DD292240A5 - PROCESS FOR PREPARING BUTTERIC ACID 2,6-DIMETHYLPHENYL ESTERS - Google Patents

Abstract

The invention relates to a process for the production of * which are processed for use in human medicine and veterinary medicine for local anesthetic purposes to preparations. The process according to the invention produces the general formula in which R 1 and R 2 are hydrogen atoms or methyl groups and R 3 and R 4 are hydrogen atoms or methyl groups or, taken together, an alkenylene chain. Formula {procedures; manufacture; * Human medicine; Veterinary medicine; local anesthesia; Preparations}

Description

^XN OC-C-CH CH N

¹ \

\ 3

CH _{3 is} hydrogenated, wherein R ₁ and R _{2 are} CH ₃ and one of the groups R ₃ and R _{4 is} an alkyl group with 1 to

4 carbon atoms and the other is a hydrogen atom, and optionally the obtained

Bases of formula I in a conventional manner in their pharmaceutically acceptable acid salts

2. The method according to claim 1, characterized in that one uses starting compounds in which Ri and R _{2 are} CH ₃ and R ₃ and R ₄ are alkyl groups having 1 to 3 carbon atoms or taken together form the pentamethylene group.

Field of application of the invention

The butt-3-hydroxy-2,6-dimethylphenols prepared by the process of the present invention can be made into local anesthetic preparations for use in human and veterinary medicine.

Characteristic of the known state of the art

Tetracaine is one of the most widely used local anesthetic agents, especially for spinal anesthesia and local anesthesia. However, this agent has certain disadvantages. It can not be administered in concentrations higher than about 1% because of the danger of toxic effects, and since it is sometimes desirable to have a longer anesthetic duration, this can not be achieved with tetracaine. In addition, tetracaine is readily hydrolyzed in aqueous solution. From the British patent 1102011 local anesthetics are known, which are disubstituted phenol esters of N, N-disubstituted alpha-amino acids. Similar compounds are also in Farmaco Ed. Be. 19, page 986 (1964). These compounds are not particularly good as spinal anesthetics, as can be seen from the following Table II, in which one of the in Farmaco Ed. Be. Compounds described with new compounds according to the invention is compared.

Object of the invention

The aim of the invention is the production of new better local anesthetics. Explanation of the essence of the invention

The object of the invention is a process for the preparation of compounds with better action than spinal anesthetics. These compounds are butyric acid 2,6-dimethylphenyl esters of the general formula

^CH 3 0 R ₁ R ₃

Ii I ¹ /

0-CC-CH ₀ -CH ₉ -N

'V

R ₂

wherein R ₁ and R _{2 are the} same or different and are hydrogen or CH ₃ groups, R ₃ and R _{4 are the} same or different and are alkyl groups having 1 to 3 carbon atoms or taken together form a (CH ₂ I _n -KeUe where η 4 to 6, or one of the substituents R ₃ or R _{4 is} a hydrogen atom and the other is an alkyl group having 1 to 4 carbon atoms, and their pharmaceutically acceptable salts.

These compounds give a surprisingly good effect as spinal anesthetics. They are more stable than tetracaine and, at least when R ₁ and R _{2 are} methyl groups, can be autoclaved without appreciable degradation. Preferred compounds of the invention are those wherein the groups R ₁ , R ₂ , R ₃ and R _{4 are} all alkyl groups. Particularly preferred is the compound wherein the groups R ₁ and R * are both methyl groups and R ₃ and R _{4 taken} together are pentamethylene.

Preferred salts according to the invention are pharmaceutically acceptable salts. The Hydrochloric) is particularly preferred for injection solutions. However, for topical application, the free base is preferred.

The compounds are prepared as follows:

A haloalkylcarboxylic acid of the formula II is dissolved together with 2,6-dimothylphenol in dichloromethane, after which trifluoroacetic anhydride is added. The resulting 4-halo-butyrate of Formula III is reacted in the next step with the appropriate amine to give a compound of Formula Γ wherein R _{1 is} as defined above and R ₃ and R _{4 are the} same or different alkyl groups of 1 to 3 carbon atoms or taken together form an alkylene chain with up to 6 carbon atoms. The resulting compound is dissolved in tetrahydrofuran, the solution is added dropwise to J-Pr ₂ -NLi (lithium diisopropylamide) in tetrahydrofuran. Methyl iodide is added and the mixture is hydrolyzed. The resulting product is a compound of formula I "wherein R3 and R 'are as defined in formula I'. In the case where a compound of formula Γ" is desired, ie a compound wherein one of R ₃ and R ₄ is a hydrogen atom and the other substituent is an alkyl group having 1 to 4 carbon atoms, the compound of the formula I "in which one of the substituents R ₃ and R _{4 is} a benzyl group and the other is an alkyl group as defined above is more than 5% Pd / C is hydrogenated to give the compound Γ ".

The preparation described above can be illustrated by the following reaction scheme:

CH 0

XCH "CH _? CH -C-

OH

- OH

CH.

(CF ₃ CO) ₂ O

.1

CHCH CH X 2 2

III + R (R) NH

0 R ₁ 0 C-CHCH ₂ CH

CH

¹¹

1) IPr ₂ NLi

2) CH ₃ I

3 CH.

O CH ₃ O CC CH ₂ CH ₂ N

CH,

CH.

I "

5% Pd / C

O CH ₁ Il I ^J

OC-C - CH, CH ₀ N

The compounds of the formulas Γ, I "and Γ" are summarized above as formula I.

embodiments

Examples 1 to 5

a) Preparation of the haloalkylcarboxylic acids (II)

The haloalkylcarboxylic acids (II) were prepared from the corresponding butyrolactone according to Olah et al. (Synthesis 1982, page 963). The crude acids were used without further purification in the following step.

b) Preparation of 4-halobutyrate (III)

The crude acid II (from 25 μmol of γ-butyrolactone) was dissolved together with 2,6-dimethylphenol (30.5 g, 25 μmol) in 100 ml of dichloromethane, after which 100 ml of trifluoroacetic anhydride were added. The reaction mixture is allowed to stand overnight at room temperature. It was then evaporated, the residue was dissolved in diethyl ether, the ether solution was washed repeatedly with aqueous sodium bicarbonate solution until neutral, then dried over magnesium sulfate. The ether was evaporated and the residue was distilled.

c) 2,6-dimethylphenyl-4-iodobutyrate

From the γ-butyrolactone, yield 80% of the ester, bp 120-125 ° C (0.02 mm Hg). The product contains about 26% of the corresponding bromine derivative according to GC. MS (Ci ₂ Hi ₆ IO ₂ ): M ⁺ 318, base peak 122 (2,6-dimethylphenol).

d) 2,6-dimethylphenyl-4-bromobutyrate

From the γ-butyrolactone, yield 73% ester, bp 118 to 122 ⁰ C (0.6 mm Hg). MS (C ₁₂ H ₁₆ BrO ₂ ): M ⁺ 270/272, base peak 122 (2,6-dimethylphenol).

e) 2,6-dimethyl-4-bromo-2-methyl butyrate

From a-methyl-Y-butyrolactone, yield 80% ester, b.p. 115-125 ° C (0.15-0.25 mm Hg). MS (C ₁₃ H ₁₇ BrO ₂ ): M ⁺ 284/286,

Base peak 122 (2,6-dimethylphenol).

f) Preparation of end products in which R | H and R _{2 is} H or CH ₃

A mixture of a 4-Halogenbutyrates (III) (2OmMoI), the appropriate amine (44mMol) and toluene (40ml) was heated at 80 to 9O ⁰ C until most of the halogen compound hattu responding. The implementation was followed by GC. The precipitated salt was filtered off, the toluene solution was extracted with excess dilute hydrochloric acid, the extracts were washed with diethyl ether and then made alkaline with dilute aqueous sodium hydroxide solution. The precipitated base was extracted with ether, the combined ether extracts were washed with water and dried over MgSO ₄ . In some cases, the base was distilled prior to conversion to the hydrochloride. Characteristic values for the various compounds can be found in Table I.

Table I

OCC-CH ₀ -CH ₉ - N '

connection Ri R ₂ R ₃ - (CH ₂ I ₆ - R4 F. as hydro No. chloride 1 H H C ₂ H ₆ C ₂ H ₆ 139-141 2 H H - (CH ₂ ) (T- 208-211 3 H H C ₃ H ₇ C ₃ H ₇ 103-105 4 H CH ₃ C ₂ H ₆ C ₂ H ₆ 110.5 to 112.5 5 H CH ₃ - (CH ₂ J ₆ - 160-164 6 CH ₃ CH ₃ CH ₃ CH ₃ 184-186 7 CH ₃ CH ₃ C ₂ H ₆ C ₂ H ₆ 140-142 8th CH ₃ CH ₃ 215-218 9 CH ₃ CH ₃ H - (CH ₂ I ₄ - C ₂ H ₆ 179 to 181.5 10 CH ₃ CH ₃ C ₂ H ₆ - (CH ₂ J ₄ - C ₃ H ₇ 11 H CH ₃ C ₂ H ₆ - (CH ₂ I ₆ - C ₃ H ₇ 12 CH ₃ CH ₃ - (CH ₂ J ₆ - 13 H CH ₃ 14 CH ₃ CH ₃ 15 H CH ₃

Compounds 1 to 5 and 11, 13 and 15 were prepared as described above.

The preparation of compounds 6 to 9 is described below in Examples 6 to 9. Compounds 10, 12 and 14 were prepared according to Examples 8 or 6.

Example 6

2,6-dimethylphenyl-2,2-dirnethyl-4-dimethylarninobutyrat

11,76g (5OmMoI) 2, e-dimethylphenyl-4-dimethylaminobutyrat with a Kp. Von87 to 92 ⁰ C (0.01 mm Hg) in 10 ml of THF were added to a solution of 140ml (6OmMoI) 0.433M 1-Pr ₂ NLI in hexane, diluted with 150 mL of THF, in a flame-dried flask purged with nitrogen and cooled to -65 ° C. After half an hour, 7.8 g (55 mmol) of methyl iodide in 15 ml of THF was added dropwise with stirring, after which the temperature of the

Reaction mixture for 2 h -40 ⁰ C reach.

The 2,6-dimethylphenyl-4-dimethylaminobutyrate was prepared as described above. However, the preparation had to be done in an autoclave.

The above reaction mixture was again cooled to -65 ⁰ C, after which a further 140 ml of 0.433 M J-Pr ₂ NLi in hexane, diluted with 150 m! THF, were added. After 45 min, another 7.8 g of methyl iodide in 15 ml of THF followed.

When the temperature of the reaction mixture after 2 h -40 ⁰ C had reached, the mixture with 50ml of saturated aqueous

Hydrolyzed sodium sulfate solution, and the organic phase was separated and dried over MgSO ₄ . The solvent

was evaporated, the residue was dissolved in dilute hydrochloric acid, the acid solution was washed twice with diethyl ether and then made alkaline with dilute sodium hydroxide solution. The base was extracted with dichloromethane and the extracts were dried over MgSO ₄ . The solvent was evaporated and the base converted to the hydrochloride with hydrochloric acid in diethyl ether. Yield 7,7g. Two recrystallizations from acetone gave 5.35 g with mp 184-186 ⁰ C.

Example 7

2,6-dimethylphenyl-2,2-dimethyl-4-di9thylaminobutyrat

This compound was prepared in the same manner from 7.90 g (30 mmol) of 2,6-dimethyl-4-diethylaminobutyrate and in total 168 mL (72 mmol) of 0.433 M 1-Pr ₂ NLi in hexane and 9.4 g (66 mmol) of methyl iodide. as described above for 4-dimethylaminobutyrate (compound 6). However, the crude base was distilled prior to conversion to the hydrochloride to give 6.21 cc of 95-102 ° C at 0.01 mm Hg. The hydrochloride was recrystallized three times from ethyl acetate to give 3.22 g with mp 140-142 ⁰ C.

Example 8 2,6-Dimethylphenyl-2,2-dimethyl-4-piperidinobutyrate

112ml (48mnMol) a solution of 0.433 M i-PRjNLi in hexane was added to 110mI THF (dry) at -65 ⁰ C was added. The base of 12.7 g (38 mmol) of 2,6-dimethylphenyl-2-methyl-4-piperidinobutyrate dissolved in 10 ml of THF was then added dropwise and the mixture was stirred at -65 ° C for half an hour. After adding 6.54 g (46 mmol) of methyl iodide in 10 ml of THF, the reaction mixture was stirred overnight while maintaining room temperature with the cooling bath. The mixture was hydrolyzed with 50 ml of saturated aqueous sodium sulfate solution. The organic phase was separated and dried over MgSC ₄ . The solvent was evaporated, the residue was dissolved in 100 ml of acetone and then a slight excess of a solution of HCl in ether was added. Yield 9.30 g of the hydrochlorides with F.214 to 217 ° C. Recrystallization from acetone yielded 8.0 g with 215 to 218 F. ⁰ C. The base was obtained from the hydrochloride in the usual way and distilled. Bp 120 to 13O ⁰ C at 0.01 mm Hg.

Example 9

a) 2,6-Dimethylphenyl-2,2-d] methyl-4- (benzylethylamino) butyrate

Like the piperidino compound (Compound 8), this compound was prepared from 12.0 g (32 mmol) of crude 2,6-dimethylphenyl-4- (benzylethylamino) -2-methyl butyrate, 90 mL (36 mmol) of 0.4OM 1-Pr ₂ NLi in hexane and 5.0 g (35 mmol) of methyl iodide. The crude base (11.6 g), 90% pure by GC, was used in the next step without further purification.

b) 2,6-dimethylphenyl-2,2-dimethyl-4-ethylaminobutyrate

The crude 4- (benzylethylamino) butyrate was dissolved in 50 ml of ethanol, 6 ml of 2N aqueous hydrochloric acid added, and the mixture hydrogenated over 1.2 g of 5% palladium on carbon at 40 ° C for 3 hours. The catalyst was removed by filtration and the filtrate was freed of solvent. The crystalline portion of the residue was recrystallized twice from acetonitrile to give 1.70 g of hydrochloride with mp 179-181.5 ° C.

Pharmaceutical preparations

dissolved, which is suitable for injections. The preparations used are aqueous solutions containing between 2.5 and 40.0 mg / ml of the active ingredient, calculated as the hydrochloride salt. Examples of topical preparations containing the base form or other suitable forms, especially pharmaceutically acceptable salts of the active ingredient, are solutions and disperse systems such as emulsions, microemulsions, suspensions, liposomes, micelles, etc. The active ingredient may also be in various types of films, strips etc. are included.

Biological studies

spinal anesthesia

The compounds of the invention were tested in mice for spinal anesthesia. The reference connections.

Lidocaine and tetracaine and the compound of the formula

Ref)

were also tested. The results are shown in the following Table II. Table III shows the acute toxicity (iv LDs ₀ ) in the

Mouse. The result of a rat local anesthetic test is shown in Table IV. tables

Spinal anesthesia (subarachnoid) in the mouse. Groups of 6 mice were injected with 5μl of test solution. The mean time to onset of blockage (in seconds) and mean duration (minutes ± standard deviation) of motor blockage were calculated from the number of blocked paws (N = 12). Blocking frequency was 100% in all experiments.

connection 1% start duration Ar No. 10 12.3 ± 0.6 16 1 10 16.8 ± 1.1 9 2 15 14.9 ± 0.5 10 3 15 20.3 ± 1.2 8th 4 9 38.8 ± 0.8 8th 5 12 11.5 ± 0.4 12 6 15 16.8 + 0.8 10 7 11 38.0 + 1.1 9 8th 15 12.8 ± 0.6 11 9 lidocaine 10 46.0 ± 0.8 7 tetracaine none 11 Ref. blocking * Two animals died.

2%

4%

duration

start

duration

37.8 + 1.3

49.2 ± 0.6

42.4 ± 2.6 68.9 ± 0.8

75.1 + 5.3 46.8 ± 1.0

67.2 + 2.9 90.2 ± 3.1 64.8 ± 3.6 10.2 + 0.5

13.2 ± 0.3

Table III

Acute intravenous toxicity (LD _M ) in the mouse. Each compound was grouped in at least four doses of six

Injected into mice.

21.8 ± 0.7 10 29.9 ± 0.2 5 31.1 ± 2.1 11 48.8 ± 1.4 5 49.3 ± 0.4 5 24.3 ± 0.4 10 40.1 ± 1.1 7 61.9 ± 1.1 5 24.0 ± 0.8 5 8th 65.9 ± 2.1 » 7.1 ± 0.4 10

Connection no. LD ₆₀ mg / kg iv 1 15 2 7 3 10 4 10 5 7 6 20 7 12 8th 9 9 16 lidocaine 18 tetracaine 6 Ref. 35 local anesthesia

Table IV

Corneal anesthesia in the rabbit. Each value is the mean duration (minutes ± standard deviation) of blocking after administration of 0.25 ml of the anesthetic solution to the conjunctival sac for 0.5 min.

Connection no.

Concentration%

duration

Number of animals

8 tetracaine

0.25

0.25

17.1 ± 0.6 14.1 ± 1.7

discussion

As can be seen from the values of Tables II and III, the novel compounds of the invention have good spinal anesthetic activity at low dosages and are less toxic than the compound tetracaine. A compound of the invention also has a better effect on topical anesthesia than tetracaine (Table IV). Thus compounds according to the invention are suitable both as spinal anesthetic and as locally anesthetic compounds.

The best mode of the invention, which is currently known, is the use of the compound of Example 8 in FIG

the form of their hydrochloride in injection solutions or the corresponding base in topically applied preparations.

Claims (1)

Invention claim: ι ¹ y O_C_C- CH ₉ -CH ₉ -N I \ or their pharmaceutically acceptable salts, wherein R ₁ and R _{2 are the} same or different and are hydrogen or CH ₃ groups and R ₃ and R _{4 are the} same or different and are alkyl groups having 1 to 3 carbon atoms or R ₃ and R _{4 taken} together Alkyl chain (CH ₂ J _n , wherein η is 4 to 6, or one of the groups R3 and R4 is an alkyl group having 1 to 4 carbon atoms and the other is a hydrogen atom, characterized in that a halocarboxylic acid of the general formula R ₁ O I II ι, XCH ₂ CH ₂ CH - C - OH with 2,6-dimethylphenol in the presence of Trifiuorigsigsäureanhydrid, the thus obtained 4-halobutyrate of the general formula .1 CHCH CH X with an amine of the formula R ₃ R ₄ NH to form a compound of the formula CH, III OR ₁ - O C-CHCH ₂ CH ₂ N CH in which R _{2 is} H and R _{1 is} H or CH ₃ and R ₃ and R _{4 are the} same or different alkyl groups or an alkylene group having 4 to 6 carbon atoms, or one of R ₃ and R _{4 is} a benzyl group and the other is an alkyl group having above definition, the compound thus obtained with lithium diisopropylamide and methyl iodide to a compound of the general formula CH. O CH M I 3 O CC CH ₀ CH ₉ N I ^{2 l} CH, ³ CH, are reacted, in which R ₁ and R ₂ are CH ₃ and R ₃ and R ₄ are as defined above, and finally the compound obtained, wherein ^ ₃ and R 4 represents one of the groups Ft a benzyl group and the other is an alkyl group as defined above, via 5% Pd / C to a compound of the general formula y CH ₃ 0 CHo C ₉ H