ALPHA-DIFLUOROMETHYL AMINO ACIDS AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME

Abstract: Novel α-difluoromethyl tyrosines and esters thereof are disclosed. The novel compounds have useful pharmacologi­ cal activity.

Description: &alpha;-DIFLUOROMETHYL AMINO ACIDS AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME BACKGROUND OF TKE INVENTION The present invention is concerned with novel a-fluoromethyl tyrosines and esters thereof. An unsubstitute4 a-fluoromethyl-aamino alkanoic acid, namely 2-fluoromethylalanine, having the formula: EMI1.1 is known Ixollonitsch et al., J. Org. Chem. 40. 3808-9 (1975)J. No specific pharmacological activity for this compound is suggested. This compound (A) is prepared by fluorodehydroxylation of the corresponding 2-hydroxymethylalanine. a-Mithyl-m-tyrosine and a-methyl-p- tyrosine are known (U.S. 2,868,818). Their use in pharmaceutical compositions is described in U.S. 3,322,630, U.S. 3,839,585 and Canadian patent 737,907. L-a-methyl-p-tyrosine is also used to treat hypertension in pheochromocytoma. a-Trifluoromethyl tyrosines are described in U.S. 3,046,300. These compounds deplete norepinephrine in the heart. a-Difluoromethyl tyrosines and esters having pharmaceutical activity have been discovered. SUMMARY OF THE INVENTION a-Difluoromethyl tyrosines and esters thereof. DESCRIPTION OF THE PREFERRED EMBODIMENTS An embodiment of the present invention is compounds having the formula EMI2.1 where R is -NH2 and R1 is H or Cl-Clnalkyl. The pharmaceutically acceptable acid addition salts of the formula I compounds are also included. In general, the salts are those of the formula I base with a suitable organic or inorganic acid. Preferred inorganic acid salts are the hydrohalides e.g. hydrochlorides, hydroiodides, hydrobromides; the sulfates, and the phosphates. The hydrohalides, and especially the hydrochlorides, are more preferred. The formula I compounds have a chiral center and may occur in optically active forms i.e., as optical isomers. These isomers are designated conventionally by the symbols L and D, + and -, 1 and d, S and R or combinations thereof. Where the compound name or formula has no isomer designation, the name or formula includes the individual isomer mixtures thereof and racemates. The compounds having the S-isomer configuration are, in general, preferred. R1 is H or C1-C18alkyl. Examples of suitable alkyl groups are methyl, octadecyl, 2-ethyihexyl, t-butyl, hexyl, isopropyl, ethyl, undecyl and the like; Cl-C6alkyl is preferred and ethyl is especially preferred. H is a most preferred definition of R1. Preferred formula I compounds are those where OH is in the 3 or 4 position with the 4 position being more preferred. Preferred Formula III esters have X, as Cl-C6alkyl, especially ethyl. R is H in the more preferred Formula III compounds. Especially preferred Formula III compounds are a-difluoromethyl-mtyrosine and a-difluoromethyl-p-tyrosine. a-Difluoromethyl-p-tyrosine is most preferred. The compounds of the present invention have antihypertensive activity. This activity is determined, in vivo, by observing the effect of a compound on blood pressure Ln a spontaneously hypertensive rat. A representative compound of Formula I was administered intrapritoneally to an (SH) rat and was found to have antihypertensive activity. The compound was also found to have enhanced antihypertensive activity when administered to an (SH) rat which had been pre-treated with the decarboxylase inhibitor carbidopa[S-a-hydrazino-a-methyl-ss-(3, 4-dihydroxyphenyl) -propionic acid monohydrate) The observed antihypertensive effect indicates that the present compounds are effective as antihypertensive agents when administered orally or parenterally either alone or in combination with a decarboxylase inhibitor in suitable amounts in an appropriate pharmaceutical dosage form to a hypertensive human. Effective daily dosages may be varied. A suitable daily dosage range is from about 100 to about 3000 mg, with 200-2000 mg being preferred and 250-1500 mg being most preferred. The ratio of ctrbidopa: Formula I compound in the combination may be varied and can range from about 1:50 to about 25:1, preferably 1:20 to 5:1 and most preferably 1:5 to 2:1. The pharmaceutical dosage forms (tablets, emulsions, solutions, dis-' persions, capsules, etc.) are prepared using conventional procedures and compounding ingredients. A process for preparing the compounds of the present invention where R is NH2 is illustrated by the following equations: EMI5.1 Esters of I are prepared using conventional esterification procedures. The following example illustrates the preparation of the Formula II compounds. All temperatures are degrees Celsius. EXAMPLE 1 A. Preparation of p-methoxybenzyl-difluoro- methylketone Twenty-three ml of diisopropylamine (176 mmol) was dissolved in 50 ml of tetrahydrofuran and treated with 66 ml of 2.42M butyllithium (in hexane) over a period of 23 minutes, keeping the temperature between 100-150C by immersion in an ice bath. After cooling the resulting solution of lithium diisopropylamide to -780C, there was added 13.28 g of p-methoxyphenylacetic acid (80 rmnol) in 80 ml of tetrahydrofuran over a peripd of 20 minutes. The temperature was raised to OOC and the solution was stirred at this temperature for 3 hours. Then the mixture was recooled to -780C and 10.3 g of ethyl difluoroacetate (83 mmol) in 50 ml of tetrahydrofuran was added over 15 minutes keeping the temperature between -780C and -600C. The solution was stirred for 2 hours at this temperature and then quenched onto 800 ml of 2N HC1 and the aqueous solution extracted with 4 x 150 ml ethyl acetate. This was backwashed with 58 NaHC03 solution and saturated aqueous sodium chloride. After drying the solution was concentrated to 13.7 g of p-methoxybenzyl difluoromethyl ketone. B. Preparation of 5-p-methoxybenzyl-5- difluoromethyl-2,4-imidazolidinedione Two grams of p-iethoxybenzyl difluoromethylketone (10 molt, 4.5 g of ammonium carbonate, 10.1 ml of ethanol and 6.6 ml of fI20 were heated under nitrogen for 15 minutes at 550C. Then 0.53 g sodium cyanide was added and the mixture stirred at 550C for 21 hr. The temperature was then raised to 900.for 35 to volatilize most of the (NH4)2C03. Acidification with conc HC1 affords 2.2 g of crude 0 hydantoin II, mp 161-162 Recrystallization from 55 ml of H2O afforded 2.0 g of 5-p-methoxybenzyl-5-difluoromethyl-2,4-imidazolidindione (73%) mp 163.5-164.50C. C. Preparation of a-difluoromethyltyrosine 0.84 g of 5-p-methoxybenzyl-5difluoromethyl-2,4-imidazolidinedione was heated in a sealed tube with 40 ml of conc HC1 for 20 hr at 1300C. After cooling the mixture was filtered and concentrated to 1.0 g of crude product. This was dissolved in a minimal amount of conc HC1 and applied to a 35-ml column of Dowex 50 x 8 H form (strong acid ion exchange resin). The column was washed with 350 ml of H20 and then with 2N aqueous ammonia. The effluent was monitored with a Uvicord II recording ultraviolet Qpectrophotometer and the UV absorbing fractions were concentrated in vacuo to 406 mg of a-difluoromethyltyrosine. Optical resolution of racemic a-difluoromethyl amino acids of this invention may be per'formed by standard methods described in the literature for resolution of amino acids, e.g., salt formation of esters formed from the a-difluoromethyl amino acids with optically active acids or alternatively by salt formation with optically active bases of N-acylated derivatives of the Q-difluoromethyl amino acids, e.g., N-acetyl or N-benzoyl derivatives thereof. Another method of optical resolution consists of separation by elution ohromatography of the diastereoisomeric amides obtained by N-acylation of the a-difluoromethrl amino acids by an optically active acid, e.g., by (+)-a-methyoxy-a-trifluoro- methylphenylacetic acid. The separated diasteroisomeric acyl amino acids on acid hydrolysis give (S) and (R) isomers of a-difluoromethyl amino acids. Claims to the Invention follow.

Claims: WHAT IS CLAIMED IS: 1. Compounds having the formula EMI9.1 and pharmaceutically acceptable salts thereof wherein R is -NH2 Cn R1 is H or C1-C18alkyl 2. Compounds of Claim 1 wherein R1 is C1-C6alkyl. 3. Compounds of Claim 1 wherein R1 is H. 4. The S-isomer of the Claim 1 compounds. 5. Compounds of Claim 1 having the formula EMI9.2 6. Compounds of Claim 5 having formula (a). 7. Compounds of Claim 6 wherein R1 is H. 8. Compounds of Claim 5 having formula (b). 9. Compounds of Claim 8 wherein R1 is H. 10. A pharmaceutical composition for treating hypertension containing an effective amount of a compound of Claim 1.

Inventors: KOLLONITSCH, JANOS, MARBURG, STEPHEN, PATCHETT, ARTHUR ALLAN
Applicants: MERCK & CO. INC.
Application year: 1979
Main classification: C07C101
IPC codes: A61K31, C07C67, C07C227, C07C49, C07C45, C07D233, C07C229, A61P9