DE1695399C3 - 3-Amino-1,2,3,4-tetrahydrocarbazole and process for their preparation - Google Patents

Description

Ν — Ν

in which R, Ri and R2 have the above meaning have reacted, cyclized this compound and optionally the tetrahydrocarbazole derivative obtained in this way converted into a salt.

Zen. They can be represented by the general formula 1

in which R is a lower alkyl radical and Ri and R _{2 are} each a hydrogen atom or a lower alkyl radical.

The compounds according to the invention can be prepared by e ^; ne compound of the general formula II

NNH ₂

in which R2 has the above meaning, with a Compound of the general formula III

The invention relates to
carbazoles, which have pharmacological properties

3 °

in which R and Ri have the above meaning, too a pheny'-hydrazone of the general formula IV

40

in which R and Ri have the meaning given above to a phenylhydrazone of the general formula IV

N-N

so in which R, Ri and R2 have the meaning given above, converts, cyclizes these compounds and so obtained tetrahydrocarbazole derivative of the general formula I optionally converted into a salt

The acidic cyclizing agent can be an inorganic hydrohalic acid such as HCl, HBr or H] or a mineral acid such as H2SO4 or H3PO4, an organic acid such as acetic acid, or a Lewis acid such as BF3 or ZnCb
The S-amino-l ^ .S.'t-tetrahydrocarbazoles can be used in the form of a desired salt such as hydroctiloride, hydrobromide, malate or oxalate or the like.

The analgesic effectiveness of the compounds according to the invention was determined with the aid of the arterial clamp test after Biaηchi, C. and Franceschini, J., Experimental Observations of Haffners Method of Testing Analgesic Drugs, Brit. J. Pharmacol., 9: 280 (1954), determined and with that of the known

Compound d-propoxyphene · HCl compared. The following results were obtained:

connection
"Oh, example

Acute oral
analgesic
effectiveness

EDso
(mg / kg)

Oral
Totality

LD-, o
(mg / kg)

Therapeutic index

(LD.o / ED-, 0) extracted with CHCb After drying and concentrating the extract at atmospheric pressure and subsequent vacuum distillation , 5.09 g of a colorless liquid with a boiling point of t05-110 ° C (15 mm) were obtained.

24.5
about 40
13.2
approx. 50
44.0

562
464
316
562
178

23

12 24 Π 4

25th

«-Propoxy-

phen · HCl

From these results, it appears that the 'compounds of the invention are at least as effective as current known compound propoxyphene, j _s but less toxic and thus the therapeutic index for the novel Verbinduneen is much better than for the comparative compound.

The preparation of the compounds according to the invention is illustrated in more detail by the following examples:

example 1

3-methylamino-1,2,3,4-tetrahydrocarbazole A. 4-methylaminocyclohexanol

230 g of p-methylaminophenol sulfate were dissolved in 800 ml of aqueous methanol (1: 3). It was hydrogenated at 100 ° C. and 105 kg / cm ² pressure using 11.0 g of ruthenium dioxide as a catalyst. The hydrogenation was complete after about 2 hours. The catalyst was filtered off and most of the solvent was distilled off in vacuo. A 20% strength sodium hydroxide solution (200 ml) was added to the remaining syrup and the resulting solution was continuously extracted _{with CHCl 3 for one day.} The extract was dried and concentrated and the residue was distilled in vacuo, 125 g of the product having a boiling point of 105 ° -110 ° C. (5 mm) being obtained. The material was poured into anhydrous ether and white crystals (108 g), mp 78-79 ° C., formed. In another sample the melting point was 88-89 ° C. This difference in melting point can be attributed to different amounts of cis and trans isomers.
Analysis for C ₇ Hi ₅ NO:
Calculated: N 10.85%;
found: N 10.59%.

B. 4-methylaminocyclohexanone

To a mixture of 12.9 g (0.10 mol) of 4-methylaminocyclohexanol and 35 g of potassium tert-butoxide a solution of 90 g of benzophenone in 200 ml of benzene was added to 300 ml of dry benzene. the The mixture was stirred at room temperature under a nitrogen atmosphere for 3 days. Then there was water (200 ml) was added and the mixture was stirred vigorously for a few minutes. The benzene layer was with Portions of 100 ml of 10% HCl extracted. The combined aqueous solutions were then washed with ether extracted. After concentrating (in vacuo) the aqueous solution to about half its volume zueeeeben solid potassium carbonate to form the free base. The solution was continuous for a day

C. 3-methylamino- 1,2,3,4-tetrahydrocarbazole A solution of 15.4 g (0.121 mol) 4-methylaminocyclohexanone and 13.5 g (0.125 mol) phenylhydrazine in 200 ml benzene containing 0.1 g p -Toluenesulfonic acid was heated under reflux for 2 hours, the water released being collected in a Dean-Stark trap. After concentration of the benzene of Phenylhydrazonsirup (24.7 g) was dissolved in 300 ml of acetic acid and the solution heated for 3 hours at 90-95 ⁰ C. The acetic acid was removed in vacuo and the residue treated with dilute NaOH Lösur.g gei-ührt After _{extraction with CHCl 3} , drying and concentration in vacuo, 20.1 g of a fatty solid with a melting point of 125-129 ° C. were obtained. For analysis, a sample from benzene ether (after treatment with charcoal) was recrystallized, mp 134-135 ^C C; υ ™ in CHCl ₃ 3480 (indole-NH), 3410 (w "CH ₃ NH-), peaks at 1630 and 1600 cm- '; L · ™ m MeOH 226 nm (ε 18,500) and 280 nm (ε 5460). Analysis for Ci ₃ Hi ₆ N ₂ :

Calculated: C 78.00, H 8.05, N 14.00%; found: C 77.48, H 8.18, N 13.96%.

DS-methylamino-U ^ -tetrahydrocarbazolmaleat 11.3 g of 3-methylamino-l, 2,3,4-tetrahydrocarbazole (mp. 125-129 ⁰ C) were dissolved in acetone The solution was treated with charcoal and the clarified filtrate was treated with 1 Molar equivalent of maleic acid in the smallest possible

treated with a small amount of acetone. About half the volume of ether was added and after a few minutes the crystallization started. The product was collected, washed with acetone-ether, pulverized and dried overnight in a drying pistol after Abderhalden at 60 ° C. Yield 13.1 g, melting point 159-160 ° C., λ ™ in methanol 224 nm (ε 25 600 ) and 279 nm (ε6040).
Analysis for C ₃ Hi ₆ N ₂ (CHCO ₂ H) ₂ :

Calculated: N (basic) 4.43, N (total) 8.86%;

found: N (basic) 4.33, N (total) 8.79%.

Example 2

3-Dimethylamino-1,2,3,4-tetrahydrocarbazole A. 4- (N - Formyl-N -methyljaminocyclohexanol ⁵ ° The compound was prepared from 120 g (0.93 mol) of 4-methylaminocyclohexanol and 500 ml of formamide heated hours at 9O ⁰ C. the excess formamide was TEM-55 verminder pressure (water aspirator) on the construction Damp removed the residue was distilled in a vacuum. This gave 127.1 g (86.7%) of N-Formyldenvats Anal. WrC ₈ Hi ₅ NO ₂ :

Calculated: C 61.12, H 9.62; N 8.90; Found: C, 61.07; H 10.02; N 8.80.

/ Λ; ι ^! 0.3300-3550 cm- ¹ OH (bound); 3620 cm " ¹ - 'OH (free); 1660 cm-' amide (C = O).

B. 4- (N-Formyl-N-methyl) aminocydohexanone

To a cold solution (10 °) of NaiCrA. 2 (375.5 g, 1.3 mol) and H ₂ SO ₄ (123.4 g, 13 mol) .η «0 ml H ₂ O was an aqueous solution of 4- (N-roniiy

methyljaminocyclohexanol (98.9 g, 0.65 mol) was added dropwise over the course of one hour. The solution was extracted with CHCl3 until the extract was colorless. The CHCl ₃ exhaust train was dried, filtered and concentrated in vacuo. The residue was distilled under reduced pressure. 52.6 g were obtained, bp 128 ° -134 ° / 0.2 mm. A further 13.1 g, bp 128 ° -134 ° / 0.2 mm were obtained by continuously extracting the aqueous phase with ethyl acetate for 18 hours. Overall yield 65.7 g (65%).

IR: v ™ ^ i675cm- • amide (C = O); 1725 cm- 'ketone (C = O).

C. 3- (N-Formyl-N-methyl) amino-1,2,3,4-tetrahydrocarbazole

A solution of 23.6 g (0.15 mol) 4- (N-formyl-N-methylaminocyclohexanone, 18.4 g (0.17 mol) phenylhydrazine and 200 ml glacial acetic acid was ^{heated to 100 °} C. for 3 hours. The solvent was heated removed in vacuo. The residue was dissolved in the smallest possible amount of CHCl ₃ and poured onto a column of magnesium silicate (Florisil). The tetrahydrocarbazole was obtained by eluting with ether in the first 1500 ml. Yield 31.5 g.

IR :, ™ ^cl '3475 cm ^-1 NH (free); 3300 cm ¹ NH (bound); 1660 cm - 'amide (C = O).

D. S-Dimethylamino-l ^^ - tetrahycrocarbazole hydrochloride

A solution of 13.5 g (0.06 mol) of the abovementioned compound in 50 ml of THF was added dropwise with stirring to a suspension of 11.2 g (0.3 mol) of LiAlH ₄ in 100 ml of THF. The mixture was stirred under reflux for 18 hours. The LiAlH. " was then destroyed in the usual way. The inorganic salts were filtered off and the filtrate was concentrated in vacuo. The amine was separated from the residue by dissolving in acetone and treating with excess cyclohexanesulfamic acid. The resulting salt was filtered off, dissolved in boiling H2O and made alkaline with K2CO3. The mixture was left to stand in the refrigerator overnight, during which time the free base crystallized out. This was collected and added by adding HCl in isopropyl alcohol. converted into the hydrochloride. The hydrochloride precipitated on cooling. After one recrystallization from isopropyl alcohol, 2.8 g of the product were obtained. Mp 259-259.5 °.
Analysis for Ci ₄ HI ₉ ClN ₂ :

Calculated: N (basic) 5.58;

N (total) (Kjeldahl) 11.16.

found: N (basic) 5.70,
N (total) 10.91.

B.4-Formsidocyclohexanol

210 g4-Formamidophenol were in an autoclave with methanol as the solvent and RuO ₂ as catalysts: or (hydrogenated 15O ⁰ C, 105 kg / cm ² (psi 15G0 "The hydrogenation required 2 days for an uptake of 3 molar equivalents of the. catalyst was filtered off and the methanol was distilled off in vacuo Upon distillation of the residual oil through a short Vigreaux column to give 137 g of product, bp. 170- 175 ⁰ C (I ₁ O mm).

C 1-4 formamidocyclohexanone

A cold solution of 238.4 g (0.8 mol) of Na ₂ Cr ₂ O _7. 2 H ₂ O and 78.4 g (0.8 mol) of H ₂ SO ₄ in 200 ml of H ₂ O was added with stirring an aqueous solution of 57.2 g (0.4 mol) of 4-formamidocyclohexanol was added dropwise. The solution was stirred in the cold for 1.5 hours, then extracted _{continuously with CHCl 3 for 2 days.} The CHCb extract was _{dried over K 2} CO ₃ , filtered and concentrated in vacuo. The residue was distilled under reduced pressure. 24.9 g of the product were obtained, boiling point 145 ° -170 ° C./0.2 mm.

IR: 1 [W'-cm ^-1 3445 amide-NH; 3325 amide-NH; 1720 C = O (ketone): 670 C = O (amide).

D.S-Fermamido-g-methyl-U ^ -ietrahydrocarbazole

A mixture of 10.7 g (0.07 mol) of 4-formamidocyclohexanone, 9.3 g (0.076 mol) of 1-methyl-1-phenyihydrazine, p-toluenesulfonic acid (catalytic amount) and 200 ml of dry benzene were refluxed for 10 hours heated. The resulting H ₂ O was collected in a Dean-Starke trap. The solution was evaporated in vacuo. 17 g of a dark, viscous oil were obtained.

IR: |. ™> cm-i 1685C = O (amide); complete disappearance of C = O (ketone) at 1710; 1600 and 1500 (strong aromatic absorption); 3445 NH (amide); 3310 (NH).

10 g of the hydrazone were heated in acetic acid for 5 hours. The solvent was removed in vacuo. the residue is dissolved in CHCl ₃ , washed with Na ₂ CO ₃ solution, _{dried over MgSO 4} and evaporated in vacuo. The residue was dissolved in benzene and poured onto a magnesium silicate (Florisil) column. The tetrahydrocarbazole was eluted with ethyl acetate. 9.4 g were obtained in this way. The compound was recrystallized from acetone-pentane. Mp 219-220 ° C
Analysis for Ci ₄ H ₁₅ N ₂ O:

Calculated: N 12.32.

found: N 12.40.

Example 3

E.

carbazole

A. 4-Formamidophenol

A solution of 10.9 g (0.1 mol) of p-aminophenol in 25 ml of 97% formic acid was refluxed for 1 hour. The formic acid was removed in vacuo and 100 ml of H ₂ O were added. Upon cooling, the product deposited as a white powder. Yield 10.7 κ. Fd. 138-139'C.

carbazole maleate

A solution of 9.4 g (0.041 mol) of 3-formamido-9-methyl-l ^ J ^ -tctrahydrocaibazole in THF was added with stirring to a suspension of 7.96 g (0.21 mol) of LiAlH ₄ in 100 ml of TIiF. The mixture was then refluxed overnight. The excess hydride was destroyed in the usual way, the inorganic salts were filtered off and the filtrate was concentrated in vacuo. The maleate was made in acetone solution and by adding dry ether

failed. The salt was recrystallized from acetone-ether. 2.2 g of the product were obtained, mp 193-194 ° C.
Analysis for C ₁₄ Hi ₈ N ₂ · C ₄ H ₄ O ₄ :

Calculated ·, C 65.39; H 6.71; N 8.48.

Found: C, 65.36; H 6.86; N 8.44.

Example 4

3- (2-propyl) amino-1,2,3,4-tetrahydrocarbazole
A. 3- (2-propyl) amino-1,2,3,4-tetrahydrocarbazole

10 g of S-amino-l ^^ - tetrahydrocarbazole were refluxed in 300 nil acetone for 24 hours. The solvent was evaporated in vacuo. The infrared spectrum showed a band at 1675 cm ^-1 (C = N). The residue was dissolved in ethanol and hydrogenated on a Parr shaker with a platinum catalyst (3.52 kg / cm ² (50 psi)). The calculated amount of hydrogen was absorbed in 3 hours. The infrared spectrum of the residue obtained on evaporation of the ethanol solution showed that the band at 1675 cm- ^{1 had} completely disappeared. The free base solidified upon stirring with ether.

B. 3 (2-propyl) amino-1,2,3,4-tetrahydrocarbazole maleate

The free base was dissolved in Acton and treated with a slight excess of maleic acid. When ethyl acetate and ether were added, the salt precipitated and was recrystallized from a mixture of isopropyl alcohol, ethyl acetate and ether. 5.6 g of the product were obtained, melting point 188 ° -189 °.
Analysis for Ci9H2 ₄ N2O ₄ :

Calculated: N (basic) 4.07; N (total) 8.14.
found: N (basic) 4.05; N (total) 8.29.

Claims (2)

Patent claims: 1. a-Amino-l ^^ - Tetrahydrocarbazole of the general Formula I. in which R is a lower alkyl radical and Ri and R2 each represent a hydrogen atom or a lower alkyl radical and their salts with pharmaceutical harmless acids. 2. Process for the preparation of the compounds according to claim 1, characterized in that one a compound of the general formula II in a manner known per se NNH, in which R2 has the above meaning, with a Compound of the general formula HI