CN1045260A - Novel local narcotic compound and preparation method thereof - Google Patents

Novel local narcotic compound and preparation method thereof Download PDF

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CN1045260A
CN1045260A CN90101085A CN90101085A CN1045260A CN 1045260 A CN1045260 A CN 1045260A CN 90101085 A CN90101085 A CN 90101085A CN 90101085 A CN90101085 A CN 90101085A CN 1045260 A CN1045260 A CN 1045260A
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compound
formula
preparation
alkyl
anesthesia
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施文·本特·阿费德·阿克曼
鲁尼·弗纳·桑德堡
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AstraZeneca AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The formula I compound and the pharmacologically acceptable salt thereof that supply toponarcosis to use, and their preparation method, pharmaceutical preparation and application.

Description

Novel local narcotic compound and preparation method thereof
The present invention relates to novel local narcotic compound, its preparation method and the application in useful in preparing drug formulations thereof.
Tetracaine is one of the most frequently used local anesthetic, especially to spinal anesthesia and surface anesthesia.But this narcotic has some shortcoming.Because the danger of toxigenicity effect is arranged, it is about 1% that its working concentration can not be higher than, and require to have the anesthesia than long duration sometimes, but this effect can not reach with tetracaine, and in addition, tetracaine is facile hydrolysis in the aqueous solution.
By English Patent 1102011 more known local anesthetics, these narcotic are N, and N-two replaces the disubstituted benzenes phenolic ester of a-amino acid.Brancaccios and Larizza A have also narrated some similar compounds (Farmaco Ed.Sci.19:986,1964).By the table 2 of this paper back as seen, these compounds are not good especially as the spinal anesthesia agent, in the table 2 a kind of compound described in the Farmaco Ed.Sci and novel cpd of the present invention contrasted.
Have now found that to have the compound of following formula I and the effect that pharmacologically acceptable salt has the good spinal anesthesia agent of accident thereof.These new compounds are more stable than tetracaine, at least at R 1And R 2Can carry out autoclaving during for methyl and not render a service reduction.Compound of the present invention is limited by the following formula I:
R wherein 1And R 2Identical or different, be hydrogen or CH 3;
R 3And R 4Identical or different, be the alkyl of 1-3 carbon atom; Or
R 3And R 4Form (CH together 2) nChain, wherein n is 4-6; Or R 3And R 4In have one for hydrogen, another is the alkyl of 1-4 carbon atom.
Preferred The compounds of this invention is those R 1, R 2, R 3And R 4Each group is the compound of alkyl.
Particularly preferably be R 1And R 2Group all is a methyl, R 3And R 4Form the compound of pentamethylene together.
Preferred salt of the present invention is pharmacologically acceptable salt.With regard to injection liquid, particularly preferably be hydrochloride.But with regard to use on the surface, the preferred bases form.
Preparation
Above-mentioned formula I compound prepares by following method:
With the haloalkyl carboxylic acid and 2 of formula II, the 6-xylenol is dissolved in the methylene dichloride together, adds trifluoroacetic anhydride then.Next step makes the 4-halo butyric ester of resulting formula III and suitable amine reaction, obtains formula I ' compound, wherein R 1As above limit R 3And R 4Be the alkyl of an identical or different 1-3 carbon atom, or form the alkylidene chain of 4-6 carbon atom together.The gained compound is dissolved in the tetrahydrofuran (THF), and it is added drop-wise to i-Pr 2The NLi(lithium diisopropylamine) in the tetrahydrofuran solution.Add methyl-iodide and make the mixture hydrolysis.Products therefrom is formula I " compound, wherein R 3And R 4Suc as formula I ' defined in.If obtain formula I ' " compound, i.e. R 3And R 4In have one for another compound of hydrogen, then with R for the alkyl of 1-4 carbon atom 3And R 4In have one for benzyl another is the formula I of alkyl as defined above " compound, with 5%Pd/C carry out hydrogenation as catalyzer and obtain chemical compounds I ' ".
Above-mentioned preparation method can illustrate with following reaction formula:
Figure 901010855_IMG8
Above-mentioned formula I ', I " and I ' " compound is referred to as formula I compound.
The preparation of haloalkyl carboxylic acid (II)
Haloalkyl carboxylic acid (II) prepares (Synthesis 1982,963) by people's such as Olah method by corresponding butyrolactone.Crude acid promptly is used for next step without being further purified.
The preparation of 4-halo butyric ester (III)
With crude acid II (being made by the 250mmol butyrolactone) and 2, (30.5g 250mmol) is dissolved in the methylene dichloride (100ml) the 6-xylenol together, adds trifluoroacetic anhydride (100ml) then.With reaction mixture in kept at room temperature overnight.Evaporation then, residue is dissolved in ether, and ethereal solution is neutral with the sodium bicarbonate aqueous solution repetitive scrubbing until ethereal solution, uses dried over mgso then.Steam ether, resistates is distilled.
4-sulphur is for butyric acid 2,6-3,5-dimethylphenyl ester
Make ester by butyrolactone, productive rate is 80%, bp120-125 ℃ (0.02mmHg).Record by gas-chromatography and wherein to contain about 26% corresponding br-derivatives.MS(C 12H 15IO 2): M +318, base peak 122(2,6-xylenol).
4-bromo-butyric acid 2,6-3,5-dimethylphenyl ester
Make ester by butyrolactone, productive rate is 73%, bp118-122 ℃ (0.6mmHg).MS(C 12H 15BrO 2): M +270/272, base peak 122(2,6-xylenol).
4-bromo-2-Methyl Butyric Acid 2, the 6-dimethyl esters
Make ester by the Alpha-Methyl butyrolactone, productive rate is 80%, bp115-125 ℃ (0.15-0.25mmHg), MS(C 13H 17BrO 2): M +284/286, base peak 122(2, the 6-xylenol).
R 1Be H, R 2Be H or CH 3The preparation of end product
With 4-halo butyric ester (III) (20mmol), the mixture of suitable amine (44mmol) and toluene (40ml) is heated to most of halide-containing and all reacts under 80-90 ℃.Utilize gas-chromatography to follow the tracks of reaction.Leach the salt that is settled out, with excessive dilute hydrochloric acid extracting toluene solution, extraction liquid washs with ether, makes it become alkalescence with dilute sodium hydroxide aqueous solution then.With the alkali that extracted with diethyl ether was settled out, the ether extraction liquid washes and uses MgSO with water after merging 4Dry.Before alkali changes into hydrochloride, it is being distilled in some cases.The data of different compounds are listed in table 1 respectively.
In following table 1, provided The compounds of this invention.
Figure 901010855_IMG9
Compound number R 1R 2R 3R 4The mp hydrochloride
1 H H C 2H 5C 2H 5139-141
2 H H -（CH 2） 5- 208-211
3 H H C 3H 7C 3H 7103-105
4 H CH 3C 2H 5C 2H 5110.5-112.5
5 H CH 3-（CH 2） 5- 160-164
6 CH 3CH 3CH 3CH 3184-186
7 CH 3CH 3C 2H 5C 2H 5140-142
8 CH 3CH 3-（CH 2） 5- 215-218
9 CH 3CH 3H C 2H 5179-181.5
10 CH 3CH 3C 2H 5C 3H 7
11 H CH 3C 2H 5C 3H 7
12 CH 3CH 3-（CH 2） 4-
13 H CH 3-（CH 2） 4-
14 CH 3CH 3-（CH 2） 6-
15 H CH 3-（CH 2） 6-
Example
Compound 1-5 prepares as stated above.Compound 11,13 and 15 can be used with quadrat method and prepare.
The preparation of compound 6-9 will be described in detail in detail below.Compound 10,12 and 14 can be by compound 8 or 6 described methods are prepared.
Compound 6
2,2-dimethyl-4-dimethylamino butyric acid 2,6-3,5-dimethylphenyl ester
With the 11.76g(50mmol among the 10mlTHF) 4-dimethylamino butyric acid 2, (this compound prepares by above-mentioned end product preparation method 6-3,5-dimethylphenyl ester.But this preparation feedback must carry out in autoclave.B.p.87-92 ℃ (0.01mmHg)) be added to 140ml(60mmol with 150mlTHF dilution) 0.443M i-Pr 2In the NLi hexane solution, this solution be contained in one through flame dry and nitrogen purging and being cooled in-65 ℃ the flask.After half an hour, stir the 7.8g(55mmol that drips down among the 15mlTHF) methyl-iodide, make the temperature of reaction mixture in 2 hours, reach-40 ℃ then.
Reaction mixture is cooled to-65 ℃ again, and then adds other 140ml0.433M i-Pr with the 150mlTHF dilution 2The NLi hexane solution adds the other 7.8g methyl-iodide among the 15mlTHF again after 45 minutes.
When the temperature of 2 hours afterreaction mixtures reaches-40 ℃,, tell organic phase and use MgSO with this mixture of 50ml saturated aqueous sodium sulfate hydrolysis 4Dry.Steam solvent, resistates is dissolved in the dilute hydrochloric acid, this acidic solution is washed secondary with ether, makes it become alkalescence with diluted sodium hydroxide solution then.With this basic solution of dichloromethane extraction, extraction liquid MgSO 4Dry.Steam solvent, utilize the diethyl ether solution of hydrogenchloride to make alkali change into hydrochloride.Productive rate 7.7g.Carry out twice recrystallization with acetone and get the 5.35g product, mp184-186 ℃.
Compound 7
2,2-dimethyl-4-diethylin butyric acid 2,6-3,5-dimethylphenyl ester
This compound is by 7.90g(30mmol) 4-diethylin butyric acid 2, the 6-dimethyl esters reaches 168ml(72mmol altogether) 0.433M i-Pr 2NLi hexane solution and 9.4g(66mmol) methyl-iodide preparation, the preparation method is identical with the above-mentioned method for preparing 4-dimethylamino butyric ester (compound 6).But rough alkali distilled before changing into hydrochloride, obtained 6.21g, bp 95-102 ℃ (0.01mmHg).Hydrochloride re-crystallizing in ethyl acetate three times obtain the 3.22g product, mp140-142 ℃.
Compound 8
2,2-dimethyl-4-piperidine subbase butyric acid 2,6-dimethyl esters
Under-65 ℃ with 112ml(48mmol) 0.433M i-Pr 2The NLi hexane solution adds among the anhydrous THF of 110ml.Dropping is by 12.7g(38mmol) 2-methyl-4-piperidino-(1-position only) butyric acid 2,6-3,5-dimethylphenyl ester makes and is dissolved in the alkali among the 10mlTHF, stirs down this mixture half an hour in-65 ℃.6.54g(46mmol among the adding 10mlTHF) behind the methyl-iodide, the reaction mixture stirring is spent the night, keep room temperature with cooling bath simultaneously.With this mixture of 50ml saturated aqueous sodium sulfate hydrolysis.Tell organic phase and use MgSO 4Dry.Steam solvent, resistates is dissolved in the 100ml acetone, add slightly excessive HCl diethyl ether solution then.Obtain the 9.30g hydrochloride, mp214-217 ℃.Obtain the 8.0g product with acetone recrystallization, mp215-218 ℃.Obtain alkali by hydrochloride in due form and distill.bp120-130℃（0.01mmHg）。
Compound 9
2,2-dimethyl-4-(benzyl ethylamino) butyric acid 2, the 6-diformazan is at phenylester
This compound is by 12.0g(32mmol) rough 4-(benzyl ethylamino)-2-methyl butyl ester 2,6-3,5-dimethylphenyl ester, 90ml(36mmol) 0.40M i-Pr 2The hexane solution of NLi and 5.0g(35mmol) methyl-iodide makes, and its form is the compound (=compound 8) that contains piperidino-(1-position only).Rough alkali is 90% through gas Chromatographic Determination purity, promptly is used for next step without being further purified.
2,2-dimethyl-4-ethylamino butyric acid 2,6-3,5-dimethylphenyl ester
With rough 4-(benzyl ethylamino) butyric ester is dissolved in the 50ml ethanol, adds the 6ml2N aqueous hydrochloric acid, and this mixture carried out hydrogenation reaction 3 hours with 1.2g 5% palladium carbon down in 40 ℃.Remove by filter catalyzer, filtrate eccysis solvent.The crystallising part of residue obtains the 1.70g hydrochloride, mp179-181.5 ℃ with acetonitrile recrystallization twice.
Pharmaceutical preparation
During the preparation injection medicine preparation, new compound is dissolved in the liquid diluent that is suitable for injection.Used preparation is for containing the aqueous solution of 2.5-40.0mg/ml active compound (pressing hydrochloride calculates).That the alkali form is contained with preparation in the surface or other suitable form is the active substance of pharmaceutical acceptable salt particularly, and the example of this class preparation has solution and dispersion system, as emulsion, microemulsion, suspension agent, liposome, micella etc.Active compound can also be included in different types of film, the adhesive tape etc.
Biological test
Spinal anesthesia
With The compounds of this invention mouse is carried out the spinal anesthesia test.The compound of also having tested control compound lignocaine, tetracaine simultaneously and having had following formula
Figure 901010855_IMG10
The results are shown in following table 2.Table 3 has shown at the intravital acute toxicity of mouse (vein LD 50).Rabbit is carried out the table 4 that the results are shown in of surface anesthesia test.
Table 2: mouse spinal cord (subarachnoid space) anesthesia.With 6 mouse is one group, each group injection 5 μ l testing liquid.Number (N=12) by the retardance leg calculates mean time (second) that retardance occurs and the time length (branch ± standard error of mean) of moving retardance.The retardance frequency all is absolutely in all tests.
1% 2% 4%
Compound number time of occurrence time length time of occurrence time length time of occurrence
Time length
1 10 12.3±0.6 16 21.8±0.7 10 37.8±1.3
2 10 16.8±1.1 9 29.9±0.2 5 49.2±0.6
3 15 14.9±0.5 10 31.1±2.1 11 42.4±2.6
4 15 20.3±1.2 8 48.8±1.4 5 68.9±0.8
5 9 38.8±0.8 8 49.3±0.4 5 75.1±5.3
6 12 11.5±0.4 12 24.3±0.4 10 46.8±1.0
7 15 16.8±0.8 10 40.1±1.1 7 67.2±2.9
8 11 38.0±1.1 9 61.9±1.1 5 90.2±3.1
9 15 12.8±0.6 11 24.0±0.8 5 64.8±3.6
Lignocaine 8 10.2 ± 0.5
Tetracaine 10 46.0 ± 0.8 7 65.9 ± 2.1 *
Contrast fluent 11 7.1 ± 0.4 10 13.2 ± 0.3
Two animal deads are arranged.
Table 3: at the intravital acute intravenously toxicity (LD of mouse 50).With 6 mouse is one group, and every group at least with every kind of compound of 4 dosage injections.
Compound number LD 50(intravenously)
1 15
2 7
3 10
4 10
5 7
6 20
7 12
8 9
9 16
Lignocaine 18
Tetracaine 6
Contrast 35
Surface anesthesia
Table 4: rabbit cornea anesthesia.Each numerical value is to conjunctival sac and uses the retardance average duration (branch ± standard error of mean) of 0.25ml anesthesia liquid after 0.5 minute.
Compound number concentration time length number of animals
%
8 0.25 17.1±0.6 3
Tetracaine 0.25 14.1 ± 1.7 3
Discuss
By table 2 and 3 as seen, new compound of the present invention has good activity of spinal anesthesia under low dosage, and toxicity is lower than tetracaine.There is a kind of The compounds of this invention also to have than the better surface anesthetic effect of tetracaine (table 4).Therefore, the The compounds of this invention through selecting both had been suitable for doing the spinal anesthesia agent, was suitable for doing the surface anesthesia agent again.
Present known enforcement best mode of the present invention is to use the example 8 compound injection liquid of hydrochloride form or uses corresponding alkali to make surperficial preparation.

Claims (10)

1, formula I compound or pharmaceutically acceptable salt thereof
Figure 901010855_IMG2
R wherein 1And R 2Identical or different, be hydrogen or CH 3
R 3And R 4Identical or different, be the alkyl of 1-3 carbon atom; Or R 3And R 4Form alkylidene chain (CH together 2) n, wherein n is 4-6; Or R 3And R 4In have one to be the alkyl of 1-4 carbon atom, another is a hydrogen.
2, a kind of compound according to claim 1 is characterized in that R 1And R 2Be CH 3, R 3And R 4Alkyl for 1-3 carbon atom.
3, a kind of compound according to claim 2 is characterized in that R 1And R 2Be CH 3, R 3And R 4Form pentamethylene together.
4, a kind of pharmaceutical preparation that is used for spinal anesthesia wherein contains the pharmacologically acceptable salt of claim 1 compound.
5, a kind of pharmaceutical preparation that is used for surface anesthesia wherein contains claim 1 compound of alkali form or other suitable form.
6, the compound of claim 1 has application in the pharmaceutical preparation of spinal anesthesia effect in preparation.
7, the compound of claim 1 has application in the pharmaceutical preparation of surface anesthetic effect in preparation.
8, a kind of preparation is characterized in that according to the method for the formula I compound of claim 1, and utilize trifluoroacetic anhydride to make formula II compound and 2, the 6-xylenol reacts, thereby obtains the 4-halo butyric ester of formula III,
Then III is heated with suitable amine and to I ', I ' be a kind of formula I compound
R wherein 2Be H, R 1Be H or CH 3, R 3And R 4Be the alkylidene group of identical or different alkyl or 4-6 carbon atom, or R 3And R 4In have one for benzyl, another is alkyl as defined above; Make then I ' with i-Pr 2NLi and methyl-iodide reaction obtain I ", I " be a kind of formula I compound,
Figure 901010855_IMG5
R wherein 1And R 2Be CH 3, R 3And R 4Limit as I ' bottom, then with 5%Pd/C to I " (R wherein 3And R 4In have one for benzyl, another is alkyl as defined above) carry out hydrogenation, obtaining I ' ", I ' " is a kind of formula I compound, wherein R 1And R 2Be CH 3, R 3And R 4In have one to be the alkyl of 1-4 carbon atom, another is a hydrogen.
Figure 901010855_IMG6
9, a kind of method of bringing out spinal anesthesia comprises the pharmacologically acceptable salt of using (comprising the people) claim 1 compound of anesthesia amount to the Mammals that needs toponarcosis.
10, a kind of method of bringing out surface anesthesia comprises claim 1 compound of using (comprising the people) the anesthesia amount to the Mammals that needs toponarcosis.
CN90101085A 1989-02-28 1990-02-28 Novel local narcotic compound and preparation method thereof Pending CN1045260A (en)

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GB1102011A (en) * 1964-05-21 1968-02-07 Richardson Merrell Spa Phenol esters of amino acids
US3812147A (en) * 1970-12-22 1974-05-21 Astra Pharma Prod Acylxylidide local anaesthetics
US4025630A (en) * 1973-09-19 1977-05-24 Abbott Laboratories Anesthesia methods using benzopyrans and esters thereof as pre-anesthesia medication
ES513980A0 (en) * 1982-07-14 1983-04-16 Medichem Sa A PROCEDURE FOR OBTAINING 2- (HEXAHIDROAZEPIN) -N- (2,6-DIMETHYLPHENYL) ACETAMIDE.
FI880581A (en) * 1987-02-13 1988-08-14 Nii Farmakol Akad Med ARYLAMIDER AV -HEXAMETHYLENE-IMINO-CARBOXYLSYROR OCH DERAS HYDROCHLORIDER.

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