SK207592A3 - Benzomorphanes, method of producing and pharmaceutical agents containing them - Google Patents

Abstract

The present invention relates to novel benzomorphan derivatives of the general formula I <IMAGE> their preparation and their use as medicaments for the treatment of cerebral ischaemial of various origin, epilepsy and neurodegenerative disorders.

Description

Technical field

The present invention relates to novel benzomorphans, processes for their preparation and their use as medicaments.

SUMMARY OF THE INVENTION

The benzomorphans according to the invention correspond to the general formula I

R

Rkdet

X may be O or _S, S, C ^ _Cg ^"a lkyl, C -C alkenyl, C ^ -C-alkynyl, aryl, hydrogen, a C _r C ₈ alkyl, C -C alkenyl, C ^ Cg- alkynyl, aryl, aralkyl,

hydrogen, C1-C6-alkyl,

0, -C-alkyl,

C-Cθ alkyl,

-2r6 may be G-C 1-6 alkyl, aryl,

T 8. - i o ·

R ' ¹ and R independently of one another may be hydrogen, C 1 -C 8 -alkyl, halogen, -OH, C 1 -C 8 -alkoxy, -O-acyl, -CN 3, -NOg, NH ₂ , -NH / C ₁ -C 8 -alkyl), -N- (C 8 -C 8 -alkyl), wherein the alkyl radicals may be the same or different, -NH-acyl or -N-acyl-(C 1 -C 8 -alkyl).

Preferred are compounds of formula I wherein

X. and can .enayenat oxygen, sulfur,

R ¹ may be a methyl, ethyl, propyl, isopropyl, phenyl,

R can be methyl, ethyl, propyl, isopropyl, allyl, propargyl, phenyl, benzyl,

R ^{3 can} be hydrogen, C 1 -C 4 -alkyl,

R ⁴ can be methyl, ethyl, propyl, isopropyl,

R can be methyl, ethyl, propyl, isopropyl, r6 can be methyl, ethyl, propyl, isopropyl, phenyl,

R can be fluoro, chloro, hydroxy, lower alkyl, lower alkoxy, acyloxy,

Q

R can be hydrogen, lower alkyl, hydroxy or alkoxy.

Particularly preferred are compounds of formula I, where it may be

X oxygen, methyl, methyl, hydrogen, methyl, methyl, methyl, hydroxy, methyl, methoxy, acyloxy, hydrogen, methyl, ethyl, hydroxy or lower alkoxy

R ¹

R ²

R ³

R ⁴

R ⁵

R ⁶ _K T

R ^S ethyl, ethyl, ethyl, ethyl, ethyl.,

R ¹

R ²

R ³

R ⁴

R ⁵

R ⁶

R ⁷

R ⁸ where a 3 * - a

Very particularly preferred are compounds of formula I, where it may be

X is oxygen, methyl, methyl, hydrogen, methyl, methyl, methyl, hydroxy, methyl, methoxy, acetoxy, hydrogen, methyl, hydroxy, methoxy or ethoxy _λ, nacházej'í position 2 possess: © R-configuration.

with R ¹ and R 2 in the 2-position

The present invention is based on the individual isomers, their mixtures and the corresponding physiologically acceptable acid addition salts, both inorganic and organic. Preferred are, for example, salts with hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, lactic, malonic, succinic, maleic, fumaric, malic, tartaric, citric or benzoic acids.

Unless otherwise indicated on a case-by-case basis, the general definitions used shall have the following meaning:

-4C1 -C6 alkyl; C 1 -C 6 -alkyl generally means a branched or unbranched hydrocarbon radical having from 1 to 6, respectively. 8 carbon atoms and optionally ¹ MHz be substituted by one or more halogen atoms, preferably fluorine, which may be the same or different. Examples which may be mentioned are the following hydrocarbon radicals: methyl, ethyl, propyl, 1-methylethyl (isopropyl), butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl,

1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-difliethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4- methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl.

3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Unless otherwise stated, lower alkyl radicals having 1 to 3 carbon atoms such as methyl, ethyl, propyl, isopropyl are preferred.

Generally, alkenyl represents a hydrocarbon radical having from 3 to 6 carbon atoms, which is straight or branched and contains one or more, preferably one, double bond which, in addition to the carbon atom, has a carbon atom. Fifth may be substituted. one or more halogen atoms, preferably fluorine, which may be the same or different.

Examples include:

2-Propenyl (allyl), 2-butenyl, 3-butenyl,

1-Methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl,

3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl,

2-methyl-2-butenyl, 3-methyl-2-butenyl,

-methyl-3-butenyl, 2-methyl-3-butenyl,

3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 2-dimethyl-2-propen.yl, 1-ethyl-2-propenyl, 2-hexenyl, _R

3-hexenyl, 4-hexenyl, 5-hexenyl, 5-hexenyl,

-methyl-2-pentenyl, 2-methyl-2-pentenyl,

3-methyl-2-pentenyl,

1-methyl-3-pentenyl,

3-Methyl-3-pentenyl

1-methyl-4-pentenyl,

4-Methyl-4-pentenyl,

4-methyl-2-pentenyl,

2-Methyl-3-pentenyl

4-methyl-3-pentenyl,

3-methyl-4-pentenyl, 1-dimethyl-2-butenyl, 1-dimethyl-3. butenyl ,. 1,2-Dimethyl-2-butenyl

1, 2-dimethyl-3-buten.yl, 1, 3-dimeth.yl-2-butenyl, 3-dimethyl-3-butenyl, _R 2,2-dimethyl-3-butenyl, _R 3-dimethyl-2- butenyl, 2,3-dimethyl-3-butenyl,

1-ethyl-2-butenyl, 1-ethyl-3-butenyl,

2-ethyl-1-butenyl, 2-ethyl-2-butenyl,

2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl,

1-ethyl-1-methyl-2-propenyl a

ethyl-2-methyl-2-propenyl.

Allyl residue is preferred »

Alkynyl generally means a straight or branched chain hydrocarbon chain having from 3 to 6 carbon atoms and having one or more triple bonds.

Preferably it is a lower alkynyl (propargyl) radical having 3 carbon atoms and a triple bond, which may optionally be substituted by one: halogen atom - preferably fluorine or more halogen atoms, which may be the same or different.

Acyl represents a general benzoyl or alkylcarbonyl radical: both straight and branched lower alkyl having 1 to about 6 carbon atoms attached through a carbonyl group, the alkyl radical optionally being substituted by one or more halogen atoms, which may be the same or different. Preferably, the alkyl radicals contain up to 4 carbon atoms. Examples are: acetyl, trifluoroacetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl as well as isobutylcarbonyl. Particularly preferred is the acetyl residue.

6-Acyloxy represents an acyl group bonded through oxygen, wherein acyl is as defined above.

Aryl generally represents an aromatic radical of 6 to 10 carbon atoms, also in composite form, wherein the aroma may be substituted by one or more lower alkyl, alkoxy, nitro, amino and / or one or more halogen atoms, which may be the same or different. A preferred aryl radical is phenyl.

Aralkyl is a generally pre-alkylene radical bonded aryl radical of 7 to 14 carbon atoms, wherein the aroma may be substituted with one or more lower alkyl, alkoxy, nitro, amino and / or one or more halogen atoms, which may be the same or different . Aralkyl radicals having 1 to 6 carbon atoms in the aliphatic moiety and 6 carbon atoms in the aromatic moiety are preferred. Unless otherwise stated, preferred aralkyl radicals are benzyl, phenethyl and phenylpropyl.

The alkoxy generally represents a straight or branched hydrocarbon radical having 1 to 8 carbon atoms through an oxygen atom. Preferred is an alkoxy radical having 1 to 3 carbon atoms. Methoxy is particularly preferred.

Anino represents, unless otherwise indicated, an N 1 group which may optionally be substituted by one or two C 1 -C 6 -alkyl, aryl or aryl-alkyl radicals, which may be the same or different.

Alkylamino represents, for example, methylamino, ethylamino. propylamino :, 1-methylethylamino, butylamino, 1-methylpropylamino, 2-methylpropylamino or 1,1-dimethylethylamino.

Dialkylamino represents, for example, dimethylamino, diethylamino, dipropylamino, dibutylamino, di- (1-methylethyl) amino, di- (1-methylpropyl) amino, di-2-methylpropylamino, ethylmethylamino, methylpropylamino.

Unless otherwise indicated, halogen represents, in particular, fluorine, chlorine and bromine. Pharmacological characteristics

Systemic administration of glutamate is known to destroy neurons in the brain in S. murine (S. R. Rothman and T. W. Oiney, Tends in Neurosciences 10 (1987) 299). Among other things, this finding leads to the conclusion that glutamate plays a role in neurodegenerative diseases / R-Schwarcz. and B. flelourun, The Lancent 11 (1985) 140.

Further, substances such as e.g. quisoualinic acid, camic acid, ibotic acid, glutamic acid and N-methyl-D-aspartic acid (NMDA) known as exogenous and / or exogenous; endogenous neurotoxins. Because of their neurotoxicity, these substances act selectively on individual cells so that functional disorders can be induced in animals by specific brain lesions. These are comparable to disorders resulting from epilepsy and other neurodegenerative diseases - such as Huntington's and ALzheimer's disease.

In vivo and in vitro experiments have shown that cells are damaged by hypoglycaemia, hypoxia, anoxia and ischemia in the brain, and functional disorders partly based on increased synaptic activity occur, with glutamatergic synapse being of particular importance. Substances and ions that suppress the activity of glutamate receptors and receptor-associated ion channels - such as. competitive and incompetent

These findings show that glutamate-receptor plays an important role in mediating ischemic damage.

Biochemical and electrophysiological studies show that the receptor-β-ion channel is highly sensitive to fluctuations in magnesium concentration. As the magnesium concentration decreases, spontaneous epileptic manifestations in the hippocampus can be suppressed by excitatory amino acid antagonists.

Surprisingly, it has now been found that the benzomorphans of formula I block the NMDA channel. and exhibit neuroprotective. efficiency.

The preparation of the ta-benzomorphine derivatives is known from DE-PS 2105743 and DE-OS 28 28 039 as well as from the literature / H. Merz and K.Stockhaus, J.I.Ch.em. 22 (1979) 1475 It is also known that such compounds have analgesic activity and can be used as non-addictive analgesics and antitussives (DE-PS 21 05 743).

The hippocampus section serves as a test system for demonstrating the NMDA-antagonistic activity of the benzomorphane derivatives. Electrodes are stimulated. sheep collateral cut in the perfusion chamber. hippocampus and the total potential generated extracellularly on the CAI region pyramid cells (H. L. Haas, B. Schaerer and M. Vosmansky, J. Neuroscience Meth.1 (1979) 323) is removed.

In addition, the neuroprotective activity of the benzomorphane derivatives of Formula I has also been demonstrated in relation to protein synthesis and release of neurotransmitters in the hippocampal section.

The receptor binding assays further show that the disclosed benzomorphane derivatives are non-competitive glutamate receptor antagonists.

Furthermore, the neuroprotective efficacy of the benzomorphan derivatives of formula I on mice was demonstrated by vivopressing N-methyl-D-aspartic acid-induced lethality (JDLeander et al., Brain Research 448 (1988) 115) and suppressing ischemia-induced cell death in mice and gerbilech.

These results provide a basis for considering that the benzomorphane derivatives of formula I may be used in neurodegenerative diseases as well as cerebral ischemia of various origins. These include, for example: status epilepticis, h.ypoglycemia, hypoxia, anoxia ?, brain trauma, brain edema, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, hypotonia, heart attack, stroke, and perinatal asph.yxia.

2. Preparations

The benzomorphane derivatives of the formula I as well as their addition salts with pharmacologically acceptable acids can be converted by known methods into conventional preparations such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions using inert pharmaceutically acceptable carriers or solvents. The proportion of the pharmaceutically active compound (s) usually lies in the range of 0.5 to 90% by weight. of the total composition, i.e. in amounts, that will enable the desired dosage range to be achieved.

The compositions may be prepared, for example, by treating the active ingredient with a solvent and / or carrier, optionally using emulsifying agents and / or dispersing agents, for example when water is used as the diluent.

- where appropriate, organic solvents used as solubilizers or. excipients to facilitate dissolution.

Excipients include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fraction (s), plant origin (e.g. peanut or sesame oil (mono- or polyfunctional alcohols) e.g. ethanol or glycerin; carriers such as e.g. natural mineral meal / e.g. kaolin, diatomaceous earth, talc, chalk /, synthetic mineral meal (eg highly dispersed silicic acid and silicates), sugar (eg ¹ . cane, milk and grape sugar), emulsifying agents (e.g. lignin, sulfite lyes, methylcellulose, starches and polyvinylpyrrolidone (and glidant) e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate.

The application is carried out in a conventional manner, preferably parenterally - in particular - especially during infusion - intravenously. In the case of oral use, the tablets may, of course, also contain excipients such as e.g. sodium citrate, calcium citrate, and dicalcium phosphate together with various disintegrants such as starches, especially potato starch, gelatin and the like, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc may also be used for tabletting. In the case of aqueous suspensions, in addition to the abovementioned excipients, the active compounds may be mixed with various flavor enhancers or colorants.

In the case of parehteral use, the active ingredient solutions may contain suitable liquid carrier materials.

The dosage for oral use is in the range of 1 to 300 mg, preferably 5 to 1.50 mg.

Nevertheless, it may be appropriate to vary said amount depending on body weight or weight. the type of application, the individual relationship to the drug, the type of its preparation and the the interval at which it is administered. Thus, in some cases it may be appropriate to start with doses less than those indicated, while in other cases the above limits must be exceeded. If larger amounts are applied, it is recommended to divide them into smaller doses during the day.

Further, the compounds of formula (I) may optionally be present. their acid addition salts also combined with: other active ingredients.

Examples of preparations

tablets

1. The tablet contains the following ingredients:

active ingredient of the formula I 0,020 parts of stearic acid 0,010 «1 dextrose 1, 890 n · total 1, 920 parts of

Production:

The ingredients are mixed together in the indicated amounts and the mixture is compressed into tablets each having a weight of 1.92 g and an active ingredient content of 20 mg.

Ampoule solution

Ingredients:

active ingredient of formula I sodium chloride water for injection

1.0 mg

45, 0 mg to 5, ml

-12Výroba:

The active ingredient is dissolved in water at its own pH or, if appropriate, at a pH of 5.5 to 6.5 and mixed with sodium chloride as an isotonic agent. The solution obtained is pyrogen-filtered and the filtrate is filled into a vial under aseptic conditions, which is finally sterilized and sealed. The capsules contain 1 mg, 5 mg and 10 mg of active ingredient.

lace:

One suppository contains: active ingredient of the formula (I), 1.0 part cocoa butter / m.p. 36 to 37 ° C / 1200.0 Carnauba wax 5.0 - ”Production:

Cocoa butter and carnauba wax will melt together. The active ingredient is added at 45 ° C and stirred until complete dispersion is achieved. The mixture is poured into a mold of appropriate size and the laces are suitably packaged.

3. Methods of synthesis

The preparation of benzomorphane derivatives which serve as starting material in various synthesis processes of type 2 is known from the prior art (DE-A 20 27 077, CA / 1971 / 125482X, EP-B 4960, CA 93/1980/4941 f / or is described in the following examples.

-149 10 * *

The substituents n and R are either identical to the desired substituents R and R, or can later be converted to these substituents.

3.1a

The introduction of any of the desired substituents on the amino function of the benzomorphane nitrogen can be accomplished by acylation with a suitable activated carboxylic acid derivative. Corresponding carboxylic acid derivatives of type 4 are known in the art or are readily accessible to the process; synthesis.

Again, for the acylation itself, there are many ways to choose from (C. Ferri, Reaktionen der organischen Synthese, Georg Thiema ⁱⁿ Stuttgart Stuttgart, 1978, p. 1). 222 et seq. And cit literature J.March, Alvanced. Gpganic Chemistry, 3rd Ed., John Wiley and Sons, New York 1985, p. 370 et seq .; RCLarock, Comprehensive Organic Transformation A Guide to Functional Group Preparations, VCH Verlagsgesellschaft, D-6940 Weinheim 1989, p. 963 et seq. and cit lit .; wherein reactions with carboxylic acid halides (ALJBeckwith in J. Abicki, The Chemistry of Anides, Interscience, New York 1970 p.73) in a solvent which is substantially inert under the reaction conditions, optionally in the presence of acid binding agents, are preferred. ^d , organic solvents which are generally unchanged under the reaction conditions, such as hydrocarbons such as e.g. benzene, toluene, xylene - or petroleum fractions or ether - such as e.g. diethyl ether, glycol dimethyl ether (glyme), diglycol dimethyl ether - or cyclic ethers such as e.g. tetrahydrofuran or dioxane - or halogenated hydrocarbons - such as e.g. carbon tetrachloride, chloroform or dichloromethane.

The production of the desired carboxylic acid halides is known in the art. 1985 / if not commercially available. Preferably, the benzomorphane derivative of type 2 reacts advantageously in halogenated hydrocarbons - in particular in; dichloromethane - and in the presence of a tertiary amine - such as e.g. triethylamine with the desired acid halide - particularly preferred with acid chloride. However, it is also possible to carry out the reaction - with respect to the Schotten-Baumann variant - in water or an aqueous alcohol in the presence of an alkali metal hydroxide or an alkali metal carbonate (see e.g. Organikum, kolektiv koloru, VEB Lutscher Verlag der Wissenschaften, 17th edition, Berlin 1988 p. 407 /. Depending on the starting materials used, it may further prove to be particularly advantageous to carry out the acylation according to the Einhorn variant, where pyridine is used, an acid binding agent also as a reaction medium.

•

In addition, it is possible to carry out acylation with a free carboxylic acid (see e.g. A.L.J.Beckwith in O.Zabicki, The? G et al. Of Anides, Interscience, New York 1970, p. 105 et seq .; J.A. Itchell and E.E.Reid, J. An.Chem.Soc. 53/1931/1879 / It may further be advantageous to use mixed anhydride instead of the free acid - e.g. with carbonic acid ester /C.Ferri., ß eaktionen der organischen Synthese, Georg ·

Thieme Verlag, Stuttgart 1978, p. A.D.J.i

Beckwith, J. Zabiek, Chemistry of Anides, Interscien-!

ce, New York 1970, p.86; J. ^ arch, Alvanced Urganic Chemistry, J. Ed., John Wiley &amp; Sons, New York 1985-, p.

371 et al., R.C. Larock, Comprehensive Organic Transformations, VCH Publishers, D-6940 Weiheim 1989, p.

J {t

In the preferred acylation of carboxylic acid halides, in particular carboxylic acid chlorides, the reaction temperature can be varied over a wide range, limited at the bottom by a low reaction rate and at the top by undesired side reactions. In an embodiment, the temperatures are in the range of -50 ° C to 150 ° C, preferably 0 to 75 ° C. The process is preferably carried out in the presence of a small excess of the acylating agent in the presence of a slightly greater excess of an acid-binding agent in order to avoid possible side reactions of the starting material.

3.1b

The following reaction step of acid amide reduction 3 is required to achieve the amine type 6.

Such acid amide reductions are known in the art and can be carried out by electrolytic reduction, alkali metal reduction as well as catalytic reduction (R-Schrater) in Houben-Weyl, 4-thethoden der organischen Chemie, Vol. XI / 1, Georg Thieme ⁱⁿ Erlag, Stuttgart 1957, p. Or diborane, respectively. hydrogen fluoride derivatives (J. Fuhrhop and G. Penzlin, Organic Synthesis - Concepts - Starting Materials - Starting Materials., VCH-Verlagsgesellschaft, Weinheim 1986, p.90).

Preferably, the reduction is carried out with complex hydrides such as alkali metal boron or aluminum hydrides or alkali metal hydrides. suitable derivatives thereof, optionally in the presence of a catalyst / N.Gaylord, Reduction with Complex Flying Hydrides, Wiley New York 1965; A. Hajos, Complex Hydrides, Elsevieir New York 1979; V. Bazant, M. Capka, M. Cerny, V. Chvalovsky, K. Kochloefl, K. Kraus and J. Malek, et al. 2. (1968), whereby lithium aluminum hydride is particularly suitable.

Suitable inert media are all inert organic solvents which do not change under the reaction conditions used. These include, in particular, an ether such as e.g. diethyl ether, diisopropyl ether, tert-butyl methyl ether, di-n-butyl ether, glycol dimethyl ether (glyme), diglycol dimethyl ether (diglyme), cyclic ethers - such as e.g. dioxane - and especially preferred tetrahydrofuran, the choice of solvents being controlled, inter alia, by the reducing agents used.

It is generally advantageous to carry out these reductions in the presence of reducing agents which represent the abovementioned complex hydrides. especially lithium alanate - which are used in the range from 5 to 100% - preferred in ^; between 10 and 50.

The reactants are usually mixed under ice-cooling or room temperature, and finally, depending on the reactivity of the starting material, they are heated to temperatures in the range of 150 ° C - preferably up to 75 ° C.

3.2

Another possibility of preparing the benzomorphane derivatives of type 6 is by reacting the benzomorphane derivative 2 with a suitable type 5 alkylating agent, wherein in the formula 5 Z represents an leaving group. Preferred leaving groups are halogen - such as e.g. Cl, Br, I - or U-C 1 -C 4 -aryl - such as e.g. tosylate - or alkylsulfonate O-C 1-6 -alkyl - such as e.g. methanesulfonate - or halogenated sulfonate or sulfate

q are either commercially available or are known in the art.

Suitable solvents are all inert solvents which do not substantially change under the reaction conditions and do not themselves affect the reactants as reaction components.

-18K especially include eg. alcohols - such as methanol, ethanol, propanol or isopropanol - or an ether - such as diethyl ether, di-n-butyl ether, tert, butyl methyl ether, glycol dimethyl ether (glyme), diethylene glycol dimethyl ether (diglyme), tetrahydrofuran and dioxane - or ketok - such as e.g. methyl ethyl ketone or acetone - or acid amides - such as e.g. hexamethylphosphoric triamide or dimethylformamide.

In addition, it is possible to use mixtures of the solvents mentioned. Tetrahydrofuran or dimethylformamide or a mixture thereof is particularly preferred. The reaction is preferably carried out in the presence of an acid-binding agent - such as e.g. an alkali metal or alkaline earth metal carbonate or a bicarbonate thereof.

The reaction temperature may vary widely during the reaction. a range that is bounded at the bottom by a very slow reaction rate and at the top by a progress. side reactions. Suitable reaction temperatures range from 0 to 150 ° C, preferably between 50 to 100 ° C.

3.J

If necessary, the conversion of R @ 5 and / or R @ ¹⁰ to R @ ⁷ g, respectively, is necessary. R are many vigorous reactions which cannot be summarized in a single reaction scheme. The paint reactions will be exemplified in the following examples.

4. Examples of embodiments of the invention

Note: Unless otherwise indicated, ether means diethyl ether

4.1. Compound 1 - produced according to Method 3.1

4.1.1. Example 1 (-) - (1R, 5S, 2R) -2'-Hydroxy-2- (2-methoxypropyl) -

5,9,9-trimethyl-6,7-benzomorph-art-hydrochloride and / or acylation

27.8 g (0.12 mol) of (+) - 2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane (DOS 20 27 077); C A 74. 125482x (1971) are mixed in 278 ml of absolute dichloromethane in the presence of

27.9 g (0.275 mol) of triethylamine with stirring for about 30 minutes with 19.2 g (0.156 mol) of (R) -2-methoxypropionic acid chloride. ^The reaction temperature is maintained in the range of 30 to 35 ° C. It is then boiled under reflux for one hour. It is cooled and washed successively with 175 ml of water, 175 ml of 2N hydrochloric acid and twice with 175 ml of water each time. After drying with sodium sulfate and filtering off the desiccant, the solution is evaporated in vacuo, finally at 80 ° C and under full water pump vacuum. The acylation product of type 1 is obtained as a residue after evaporation in a yield of 42.3 g of approximately 100% of theory.

b / Reduction. The acylation product obtained in the above procedure is dissolved in 425 ml of absolute tetrahydrofuran. The solution was added dropwise to a suspension of 9.1 g (0.24 mol) of lithium aluminum hydride (lithium tetrahydridoanalate) in 300 ml of tetrahydrofuran under stirring at ice for 10 hours at 10-15 ° C. The reaction mixture is then boiled under reflux for two hours. It is then treated dropwise with 25 ml of water while cooling in an ice bath and stirred, and then, after the addition of

-2070 ml of water and saturated ammonium tartrate solution (890 ml) were shaken in a lengthening funnel. The separated tetrahydrofurab phase is evaporated in vacuo and the aqueous phase is extracted three times with 175 ml of dichloromethane each time. The residue from evaporation of the tetrahydrofuran phase is dissolved by extraction in dichloromethane and the solution is washed twice with 100 ml of water each time. ^Ο ο drying with sodium sulfate and filtering out the desiccant, evaporate the solution, finally at 80 ° C and complete vacuum of the water pump. Residue are left / 37 g / esi 100% of theory /, and a mixture of the two diastereomeric compounds clipping · »chromatograms of the thin layer / DC / compare diastereomers show _Rf values of 0.42 to wish.

0.51 (silica gel 60, chloroform-methanol-conc. Ammonia 95: 5: 0.1).

The diastereomers may be separated by crystallization of the hydrochlorides. Therefore, the basic mixture was dissolved in 120 ml of absolute ethanol and acidified with a solution of hydrochloric acid (12 ml of 32% hydrochloric acid). The title compound (Rp = 0.42) crystallized immediately and was filtered off with suction after cooling (ice bath), washed in portions with ice cold ethanol (40 ml) and finally dried to constant weight at 80 ° C. The yield is 15.0 g (73.5% of the theoretical maximum). The substance melts at 264 ° C with decomposition and has a specific optical rotation ([α] D = -116.9 ° (c = 1, CH 2 OH)). A sample recrystallized from a mixture of methanol and diethyl ether melts the same at 264 ° C (dec.) And exhibits a specific rotation (° </ ^ = -118.6 ® / c = 1, CH 2 OH) »

4.1.2. Example 2 (+) - (1S, 5R, 2R) -2'-Hydroxy-2- (2-methoxypropyl) -

The 5,9,9-trimethyl-6,7-benzomorphane hydrochloride liquors obtained in the process of Example 1 contain, in particular, a diastereomer having an R-value of 0.51. Evaporate and heat the residue (25 g) with 40 ml of isopropanol for one hour at reflux. Thus created

The crystalline suspension is allowed to stand at room temperature for about 12 hours, then suctioned off and washed in portions with a small amount of cold isopropanol. The crystallizate is formed in particular by the title compound leading the remaining diasteromers (Example 1). The title compound was converted to the free base form and purified by column chromatography. To this end, the crystallizate was shaken with water (75 ml), dichloromethane (75 ml) and excess ammonia (6 ml, 25%). After phase separation, the aqueous layer is extracted once more with 25 ml of dichloromethane in methane. The combined dichloromethane extracts are washed twice with 25 ml of water each, then dried over sodium sulphate, after filtering off the desiccant, evaporated, finally at 60 ° C under full vacuum of the water pump. The residue (15.4 g) was purified by column chromatography on 2 kg silica gel (MN K 60, 230-400 mesh ASTM), from Macherey and Nagel using dichloromethane / methanol / ammonia 95: 5: 0.1 as eluent. Interactions with the pure substance yield, after evaporation, a residue (6.8 g) which is formed by the base of the title compound. Dissolve the residue in 14 ml of absolute; ethanol and the solution was acidified with 2,52.5N ethanolic hydrochloric acid. Upon addition of diethyl ether, the title compound crystallizes to a permanent turbidity. Leave to stand in the refrigerator for about 12 hours, then filter off with suction and wash first with 1: 2 methanol-ether, then with ether. After drying, finally with the 80 DEG C. to give 6- _f, 4 g of the title compound / 31, 4% of the theoretically maximum possible amount / MP: 236 DEG C. dec and a specific rotation / (X / 25 ₌ +88. 0 DEG ( _c = 1, CH2 OH).

4.1.3 Example 3 (+) - (1S, 5R, 2'S) -2-hydroxy-2- (2-methoxypropyl) -

5,9,9-trimethyl-6,7-benzomorphanhydride chloride;

Starting from 9.25 g (0.040 mol) of (+) - 2'-hydroxy-5,9,9-22-trimethyl-6,7-benzomorphane and 6.37 g (0.52 mol) of acid chloride (S) - 2-methoxypropionic, the procedure is analogous to Example 1 to give the title compound in a yield of 5.1 g / 75.0% of theory / _Rf value of 0.42, a melting point of 270 DEG C. dec and specific otáč.ivostí / [.Alpha.] D @ 20 = + 117 DEG (c = 1, CH3 OH).

4.1.4 Example 4.

(-) - (1R, 5S, 2S) -2 * -Hydroxy-2- (2-methoxypropyl) -

5.9.9-trimethyl-6,7-benzomorphane hydrochloride

The mother liquors obtained from Example J, which are analogous to Example 2, yield the title compound in a yield of 3.2 g (47.1% of theory) with a melting point of 235 ° C (dec.) And a specific rotation of -89.9 ° (c-). 1, CH 2 OH).

4.1.5. Example 5 (-) - (1R, 5S, 2R) -2 * -Hydroxy-2- (2-methoxypropyl) -

5.9.9-trimethyl-6,7-benzomorphane hydrochloride

The procedure is analogous to Example 1, but using 2.31 g (0.010 ml) of the enantiomeric (-) - (hydroxy) -5,9,9-trimethyl-6,7-benzomorphane s. 1.60 g (0.013 mol) of (R) -2-methoxypropionic acid chloride, instead of a mixture of diastereomeric bases, first a sterically pure base of the title compound and from this hydrochloride is obtained. Yield: 3.0 g (88.4% of theory), m.p. 264 DEG C. (decomposition), and specific rotation: [.alpha.] D = -117.5 DEG (c = 1, CH3 OH).

4.1.6 Example 6 (-) - (1R, 5S, 2S) -2 * -Hydroxy-2- (2-methoxypropyl) -

5,9,9-trimethy1-6,7-benzomorphan hydrochloride

The acid synthesis described in Example 5 was carried out

-23 (S) -2-methoxypropionic acid, thus obtaining the title compound in a yield of 2.9 g (85.3% of theory) with a melting point of 235 [deg.] C. (dec.) And a specific rotation ([delta] ⁼ -89.7). ° (c = 1, ch ₃ oh).

4.1.7 Example 7 (- / -) 1R, 5S, 2'R) -2'-Hydroxy-2- (2-methoxypropyl) -

5.9.9-Triethyl-6,7-benzomorphine hydrochloride

Starting from 4.62 g (0.020 ml) of (-) - 2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 3.20 g (0.026 mol) of the acid chloride (R / S) -2- methoxypropionic, obtained analogously to Example 1 with a mixture of the expected diastereomeric bases, which is separated by column chromatography analogously to Example 2. Slowly! moving substances / R ₌ 0.42 / then as therein described was crystallized as the hydrochloride salt. This gave the title compound in an overall yield of 2.1 g / 61.8% of theory / MP: 264 DEG C. dec and a specific rotation / • ^ / P ⁵ = -117.9 ° / c = 1, CH? OH /.

4.1 .8 Example 8 (-) - (1R, 2S, 2'S) -2 '-Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

Starting from the faster moving substance (H 2 = 0.51) separated in Example 7 and converting to the hydrochloride analogous to Example 2, the title compound is obtained in a yield of 2.2 g (64.7% of theory) with a melting point of 235 °. δ (decomposition) and specific rotation ([.alpha.] D @ 20 = -88.6 DEG ( _c = 1, CH3 OH).

4.1.9 Example 9 (+) - (1S, 5R, 2S) -2'-Hydroxy-2- (2-methoxypropyl) -

5.9.9-trimethyl-6,7-benzomorphine hydrochloride

2.60 g (0.025 mol) of (S) -2-methoxypropionic acid chloride was stirred in 100 ml of absolute tetrahydrofuran with 4.04 g (0.025 mol) of 1,1'-carbonyldiimidazole for two hours at room temperature. After addition of 4.62 g (0.020 mol) of (+) - 2-24-hydroxy-5,9,9-trimethyl-6,7-benzomorphane, it is further stirred for two days at room temperature. It is evaporated, the residue is taken up in 75 ml of dichloromethane and washed successively with 2N HCl and twice with water. After separation, the organic phase is dried over sodium sulphate and, after filtering off the desiccant, is evaporated off under vacuum, finally at 80 DEG C. under full vacuum of the water pump. The evaporation residue - as described in Example 1 - is reduced with lithium aluminum hydride (lithium tetrahydridoanalate) and the reduction product crystallizes analogously to Example 2 as the hydrochloride. Oxyacetate the title compound in a yield of 6.9 g / 81.3% of theory / MP: 264 ° C / dec. / And the specific rotation / <A / D ⁵ = + 117.4 ° / c = 1, CH ₃ OH /.

4.1.10 Example 10 (- / -) 1R, 5S, 2'R) -9,9-Dimethyl-5-ethyl-2'-hydroxy-

2- (2-methoxypropyl) -6,7-benzomorphane hydrochloride Starting from 1.69 g (0.006 mol) of (+) - 9,9-dimethyl-5-ethyl-2'-hydroxy-6,7-benzomorphane hydrochloride / LOS 2027 077; CA 24, 125482χ (1971), 1.82 g (0.018 mol) of triethylamine and 0.96 g (0.0078 mol) of (R) -2-methoxypropionic acid chloride are obtained analogously to Example 1 of the mixture of the expected diastereomeric bases. 1.7 g), which was separated by column chromatography (analogously to Example 2). A slower moving substance (0.6 g, Rf = 0.40) crystallized analogously to Example 2 as the hydrochloride. The title compound is obtained in a yield of 0.6 g (56.6% of theory) with a melting point of 275 DEG C. (decomposition) and a specific rotation ([.alpha.] D = -100.5 DEG (c -1, ch ₃ oh). .

4.1.11. Example 11 (+) - (1S, 5R, 2R) -9,9-Dimethyl-5-ethyl-2'-hydroxy-

2- (2-methoxypropyl) -6,7-benzomorphane hydrochloride ^;

Example 10 separated by column chromatography

-25leji moving diastereomer / 0.7 g, R _f. 0.45 / crystallized analogously to Example 2 as the hydrochloride. The title compound is obtained in a yield of 0.23 g (21.7% of theory) with a melting point of 216 DEG C. (decomposition) and a specific rotation ([.alpha.] D @ 20 = + 62.4 DEG ( _C = 1, ch ₃ oh). .

4.1 12 Example 12 (+) - (1S, 5R, 2S) -9,9-Dimethyl-5-ethyl-2'-hydroxy-2 '(2-methoxypropyl) -6,7-benzomorphane hydrochloride Starting from 1.69 g (0.006 mol) of (+) - 9,9-dimethyl-5-ethyl-2'-hydroxy-6,7-benzomorphane hydrochloride, 1.82 g (0.018 mol) of triethylamine and 0.96 g (0), [0078] In a similar manner to Example 1, a mixture of the expected diastereomeric bases (1.7 g) is obtained, which analogously to Example 2 is separated by column chromatography. The slower moving substance (0.6 g, Rf = 0.40) crystallizes analogously to Example 2 as the hydrochloride. The title compound is obtained in a yield of 0.6 g (56.6% of theory) with a melting point of 275 DEG C. (decomposition) and a specific rotation ([.alpha.] D @ 25 ₌ + 102.5 DEG (c = 1).

4.1.13 Example 13 (-) - (1 R, 5S, 2S) -9,9-Dimethyl-5-ethyl-2'-hydroxy-2- (2-methoxypropyl) -6,7-benzomorphane hydrochloride According to Example 12, Column The diastereomer (0.6 g, 0.45) separated by chromatography, chromatographically separated and crystallized in analogy to Example 2 as the hydrochloride. The title compound is obtained in a yield of 0.65 g (61.2% of theory) with a melting point of 219 DEG C. (slurry) and a specific rotation ([.alpha.] D @ 25 ₌ -67.5 DEG (c = 1, CH3 OH).

4.1.14. Example 14 (-) - 9,9-Dimethyl-2'-hydroxy-2 - [(R) -2-methoxypropyl] -

5-phenyl-6,7-benzomorphan

Starting from 1.76 g (6 mmol) of (+) - 9,9-dimethyl-2'-hydroxy-5-phenyl-6,7-benzomorphane (EP-B-4960) CA 93 * 4941 (1980) Starting from 0.96 g (7.8 mmol) of (R) 2-methoxypropionic acid chloride analogously to Example 1, a mixture of the expected diastereomeric bases (2.1 g) with 0.50 and 0.55 values is obtained. Example 2 /. The mixture was crystallized in analogy to Example 2 as the hydrochloride (2.4 g) and was again converted to the corresponding free base (1.8 g after evaporation). This residue of the base was crystallized from 6 ml of ethyl acetate and 18 ml of petroleum ether (80 ° C). There was thus obtained the title compound in a yield of 0.72 g (65.5% of theory) with a melting point of 202 DEG C., an Rf value of 0.50 and a specific rotation of [.alpha.] D @ 25 = -24.4 DEG / c = 1. CH 2 OH.

4.1.15 Example 15 (+) - 9,9-Dimethyl-2'-hydroxy-2 - [(R) -2-methoxypropyl] -5-phenyl-6,7-benzomorphane hydrochloride of Example 13 (acetic acid ester (petroleum ether)) is evaporated, the residue (1.2 g) is dissolved in 5 ml of ethanol and the solution is acidified with 2.5N ethanolic hydrochloric acid. After the addition of diethyl ether to the turbidity, hydrochloride (0.4 g) crystallized as a contaminated crude product, the liquor containing pure title compound which was isolated as a residue after evaporation: yield 0.75 g (62.0% of theory), temperature mp 168 ° C (dec.), Rf = 0.55, specific rotation ([.alpha.] D @ ²⁵ = + 11.6 DEG (c = 1, CH3 OH).

4.1.16 Example 16 (-) - (1R, 5S, 2R) -3'-Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride and The starting compound

The (+) - 3'-hydroxy-5,9,9-27trimethyl-6,7-benzomorphane required in this and other examples is not known in the art. For example, it can be made from the known 2'-hydroxy-isomer / LOS 2027 077; CA 74 (1971), 125482x) using m-methoxybenzyllithium instead of p-methoxybenzyllithium. In the last case, the ring closure of the benzomorphane system produces two isomeric compounds which are further used. like a mixture. The obtained mixture of 1'-hydroxy and 3'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane was separated by flash column chromatography on 100-fold amount of silica gel (iSHl K 60, 230-400 mesh ASTM, from i4acherey and Nagel) using a mixture. ethyl acetate-methanol-conc. ammonia 80: 20: 5 as eluent. Oxyacetate as a / + / - * 1-hydroxy-5,9,9-trimethyl-6,7-benzomorphan / _Rf = 0.20 / a / + / - * 3-hydroxy-5,9,9-trimethyl ₍ yl-6,7-benzomorphane (Rf = 0.14) 1: 2 in the form of thick liquid oils (Rg value: DC, silica gel 60, eluting with the above eluents).

b) Conversion to the title compound

Starting from 2.31 g (0.010 mol) of (+) - 3'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 1.6. g (0.013 mol) of (R) - (2-methoxypropionic acid chloride) was obtained analogously to Example 1 of a mixture of the expected diastereomeric bases, which was separated analogously to Example 1 by column chromatography on 100 times silica gel. The slower moving substance (Rf = 0.65), as described therein, crystallizes as the hydrochloride. The title compound is obtained in a yield of 0.86 g (50.6%) with a melting point of 240 DEG-242 DEG C. (decomposition) and a specific rotation ([.alpha.] D = -90.9 DEG (c = 1, CH3 OH)). .

4.1.17. Example 17 (+) - (1S, 5R, ^2M R) -3 ^- Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

In Example 16, the separated, faster moving substance (1 = 0.74) crystallizes analogously to Example 2 as the hydrochloride. The title compound is obtained in the yield

1.28 g / 75.3% of theory / MP: 250-252 DEG C. and a specific rotation / vk / ² ^ ⁰ = +57.1 / c = 1, CH? OH /.

4.1.18 Example 18 (+) - (1S-5R-2'S) -3'-Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphine hydrochloride

Starting from 2.31 g / 0.010 mole / / + / - ^3-hydroxy-rf 5,9,9-trimethyl-6,7-benzomorphan / see Example 16 / and 1.60 g / 0.013 mol / chloride / The (2-methoxypropionic) analogue of Example 1 yields a mixture of the expected diastereomeric bases, which is separated by chromatography-analogous to Example 2 in 10 times the amount of silica gel. Slow! moving substance / R? = 0.65 / sec, as described therein, crystallizes as the hydrochloride. To give the title compound in a yield of 0.57 g / 33.4% of theory / m.p. 239-240 ° C dec and a specific rotation / 0 (/ ^ = + 90.7 ° / c = 1, CH ₃ oh /.

4.1.19. Example 19 (-) - (1R, 5S, 2S) -3 * -Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride.

In Example 18 a separated, faster moving substance? / _Rf = 0.74 / crystallized analogously to Example 2 as the hydrochloride. To give the title compound in a yield ^υ, 6γ g / 39.2% of theory / m.p. 250-251 ° C dec and a specific rotation / = -56.5 DEG / c = 1, CH ₃ OH /.

4.1.20. Example 20 (- / -) 1R, 5R, 2R) -1'-Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphanohydride

Starting from 2.31 g (0.10 mol) of (+) - 1'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane (see Example 16) and 1.60 g of acid chloride (R) - 2-methoxypropionic. Analogously to Example 1, a mixture of the expected diastereomeric bases is obtained, which analogously to Example 2 is separated on a 100-fold amount of silica gel. The slower moving substance (Rf = 0.52) crystallizes analogously to Example 2 as the hydrochloride. To give the title compound in a yield of 0.70 g / 41.2% of theory / m.p. 128-135 ° C dec and a specific rotation / a /? ⁵ = -100.5 ° / c = 1, CH ₃ 0H /.

4.1.21. Example 21 (+) - (1S, 5S, 2'R) -1'-Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

In Example 20, the separated, faster moving substance (Rf = 0.56) analogously to Example 2 crystallizes as hydrochloride. To give the title compound in a yield of 0.40 g / 23.6% of theory / MP: 88 DEG-89 DEG C. dec and a specific rotation / c </ p5 = 50,4 ° / c = 1, CH ₃ OH /.

4.1.22 Example 22 (+) - (1S, 5S, 2S) -1 * -Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

Starting from 2.31 g (0.010 mol) (±) -1'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane (see Example 16) and 1.60 g (0.013 mol) chloride (S). -2-methoxypropionic acid. Analogously, 1 mixture of the expected diastereomeric bases is obtained, which analogously to Example 2 is distributed over a 100-fold amount of silica gel. The slower moving substance (Rf = 0.52) crystallizes analogously to Example 2 as the hydrochloride. The title compound is obtained in a yield of 0.63 g (36.8% of theory) with a melting point of 85-90 ° C. and specific rotation (? /? ⁵ = +96.2 ^tt / c = 1, CH 2 OH).

4.1.23. Example 23 R - 5R, 2 ^M S (-1 * -Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride)

Example 22 separated, the faster moving substance / _Rf = 0.56 / analogously to Example 2, crystallized as the hydrochloride. The title compound is obtained in a yield of 0.50 g (29.4% of theory) with a melting point of 90-91 ° C (decomposition) and a specific rotation ([α] D = -64.0 ° (c = 1, CH 3 OH)). .

4.1.24 Example 24 (-) - (1R, 5S, 2 '-4'-Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride a) Preparation of the starting compound

The preparation of the (+) 4'-hydroxyoxy-5,9,9-trimethyl-6,7-benzomorphane required in this and other examples is not yet known in the art, but has been prepared, for example, by a known synthesis for the art. known 2'-hydroxy-isomer (DOS 20 27 077, CA 125482x (1971)), in which o-methoxybenzyllithium is used instead of p-methoxybenzyllithium. The title compound crystallizes as a base from an isopropanol / petroleum ether mixture, m.p. 227 ° C. TLC / silica gel 6o, chloroform-methanol-conc. ammonia (65: 35: 3) has an Rf value. 0.20.

b / Conversion to the title compound

Starting from 2.31 g (0.10 mol) of (±) -4'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 1.60 g (0.01 mol) of acid chloride (R). (-2-methoxypropionic acid) was obtained analogously to Example 1 with a mixture of the expected bases (3.0 g) which was separated analogously to Example 2 by column chromatography over 450 g of silica gel. This gave 0.9 g of the slower moving compound (Rf = 0.34) and 1.3 g of a fast moving compound. moving compounds.

The first crystallizes analogously to Example 2 as the hydrochloride. The title compound is obtained in a yield of 0.95 g (55.9% of theory) with a melting point of 263 DEG C. (decomposition) and a specific rotation ([alpha] D = -86.9 DEG (c-CH3 OH)). .

4.1.25 Example 25 (+) - (1S, 5R, 2R) -4 * -Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphine hydrochloride

In Example 24, the separated, faster-moving compound (Rf0.43) analogously to Example 2 crystallizes as the hydrochloride. The title compound is obtained in a yield of 1.23 g (72.4% of theory) with a melting point of 258 DEG C. (decomposition) and a specific rotation (Dt) of + 51.7 DEG (c ^with 1, CH3 OH). .

4.1 .26 'Example 26 (+) - (1S, 5R, 2S) -4‘-Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

Starting from 2.31 g (0.10 mol) (+) - 4'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane (see Example 24) and 1.6 g (0.013 mol) (S) -2-methoxypropionic acid chloride. Analogously to Example 1, a mixture of the expected diastereomeric bases (3.1 g) was obtained, which was analogously to Example 2 separated by silica gel column chromatography. There are obtained while 1.0 g of the slower poh.ybující compound / _Rf = 0.34 / and 1.2 g of the faster moving compound. The first, analogously to Example 2, crystallized in the hydrochloride form to give the title compound in a yield of 1.15 g (67.7%) with a melting point of 260 ° C (decomposition) and a specific rotation (c) = -51.2 ° (c = 1, ch ₃ oh).

4.1.27 Example 27 (-) - (1R, 5S, 2S) -4 * -Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

In Example 26, the separated, faster moving substance (Rf = 0.43) crystallizes in analogy to Example 2 as the hydrochloride to give the title compound in a yield of 0.95 g (55.9% of theory) with a melting point of 261 DEG C. (dec.). [.alpha.] D @ 20 = + 86.1 DEG (c = 1, CH3 OH).

4.1.28 Example 28 (-) - (1R, 5S, 2R) -2 * -Methoxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane methanesulfonate Starting from 2, 45 g (0.010 mol) of (2-methoxy-5,9,9-trimethyl-6,7-benzomorphane) DOS 20 27 077; CA 125482x (1971) and 1.35 g (0.011 mol) of (R) -2-methoxypropionic acid chloride. Analogously to Example 1, a sterically uniform title compound was obtained in the form of Trole base (2.3 g). This was dissolved in 5 ml of absolute ethanol. The resulting solution was acidified. with methanesulfonic acid is mixed with diethyl ether until turbidity. From this _, while the methanesulfonate crystallizes, the same amount of ether is added once more with stirring. The reaction mixture was then cooled in an ice bath for 4 hours. It is then filtered off with suction, firstly a 1: 2 mixture of ethanol-ether is added, then washed with ether, after drying at 80 [deg.] C., the title compound is obtained in a yield of 3.3 g. / 79.8% of theory / m.p. 165-166 ° C dec and a specific rotation / C \ / £ ⁵ = -92.4 ^a / c = 1, CH ₃ OH /.

4.1.29 Example 29 (+ / - / 1S, 5R, 2'S) -2'-Methoxy-2- (2-methoxypropyl) -

5,9,9-trimethyl-6,7-benzomorphan methanesulfonate

Starting from 2.45 g (0.010 mol) of (+) - 2-methoxy-5,9,9-trimethyl-6,7-benzomorphane (DOS 20 27 077); ΟΆ 74. 125482x

(1971) and 1.35 g (0.011 mol) of (S) -2-methoxypropionic acid chloride. Analogously to Example 28, the title compound is obtained in a yield of 3.1 g (75.0% of theory) with a melting point of 165-167 (decomposition) and a specific rotation of [α] D = + 92.3 ° (c = 1, CH OH). /.

4.1.30 Example 30 (- / -) 1R, 5S, 2R / -2- (2-Methoxypropyl) -5,9,9-trimethyl 1-6-, 7-benzomorphane hydrochloride a) Production of the starting compound

Production here and in other examples needed / + / -

5,9,9-trimethyl-6,7-benzomorphane is not known in the art. It can be produced, for example, by the synthesis used for the known 2'-hydroxy derivative / DOS 20 27 077; C A (1971) (125482x) using benzyllithium instead of p-methoxybenzyllithium. The title compound crystallizes as hydrobromide from an isopropanol-ether mixture, m.p. 259 DEG C. (dec.).

b / Converting to the title compound

Starting from 2.96 g (0.010 mol) of (+) - 5,9,9-trimethyl-6,7-benzomorphane and 1.35 g (0.011 mol) of (R) -2-methoxy-propionic acid chloride. Analogously to Example 1, a mixture of the desired diastereomeric bases is obtained. Analogously to Example 2, these were separated by column chromatography over 100-fold silica gel. The slower the substance / R = °, ⁶ 3 / SE to the same place popsáno- crystallized as hydrochloride. The title compound is obtained; yield of 1.3 g / 76.5% of theory / MP: 225 DEG C. dec and a specific rotation / (\ / p ⁵ = -101.7 ° / c = 1, CHjOH /.

4.1 .31 Example 31 (+ / - / 1S, 5R, 2''R) -2- (2-Methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane oxalate

In Example 30, the separated, faster moving substance (Rf = 0.67) was dissolved in 5 th ethanol. After acidification with oxalic acid, the solution was mixed with diethyl ether until turbid. While crystallization is in progress, half the original amount of ether is added once more and left in the refrigerator for about 12 hours. After aspiration, washing the mixture with ethanol ether and drying at 80 ° C, the title compound is obtained in a yield of 1.1 g (60% of theory) with a melting point of 135 ° ^C (decomposition) and a specific rotation (c /) = +60.2 ° (c = 1, CH 2 OH).

4.1.32 Example 32 (-) - / 1R, 5S, 2R / -2- (2-Methoxypropyl) -2 *, 5,9,9-tetramethyl-6,7-benzoforane hydrochloride a) Production of the starting compound

The (+) - 2,5,9,9-tetramethyl-6,7-benzomorphane required in this and other examples is not known in the art. However, it can be produced, for example, by the synthesis known for the 2'-hydroxy analogue, in which p-methylbenzyllithium is used instead of p-methoxybenzyllithium. The intermediate thus obtained is crystallized from an isopropanol-diethyl ether mixture as the hydrobromide, which melts at 227 DEG C. with decomposition.

b / Converting to the title compound

Starting from 1.51 g (5 mmol) of (+) - 2 ', 5,9,9-tetramethyl-

Of 6,7-benzomorphane and 0.68 g (5.5 mmol) of (R) -2-methoxypropionic acid chloride. Analogously to Example 1, a mixture of the expected diastereomeric bases is obtained which, as described therein, crystallizes as the hydrochloride and is separated. The title compound was obtained in a yield of 0.7 g / after recrystallization

0.4 g = 47.3 $ of theory / MP: 212 DEG C. dec and a specific rotation / -110.0 ⁰ / C = 1, CH? OH /.

4.1.33. Example 33 (+) - 1S, 5R, 2S / -2- (2-Methoxypropyl) -2 * -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

Starting from 1.51 g (5 mmol) of (+) - 2 * -5,9,9-tetramethyl-6,7-benzomorphane and 0.68 g (5.5 mmol) of acid chloride (S) -2- methoxypropionic. Analogously to Example 32, the title compound was obtained in a yield of 0.4 g (47.3% of theory) with a melting point of 212 DEG C. (decomposition) and a specific rotation of [.alpha.] D @ 25 ₌ + 111.8 DEG (c = 1; CH3 OH). /.

4.1.34 Example 34 (-) - (1R, 5S, 2'R) -2'-Anino-2- (2-methoxypropyl) -

5,9,9-trimethyl-6,7-benzomorphine-dihydrochloride a) Preparation of the starting compound

In this and other examples, the necessary (+) - 2 * -nitro-

5,9,9-trimethyl-6,7-benzomorphane is not yet known in the art. For example, it can be prepared by nitration of (+) - 5,9,9-trimethyl-6,7-benzomorphine (Example 30) analogously to the procedure described by ELMpy and EMFry (J. Org. Chem. 22 (1957) 1366). /. The resulting intermediate crystallized as the hydrochloride from an ethanol-ether mixture, which melts at 289 ° C (dec.).

b / Acylation

2.97 g (0.01 mol) of (+) - 2'-nitro-5,9,9-trimethyl-6,7benzomorphane hydrochloride were acylated in the presence of 3.04 g (0.03 mol) of triethylamine analogously to Example 1 1.35 g (0.011 mol) of (R) -2-methoxypropionic acid chloride. After working up, 3.5 g (almost 100% of theory) of the intermediate type 3 are obtained.

-35c) Catalytic hydrogenation of 2'-nitro and 2'-amino

3.5 g of intermediate b) were dissolved in 70 ml of methanol and hydrogenated in the presence of 0.4 g of palladium on carbon / Pd content: 5% / pM 20 [deg.] C. under a hydrogen pressure of 0.5 MPa. Hydrogen uptake stops after 4 hours - after the calculated amount has been consumed -. After filtering off the catalyst, the reaction mixture was evaporated, finally at 80 ° C and under full vacuum. The rest 3.1 g (almost 100% of theory).

d / Lithium aluminum hydride bedding

The residue obtained above (3.1 g) was reduced, analogously to Example 1, with 1.3 g of lithium aluminum hydride (lithium tetrahydridoanalate). The mixture of the two expected diastereomers (2.7 g) was separated analogously to Example 2 by column chromatography over 500 g of silica gel. Slow! The moving substance (0.7 g, 0.65) was analogous to Example 2 (but with two equivalents of hydrochloric acid) crystallized as the dihydrochloride. The title compound is obtained in a yield of 0.95 g (50.6% of theory) and a melting point of 260 DEG C. (decomposition) and a specific rotation (.alpha.) = -93.4 DEG (c = 1, CH3 OH).

4.1.35. Example 35 (+) - (1S, 5R, 2R) -2-Amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane dimethanesulfonate

0.9 g of the Example 34 single, faster moving substance / _Rf = 0.70 / analogously to Example 43 / but with 2 equivalents of methanesulfonic acid / crystallized from methanol-diethyl ether. The title compound is obtained in a yield of 0.48 g (19.4% of theory) with a melting point of 189 DEG C. (decomposition) and a specific rotation (<.alpha.) = + 55.6 DEG (c = 1, CH3 OH). /.

EXAMPLE 36 (+) - (1S, 5R, 2'S) -2'-Anino-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride. starting from 2,97 g (0,01 mol) of (+) - 2'-nitro-5,9,9-trimethyl-6,7-benzomorphane hydrochloride, 3,04 g (0,03 mol) of triethylamine and 1, 35 g (0.011 mol) of (S) 2-methoxypropionic acid chloride, 3.5 g (almost 100% of theory) of the desired acylation product are obtained, which - as described therein - is catalytically hydrogenated (3.2 g of hydrogenation product). and finally reduced with lithium aluminum hydride (lithium tetrahydridoanalate). The reducing product (2.8 g), which is a mixture of the expected diastereomeric bases, is dissolved in 10 ml of isopropanol with heating. After about 12 hours of crystallization on standing in the refrigerator, the precipitate is slowly chromatographed. moving substance / R ^? 0.65 (as base) 0.75 g = 49.0% of theory (m.p. 142 DEG C.). Analogously to Example 32, 0.3 g of the dihydrochloride crystallized. The title compound (0.37 g) was obtained with a melting point of 265 DEG C. (decomposition) and a specific rotation of [.alpha.] D @ 20 ⁼ + 92.5 DEG. 1, CH-OH).

4.1.37 Example 37 (-) - (1R-5S-2S) -2 * - Anino-2- (2-methoxypropyl) -

The 5,9,9-trimethyl-6,7-benzomorphane dihydrochloride of the isopropanol mother liquor from Example 34 was evaporated and the residue (2.0 g) was chromatographed on 300 g of silica gel analogous to Example 2. It yields 0.3 g of another slower moving material. substance / R = 0.65, example 34 / gave a faster running subatance / 1.2 g, _Rf = 0.70 / diastereomer which was crystallized analogously to example 32 as a dihydrochloride. The title compound is obtained in the yield

1.48 g (78.8% of theory) with a melting point of 259 DEG C. (decomposition) and a specific rotation of -68.4 DEG (c = 1, CH3 OH).

4.1.38 Example 38 (+) - 2 * -Hydroxy-2- (2-methoxyisobutyl) -5,9,9-trimethyl-6,7-benzomorph anhydrobromide

Starting from 1.16 g (0.005 mol) of (+) - 2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 0.75 g (0.055 mol) of 2-methoxyisobutyric acid chloride, Analogously to Example 1, the basic form of the title compound (1.1 g) was initially dissolved in 5 ml of methanol and, after acidification with H3r (62%), the solution was mixed with diethyl ether until turbid. After standing in a refrigerator for about 12 hours, the title compound crystallized, filtered off with suction, washed with ethanol-ether and dried at 80 ° C. Yield 1.1 g (55.2% of theory), m.p. 232 DEG C. (dec.), Sample recrystallized from methanol-ether melts at 240 DEG C. (dec.).

4.1.39 Example 39 (-) - (1R, 5S, 2'R) -2 '-Hydroxy-2- (2-methoxybutyl) -5,9,9-trimethyl-6,7-benzomorphine hydrochloride!

a) Preparation of the starting compound

In this and other examples, the (R) -2-methoxybutyric acid chloride required may be produced e.g. from the known (R) -2-methoxybutyric acid / N.K.Kochetkov, A. 14. Likhosherstov and V, N, Kulakov, Tetrahedron 25 (1969) 2313) th thionylchlorifu at room temperature. The acid chloride remaining after removal of excess thionyl chloride is used without purification in the next step.

b / Converting to the title compound

Starting from 3.47 g (0.015 mol) of (+) - 2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 2.46 g (0.018 mol) of the acid chloride (R) -2- methoxybutyric and obtained analogously to Example 1 the title compound in a yield of 1.8 g (67.8% of theory)

-38s melting point of 246 C dec ^Q and a specific rotation / a (/ ₌ 25, ₁ 18,4 ° / c = 1, CH-Joh /.

4.1.40 Example 40 (+) - (1S, 5R, 2R) -2 * -Hydroxy-2- (2-methoxybutyl) -5,9,9-trimethyl-6,7-benzomorphan-1-yl, hydrochloride

The mother liquor of Example 39 was evaporated. Analogously to Example 2, the title compound is obtained in a yield of 1.3 g (48.9% of theory) with a melting point of 228 DEG C. (decomposition) and a specific rotation ([.alpha.] D @ ²⁰ = + 79.9 DEG). 1, CH-OH).

4.1.41. Example 41 (-) - (1R, 5S, 2'S) -2'-Hydroxy-2- (2-methoxybutyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride a / Production of the title compound

The (S) -2-methoxybutyric acid chloride required in this example and in other examples can be prepared e.g. from the known acid (S) -2-methoxybutyric acid / Tetrahedron 25 (1969) 2322, analogously to Example 39.

b / Converting to the title compound

Starting from 3.47 g (0.015 mol) of (+) - 2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 2.46 g (0.018 mol) of acid chloride (S) -2-methoxybutyric acid , analogously to Example 1, the title compound is obtained in a yield of 1.6 g (60.3 g of theory) with a melting point of 246 DEG C. (decomposition) and a specific rotation ([ ^delta] = + 119.2 DEG / c = 1), CH ₃ OH].

4.1.42 Example 42 (+) - (1S, 5R, 2S) -2 * -Hydroxy-2- (2-methoxy-butyl) -5,9,9-trimethyl-6,7-benzomorphine hydrochloride from Example 41 was evaporated. Analogously to Example 2, the title compound is obtained in a yield of 0.6 g (22.6% of theory) with a melting point of 228 DEG C. (decomposition) and a specific rotation ([.alpha.] D = -71.7 DEG (c = 1)). CH 2 OH.

4.1.43 Example 43 / - / - / 1 R-2 R-5 S / -2- / ^2-ones enzyloxypropyl / -2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan hydrochloride and / Production of the starting compound

The (R) -2-benzyloxypropionic acid chloride used in this and other examples can be prepared, for example, as follows:

The commercially available (R) - (+) - lactic acid isobutyl ester in the presence of silver oxide O-benzylated with benzyl bromide. Subsequent saponification with sodium hydroxide affords (R) -2-benzyloxypropionic acid having a specific rotation value (Οζ) of [α] D = + 79.5 ° (c = 1, CH 2 OH). Analogously to Example 39, the corresponding acid chloride is obtained.

b / Converting to the title compound

Starting from 3.47 g (0.015 mol) of (X) -2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 3.3 g (0.0165 mol) of acid chloride (R) The 2-benzyloxypropionic acid is obtained analogously to Example 1 of a mixture of the expected diastereomers, which, as described therein, is separated by crystallization of the corresponding hydrochlorides. The title compound is obtained in a yield of 2.39 g (76.6% of theory) with a melting point of 250 DEG C. (dec.) And a specific rotation of [.alpha.] D @ ²⁵ = -119.3 DEG (c = 1, CH3 _). OH /.

4.1.44 Example 44 (+) - (1S, 5R, 2'S) -2- (2-Benzyloxypropyl) -2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane hydrochloride a) Production of the starting compound

The (S) -2-benzyloxypropionic acid chloride used in this and other examples may be e.g. t prepared analogously to Example 43 from the acid / S / 2-benzyloxypropionic / specific rotation / CH / J · · ² »-78.5 DEG / c = 1, CH ₃ OH //.

b / Converting to the title compound

Starting from 3.47 g (0.015 mol) of (+) - 2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 3.3 g (0.0165 mol) of acid chloride (S) - The title compound was obtained in a yield of 2.56 g (82.1% of theory), with a melting point of 250 DEG C. (decomposition) and a specific rotation of [.alpha.] D @ 25 = + 119.5 DEG (c = 1). CH ₃ OH].

4.1.45 Example 45 (-) - (1R, 5S, 2R) -2'-Hydroxy-2- (2-methylthiopropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride a) Preparation of the starting compound

The (R) -2-methylthiopropionic acid chloride which is required in this and other examples can be prepared analogously to Example 39 from the known (R) -2-methylthiopropionic acid) by L.N.Owen and M.B.Rahman, J. Chem. Soc. (c) 1971, 2432].

b / Converting to the title compound

1.62 g (0.007 mol) of (+) - 2'-hydroxy-5,9,9-trimethyl-6,7-41benzomorphane were reacted in analogy to Example 1 with 07 g (7.7 mmol) of the acid chloride. / 2-methylthiopropionic. Reduction of the resulting reaction product 1 with lithium aluminum hydride (LiAlH 2) yields a mixture of the expected diastereomers which are separated by crystallization of their nitrates. A substance that crystallizes from ethanol after acidification with 65 $ nitric acid and mixing with diethyl ether. until it becomes turbid, sucked off after about 12 hours in the refrigerator, washed with ethanol-ether and then with ether, and dried at 80 ° C. The nitrate (0.67 g) was recrystallized from boiling ethanol (0.52 g), converted to the free base and finally crystallized as the hydrochloride analogously to Example 2. The title compound is obtained in a yield of 0.43 g (34.4% of theory) with a melting point of 265 DEG C. (decomposition) and a specific rotation (.delta. OH ^ /.

4.1.46 Example 46 (+) - (1S, 5R, 2R) -2 * -Hydroxy-2- (2-methylthiopropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride Fatty liquors from Example 45 after the first crystallization of the nitrate is evaporated and the nitrate residue is converted to the free base. This (1 g) is analogously to Example 53 filtered through 20 g of alumina and then crystallized as the hydrochloride (ethanol-ether). This (0.29 g) was recrystallized from a mixture of 2 ml of methanol and diethyl ether. The title compound is obtained in a yield of 0.21 g (16.8% of theory) with a melting point of 238 DEG C. (decomposition) and a specific rotation ([.alpha.] D @ 25 = + 73.0 DEG (c = 0.5, CH). OH /.

-424.1.4? Example 47 / - / - / 1 R, 5S, 2S / -2 * -Hydroxy-2- (2-methylthiopropyl-5,9,9-trimethyl-6,7-benzomorphane hydrochloride a) Preparation of the starting compound

In this and other examples, the required (S) -2-methylthiopropionic acid chloride can be prepared, for example, from the known (S) -2-methylthiopropionic acid. 1971, 2437 (analogous to Example 39 * b) Conversion to the title compound

Starting from 1.62 g (0.007 mol) of (+) - 2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane, analogously to Example 45 ', the title compound is obtained in a yield of 0.42 g (33%), 6% of theory / mP: 265 DEG C. dec and a specific rotation / C </ = ²⁵ + 135.1 ° / c = 0.5, CH ₃ OH /.

4.1.48 Example 48 (-) - (1 R, 58,2S) -2 * -Hydroxy-2- (2-methylthiopropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

Starting from the nitrate mother liquors of Example 47 and analogously to Example 46, the title compound is obtained in a yield of 0.34 g (27.2% of theory) with a melting point of 238 DEG C. (dec.) And a specific rotation ([beta] = -73). 9 ° (c = 0.5, CH 2 OH).

4.1.49 Example 49 (+) - (1S, 5R, 2S) -2- (2-AL1, yloxypropyl) -2'-hydroxy-

5,9,9-trimethyl-6,7-benzomorphane hydrochloride a) Preparation of the starting compound

The (S) - (-) - 2-allyloxypropionic acid chloride used may be prepared e.g. The commercially available (S) - (-) - lactic acid ethyl ester in the presence of silver oxide O-allyl is allyl bromide. Subsequent saponification with sodium hydroxide affords (S) -2-allyloxypropionic acid having a temperature of 110-112 at a pressure of 0.0015 ° C of specific rotation (λ ° C) = 79.4 ° (c = 1 CH ₃ OH). Analogously to Example 39, the corresponding acid chloride is obtained.

b / Converting to the title compound

Starting from 3.47 g (0.015 mol) of (+) - 2H-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 3.3 g (0.0165 mol) of acid chloride (S) -2. The allyloxypropionic and analogous Example 1 yields a mixture of the two expected diastereomers which, as described therein, is separated by crystallization of the corresponding hydrochlorides. To give the title compound in a yield of 1.4 g / 51% /, melting point 245 DEG C. dec and a specific rotation / C \ / § ⁵ = 120 ° / c = 1, CH? OH /.

4.1.50. Example 50 (-) - (1S, 5R, 2'S) -2- (2-Allyloxypropyl) -2'-hydroxy-5,9,9-trimethyl-6,7-benzomorph an-h. The hydrochloric acid of Example 49 was evaporated. From the residue, analogously to example 2 the title compound in a yield of 0.62 g / 22.6% of theory / MP: 213 DEG C. and a specific rotation / q ⁵ = -38.6, DEG / c = 1, CH? OH / .

4.1 .51 Example 51 / - / - / 1 R, 5S. 2R / -2 * -Hydroxy-2- (2-phenoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

2.31 g (0.010 mol) (+) - 2'-hydroxy-5,9,9-trimethyl-

Of 6,7-benzomorphane and 2.03 g (0.011 mol) of (R) -2-phenoxypropionic acid chloride prepared analogously to Example 39 from the corresponding acid (CA 72. 12917d) were reacted analogously to Example 1. A mixture of the two expected diastereomers is obtained, which, as described therein, is separated by crystallization of the corresponding hydrochloride. There was thus obtained the title compound in a yield of 1.6 g / 79.6% of theory / MP: 279 DEG C. dec and a specific rotation / a / d ⁵ = -142.9 ° / c = 1, CH ₃ OH /.

4.1.52 Example 52 (+) - (1S, 5R, 2S) -2'-Hydroxy-2- (2-phenoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride analogously to Example 51 with (S) -2-phenoxypropionic acid chloride to give the title compound in a yield of 1.6 g with a specific rotation (ο ([α] +143.3 ° C / c = CH ₃ OH).

4.1.53 Example 53 (-) - (1R, 5S, 2R) -3 * -Hydroxy-2- (2-methoxypropyl) -5,9,9-2'-tetramethyl-6,7-benzomorphane hydrochloride and The starting compound. In this and the other examples, the (+) - 3'-hydroxy-5,9,9,9-tetremethyl-6,7-benzomorphane required is not known in the art. It can be prepared, for example, by the method known for 2'-hydroxy derivative / DOS 20 27 077; C A 74 (1971), 125482x), in which instead of p-methoxybenzyllithium is used

3-methoxy-4-methylbenzyllithium. Ring closure on the benzomorphane system yields predominantly 3'-hydroxy-5,9,9,2'-tetramethyl-6,7-benzomorphane, which is purified by flash column chromatography (cf. cf.). 16 /.

-45b / Converting to the title compound

Starting from 2.44 g (0.010 mol) of (+) - 3'-hydroxy-5,9,9,2'-tetramethyl-6,7-benzomorphane and 1.6 g of (R) -2-methoxypropionic acid chloride (0.013 mol) was obtained analogously to Example 1 with a mixture of the expected diastereomeric bases which were separated by column chromatography on 100 times the amount of silica gel analogously to Example 2. Slowly! The moving substance (0.25) is crystallized as the hydrochloride. The title compound is obtained in a yield of 1.0 g (59.9%) with a melting point of 181-182 ° C and a specific rotation (λ) = -89.5 ° (c = 1.0, CH 3 OH).

4.1.54 Example 54 / + / - /! S, 5R, 2R (-3 * -Hydroxy-2- (2-methoxypropyl) -5,9,9,2'-tetramethyl-6,7-benzomorphane hydrochloride;

In Example 53, the separated, faster moving substance (Rf = 0.34) is eliminated analogously to Example 2 as the hydrochloride. To give the title compound in a yield of 1.24 g / 70.1% / as an amorphous powder with a specific rotation / 'E ⁵ = + 55.9 ° / c = 1, CH ₃ OH /.

4.1.55. Example 55 (+ / - / 1S, 5R, 2'S) -3'-Hydroxy-2- (2-methoxypropyl) -5,9,

9,2-tetramethyl-6,7-benzomorphane hydrochloride

Starting from 2.44 g (0.010 mol) (±) -3'-hydroxy-5,9,9,2'-tetramethyl-6,7-benzomorphane (see Example 53) ^and 1.6 g (0.013 mol) of the acid chloride / S / 2-methoxypropionic. Analogously to Example 1, a mixture of the expected diastereomeric bases is obtained which is resolved by column chromatography over 100 times the amount of silica gel. The more slowly moving substance (Rf = 0.25) is crystallized as hydrochloride-46rid. The title compound is obtained in a yield of 1.48 g (83.6%) with a melting point of 186 DEG-188 DEG C. and a specific rotation ([.alpha.] D = + 88.2 DEG ( _c = 1, CH3 OH)).

4.1.56 Example 56 / - / - / 1 R, 5 S, 2 S / -3 * - ^hl Hydroxy-2- / 2-methoxypropyl / -5,9,9,2'-tetramethyl-6,7-benzomorphan

In Example 55, a separated, slower moving substance (Rf = 0.34) is eliminated analogously to Example 2 as the hydrochloride. To give the title compound in a yield of 1.40 g / 79.1% / as an amorphous powder S® specific rotation ^{/ £} / f ⁵ = -56.8 DEG / c = 1, CH ₃ 0H /.

4.1.57 Example 57 (- / -) 1R, 5S, 2''R) -2'-Hydroxy-2- (2-methoxylpropyl) -5,9,9,3 * -tetramethyl-6,7 -benzomorphane hydrochloride a) Starting compound

The (+) - 2'-hydroxy-5,9,9,3'-tetramethyl-6,7-benzomorphane required in this and other examples is not known in the art. For example, the process known for the 2'-hydroxy derivative / DOS 20 27 077 can be produced; C A (1971), 1254823], in which 4-methoxy-3-benzyllithium is used instead of p-methoxybenzyllithium. By ring closure on the benzomorphane system, the 2 &apos; -hydroxy-5,9,9,3 &apos; -tetramethyl-6,7-benzomorphane is predominantly obtained and is purified by flash chromatography on a column cf. 16 /.

b / Converting to the title compound

Starting from 2.44 g (0.010 mol) of (+) - 2'-hydroxy5,9,9,3 * tetramethyl-6,7-benzomorphane and 1.6 g (0.013 mol) of acid chloride (R) -2 The methoxypropionic analogue of Example 1 is obtained by a mixture of the expected diastereomeric bases which is separated by column chromatography on 100 times the amount of silica gel according to Example 2. The slower moving substance (Rf = 0.26) crystallizes as the methanesulfonate. To give the title compound in a yield of 1.64 g / 79.3% /, melting point 266-268 DEG C. and a specific rotation / λ / ⁵ ο = -95.4 DEG / c = 1, CH ₃ OH /.

4.1.58 Example 58 (+ / -) 1S, 5R, 2'R (-2 ⁾ -Hydroxy-2- (2-methoxypropyl) -5,9,9,3 * -tetramethyl-6,7-benzomorphane hydrochloride

In Example 57, a separated, more rapidly moving substance (Rf = 0.29) is excreted analogously to Example 2 as the hydrochloride. The title compound is obtained in a yield of 1.60 g (90.4%) as an amorphous powder having a specific rotation ([α] D ₌ + 73.4 ° ( _{c = 1} , CH ₃ OH)).

4.1.59 Example 59 (+) - (1S, 5R, 2'S) -2-hydroxy-2- (2-methoxypropyl) -5,9,9,3'-tetramethyl-6,7-benzomorphane methanesulfonate ^ starting from 2.44 g (0.010 mol) (+) - 2'-hydroxy-5,9,9,3'-tetramethyl-6,7-benzomorphane (see Example 57) and 1.6 g (0.013 mol) (S) -2-methoxypropionic acid chloride and analogously to Example 1 of a mixture of the expected diastereomeric bases, which is separated by column chromatography on 100 times the amount of silica gel analogously to Example 2. The slower moving substance (Rf = 0.26) crystallizes as methanesulfonate . Live _with ka the title compound in a yield of 1.56 g / 88.1%, melting point of 265-267 and a specific rotation / ^ 7 ^ = + 96.9 ° / c = 1, CH ₃ OH /.

4.1.60 Example 60 (-) - (1R, 5S, 2'S) -2'-Hydroxy-2- (2-methoxypropyl) -5,9,9,3'-tetramethyl-6,7-benzomorphane- hydrochloride

In example 59 separated, the faster moving substance / _Rf = 0.29 / precipitated analogously to Example 2 as the hydrochloride. Live _with ka the title compound in a yield of 1.36 g / 76.8% / as an amorphous powder with a specific rotation / ^ / ^ = - 74,9 ° / c = 1, CH ₃ 0H /.

4.1.61 EXAMPLE 11 (R) 5S, 2R (-2 '), 3'-Dihydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride a) Starting compound

The (+) - 2 *, 3 * duhydroxy-5,9,9-trimethyl-6,7-benzomorphane required in this and other examples is not known in the art. For example, it can be prepared in a manner known per se for the 2'-hydroxy derivative / DOS 2 &lt; 27 077; C 74 (1971) (125482x), in which p-methoxybenzyllithium is used

3,4-dimethoxybenzyllithium. On ring closure on the benzomorphane system, the predominantly obtained 2 ‘, 3'-dihydroxy-5,9,9-trimethyl-6,7-benzomorphane is obtained, which is purified by flash column chromatography (cf. c.). 16 /.

b / Converting to the title compound

Starting from 8.51 g / 0.03 mol / / + / - 2 ', 3' -dihydroxy-

5,9,9-trimethyl-6,7-benzomorphane hydrochloride and 4.1 g (0.033 mol) of (R) -2-methoxypropionic acid chloride. Analogously to Example 1, a mixture of the expected diastereomeric bases is obtained which is separated by flash column chromatography on a 100-fold amount of silica gel analogously to Example 2. The slower moving substance (Rf = 0.21) crystallizes as the hydrochloride.

The title compound was obtained in a yield of 2.54 g (47.6%) with a melting point of 167 ° C (dec.) And a specific rotation ([α] 25 = -93.0 ° / c = 0.5, CH ₃ OH). /.

4.1.62 Example 62 / + / - / 1 S, 5 R, 2 'R / 2' 3 _{'T-Dihydroxy-2/2-methoxypropyl} / -5,9,9-Trimethyl-6,7-benzomorphan hydrochloride

In Example 61, the separated, more rapidly moving substance (Rf = 0.29) is eliminated analogously to Example 2 as the hydrochloride. To give the title compound in a yield of 2.28 g / 42.7 35 / MP: 251 DEG C. dec and specific otáčivistí / / 2 ⁵ = + 64.3 ^H / C = 0.5, CH-Joh / .

4.2 Compounds (1) according to Method 3 · 2

4.2.1 Example 63 (+) - 2 * -Hydroxy-2- (2-methoxyethyl) -5,9,9-trimethyl-6,7-benzomorphane hydrobromide

0.6 g (0.003 mol) of (+) - 2'-hydroxy-5,9,9-trimethyl-6,7benzomorphane, 0.72 g (0.0075 mol) of 2-methoxyethyl chloride, 0.11 g (0), Sodium iodide (0075 mol) and sodium bicarbonate (0.95 g, 0.0113 mol) in absolute dimethylformamide (10 ml) were stirred at 95 ° C for 23 hours. Then the reaction mixture was evaporated on a rotary evaporator, finally at 95 ° C and under full vacuum of the water pump. The residue is taken up in 25 ml of water and 25 ml of dichloromethane and the separated aqueous phase is extracted again with 10 ml of dichloromethane. The combined extracts were washed with water, dried over sodium sulfate and, after filtering off the desiccant, evaporated in vacuo as described above. The free base residue of the title compound crystallizes analogously to Example 38 as hydrobromide. Z ka _of the title compound in a yield of θ, 48 g / 43.5% of theory / MP: 247 ° C / dec · / ·

4.2.2 Example 64 / - / - / 1 R, 5 S, ^M R 2/2 '-hydroxy-2/2-methoxypropyl / -5,9,9-Trimethyl-6,7-benzomorphan hydrochloride

3) Production of an alkylating agent by the prior art known acid (+) - (R) -. 2-methoxypropionic lithium aluminum hydride (LiAlH 4) is obtained (-) - (R) -2-methoxypropanol with a boiling point of 70 ° C at a pressure of 0.0076 MPa and a specific rotation / =

-15, θ ° (c = 100). Analogously, it is obtained from the known (-) - (S) -2-methoxypropionic acid corresponding to (+) - (S) -2-methoxypropanol having a boiling point of 70 DEG C. at a pressure of 0.0076 MPa and a specific rotation of < = + 16.5 ° (c = 100).

The reaction of (-) - (R) -2-methoxypropanol with p-toluenesulfonic acid chloride in pyridine analogously to the method of RSTipson (J. Org.Chem.2) (1944) 235 // yields (+) - (R) 2- methoxypropyl p-toluenesulphonate in the form of a yellowish oil with a specific rotation of A 1 / = = + 3.7 (c = 100) and in an analogous manner from (+) - (S) -2-methoxypropanol corresponding to (-) (S) -2 -methoxypropyl p-toluenesulfonate having a specific rotation = -3.7 ° (c = 100).

b / Converting to the title compound

1.16 g (5 mmol) of (+) - 2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane (Example 1) was heated with 1.83 g (7.5 mmol) of (R). (-2-methoxypropyl p-toluenesulfonate), 1.26 g (0.015 mol) sodium bicarbonate and 1.12 g (7.5 mmol) sodium iodide in a mixture of 15 ml of absolute dimethylformamide and 25 ml of absolute tetrahydrofuran for 60 hours with stirring on the reflux temperature. Finally, it is worked up analogously to Example 63. A mixture of the two expected diastereomeric bases (2 g) is obtained, which can also be prepared according to Example 1 in another manner. The crystals were separated by crystallization of the hydrochlorides as described and the title compound was obtained in a yield of 0.55 g (64.7% of theory) with a melting point of 264 DEG C. (dec.).

-51a specific rotation [.alpha.] D @ 20 = -118.2 DEG (c = 1, CH3 OH). Analogously to Example 2, the (+) - (1S, 5R, 2'R) diastereomer can be obtained from the mother liquors.

4.2.3 Example '65 / - / - / 1 R, 5S, 2 'R (-2- / 2-Methoxypropyl) -2-nitro-5,9,9-trimethyl-6,7-benzomorphane hydrochloride

2.97 g (0.010 mol) of (+) - 2'-nitro-5,9,9-trimethyl-6,7benzomorphane hydrochloride (Example 34) were treated analogously to Example 54 with 2.68 g (0.011 mol) of () R (-2-methoxypropyl p-toluenesulfonate), 1.65 g (0.011 mol) sodium iodide and 2.1 g (0.025 mol) sodium bicarbonate.

As a reaction product, a mixture of both expected diastereomeric bases (3.2 g) is first isolated as described therein. To separate the by-products, it is dissolved in 64 ml of dichloromethane and the solution is filtered through a column of 64 g of alumina (activity III - neutral Brockmann). After elution with an additional 128 ml of dichloromethane, the phthalate is evaporated on a rotary evaporator - finally at 80 ° C and under full vacuum of the water pump. The residue (2.4 g) was dissolved in 10 ml of methanol and, after acidification with 2.5N ethanolic hydrochloric acid, treated with diethyl ether until turbidity started. The title compound crystallized, which was sucked off after 3 days at room temperature, washed with ethanol-ether (1: 1), then ether and dried at 80 ° C. The title compound is obtained in a yield of 0.84 g (45.5% of theory) (3), m.p. 226 DEG C. (dec.), Specific rotation ([.alpha.] D = -120 DEG (c = 1, CH OH)). From mother liquors. if desired, a stereoisomeric (+) - (1S, 5R, 2'R) -compound can be obtained.

4.2.4. Example 66 (+) - (1S, 5R, 2S) -2- (2-Methoxypropyl) -2'-nitro-5,9,9-trimethyl-6,7-benzomorphane hydrochloride

Starting from 2.97 g (0.010 mol) + / - ^2-4- nitro-5,9,9-trimethyl-6,7-benzomorphane hydrochloride and 2.68 g (0.011 mol) (S) -2- of methoxy-p-toluenesulfonate, analogously to Example 65, the title compound is obtained in a yield of 0.96 g (52.0% of theory) with a melting point of 226 DEG C. (decomposition) and a specific rotation (c (.beta. = + 21 DEG)). Example 2 The sterebisomeric (-) - (1R, 5S, 2S) -form can be obtained from the mother liquors analogously to Example 2.

4.2.5. Example 67 (-) - (1R, 5S, 2R) -2- (2-ethoxypropyl) -3 * -nitro-

5,9,9-trimethyl-6,7-benzomorphane a) Preparation of the starting compound

In this and other examples, the necessary (+ / -) 3 -nitro-,

5,9,9-trimethyl-6,7-benzomorphane forms the (+) - 2'-nitroisomer in the nitration of 5,9,9-triethyl-6,7-benzomorphane (Example 34) in a ratio of about 1: 3. The reaction is carried out from the mother liquors, 2'-nitro-isomers, crystallizing as the hydrochloride, via the initially prepared base. Crystallized as oxalate (m.p. 158 ° C, dec.) From a 10-fold amount of methanol. The oxalate is recovered on a base / non-crystalline basis, which is used for the reaction described below. A sample of the base, crystallized as methanesulfonate, melts at 242 ° C (dec.).

b / Converting to the title compound

5.2 g (0.02 mol) of (+) - 3'-nitro-5,9,9-trimethyl-6,7-benzomorphane were treated analogously to Example 65 with 5.36 g (0.022 mol) of (R) -2. methoxypropyl-p-toluenesulphonate. ⁱⁿ that the reaction product was a mixture of the two expected stereoisomeric base / 8 g /, which - as described in Example 65-a flltrací purified through alumina / 4.7 g of purified base mixture /. In a thin-layer chromatogram (Kieselgel 60, toluene-ethyl acetate 85M5, 3 times developed)

-53 show diastereoisomers R? 0.81 and 0.85. Separation of 1 g of diastereomeric mixture on 300 g of silica gel by column chromatography eluting the title compound (100 mg) with a value of 0.81 as a brownish, very viscous oil which did not crystallize.

4.2.6. Example 68 (+) - (1S, 5R, 2R) -2- (2-Ethoxypropyl) -3'-nitro-5,9, investigating thiyl-6,7-benzomorph or column chromatography as described in Example 67, the diastereomeric mixture also isolates, apart from the (-) - (1R, 5S, 2R) -forms (R ^ = 0.81) also 100 mg (+) - (1S, 5R, 2S). of the form (R ^ = 0.85) as a brownish, very viscous oil which does not crystallize.

4.2.7 Example 69 (- / -) 1R, 5S, 2R) -2 * -Chloro-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride a compounds

(+) - 2‘-Chloro-

5,9,9-trimethyl-6,7-benzomorphane can be e. from the 2 * nitro analogone (Example 34), where the last is hydrogenated to a 2''-amino compound (dihydrochloride: mp 283 ° C, dec.) and this is converted by Sandmeyer reaction to the desired 2'-chloro compound / hydrobromide: . mp 310 ° C, (dec.).

b / Converting to the title compound

3.3 g (0.010 mol) of (+) - 2'-chloro-5,9,9-trimethyl-6,7benzomorphane hydrobromide and 2.68 g (0.011 mol) of (R) -2-methoxypropyl p-toluenesulfonate were reacted in analogy to Example 65 to a mixture of both desired diastereomeric bases and, as described therein, purified by filtration through alumina. The purified mixture of diastereomers was analogously to Example 1 separated by crystallization of the hydrochlorides. The title is obtained

t ŕ

-54sloučenina in a yield of 0.27 g / 15.1% of theory / MP: 287 DEG C. dec and a specific rotation / ^ / ^ = - 102.6 ⁰ / C = 1, CH-Joh /.

4.2.8. Example 70 (+) - (1S, 5R, 2'R) -2'-Chloro-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

The mother liquors of Example 69 were evaporated and the residue dissolved in the necessary amount of boiling methanol. ^p of addition of diethyl right-to commencing cloudy and crystallization to give the title compound which. The mixture is suctioned off after standing for about 12 hours at room temperature, washed with ethanol / ether 1: 1, then with ether, and dried at 80 ° C. Yield 0.56 g (31.3% of theory), m.p. 289 DEG C., specific rotation (.lambda.) = + 67.9 DEG.

4.2.9. Example 71 (+ / - / 1S, 5R, 2S) -2 * -Chloro-2- (2-methoxypropyl) -

5,9,9-trimethyl-6,7-benzomorphan-hydrochloride

Starting from 3.3 g (0.010 mol) of (+) - 2'-chloro-5,9,9-trimethyl-6,7-benzomorphane and 2.68 g (0.011 mol) of (S) -2-methoxypropyl- p-toluene sulfonate to yield analogously to Example 69 was yielded in 0.41 g / 22.9% of theory / mP: 288 DEG C. dec and a specific rotation / (ξ / 25 _{= +} IOI, 7 ⁰ / C = 1, CH 2 OH).

4.2.10. Example 72 (-) - (1R, 5S, 2S) -2'-Chloro-2- (2-methoxypropyl) -

5,9,9-trimethyl-6,7-benzomorphan-hydrochloride

From the mother liquors of Example 61, the title compound is obtained analogously to Example 70 in a yield of 0.75 g (41.9% of theory) with a melting point of 288 DEG C. and a specific rotation of [.alpha.] D @ 25 = -68.6 DEG (c = 1). CH 2 OH.

3.4 Compounds (1) according to Method 3.3

4.3.1. Example 73 (-) - (R, 5S, 2S) -2- (4-Ethoxy-2- (2-methoxypropyl) -

5,9,9-trimethyl-6,7-benzomorphan methanesulfonate

0.68 g (2 mmol) of [alpha] - (1R, 5S, 2S) -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphine hydrochloride] Example 4) was mixed in 20 ml of absolute dimethylformamide with stirring and ice cooling with 0.13 g of a 77% suspension of sodium hydride in paraffin (4.2 mmol). After stirring for 30 minutes, 0.31 g (2.2 mmol) of methyl iodide dissolved in 5 ml of dimethylformamide is added dropwise over 5 minutes. The mixture is then stirred for 3 hours at room temperature and then evaporated on a rotary evaporator, finally at 95 and full. vacuum of water pump. The residue was shaken with 25 ml of dichloromethane and 25 ml of water. The separated aqueous phases are extracted once more with 15 ml of dichloromethane. After washing with 15 ml of water, the combined extracts are evaporated and the residue is crystallized in analogy to Example 28 as the methanesulfonate. The title compound is obtained in a yield of 0.38 g (46.0%) with a melting point of 150 DEG-152 DEG C. (decomposition) and a specific rotation ([.alpha.] D = -68.7 DEG (c = 1, _3h ) _). /.

4.3.2. Example 74 (+) - (1S, 5R, 2R) -2'-Methoxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane methanesulfonate

Starting from 0.68 g (2 mmol) of (+) - (1S, 5R, 2R) -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphine hydrochloride / example 2 /, is obtained analogously to example 73 was yielded in 0.38 g / 46.0% of theory / m.p. 150-152 ° C dec and a specific rotation / ^ x / p = ⁵ + 67.2 ° (c = 1, CH ₃ OH).

4.3.3 Example 75 (R) 5S, 2R (2R) -2-Ethoxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane methanesulfonate from 0.34 g (1 mmol) of (-) - (1R, 5S, 2'R) -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7- of benzomorphan hydrochloride (Example 1) and 0.17 g (0.0011 mol) of ethyl iodide are obtained analogously to Example 63, the title compound in a yield of 0.30 g (70.2% of theory), m.p. 146-148 ° C. decomposition and specific rotation ([α] D - 93.4 ° (c = 1, CH 3 OH)).

4.3.4 Example 76 / - / - / 1 R, 5 S, 2 "R / -2'-acetoxy-2- / 2-methoxypropyl / _{-5,9,9-Trimethyl-6>} from-an-methanesulfonyl benzomorf oná t

0.68 g (2 mmol) of (-) - (1R, 5S, 2'R) -2'-Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphine of the hydrochloride (Example 1) was dissolved in 15 ml of absolute dichloromethane. After the addition of 0.51 g (5 mmol) of triethylamine, the solution is mixed with 0.19 g (2.4 mmol) of acetyl chloride dissolved in 2 ml of dichloromethane at room temperature with stirring for about 10 minutes. It was then stirred at room temperature for 2 hours. It is then washed three times with 10 ml of ice-water each time, dried over sodium sulphate and, after filtering off the drying agent (rotary evaporator, finally at 80 DEG C. and under full vacuum of the water pump), it is evaporated. The residue consisting of the free base of the title compound (0.6 g, 1.74 mmol) was dissolved in 3 µl of ethanol and acidified by the addition of methanesulfonic acid (0.16 g, 1.74 mmol) in 3 ml of ethanol to pH 4. After addition of diethyl ether until turbidity, the title compound crystallizes, which, after standing for about 12 hours in a refrigerator, is filtered off with suction, washed with ethanol-ether 1: 2 and dried at 80 ° C. Yield 0.7 g / 79.3 of theory / mp 183-184 ° C / dec. /, = -83.9 DEG / _{c = i}} CHjOH /.

4.3.5 Example 77 (+ / - / 1S, 5R, 2'S) -2 '- Acethoxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane methanesulfonate * starting from 0.68 g (0.002 mol) of (+) - (1S, 5R, 2S) -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl, 6,7- benzomorf an HCl / example 3 / a in analogy to example 76 to give the title compound in a yield of 0.6 g / 68.0% of theory / m.p. 183-184 ° C dec and a specific rotation / ⁵ IVD = θ2 + 8 ° (c-1, CH-OH).

4.3.6 Example 78 (-) - (1R-5S, 2S) -2'-Alethoxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane methanesulfonate

Starting from 0.68 g (0.002 mol) - / - (1R, 5S, 2S) -2 * hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane- h.ydrochloridu / example 4 / a is obtained analogously to example 76 was yielded in 0.58 g / 65.7% of theory / mP: 183 ° C / dec, / and the specific rotation of M / p ⁵ = -57.1 (C = 1, CH-OH).

4.3.7 Example 79 (+) - (1S, 5R, 2R) -2'-Acetoxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane methanesulfonate

Starting from 0.68 g (2 mmol) of (+) - (1S, 5R, 2R) -2 * -hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7 Benzomorph anhydrochloride (Example 2), analogously to Example 76, yielding the title compound in a yield of 0.67 g (75.9% of theory) with a melting point of 183 ° C and a specific rotation (t + 58.2 °). (c = 1, CH 2 OH).

4.3.8 Example 80 / - / - / 1 R, 5 S, 2''R / -2- / 2-methoxypropyl / 2 '-propionoxy-5,9,9-trimethyl-6,7-benzomorphan methanesulfonate ⁱⁿ starting from 0.34 g (1 mmol) of (-) - (1R, 5S, 2R) -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7- benzomorphan hydrochloride (Example 1) and 0.15 g (1.1 mmol) of propionic anhydride, analogously to Example 76 ', the title compound are obtained in a yield of 0.21 g (46.1% of theory), m.p. 145 DEG C. and specific rotation -78.3 (c = 1, CH 3 OH).

4.3.9. Example 81 (-) - (1R, 5S, 2R) -2- (2-ethoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride and / - / - / 1R, 5 s, 2 R / -2- / 2-ethoxypropyl ^ / -2 * - / 1-phenyl-5tetrazolyloxy / -b, _{9,9-trimeth.yl-6)} t-benzomorphan

1.36 g (4 mmol) of (-) - (1R, 5S, 2R) -2-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride (Example 1) is heated with 0.79 g (4.4 mmol) of 5-chloro-1-phenyltetrazole and 1.36 g (0.01 mol) of dry, fine powdered potassium carbonate in 78 ml of absolute acetone for 6 days with stirring to the temperature The solution was evaporated and the residue was treated with 50 ml of water. It is extracted twice with 25 ml of dichloromethane and the combined extracts are washed with 15 ml of water. After drying with sodium sulfate and filtration. The drying mixture was evaporated in a rotary evaporator, finally at 80 ° C under full vacuum of the water pump. The rest? Dissolve in 5 ml of ethanol and, after acidification with ethanolic hydrochloric acid, mix with diethyl ether until turbidity, crystallize the intermediate which, after standing for about 12 h in a refrigerator, is sucked off, then washed with ethanol-ether (1: 1) then ether and dried at 80 ° C. Yield 1.67 g (86.3% of theory), m.p. 241 DEG C. (dec.).

-59b / Hydrogenation? intermediate to the title compound

The intermediate (1.67 g, 3.5 mmol) was hydrogenated in the presence of 0.7 g of 10% palladium on carbon in 70 ml of glacial acetic acid at 50 psi hydrogen at ambient temperature until completion of the reaction (6-10 µl) ^. Odin /. The catalyst was filtered off with suction, the filtrate was evaporated and the residue - after mixing with 50 ml of water and excess ammonia - was extracted with dichloromethane (2 x 25 ml). The combined extracts were washed with water, dried over sodium sulfate and, after filtering off the desiccant, evaporated, finally at 80 ° C and under full vacuum of the water pump. The residue was crystallized analogously to Example 2 as the hydrochloride. The title compound is obtained in a total yield of 0.5 g (38.5% of theory) with a melting point of 225 DEG C. (decomposition) and a specific rotation ([.alpha.] D = -101.5 DEG (c = 1, CH3) _). oh /.

4.3.10 Example 82

N - (1S, 5R, 2'S) -2- (2-Methoxypropyl) -5,9,9-trimethyl 1-6,7-benzomorphane hydrochloride

Starting from 1.36 g (0.004 mol) of (+) - (1S, 5R, 2S) -2-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride (Example) 3), analogously to Example 81 above, the corresponding intermediate (1.65 g, 85.1% of theory, m.p. 241 DEG C.) decomposed// title compound in a total yield of 0.64 g (49.4% of theory) melting point 225 DEG C. (decomposition) and specific rotation ([.alpha.] D @ 20 = + 10.9 DEG (c = 1, CH3 OH).

4.3.11. Example 83 (-) - (1R-5S-2S) -2- (2-Methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane oxalate

Starting from 1.36 g (4 mmol) of (-) - (1R, 5S, 2S) -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorph of the hydrochloride (Example 4), and analogously to Example 81 via the corresponding intermediate (1.73 g, 89.4) (theory), m.p. 218.5 DEG C. (dec.).

The free base (0.7 g) was dissolved in 2 ml of isopropanol and mixed with the corresponding molar amount of oxalic acid (0.22 g). The title compound crystallizes with the addition of 50 ml and stirring. After storage for about 12 hours in a refrigerator, it is filtered off with suction, washed with a mixture of isopropanol-ether, then with ether and dried at 80 ° C. The title compound is obtained in a total yield of 0.8 g (53.0% of theory) with a melting point of 135 DEG C. (decomposition) and a specific rotation ([.alpha.] D = -60.0 DEG (c = 1, CH3OH).

4.3.12. Example 84 (+) - (1S, 5R, 2R) -2- (2-Ethoxypropyl) -5,9,9-trimethyl-7-benzomorphine oxalate

Starting from 1.36 g (4 mmol) of (+) - (1S, 5R, 2R) -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorph of hydrochloride / Example. 2), analogously to Example 81 over the corresponding intermediate (1.65 g, 85.1%), m.p. 217 DEG C. (decomposition) of the title compound, which analogously to Example 83 crystallizes as the oxalate. ^ VERALL Yield 0.6 g / 39.7% of theory / mp 135 DEG C. dec. Specific rotation / · Λ / ρ ^ = + 60.2 ° / c = 1, CH ₃ OH /.

4.3.13. Example 85 (-) - (1R, 5S, 2R) -2 * - Acetamido-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

0.70 g (1.87 mmol) (-) - (1R, 5S, 2R) -2'-amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane dihydrochloride] Example 34) is dissolved in 20 ml of absolute dichloromethane, mixed with 0.76 g (7.4 mmol) of triethylemine and then dropwise with stirring at room temperature with 0.17 g (2.1 mmol) of acetyl chloride, dissolved in 5 ml. ml of dichloromethane. It is then heated at reflux for one hour, cooled, washed three times with 10 ml of water each time, dried over sodium sulphate and, after filtering off the desiccant, evaporated on a rotary evaporator, finally at 80 ° C under full vacuum.

-61vývévy. The residue was dissolved in 2 ml of methanol and, after acidification with 2.5N ethanolic hydrochloric acid, treated with diethyl ether until turbidity started. The precipitated crystals are filtered off with suction after standing for 12 hours in the refrigerator, washed with ethanol-ether (1: 1), then with ether and dried at 0 ° C. The title compound is obtained in a yield of 0.49 g (68.8% of theory) with a melting point of 252 DEG C. (decomposition) and a specific rotation of [.alpha.] D @ -10 -10.2 DEG (c = 1, ch ₃ oh). .

4.3.14. Example 86 (+) - (1S, 5R, 2S) -2 * - A: ethoxy-2- (2-methoxypropyl) -

5.9.9-trimethyl-6,7-benzomorphane hydrocyl chloride

Starting from 1.07 g (2.58 mmol) of (+) - (1S, 5R, 2S) -2-amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorph an- hydrochloride (Example 36) and analogously to Example 85 the title compound is obtained in a yield of 0.73 g (74.3% of theory) with a melting point of 249 DEG C. (dec.) and a specific rotation (.delta.). ⁵ + 1 = 09,5 ° / c = 1, CH Gh /.

4.3.15. Example 87 (- / -) 1 R, 5S, 2 * S (-2 *) - etamido ~ 2- (2-methoxypropyl) -

5.9.9-trimethyl-6H-benzomorphar

1.0 g (0.0026 mol) of (-) - (1R, 5S, 2S) -2'-amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane dihydrochloride The reaction product was worked up analogously to Example 85. is isolated as described therein * and crystallized from 5 ml of petroleum ether and 0.5 ml of isopropanol. To give the title compound in a yield of 0.7 g / 76.4% of theory / MP: 128 DEG C. and a specific rotatory value of / c / ^ = -89.3 DEG / c = 1, CH ₃ OH - HCl 1N 1: 1 /.

4.3.16 Example 88 (+) - (1S, 5R, 2R) -2 * - Acetido-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane

Starting from 1.11 g (2.5 mmol) of (+) - (1S, 5R, 2R) -2'-amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6, Of 7-benzomorphine dimethynsulfonate (Example 35) to give analogously to Example 87 the title compound in a yield of 0.37 g (47.7% of theory) with a melting point of 129 ° C and a specific rotation ([α] D = + 89.9 °). (c = 1, CH 3 OH -1N HCl 1: 1).

4.3.1 7 Example 89 / - / - (1R, 5S, 2R) -3'-Bromo-2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphine -hydrochloričf

0.8'5 g (2.5 mmol) of (-) - (1R, 5S, 2R) -2'-hydroxy-2- (2-methoxypropyl) -9,9-trimethyl-6,7- benzomorphane hydrochloride. (Example 1) and suspended in 30 ml of glacial acetic acid. The suspension is mixed with 0.15 ml (0.47 g, 2.9 mmol) of bromine at room temperature with stirring. After two hours of stirring, evaporate on a rotary evaporator, finally at 80 ° C and under full vacuum water pump. 25 ml of water and 25 ml of dichloromethane with excess ammonia are added to the residue with shaking. The separated aqueous phase is extracted once more with 15 ml of dichloromethane, the combined extracts are washed with 15 ml of water, dried with sodium sulphate and, after filtering off the desiccant, evaporated as above. The residue (1 g) was purified over a column of 250 g of silica gel - analogously to Example 2- using a dichloromethane / methanol / conc. Ammonia 90: 10: 0.5 mixture. with the pure substance was evaporated as above and the residue crystallized analogously to Example 2 as the hydrochloride. To give the title compound in a yield of 0.75 g / 65, ^8% of theory / MP: 245 DEG C. dec and a specific rotation / C \ / ^ - -82.5 DEG / c = 1, CHjOH /.

4.3.18 Example 90 (+) - / 1R, 5R, 2R / -2'-Hydroxy-1'-nitro-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane- hydrochloride

0.85 g (2.5 mmol) of (-) - (1R, 5S, 2'R) -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane The hydrochloride was suspended at 20 ° C in 30 ml of glacial acetic acid and 0.18 ml (0.25 g) of 65% nitric acid (2.6 mmol of HNO4) was added with stirring. Within about 10 minutes, a clear, yellow solution was formed, which turned brown after a further 5 minutes and was quenched by precipitation of the crystalline compound. After about one hour, it is filtered off with suction and washed with glacial acetic acid-diethyl ether (1: 1), then with ether, and dried at 80 ° C. The crystals (0.35 g) were dissolved in a hot methanol-water mixture (17.5 ml + 1.75 ml) and the solution was mixed with diethyl ether. rem; (40 ml). The crystallized substance is suction filtered after cooling in an ice bath, washed with ether and dried at 80 ° C. The title compound is obtained in a yield of 0.32 g (33.3% of theory), m.p. 245 DEG C. (with gradual brown and decomposition), specific rotation (.lambda.) + 87.0 DEG (c = 1). CH-Joh /.

4.3.19 Example 91 (- / -) 1R, 5S, 2''R '- 2'-Hydroxy-2- (2-methoxypyropyridine) -3'-nitro-5,9,9-trimethyl- 6, Z-benzomorphan-hydrochloride

Example 90 as described for the nitration of the starting compound formed / R = 0.57 / 1 ' described above nitro derivative / R ₌ 0.45 /, the isomeric 3 '-nitroderivát / R = 0.72 / 1 and *. 3'-dinitro derivative (Rf = 0.10) (DC; Kieselgel 60, chloroform-methanol-ammonia 90: 10: 0.5). The residual lye left after aspiration of the 1'-nitro compound (example 90) was evaporated and the residue was converted to the free base, dissolved in 10 ml of dichloromethane and the yellow solution filtered through 25 g of alumina (activity H1, neutral). Elute with dichloromethane until the eluate is no longer a yellow color and the eluate is evaporated. rest

-64 (0.35 g) is dissolved in 2.5 ml of ethanol and, after acidification with ethanolic hydrochloric acid, the solution is mixed with the starting ether with diethyl ether. After standing in the refrigerator for about 12 hours, it is filtered off with suction, washed with ethanol-ether (1: 1) and dried at 80 ° C. The title compound is obtained in a yield of 0.40 g (41.6% of theory) with a melting point of 229 DEG-230 DEG C. (decomposition) and a specific rotation (.alpha.) = -110.1 (c = 1, CH-). Joh /.

4.3.20 Example 92 (+) - / 1R, 5R, 2 ”R / -1 *, 3 * -Dinitro-2 * -hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl 6,7-benzomorphan hydrochloride

1.52 g (5 mmol) of (-) - (1R, 5S, 2'R) -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane] Example 1) was dissolved in 3 ml of glacial acetic acid and the solution was mixed with 3.4 ml of glacial acetic acid and 5.42 ml of 100% nitric acid with stirring at 3-4 ° C for 1.5 hours. The mixture was stirred at room temperature for 3 hours. Then the yellow reaction mixture was poured into 50 g of ice water, the solution was ammonia. alkaline and extracted three times with 20 ml of dichloromethane each time. After washing the combined extracts with water and drying over sodium sulfate as well as filtering off the desiccant, the reaction mixture is evaporated on a rotary evaporator, finally at 80 ° C and under full vacuum of the water pump. The residue crystallized from an ethanol-ether mixture. The title compound is obtained in a yield of 1.0 g (46.5% of theory) with a melting point of 300 DEG C. (decomposition) and a specific rotation ([.alpha.] D @ 20 = + 27.9 DEG (c = 1, CH3)). OH /.

4.3.21 Example 93 (-) - (1R, 5R, 2R) -1'-Amino-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

0.35 g (1.0 mmol) of (+) - (1R, 5R, 2R) -2'-hydroxy-2- (2-methoxypropyl) -1'-nitro-6,7-benzomorphane hydrochloride (Example 90) The reaction mixture was hydrogenated in 40 ml of methanol in the presence of 0.1 g of palladium on carbon (5% Pd) for 4 hours under 0.5 bar of hydrogen at room temperature. After filtering off the catalyst, the reaction mixture was evaporated in a rotary evaporator, finally at 80 ° C and under full vacuum of the water pump, and the residue was crystallized from 10 ml of ethanol. After cooling, the crystals were suction filtered, washed with ethanol-ether mixtures and dried at 80 ° C. To give the title compound in a yield of 0.17 g / 52.7% of theory / MP: 282 ° C / slow decomposition at 250 ° C / and the specific rotation / $ / P ⁵ = -128.3 ° / c = 1 CH 2 OH.

4.3.22 Example 94 (- / -) 1R, 5S, 2'R) -3 * -Anino-2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7- benzomo rf an> hydrochloride

Starting from 0.39 g (1.0 mmol) of (-) - (1R, 5S, 2R) -2'-hydroxy-2- (2-methoxypropyl) -3'-nitro-5,9,9-trimethyl -6,7-benzomorphan hydrochloride (Example 91), analogously to Example 93, yielding the title compound in a yield of 0.27 g (76.1% dec.) With a melting point of 268 ° C (dec.) And a specific rotation (<A) of ⁵ -99.7 / c = 0.5, CH ₃ OH /.

4.3.23 Example 95 (- / -) 1R, 5R, 2'R) -1 *, 3'-Diamino-2'-hydroxy-2- (2-methoxypropyl) -5,9,9- trimethyl-6,7-benzomorphane hydrochloride

Starting from 0.70 g (1.63 mmol) of (+) - (1R, 5R, 2R) -1,3-dinitro-2'-hydroxy-2- (2-methoxypropyl) -5,9,9- trimethylli

Of 6,7-benzomorphane hydrochloride (Example 93), analogously to Example 93, the title compound is obtained in a yield of 0.20 g (33.2% of theory) with a melting point of 228 DEG C. (dec.) And a specific rotation of [.alpha. -111.7 ° (c = 0.5, CH 2 OH).

4.3.24 Example 96 (-) - (1R, 5S, 2R) -3 * - Anino-2- (2-methoxypropyl) -

5,9,9-trimethyl-6,7-benzomorphan

The diastereomeric mixture of (-) - (1R, 5S, 2R) - and / + / - (1S, 5R, 2R) -2- (2-methoxypropyl) -3'-nitro-5,9,9-trimethyl obtained according to Example 67 -6,7-benzomorphane (3.7 g) is dissolved in 75 ml of methanol and hydrogenated in the presence of 0.8 g of palladium on carbon (5% Pd) under a hydrogen pressure of 0.5 MPa at 20 ° C until completion hydrogen consumption (about 3 hours).

On thin-layer / gel 60, chloroform-methanol-concentrated ammonia 90: 10: 0.5 / clear the complete conversion of the nitro compound 3 ' / R = 0.73 / 3 &apos; to the corresponding amino compound / _Rf = 0.61 /. After filtering off the catalyst, the reaction mixture was evaporated on a rotary evaporator, finally at 80 ° C and under a complete vacuum of the water pump. The residue (3.1 g) was subjected to column chromatography on 600 g of silica gel analogously to Example 2. Ethylene diastereomeric 3'-amino compounds were monitored by thin layer chromatography (Kieselgel 60, chloroform-methanol-ammonia 95: 5: 0.1, developed twice). The title compound was obtained with a lower Rf value of 0.63 in a yield of 0.95 g as the residue of the corresponding eluate, with a specific rotation ([.alpha.] D @ 25 = -39.8 DEG (c = 1, CH3 OH)). about crystallization.

4.3.25 / Example 97 / + / - (1S, 5R, 2R) -3 * -Anino-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane

At the above diastereomeric column chromatography length (Example 96), a higher substance is obtained

- $ Ί ~

Rf value 0.69 of the title compound as the residue of the corresponding eluate (1.0 g), specific rotation ([.alpha.] D @ + = 104 DEG (c = 1, CH3 OH)) which resists all crystallization attempts.

4.3.26 Example 98 (+) - (1S, 5R, 2'S) -3'-Anino-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane and Nitro-degree (diastereomeric mixture)

Starting from 5.2 g (0.02 mol) of (+) - 3'-nitro-5,9,9-trimethyl-6,7-benzomorphane and 5.36 g (0.022 mol) of (S) -2- methoxypropyl p-toluenesulfonate and analogously? of Example 67, the mixture is obtained. of both the expected diastereomeric bases, which are purified by filtration through alumina to give 4.7 g of purified base mixture.

b / 3 * -Anino compounds / diastereomeric mixture /

The 3'-nitro compound (4.7 g of the purified diastereomeric mixture) was hydrogenated analogously to Example 96 to the corresponding 3'-amino compound (3.7 g of the diastereomeric mixture).

c) Separate title compounds by column chromatography A mixture of diastereomeric 3'-amino compounds (3.7 g) was separated analogously to Example 96 by column chromatography on silica gel. The title compound of less than 0.63 was obtained in a yield of 1.0 g as a residue of the corresponding eluate with a specific rotation ([.alpha.] D @ 20 = + 40.5 DEG (c = 1, CH3 OH)) which resists all crystallization attempts.

4.3.27 Example 99 (- / -) 1R, 5S, ^2M S) -3-amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane

In the above column chromatography (Example 98), a second substance with a higher Rf value of the title compound (Rf = 0.69) was obtained as a residue of the corresponding eluate (1.1 g, specific rotation). 105 ° (c = 1, CH 2 OH), which does not crystallize.

4.3.28 Example 100 (- / -) 1R, 5S, 2'R '-3' '- [E] amido-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane

0.95 g (3.14 mmol) of (-) - (1R, 5S, 2R) -3'-amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6 (benzomorphane) example 95) was acetylated analogously to Example 85. The acetylation product was purified by filtration through alumina analogous to Example 65. In a thin layer chromatography (Kieselgel 60, chloroform-methanol-ammonia 90: 10: 0.5) the starting compound had an Rf value of? 0.64 and the acetylation product R1. value of 0.57. The residue (0.69 g), which resists all crystallization attempts, exhibits a specific rotation (-53.6 [deg.] (C = 1, ₃ h).

4.3.29 Example 101 (+) - (1S, 5R, 2'R) -3 * -A: Etamido-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane oxalate

Starting from 1.0 g (3.31 mmol) of (+) - (1S, 5R, 2R) -3'-amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7- benzomorphane (Example 97). with analogy to Example 90, the title compound. The residue of the substance purified over alumina (0.5 g of substance) is crystallized analogously to Example 83 in the form of oxalate. To give the title compound in a yield of 0.4 g / 27.8% of theory / MP: 148 DEG C. dec and a specific rotation / if / P ⁵ = + 39.3 ° / c = 1, CH ₃ OH / .

4.3.30 Example 102 / + / - / 1 S, 5 R, 2 S ^F / -3 * -Ac et amido-2/2-methoxypropyl / -5,9,9-Trimethyl-6,7-benzomorphan

Starting from 1.0 g (3.31 mmol) of (+) - (1S, 5R, 2S) -3 * -amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7- benzomorphane (Example 98), analogously to Example 100, gave the title compound as a non-crystalline residue (0.6 g, 41.7% of theory) with an H value of 0.57 and a specific rotation. / c \ / p = + 52.8 (c = 1, ch ₃ oh).

4.3.31 Example 103 (-) - (1R, 5S, 2'S) -3'-Acetamido-2- (2-methoxypropyl) -5,9, γ-trimethyl-6,7-benzomorphane oxalate

Starting from 0.95 g (3.14 mmol) of (-) - (1R, 5S, 2 / S) -3 * -amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6 7-Benzomorphine (Example 99), analogously to Example 101, yields the title compound in a yield of 0.7 g (51.1%) with a melting point of 148 DEG C. (decomposition) and a specific rotation of [.alpha.] D @ 20. 39.2 ° (c = 1, ch ₃ oh).

4.3.32 Example 104 (-) - (1R, 5S, 2R) -3'-Ethoxy-2- (2-methoxypropyl) -5,9,9,2'-tetramethyl-6,7-benzomorphane hydrochloride

Starting from 0.71 g (2 mmol) of (-) - (1R, 5S, 2R) -3-hydroxy-2- (2-methoxypropyl) -5,9,9,2 * -1-trimethyl-6,7- of benzomorphine hydrochloride (Example 53) and analogously to Example 73, the title compound is obtained in a yield of 0.38 g (52.0%) with a melting point of 221-224 ° C and a specific rotation (0 ( ²⁵ = -82.6 °)). c = 1, CH ₃ OH).

-70 »-

4.3.33. Example 105 (+) - (1S, 5R, 2R) -3 * -Methoxy-2- (2-methoxypropyl) -5,9,9,2 * -tetramethyl-6,7-benzomorphane hydrochloride

Starting from 0.71 g (2 mmol) of (+) - (1S, 5R, 2R) -3'-hydroxy-2- (2-methoxypropyl) -5,9,9,2 * -tetrameth, yl-6,7-benzomorphine hydrochloride (Example 54) and analogously to Example 73 the title compound was obtained in a yield of 0.44 g (59.8%) as an amorphous powder and having a specific rotation (0 (^5 = +42) , 2 ° / c = 1, CH ₃ OH /.

4.3.34 Example 106 (+) - (1S, 5R, 2'S) -3'-Methoxy-2- (2-methoxypropyl) -5,9,9-2'-tetramethyl-6,7- benzomorphan hydrochloride

Starting from 0.71 g (2 mmol) of (+) - (1S, 5R, 2S) -3'-hydroxy-2- (2-methoxypropyl) -5,9,9,2'-tetramethyl-6, Of 7-benzomorphan hydrochloride (Example 55) and analogously to Example 73 the title compound is obtained in a yield of 0.40 g (54.7%) with a melting point of 221-224 and a specific rotation (mesh) of 25 _{= + 81> 7} ° / _{c = 1>} CH ₃ OH /.

4.3.35 Example 107 (-) - (1R, 5S, 2S) -3 * -Methoxy-2- (2-methoxypropyl) -5,9,9,2-tetramethyl-6,7-benzomorphane hydrochloride

Starting from 0.71 g (2 mmol) of (-) - (1R, 5S, 2S) -3 * -hydroxy-2- (2-methoxypropyl) -5,9,9,2 * -tetramethyl-6,7-benzomorphane hydrochloride (Example 56), analogously to Example 73, yielding the title compound in a yield of 0.42 g 56.1% (as an amorphous powder, specific rotation (λ) = -41.0 ° (c = 1, _3h) ) .

4.3.36 Example 108 (-) - (1R, 5S, 2R) -2'-Methoxy-2- (2-methoxypropyl) -5,9,9,3'-tetramethyl-6,7-benzomorphane hydrochloride

Starting from 0.71 g (2 mmol) of (-) - (1R, 5S, 2R) -2'-hydroxy-2- (2-methoxypropyl) -5,9,9,3'-tetramethyl-6,7- of benzomorphan hydrochloride (Example 57), analogously to Example 73, yielding the title compound in a yield of 0.36 g (49.3%), m.p. 224 DEG-226 DEG C. and specific rotation ([.alpha.] D @ -112.2 DEG). = 1, CH ₃ OH).

4.3.37 Example 109 (+) - (1S, 5R, 2'R) -2'-Methoxy-2- (2-methoxypropyl) -5,9,9,3 * -thiomethyl-6 , 7-benzomo rf anhydroxyl chloride Starting from 0.71 g (2 mmol) of (+) - (TS, 5R, 2R) -2'-hydroxy-2- (2-methoxypropyl) -5,9, Of 9,9,3'-tetramethyl-6,7benzomorphane hydrochloride (Example 58), analogously to Example 73, yielding the title compound in a yield of 0.39 g (53.0%) as an amorphous powder with a specific rotation ([beta] = p = +). 72.4 ° (c = 1, CH ₃ OH).

4.3.38 Example 110 (+) - (1S, 5R, 2S) -2'-Methoxy-2- (2-methoxypropyl) -5,9,9,3'-tetramethyl-6,7-benzomorphane hydrochloride

Starting from 0.64 g (2 mmol) of (+) - (1S, 5R, 2''S) -2'hydroxy-2- (2-methoxypropyl) -5,9,9,3'-tetramethyl- 6.7benzomorphane (Example 59), analogously to Example 73, yielding the title compound in a yield of 0.45 g (61.5%) with a melting point of 228-229 ° C and a specific rotation of + 111.5 ° (c = 1, CH _3). OH /.

4.3.39 Example 111 (-) - (1R, 5S, 2S) -2 * -Ethoxy-2- (2-methoxypropyl) -5,9,9-3 * -tetramethyl-6,7- benzomorphan hydrochloride ⁱⁿ ychází of 0.71 g / mmol 2 / / - / - / 1 R, 5 S, 2 'S / ^z -2-hydroxy-2- / 2-methoxypropyl / -5,9,9,3 - tetramethyl-6,7benzomorphane hydrochloride (Example 60), analogously to Example 73, the title compound was obtained in a yield of 0.40 g (53.4%) as an amorphous powder, specific rotation (λ) β -71.8 ° C = 1, CH ₃ OH).

4.3.40 Example 112 / - / - / 1R, 5S, 2R / -3 * -Hydroxy-2 * -methoxy-2- / 2-

methoxypropyl / -5,9,9-Trimethyl-6,7-benzomorphan

Starting from 3.56 g (10 mmol) of (-) - (1R, 5S, 2'R) -2 ', 3'-dihydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6 7-Benzomorphan hydrochloride (Example 61) and analogously to Example 73 gave two equivalents of sodium hydride / a mixture of both isomeric monomethoxy derivatives and dimethoxy derivatives, which was separated by column chromatography on a 100-fold amount of silica gel analogously to Example 2; dichloromethane-isopropanol-end ammonia 97: 3: 0.3). The compound moving as intermediate substance (Rf = 0.73) is crystallized as the hydrobromide. The title compound is obtained in a yield of 0.62 g (15.0%) with a melting point of 212 DEG C. (decomposition) and a specific rotation ([.alpha.] D = -78.4 DEG (c = 0.5, CH3)). OH /.

4.3.41 Example 113 (-) - (1R, 5S, 2R) -2 * -Hydroxy-3'-ethoxy-2- (2-methoxypropyl) -5,9,9-trimethyl-b, 7-benzomorph anhydro bromide

In Example 112, the separated, slower moving substance (Rf > = 0.68) is precipitated as the hydrobromide. The title compound is obtained in a yield of 0.88 g (21.2%) with a melting point of 235 DEG C. (dec.). and specific rotation ([α] D = -93.1 ° (c = 0.5, CH ₃ OH)).

4.3.42 Example 114 (-) - (1R, 5S, 2R) -2 *, 3 * -Dimethoxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

In Example 112, the separated, faster moving substance (Rf = 0.86) is precipitated as the hydrochloride. The title compound is obtained in a yield of 0.87 g (22.7%) with a melting point of 193 ° C (dec.) And a specific rotatory / (X / ^ = -93.2 DEG / c = 0.5, CH ₃ OH /.

4.4 Compounds 1 in special ways

4.4.1 Example 115 (-) - (1R, 5S, 2R) -2 * -Hydroxy-2- (2-hydroxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

1.5 g (3.60 mmol) of (-) - (1R, 5S, 2'R) -2- (2-benzyloxypropyl) -2'-hydroxy-5,9,9-trimethyl-6,7-benzomorph The hydrochloride (Example 43) is dissolved in 75 ml of methanol and hydrogenated under a pressure of 0.5 MPa at 70 DEG C. until the reaction is complete (in the presence of palladium hydroxide on activated carbon (0.6 g of wet Pearlman catalyst)). 6.2 h /. Then the catalyst is filtered off and the filtrate is evaporated on a rotary evaporator, finally at 80 ° C and under complete vacuum of the water pump. The residue was dissolved in 10 ml of methanol and treated with 30 ml of diethyl ether. After standing for about 12 hours at room temperature, the precipitated crystals are filtered off with suction, washed first with ethanol-ether (1: 1), then with ether and dried at 80 ° C. The title compound is obtained in a yield of 1.0 g (85.5% of theory) with a melting point of 276 DEG C. (decomposition) and a specific rotation of [.alpha.] D = -127.4 DEG (c = 1, ch ₃ oh). /.

4.4.2 Example 116 (+) - (1S, 5R, 2'S) -2'-Hydroxy-2- (2-hydroxypropyl) -5,9,9-trimethyl-6,7-benzomorphine hydrochloride

Starting from 1.5 g (3.6 mmol) of (+) - (1S, 5R, 2S) -2- (2-benzyloxypropyl) -2H-hydroxy-5,9,9-trimethyl-6 Of 7-benzomorphan hydrochloride (Example 44), analogously to Example 115, gives the title compound in a yield of 1.0 g (85.5% of theory P) with a melting point of 276 ° C (° C) and specific rotation (Ck) of ²⁵ = +126. 8 ° (c = 1, CH ₃ OH).

4.4.3 Example 117 (-) - (1R, 5S, 2S) -2 * -Hydroxy-2- (2-hydroxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

The diastereomen remaining in Example 44 in the mother liquors (3.17 g of evaporators) was hydrogenated analogously to Example 115. The title compound was obtained in a yield of 1.5 g (56.2% of theory) with a melting point of 247 247 ° C (dec.) And specific rotation / (\ / ^2? = -86.8 DEG / c = 1, CH ₃ OH /.

4.4.4 Example 118 / + / - / 1 S, 5 R, 2 R / -2 '- ^{Hydroxy-2/2-hydroxypropyl} / -5,9,9-Trimethyl-5,7-benzomorphan hydrochloride

The diastereomer remaining in the mother liquors from Example (3.17 g of evaporators) was hydrogenated analogously to Example 115. The title compound was obtained in a yield of 1.5 g (56.2% of theory) with a melting point of 247 ° C (dec.) And specific rotation. . / ^ / ^ = + 86.4 ° / c = 1, CH ₃ OH /.

4.4.5. Example 119 (+ / - / 1R / 5S / R, 2S / -2 * -Fluoro-2- (2-methoxypropyl) -

5,9,9-trimethyl-6,7-benzomorphane oxalate a) Starting compound: (1R), 5S (R, 2S) -2'-Fluoro-2- (2-methoxypropionyl) -5,9,9 -trimethyl-6,7-benzomorphane (di astereomeric mixture)

5.94 g (0.02 mol) of (+) - 2'-nitro-5,9,9-trimethyl-6,7-benzomorphan hydrochloride are acylated analogously to Example 32, 2.68 g (0.22 mol) of acid chloride) S / 2-methoxypropionic. The resulting acylation product (7.0 g) is hydrogenated to the corresponding 2 amino analogue as described therein. This is known in the art (TLFietcher and MJNamkung, Chem.). and Ind. 1961-179 converts to the corresponding 2'-fluoride derivative (5.7 g). This creates a mixture of the expected diastereomers, which can not be divided in the chromatography by thin-layer / _Rf = 0.73, silica gel, chloroform-methanol-concentrated ammonia 90: 10: 0.5 /; b / converted to the title compound

The intermediate (1.58 g, 5 mmol) was reduced in analogy to Example 32 with lithium aluminum hydride (LiALH 4) to the title compound and, as described therein, purified by silica gel column chromatography. The eluate residue with purified substance (0.4 g, Rf = 0.78) was crystallized analogously to Example 83 as the oxalate. The title compound is obtained in a yield of 0.35 g (17.7% of theory) with a melting point of 165 DEG C. (decomposition) and a specific rotation ([.alpha.] D = + 9.7 DEG (c = 1, CH3 OH)). The substance is a mixture of the expected diastereomers (1R, 5S, 2S) - and (1S, 5R, 2S) compound (in a ratio of about 1: 1 (according to ¹ H-NMR spectroscopy).

4.4.6 Example 120 / - / - / 1R (5S, 5S / R, 2R) -2 * -Fluoro-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane oxalate a) Starting compound: (1R/S,5S/R,2R/-2*-Fluoro-2-/2methoxypropionyl/-5,9,9- trimethyl-6,7-benzomorphine / mixture of diastereomers) from 2.97 g (0.01 mol) of (+) - 2'-nitro-5,9,9-trimethyl-6,7-benzomorphine hydrochloride and obtained using 1.34 g) 0.011 mol of (R) -2-methoxypropionic acid chloride of the expected diastereomeric 2 * fluoro-2- (2-methoxypropionyl) -5,9,9-trimethyl-6,7-benzomorphane (reaction procedure according to Example 119), which cannot be separated thin layer chromatography (Rf = 0.73, silica gel, chloroform-methaaol-conc. ammonia 90: 10: 0.5), yield 2.9 b / conversion to the title compound

2.9 g (9.2 mmol) of the above intermediate were reduced analogously to Example 119 with lithium aluminum hydride. The reaction product was purified as described therein. The pure fraction residue (0.9 g) was crystallized analogously to Example 98 as the oxalate. The title compound is obtained in a yield of 0.88 g (22.3% of theory) with a melting point of 169 DEG C. (decomposition) and a specific rotation ([.alpha.] D = -9.5 DEG (c = 1, CH3 OH) as a mixture of the expected diastereomers // 1 R, 5S, 2 "R / and / 1 S, 5R, 2" R / compound.

Claims (7)

What is claimed is: 1. A compound of the formula I as defined in claim 1 X oxygen or sulfur, R ¹ C-Cθ alkyl, alkenyl CYCY, CyCg-alkynyl, aryl, R 6 is hydrogen, C 1 -C 8 -alkyl, CYCG alkenyl, CyCg-alkynyl, aryl, aralkyl, R 4 is hydrogen, C 7 -C ₈ alkyl, ^{R 4} C ₈ -C ₈ -alkyl, -78R ⁵ C _r -C ₈ alkyl, C 1 -C 6 -alkyl, aryl, And R 8 independently of one another are hydrogen, C 1 -C 8 -alkyl, halogen, -OH, C 1 -C 8 -alkoxy, -O-acyl, -CN, -NO 4, NH 4, -NH / C 1 -C 8 -alkyl (-K (C1-C6-alkyl), wherein the alkyl radicals may be the same or different, -NH-acyl or -N-acyl-Z (C1-C6-alkyl). 2. Benzomorphans of the general formula I, where it may be X oxygen, sulfur, R ^{1 is} methyl, ethyl, propyl, isopropyl, phenyl, R is methyl, ethyl, propyl, isopropyl, allyl, propargyl, phenyl, benzyl, hydrogen, C1-C4-alkyl, R is methyl, ethyl, propyl, isopropyl, R is methyl, ethyl, propyl, isopropyl, g R is methyl, ethyl, propyl, isopropyl, phenyl, γ R is fluorine, chlorine, hydroxy, lower alkyl, lower alkoxy, acyloxy, R is hydrogen, lower alkyl, hydroxy or alkoxy. 3. Benzomorphans of the general formula I, in which it can be changed X oxygen, βΐ methyl, ethyl, methyl, ethyl, R 4 is hydrogen, methyl, ethyl, R is methyl, ethyl, r6 is methyl, ethyl, R is hydroxy, methyl, methoxy, acyloxy, R is hydrogen, methyl, ethyl, hydroxy or lower alkoxy. 4. A compound of formula (I) wherein it may be X oxygen, r1 methyl, R 4 methyl, R 4 is hydrogen, R 4 is methyl, methyl, -80methyl. R is hydroxy, methyl, methoxy, acetoxy, g R is hydrogen, methyl, hydroxy or lower alkoxy. 5 6 9 9 ¹ R @ 1 and R @ 2 are as defined above and R @ 1 and R @ 2 are either as defined for R @ 1 and R @ 2 or are substituents convertible into said substituents in a known manner. - the presence of a binding agent acid derivatives kyu? Carboxylic acids of Formula 4 wherein Y is a secondary amino group displaceable leaving group from the group consisting of halogen, hydroxy, OC / 0 / alkyl, O-acyl, 0S0 _{of the} alkyl and 0S0 _of aryl and 12 3 R, R R and R ^J and X are as defined above - (H) (2) and the resulting acid amide (3) is then reduced in known manner in an inert solvent to the amine (6,6). -83a and if appropriate the substituents R ^ and R ^ ¹ is converted to the R? and Q R and isolating the reaction mixture (1) or b) leaving the benzomorphane 2 (6) R ' -84 where R R and R ^ are as defined above, and R ^ and R ^ are either 5. A compound of formula (I) wherein they may be X oxygen, r1 methyl, R ² methyl, R 4 is hydrogen, R 4 methyl, R 4 methyl, R 4 methyl, R hydroxy, methyl, methoxy, acetoxy, 'g R is hydrogen, methyl, hydroxy, methoxy or ethoxy and R and R are the ^2t-positions and the 3-position and two atoms -atom has the R-configuration. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 6, and its acid addition salt leads to conventional excipients and carriers. Use of compounds according to any one of claims 1 to 6 as medicaments. i i Use of the compounds according to any one of claims 1 to 6 and their acid addition salts for the manufacture of a medicament for the therapeutic treatment of cerebral ischemia of various origins, epilepsy and neurodegenerative diseases. 9. A process for the preparation of compounds of formula (I), characterized in that it is either a compound of formula (I); II, in which Or may be converted to these values in known manner in a known manner in inert solvents, optionally in the presence of an acid-binding agent with an alkylating agent of formula (5), wherein Z is a secondary amino group replaceable by a leaving group; halogen, such as e.g. Arylsulfonate OSC1- aryl- such as e.g. tosylate or alkylsulfonate - such as e.g. methanesulfonate or halomethanesulfonate, or sulfate: group, to tertiary amine type 6