DE2303021A1 - NORACYMETHADOL CARBAMATES AND THE METHOD FOR THEIR MANUFACTURE - Google Patents

Description

PATENT LAWYERS

DR- I. MAAS

DR. F. VOITHENLEITNER 8 MUNICH 40

SCHUISSHEIMER Snt-299-Ta. 3592201/205

88551 / X-3526

Eli Lilly and Company , Indianapolis, Indiana / V.St.A.

Noracymethadol carbamates and processes for their preparation

The invention relates to noracymethadol carbamate compounds the general formula

CH-,

ι -5

CH ₉ O

ι * ir -τ-

CH-OCR ¹

C- CH ₉ -CH-NCOR

* I I It

CH ₃ CH ₃ Y

wherein Y is oxygen or sulfur, R ^{1 is} a methyl or ethyl group and R is an alkyl group having 1 to 5 carbon atoms or a phenyl group.

The compounds of formula I are obtained by acylating or thioacylating noracetylmethadol or its propionic acid analog of formula II:

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CH ₃ O ι NH
ι CH ₀ Il CH ₃ ι ^ C-R CH - -CH-
ι ι CH ₃ ^, - ο - CH ₂

wherein R ^{1 has} the meaning given above, prepared.

Methadone (systematic name dl-4,4-diphenyl-6-dimethylamino-3-heptanone), is an analgesic substance that is normally not addictive. Therefore this offered itself Link for considering its usefulness in treating heroin addiction because it creates an opportunity for that Suppressing the symptoms that heroin addicts experience when they are deprived of heroin. During the During the weaning process, the addict can do without heroin by daily intake of methadone and still do useful work and earn a living, although doing so can make him addicted to methadone. The addict then needs no criminal acts such as burglary or assault to satisfy his habituation-based needs to commit or engage in prostitution. Methadone is administered orally and is the daily cost of doing it for an addict are much inferior to those of heroin.

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Methadone has been used as a means of treating heroin addiction however, the disadvantage that it can be administered intravenously like heroin and, when administered in this way, euphoria caused to a greater extent and is therefore more addictive than when it is administered orally. Further it is desirable to have a connection that can replace heroin in an addict, but a longer one Methadone lasts longer than methadone so that the addict does not have to be called in for treatment on a daily basis.

Methadone was invented in Germany during World War II and was brought onto the market as an analgesic in most countries around the world after the end of the war. The reduction products of methadone are alcohols called metharlols, and the acyl derivatives of these alcohols are called acymethadols. * Both the methadols and the acymethadols are very effective analgesics. The no-derivatives of methadone ("nor" denotes compounds which have a methylamino group instead of the dimethylamino group of methadone) are unstable, whereas the uro derivatives of methadols and acymethadols are quite stable. The noracymethadols are described in U.S. Patent 3,021,360. _s

For examples of alkyl groups with 1 to 5 carbon atoms, one of the meanings that R can have include methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl, t-butyl, 2-pentyl, n-aroyl, isoamyl, 3-pentyl, 3-methyl-2-butyl and 2-methyl-2-butyl.

Examples of compounds of the formula I given above include the following:

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t -Butyl-N-methyl-N- (1-methy1-3, 3-dipheny1-4-acetoxyn-hexyl) carbamate

Neopentyl N-methyl-N- (1-methyl-3,3-diphenyl-4-propionoxyn-hexyl) carbamate

sec-Amy1-N-methy1-N- (1-methyl-3,3-diphenyl-4-acetoxyn-hexyl) carbamate

n-Propyl-N-methyl-N- (1-methyl-3,3-diphenyl-4-propionoxyn-hexyl) carbamate.

It should be noted that the compounds of the above Formula I have two asymmetric carbon atoms. Therefore each compound can be in four different ways There are forms that consist of two diastereoisomeric pairs, each of which can be split into dextrorotatory and levorotatory isomers. Since it is currently not possible To ascribe an absolute spatial configuration to the diastereoisomeric pairs, they are tentatively referred to as the alpha- and beta isomers, the term alpha referring to the diastereoisomeric pair or, more precisely, the racemic pair Pair that has the lower solubility.

Both the alpha and beta-dlasterioisomeric pair can be used commercially, as both are analgesic. In the case of the alpha-dl pair, the analgesic effect is from 1-isomer causes the d-isomer to be analgesic inactive is. Although the pure alpha-1 isomer is preferably used as Analgesic or used for the treatment of symptoms associated with heroin withdrawal, but it is also uncleared alpha-dl or diastereoisomeric pair due to its Content of analgesic substance corresponding to half the content of the pure active 1-isomer for which usable for the same purposes.

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In the case of the beta-dl diastereoisomeric pair comes the beta-1 isomer the greater analgesic effect. As in the case of the alpha-dl pair, however, here too the racemate is not split Can be used as an analgesic and to remedy the symptoms associated with heroin withdrawal.

Viie mentioned earlier

the compounds of the formula I given above have an analgesic effect, which is determined by the method of Robbins, J. Am, Pharm. Assoc. (Sci. Ed.) 44, 497 (1955). When applying this Method which is a modification of the method of Davies et al, Brit. J. Pharmacol. 1, 255 (1946) is the one to be tested Analgesic administered to different groups of 4 rats each at a dose level per group of rats. One group of rats serves as a control group that is responsible for the medium used to administer the analgesic alone is administered orally. The analgesic potency of the Compounds administered is determined by the increase in the time it takes to respond to a painful stimulus compared to the The time taken for the control group of rats to respond to the same stimulus was determined. In this case, the painful one Stimulus generated by heat, with the tail of the rat with thumb and forefinger equidistant between two electrically heated rods is held.

In the following Table I are the results of the testing of exemplary compounds of the formula I as Anaigetica by the method described above. In column 1 of the table, the meaning of the substituent Y in the formula is am At the top of the table, in column 2 the meaning of the substituent R, in column 3 the orally administered dose in mg / kg, in column the time of the peak analgesic effect, i.e. the time at which the analgesic effect is measured, and in column 5 the extension of the time in seconds until the reaction of the treated group to the painful stimulus compared to the response time of the control group.

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Table I.

? 2 ^H 5

CH - O - CO - CH.

^{C 6 ^H 5> 2

C - CH ₂ - CH - N - C -

- R

R. Oral
dose
mg / kg CH ₃ CH ₃ Y Min.
Min.
Hour renewal
the time in
Sec. Y Ethyl (alpha-dl) 10.0
5.0
2.0 Plant
tlsche
sharpen
effect Min. 13.3
approx. 6.5
approx. 2.0 O Ethyl (alpha-d) 20th 3
3
3 Hour
Hour inactive O Ethyl (alpha-1) 5.0
2.5 4th Hour
Hour Max.
approx. 9.5 O Ethyl (beta-dl) 20th
10 4th
4th Min. 13.7
3.9 O Isopropyl
(alpha-dl) 20th 4th
4th Hour 7.65 O Phenyl
(alpha-dl) 20th 3 Hour
Min. 3.0 O sec-butyl
(alpha-dl)
n-butyl
(alpha-dl) 20th
20th 3 Hour 21, 9
16.3 O
O ethyl
(alpha-dl) 20th 3
3 9.55 S. 3

3 0 9 8 3 2/1199

Other compounds of the formula I have a comparable analgesic effect. In some cases, however, the Dose required to extend the time by 6.5 seconds may be slightly higher than that in the previous one Table is given. In addition, the peak analgesic effect varies slightly from compound to connection. The time of peak analgesic action is around 3 hours for some compounds and for another about 4 hours.

The analgesic effect of the compounds of the formula I can also be achieved by the methods described by Koster et al. Fed. Proc. Soc. Exptl. Biol. 18, 412 (1969) described convulsive syndrome test can be detected in the mouse.

The compounds of the formula I are relatively non-toxic in that their analgesically effective doses are very low compared to the doses at which signs of toxicity occur. In the following table II the lethal dose (LD ₅₀ ) of alpha-dl-ethyl-N-methyl-N- (1-methyl-3,3-diphenyl-4-acetoxyn-hexyl) carbamate is given for 50% of the rats . In column 1 of the table the route by which the compound is administered is given, and in column the LD _{50 is} given, which results from the mortality of different groups of rats at different dosage levels.

Table II

Toxicity of alpha-dl-ethyl-N-methyl-N- (1-methyl-3,3-diphenyl-4-acetoxy-n-hexyl) carbamate

Route of administration ^{LD 5O}

oral 116.6 ± 6.7

intraperitoneally 130.4 J 15.7

subcutaneous 656.4-43.4

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Since the compounds of the formula I are analgesic when administered orally, this type of administration is used preferred. For oral administration, the compounds can be packed in hard gelatin capsules with or without conventional pharmaceutical excipients be filled. The compounds can also be mixed with various carriers, binders, and the like and compressed into tablets. In addition, the compounds can also be in a suspension, usually in a Orally administer saline solution containing about 1% of a surfactant such as polyoxyethylene sorbitan monooleate. Further For example, the compounds can be administered intraperitoneally or subcutaneously as an aqueous suspension of the type mentioned above. The compounds are insoluble in water and do not form water-soluble salts. Therefore, they are not suitable for intravenous injection and therefore cannot be used in self-treatment like methadone. This goes without saying an essential advantage of the compounds of the formula I, because this makes abuse possible with methadone locked out.

A second advantage of the compounds of formula I is their relatively long-lasting action, which in some cases Exceeds 6 hours.

The compounds of formula I are white crystalline solids. They are generally made by the acylation of noracetylmethadol or its propionic acid analog. The preparation of these starting materials is described in US Pat. No. 3,021,36. The acylating agent is preferably a chlorocarbonate, for example ethyl chlorocarbonate and n-butyl chlorocarbonate used. The manufacturing process is explained in more detail in the following examples.

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-S-

example 1

alpha-1-ethyl-N-methyl-N- (1-methyl-3,3-diphenyl-4-acetoxy-n

hexyl) carbamate

8 g of alpha-1-noracetyliTvethadol in the form of the free base obtained from the corresponding hydrochloride salt are dissolved in a mixture of 10 ml of pyridine and 100 ml of benzene. After cooling the mixture to about 0 ⁰ C 2.4 g Xthylchlorcarbonat in 20 ml of benzene is slowly Rüh ~ ren added. After the addition is complete, stirring is continued for about 2 hours at about 0 ° C. Then the reaction mixture is poured into water. The organic layer is washed successively with dilute aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and water and dried. Removal of the solvent in vacuo gives about 8 g of a yellow oil as a residue. Chromatography of this oil on silica gel using ethyl acetate / benzene (1:10) as solvent gives about 6 g of a colorless oil which crystallizes from hexane. This crystalline product, alpha-1-ethyl-N-methyl-N- (1-methy1-3,3-dipheny1-4-acetoxy-n-hexy1) -carbamate melts at about 89 to 90 ⁰ C after recrystallization from hexane: ^ alpha /, "-35.31 ° (c" l in ethanol).

Analysis calculated: C 72.96; H 8.08; N 3.40; Found: C 72.72; H 8.19; N 3.41.

The following compounds, among others, can be established using the procedure described above:

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alpha-dl-ethyl-N-methyl-N- (1-methyl-3, 3-dir> henvl-4-acetoxy-nhexyl) carbamate, F. = 82 - 83 ⁰ C.

Analysis calculated: C 72.96; H 8.08; N 3.40; Found: C, 73.16; H 8.29; N 3.21.

beta-dl-ethyl-N-methyl-N- (1-methyl-3, 3-diphenyl-4-acetoxy-nhexyl) carbamate, F. = 95 - 96 ⁰ C.

Analysis calculated: C 72.96; H 8.08; N 3.40; Found: C, 73.13; H 8.33; N 3.68.

alpha-dl-n-Buty1-N-methy1-N- (1-methyl-3,3-diphenyl-4-acetoxy-nhexy1) carb amat. oil.

Analysis calculated: C 73.77; H 8.48; N 3.19; Found: C 74.04; H 8.23; N 2.99.

alpha-dl-sec-butyl-N-methyl-N- (1-methyl-3, S-acetoxy-n-hexyl) carbamate, F. = 61-62 C.

Analysis calculated: C 73.77; H 8.48; N 3.19; Found: C, 73.98; H 8.29; N 3.05.

Compounds of formula I for which Y is sulfur by converting alpha-dl-noracetylmethadol or alpha-I-noracetylmethadol or their propionyl or beta-dl or beta-1 analogs with thiophosgene and reaction of the intermediate formed thiocarbamyl chloride with an alcohol or phenol, R-OH, to form the desired thiocarbamate manufactured.

The alpha-dl-ethyl-N-methyl-N- (i ^ -methyl-3 , 3-diphenyl-4-acetoxy-n-hexyl) thiocarbamate synthesized according to this procedure is a high-boiling oil with the following analytical values: calc .: N 3.28; S 7.50; Found: N 3.09; S 7.49.

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All compounds described above have NMR spectra, which are consistent with the structure ascribed to them.

In addition to the procedure described in US Pat. No. 3,021,360, the noracetylmethadol used as the starting material can be used can also be prepared according to the procedure described below.

Example 2 alpha-1-noracetylmethadol

30 g of alpha-1-acetylmethadol hydrochloride are converted into the free base, which is mixed with 15 g of diethyl azodicarboxylate in 200 ml of η-hexane. The mixture is left to stand at room temperature overnight. After removing the solvent in vacuo, an oil remains which is dissolved in 200 ml of 1N aqueous hydrochloric acid. Ethanol is added to dissolve completely. Then, the mixture is heated for about 4 hours to about 1OO ⁰ C, cooled and extracted with ether. The ether layer is separated and discarded. The aqueous layer is made alkaline with dilute ammonium hydroxide and the alpha-1-noracetylmethadol free base formed is extracted with ether. The aqueous alkaline layer is extracted again with ether and the ether layers are combined, washed with water and dried. Removal of the solvent in vacuo gives about 30 g of an oil which is dissolved in ether. The ethereal solution is saturated with dry gaseous hydrogen chloride. The hydrochloride of alpha-1-noracetylmethadol thus formed is filtered off and recrystallized from an ethyl acetate-ether mixture.

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The preparation of the carbamate derivatives of noracymethadoles is based on the example of a purely optical analgesic Isomers have been illustrated, but the same preparative method can also be used for the preparation of racemic Mixtures (alpha-dl or beta-dl) can be used. The pure ones optically active noracymethadole obtained in the case of the above Reaction used as starting materials, but are usually not made from the noracymethadols themselves produced, but the separation into the optically active antipodes takes place in an earlier stage of the production of the noracymethadole. Those preferred for the preparation of the pure optical isomers of noracymethadol carbamates The procedure begins with the separation of 2,2-diphenyl-4-dimethylaminopentanonitrile into its d and 1 isomers. The raeemische The form of 2,2-diphenyl-4-dimethyl-aminopentanonitrile can be by a well-known sequence of reactions smoothly into methadone convert and this same reaction sequence is used to produce the optically active d-methadone and 1-methadone applied. The reduction of d-methadone in a stereospecific reaction by low pressure hydrogenation in the presence a platinum catalyst delivers the pure isomeric alpha-1-methadol, which is then acylated to alpha-1-acymethadol. That alpha- 1-acym.ethadol is illustrated by that illustrated in Example 2 Reaction with dietary azodicarboxylate converted into the corresponding uro derivative. A stereospecific Reduction of 1-methadone with sodium in ethanol leads to the pure optical isomer beta-1-methadol. By acylation this alcohol and subsequent reaction with dietary azodicarboxylate results in an isomer with an analgesic effect, namely beta-1-noracetylmethadol or beta-1-norpropionylmethadol.

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Claims (10)

Claims wherein Y is oxygen or sulfur, R ^{1 is} a methyl or ethyl group and R is an alkyl group having 1 to 5 carbon atoms or a phenyl radical. 2. As a compound according to claim 1 alpha-dl-ethyl-N-methyl-NM-methyl-3 _f 3-diphenyl-4-acetoxy-n-hexyl) carbamate. 3. As a compound according to claim 1 beta-dl-ethyl-N-ethyl-M- (1-methyl-3,3-dipheny1-4-acetoxy-n-hexyl) carbamate. 4. As a compound according to claim 1 alpha-1-ethyl-N-methyl-N- (1-methyl-3,3-dipheny1-4-acetoxy-n-hexyl) carbamate. 5. As a compound according to claim 1 alpha-dl-sec-butyl-N-methyl-N ~ (1-methyl-3,3-diphenyl-4-acetoxy-n-hexyl) carbamate. 309832/1199 6. Process for the preparation of the compounds according to claim 1, characterized in that one noracetylmethadol or be Propionic acid analogs of the formula II Il -CR ¹ CIl - NH ι % CIU CIL wherein R ^{1 has} the meaning given in claim 1, acylated or thioacylated. 7. The method according to claim 6, characterized in that one noracetylmethadol with ethyl, η-butyl or sec-butyl chlorocarbonate acylated. 8. The method according to claim 6, characterized in that a compound of formula II with thiophosgene and then the formed carbamyl chloride derivative with an alcohol of the formula ROH, in which R has the meaning given in claim 1, implements. 309832/1199 9. The method according to claim 7, characterized in that alpha-dl-ethyl-N-methyl-N- (1-methyl-3,3-diphenyl-4-acetoxy-n-hexyl) carbamate; beta-dl-ethyl-N-methyl-N- (1-methyl-3 3-diphenyl-4-acetoxy-n-hexyl) carbamate; alpha-1-ethyl-N-methyl-N- (1-methyl-3,3-diphenyl-4-acetoxy-n-hexyl) carbamate or alphadl-sec-butyl-N-methyl-N- (1-methyl-3,3-diphenyl-4-acetoxyn-hexyl) carbamate manufactures and wins. 10. Pharmaceutical preparation, characterized in that it is a Noracvmethadolcarbanat according to claim 1 and one contains pharmaceutically acceptable carrier. 309832/1 199