DE2655150A1 - NEW ORGANIC COMPOUNDS, THEIR PRODUCTION AND USE - Google Patents

Description

'β.

SANDOZ-PATENT-GMBH 7850 Loerrach

Case 100-4470

New organic compounds, their production and uses

The invention relates to cis-4a-phenyl ~ isoquinolines.

The present invention includes compounds of formula I,

-OR.

NO,

wherein (i) R _{1 represents} hydrogen or alkyl with 1 to

4 carbon atoms, R for hydrogen,

709826/103 *.

-Jt- 100-4470

" 40 '

R_ and R ₄ together represent oxygen, and R _c and R ^ represent hydrogen, or

D O

(ii) R. for hydrogen, alkyl with 1 to

4 carbon atoms, or alkanoyl with 1 to 4 carbon atoms, and R for alkyl with 1 to 6 carbon atoms, a radical of formula II,

-CH ₂ -CH = C. II

wherein R “and R _{0 are} independent of one another

/ O

Denotes hydrogen or alkyl having 1 to 4 carbon atoms, a radical of the formula III,

-CH ₀ -CH (CH ₀ ) III

2 vv 2 m

wherein m is an integer from 2 to 4, a radical of the formula IV,

where η is an integer 1 or 2, or a radical of the formula V _f

where ρ is an integer 1 or 2

709825/1032

- <X - 100-4470

and R is hydrogen, halogen, trifluoromethyl, lower alkoxy or Mean lower alkyl, amino, or di (lower alkyl) amino, and

a) either R for azido or hydroxy, and

R. for hydrogen, or

R_ and R. together for oxygen or

Methylene, and
R and R each represent hydrogen, or

b) either R_ and R together form a bond, and R. and R ₅ each represent hydrogen, or R. and R together form a bond, and R, and R_ each represent hydrogen,

ό D

with the proviso that when R is hydroxy and R is hydrogen, or when R ₃ and R ₄ together form oxygen, and

(i) if R is a radical of the formula IV, then

is η. an integer 1, or (ii) if R _? means a radical of the formula V, then

ρ is an integer 2, and

R _q is hydrogen or halogen.

Unless otherwise stated, a lower alkyl contains or alkoxy radical, preferably 2, or especially carbon atom.

If R _{1 stands} for alkanoyl, this preferably means formyl and in particular acetyl. The radical OR is preferably in the meta position.

R- preferably denotes hydrogen.

709825/1032

100-4470

If R represents alkyl, then this preferably contains 1 to 4 carbon atoms and in particular 1 to 2 carbon atoms. R_ and R _R are preferably identical and are usually both hydrogen, m is preferably 2 or 3. η is preferably 1. ρ is preferably 2. Rq is preferably in the para position, R _{g is} halogen, it is preferably in the ortho division . R _Q usually represents hydrogen or halogen. Halogen means fluorine, chlorine or bromine. Preferably the halogen atom is a fluorine or chlorine atom.

R_ preferably denotes alkyl.

If R is azido or hydroxy and R is hydrogen, then R can be in a cis-pheny! Group stand in the 4 position.

Hydrogen, then R can be in cis or trans position to

Preferably, _{R 1 and R 4} together represent oxygen or, preferably, R _{3 represents} azido and R _{4 represents} hydrogen.

The present invention also encompasses processes for the preparation of compounds of the formula I by

a) from a compound of the formula VI,

VI

709825/1032

-y-

100-4470

wherein R represents hydrogen or an alkyl group with

1 to 4 carbon atoms, and R stands for an amino protecting group, splitting off the amino protective group, a compound of the formula Ia,

wherein

'ί

Yes

N-H

has the above meaning, is obtained, or

b) by adding a compound of the formula Ia, or the corresponding compound in which the keto group is protected, alkylated, if necessary the Keto protective group is split off in the resulting product, a compound of the formula Ib,

- OR,

Ib

where R- ^ has the above meaning, and

Ri has the meaning R ₉ , with the proviso that it is different from hydrogen, or

709825/1032

100-4470

c) by adding a compound of the formula Ic,

I— OR,

Ic

No;

where R and R have the above meaning, reduced, where a compound of the formula Id,

—OR,

Id

No:

where R, and R_ have the above meaning, _r or is obtained

d) by in a compound of the formula VII,

VII

709825/1032

100-4470

where R ^ for alkyl or alkanoyl with 1 to 4 carbon atoms,

R "has the above meaning and R _{1 is} an exchangeable radical, R _{1 is} replaced by an azido group, where

a compound of the formula Ie,

Ie

wherein R., and R have the above meaning will, or

e) by converting from a compound of the formula VIII,

VIII

wherein R ₁₁ and R_ have the above meaning, and

R is a group which can be split off under the reaction conditions, alkyl or alkanoyl having 1 to 4 carbon atoms, _{1 is} eliminated, a compound of

Formula If,

709825/1032

No:

100-4470

If

wherein R ₁ and R have the above meaning, and either R ^ and Rj together form a bond, and each

ο 6

from

and

from

will, or

Hydrogen mean, or

* and R * together form a bond,

and each
_ and R _{f are} hydrogen

f) by converting from a compound of the formula IX,

IX

wherein R ~, R, R-, R ₅ and R have the above meaning, with the proviso that, when R_ and R together form oxygen, the keto group can be in free form or in protected form, and
R- _{3 is} a hydroxy protecting group, the hydroxy

protecting group R, _ splits off, where a Compound of the formula I in which R. is hydrogen is obtained, or

709825/1034

100-4470

g) by acylating a compound of the formula I in which R _{1 is} hydrogen, a ver. bond of the formula I, in which R _{1 is} alkanoyl having 1 to 4 carbon atoms, is obtained, or

h) by reducing the oxygen of the keto group of a compound of the formula Ic with methylene Wittig conditions replaced, with a compound of the formula Ig,

Ig

wherein R- has the meaning given in formula I.

and R _? have the above meaning is obtained.

The amino protective group can be split off in accordance with method a) in a manner known per se. The amino protective group can preferably be hydrolytically, in particular under acidic conditions, split off.

For example, R. can _{n is} an acyl group having 2 to 11 carbon atoms, for example, an aroyl group such as benzoyl, or an alkanoyl group acetyl loading _K indicate like. However, R ₁₀ can also mean an alkoxycarbonyl group with 2 to 6 carbon atoms or the phenoxycarbonyl group.

709825/1032

100-4470

A suitable acid is hydrochloric acid. the The reaction can take place in the presence of an inert solvent such as aqueous n-butanol. Suitable temperatures for carrying out the reaction are between 50 ° and 110 ° C.

Process b) can be carried out by methods known per se for the alkylation of a secondary amine be performed.

Suitable alkylating agents include compounds of the formula X,

where R_ has the above meaning and X stands for an exchangeable radical.

X denotes, for example, halogen, such as chlorine, bromine or iodine, or the acid residue, an organic one Sulfonic acid containing up to 10 carbon atoms, e.g. Alkylsulfonyloxy radical such as mesyloxy or an arylsulfonyloxy radical like tooxyloxy. The reaction usually takes place in the presence of an acid binding agent such as Triethylamine instead. The reaction kemn in presence an inert solvent such as methanol take place. Suitable temperatures are between 0 ° and 100 ° C.

The keto group is preferably protected. This can be an open chain or a cyclic one Ketal, thiooxoketal or thioketal act, the

709825/1032

-Jff- 100-4470

open chain or the cyclic one. Part, for example, 2 to 4 carbon atoms can contain. Such Protected forms can be freed from the protective group in a manner known per se.

Process c) can be used for the reduction of a cyclohexanone to a cyclohexanol are carried out methods known per se.

The reduction can be carried out hydrogenolytically will. A suitable catalyst for such hydrogenolysis is, for example, platinum. The procedure can be carried out for example at room temperature under normal pressure. Suitable solvents are Tetrahydrofuran and ethyl acetate.

The reduction can also be carried out with a complex hydride, e.g. with lithium aluminum hydride, sodium dihydro-bis (2-methoxyethoxyethoxy) aluminate, be carried out, however, sodium borohydride is preferably used. The reaction can be carried out with sodium borohydride in one inert solvents, e.g. in methanol. Suitable temperatures are between 0 ° to 50 ° C.

It can be assumed that the reduction is not stereospecific in that the two epimers, i.e. a compound in which the hydroxy group is cis to the 4a-phenyl group [e.g. the (4aRS, 6RS, 8aRS) isomer], and a compound wherein, the hydroxy group trans to the 4a-phenyl group [e.g. the (4aRS, 6SR, 8aRS) Isomers]. Such connections can be separated in a manner known per se, e.g. Chromatography on silica gel.

709825 / f032

100-4470

The nucleophilic substitution according to method d) can in a manner known per se in the presence of an azido anion source, e.g. as described in Example 5b, be performed.

The process preferably takes place in a polar inert solvent such as dimethyl sulfoxide or Dimethylformamide instead. The suitable temperatures are between 40 ° and 100 ° C.

The azido source can be an alkali metal azide such as sodium azide.

R .. can, for example, an alkanoyloxy group with 1 to 4 carbon atoms, or a radical R .SO-O-, wherein R .. alkyl with 1 to 4 carbon atoms, preferably methyl, or phenyl or p-alky! phenyl with 7 to 11 carbon atoms, especially p-tolyl / means to represent.

For mechanistic considerations, the azido group "of the end product will be epimeric to the group R _{1 of} the starting material.

Process e) can be carried out according to elimination reactions customary for such processes.

R ,, has the preferred meaning given above. If R. is a group that falls under the Reaction conditions can be split off, so it stands, for example, for alkyl

709825/1032

100-4470

with 1 to 3 carbon atoms or a radical R SO, in which R. has the above meaning. In this pail the final product will be a compound of the formula If, where R is hydrogen.

The reaction is preferably carried out in a polar inert solvent such as dimethyl sulfoxide or Dimethylformamide carried out. Suitable temperatures are between 40 ° and 100 ° C. The reaction can proceed as a side reaction to process e).

Process f) can be used for the splitting off of protective groups in the case of analogous phenolic derivatives known methods.

R, _ can be, for example, a protecting group, the can be split off during hydrolysis. In particular, such a group is used when R Azido means. This can be a group of the formula R .SO -, in which R .. has the above meaning, Act. The hydrolysis can be carried out by methods known for the hydrolysis of similar sulfonic acid esters will. E.g. the reaction can be carried out under basic conditions, e.g. in the presence of N-ethyl-diisopropyl-amine, be performed. Suitable temperatures are between 20 ° and 100 ° C.

On the other hand, R ₁₃ can be a group which can be split off under the conditions of the splitting off of ether. Such a group is preferably used when R- is not azido.

709825/1032

100-4470

The ether cleavage can be carried out by methods known for the dealkylation of phenyl alkyl ethers. For example, Lewis acids such as boron tribromide or aluminum trichloride, or strong mineral acids such as hydrobromic acid or hydroiodic acid can be used. Suitable temperatures here are between - 20 ° and +30 ⁰ C. A suitable inert solvent such as methylene chloride may be present.

If R_ and R. together mean oxygen, the keto group is in the starting material of the Formula IX in a protected form. The protecting group is added during the reaction or during the workup process cleaved. The keto group can be protected in the form of an open-chain or cyclic ketal, thiooxoketal or thioketal, wherein the open chain or the cyclic part, for example, may contain 2 to 4 carbon atoms. Such ge Protected forms can be released in a manner known per se. Finds the release under acidic Conditions take place, it takes place, for example, simultaneously with a dealkylation with a strong acid. Process g) can be carried out in a manner known per se by methods known for acylation. A suitable reagent for the introduction of a formyl group can be the mixed anhydride of formic acid and the acetic acid. Alkanoyl radicals having 2 to 4 carbon atoms can be obtained using the corresponding acid chlorides, bromides or anhydrides are introduced.

709825/1032

100-4470

Usually a tertiary amine such as pyridine is present. However, if R is a radical of the formula V in which R_ is amino, acidic conditions are preferably used. An inert organic solvent such as toluene can be present. Suitable temperatures lies between 10 ° and 50 ⁰ C.

Process h) can be carried out by a method known for the Wittig reaction. A suitable Wittig salt is methyl triphenylphosphonium bromide. A suitable solvent is dimethylformamide. Suitable temperatures lies between 10 ° and 70 ⁰ C.

The compounds of formula VI can be prepared by a process which is characterized in this is that you have a compound of formula XI,

XI

where R.- has the above meaning with a compound of formula XII,

XII

wherein R _{1 has the} above meaning, and

709825/1032

100-4470

Y means lithium, or MgHaI, where Hai stands for Stands for chlorine, bromine or iodine,

in the presence of a copper salt, at temperatures of - 60 ° to 0 ⁰ C, is reacted.

The reaction can take place after a copper-induced 1,4-addition at an α, β-unsaturated Ketone known method can be carried out.

The copper salt used is, for example, copper (I) iodide. Hydroquinone is preferably present in the reaction. The reaction usually takes place at temperatures of - 43 ° to 0 ⁰ C statü. The reaction usually takes place in an inert solvent such as tetrahydrofuran.

R- is preferably alkyl.

Compounds of the formula VIII in which R _{11 stands} for R SO O- and R for R or ^ ₁ / SO can be obtained by reacting a compound Id with R ₁₄ SO Cl by methods known per se.

The -OSO R group in position C _{g of} the end product and the hydroxyl group in position C of the starting product will generally have the same configuration.

It should be noted that a compound of the formula VII is a compound of the formula VIII in which R _{1 is} alkyl or alkanoyl.

709825/1032

-W-

100-4470

Compounds of the formula IX in which R is azido and R R.-SO - mean can through a nucleophile

Χ.ΓΧ it

Substitution with an azide anion in a manner analogous to process d) from a compound of the formula Villa,

villa

No;

where R
will be presented.

Around

have the above meaning, herge

Insofar as the preparation of the starting compounds has not been specifically described, these are known or by methods known per se or in analogy to the methods described here or manufactured and purified by known methods.

The compounds of the formula I can exist in racemic or optically active form. The optically active forms can in a manner known per se, such as fractional crystallization of the diastereomeric Salts are produced. According to a customary method, compounds of the formula Ia by way of their diastereomeric salts can be separated with (+) or (-) tartaric acid. Other optically active compounds of formula I can be prepared using methods b) to h) as set out above.

709825/1032

100-4470

The compounds of the formula I can be used in free form as a base or in the form of their addition salts Acids are present. Acid addition salts can be prepared from the free bases in a known manner or the other way around. Suitable acids for salt formation are fumaric acid and tartaric acid.

The compounds of the formula I and the physiologically acceptable acid addition salts of these compounds show interesting pharmacodynamic properties in animal experiments Properties on. They can therefore be used as a remedy.

In particular, they have analgesic properties. Because of their analgesic effectiveness, they can used to treat pain of various origins.

In addition, they also have an effect on the central nervous system and are due to this effect suitable as antidepressants, tranquilizers and sleeping pills.

The compounds of the formula I can be administered alone or in a suitable dosage form. the Pharmaceutical forms, for example a tablet, can be produced analogously to known methods.

The invention also relates to medicaments which contain the compounds of the formula I, as well as the Manufacture of these remedies in a manner known per se. For their production, those in the

709825/1032

- eat- - 100-4470

Auxiliary and carrier materials commonly used in pharmacy be used.

In the following examples, all temperatures are given in degrees Celsius and have not been corrected.

Unless otherwise stated, all compounds obtained are in racemic form.

709825/1032

Example 1; Octahydro-4a- (3-methoxyphenyl) -cis-6 (2H) -isoquinolinone (method a)

36.35 g (0.1 mol) 2-benzoyl-octahydro-4a- (3-methoxyphenyl) -cis-6 (2H) -isoquinolinone, 100 ml butanol, 33.1 ml approx. 37% aqueous hydrochloric acid (0 , 4 mol) and 66.9 ml of water were mixed and refluxed for 40 hours. The acidic reaction solution was extracted with hexane, made basic with aqueous ammonia, extracted with methylene chloride and the methylene chloride phases were evaporated. The title compound is obtained as a viscous oil which crystallizes as hydrogen fumarate from 2-propanol. M.p. 130 ^υ .

Separation of the optical isomers:

25.93 g (100 m mol) of octahydro-4a- (3-methoxyphenyl) -cis-6 (2H) -isoquinoline are combined with 15.01 g (100 m mol) of L (+) - tartaric acid in 40 ml of water and 160 ml Dissolved methanol warm, crystallized at 0 ° and the crystals were filtered off while cold. After three recrystallization the crystals of methanol / water (80:20) give a tartrate with the rotation value

20th
[a] P (1% in H ₂ O) = + 28 °. Analogous treatment of the

Base with D (-) - tartaric acid released from the mother liquors provides the antipodal tartrate with the

20th

Rotation value [cc] (1% in H ₂ O) = - 28 °. For further processing of the optically active materials, the corresponding bases are released from the salts by partitioning between methylene chloride / ethanol (80:20) and aqueous ammonia.

709825/1032

100-4470

The starting product is obtained as follows:

A mixture of 600 ml of abs. Tetrahydrofuran, 112.2 g (0.6 mol) 3-bromo anisole and 661 mg (6 mol) hydroquinone 278 ml of 2.2 N butyllithium solution (612 m mol) are added under nitrogen at -65 °, Maintained at - 50 ° for 30 minutes, with 57.13 g (0.3 mol) Copper (I) iodide added, stirred for 60 minutes at - 43 °, with 51.06 g (0.2 mol) of (+) - 1,3,4,7,8,8a-hexahydro-2-methyl-6 (2H) -isoquinoline mixed, warmed to 0 ° for 2 hours and left to react for 16 hours at 0 °. After moving the The resulting reaction mixture with 1.2 liters of water and 79.28 g (0.6 mol) of ammonium sulfate is the product extracted with toluene and the oily residue obtained from evaporation chromatographed on silica gel with ethyl acetate and then crystallized from methanol. Colorless crystals of 2-benzoyl ~ are obtained octahydro-4a- (3-methoxyphenyl) -cis-6 (2H) -isoquinolinone (M.p. 78 °).

Example 2: Octahydro-4a- (3-methoxyphenyl) -2- methyl cis-6 (2H) -isoquinolinone (method b)

25.93 g (0.1 mole) octahydro-4a- (3-methoxyphenyl) -eis-6 (2H) -isoquinolinone (see Example 1) are mixed with 100 ml of benzene, 11.2 ml of ethylene glycol (0.2 mol) and 8.1 ml (125 mol) of methanesulfonic acid and boiled for 3 hours with separation of water. After basic steeping with aqueous ammonia is with Methylene chloride extracted and evaporated to give

709825/1032

100-4470

♦ 30.

Octahydro-4a- (3-methoxyphenyl) -cis'-δ (2H) -isoquinolinone ketal. The ketal is abs in 50 ml. Dissolved methanol and 13.91 ml (0.1 mol) of triethylamine at 0 ° with 7.46 ml (120 mol) of methyl iodide are added and

Left to react for 1 hour at 22 °.

The reaction solution containing octahydro-4a- (3-methoxyphenyl) -2-methyl-cis-6 (2H) -isoquinolinone ethyl ketal, is mixed with 20 ml of dioxane, evaporated, the remaining oil with 100 ml of dioxane and 100 ml of 2 N aqueous hydrochloric acid are added,

Stirred for 2 hours at 40 °, made basic with aqueous ammonia, extracted with toluene and evaporated. The title compound is obtained in oily form, which can be crystallized as hydrogen fumarate Ethanol, m.p. 182 °.

The following connections can be established in an analogous manner:

(i) 2-Allyl-octahydro-4a- (3-methoxyphenyl) -cis-6 (2H) -isoquinolinone

(ii) 2-Cyclopropylmethyl-octahydrc ~ 4a- (3-methoxyphenyl) -cis-6 (2H) -isoquinolinone

(iii) 2-Cyclobutylmethyl-octahydro-4a- (3-methoxyphenyi) -cis-6 (2H) -isoquinolinone

(iv) 2- (o-Chlorophenylethyl) -octahydro ^ a- (3-methoxyphenyl) -cis-6 (2H) -isoquinolinone

709825/1032

_ 100-4470

Example 3: Octahydro-4a- (3-hydroxyphenyl) -2-methylcis-6 (2H) -isoquinolinone (method f)

To a solution of 28 g of octahydro-4a- (3-methoxyphenyl) -2-methyl-cis-6 (2H) -isoquinolinone-ethyl ketal, obtained as described in Example 2 , in 200 ml of methylene chloride is at -50 ° under nitrogen with a solution of 2 8.44 ml (0.3 mol) of boron tribromide in 100 ml of methylene chloride, stirred for 30 minutes at 0 °, at -40 ° with 50 ml of abs. Methanol is added, the reaction solution is evaporated, the residue is dissolved in 150 ml of dioxane and 200 ml of water, stirred for 1 hour at 40 °, partitioned between aqueous ammonia and methylene chloride, the organic phases on silica gel with a mixture of methylene chloride / methanol / conc. aqueous ammonia = 95 / 4.5 / 0.5 and the amorphous title compound obtained on evaporation crystallized from 2-propanol, melting point 175 °.

The following connections can be established in an analogous manner:

(i) 2-Allyl-octahydro-4a ~ (3-hydroxyphenyl) -cis-6 (2H) -isoquinolinone

(ii) 2-Cyclopropylmethyl-octahydro-4a- (3-hydroxyphenyl) -cis-6 (2H) -isoquinolinone

(iii) 2-cyclobutylmethyl-octahydro-4a- (3-hydroxyphenyl) -cis-6 (2H) -isoquinolinone

(iv) 2- (o-Chlorophenethyl) -octahydro-4a ~ (3-hydroxyphenyl) -cis-6 (2H) -isoquinolinone

70 9825/1032

100-4470

Example 4: The (4aRS, 6S R, 8aRS) - and (4aRS, 6RS, 8aRS) - epimers of decahydro-6-hydroxy-4a ~ (3-hydroxyphenyl) -2-methyl-cis-iso c hinolinone (method c)

25.94 g (0.1 mol) of octahydro-4a ~ (3-hydroxyphenyl) -2-methyl-cis-6 (2H) -isoquinolinone (Example 3) are suspended in 200 ml of methanol at 0 ° with stirring with 5.68 g (0.15 mol) of sodium borohydride and left to react for 16 hours at 22 °. After adding of 50 ml of acetone at 0 °, 39.6 g (0.3 mol) of ammonium sulfate and 200 ml of water is the reaction solution rr.with a mixture of methylene chloride / ethanol = 80/20 extracted, the organic phase evaporated and the residue after mixing with 19.02 g (0.1 mol) of p-toluenesulfonic acid hydrate and 200 ml of ethanol at 0 crystallized. The crystalline p-toluenesulfonate of the less polar (4aRS, 6SR, SaRS) ~ is obtained in this way Epimers of the title compound, m.p. 253 °.

The more polar epimer of the title compound can be obtained from the mother liquor residue by this between aqueous ammonia and methylene chloride / ethanol = 80/20 is distributed and on silica gel with a mixture of methylene chloride / methanol / conc. watery Ammonia = 80/18/2 is chromatographed. This gives the more polar (4aRS, 6RS, 8aRS) epimer than colorless, amorphous powder, which liquefies at approx. 110.

The following connections can be established in an analogous manner:

709825/1032

100-4470

(i) (4aRS, 6SR, 8aRS) and (4aRS _f 6RS, 8aRS) 2-Allyldecahydro-6-hydroxy-4a- (3-hydroxyphenyl) -cis-

isoquinoline
(ii) (4aRS, 6SR, 8aRS) and (4aRS, 6RS, 8aRS) 2-Cyclopropylmethyl-decahydro-6-hydroxy-4a- (3-hydroxy ~

phenyl) -cis-isoquinoline
(iii) (4aRS, 6SR, 8aRS) and (4aRS, 6RS, 8aRS) 2-cyclobutylmethyl-decahydro-6-hydroxy-4a- (3-hydroxy-

phenyl) -cis-isoquinoline
(iv) (4aRS, 6SR, 8aRS) and (4aRS, 6RS, 8aRS) 2- (o-chloro ~ phenethyl) -decahydro-6-hydroxy-4a- (3-hydroxyphenyl) -cis-isoquinoline

Example 5: (4aRS, 6RS, 8aRS) -6- Azido-decahydro ~ 4a- (3-hydroxyphenyl) -2-methyl-cisisoquinoline (method f)

a) 4.336 g (10 m mol) of non-polar (4aRS, 6RS, 8aRS) -decahydro-6-hydroxy-4a- (3-hydroxyphenyl) -2-methylcis-isoquinoline-p-toluenesulfonate (Example 4), 10 ml abs. Pyridine and 4.29 g (22.5 m mol) of p-toluenesulfonyl chloride are added under nitrogen 0 ° mixed and stirred for 16 hours at 22 °. Then 20 ml of toluene and 20 ml of 2N aqueous Sodium carbonate solution added, stirred for a further 15 minutes at 22, extracted with toluene and the evaporated organic phases.

b) The amorphous powder (bis-tosylate) obtained is in 10 ml of abs «dimethyl sulfoxide dissolved, mixed with 1.30 g (20 mol) of sodium azide, for 16 hours Nitrogen stirred at 70 °, between toluene and

709825/1032

100-4470

26551!

Ä.

Distributed 2N aqueous sodium carbonate and evaporated the organic phases.

c) The 4aRS, 6RS, 8aRS) -ö-azidodecahydro-4a- (3-p-tosyloxyphenyl) -2-methyl-cis-isoquinoline obtained in this way is dissolved in 10 ml of 2N methanolic potassium hydroxide solution, boiled for 60 minutes, after adding of 20 ml of toluene and 20 ml of water with carbon dioxide adjusted to a pH value between 8 and 10, distributed, the organic phases, evaporated and the residue crystallized from 2-propanol. Man receives colorless crystals of the title compound with a melting point of 198 ° (decomp.).

The following connections can be established in an analogous manner:

(i) (4aRS, 6RS, 8aRS) -2-allyl-6-azido-decahydro-4a- (3-hydroxyphenyl) -cis -isoquinoline; M.p. 125 ° (decomp.)
(ii) (4aRS, 6RSjSaRS) -2-cyclopropylmethyl-6-azido-

decahydro-4a- (3-hydroxyphenyl) -cis-isoquinoline (iii) (4aRS, 6RS, 8aRS) ^ -Cyclobutylmethyl-e-azido-

decahydro-4a- (3-hydroxyphenyl) -cis-isoquinoline (iv) (4aRS, 6RS, 8aRS) -2- (o ~ chlorophenethyl) -6 ~ azidodecahydro-4a- (3-hydroxyphenyl) -cis-isoquinoline

709825/1032

-TT- 100-4470

Example 6: 1,2,3,4,4a, 5,8,8a-Octahydr o-4a ~ (3- hydroxyphenyl) -2-methyl-cis -isoquinoline and 1,2,3,4,4a , 7,8,8a-octahydro-4a- (3-hydroxy phenyl) -2- meth yl-cis- iso quinoline (method e)

(4aRS, 6SR, 8aRS) "Decahydro-6 ~ tosyloxy ~ (3-tosyloxyphenyl) -2-methyl-cis -isoquinoline (see Example 5 a) are in 10 ml of absolute dimethyl sulfoxide and 1 ml of N-ethyl-diisopropylamine at 70 ° for 16 hours heated under nitrogen and then partitioned between toluene and 2N aqueous sodium carbonate solution. the organic phase is concentrated by evaporation and on silica gel with acetone / triethylamine (99: 1) chromatographed, whereby first 1,2,3,4,4a, 5,8,8a-octahydro ~ 4a- (3-hydroxyphenyl) -2-methyl-cisoquinoline, M.p. 159 ° (from toluene / methylene chloride) and then 1,2,3, 4, 4a, -7, 8, 8a-octahydro-4a ~ (3-hydroxyphenyl) -2-methyl-cis-isoquinoline, Sir.p. 183 ° (from Toluene / methylene chloride) is obtained.

Example 7: 4 a- (3-Acet qxyphenyl) -octahydro-2-methylcis-6 (2H) -isoquinolinone (method g)

To a mixture of 5.19 g (20 mol) of octahydro-4a- (3-hydroxyphenyl) -2-methyl-cis-6 (2H) -isoquinolinone (see Example 3), 3.22 ml (40 mol) Pyridine and 20 ml of toluene v / earth at 5 ° with stirring, 3.77 ml (40 mol) of acetic anhydride added dropwise and then left to react for 2 hours at 22 °. After adding 20 ml of water at 5 ^{° C.} , stirring for 30 minutes at 22 °

709825/1032

oc. _ 100-4470

and adding 40 ml of methylene chloride, the aqueous phase of the two-phase mixture is 4 g Sodium carbonate adjusted to pH 7 with stirring, re-extracted with methylene chloride and the organic phases are washed, dried, evaporated and dried in a high vacuum. You get the title compound as a viscous oil, which can be crystallized as hydrogen fumarate from 2-propanol. M.p. 194 ° (dec.).

Beispio_l__ $ j_ 2.§5? Ϋ ^ Χ ^ - ^r ° "4a ~ (3 ΖΪ3 ^Τ §- ^ 9Ξ ^ ^Τ P'i £ * lZl · - JI ^ -met hy1- 6-methylene"Cis; -isoc hino lin (method h)

3.9 3 g (1.1 m mol) of methyltriphenylphosphionium broraide are in absolute dimethylformamide under nitrogen with 1.01 g of a 50 percent sodium hydride dispersion (21 m mol) added, left to stir at room temperature for 1 hour, with 2.59 g of octahydro-4a- (3-hydroxyphenyl) -2-methyl-cis-6 (2H) -isoquinolinone added and the reaction mixture 16 hours at 40 ° let stir. After partitioning between methylene chloride and aqueous ammonium sulfate solution, evaporate the organic phases, drying the residue and Chromatography on silica gel gives the title compound.

Analogously to Example 7, the following compounds of the formula I are obtained, in which R = Orto and Para nC H CO, R = N, R ₄ = R ₅ = R = H, and R ₃ =:

709825/1032

i) n-hexyl,

ii) -CH ₂ -CH = C

iii) -CH.

nC ₃ H ₇ )

iv) -

v) -I

vi) "

Vii) -

Cl

CF.

viii) -1 CH ₂ ] Λ VnC ₃ H ₇

ix) -ICH ₇ I ₂

x) - ICU ₂ ]

Xi) -

7139825/1 ^ 32

Claims (3)

Claims; NO, wherein (i) R _{1 represents} hydrogen or alkyl with 1 to 4 carbon atoms,
R for hydrogen, R and R together for oxygen, and R _c and 5 stand for hydrogen, or (ii) R for hydrogen, alkyl with 1 to 4 carbon atoms, or alkanoyl with 1 to 4 carbon atoms, and R "for alkyl with 1 to 6 carbon atoms, a radical of the formula II, ^V 8 where R_ and R _R independently of one another are hydrogen or alkyl having 1 to 4 carbon atoms, a radical of the formula III, 709825/1032 100-4470 -ClI ₂ -CH (CII ₂ ) _m III wherein m is an integer from 2 to 4, a radical of the formula IV, IV where η is an integer 1 or 2, or a radical of the formula V, where ρ is an integer 1 or 2 and R is hydrogen, halogen, Trifluoromethyl.1, lower alkoxy or lower alkyl, amino, or di (lower alkyl) amino mean, and a) either R for azide or hydroxy, and R. for hydrogen, or R and R ₄ together for oxygen or Methylene, and
R and R _fi each stand for hydrogen, or b) either R and R _g together form a bond, and R. and R ₁ . each mean hydrogen, or R. and R_ together form a bond, ft O and R_ and R_ each mean hydrogen, J b with the proviso. That when R is hydroxy and 709825/1032 100-4470 R. mean hydrogen, or when R_ and R. 4 3 together form oxygen, and (i) if R is a radical of the formula IV, then η is an integer 1, or (ii) if R is a radical of the formula V, then ρ is an integer 2, and R means hydrogen or halogen, and their acid addition salts. 2. Process for the preparation of compounds of the formula I and their acid addition salts, in which R 1' ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R _g , n, m and ρ have the above meaning, characterized in that one a) from a compound of the formula VI, NO 10 VI 709825/103 2 100-4470 wherein R represents hydrogen or an alkyl group with 1 to 4 carbon atoms, and R stands for an amino protecting group, splitting off the amino protective group, a compound of the formula Ia, where R ' Yes H-H has the above meaning, _r or is obtained b) a compound of the formula Ia, or the corresponding compound in which the keto group is protected, alkylated, if necessary the keto protecting group in the resulting product is split off is, where a compound of the formula Ib, Tb where R- ^ has the above meaning, and Ri has the meaning R, with the proviso, that it is different from hydrogen, or 709825/1032 c) a compound of the formula Ic, 100-4470 Jc where R and R have the above meaning, reduced, where a compound of the formula Id, NO Il Id wherein R ₁ and R "have the above meaning, is obtained, or d) in a compound of the formula VII, II VII 7 09825/1032 100-4470 wherein R- stands for alkyl or alkanoyl with 1 to 4 carbon atoms, R_ has the above meaning, and R means an interchangeable remainder, R replaced by an azido group, where a compound of the formula Ie, Ie wherein R 'and R are as defined above will, or e) from a compound of the formula VIII, VIII where R., and R "have the above meaning, and R" denotes a group which can be split off under the reaction conditions, alkyl or alkanoyl having 1 to 4 carbon atoms, HR ₁ - eliminated, whereby a compound of the formula If , 709825/1032 ν-η 100-4470 wherein R ₁ and R "have the above meaning, and either R ^ and Rj together are a bond, and each of R? and R * are hydrogen, or R ^ and R ^ together form a bond, and each from
-wi-r-eU- or R_ and R "mean hydrogen f) from a compound of the formula IX, IX where R, R, R, R and R have the above meaning with the proviso that when R_ and R. together form oxygen, the keto group can be in free form or in protected form, and R-_ is a hydroxy protecting group, the hydroxy protecting group R ₁ ^ splits off, whereby a compound of the formula I, in which R _{1 is} hydrogen, is obtained, or 709825/1032 100-4470 g) acylating a compound of the formula I in which R _{1 is} hydrogen, a compound of the formula I in which R is alkanoyl having 1 to 4 carbon atoms being obtained, or h) the oxygen of the keto group of a compound of formula Ic by methylene Wittig conditions replaced, with a compound of the formula Ig, ν-r: in which R _{1 has} the meaning given in formula I and R_ has the above meaning, and the compounds of the formulas Ia, Ib, Id, Ie, If, Ig and I thus obtained are converted, if desired, into their acid addition salts. 3. Medicament, characterized in that it is a compound of the general formula I, in which R-, R_, R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , n, m and ρ have the above meaning or contains their acid addition salts. 3700 / BA / ER 709825/1032