g. of B-[4'-(o-ethoxy phenyl)l piperazino] ethyl 2-propyl thiazole S-carboxylate in solution in c.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 B-[4-(o-ethoxy-phenyl) l'-piperazino] ethyl 2-propyl thiazole S-carboxylate maleate m.p. 77C.
Calculated (3% 57.78 H% 6.40 N% 8.09 5% 6.17 Found 57.5 6.3 8.2 5.9
Example XIV: B-[4'-(o-methoxy phenyl) l'- piperazino] ethyl 2-propyl thiazole S-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 S-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 y filtsrinaw shes theet lerc 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.= 65-75C), dries them and obtains 692g. of B-[4'-(o-methoxy phenyl) 1-piperazino] ethyl 2-propyl thiazole S-carboxylate m.p. 59C.
Beginning with the ethereal filtrate and the petroleum ether, one recovers a second yield of 72g. of ,B-[4'-(o-methoxy phenyl) l -piperazino] ethyl 2-propyl thiazole S-carboxylate.
c. dihydrochloride:
671g. of B-[4-(o-methoxy phenyl)l'-piperazino] ethyl 2-propyl thiazole S-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 0C, isolates the crystalsformed by suctionfiltering, washes them with ether, crystallizes them in ethanol while treating them with active charcoal, and obtains 642g. of B-[4'-(o-methoxy phenyl)] piperazino] ethyl Z-propyl thiazole S-carboxylate dihydrochloride m.p. 190C.
Analysis: Calculated Found This compound is identical to that obtained by the process of example ll.
Example XV: B-[4'-(o-methoxy phenyl) l'-piperazino] ethyl 2-butyl thiazole 5-carboxylate oxalate:
One mixes 10.66g. of ethyl 2-butyl thiazole 5- carboxylate and l 1.82g. of 4-(o-methoxy phenyl)- piperazino ethanol under an atmosphere of nitrogen, adds l0.6g. of sodium methylate, heats the mixture to 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:!) chloroform-acetone mixture.
One thus isolates 9.9g. of B-[4'-(o-methoxy phenyl)l '-piperazino] ethyl 2-butyl thiazole S-carboxylate.
Analysis: C,=,H, N O,S 493.57 Calculated C% 55.96 H% 6 33 N%8.5l 5% 6.49 Found 56.0 6.5 8.5 6.3
We claim: I. A compound of the formula l l cmcm -ii o (Clm -N N cm) ,.-1t
wherein n represents the whole numbers 0, l, 2, 3, 4, 5, n represents the whole numbers 1, 2, 3, 4, 5, m represents the whole numbers 0, l, 2, 3, 4, 5, and R is a member of the group consisting of a phenyl of the formula wherein X and X identical or different, represent a member of the group consisting of a hydrogen atom, a chlorine atom, a bromine atom, an iodine atom, an alkyl containing from 1 to 6 carbon atoms. an alkyloxy containing from 1 to 6 carbon atoms, trifluoro methyl and pyridyl; and their non-toxic, pharmaceutically ac ceptable acid addition salts.
2. The compound of claim 1 being i3-[4'-(o-methoxy phenyl) l'-piperazino] ethyl 2-propyl thiazole 5- carboxylate, its maleate and its dihydrochloride.
3. The compound of claim 1 being B-(4'-phenyl 1'- piperazino) ethyl 2-propyl thiazole S-carboxylate and its dihydrochloride.
4. The compound of claim 1 being B-[4-(ochlorophenyl) l'-piperazinp] ethyl Z-propyl thiazole S-carboxylate and its hydrochloride.
5. The compound of claim 1 being m[4-(o-methoxy phenyl)l-piperazino]butyl 2-propyl thiazole 5- carboxylate and its dihydrochloride.
6. The compound of claim 1 being B-[4-(0, 0-- dimethyl phenyllllpiperazino} ethyl Z-propyl thiazole 5-ca r bo x late and its monohydrochloride.
7. The compound of claim 1 being B-(4'-benzyl lpiperazino) ethyl 2-propyl thiazole S-carboxylate and its dihydrochloride.
S. The compound of claim 1 being B(4'-p-tolyl lpiperazino) ethyl 2-propyl thiazole S-carboxylate and its dihydrochloride.
9. The compound of claim 1 being B-(4-o-tolyl lpiperazino) ethyl 2-propyl thiazole S-carboxylate and its hydrochloride.
10. The compound of claim 1 being B-[4'(pmethoxy phenyl) l-piperazino] ethyl 2-propyl thiazole S-carboxylate and its dihydrochloride.
11. The compound of claim 1 being B-(4-a-pyridyl l-piperazino) ethyl Z-propyl thiazole i-carboxylate and its maleate.
12. The compound of claim 1 being B-[4-(mtrifluoro methyl phenyl) l-piperazino} ethyl 2-propyl thiazole S-carboxylate and its monohydrochloride.
13. The compound of claim 1 being B-[4-(o-ethoxy phenyl) l-piperazino} ethyl 2-propyl thiazole 5- carboxylate and its maleate.
14. The compound of claim 1 being B-[4'-(omethoxy phenyl) l-piperazino] ethyl 2-methyl thiazole S-carboxylate and its maleate.
15. The compound of claim 1 being ,8-[4-(omethoxy phenyl) piperazino} ethyl 2-butyl thiazole 5- carboxylate and its oxalate.

Claims (15)

1. A COMPOUND OF THE FORMULA
2. The compound of claim 1 being Beta -(4''-(o-methoxy phenyl) 1''-piperazino) ethyl 2-propyl thiazole 5-carboxylate, its maleate and its dihydrochloride.
3. The compound of claim 1 being Beta -(4''-phenyl 1''-piperazino) ethyl 2-propyl thiazole 5-carboxylate and its dihydrochloride.
4. The compound of claim 1 being Beta -(4''-(o-chlorophenyl) 1''-piperazinp) ethyl 2-propyl thiazole 5-carboxylate and its hydrochloride.
5. The compound of claim 1 being omega (4''-(o-methoxy phenyl)1''-piperazino) butyl 2-propyl thiazole 5-carboxylate and its dihydrochloride.
6. The compound of claim 1 being Beta -(4''-(0, 0--dimethyl phenyl) 1''-piperazino) ethyl 2-propyl thiazole 5-carboxylate and its monohydrochloride.
7. The compound of claim 1 being Beta -(4''-benzyl 1''-piperazino) ethyl 2-propyl thiazole 5-carboxylate and its dihydrochloride.
8. The compound of claim 1 being Beta -(4''-p-tolyl 1''-piperazino) ethyl 2-propyl thiazole 5-carboxylate and its dihydrochloride.
9. The compound of claim 1 being Beta -(4''-o-tolyl 1''-piperazino) ethyl 2-propyl thiazole 5-carboxylate and its hydrochloride.
10. The compound of claim 1 being Beta -(4''-(p-methoxy phenyl) 1''-piperazino) ethyl 2-propyl thiazole 5-carboxylate and its dihydrochloride.
11. The compound of claim 1 being Beta -(4''- Alpha -pyridyl 1''-piperazino) ethyl 2-propyl thiazole 5-carboxylate and its maleate.
12. The compound of claim 1 being Beta -(4''-(m-trifluoro methyl phenyl) 1''-piperazino) ethyl 2-propyl thiazole 5-carboxylate and its monohydrochloride.
13. The compound of claim 1 being Beta -(4''-(o-ethoxy phenyl) 1''-piperazino) ethyl 2-propyl thiazole 5-carboxylate and its maleate.
14. The compound of claim 1 being Beta -(4''-(o-methoxy phenyl) 1''-piperazino) ethyl 2-methyl thiazole 5-carboxylate and its maleate.
15. The compound of claim 1 being Beta -(4''-(o-methoxy phenyl) piperazino) ethyl 2-butyl thiazole 5-carboxylate and its oxalate.
US00262785A 1971-06-14 1972-06-14 Esters of 2-alkyl thiazole 5-carboxylic acid Expired - Lifetime US3853875A (en)

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FR7121466A FR2141526B1 (en) 1971-06-14 1971-06-14
FR7306847A FR2247243B2 (en) 1971-06-14 1973-02-27

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JP (1) JPS5519251A (en)
AT (1) AT317895B (en)
BE (1) BE784777A (en)
CA (1) CA1001629A (en)
CH (1) CH555362A (en)
FR (2) FR2141526B1 (en)
GB (1) GB1382887A (en)
NL (2) NL176072C (en)
SE (1) SE389673B (en)

Cited By (1)

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DE4339617A1 (en) * 1993-11-20 1995-05-24 Vortex Gmbh Dt Non-return valve for water circulation system with shutting-off element in valve housing

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US4411900A (en) * 1980-01-03 1983-10-25 Fujisawa Pharmaceutical Co., Ltd. Benzhydrylpiperozinyl thiazole derivatives and pharmaceutical composition comprising the same
DE3002989A1 (en) * 1980-01-29 1981-07-30 Hoechst Ag, 6000 Frankfurt HYDROXYPHENYL-THIAZOLE, -THIAZOLINE AND -THIAZOLIDINE-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE FOR INFLUENCING COLLAGEN METABOLISM
US6083966A (en) 1998-08-31 2000-07-04 University Of Florida Thiazoline acid derivatives
WO2000016763A2 (en) 1998-09-21 2000-03-30 University Of Florida Research Foundation, Inc. Antimalarial agents
WO2005034949A1 (en) 2003-09-09 2005-04-21 University Of Florida Desferrithiocin derivatives and their use as iron chelators
BRPI0610644B8 (en) 2005-04-04 2021-05-25 Univ Florida compound and pharmaceutical composition comprising such compound and a pharmaceutically acceptable carrier or diluent.
JP5439193B2 (en) 2007-03-15 2014-03-12 ユニバーシティー オブ フロリダ リサーチ ファンデーション， インク． Desferrithiocin polyether analogue
JP6539046B2 (en) 2011-12-16 2019-07-03 ユニバーシティー オブ フロリダ リサーチ ファンデーション， インク． Use of 4'-desferrithiocin analogues
CA2930966A1 (en) 2013-11-22 2015-05-28 University Of Florida Research Foundation, Inc. Desferrithiocin analogs and uses thereof
EP3288557A4 (en) 2015-04-27 2018-11-07 University of Florida Research Foundation, Inc. Metabolically programmed metal chelators and uses thereof

Citations (2)

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US3238203A (en) * 1962-10-12 1966-03-01 Olin Mathieson Basic esters of n-alkenoylanthranilic acid
US3752819A (en) * 1969-12-23 1973-08-14 Ferlux 5-phenyl-isoxazole-3-carboxylic acids and their derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3238203A (en) * 1962-10-12 1966-03-01 Olin Mathieson Basic esters of n-alkenoylanthranilic acid
US3752819A (en) * 1969-12-23 1973-08-14 Ferlux 5-phenyl-isoxazole-3-carboxylic acids and their derivatives

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4339617A1 (en) * 1993-11-20 1995-05-24 Vortex Gmbh Dt Non-return valve for water circulation system with shutting-off element in valve housing

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NL7208138A (en) 1972-12-18
JPS5519251A (en) 1980-02-09
DE2228805A1 (en) 1972-12-21
GB1382887A (en) 1975-02-05
NL176072B (en) 1984-09-17
AT317895B (en) 1974-09-25
FR2141526A1 (en) 1973-01-26
NL7908300A (en) 1980-03-31
FR2247243B2 (en) 1976-12-03
NL176072C (en) 1985-02-18
CH555362A (en) 1974-10-31
BE784777A (en) 1972-12-13
CA1001629A (en) 1976-12-14
FR2141526B1 (en) 1975-05-30
FR2247243A2 (en) 1975-05-09
SE389673B (en) 1976-11-15
DE2228805B2 (en) 1977-03-31

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