PT93273A - PROCESS FOR THE PREPARATION OF NEW N-SUBSTITUTED BUTIRATES WITH LOCAL ANESTHETIC ACTIVITY AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM - Google Patents

Description

/ 1 AKTIEBOLAGET ASTRA " PROCESS FOR THE PREPARATION OF NEW N-5 SUBSTITUTE BUTIRATES WITH LOCAL ANESTHETIC ACTIVITY AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM " Field of the Invention The present invention relates to novel compounds having local anesthetic action a process for their preparation and their application in the preparation of pharmaceutical compositions.

BACKGROUND OF THE INVENTION Tetracaine is one of the most frequently used local anesthetics especially for spinal and topical anesthesia. This agent, however, has certain drawbacks. It can not be administered in concentrations greater than approximately 1% because of the risk of toxic effects, and as sometimes it is necessary to obtain a longer anesthetic time # tetracaine can not therefore be applied. In addition tetracaine is easily hydrolyzed in aqueous solution.

Technical Background

In British Patent No. 2,121,111,

the local anesthetics which are disubstituted phenolic esters of known Î ±, β-disubstituted alpha-amino acids. Identical compounds are also described in Farmaco Ed. Sci. 19, p. 986 (1964), by Brancaccio S. and Larizza A. These compounds are not especially good as spinal anesthetics as can be seen in Table 2 below, where one of the compounds described in Farmaco Ed. Sci. is compared with the novel compounds according to the present invention.

Description of the invention

It has been found that the compounds of Formula I, or pharmaceutically acceptable salts thereof, have a good, unexpected effect as spinal anesthesiates. The novel compounds are more stable than tetracal and may, at least when R 2 and R 2 represent a methyl group, undergo a self-cleavage without marked degradation. The compounds according to the invention of the general formula. Ch

CH3

In which R 2 and R 2, which may be the same or different, each represent a hydrogen atom or a methyl group; R 3 and R 4, which may be the same or different, each represents a C 1 -C 3 alkyl group or taken together form an alkenylenic chain of the general formula wherein n is an integer from 4 to 6; or one of R1 and R2 is C1-4 alkyl and the other is hydrogen.

Preferred compounds according to the present invention are those wherein R1 and R2 represent R3 and R4 represent all alkyl groups. Especially preferred are those compounds in which the groups R 1 and R 2 are each methyl and R 3 and R 4 together represent a pentamethylene group.

Preferred salts according to the present invention are the pharmaceutically acceptable salts. Especially preferred is the hydrochloride # for injectable solutions. The base is preferred for topical application.

Preparation

The above-mentioned compounds of Formula I # are prepared according to the following methods. A halocarboxylic acid of formula II was dissolved in the same manner as 2,6-dimethylphenol in dichloromethane and trifluoroacetic anhydride was then added. The resulting 4-halogenobutyrate of general formula III # 4 in the next step # reacted with an appropriate amine to give a compound of formula I *, wherein R 2 is as defined above and R 3 and R 4, which may be the same or different, each represent a group alkyl of 1 to 3 carbon atoms or together form an alkylene chain having 4 to 6 carbon atoms. The obtained compounds were dissolved in tetrahydrofuran and lithium diisopropylamide in tetrahydrofuran was added dropwise. Methyl chloride was added and the mixture was hydrolyzed. The resulting product was a compound of formula I " in which R 3 and R 4 are as defined for the compounds of formula 1 '

In the case where a compound of formula I is intended it is a compound in which one of R3 or R4 is a hydrogen atom and the other is an alkyl group having 1 to 4 carbon atoms the compound of formula wherein each of R4 represents a benzyl group and the other an alkyl group as defined above which is hydrogenated with 5% palladium on carbon to give a compound of formula III '. The preparation described above may be represented by the following formulas:

II 5 t

H.

5% Pd / C

1) iPr0NLi - = - 5 2) CH3I

R 2 and R 3 are as defined above. 6 '

The compounds of general formula I # II * and III * are represented by the general formula I mentioned.

Detailed description of the preparation

Preparation of halogenoalkylcarboxylic acids (11)

The halogenoalkylcarboxylic acids II are prepared from the corresponding butyrolactones according to the method of Olab et al. (&Quot; Synthesis ", 963,1982). the crude acids were used without further purification in the next step.

Preparation of 4-halogenobutyrate (III)

The crude acids II (from 250 mmol of a G-butyrolactone), were dissolved together with 2,6-dimethylphenol (30.5 g, 250 mmole) in 100 ml of dichloromethane and then added 100 ml of trifluoroacetic anhydride. The reaction mixture was kept at ambient temperature overnight. It was then evaporated the residue which was dissolved in diethyl ether. The ether solution was washed repeatedly with aqueous sodium hydrogen carbonate until the reaction became neutral and then dried over magnesium sulfate. The ether was evaporated and the residue was distilled. 2,6-dimethylphenyl 4-iodobutyrate From di-butyrolactone. Yield 80% ether, boiling 120ø-125øC (0.02 mm Hg). Containing about 26% of the corresponding brominated derivative

- 7 F

I02 >. according to gas chromatography. (2,6-dimethylphenol) 2,6-dimethylphenyl 4-bromobutyrate From t-butyrolactone Yield 73% Sster with boiling point 118 ° -122Â ° C (0.6 mm of mercury). Ms (CH2 Cl2 H15 Bro2 + M + 270/272, peak of the base 122 (2,6-dimethylphenol), 2-methylbutyl- 6-dimethyl ester From dec-methyl-Y-butyrolactone, yield 80% ester with boiling point 115 ° -125 ° C (0.15-0.25 mm mercury). ): M + 284/286, peak 2] of base 122 (2,6-dimethylphenol).

Preparation of the end products in which represents a hydroxyl and R 6 represents a hydrogen atom or a methyl group

A mixture of 20 mmol of 4-halogenobutyrate (III), 44 mmol of the appropriate amine and 40 ml of toluene was cooled to 80-90 ° C until the major part of the halogenated compound had reacted. The reaction was followed by gas chromatography. The precipitated salt was pelleted, the toluene solution was extracted with excess dilute hydrochloric acid, the extracts were washed with diethyl ether and then dilute aqueous sodium hydroxide solution was added until the reaction became alkaline . The precipitated base was extracted with diethyl ether, the extracts were washed,

The organic extracts were combined with water and dried over magnesium sulfate. In some cases the base was distilled prior to conversion to the hydrochloride. The individual results for the different compounds are listed in Table 1. The compounds according to the present invention are mentioned in Table 1 below.

Table 1

Com- P.P. HCl - (ch2) 5 208-211 3 HH C3 H7 C3 H7 103-105 4 H CH3 C2 H5 C2 H5 110.5-112.5 5 H Ci 3 -t CH 2 5 - 160-164 6 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CK 3 C 2 H 5 C 2 H 5 140-142 8 CH 3 CK 3 - (CH 2) 5 215-218 9 CH 3 CK 3 K C 2 H 5 179-181.5 10 CH 3 CH 3 C2K5 C3H7

Table 1 (continued)

(Ch2) 6- 15 H ch3 - (ch2) 4-3 H ch3 -Cch2> 4-3 ch3 ch3 - (ch2) 6- 15 H ch3 - (ch2) Mp.

Examples

Compounds numbers 1 to 5 were prepared as described above. Compounds 11 # 13 and 15 can be prepared in the same manner. The preparation of the compounds with the numbers 6 to 9 is described in detail below. Compounds 10, 12 and 14 can be prepared as described for compound 8 or for compound 6.

Compound 6 2,6-dimethylphenyl 2,2-dimethyl-4-dimethylaminobutyrate 11.76 g (50 mmol) 2,6-dimethylphenyl 4-dimethylaminobutyrate. This compound was prepared as described in the preparation of the final products on page 5 of this specification. The preparation should, however, be carried out in a car key. Boiling point 87ø-92øC (0.01 mm of mercury) in 10 ml of tetrahydrofuran was added to a 0.433 M solution of lithium diisopropylamine (140 mmol) in hexane diluted with 150 ml of tetrahydrofuran was placed in a flask-dried and cooled flask cooled to -65 ° C. After 30 minutes at one hour, methyl iodide (7.8 g, 55 mmol) was added in 15 ml of tetrahydrofuran was added dropwise under stirring, whereupon the temperature of the reaction mixture was maintained for 2 hours at -40 ° C.

The reaction mixture was cooled to -65 ° C and then a further 140 ml of a 1: 433 M solution of lithium diisopropylamide in hexane, diluted with 150 ml of tetrahydrofuran was added after 45 minutes followed of an additional 7.8 g of methyl iodide in 15 ml of tetrahydrofuran.

When the temperature of the reaction mixture after 2 hours reached -40Â ° C was hydrolyzed with 50 ml of a saturated aqueous solution of sodium sulfate and the organic phase was separated and dried over magnesium sulfate. The solvent was evaporated and the residue was dissolved in dilute hydrochloric acid. The acid solution was washed twice with diethyl ether and then sodium hydroxide was added until alkalinity was attained. The base was extracted with dichloromethane and the extracts were dried over magnesium sulfate. The solvent was evaporated and the base was converted to the hydrochloride by means of hydrogen chloride in diethyl ether. 7 # 7 g. Two crystallizations in acetone provided 5 g of melting point 11

Compound 7 2,6-dimethylphenyl 2,2-dimethyl-4-dimethylaminobutyrate

This compound was prepared from 7.90 g (30 mmol) of 2,6-dimethyl 4-diethylaminobutyrate making 168 ml (72 mmol) of a 0.43 M solution of lithium diisopropylamine in hexane and 9.4 g (66 mmol) of methyl iodide, as described above for 4-dimethylaminobutyrate (compound 6). However, the impure base was distilled prior to conversion into the hydrochloride to give 6.21 g, boiling point 95ø-10øC at 0.01 mm of mercury. The hydrochloride was reserted three times in ethyl acetate to give 3.22 g, mp 140 ° -1 142 ° C.

Compound 8 2,6-dimethoxy-2,2-dimethyl-4-piperidinebutyrate

A 0.433 M solution of lithium diisopropylamine (112 mmol, 48 mmol) in hexane in dry tetrahydrofuran at -65 ° C was added. The base of 12.7 g 38 mmol) of 2,6-dimethylphenyl 2-methyl-4-piperidinobutyrate was dissolved in 10 ml of tetrahydrofuran and the mixture was then added dropwise at -60 ° C for 30 minutes. After adding 6.54 g (46 mmol) of methyl iodide in 10 ml of tetrahydrofuran, the reaction mixture was stirred overnight while the cooling bath was brought to room temperature. The mixture was triturated with 50 ml of a saturated aqueous solution of sodium sulfate. The organic layer was separated and dried over magnesium sulfate. The solvent was evaporated and the residue was dissolved in 100 ml of acetone and then a slight excess of hydrochloric acid in ether was added. 9.30 g of hydrochloride mp 214-217Â ° C were obtained. Recrystallization from acetone gave 8.0 g of the title compound as a melting point of 215 DEG-218 DEG C. The base from the hydrochloride in the usual way, by distillation. Boiling point 120 ° -130 ° G at 0,01 mm of mercury.

Compound 9 2,6-Dimethyl-2-phenyl-2-2-dimethyl-4-benzyl ethylamino) butyrate

This compound was prepared as the piperidino compound (equal to compound 8) from 12.0 g (32 mmol) of crude 2,6-dimethylphenyl 4- (benzylethylamino) -2-methylbutyrate, 90 ml (36 mmol ) of 0.40 M lithium dl-isopropylamine in hexane and 5.0 g (35 mmol) of methyl iodide. The crude base (11.6 g), 90% purity as assessed by gas chromatography was used as such in the next step. 2,6-dimethylphenyl 2,2-dimethyl-4-ethylaminobutyrate

The crude 4- (benzylethylamino) butyrate was dissolved in 50 ml of ethanol and 6 ml of a 2N aqueous hydrochloric acid solution was added and the mixture was hydrogenated with 1.2 g of palladium on charcoal at 5 at 13 ° C.

40 ° C for 3 hours. The catalyst was removed by filtration and the solvent was removed from the filtrate. The crystalline part of the residue was crystallized twice from acetonitrile to give 1.70 g of hydrochloride, m.p. 179-181.5 ° C.

Pharmaceutical Compositions

For the preparation of injectable pharmaceutical compositions the novel compound was dissolved in a liquid solvent suitable for injection. The compositions used are aqueous solutions containing 2.5 to 40.0 mg / ml of active compound calculated as the hydrochloride. Examples of topical preparations containing the basic form or other suitable forms especially the pharmaceutically acceptable salts of the active substance are dispersed systems such as emulsions, microemulsions, suspensions, liposomes, micelles, etc. The active component may also be included in different types of films, tapes, etc.

Biological studies Spinal anesthesia

The compounds of the present invention were tested for determination of spinal anesthesia in the rat. The reference compounds have also been tested for lidocaine and tetracaine and the compound of formula

Ref)

The results are presented in Table 2 below. Table 3 shows the acute toxicity (LD50 iv) in the rat. The results of a rabbit topical anesthetic assay are shown in Table 4.

Table 2

Subarachnoid spinal anesthesia in the rat. Groups of 6 mice were injected with 50 ml of assay solution. The mean time to the start of the blockade (in seconds) and the mean duration (minutes - S.E.M.) of the motor block were calculated from the locking leg drawer (Nsl2). the blockade frequency was 100¾ in all assays - 15β

0 <0 Φ 00 ΓΟ ο α \ Η νΟ ΙΩ ΓΟ «0 κ * κ« Ν «S * s *» <κ Κ • "ν 0 Η Ο &lt; Ν ο. Ω Ω Η Ο Ο d Φ Φ Φ Φ Φ OJ OJ OJ OJ OJ OJ OJ OJ OJ OJ OJ OJ OJ OJ OJ OJ OJ OJ OJ OJ. · * '. • Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω. m Ι Ι Ι Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η * Ν Ν Ν ο. Μ Η Ο, Ο rH ιΗ Ο 03 Ο (0 +1 +1) +1 +1 +1 +1 +1 +1 +1 +1 +1 Μ 00 σ Η Η ΓΟ ΓΟ-- • Ν Ν ν Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Η V Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η * 0 Ο Η Ο 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 Ι 00 00 00 00 00 00 Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Φ Η Ι Ι-------------------------------Η Η Η Η Η Η Η Η Η Η Η Η Η 2 Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι + 0 &quot; 00 σ \ «Η α; tt 16

Table 3

Acute endovenous toxicity (DL5q) in rat. Each compound was injected in at least four doses into groups of six mice.

Compound LD50 m9 / kg iv

No. 1 15 2 7 3 10 4 10 5 7 6 20 7 12 8 9 9 16 Lidocaine 18 Tetracaine 6 Ref. 35 Tonic anesthesia Table 4

Corneal anesthesia in the rabbit. Each value is the mean duration (minutes ± of blockade after the application of 0.25 ml of anesthetic solution in the conjunctival sac for 0.5 minutes.

Compound Cone. Duration Number of animals No.% 8 0.25 17.1 + 0.6 3 tetracaine 0.25 14.1 + 1.7 3

Discussion

As can be seen from the data in Tables 2 and 3, the novel compounds according to the present invention have good low dose final anesthetic activity and are less toxic than tetracaine. A compound according to the present invention also has a better effect as a topical anesthetic than tetracaine (Table 4). Therefore, the chosen compounds of the present invention are suitable as topical and spinal anesthetic agents. The best known manner of applying this invention to the present is the use of the compound according to example 8 in the form of the hydrochloride in injectable solutions or the corresponding base in topical preparations.

Claims (4)

-18- A process for the preparation of compounds of general formula in which and R '2, the same or different, each represent a hydrogen atom or a CH 2 group; â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ wherein R 4 and R 6 are independently selected from the group consisting of hydrogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, (II) in which represents a hydrogen atom or a CH 2 group, and X represents a halogen atom, with 2,6-dimethylphenol of formula in the presence of trifluoroacetic acid anhydride to provide a compound of general formula in which -20- and X are as defined above, and (a) for the preparation of compounds of general formula I in which R 2 represents a hydrogen atom, heating the resulting compound of formula III with an appropriate amine of formula R4 and R4 are the same or different, represent an alkyl or alkylene group having 4 to 6 carbon atoms or one of R3 and R4 is benzyl and the other is an alkyl group as defined. to give a compound of general formula in which R 1, R 3 and R 4 are as defined above, (b) for the preparation of compounds of general formula I in which R 1 and R 2 each represent a CH 3 group, in which the resulting compound of formula General 1 'with lithio-diisopropylamide and methyl iodide to give a compound of general formula -21- I &quot; (c) for the preparation of compounds of general formula I in which R 2 and R 2 are each CH 2 and R 1 and R 2 are as defined above, represents the alkyl group and the other is a hydrogen atom, to be hydrogenated using 5% palladium on charcoal, a compound of the general formula II, wherein one of R3 and R4 is benzyl and the other is alkyl group to obtain a compound of formula (I.e. 2. A process according to claim 1 for the preparation of compounds of general formula I in which R 1 and R 2 each represent a CH 3 group and R 2 and R 3 are each, an alkyl group characterized in that correspondingly substituted starting compounds are used. 3. A process according to claim 2 for the preparation of compounds of general formula I in which R 2 and R 2 each represent a CH 3 group and R 3 and R 4 together represent a pentamethylene group, of correspondingly substituted starting compounds. 4. A process for the preparation of pharmaceutical compositions used as anesthetics for administration topically or by injection into the spinal cord, characterized in that an effective amount of a compound of formula I is mixed when prepared by the process according to Claim 1, as the active ingredient, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier. Lisbon, 26 February 1990 The Official Agave of the Indusfri