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(11) | EP 0 000 034 A1 |
| (12) | EUROPEAN PATENT APPLICATION |
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| (54) | Fluorinated amines, compositions and process for preparing said compounds |
| (57) Fluorinated Amino acids and amines, compositions and process for preparing said compounds. a-Difluoromethyl-3,4- di-OR-phenylalanines and its esters, and (1-difluoromethyl)- and 1-(trifluoromethyl)-2-(3,4-di-OR- phenyl) ethylamines, wherein R is hydrogen or a C2-C6 alkanoyl, have been prepared. Homoveratric acid is transformed into veratryl- difluoromethyl- ketone or veratryl- trifluoro- methyl- ketone, this reacts with methoxyamine, and the obtained O-methyl-oxime is reduced to the amine. The 3- and 4-methoxygroups are hydrolysed into hydroxy-groups. Reaction of veratryl- difluoromethylketone with ammonium-carbonate and sodium cyanide yields a-difluoromethyl -5-(3',4'- dimethoxybenzyl)-2,4-imidazolidine-dione, hydrolysis results in α-difluoromethyl-3- hydroxytyrosine. The compounds have Dopa-decarboxylase inhibiting activity and some of them are antihypertensive agents. |
BACKGROUND OF THE INVENTION
[0001] The present invention is concerned with certain difluoromethylphenylalanines and difluoro-or trifluoromethyl phenylethylamines.
[0002] a-Methyl-3,4-dihydroxyphenylalanine, particularly its L-isomer, is a known antihypertensive agent. (U. S. 2,868,818; U.S. 3,344,023).
[0003] Novel a-difluoromethyl-3,4-di-OR-phenylalanines and a-difluoromethyl- or a-trifluoromethyl -3,4-di-OR-ethylamines have been discovered. These compounds have biological activity including decarboxylase inhibition.
SUMMARY OF THE INVENTION
[0004] a-Difluoromethyl-3,4-di-OR-phenylalanines and a-difluoromethyl- or a-trifluoromethyl -3,4-OR-phenylethylamines and their salts.
DESCRIPTION OF THE PREFERRED EMBODIMENTS -
[0005] The present invention is embodied in compounds having the formula
wherein
R is H or COOR1 is H or C1-C18 alkyl and
R2 is H or C2-C6 alkanoyl.
[0006] The pharmaceutically acceptable salts of the formula I-II compounds are also included. These salts generally are acid addition salts of suitable organic or inorganic acids. Preferred salts are the hydrohalides such as the hydrobromides, the hydrochlorides, the hydrogen iodides. Most preferred salts are the hydrochlorides.
[0007] The compounds of formula I-II have a chiral center and may occur in optically active forms, i.e., as optical isomers. These isomers are conventionally designated as D and L, d and 1, + and -, (S) and (R) or by a combination of these symbols. Where the compound name or formula does not specify the isomer form, all forms are included, i.e., the individual isomers, mixtures thereof and racemates.
[0008] R is H or COOR1, R1 may be H or an alkyl group, preferably a C1-C18 alkyl group. Examples of suitable alkyl groups are octadecyl, 2-ethylhexyl, lauryl, undecyl, methyl,isopropyl, hexyl, and the like. Preferred R1 groups are H and Cl-C6 alkyl. Most preferred R1 groups are H and ethyl.
[0009] R2 includes H and C2-C6 alkanoyl groups. Examples of suitable alkanoyl groups are acetyl, octanoyl, pivaloyl, 2-methylpropanoyl, heptanoyl, butanoyl and the like. The most preferred R2 substituent is hydrogen.
[0010] A preferred compound is the trifluoromethyl compound having the formula
The R-isomer of III is more preferred.
[0011] A preferred class of compounds of the present invention is that having the formula
Especially preferred are formula IV compounds where R1 is hydrogen or Cl-C6 alkyl, preferably ethyl.
[0013] Another preferred compound of the present invention is that having the formula
The R-isomer form of the formula V compound is also more preferred.
[0014] The compounds of the present invention have 3,4-dihydroxyphenylalanine (DOPA) decarboxylase inhibiting activity. This activity was determined by conventional in-vitro assay procedures. This biological activity permits the present compounds to be used as diagnostic tools to determine the presence and importance of the corresponding decarboxylase in relation to diseases or to functioning of biological systems. Also the present compounds may be used in combination with DCPA to improve DOPA's effectiveness in treating Parkinson's disease.
[0015] In addition, some of these compounds, e.g., those of formula IV, the phenylalanines, also have pharmaceutical activity as antihypertensive agents. Thus, these compounds are use- . ful for treating hypertension in humans.
[0016] For treating hypertension, the formula IV compounds or their salts may be administered to the hypertensive patient orally, parenterally or via any other suitable administration route. Conventional dosage forms are used such as tablets, troches, capsules, liquid formulations, e.g. solutions, dispersions, emulsions, elixirs and the like. Conventional compounding ingredients, i.e., diluents, carriers, etc., and conventional preparation procedures are utilized.
[0017] The daily dosage of the formula IV compounds may be varied as required. In general, a daily dosage range for the hypertensive patient is about 50 mg to about 5000 mg. A preferred daily dosage range is about 100 mg to about 3500 mg. A more preferred daily dosage range is about 250 to about 1500 mg.
[0019] One such process scheme for preparing the difluoro compounds is illustrated by the following reaction sequence:
[0020] Homoveratric acid and its derivatives such as dialkyl amides, esters and thioesters may be transformed into an anionic species with such bases as metalated dialkyl amides (e.g., lithium diisopropylamide), metalated alkyls (e.g., butyl lithium), hydrides (NaH) or metal amides (KNH2). Such anions may be condensed with activated forms of difluoroacetic acid such as its ester, or acid chlorides. Except in the case of homoveratric acid itself, these condensation products require hydrolysis to effect decarboxylation to the difluoromethyl veratryl ketone 1. A carbon nitrogen bond may be introduced at the ketonic position with the usual amine reagents such as NH3 and hydroxylamine. However, this is most conveniently done by using methoxy amine to form the ketone o-methyl oxime, 2. This compound may be reduced to the amine 3 using metal catalysts and hydrogen, active metals (e.g., Zn) and most conveniently boranes such as BH3. The cleavage of the phenol ethers can be accomplished with reagents such as BBr3 but is easily effected by heating with hydrohalic acids such as aq. HCl, aq. HBr and the like.
[0021] The transformation of the ketone 1 to the a-difluoromethylamino acid 6 is most conveniently accomplished via the hydantoin 5. 5 may be hydrolyzed by acid but most conveniently with HCl. The conversion of 1 to 6 can also be realized using NH 4Cl and NaCN followed by acid hydrolysis.
[0022] A process for preparing the trifluoro compounds is illustrated by the following reaction scheme:
[0023] Homoveratric acid and its derivatives such as dialkyl amides, esters and thio esters may be transformed into an anionic species with such bases as metalated dialkyl amides (e.g., lithium diisopropylamide), metalated alkyls (e.g., butyl lithium), hydrides (NaH) or metal amides (KNH2). Such anions may be condensed with activated forms of trifluoroacetic acid such as its ester or acid chloride. Except in the case of homoveratic acid itself, these condensation products require hydrolysis to effect decarboxylation to the trifluoromethyl veratryl ketone 7. A carbon nitrogen bond may be introduced at the ketonic position with the usual amine reagents such as ammonia and hydroxylamine. However, this is most conveniently done by using methoxy amine (NH20CH3) to form the ketone o-methyl oxime 8. This compound may be reduced to the amine 9 using metal catalysts and hydrogen, active metals and most conveniently boranes such as BH3. The cleavage of the phenol ethers can be accomplished with reagents such as BBr3 but is easily effected by heating with hydrohalic acids such as aqueous HC1, aqueous HBr and the like.
[0024] The pharmaceutically acceptable salts of the present compounds may be obtained directly from the acid hydrolysis steps described above. ' Such salts may also be obtained by treatment of the formula I-II free base with an appropriate acid under suitable conditions.
[0025] Where the compounds of the present invention are obtained as racemates, they may be separated into the individual enantiomers by conventional resolution techniques. Such techniques commonly involve the formation of a salt of a) a present racemic acid with an optically active base or b) a present racemic amine with an optically active acid.
[0026] The resolution of the racemic is preferably carried out on the O,O,N-triacyl derivatives of the racemic acid. These acyl derivatives are prepared by treatment of the free racemic acid with a suitable acylating agent as illustrated by the following equation:
The resolution procedure including hydrolysis of the resolved acylated acids is exemplified in U.S. 3,344,023.
[0027] Compounds of the present invention where R2 is lower alkanoyl are prepared by appropriately acylating the corresponding compound where R1 and R2 are each H, as illustrated by the following equation:
To prevent acylation of the a-NH2 group the reaction may be carried out in an acid medium, e.g., glacial acetic acid. An example illustrating such an acylation system is in U.S. 3,983,138.
[0028] Where R1 in formula IV is an alkyl group, the compound is prepared by conventional esterification of the corresponding compound where R1 is H as illustrated by the following equation:
[0029] The following examples illustrate the preparation of compounds of the present invention. All temperatures are in °C. The melting points were obtained in open capillary and are uncorrected.
EXAMPLE 1
PREPARATION OF a-DIFLUOROMETHYL-2-(3',4'-DIHYDROXYPHENYL)ETHYLAMINE
a. Veratryl difluoromethyl ketone (1)
[0030] A 1-liter three-neck flask, fitted with a magnetic stirrer, condenser, nitrogen inlet, and septum was charged with 23 ml of diisopropylamine (176 mmoles) and 50 ml of tetrahydrofuran (THF). The solution was cooled to 0°C followed by addition of 76 ml of 2.lM n-butyl lithium in hexane (159.6 mmoles) over a period of 15 min. The solution was then cooled to -78°C and to it was added 15.68 g of homoveratric acid (80 mmoles) in 80 ml of THF. The addition required 25 min and the temperature was not permitted to exceed -40°C. On completion of the addition, 35 ml of THF were added and the resulting mixture was stirred in an ice bath for 3 hours. It was then recooled to -78°C and 10.3 g of ethyl difluoroacetate (83 mmoles) in 90 ml of THF were added. The mixture was then aged at -78°C for 2 hrs, and 1 hr. at 0°C, after which it was worked up by quenching onto 600 ml of 2N HC1, extracting with 3 x 300 ml of ethyl acetate, backwashing with 5% aq. NAHCO3 and saturated NaCl solution. The organic solution was concentrated to give veratryl difluoromethyl ketone (1); this compound forms a crystalline 2,4-dinitrophenyl hydrazone, m.p. 107-109°C. Small amounts of this ketone were purified by preparative thin layer chromatography as follows: A 1000µ silica gel plate was spotted with 175 mg of crude 1 and developed with a 70:30 chloroform:acetone mixture affording about 110 mg of single spot material.
b.) Veratryl difluoromethyl ketone 0-methyl oxime (2)
[0031] 125 mg of 1 was dissolved in 1.1 ml of pyridine and treated with 125 mg of methoxyamine hydrochloride and the mixture was allowed to remain overnight at toom temperature. It was then quenched on water. The aqueous mixture was extracted with ethyl acetate, dried and concentrated to 120 mg of single spot material (70:30 chloroform:acetone, silica plates). This material had an NMR spectrum which was consistent with a syn-anti mixture of the desired oxime 2. c.) R,S-l-Difluoromethyl-2-(3',4'-dimethoxyphenyl)ethylamine hydrochloride (3) 120 mg of 2 was charged to a 2-neck 15-ml flask fitted with a septum and condenser and N2 inlet. The material was dissolved in 1 ml of THF, cooled in an ice bath. After 1.5 ml 1M BH3 in THF had been slowly added through the septum using a syringe, the solution was stirred at reflux for 2 hrs. and then at room temperature for 16 hrs. It was then quenched-onto 10 ml of methanol. To this was added 1 ml conc. HC1 and the solution aged for 2 hrs. and then concentrated to dryness to afford R,S-1-difluoromethyl-2-(3',4'-dimethoxyphenyl)ethylamine hydrochloride (3), m.p. 164-167°C (mass spectrum m/e = 231).
d.) R,S-1-Difluoromethyl-2-(3',4'-dihydroxyphenyl)ethylamine heminaphthalene 1,5-disulfonate (4)
[0032] 650 mg of 3 was dissolved in 13 ml of conc. HC1 and the solution heated under N2 in a sealed tube at 130°C for 30 min. The solution was concentrated to dryness in vacuo, the residue applied to a 15-ml AG-50X8 (200-400 mesh) Dowex 50 cation exchange resin column H+ form. The column was washed with 250 ml H20 and then eluted with 3N HC1 containing 10% methanol. 20 ml fractions were collected and the effluent monitored by a UV detector. Fractions 2-51 were combined and concentrated to give R,S-difluoromethyl-2-(3',4'-dihydroxyphenyl)ethylamine (R,S-α-difluoromethyl-2-(3',4'-dihydroxyphenyl)ethylamine heminaphthalene 1,5-disulfonate (4) hydrochloride. 360 mg of this material were dissolved in 3 ml of 2-propanol and 216 mg of naphthalene 1,5-disulfonic acid were added. The solution was concentrated to dryness and the residue redissolved in 2-propanol and reconcentrated. This procedure was repeated three times (to remove HC1). Before the final concentration, the solution was filtered through analytical filter aid (Celite). Concentration followed by trituration with acetonitrile afforded the hemi naphthalene 1,5-disulfonate of 4, m.p. 244-247°C Dec.
EXAMPLE 2
R,S-d-Difluoromethyl-3-Hydroxy-Tyrosine
a.) R,S-a-Difluoromethyl-5-(3',4'-dimethoxybenzyl)-2,4-imidazolidine dione (5)
[0033] To 137 mg of veratryl difluoromethyl ketone charged to a 5-ml flask, there was added 267 mg of ammonium carbonate, 0.6 ml of ethanol and 0.4 ml of H20. The mixture was stirred at 55°C for 15 min and then 30 mg of sodium cyanide was added. The mixture was heated for 24 hrs at 55° and then allowed to remain at room temperature for 60 hrs. Then it was acidified to pH 5 with conc. HC1 (gas is evolved) and a crystalline precipitate is formed which is washed with H20 (2 x 1 ml) and air dried affording the hydantoin, 5-difluoromethyl-5-(3',4'-dimethoxybenzyl)-2,4-imidazolidine dione (5), m.p. 222-225°C.
b.) R,S-a-Difluoromethyl-3-HydroxyTyrosine
[0034] 250 mg of the hydantoin 5 was dissolved in 10 ml of conc. HC1 and heated at 130° for 18.5 hrs. The solution was then concentrated to dryness and the residue was applied to a 10-ml column of AG-50X8 (200-400 mesh) cation exchange resin H form and eluted with H20. 20-ml fractions were collected and the effluent was monitored by a LKB UVICORD II UV monitor. The UV absorbing fractions 5-34 gave positive ninhydrin tests and were combined and concentrated in vacuo to dryness to give R,S-a-difluoromethyl-3-hydroxy-tyrosine, m.p. 268-270°C dec.
EXAMPLE 3
Preparation of R,S-1-α-Trifluoromethyl-2-(3',4'-dihydroxyphenyl)ethylamine
a. Veratryl trifluoromethyl ketone (7)
[0035] A 250 ml. flask fitted with stirrer, condenser, nitrogen inlet and septum was charged with 2.76 ml of diisopropylamine and 20 ml of THF. The solution was cooled to 0°C. followed by addition of 19 ml of 2.1M butyl lithium in hexane over a period of 15 minutes. The solution was then cooled to -78°C and to it was added 3.92 g of homoveratric acid in 50 ml of- THF. The flask was removed from the -78° bath and immersed in an ice bath for 3 hours. The solution was recooled to -78°C. and to it was added 2.84 g ethyl trifluoroacetate in 20 ml of THF. After stirring at -78° for 0.5 hours, the solution was warmed to 0° and stirred for 1.5 hours at this temperature.
[0036] It was then quenched into 100 ml 3N HC1, which was then extracted with 3-x 75 ml of ethyl acetate, backwashed with H20 and 5% aqueous NaHCO3 and saturated NaCl solution. The organic layer was dried over Na2S04 and concentrated to give crude veratryl trifluoromethyl ketone (7). This was purified by thin layer chromatography (80:20 chloroform:acetone, silica gel) and recrystallized from cyclohexane to afford pure 7, m.p. 86-88°C.
b.) Veratryl trifluoromethyl ketone-0-methyl oxime (8)
[0037] 530 Mg of 7 was dissolved in 3 ml of pyridine and treated with 500 mg of methoxyamine hydrochloride and the resulting solution was allowed to remain at room temperature overnight. The pyridine was concentrated to a small volume and the residue extracted with ethyl acetate and water. Drying and concentration of the organic layer afforded the crude 0-methyl oxime 8.. Purification was effected by thin layer chromatography (80:20 chloroform:acetone, silic gel) and the lead spot proved to be pure 8.
c.) R,S-l-trifluoromethyl-2-(3',4'-dimethoxyphenyl)ethylamine (9)
[0038] 200 Mg of 8 was dissolved in 2 ml of THF and charged to a 15 ml 2-neck flask fitted with a septum and condenser. The flask was cooled in an ice bath and 3 ml of 1M BH3 in THF was added. The solution was then refluxed for 1.5 hours and then allowed to remain at room temperature overnight. The solution was quenched into 5 ml of methanol and 1 ml of concentrated HC1 was added. After aging for 2 hours, it was concentrated, redissolved in 5 ml of concentrated HC1 and reconcentrated to 250 mg of crude 9 hydrochloride. The material was dissolved in H20, basified with 2.5N NaOH and extracted with ethyl acetate. The organic layer was dried and concentrated to give R,S-1-trifluoromethyl-2-(3', 4'-dimethoxyphenyl)ethylamine (9).
[0039] (The hemi naphthalene 1,5-disulfonate salt was prepared by treating 40 mg of 9 with 23 mg of naphthalene 1,5-disulfonic acid in 2-propanol and concentrating to dryness. The residue was twice redissolved and reconcentrated and then triturated with acetonitrile to give the crystalline hemi naphthalene disulfonate salt of 9, m.p. 265-268°C.).
d.) R,S-l-trifluoromethyl-2-(3',4'-dihydroxyphenyl)ethylamine (10)
[0040] 730 Mg of 9 was dissolved in 7 ml concentrated HCl and heated at 130° in a sealed tube for 1.25 hours. The solution was then concentrated to 725 mg of crude hydrochloride of 10. This was dissolved in 20 ml of 2-propanol and treated with 406 mg of naphthalene 1,5-disulfonic acid. The solution was concentrated to dryness and redissolved in 2-propanol. This procedure was repeated twice and finally concentrated to dryness. Trituration of the residue with 30 ml of acetonitrile afforded the hemi naphthalene 1,5-disulfonate of R,S-1-trifluoromethyl-2-(3',4'-dihydroxyphenyl)ethylamine (10), m.p. 287-290°C. dec.
1. Compounds having the formula
wherein
wherein
R is H or COOR1 wherein
R1 is H or C1-C18 alkyl and
R2 is H or C2-C6 alkanoyl and pharmaceutically acceptable salts thereof.
2. Compounds of Claim 1 wherein R2 is hydrogen .
3. Compounds of Claim 1 wherein R1 and R2 are each H.
4. Compounds of Claim 1 having the formula
5. Compounds of Claim 4 wherein R2 is H, R1 is H or ethyl.
6. Compounds of Claim 5 wherein R1 is H.
7. Compounds of Claim 6 having the S-isomer configuration.
8. Compounds of Claim 1 having the formula
9. Compounds of Claim 8 wherein R2 is H.
10. Compounds of Claim 9 having the R-isomer configuration.
11. A pharmaceutical composition containing a compound of Claim 1.
12. A process for preparing a compound of Claim 1 wherein R1 and R2 are each hydrogen which comprises hydrolyzing
(a) a compound having the formula
where R is -COOH,
(b) a compound having the formula
to obtain said Claim 1 compound (I) where R is H. or
(c) a compound of the formula
to obtain said Claim 1 compound.
13. Compound of Claim 1 havinq the formula
14. Compound of Claim 13 having the R-isomer configuration.