CS212245B2 - Method of making the 2-/4-/4- chlorphenyl/benzyloxy/alkane acids - Google Patents

Abstract

The present invention relates to novel derivatives of hydroxyacetic acid having an active antiviral agent arthritic properties along with desired pharmacokinetic properties and minimis side effects. According to the invention, hydroxyacetic acid derivatives of the formula I are produced, R, (i) ci cHz ° ~ c ° zH R2 where it means H 1 is hydrogen or alkyl of 1 to 4 carbon atoms and p R is phenyl, optionally substituted by halogen, or a pharmaceutically acceptable base addition salt thereof in racemic or optically active form with antiarthritic properties by hydrolysis of compounds of formula 11 ',

Description

The present invention relates to novel hydroxyacetic acid derivatives having effective anti-arthritic properties along with the desired pharmacokinetic properties and minimizing adverse effects.

According to the present invention, the hydroxyacetic acid derivatives of the general formula I, _R , (i) ^{or (c) c H 2} where R ² is

H ^{1 is} hydrogen or alkyl of 1 to 4 carbon atoms and the like

R is phenyl, optionally substituted with halogen, or a pharmaceutically acceptable base addition salt thereof in a raoemic or optically active form having antiarthritic properties, by hydrolysis of the compounds of formula 11 ',

Cl

(II) in which amended

C 1 -C 6 alkoxycarbonyl of the felkoxy, benzyloxycarbonyl or cyano group, in the preparation of a pharmaceutically acceptable base addition salt, an acid of formula I is reacted with a suitable base to provide a suitable ketone when an optically active isomer of the compound is required of formula (I), either cleaving the racemic form of the acid by reaction with an optically active form of an organic base, separating the resulting salt and liberating the optically active form of the acid of formula (X) by acidifying the above salt;

It will be appreciated that the compounds of formula (I) may exist in both racemic and two optically active forms. The present disclosure relates to a process for the preparation of the racemic form of the compounds of formula I and any individual optically active form having the aforementioned active effects. It will be apparent from the art and from the following examples how to prepare the optically active form of hu3 by resolution of the racemic form, or by carrying out the process of the invention using an optically active compound of formula II.

When r 'is C 1 -C 4 alkyl, it may be, for example, methyl or ethyl.

In the case of halogen substitution on R, the halogen may be fluorine, chlorine or bromineT

A particular meaning of R is, for example, when it is phenyl, 4-fluorophenyl, 4-chlorophenyl or 4-bromophenyl.

A preferred group of compounds which can be prepared by the process of the invention comprises those compounds of formula I wherein R is methyl or ethyl and R is phenyl and their pharmaceutically acceptable base salts.

The base addition salts of the compounds of formula I are, for example, alkali metal or alkaline earth metal salts, for example sodium, potassium, calcium or magnesium salts, aluminum salts, for example disodium aluminum hydroxide, ammonium salts, or organic base salts providing a pharmaceutically acceptable cation, for example triethanolamine or tris (hydroxymethyl) methylamine.

Certain compounds obtainable by the process of the invention are described in the Examples below. Particularly preferred compounds of the invention are 2- [4- (4-chlorophenyl) benzyloxy] -2-phenylpropionic acid and 2- [4- (4-chlorophenyl) benzyloxy] -2-phenylbutyric acid or a pharmaceutically acceptable base addition salt thereof.

A particularly suitable value of the substituent Q when C1 -C6 alkoxycarbonyl means, for example, is methoxycarbonyl or ethoxycarbonyl.

The hydrolysis is conveniently carried out, for example, by reacting a compound of formula II with a suitable base, for example an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide in an organic solvent such as methanol or ethanol, optionally mixed with water. Hydrolysis can be carried out, for example, at 15 to 100 ° C, and at 60 to 80 ° C is particularly suitable.

The starting compounds of formula II in which the meaning of the substituent Q is other than cyano can be conveniently obtained by reacting 4- (4-chlorophenyl) benzyl chloride and the sodium salt of a suitable hydroxy compound of formula III,

HO-CO, ^R> (III) wherein R3 represents alkyl of 1-6 carbon atoms, benzyl or phenyl, and the other symbols are as defined above, suitably at 15 to 30 ° C and in a suitable inert solvent such as dimethylformamide, dimethylsulfoxide or hexamethylphosphoramide, optionally together with tetrahydrofuran as exemplified.

The corresponding cyano compounds of formula II can be obtained in a similar manner, but substituting the sodium salt of the hydroxy compound of formula III with the forensic salt of the compound of formula IV,

HO-C-CN (IV) wherein the general symbols are as defined above.

If it is desired to prepare a pharmaceutically acceptable acid addition base salt of formula (I), said acid is reacted in conventional manner with the desired base to provide a pharmaceutically acceptable cation. When an optically active isomer is desired, either the racemic acid form is resolved by treatment with an optically active base, for example (+) or (-) alpha-methylbenzylamine, the resulting salt is separated and the optically active form of the acid of formula I is liberated by acidification an acid such as sulfuric acid, or the above procedure is carried out using optically active starting materials.

As mentioned above, the compounds of formula I have valuable antiarthritic properties which can be demonstrated by the following standard laboratory method, based on the Newbould principle (Brit. J. Pharmacol 1963, 21, 127-136). The procedure involves inducing arthritis in rats by intradermal injection of a suspension of heat-killed tuberculous bacilli in paraffin oil into one hind paw of each rat, and then measuring the effects of daily oral doses of test compound on swelling of the test paw and inhibiting elevations in blood serum alpha-acids. at least 28 days. In this test, the compounds of formula (I) showed significant efficacy at a daily dose of 100 mg / kg or less and without any apparent toxic effects. For example, (S) -2-L4- (4-chlorophenyl) benzyloxy] -2-phenylbutyric acid provides 38% inhibition of paw edema growth and 47% inhibition of serum α, β-glycoprotein levels after 28 days of oral administration of a daily dose of 80 mg / day. kg, showing no apparent toxic or other side effects. Similarly, no such side effects were observed after 14 days of oral administration of 300 mg / kg of this compound to normal rats.

As mentioned above, the compounds of formula I also have desirable pharmacokinetic properties, as indicated, for example, by its relatively short elimination half-lives from blood serum in experimental animals. For example, (R) -2- [4- (4-chlorophenyl) benzyloxy] -2-phenylbutyric acid has an elimination half-life from rat blood serum of about 10 hours, whereas the known compound, 2- [4- (4-chlorophenyl) benzyloxy] - 2-methylpropionic acid has an elimination half-life in rats of about 5 days.

The relatively short elimination half-life is particularly important as it allows therapeutic levels of these compounds to be reached rapidly using a simple dosage regimen comprising regular dosing intervals of less than 1 day between doses.

Likewise, in the event of any adverse effect of these compounds, the relatively short elimination half-life ensures that the serum level of these compounds rapidly decreases to an acceptable level upon discontinuation of administration.

There is no specific theory as to the mechanism of action of the compounds of formula (I) yet. Their efficacy is believed to be essential for the arthritic disease process causing tissue damage, rather than a mere mitigating effect on the resulting arthritis inflammation.

It is therefore contemplated that the compounds obtainable according to the invention will be of value in the treatment of other connective tissue diseases, such as atheroclerosis, in addition to their use in the treatment of arthritic joint diseases such as rheumatoid arthritis, arthropathic psoriasis and ankylosing spondylitis.

In order to induce antiarthritic effects in warm-blooded animals, the compounds of formula I will generally be administered at a daily oral dose of, for example, 5 to 100 mg / kg. For example, in humans, a total daily dosage of 125 to 2500 mg, administered in divided doses, if desired, is suitable.

The invention is illustrated by the following non-limiting examples, in which:

all evaporations, unless otherwise indicated, are carried out by rotary evaporation, reactions at room temperature are carried out at 18-25 ° C, yields (where indicated) are purely illustrative and should not be construed as yields are as achievable as possible for the above processes and all compounds, unless otherwise indicated, are in racemic (i) form.

He did

A solution of 7.9 g of 2- [4- (4-chlorophenyl) benzyloxy] -2-phenylpropionic acid ethyl ester in 100 ml of methanol containing 11.0 g of potassium hydroxide is refluxed for 2 hours and evaporated. The residue was partitioned between 100 mL of water and 30 mL of ether. The aqueous phase was separated and acidified to pH 2-3 with 4N hydrochloric acid and extracted with ether (3.times.30 ml). The ether extracts were washed with water, dried (MgSO4) and evaporated. The residue was recrystallized from ethyl acetate / hexane to give 3.5 g of 2-Q4- (4-chlorophenyl) benzyloxy] -2-phenylpropionic acid, mp 125-126 ° C.

The above substituted propionate is obtained as follows: 1.05 g (50% w / w dispersion in mineral oil) of sodium hydride is added to a stirred solution of 3.48 g of 2-hydroxy-2-phenylpropionic acid ethyl ester in 100 ml of dimethylformamide at 100 ml of dimethylformamide. Low: 14 ° C. After 1 hour, 4.74 g of 4- (4-chlorophenyl) benzyl chloride are added and stirred continuously for 1 hour at 4 ° C and then for 20 hours at room temperature. The mixture was neutralized by addition of 1 N hydrochloric acid and extracted with ether. The extracts were washed with water, dried (MgSO4) and evaporated to give a white solid

7.9 g of 2- [4- (4-chlorophenyl) benzyloxy] -2-phenylpropionic acid ethyl ester as an oil.

Example 2

Using the method described in Example 1, 2- [4- (4-chlorophenyl) benzyloxy] -2-phenylbutyric acid was obtained as a solid in 53% overall yield, mp 128-130 ° C after recrystallization from a mixture of ethyl acetate and hexane . Methyl 2-hydroxy-2-phenylbutyrate is used instead of 2-hydroxy-2-phenylpropionic acid ethyl ester, with intermediate isolation of methyl 2- [4- (4-chlorophenyl) benzyloxy] -2-phenylbutyrate as an oily solid of satisfactory purity.

Example 3

Using the same method as in Example 1, S - (-) - 2- [4- (4-chlorophenyl) benzyloxy] -2-phenylbutyric acid was obtained in 15% yield, mp 115-116 ° C, [α] [.Alpha.] D = -52.3 DEG, (e = 1.098, chloroform), by hydrolysis of the corresponding S-methyl ester.

The S - (+) - methyl-2-hydroxy-2-phenylbutyrate required for the preparation of the starting S-methyl ester is obtained according to the method of Mc Kenzie and Ritchie (Chem. Ber., 1937, 70, 23) and the absolute configuration is determined. according to the absolute configuration of S - (+) - 2-hydroxy-2-phenylbutyric acid, as determined by Mitsui et al. (Chemistry and Induatry, 1964,333).

Example 4 ml of (+) - alpha-methylbenzylamine was added to a solution of 200 g of (±) -2- [4- (4-chlorophenyl) benzyloxy] -2-phenylbutyric acid in 1.4 L of ethanol. After 10 hours at room temperature, the solid which precipitates is collected by filtration and the solid and filtrate (A) are retained.

The solid ae is recrystallized twice from ethanol and shaken with 800 ml of sulfuric acid. The resulting mixture was extracted with ether (1.2 L), washed with water, dried (MgSO4) and evaporated. The solid residue was recrystallized from ethyl acetate / hexane to give 36.0 g (in two yields) of S - (-) - 2- [4- (4-chlorophenyl) benzyloxy] -2-phenylbutyric acid, mp 116-117 ° [.Alpha.] D @ ²⁵ = -55.5 DEG (c = 1, chloroform).

Example 5

The filtrate A obtained in Example 4 was shaken with 1 L of 2N sulfuric acid and extracted with 0.8 L of ether. The extract was washed with water, dried with magnesium sulfate and evaporated; 120 g of the residue obtained, containing both the racemic form (±) and the (+) - form of 2- [4- (4-chlorophenyl) benzyloxy] -2-phenylbutyric acid, are dissolved in 1 l of ethanol. 50 ml of (-) - alpha-methylbenzylamine are added to the solution. After 1.8 hours at room temperature, the precipitated solid was collected by filtration and recrystallized twice from ethanol. The obtained crystalline material is suspended in 2M sulfuric acid and the mixture is extracted with ether as described in Example 4. Thus, 30.9 g of R - (+) - 2- [4-] are obtained in two yields from the dried ether extract. (4-chlorophenyl) benzyloxy] -2-phenylacetic acid, m.p. 117 DEG-118 DEG C., [.alpha.] D ⁼ + 54.5 DEG (c = 1, chloroform) after recrystallization from ethyl acetate / hexane.

Example 6

A solution of 0.407 g of sodium hydroxide in 10.25 ml of water was added to a stirred suspension of 4.0 g of 2- [4- (4-chlorophenyl) benzyloxy] -2-phenylbutyric acid in 100 ml of water. The mixture was stirred for 15 minutes and the insoluble material was filtered off. The filtrate was evaporated. The remaining solid was further evaporated twice with toluene (2 x 20 mL) and then dried under vacuum over phosphorus pentoxide to constant weight. 3.95 g of 2- [4- (4-chlorophexyl) benzyloxy] -2-phenylbutyric acid sodium salt are obtained.

Microanalysis: CggHgQClNaO ^ requires: C, 68.57; H, 5.0%. Found: C, 68.2%;

Example 7

Using the same procedure as in Example 6, but replacing sodium hydroxide with a solution of 0.576 g of potassium hydroxide in 14.8 ml of water, 3.7 g of potassium acid salt was obtained.

2- [4- (4-chlorophenyl) benzyloxy] -2-phenylbutyric acid.

Microanalysis: C ^ HH ^ ClClKOO requires: C, 65.93; H, 4.81; Found: C, 65.9; H, 4.9.

Example 8

Using the same procedure as in Example 6, but replacing sodium hydroxide with a solution of 1.211 g of tris (hydroxymethyl) methylamine in 10 ml of water and using 3.81 g of 2- [4- (4-chlorophenyl) benzyloxy] -2-phenylbutyric acid yields tris (hydroxymethyl) methylsmonium 2-C 4- (4-chlorophenyl) benzyloxy] -2-phenylbutyrate (4.56 g).

Microanalysis: C ₂₇ H ₃₂ ClNO. 0.25 H ₂ 0: calculated: 64.0% C 6.4% H 2.8% N Found: 63.8% C, 6.3 »H, 2.5% N.

Example 9

The procedure of Example 6 was repeated to give an aqueous solution of 2- [4- (4-chlorophenyl) benzyloxy] -2-phenylbutyric acid sodium salt. To the aqueous solution was added a solution of 0.564 g of calcium chloride in 50 mL of water. The thick precipitate which forms is collected by filtration and washed with water and ethanol, dried under vacuum over phosphorus pentoxide at 90 ° C to constant weight to give 3.86 g of 2- [] 4- (4-chlorophenyl) calcium salt. (benzyloxy) -2-phenylbutyric acid.

Microanalysis: ^C 46 ^H 4 O 2 ^C1 OgCa . 1.5 H ₂ 0 calculated: 66.8% C, 5.2 % H, 8.6 % Cl, found: 66.6% C, 5.2 ® H, 8.2 ® Cl. Example 10 Ammoniacal excess of methanol is added to oxy] -2-phenylbutyric acid lazy in 50 ml of methanol. ! The mixture was separated from a mixture of ether and h exane to form ammonium -2-phenylbutyric (3.68 g) • Microanalysis: C ^ HH ^CINO 3 ’< ), 25 H ₂ 0 calculated: 68.7% C, 6.1 % H, 3.5 % N, found ^ 68.7 $ C, 6.1 % H, 3.2 £ N. Examples 11 to 14 Using similar procedure as is described '

of sodium hydroxide, the above-mentioned acids of formula I are obtained in yields of 60 to 85% by hydrolysis of the corresponding methyl or ethyl esters followed by recrystallization of the crude product from an ethyl acetate / hexane mixture.

. 212245

Example R ¹ R ² Optical Melting Point Form (° C)

11 H Ph (±) 136 to 137 12 H Ph (+) 119 to 121 (note a) 13 H Ph (-) 120 to 121 (note b) 14 H 4-Cl-Ph (and) 120 to 122

Note: _α : Γ _α 1 ² ^ = + 104 ° (c = 1, chloroform)

LJ _D note. b = -104 ° (c = 2.1, chloroform) ^LJ D

The starting materials of formula III can be obtained in a manner analogous to that described in Example 1.

Claims (4)

P 6 'E D M 6 T Process for the preparation of 2- [4- (4-chlorophenyl) benzyloxy] alkanoic acids of the general formula I, R ¹ Cl R ² in which is R ^{1 is} hydrogen or C 1 -C 4 alkyl and o R is phenyl, optionally substituted with halogen, or a pharmaceutically acceptable base addition salt thereof, in racemic or optically active form, characterized in that the compound of formula (II) is hydrolyzed in which: C 1 -C 6 alkoxycarbonyl or cyano; R @ 1 and R @ 2 are as hereinbefore defined and optionally, for the preparation of a pharmaceutically acceptable base addition salt, an acid of formula I is reacted with a base providing a pharmaceutically acceptable cation, and optionally for the preparation of an optically active isomer of acid of formula I the optically active form of the organic base, the resulting salt is separated and the optically active form of the acid of formula I is liberated by acidifying the above salt, which process is carried out with the optically active form of the compound of formula II. 2. A process according to claim 1, wherein the hydrolysis is carried out by reacting a compound of formula II with a base in an organic solvent, optionally mixed with water, at a temperature of from 15 to 100 [deg.] C. 3. The process of claim 2 wherein the base is an alkali metal hydroxide, such as sodium or potassium hydroxide, as the organic solvent of methanol or ethanol, and the hydrolysis is carried out at a temperature in the range of from 60 to 80 ° C. 4. Method according to claim 1, 2 or 3, characterized in that it uses a starting compound of formula II wherein R ¹ is methyl or ethyl, R ^{Z is} phenyl, and Q my abovementioned meaning.