US3130227A

US3130227A - N-camphoryl-amino acetamides

Info

Publication number: US3130227A
Application number: US46886A
Authority: US
Inventors: Takahashi Torizo; Fujimura Hajime; Hamashima Yoshio
Original assignee: Chugai Pharmaceutical Co Ltd
Current assignee: Chugai Pharmaceutical Co Ltd
Priority date: 1959-08-27
Filing date: 1960-08-02
Publication date: 1964-04-21
Anticipated expiration: 1981-04-21
Also published as: GB959993A; CH411847A; DE1226570B

Description

United States Patent M 3,130,227 N-CAMPHGRYL-AMENG ACETAP/HDES Torizo Takahashi and I-lajirne Fuiimura, Sakyo-lru,

Kyoto=shi, and Yoshio Hamashima, Atsumi-cho, Atsumi-gun, Aiehi-ken, Japan, assignors to Chugai Seiyaku Kabushiki Kaisha, Tokyo, Japan, a corporation of Japan No Drawing. Filed Aug. 2, 1964 Ser. No. 46,886 Claims priority, application Japan Aug. 27, 1959 13 Claims. (Cl. 260-557) invention relates to new carnphor derivatives and to processes for the production of the same. The substances of the present invention show analgesic activity and may be used as a medicine.

According to the invention, the camphor derivatives are those in which alphaamino aliphatic acid amide or its derivatives are introduced in the 3-position of the camphor molecule, and they are expressed with the following formula;

wherein R stands for a hydrogen atom, lower alkyl or acetyl radical; R R and R stand for a hydrogen atom or lower alkyl radical, respectively.

All of these compounds may form a salt such as hydrochloride etc.

The analgesic activity of these compounds may vary more or less, depending on a manner of selection of the radicals, R R R and R but it is always excellent and has low toxicity.

The compounds in the invention are produced by the following processes in which R R R and R stand for the same radicals as those defined above unless otherwise stated.

(A) A NR R substituted-(alpha-halogeno aliphatic acid) amide is reacted with a NR substituted- 3-aminocamphor, and this process is expressed by the following equation:

wherein X stands for a halogen atom.

(B) An alpha-halogeno aliphatic acid ester is reacted with a NR substituted-3-an1-inocamphor to form a N- camphoryl-(3)- z-amino aliphatic acid ester which is subsequently reacted with a R R -su'ostituted amine, and this process is expressed by the following equation:

wherein R stands for a lower alkyl radical.

3,130,227 Patented Apr. 21, 1964 The compounds of the general formula:

which are intermediately formed in the above process (B) are new compounds when the R and R do not stand for hydrogen simultaneously.

The substances of the invention may be prepared as stated above, but these substances are convertible from one to another as shown below.

(C) The compounds of the invention in which R is hydrogen may be converted by acetylation into those in which R is an acetyl radical, and this process is expressed by the following equation:

(D) The compounds of the invention in which R is hydrogen may be converted by alkylation into those in CHCON which R is an alkyl radical, and this process is expressed by the following equation:

Alkyl R2 R4 These processes are the methods for the production of the camphor derivatives in accordance with the in-.

reaction may be preferably carried out at -150" C.

using a solvent such as d'nnethylformamide etc. and conveniently in the presence of a catalytic quantity of an I alkali in the reaction system; and the second step in which the reaction may preferably be carried out at 100-150 C. in a sealed tube using a solvent such as methanol or ethanol etc.

The process (C) may be performed by conventional procedure of acetylation.

'The process (D) may be effected by conventional procedure using as alkylation agent, for example, alkyl halogenide, dialkyl sulfate or alkyl arylsulfonate etc.

I Examples are now given to illustrate but do not restrict the processes for the production of the camphor derivatives according to the invention.

EXAMPLE 1 N-Camph0ryl-(3 -Glycine Dimethylamide petroleum ether, there is obtained as colorless columnar EXAMPLE 2 N-Camphoryl- (3 -Glycine Diethylamide 2 mols. of S-aminocamphor and 1 mol. of N,-N-diethylchloroacetamide are heated in benzene for 5 hours under reflux. After cooling, the precipitated crystals are filtered and the benzene is removed from the filtrate. The residue is distilled under reduced pressure, there is obtained N-carnphoryl-(3)-glycine diethylamide as a pale yellow oil; B.P. l64-l65 C./0.02 mm. Hg. Yield 79%.

N-camphoryl-(3)-glycine diethylamide hydrochloride are colorless needles of a melting point of 190 C.

Analysis (as C H O N -HCl): Theoretical-C, 60.64%; H, 9.22%. FoundC, 60.88%; H, 9.30%.

EXAMPLE 3 N -M ethyl-N -Cam phoryl- (3 -Glycine Amide 2 mols. of 3-methylaminocamphor and 1 mol. of chloroacetamide are heated in benzene in a sealed tube at 100 C. for 7 hours. After cooling, the reaction mixture is Washed with water, dried over anhydrous sodium sulfate and distilled to remove the benzene. When the residue is recrystallized from benzene, there is obtained colorless N-methyl-N-camphory1-(3)-glycine amide of a melting point of 139.5 C. Yield 63%.

Analysis (as C H O N Theoretical-C, 65.51%; H, 9.31%. Found-C, 65.75%; H, 9.48%.

EXAMPLE 4 N-Methyl-N-Camphoryl- (3)-Alanine Amide 2 mols. of 3-methylaminocamphor and 1 mol. of abromopropionamide are treated similarly to Example 3. On recrystallization from ether, there is obtained N-methyl-N-camphoryl-(3)-alanine amide as colorless plates of a melting point of 109 C. Yield 54%.

Analysis (as C H O N Theoretical-C, 66.63%; H, 9.95%. Found-C, 66.87%; H, 9.65%.

EXAMPLE 5 N-Methyl-N-Camphryl-(3)-Glycine Dimethylamide 2 mols. of 3-methylaminocamphor and 1 mol. of N,N dimethylchloroacetamide are heated in benzene for hours under reflux. After cooling, the liquid reaction mixture is washed with water. When the residue is distilled under reduced pressure, there is obtained N-methyl- 2N:camphoryl-(3)-glycine dimethylamide as a pale yellow oil of a boiling point of 138140 C./ 0.1 mm. Hg. Yield 68%.

Analysis (as C H O N Theoretical-C, 67.63%; H, 9.84%. FoundC, 67.49%; H, 9.92%.

Infra-red absorption shows an absorption of five-membered carbonyl at 1740 cm.-

. N-methyl-N-camphoryl-(3)-glycine dimethylarnide hydrochloride comprises short columnar crystals of a melting point of 174 C.

Analysis (as C H N O -HC1): TheoreticalC, 59.48%; H, 8.99%. FoundC, 59.72%; H, 9.17%.

4 EXAMPLE 6 N-Camph0-ryl-(3)-Alanine Dimethylamide 2 mols. of 3-aminocamphor and 1 mol. of N,N-dimethyl-ot-chloropropionamide are heated in benzene for 6 hours under reflux. After cooling, the precipitated crystals are filtered and the benzene removed from the filtrate by distillation. When the residue is then recrystallized from petroleum ether, there is obtained as colorless plates N-camphoryl-(3)-alanine dimethylamide of a melting point of 985 C. Yield 65%.

Analysis (as C H O N Theoretical C, 67.63%; H, 9.84%. Found-C, 67.85%; H, 10.06%.

EXAMPLE 7 N -M ethy l-N -Camphory l- (3 -A lanine Dimethylamide 2 mols. of 3-methylaminocamphor and 1 mol. of N,N- dimethyl-a-bromopropionamide are heated in benzene in a sealed tube at C. for 20 hours. After cooling, the

insoluble matter is filtered and the filtrate has the benzene removed by distillation. The residue is then distilled under reduced pressure, there is obtained N-methyl-N- camphoryl-(3)-alanine dimethylamide as a pale yellow oil of a boiling point of 138-140 C./0.01 mm. Hg. Yield 62%.

N-methyl-N-camphoryl-(3)-alanine dimethylamide hydrochloride comprises colorless needles of a melting point of 200 C. (decomposition).

Analysis (as C H O N -HCl): TheoreticalC, 60.64%; H, 9.22%. Found-C, 60.89%; H, 9.45%.

EXAMPLE 8 N -M ethy l-N -Cam phoryl- (3 -A lam'ne Diethylam'ide 2 mols. of 3-methylaminocamphor and 1 mol. of N,N- diethyl-a-bromopropionamide are heated in toluene for 20 hours under reflux. After cooling, the insoluble matter is filtered and the toluene is removed from the filtrate by distillation. When the residue is distilled under reduced pressure, there is obtained N-methyl-N-camphoryl- (3)-alanine diethylamide as a pale yellow oil of a boiling point of 140 C./0.01 mm. Hg. Yield 34%.

Analysis (as C H O N Theoretical-C, 70.09%; H, 10.46%. Found-C, 69.85%; H, 10.68%.

EXAMPLE 9 N-Methyl-N-Camphoryl-(3)-Glycine Ethylester 2 mols. of 3-methylaminocamphor and 1 mol. of ethyl chloroacetate are heated in dimethylformamide at 120 C. for 8 hours. After cooling, the solvent is distilled off in vacuo and the residue extracted with ether. After the ether is removed, the remainder is distilled under reduced pressure to give N-methy1-N-camphoryl-(3)-glycine ethylester as a pale yellow oil of a boiling point of 117 C./0.3 mm. Hg. Yield 68%.

N-methyl-N-camphoryl-(3)-glycine ethylester hydrochloride comprises colorless fine crystals of a melting point of 163-164 C.

Analysis (as C H O N-HCl): Theoretical- C, 59.29%; H, 8.63%; N, 4.61%. FoundC, 59.39%; H, 8.67%; N, 4.89%.

EXAMPLE 10 N -Camphoryl- (3 -A lanine Methylester pale yellow oilof a boiling point of 107109 C./ 0.2 mm. Hg.

Analysis (as C H O N) TheoreticalC, 66.37%; H, 9.15%. Found-C, 66.65%; H, 9.38%.

EXAMPLE 1 1 N -M ethyl-N -Camphryl-(3 -A [an ine M ethylester EXAMPLE 12 Theoretical N,

N-Camphoryl-(3 )-Glycine Dimerhyiamide 1 mol. of N-camphoryl-(3)-g1ycine ethylester and an excess of 40% dimethylamine in methanol are heated in a sealed tube at 100C. for hours until the yellowish green contents become colorless.

After cooling, the methanol is distilled off. When the residue is recrystallized from benzene/petroleum ether, there is obtained N-camphoryl-(3)-glycine dimethylamide as colorless columnar crystals; melting point 126 C. Yield 90% Analysis (as C H O N Theoretical-C, 66.63%; H, 9.59%. FoundC, 66.52%;H, 9.62.

The resulting N-camphoryl-(3)-glycine dimethylamide is added to methanol/hydrochloric acid and the methanol distilled oil to leave a syrup which, on recrystallization from methanol/ ether, gives N-camphoryl-(3)-glycine dimethylamide hydrochloride as flaky crystals; melting point 196 C. (decomposition).

Analysis (as C H O N -HCl-H O): Theoretical-C, 54.80%; H, 8.87%. Found-C, 54.63%; H, 8.96%.

EXAMPLE 13 N-Camplzoryl-(3 -Glycine Diethylamide 1 mol. of N-camphoryl-(3)-glycine ethylester and 1.2 mols. of die'thylamine are heated in ethanol in a sealed tube at 100 C. for 5 hours. After cooling, the ethanol is distilled off and the residue is subjected to distillation under reduced pressure to give N-camphoryl-(3)-glycine diethylamide as a pale yellow oil of boiling point of 164 165 C./0.02 mm. Hg. Yield 87%.

Ncamphoryl-(3)-glycine diethylamide hydrochloride are colorless needles of a melting point of 190 C.

Analysis (as C H O N -HCl): Theoretical C, 60.64%; H, 9.22%. Found: C, 60.51%; H, 9.39%.

EXAMPLE 14 N -M ethyl-N -C am ph0ryl-(3) Glycine Dimethylamide 2 g. of N-methyl-N-camphoryl-(3)-glycine ethylester and an excess of 40% dimethylamine in methanol are heated in a sealed tube at 100 C. for hours.

After cooling, the reaction mixture is treated similarly to Example 13 to give 1.6 g. of N-methyl-N-camphoryl- (3)-glycine dimethylamide as a pale yellow oil of a boiling point of 143-145 C./ 0.2 mm. Hg.

N-methyl-N-camphoryl-(3)-glycine dimethylamide hydrochloride as short columnar crystals of a melting point of 174 C.

Analysis (as C H O N -HCl): Theoretical C, 59.48%; H, 8.99%. FoundC, 59.59%; H, 9.15%.

6 EXAMPLE 15 N -Camph oryl- (3 -A lanine Dimethylamz'de 2 g. of N-camphoryl-(3)-alanine methylester and an excess of 40% dimethylamine in methanol are heated in a sealed tube at C. for 10 hours.

After cooling, the methanol is distilled off. When the residue is recrystallized from petroleum ether, 1.5 g. of N-camphoryl-(3)-alanine dimethylamide is obtained as colorless plates of a melting point of 98 C.

Analysis (as C H O N TheoreticalC, 67.63%; H, 9.84%. FoundC, 67.51%; H, 9.98%.

7 EXAMPLE 16 N -M ethyl-N -Camphoryl- (3) -A lanz'ne Dimethylamide 2 g. of N-methyl-N-camphoryl-(3)-alan.ine methylester and an excess of 40% dimethylamine in methanol are heated in a sealed tube at 100 C. for 12 hours. After cooling, the solvent is distilled ofl? and the residue is subjected to distillation to give 1.4 g. of N-methyl-N-camphoryl-(3)-alanine dimethylamide as a pale yellow oil of a boiling point of C./0.1 mm. Hg.

N-methyl-N-camphoryl-(3)-alanine dimethylamide hydrochloride are colorless needles of a melting point of 200 C. (decomposition).

Analysis (as C H O N -HCl): TheoreticalC, 60.64%; H, 9.22%. F0undC, 60.73%; H, 9.40%.

EXAMPLE 17 N -A cetyl-N-Camph oryl- (3 -Glycine Dimethylamide 1 g. of N-camphoryl-(3)-glycine dimethylamide is dissolved in 10 cc. of acetic anhydride and the solution is heated up on a boiling water bath for 3 hours. After cooling, the acetic anhydride is distilled oil in vacuo and impurities are removed from the residue by chromatography with an alumina column using chloroform as the solvent. On recrystallization from benzene/ ether, there is obtained N-acetyl-N-camphoryl-(3)-glycine dimethylamide as colorless needles; melting point 131 C. Yield s almost quantitative. 1

Analysis (as C H O N TheoreticalC, 65.28%; H, 8.90. Found C, 65.57%; H, 9.08%.

EXAMPLE 18 N -Acetyl-N -Cam phoryl- (3 -Glycine Diezhylamide 1 g. of N-camphoryl-(3)-glycine diethylamide is dissolved in 10 cc. of acetic anhydride and the solution is warmed over a boiling Water bath for 5 hours. After cooling, the acetic anhydride is distilled off. When the residue is recrystallized from ether/petroleum ether, there is obtained N-acetyl-N-camphoryl-(3)-glycine diethylamide as colorless needles; melting point 62 C. Yield is quantitative.

Analysis (as C H O N /2H O): Theoretical-C, 65.23%; H, 9.43%. Found-C, 65.68%; H, 9.41%.

EXAMPLE l9 N-Acetyl-N-Camphoryl- (3 )Alanine Dimethylamide 1 g. of N-camphoryl-(3)-alanine dimethylamide is dis solved in 15 cc. of acetic anhydride and the solution heated over a boiling water bath for 6 hours. After cooling, the acetic anhydride is distilled off and the residue is freed from impurities by chromatography With an alumina column using chloroform as the solvent. On recrystallization from benzene, there is obtained N-acetyl-N-camphoryl-(3 )-alanine dimethylamide as a colorless columnar crystal; melting point 215 C. Yield is quantitative.

Analysis (as C 7H23O3N Theoretical-C, 66.20; H, 9.15%. FoundC, 66.24; H, 9.29%.

EXAMPLE 20 N -M ethyl-N -Cam phoryl- (3 -Glycine Dimethylamide 2 g. of N-camphoryl-(3)-glycine dimethylamide is dissolved in methanol and the solution is mixed with 1.5 g. of methyl iodide and (then) with an excess of potassium carbonate. The mixture is subsequently heated in a sealed tube at 100 C. for hours. After cooling, the solvent is distilled off and the residue extracted with ether. When the ether layer is distilled under reduced pressure, there is obtained 1.8 g. of N-methyl-N-camphoryl-(3)-glycine dimethylamide as a pale yellow oil of a boiling point of 145 C./ 0.4 mm. Hg.

N-methyl-N-camphoryl-(3)-glycine dimethylamide hydrochloride shows a melting point of 174 C.

EXAMPLE 21 N-Methyl-N-Camphoryl-(3)-Glycine Dimezhylamide 2 g. of N-camphoryl-(3)-glycine dimethylamide is suspended in 50% methanol and 2 g. of dimethyl sulfate are slowly added to the suspension drop-by-drop with stirring While caustic soda is added so as to keep a slight alkalinity.

After standing for 3 hours with stirring, the reaction mixture is extracted with ether. When the ether layer is distilled under reduced pressure, there is obtained 1.3 g. of N-methyl-N-camphoryl-(3)-glycine dimethylamide as a pale yellow oil of a boiling point of l39l41 C./ 0.1 mm. Hg.

EXAMPLE 22 N-Methyl-N-Camphoryl-(S)-Glycine Dimethylamide 8 What we claim is: 1. A compound of the following Formula 1:

wherein R is a member selected from the group consisting of hydrogen, lower alkyl and acetyl; R R and R are members selected from the group consisting of hydrogen and lower alkyl.

. N-camphoryl-(3)-glycine dimethylamide.

N-camphoryl- (3 -glycine diethylamide.

. N-methyl-N-camphoryl-(S)-glycine amide.

. N-methyl-N-camphoryl-(3)-alanine amide.

. N-methyl-N-camphoryl-(3)-glycine dimethylamide.

. N-camphoryl-(3)-alanine dimethylamide.

. N-methyl-N-camphoryl-(3)-alanine dimethylamide.

N-methyl-N-camphoryl-(3)-alanine diethylamide. 10. N-acetyl-N-camphoryl-(3)-glycine dimethylamide. ll. N-acetyl-N-camphoryl-(3)-glycine diethylamide. l2. N-acetyl-N-camphoryl-(3 )-alanine dimethylamide. 13. A pharmaceutically acceptable addition salt of a compound of the Formula I as defined in claim 1.

References Cited in the file of this patent UNITED STATES PATENTS 2,192,894 Carswell Mar. 12, 1940 2,692,265 Bruce et al Oct. 19, 1954 2,746,901 Bruce et a1. May 22, 1956 2,901,507 Speeter et al Aug. 25, 1959 2,906,777 Denss et a1 Sept. 29, 1959 FOREIGN PATENTS 663,903 Great Britain Dec. 27, 1951 206,380 Australia Nov. 17, 1955 OTHER REFERENCES Noller: Chemistry of Organic Compounds, pub. by W. B. Saunders Co. (Phila, Pa), pages 238-240 (1951).

Claims

1. A COMPOUND OF THE FOLLOWING FORMULAI:

2. N-CAMPHORYL-(3)-GLYCINE DIMETHYLAMIDE.