IE42155B1 - A substituted-phenyl ketone containing a dipeptide residueand a process for the manufacture thereof - Google Patents

Description

The present invention is concerned with a substituted-phenyl ketone, with salts thereof and with a process for the manufacture thereof.

The present invention provides the compound L-lysyl-N-(25 -benzoyl-4-chlorophenyl)-N-methylglycinamide of the formula and acid addition salts thereof.

According to the process provided by the present invention, L-lysyl-N-(2-benzoy1-4-chlorophenyl)-N-methylglycinamide of formula I hereinbefore and acid addition salts thereof are manufactured by (a) cleaving off in accordance with methods known per se the protecting groups present in a compound of the general formula (II) 2 , wherein R and R each amino-protecting group, represent an or (b) resolving racemic lysyl-N-(2-benzoy1-4-chlorophenyl)-N-methylglycinamide into its optical isomers and isolating the L-isomer, and, if desired, converting the free base obtained into an acid addition salt or converting an acid addition salt obtained into the free base or into a different acid addition salt. 2 The amino-protecting groups denoted by R and R in a compound of formula II can be any amino-protecting groups which are well-known in peptide chemistry. Especially suitable amino-protecting groups for the purpose of the present invention are aralkoxycarbonyl groups, particularly the benzyloxycarbonyl group, and the tert.butoxycarbonyl group. The amino-protecting group may also be a formyl, -trityl or trifluoroacetyl group.

The removal of the amino-protecting groups denoted by R1 and R in a compound of formula II is oarried out in accordance with methods known per se; that is to say, methods in actual use for or described in the literature on the removal of protecting groups. In a preferred embodiment of the present process, the amino-protecting groups are groups which are removable by hydrolysis. Thus, for example, an aralkoxycarbonyl group (e.g. benzyloxycarbonyl) or the tert.butoxycarbonyl group may be removed by treatment with a mixture of hydrogen bromide and acetic acid. The tert.butoxycarbony1 group may also be removed by means of hydrogen chloride in an organic solvent (e.g. dioxan) or by means of trifluoroacetic acid. A benzyloxy10 carbonyl or tert.butoxycarbonyl group may also be removed by treatment with boron trichloride or boron tribromide in an inert organic solvent such as dichloromethane.

Racemic lysyl-N-(2-benzoy1-4-chlorophenyl)-N-methylglycinamide can be split up into its optical isomers in accordance with known methods; for example, with the aid of an appropriate optically active acid. The desired L-isomer can be obtained according to known methods such as fractional crystallisation of the diastereoisomeric salts obtained.

The starting materials of formula II hereinbefore are claimed per se in Patent Specification No.and can be prepared as described therein.

L-Lysyl-N-(2-benzoy1-4-chlorophenyl)-N-methylglycinamide of formula I hereinbefore forms acid addition salts with inorganic acids (e.g. hydrohalic acids such as hydrochloric acid and hydrobromic acid, sulphuric acid, phosphoric acid and nitric acid) and with organic acids (e.g. acetic acid, succinic acid, glycolic acid, lactic acid, gluconic acid, tartaric acid, citric acid, maleic acid, malic acid, fumaric acid, methanesulphonic acid, paratoluenesulphonic acid, oxalic acid, ascorbic acid, benzoic acid, hydroxyethane sulphonic acid and 1,2-diethane sulphonic acid). The pharmaceutically acceptable acid addition salts are preferred. The acid addition salts can be prepared according to well-known methods; for example, by treating the base with an appropriate acid. An acid addition salt may also be converted into a different acid addition salt by means of a suitable anion exchange resin (e.g. Amberlite IRA-401 in the chloride form - Amberlite is a trade mark).

L-Lysyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide of formula I hereinbefore and its acid addition salts possess sedative, muscle relaxant and anticonvulsant activity. Of particular interest are those pharmaceutically acceptable acid addition salts which are water-soluble since they can be readily administered by injection; for example, in dentistry for the induction of anaesthesia and in the management of acute convulsive disorders and status epilepticus.

L-Lysyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide of formula I and its pharmaceutically acceptable acid addition salts may be used as medicaments; for example, in the form of pharmaceutical preparations which contain said compound or a pharmaceutically acceptable acid addition salt thereof in association with a compatible pharmaceutical carrier material. This carrier material can be an organic or inorganic carrier - 6 material suitable for enteral or parenteral administration (e.g. water, lactose, gelatin, starches, magnesium stearate, talc, vegetable oils, gums, polyalkyleneglycols or petroleum jelly). The pharmaceutical preparations can be made up in a solid form (e.g. as tablets, dragees or capsules) or in a liquid form (e.g. solutions, suspensions or emulsions). Pharmaceutical preparations in a form adapted for injection purposes are preferred. The pharmaceutical preparations may be subjected to conventional pharmaceutical operations such as sterilisation and/or may contain conventional pharmaceutical adjuvants such as preservatives, stabilisers, wetting agents, emulsifiers and buffers.

The dosages in which L-lysyl-N-(2-benzoy1-4-chlorophenyl)-N-methylglycinamide of formula I and its pharmaceutically acceptable acid addition salts may be administered can vary depending on the requirements of the patient and the directions of the attending physician. A dosage of from 0.01 mg/kg/day to 1 mg/kg/day is, however, preferred.

The following Example illustrates the process provided by the present invention: Example (A) The preparation of the starting material: (Na,NE-Bisbenzyloxycarbonyl-L-lysyl)-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide) was prepared as described in Example 8 of Patent Specification No. /j2.(Fb (B) The process: (i) (Na,NE-Bisbenzyloxycarbonyl-L-lysyl)-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide was converted using a 30% solution of hydrogen bromide in glacial acetic acid into L-lysyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide dihydrobromide which was obtained as a hygroscopic powder of melting point 145°-160°C (decomposition); [α]£ = +15.6° (c = 1 in water).

Analysis for C^H^Br^lN^O^ (^92.8): Calculated: C: 44.58; H: 4.93; N: 9.45; Br ion: 26.96. Pound: C: 43.58; H: 5.17; N: 9.21; Br ion: 27.43; H20: 0.99. Water-free: C: 44.02; H: 5.11; Ns 9.30; Br ion: 27.70.

Treatment of the foregoing dihydrobromide in aqueous solution by passage over an excess of an anion-exchange resin such as AMBERLITE IRA-401 in the chloride form followed by lyophilisation of the eluate gave, in quantitative yield, L42155 -lysy1-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide dihydro· chloride as a hygroscopic white light-sensitive powder of melting point 125°-145°C (slow decomposition); [a]20 = +19-3° (c = 1 in water).

Analysis forC22H29C13N 4°3 (503. 86) : Calculated: C: 52.45; H: 5.80; N: 11.12; Cl: 21.12. Found: C: 51.58; H: 5.80; N: 11.18; Cl: 20.80; H20: 0.99. Water-free: C: 52.10; H: 5.75; N: 11.29; Cl: 21.10. (ii) 1.4 g of (Na,Ne-bisbenzyloxycarbohyl-L-lysyl)-N-(2-benzoy1-4-chlorophenyl)-N-methylglycinamide Were dissolved in 30 ml of dry dichloromethane, cooled to approximately -70’C and treated, while stirring, with 2 ml of pre-cooled boron trichloride. The mixture was stirred under anhydrous . conditions at approximately -70°C for 30 minutes and then allowed to warm slowly to room temperature over a period of 2 hours. The mixture was evaporated to dryness in vacuo, the residue re-dissolved in 30 ml of fresh dry dichloromethane and the solution again evaporated to dryness in vacuo. This operation was repeated twice using dichloromethane and then four times using methanol in order to remove the residual boron compounds as volatile trimethyl borate. A concentrated methanolic solution of the residue was added slowly to 750 ml of anhydrous diethyl ether with vigorous stirring, the solid hygroscopic product collected by filtration and dried in vacuo.

This product was dissolved in 30 ml of water, shaken with three 20 ml portions of ethyl acetate to remove traces of 5-chloro-2-methylaminobenzophenone and the aqueous solution lyophilised to give 0.7 g of L-lysy1-N-(2-benzoy1-4-chlorophenyl)-N-methylglycinamide dihydrochloride which was identical to that described in part (i) hereinbefore.

The following Example illustrates a typical pharmaceutical 5 preparation provided by this invention: Example An injection solution containing the following ingredients is prepared in a conventional manner: L-Lysyl-N-(2-benzoy1-4-chloro10 phenyl)-N-methylglycinamide dihydrochloride 10.00 mg Sodium acetate 3.1^0 22.32 mg Acetic acid 2.16 mg Chlorocresol 1.00 mg Sodium chloride a-s. Water for injection ad 1.00 ml The foregoing solution should be protected from light prior to use.

Claims (7)

CLAIMS:

1) L-Lysyl-N-(2-benzoy1-4-chlorophenyl)-N-methyIglycinamide of the formula and acid addition salts thereof.

2. ) L-Lysyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide dihydrochloride.

3. ) A process for the manufacture of L-lysyl-N-(2-benzoy1-4-chlorophenyl)-N-methylglycinamide and acid addition salts thereof, which process comprises (a) cleaving off in accordance with methods known per se the protecting groups present in a oompound of the general formula (II) 1 2 , wherein R and R each represent an amino-protecting group, or (b) resolving racemic lysyl-N-(2-benzoy1-4-chlorophenyl)5 -N-methylglycinamide into its optical isomers and isolating the L-isomer, and, if desired, converting the free base obtained into an acid addition salt, or converting an acid addition salt obtained into the free base or into a different acid addition salt. 10

4. ) A process according to claim 3, wherein L-lysyl-N-(2-benzoy1-4-chlorophenyl)-N-methylglycinamide dihydrochloride is manufactured.

5. ) A process for the manufacture of L-lysyl-N-(2-benzoy1-4-chlorophenyl)-N-methylglycinamide and acid addition salts 15 thereof, substantially as hereinbefore described with reference to Example (B).

6. ) L-Lysyl-N-(2-benzoy1-4-chlorophenyl)-N-methylglycinamide and acid addition salts thereof, when manufactured by the process claimed in any one of claims 3 to 5 inclusive. 20

7) A pharmaceutical preparation containing L-lysyl-N-(2-benzoy1-4-chlorophenyl)-N-methylglycinamide or a pharmaceutically acceptable acid addition salt thereof in association with a compatible pharmaceutical carrier material.