DE2235667A1 - HEXAHYDROBENCE / E / INDOLDERIVATE - Google Patents

Description

DR. MOLLER-BORe DIPL.-PHYS. DR. MANlTZ DIPL.-CHEM. DR. DEUFEL DIPL.-ING. FINSTERWALO DIPL.-ING. GRÄMK0W

PATENT LAWYERS

July 20, 1972

dZbf - T 1197

Tanabe Seiyaku Co., Ltd »

Osaka, Japan

21 j Doshomachi 3-chome, Higaslii-ku

HexahydrobenzZe / indole derivatives

Priority: Japan 22 _β July 1971 No. 55098Z71

The invention relates to new HexahydrabenzZe / indole derivatives and a method of making them. In particular, the invention relates to derivatives of the formula

(ι)

wherein R is methyl or phenyl and η is the integer 1 or 2, and pharmaceutically acceptable acid addition salts thereof.

It has been found that the above HexahydrobenzZe / indolderi vate (I) and acid addition salts thereof are valuable analgesics without the risk of addiction. The analgesic effectiveness of the The derivative (I) according to the invention is that of codeine

309 809/1150

think. The analgesic efficacy and acute toxicity of the derivatives (I) on mice in comparison with codeine are shown in Table 1.

309809/1150

Table Λ

Compound Anal Fetish Efficacy E (mg / kg subcutaneous)

Hot plate Haffner acid method + Method ++ curvature

method +++

ciS ~ 3- (2-aoetyl-ethyl)

8-hydroxy-9b-n-propyl- ^^^ hhd

3H <-benz / e / indole hydrobromide

cio ~ 3- ^l> henaoyl-8-hydroxy-9b-n-propyl-1,2,3a, 4,5,9b-hexahydro-3H-benz / e / indole oxalate

cis -3 (2-benzoyl-ethyl) -13.3

10.8

bromide

Codeine 27.1

21.7

26.2

25.4-

3.0

1.5

11.5

203.3

285.1

265.6

231.2

ro ro co

cn cn cn

Remarks +; Calculated from the 50% increase in

Fußleckzeit on the hot plate at 55 ⁰ C in 50% of 10 mice.

++: Calculated from the loss of öchjnerz-

tail clamping response in 50 % of 10 mice.

+++: Calculated from the loss of acetic acid-induced curvatures in 50 % of 10 mice.

++++: Calculated from the mortality of groups of 5 mice 24 hours after subcutaneous Injection of the agent.

In addition, the hexahydrobenzene / indole derivatives (I) of the invention are practically free from the risk of addiction. Monkeys that were physically dependent on 3.0 mg / kg morphine sulfate, this was withdrawn until a moderate severity of abstinence syndrome was observed. At this point cis -3- (2-acetylethyl) -8-hydroxy-9b-n-propyl-1,2,3a, 4,5t9b-hexaliydro-3H-benz / e / indole hydrobromide subcutaneously to the monkey at a dose of 2.0; 4.0; 8.0 or 16.0 mg / kg injected. In all In these cases, no suppression of the abstinence syndrome was observed up to 6 hours after the injection.

According to the invention, the hexahydrobenz / e / indole derivatives (I) can be prepared v / ground durc'i Konde) ΐα ration of in 8-, j ;;;; ll · ,; , ■, - \ v ) .- ti tuiei'tur.i 9b-n-propyl-1,2, 3a, 4,5,9b-hexa-

hydro-3H-benz / e / indole der

309809/1 1BO

R ¹ O _ /

- II

wherein H * is hydrogen or methyl, with a compound the! formula:

X ~ (CHoO _n - ^G0R (HI)

wherein X is halogen and R and η are as defined hereinbefore, to yield in 3 »8-ötellung disubstituted 9b-n-propyl-1,2,3a" ² f-i5j9b benz / m / indole of formula!:

CH, CH ₀ CH ₀ . f T (IV)

Odd —-— χ *

-N ¹ -. (CHo) _n - 0OR

wherein the Q symbols have the meanings given above, and where, if R ^{1 is} methyl, the product IV is further subjected to a dealkylation.

The starting compound II is easily accessible. JLSi e can, for example, by condensation of 1-n-propyl-7-mebhoxy-3, ⁱ t-dihydro-2 (1H) -naphbhaLinon with chloroacetonitrile in the presence of an alkali metal hydride (eg. Potassium hydride or tabrium hydride) at room temperature in a solvent , (Z ₀ B ₀ dirnethyl sulfoxide, benzene, dioxane, dirnebhoxyethane, toluene, dimethyl formamide) and subsequent catalytic reduction of the obtained 1-n-propyl-1-gyanomebliyl-7-fliethoxy'-3,4-dihydro-2 (1li ) -naphthalinons in the presence of a catalyst (e.g. Raney nickel or ttaneycobalt) at 50 ° - IQO ⁰ C below 50 -

3 0 9 8 09/1150

Atmospheric pressure in a solvent, e.g. dioxane, Methanol, ethanol or benzene.

The condensation reaction of the compound II with the compound

III, in the presence of an inorganic base such as an alkali metal hydroxide, eg sodium hydroxide, Kaiiumhydroxid, lithium hydroxide, or an alkali metal carbonate, for example, ₀ sodium carbonate, potassium carbonate, or, be effected pyridine in a solvent an organic base, for example triethylamine. The reaction is preferably carried out at room temperature. Dimethylformamide, acetone, toluene, methanol and ii.than.oL are suitable solvents. When R ^{1 is} Lebayl , the dealkylation of the compound (IV) can be carried out in the usual way.

For example, the reaction is initiated by heating the compound

IV with hydrobromic acid, hydroiodic acid, hydrochloric acid, aluminum oh Lu- 'Ld mi -..-! · Ityr.iriLnn./d, -oci. L <. ■ · !. '.; ■ ■ leads. in: .i \> üi.ou: iijv <.i '' 1 -, 'J .iigo .Brc) iru /: ii ::.;'JLv; ου ι 'i'üaure is preferred for this purpose.

The iiexahydrobenz / e / indoldorivato I according to the invention differ η the number ?. means, can aucti hergostol Lb were made by reacting the compound Li with a compound dor formula:

IiOO - CII ₂ OII ₂ - If (Ot ^) ₃ X ¹ (V)

where λ ¹ denotes fiaLogen and R denotes the meaning indicated above

bosit / it, odor with a mixture of iJ'ormaLdohyd urwl oiner Connection of the B'ormeL:

UIU - UO - R (VI)

wherein R has the above meaning, forming a compound the formula:

309809/1 1 50

(VII)

in which the symbols have the meanings given earlier, and where, if R ^{1 is} methyl, the product VII is further subjected to dealkylation. .

The reaction of compound II with compound V may be effected in the presence of an inorganic base such as alkali metal hydroxide, such as sodium hydroxide _e, Kaiiumhydroxid or lithium hydroxide, or alkali metal carbonate, for "B _o potassium carbonate, or sodium carbonate, or an organic base, _e B _o triethylamine or pyridine, in a solvent. The reaction is preferably carried out at room temperature. Dimethylformamide, dimethyl sulfoxide, methanol and ethanol are suitable solvents. Alternatively, the reaction of the compound II or its acid addition salt can with ei ~ nem mixture of formaldehyde and the compound VI under heating at 60 ° to 80 ⁰ G in a solvent are performed !! ethanol and ethanol are suitable as solvents · when R ¹ is methyl means, the dealkylation of the product VII can be carried out in the same way as described for the compound IV *

The hexahydrobenz / e / indole derivatives I of the invention can be used for pharmaceutical purposes either as the free base or as a salt thereof. The base and salt are light can be converted into one another in a conventional manner «Pharmaceutical acceptable acid addition salts are, for example Hydrochloride, hydrobromide, perchlorate, nitrate, sulfate, phosphate, eormiat, acetate, propionate, glycolate, lactate, pyruvate,

309809/1150

Oxalate, malonate, succinate, maleate »fumarate, malate, citrate» tartrate, ascorbate, hydroxymaleinate, phenyl acetate, aminobenzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate, sulphanilate, aspartate or glutamate I hexahydrobene piezol can be used in pharmaceutical preparations in conjunction with or in admixture with a pharmaceutical excipient suitable for enteral or parenteral administration. The selected excipient should be such that it does not react with the hexahydrobenz / indole derivative I. Suitable excipients include for example gelatin, lactose, glucose, sodium chloride, starch, magnesium stearate, talc, vegetable oil, benzyl alcohol and gums. Other known excipients for medical purposes can also be used. The pharmaceutical preparation can be a solid dosage form such as a tablet, a dragee, a pill or a capsule, or a liquid dosage form such as a solution, a suspension, an emulsion. The pharmaceutical preparation can be sterilized and / or contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers. The pharmaceutical preparation can also contain other therapeutically useful substances.

·. # The following examples illustrate the invention:

example 1

7.63 6 of a 65% suspension of sodium hydride in oil are suspended in 150 ml of dimethyl sulfoxide at room temperature under a nitrogen atmosphere. The suspension is one hour at 58 - 62 ⁰ C heated and cooled therein. A solution of 3716 g of 1-n-Frop, y "l-3,4-dihydro-7-methoxy-2 (1H) -nRphthalinon in 50 ml of dimethyl sulfoxide is carried out at 15 ° -. Lifted 20 ⁰ C sur suspension The mixture is Stirred for one hour at room temperature 17.4 g of chloroacetonitrile are added dropwise

309809/1150

■ 1 2235687

toe to the mixture! 20 ° <* 30 ⁰ G added * The addition is completed in 15 minutes. The mixture obtained is stirred at room temperature for 3 hours and then for 1 hour at 50 ° G. After cooling, the reaction mixture is poured into bis water aqueous mixture is extracted with Ither the Itherextrakt is washed with water, dried and evaporated to remove the solvent the oily residue thus obtained is distilled under a pressure of 0.33 X nm _Hg% and distilling over at 160 ° ~ 178 ° G fractions are collected and crystallized with Ither. 22.8 g of 1-n-propyl-1-eyanomethyl-3,4-dihydro-7-methoxy-2 (IH) -naphthalenone are obtained. · 77 ⁰ C *.

1 g of 1-n-propyl-1-oyanomethyl-3t ^ -dihydro-7-methoxy-2 (1l) -naphthalenone are dissolved in 17 ml of dioxane 3 ml of concentrated ammonia and 1 ml of Raneyeobalt are added to the solution, and the mixture is ^{catalytically filtered at 80-95 0} ^ under a bridge of 60 atm. Then the catalyst is filtered off and the I'll step is evaporated to remove the solvent. The oily residue obtained in this way is dissolved in Ither and treated with ethanolic hydrochloric acid. 0.91 g of ci0-8-methoxy-9b-n-propyl-1:, 2,3a, 4- _t 5,9bhexahydro-3H ~ are obtained benz / e / indole hydrochloride yield 83.2%, F *: 188 - 189 ^e C «

The free base obtained from 0.7 g of cis-8-methoxy-9b-n-propyl-1 _t: 2,3ä, 4,5,9b-hexahydro-3H-benz / e / indole-hydrochloride is a mixture of 20 ml of acetone and 0.203 g of 37% formaldehyde solution added *. The mixture is refluxed for 2 hours, and then ethanolic hydrochloric acid and ether are added to the mixture, and the crystalline precipitate is crystallized from a mixture of ethanol and ither
pr opyi-1 ₁ 2 ₁
Yield ϊ 86,% _t fj I50 -

9 *

g of cis-3- (2-acetyl-ethyl) -8-methoxy-9b-n-propyl ^ 1,2,3a, 4,5 »9b-iiexahydro-3H-benz / e / indole hydrochloride are in 5 ml 48% hydrobromic acid dissolved, the solution is refluxed for 30 minutes and then evaporated to dryness under reduced pressure. Acetone is added to the residue and the resulting crystals are collected by filtration. The crystals are recrystallized from a mixture of ethanol and ether. 0.34 g of cis-3- (2-acetyl-ethyl) -8-hydroxy-9b-n-propyl-1,2,3a-4,5,9b-hexahydro-3H-benz / e / indolT are obtained. hydrochloride from F .: 115 ° - 118 ⁰ C,

Analysis: G ₁ QH ₂₈ NO ₂ Br. V2 GH ₅ COCH ₅ calc.i C-59 | 85} H "7.60;'N-3.38% found: C" 59.97 H-7.62 ; N-3.35%

Example 2

A mixture of 4 g of cis-8-methoxy-9b-n-propyl-1,2,3a, 4,5,9b-

HejLahydro-3H-benz / e / indole hydrochloride and 30 ml of 48% hydrobromic acid are refluxed for 30 minutes. Then the mixture is concentrated under reduced pressure. The residue obtained in this way is recrystallized from acetone. To give 3 "92 g of cis-8-hydroxy-9b-n-propyl-1,2,3a, 4,5 * 9bhexahydro-3H-benz / m / indole hydrobromide from F .: 159 ° - 160 ⁰ G. The free base of the product has an F .; 158 ° - 160 ⁰ C.

A mixture of 1.5 g of cis-8-hydroxy-9b-n-propyl-'1,2,3a, 4 _f 5 »9b-hexahydro-3H-benz / e / indole, 2.23 g of 2-benzoyl- ätliyl-trimethylammonium-ijodid and 675mg sodium carbonate is suspended in 8 ml dimethylformamide. At room temperature, nitrogen gas is bubbled into the mixture for 4 hours with stirring, then the mixture is poured into ice water * The crystalline precipitate is collected by filtration and the crystals are washed with water, dried and then from a mixture of tetrahydrofuran and η-hexane recrystallized. Cis-3- (2-benzoyl-ethyl) -8-hydroxy-9b-n- is obtained

- 10 -

309809/1150

propyl-1 ^, Jaj ^ j ^ fSb-liexahydro-JH-benz / e / iiiclol in the form of crystals from BV: 157 ° b 159 ⁰ O. The product is converted into the corresponding hydrochloride in the usual way and from a mixture of Recrystallized methanol and ether. 2.12 g of cis-3- (2-benzoyl-ethyl) -8-hydroxy-9b-n-propyl-1,2,3a _f ^ i5 »9b-hexahydro-3H-benz / e / indole- are obtained hydrochloria from Ϊ »: 203 ° - 205 ⁰ C. · ■.

Analysis: C ^ H ^ OgNCl ·.

calc .: 0 = 72.07 \ H »7.56; N = 3.5O% found i 0 = 72.45; H = 7.4-8; N = Y, 59%

Example 3

benz / e / indole are dissolved in 80 ml of acetone, and a mixture of 3 g of potassium carbonate and 1.87 g of phenacyl bromide is used for Solution given. The mixture is stirred at room temperature for 2/2 hours. Insoluble material is filtered off and washed with acetone. Then 100 ml of an ethereal solution containing 1 g of oxalic acid are added to the filtrate.

The crystalline precipitate is collected by filtration, washed with acetone and then recrystallized from a mixture of methanol and mineral. ... 'an receives 1.71 g cis-3-J'"hent,cyl-6-" ι, ^r dro: ry-9b-n-prop _t 7l-1,2, 3a, 4 ·, 5 » 9b-hexahydro-3H-benz / e / indole

oxalate from F .: 118 ° - 120 ⁰ O.

Analysis: G ₂ CH ₂ QO ₆ N.V2H ₂ 0

calc .: 0-66.94 ·; H = 6.74-; Ιϊ = 3.12%,

Found: 0 = 66.67;

Example 4-

10g cis-8-hydroxy-9b-n ~ propyl-1,2,3a, 4,5,9b-hexahydro-pH-benz / e / indole * -h, vdrobromide and 3 »6 g 37% formaldehyde solution become a mixture of 100 ml of acetone and 50 ml of ethanol added. The mixture is refluxed for 10 hours and then concentrated under reduced pressure. To the arrears

- 11 -

3 0-9-8-0-9 / -1-1-SQ

acetone is given. The crystalline precipitate is collected by filtration and the crystals are recrystallized from a mixture of ethanol, acetone and ether. 10.51 g of cis-3- (2-acrylic-ethyl) -8-h3rdroxy-9b-n-propyl-1.2 _t 5a, ^, 5,9b-hexahydro-3H-benz / e / indole- are obtained hydrobromide from F * * 115 * - 118 ° C * "_;

- 12 -

309809/1150

Claims (1)

Claims .... ·. - · '. ..λ - where E is methyl or phenyl and η is the integer 1 or 2 or pharmaceutically acceptable .acid addition salts thereof » 2 »" The compound of. Claim 1, wherein R is methyl. And η the number 2 means. 3 ″, compound according to claim 1, wherein R is phenyl and η the number 1 means « 4-, compound according to claim i, wherein R is phenyl and η is the number 2 . 5 * Method of making "compounds of the HO * Don
in which R / methyl or phenyl radical and η represents the number 1 or 2, characterized in that a compound of the formula - 13 - 3Q98Q9 / H wherein R ^{1 is} hydrogen or methyl, with a compound of the formula X - (CH ₂ ) _n - COR wherein X is halogen and R and η have the meanings given above, condensed and a compound of formula CH ₃ , CHpCHp ._ N- (CH ₂ ) _n - COR obtained, in which the symbols have the meanings given earlier, and where, if R ^{1 is} methyl, the condensation product is further subjected to a dealkylation. 6 · Modification of the method according to claim 5 for production of compounds of the formula HO - CH ₃ CH ₂ CH ₂ -CH ₂ CH ₂ COR where R is methyl or phenyl, thereby g e k e η η draws that one is a compound of the formula 309809/1150 wherein R * is hydrogen or methyl, with a compound of the formula. ~ 9 © RGO - CH ₂ GH ₂ - N (CH,), X ' in which X ^{1 is} halogen and R is as defined above, or with a mixture of formaldehyde and a compound of the formula CH ₃ - CO - R wherein R is as defined above, to form a compound of the formula R ¹ O - in which the symbols have the meanings given above, and, if R ^{1 is} methyl, the product obtained is further dealkylated. ■ '".. 30 9809/115 Q / ORIGINAL INSPECTED