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United States Patent (19) (11) 4,255,433 Errmann Et Al

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United States Patent (19) (11) 4,255,433 Errmann Et Al United States Patent (19) (11) 4,255,433 errmann et al. 45) Mar. 10, 1981 54 (+)-(3-METHYL-4-OXO-5N-PIPERIDINO 52 U.S. C. ..................................... 424/267; 546/209 THIAZOLIDIN-2-YLIDENE)ACETIC ACID 58 Field of Search ......................... 546/209; 424/267 ESTERS, METHOD OF PREPARATION AND USE 56 References Cited 75) Inventors: Wolfgang Herrmann, Merzhausen; U.S. PATENT DOCUMENTS Gerhard Satzinger, Denzlingen; 3,072,653 1/1963 Satzinger et al. .................... 546/209 Manfred Herrmann, St. Peter; 4,012,395 3/1977 Satzinger et al..................... 546/209 Wolfgang Steinbrecher, Primary Examiner-John D. Randolph Gundelfingen; Heinrich Bahrmann, Assistant Examiner-Robert T. Bond Kirchzarten, all of Fed. Rep. of Attorney, Agent, or Firm-Stephen I. Miller Germany 57 ABSTRACT 73) Assignee: . Godecke Aktiengesellschaft, The invention discloses (--)-(3-methyl-4-oxo-5N Freiburg, Fed. Rep. of Germany piperidinothiazolidin-2-ylidene)acetic acid esters and a 21 Appi. No.: 132,577 process for their preparation. The process provides the dextrorotatory isomers substantially free from the cor 22 Filed: Mar. 21, 1980 responding levorotatory isomers. Antihypertensive 30 Foreign Application Priority Data pharmaceutical compositions comprising the dextroro Mar. 22, 1979 IDE Fed. Rep. of Germany ....... 291296 tatory esters and methods for using said compositions Dec. 29, 1979 (DE) Fed. Rep. of Germany ....... 2952704 are also disclosed. 5l Int. Cl.................... A61K 31/445; CO7D 417/04 14 Claims, 1 Drawing Figure U.S. Patent Mar. 10, 1981 4,255,433 Diuresis in awake rats with intragastral administration Excretion in ml/kg in 4 hours 120 1 O E CONTROL in 88 1 OO C COMPOUND A III, COMPOUND C 9 O COMPOUND B 8O 7 O t ame is as an up a l, it it 25 mg/kg 50 mg/kg 100 mg/kg 200 mg/kg 4,255,433 1. 2 substantially free from the corresponding levorotatory (+)-(3-METHYL-4-OXO-5N-PPERDINO isomer, wherein (+)-ozolinone of formula II: THAZOLDIN-2-YLIDENE)ACETIC ACID ESTERS, METHOD OF PREPARATION AND USE I 5 BACKGROUND OF THE INVENTION H Ethyl (3-methyl-4-oxo-5N-piperidinothiazolidin-2- --N ylidene)acetate (etozoline) is a known compound see HO-C-CH=C. C=O Liebigs Ann. Chem., 665, 150(1963) and its diuretic action has also already been described. 10 CH3 This compound contains an asymmetric carbon atom is rapidly mixed, in a solvent which is inert under the in the 5-position; thus, etozoline is a racemate. Because reaction conditions with regard to racemization, at a of the particular structural characteristics of etozoline, temperature of from about -10 C. to about 40 C. with the separation of the racemate into its optically active 15 an excess of a compound chosen from among thionyl isomers has hitherto not been carried out for certain chloride, phosphorous oxychloride, phosphorous pen technical reasons. Etozoline is a very weak base which tachloride, and phosphorous trichloride and after a does not form salts with the usual chiral acids, for exam reaction period of about 10 to about 60 minutes, an ple (+)-tartaric acid, (+)-dibenzoyltartaric acid and excess of an alcohol of the general formula III: (+)-camphorsulphonic acid. Thus, this racemate has 20 not been separated by known methods. R-OH (III) Esterification of the known, optically-active (--)-(3- in which R has the same meaning as above, is added methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)- thereto, the reaction mixture is allowed to react, option acetic acid (--)-ozolinone (see Federal Republic of ally with slight cooling, whereafter the desired product Germany Patent Specification No. 26 58858) also can 25 is isolated. not be carried out with agents which can be used on a The invention also relates to pharmaceutical compo large scale because it racemizes under the esterification sitions which comprise an antihypertensive-effective conditions. Thus, for example, (+)-ozolinone racemizes amount of a dextrorotatory isomer of a compound of to an extent of 15% in 0.1N hydrochloric acid in less the formula I. than 1 hour. Even in chloroform, in the same period of 30 The invention also relates to a method for treating time, the degree of racemization which occurs is about hypertension in a mammal which method comprises 10%. administering to a mammal in need thereof an antihy We have now surprisingly found that (+)-ozolinone pertensive effective amount of a dextrorotary isomer of can be esterified without racemization via the acid chlo a compound of formula I. ride. Thus, pure (+)-etozoline is obtained when a solu 35 tion of the free (--)-carboxylic acid (+)-ozolinone is DESCRIPTION OF THE INVENTION quickly mixed at a low temperature with an excess of a The dextrorotatory isomers of the compounds of compound chosen from among thionyl chloride phos formula I are prepared, substantially free from the cor phorous oxychloride, phosphorous pentachloride and responding levorotatory isomers, in the following man phosphorous trichloride; thereafter anhydrous ethanol, le: also in excess, is added thereto. In the case of this The dextrorotatory isomer of the compound of for method of esterification, surprisingly, no racemization mula II (--)-ozolinone is first dissolved in a solvent. takes place and pure (+)-etozoline is obtained. The solvents used for the reaction can be all solvents The method according to the present invention has which are inert under the reaction conditions with re also proved to be useful for the preparation of other 45 gard to racemization, especially preferred are chlori optically pure esters of ozolinone and permits the large nated hydrocarbons, such as dichloromethane and chlo scale preparation of these optically-active compounds roform. The addition of a dipolar, aprotic solvent, such in an especially favorable one-pot process. as hexamethylphosphoric acid triamide, has also proved to be useful. The dissolved carboxylic acid is mixed at a SUMMARY OF THE INVENTION 50 temperature of from about -10° C. to about 40 C. and The present invention relates to the dextrorotatory preferably at ambient temperature, optionally with isomer, substantially free from the levorotatory isomer, cooling, with an excess of a compound chosen from of an optically-active compound of the general formula among thionyl chloride, phosphorous oxychloride, I: phosphorous pentachloride and phosphorous trichlo 55 ride. Thereafter, the reaction is allowed to continue for 15 to 60 minutes. Subsequently, a comparatively large H excess (up to 50 equivalents) of the alcohol component O S of general formula III is added thereto; and the reaction -N mixture is then allowed to stir for about 30 minutes at Ro-c-CH=cs 1. CEO 10' C. to 25 C. The reaction mixture is then extracted with cold CH3 dilute ammonia solution in order to remove inorganic acids, alcohol and unreacted starting carboxylic acid. in which R is a straight- or branched-chain alkyl group The organic phase is subsequently dried, the solvent is containing from 1 to 4 carbon atoms and "C denotes an 65 distilled off and the residue is crystallized, by means of asymmetric carbon atom. the addition of a solvent in which the dextrorotatory The invention also relates to a process for the prepa isomers of the compounds of general formula I are ration of the optically-active dextrorotatory isomer I, sparingly soluble, for example benzene or cyclohexane. 4,255,433 3 4. This process can, of course, be modified with regard diuretic and saluretic properties and had a good antihy to the reaction conditions but the above-described em pertensive activity. These findings have already been bodiment of the process has proved to be especially published for the compound in which R is ethyl (etozo advantageous. lin) see Arzneimittelforschung/Drug Research, (II), The pharmacological investigation of the alkyl esters No. 9a, 1745(1977)). of (+)-ozolinone according to the present invention The diuretic action of the compounds of formula I is gave completely unexpected results in that the diuretic completely limited to the levorotatory enantiomers, the activity present in the racemate is not present in the dextrorotatory enantiomers being completely inactive pure dextrorotatory isomers. However, the pure dex with regard to diuresis. Indeed, the dextrorotatory en trorotatory isomers nevertheless were surprisingly 10 antiomers even exhibit a furosemide antagonistic action found to possess a strong antihypertensive action. Hith to the kidneys. erto, even in potent diuretics, a more or less strongly In the case of rats with renovascular high blood pres antihypertensive action has admittedly been found. This sure, the levorotatory enantiomers, in the diuretically antihypertensive effect is generally regarded as a causal effective dosage range, lower somewhat, as is to be consequence of the anti-edematous properties of potent 15 expected, the average blood pressure of the hyperten diuretics normalizing the electrolyte equilibrium. It has sive animals because of the saluretic action. also previously been observed in the case of etozoline However, the diuretically absolutely ineffective pure that, even at subdiuretic doses, an antihypertensive dextrorotatory enantiomers possess a considerably effect occurs (cf. Federal Republic of Germany Patent stronger antihypertensive action. Specification No. 25 32 180). However, from these 20 Thus, with the pure dextrorotatory enantiomers of findings, it could only have been concluded that, even general formula I, there is provided a completely new in the case of pure optical isomers, both directions of principle for the treatment
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