HRP20020460A2 - Substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and the use thereof as medicaments - Google Patents

Description

The subject of the proposed invention are substituted 1,2,3,4,5,6-hexahydro-2,6-methane-3-benzazocines of general formula 1

[image]

where

R1 and R2, the same or different, represent hydrogen, C1-C6-alkyl, C1-C6-alkyloxy, OH, F, Cl or Br;

R3 and R3', the same or different, represent hydrogen, F, Cl, Br, methyl, ethyl, OH, CF3, methoxy or phenyl, which, if necessary, can be substituted with a radical selected from the group consisting of F, Cl, Br, methyl, ethyl , OH, CF3 and methoxy;

R4, R5 and R6, the same or different, represent hydrogen, methyl or ethyl,

X is NH2, NH-(C1-C6-alkyl), N(C1-C6-alkyl)2, where two C1-C6-alkyl groups can be the same or different, NH-COH, NH-CO(C1-C6 -alkyl) or F;

A is -(CH2)3-, -CH2-CH2-O-, -CH2-O-CH2-, -(CH2)4-,

-CH (C1-C6-alkyl) -O-CH2-, - (CH2) 2-O-CH2-, - (CH2)3-O-,

-(CH2)5-, -CH2-O-(CH2)3- -(CH2)2-O-(CH2)2-, - (CH2) 3-O-CH2-,

-(CH2)4-O-, -CH2-0TCH2-CH2-O-,

[image]

if necessary in the form of their racemates, their enantiomers, their diastereomers and their mixtures, as well as if necessary their pharmacologically unambiguous acid addition salts.

Compounds of the general formula 1 in which

R1 and R2, the same or different, represent hydrogen, methyl, ethyl, methyloxy, ethyloxy, OH, F, Cl or Br;

R3 and R3', the same or different, represent hydrogen, F, Cl, Br, methyl, ethyl, OH, methoxy or phenyl, which is substituted with a radical selected from the group consisting of F, Cl, Br, and preferably methyl;

R4, R5 and R6, the same or different, represent hydrogen or methyl;

X is NH2, NH-(methyl), N(methyl)2, NH-(ethyl), N(ethyl)2, NH-COH, NH-COMe or F;

A is -CH2-CH2-O-, -CH2-O-CH2-, -CH (methyl) -O-CH2-,

-CH(ethyl)-O-CH2-, -CH (iso-propyl) -O-CH2-, -(CH2)2-O-CH2-,

-(CH2)3-O-, -CH2-O-(CH2)3-, -(CH2)2-O-(CH2)2-, - (CH2) 3-O-CH2-,

- (CH2) 4-O-, -CH2-O-CH2-CH2-O-,

[image]

if necessary in the form of their racemates, their enantiomers, their diastereomers and their mixtures, as well as if necessary their pharmacologically unambiguous acid addition salts.

Particularly preferred are compounds of the general formula 1 in which R1 and R2, the same or different, represent hydrogen or F;

R3 and R3', the same or different, represent hydrogen, F, Cl, Br, CF3 or methyl;

R4, R5 and R6, the same or different, represent hydrogen or methyl;

X is NH 2 , NH-(methyl), N(methyl) 2 , NH-COH, NH-COMe or F;

A is -CH (methyl) -O-CH2-, -CH2-O-CH2- or [image]

as appropriate in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and as appropriate their pharmacologically unambiguous acid addition salts.

According to the invention, the compounds of the general formula 1, in which

R1 and R2, the same or different, represent hydrogen or F;

R3 and R3', the same or different, represent hydrogen, F, Cl, Br, CF3 or methyl;

R4, R5 and R6, the same or different, represent hydrogen or methyl;

X is NH 2 , NH-(methyl) or NH-COH;

A is -CH (methyl)-O-CH2-, -CH2-O-CH2- or[image]

as appropriate in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and as appropriate their pharmacologically unambiguous acid addition salts.

According to the invention, the compounds of general formula 1 in which

R1 and R2, the same or different, represent hydrogen or F;

R3 and R3' are hydrogen;

R4, R5 and R6, the same or different, represent hydrogen or methyl;

X is F;

A is -CH(methyl)-O-CH2-,

if necessary in the form of their racemates, their enantiomers, their diastereomers and their mixtures, as well as if necessary their pharmacologically unambiguous acid addition salts.

In the aforementioned compounds of the general formula 1, if R1 is different from hydrogen, it is preferably in the ortho or para position, especially preferably in the ortho position in relation to bridge A. In the aforementioned compounds of the general formula 1, if R2 is different from hydrogen, it is primarily in the ortho position towards bridge A.

In the aforementioned compounds of the general formula 1, if R3 is different from hydrogen, it is preferably in position 7, that is, even in relation to group X. In the aforementioned compounds of the general formula 1, if R3 is different from hydrogen, it is preferably in the position 9, so ortho in relation to group X.

According to the invention, compounds of formula 1 in which R3' represents hydrogen are particularly preferred.

Of particular interest are the compounds of general formula 1 which are selected from the group consisting of:

(2R,6S,2S')-10-amino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11- trimethyl-2,6-methane-3-benzazocine dihydrochloride;

(2R,6S,2S')-10-amino-3-[2-(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6- methane-3-benz-azocine-dihydrochloride;

(2R,6S,11R,2"S)-10-amino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11 -dimethyl-2,6-methane-3-benzazocine-dihydrochloride;

(2R,6S,11S,2"S)-10-amino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11 -dimethyl-2,6-methane-3-benzazocine-dihydro chloride;

(2R,6S)-10-amino-3-[2,2,6-difluorophenyl-methoxy)-ethyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2 ,6-methane-3-benzazocine dihydrochloride;

(2R,6S,2"S,5"S)-10-amino-3-[5-phenyl-tetrahydrofuran-2"-yl)methyl]-1,2,3,4,5,6-hexahydro-6 ,11,11-trimethyl-2,6-methane-3-benzazocine dihydrochloride;

(2R,6S,2"S)-10-acetamino-3-[2(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6- methano-3-benz-azocine hydrochloride;

(2R,6S,2"S)-10-acetamino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11 -trimethyl-2,6-methane-3-benzazocine hydrochloride;

(2R,6S,2"S)-10-formylamino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11 -trimethyl-2,6-methane-3-benzazocine hydrochloride;

(2R,6S,2"S)-10-methylamino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11 -trimethyl-2,6-methane-3-benzazocine-dihydrochloride;

(2R,6S,2"S)-10-dimethylamino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11 -trimethyl-2,6-methane-3-benzazocine-dihydrochloride;

(2R,6S,2"S)-10-ethylamino-3-[2(2,6-difluoroenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11 ,11-trimethyl-2,6-methane-3-benzazocine dihydrochloride;

(2R,6S,2"S)-10-amino-7-methyl-3-[2-(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl -2,6-methane-3-benz-azocine-dihydrochloride;

(2R,6S,2"S)-10-amino-7-methyl-3-[2-(2,6-difluorophenyl-methoxy)propyl]-1,2,3,4,5,6-hexahydro-6 ,11,11-trimethyl]-2,6-methane-3-benzazocine dihydrochloride;

(2R,6S,2"S)-10-amino-7-chloro-3-[2(benzyloxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl -2,6-methane-3-benz-azocine-dihydrochloride;

(2R,6S,2"S)-10-amino-7-chloro-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6 ,11,11-trimethyl-2,6-methane-3-benzazocine dihydrochloride;

(2R,6S,2"S)-10-amino-7-bromo-3-[2(benzyloxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl -2,6-methane-3-benz-azocine-dihydrochloride;

(2R,6S,2"S)-10-amino-7-bromo-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6 ,11,11-trimethyl-2,6-methane-3-benzazocine dihydrochloride;

(2R,6S,2"S)-10-amino-7-fluoro-3-[2-(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl -2,6-methane-3-benz-azocine-dihydrochloride;

(2R,6S,2S,2"5"S)-10-amino-7-methyl-3-[5"-phenyl-tetra-hydrofuran-2"-yl)methyl]-1,2,3,4, 5,6-hexahydro-6,11,11-trimethyl-2,6-methane-3-benzazocine dihydrochloride;

(2R,6S,2"S)-10-amino-7-trifluoromethyl-3-[2(benzyloxy)-propyl]-1,2,3,4,5,6-hexahydro-6-methyl-2,6 -methane-3-benz-azocine-dihydrochloride;

(2R,6S,2"S)-10-amino-7-(4-methylphenyl)-3-[2(2,6-di-fluorophenyl-methoxy)-propyl]-1,2,3,4,5 ,6-hexahydro-6-methyl-2,6-methane-S-benzazocine-dihydrochloride.

C1-C6-alkyl is an unbranched or branched hydrocarbon residue with 1 to 6 carbon atoms which, if necessary, can also contain a ring system. Alkyl substituents can be the same or different and, if necessary, can be substituted with one or more halogen atoms, preferably with fluorine. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl. If necessary, common abbreviations such as Me for methyl, Et for ethyl, Prop for propyl, etc. are also used for the aforementioned alkyl groups.

C1-C6-alkyloxy is an unbranched or branched hydrocarbon radical of 1 to 6 carbon atoms, which is connected through one oxygen atom. Alkyloxy substituents can be the same or different. Examples include methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, cyclopropylmethyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. If necessary, the name alkoxy is also used for the aforementioned alkyloxy groups. Accordingly, instead of methyloxy, methoxy can also be used, for ethyloxy also ethoxy, for propyloxy also propoxy, etc. If necessary, for the aforementioned alkyloxy groups, the usual abbreviations are also used, for example MeO for methyloxy, EtO for ethyloxy, PropO for propyloxy etc.

According to the invention, doubly connected groups representing group A can be connected in both possible directions with their adjacent radicals.

If necessary, the compounds of the general formula (1) can be translated into their salts, especially for pharmaceutical use into their pharmacologically unambiguous acid addition salts with inorganic or organic acids. Suitable acids for this purpose are, for example, succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulfuric acid, tartaric acid or citric acid. Furthermore, mixtures of the mentioned acids can be used.

The compounds according to the invention are voltage-gated sodium channel blockers. These are compounds that, with high affinity (Ki<1000 nM), competitively or non-competitively suppress batrachotoxin (BTX) at the binding site on the sodium channel. Such substances show "use-dependency" when sodium channels are blocked, i.e. to bind to sodium channels, sodium channels must first be activated. Maximum blockade of sodium channels is achieved only after repeated stimulation of sodium channels. This is why substances bind primarily to sodium channels that are activated multiple times.

This is why these substances can be effective primarily in parts of the body that are pathologically overstimulated. These include diseases such as arrhythmias, spasms, cardiac and cerebral ischemia, pain, as well as neuro-degenerative diseases of various genesis. Examples include epilepsy, hypoglycemia, hypoxia, anoxia, brain trauma, cerebral edema, stroke, perinatal asphyxia, cerebellar degeneration, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotonia, heart attack, disorders heart rhythm, angina pectoris, chronic pain, neuropathic pain as well as local anesthesia.

A further aspect of the invention therefore relates to the use of the compounds of general formula 1 as a medicament, particularly as a medicament for conditions in which blockade of voltage-gated sodium channels may be therapeutically useful.

It is preferable to use compounds according to the invention of the general formula 1 for the production of a drug for the prevention or treatment of arrhythmias, spasms, cardiac and cerebral ischemia, pain and neurodegenerative diseases.

The aforementioned use of compounds according to the invention of the general formula 1 for the production of a drug for the prevention or treatment of epilepsy, hypoglycemia, hypoxia, anoxia, brain trauma, cerebral edema, stroke, perinatal asphyxia, cerebellar degeneration, amyotrophic lateral sclerosis, Huntington's disease, is particularly advantageous. Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotonia, heart attack, heart rhythm disorders, angina pectoris, chronic pain, neuropathic pain, as well as for local anesthesia.

The binding of BTX to the sodium channel serves as an experimental system for proving the effect of sodium channel blocking [S.W. Postma & W.A. Catterall, Mol. Pharmacol 25, 219-227 (1984)] as well as patch-clamp experiments in which it can be shown that the compounds of the invention can block electrically stimulated sodium channels in a use-dependent manner [W.A. Catterall, Trends Pharmacol. Sci., 8, 57-65 (1987)]. By choosing a cell system (eg, neuronal, cardiac, DRG cells), the effect of a substance on different subtypes of sodium channels can be investigated.

The sodium channel blocking property of the compounds of the invention can be demonstrated by blocking veratridine-induced glutamate release [S. Villauneva, P. Frenz, Y. Dragnic, F. Orrego, Brain Res. 461, 377-380 (1988)]. Veratridine is a toxin that permanently opens sodium channels. This leads to an increased current of sodium ions entering the cells. Through the cascade described above, this sodium input current in the neuronal tissue leads to an increased release of glutamate. This release of glutamate can be antagonized with compounds according to the invention.

The anticonvulsant properties of the substance according to the invention are characterized by a protective effect against convulsions induced with maximal electroshock in mice [M.A, Rogawski & R.J. Porter, Pharmacol. Rev. 42, 223-286 (1990)].

Neuroprotective properties were characterized with a protective effect in the MCAO rat model [U. Pschorn & A.J. Carter, J. Stroke Cerebrovascular Diseases, 6, 93-99 (1996)], to a malonate-induced lesion model [M.F. Beal, Annals of Neurology, 38, 357-366 (1995) and J.B. Schulz, R.T. Matthews, D.R. Henshaw and M.F. Beal, Neuroscience, 71, 1043-1048 (1996)] as well as the MPTP-induced degeneration model [J.P. Steiner, et al. Proc. Natl. Acad. Sci. 94, 2019-2024 (1997)].

Analgesic action was demonstrated in the formalin-induced pain model [D. Dubuisson and S.G. Dennis, Pain, 4, 161-174 (1977)] as well as in the ligature model [G.J. Bennett & Y.-K. Xie, Pain 33, 87-107 (1988)].

It has also been described that sodium channel blockers can be used to treat cyclophrenia (manic depressive illness) [J.R. Calabrese, C. Bowden, M.J. Woyshville; in Psychopharmacology, The Fourth Generation of Progress (ed.: D.E. Bloom and D.J. Kupfer) 1099-1111, New York, Raven Press Ltd.].

The compounds according to the invention can be produced analogously to known synthesis methods. A possible synthesis route is shown in Scheme 1.

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Scheme 1:

The key step is the conversion of phenol 2 into the compound of formula 1 in which X represents NH2, which takes place via the Buchwald reaction [J.P. Wolfe, J. Ahman, J.P. Sadighi, R.A. Singer, S.L. Buchwald, THL 1997, 6367-6370],

The triflates 3 required for this conversion can be prepared starting from compounds 2 with trifluoromethanesulfonic acid anhydride in the presence of an auxiliary base. As auxiliary bases according to the invention, organic amines such as, for example, dimethylaminopyridine, pyridine or also tert. amines such as trimethylamine, triethylamine, diisopropylethylamine or DBU (diazabicycloundecene). Of the previously mentioned amines, preference is given to the use of tert. amine, triethylamine is particularly advantageously used as an auxiliary base. The conversion is carried out in an aprotic, organic solvent, preferably a solvent selected from the group consisting of dimethylformamide, dimethylacetamide, methylene chloride, toluene or also tetrahydrofuran. Methylene is mentioned as particularly favorable at this point. The conversion to triflate 3 is preferably carried out at a temperature below room temperature, particularly advantageously at -50°C-0°C, and most advantageously between -30°C and -5°C. After 0.5 to 4 h at room temperature, mix approx. 1 - 12 h. After processing, the thus obtained crude products 3 are reacted without further purification in an aromatic organic solvent selected primarily from the group consisting of toluene, benzene or xylene, especially preferably toluene, with a palladium catalyst, preferably in the presence of phosphine ligands, with a nitrogen source, preferably with ketimines , especially advantageous with benzophenone-imines. As palladium catalysts according to the invention, tris(dibenzylideneacetone)-dipalladium, palladium (II)acetate or, for example, tetrakistriphenylphosphine-palladium are suitable. As phosphine ligands, for example, ligands selected from the group consisting of DPPF, BINAP, p-tolBINAP, PPh2-CHMe-P(tBu)2, phosphine-substituted ferrocene or also triphenylphosphine can be used. Tris(dibenzylideneacetone)-dipalladium/BINAP is primarily used as a catalyst system. The reaction is carried out with the exclusion of moisture and oxygen, preferably at an elevated temperature. The conversion takes place primarily under the reflux of the solvent used.

The intermediately obtained imine adduct can be converted into compound 1 according to the invention (with X = NH2) by acid hydrolysis, preferably with dilute mineral acids, especially preferably with dilute hydrochloric acid. Purification of the product is done by chromatography on silica gel or by crystallization, preferably by crystallization of a pharmacologically tolerable acid addition salt, for example hydrochloride.

As can be seen from the aforementioned embodiment, the triflates of general formula 3 are of central importance in the synthesis of compounds according to the invention of general formula 1.

Accordingly, a further aspect of the proposed invention relates to intermediate compounds of general formula 3

[image]

in which the radicals R1, R2, R3, R3', R4, R5, R6 and A can have the aforementioned meanings.

For the synthesis of the compounds according to the invention of the general formula 1, in which X is different from NH2, the procedure can be as described below.

Compounds of formula 1, in which X represents NHC1-C6-alkyl or N(C1-C6-alkyl)2, can be obtained by known methods by alkylation of compound 1, in which X represents NH2, by reductive amination or acylation as necessary in the presence of an organic base, and at the end by reduction.

Alkylation can be done as follows. The compound of general formula 1, with X = NH2, dissolves in a polar organic solvent, such as dimethylformamide, dimethylacetamide, methylene chloride, tetrahydrofuran, preferably dimethylformamide or methylene chloride. The solution thus obtained is mixed with a base and with a suitable alkylating agent. As bases, alkaline and alkaline earth hydrides come into consideration, primarily sodium hydride. Alkyl halides, such as alkyl chloride, alkyl bromide, especially alkyl iodide, as well as alkyl tosylates, -mesylates, -triflates, -dialkyl sulfates, can be used as alkylating agents. After the usual treatment, the alkylated compounds of the general formula 1 can be purified by chromatography on silica gel or by crystallization, if necessary in the form of their pharmacologically tolerable acid addition salts, preferably as hydrochlorides.

For the preparation of compounds of general formula 1 via reductive amination under usual reaction conditions, with cooling, preferably -50°C to room temperature, especially preferably between -30°C and 0°C, amine 1, with X = NH2, in the presence of an acid as which is dilute hydrochloric acid, dilute acetic acid or also dilute sulfuric acid, is mixed with aldehydes or ketones and the intermediate Schiffschen bases or iminium salts thus obtained are finally reduced. Reduction is carried out using metal hydrides such as sodium borohydride, LiAlH4, Li-alkoxyhydride, NaBH4, NaBHCN3, NaBH(OAc)3, but sodium borohydride is primarily used. After the usual work-up, the alkylated compounds of general formula 1 can be purified by chromatography on silica gel or by crystallization, if necessary in the form of their pharmacologically tolerable acid addition salts, preferably as hydrochlorides.

Compounds of formula 1 with X = NHCO (C1-C6-alkyl) can be obtained by known methods by acylating compound 1 with X = NH2, preferably with acid chlorides or anhydrides. For this purpose, the amino compound of formula 1, with X = NH2, is suspended in an organic solvent, mixed with an organic base and the desired acid chloride or anhydride is added. The mixture is kept for 40 to 60 minutes, preferably 25 to 45 minutes at room temperature. Suitable organic solvents are dimethylformamide, dimethylacetamide, methylene chloride, toluene or also tetrahydrofuran, with methylene chloride being preferred. Suitable organic bases are dimethylaminopyridine, pyridine, tert-amine, for example trimethylamine, triethylamine, diiso-propylethylamine, DBU (diazabicycloundecene). After processing, the products are purified by silica gel chromatography or crystallization, preferably by crystallization of pharmacologically tolerable acid addition salts, for example hydrochloride.

Starting with the compounds of formula 1, which can be obtained in the previously described manner, in which X = NHCO (C1-C6-alkyl), by reduction with metal hydrides, such as for example LiAlH4, Li-alkoxyhydride, NaBH4, NaBHCN3, NaBH ( OAc)3, preferably with sodium borohydride, compounds of formula 1 can also be obtained in which, for example, X = NH (C1-C6-alkyl). These conversions are carried out preferably in ethereal organic solvents, preferably in tetrahydrofuran or dioxane in the presence of a Lewis acid, preferably boron trifluoride ether, at an elevated temperature, preferably above 50°C, especially advantageously under reflux of the solvent used. After processing, the product can be purified by chromatography on silica gel or by crystallization, preferably by crystallization of pharmacologically tolerable acid addition salts.

Formulated compounds of formula 1 (X = NHCOH) can be obtained, for example, by converting compounds of formula 1, with X = NH2, with formic acid at elevated temperature, preferably under reflux. After processing, the product can be purified by chromatography on silica gel or by crystallization, preferably by crystallization of pharmacologically tolerable acid addition salts, for example hydrochloride.

Compounds 1 substituted with fluorine (with X = F) can be obtained by known procedures by diazotizing compounds 1, with X = NH2, and then boiling with BF4-. The reaction with NOBF4 is preferably carried out as a reagent for diazotization and fluorination in an ether solvent, preferably in tetrahydrofuran or dioxane, at an elevated temperature, preferably above 50°C, especially preferably under reflux of the solvent used. After processing, the product can be purified by chromatography on silica gel or by crystallization, preferably by crystallization of pharmacologically tolerable acid addition salts, for example hydrochloride.

The starting compounds named 1,2,3,4,5,6-hexahydro-2,6-methane-3-benzazocin-10-ol (2) in scheme 1 can be obtained by synthesis methods known from the state of the art. In this connection, reference is made at this point to the European patent application EP 521422 as well as to the international patent applications WO 97/06146 and WO 99/14199.

Compounds of general formula 2 in which R3 represents hydrogen can be obtained starting from compounds of general formula 4 analogously to the synthesis method described in WO 99/14199. For the preparation of compounds of the general formula 1 in which R3 is different from hydrogen, it is necessary to first modify the compounds of the general formula 4. This is done analogously in principle to known synthesis procedures in the manner described in the following schemes.

The introduction of a p-methyl substitution (R 3 is methyl) can be carried out for example according to the procedure shown in Scheme 2.

For the preparation of brominated compounds of formula 5, compounds of formula 4 are dissolved in a suitable solvent, preferably in acetic acid or in trifluoroacetic acid, particularly preferably in a mixture of acetic acid and trifluoroacetic acid and at 0-23°C, preferably at 10°C, in portions are mixed with NBS (N-bromosuccinimide). The reaction is complete after approx. 1 to 5 hours. Processing is done in the usual way. Purification of the product is done, depending on the tendency of compound 5 to crystallize, by crystallization or chromatography.

[image]

Scheme 2:

The benzylation of compounds 5 into compounds 6 is preferably carried out in an organic solvent, preferably in a solvent selected from the group consisting of dichloromethane, dimethylformamide and dimethylacetamide, especially preferably in dimethylacetamide. For this purpose, compounds 5 are dissolved in a solvent and mixed with benzyl chloride in the presence of a base at a temperature of 0-50°C, especially preferably at room temperature (approx. 23°C). Organic or inorganic bases can be used as bases. As inorganic bases, alkaline or alkaline earth carbonates of lithium, sodium, potassium, calcium such as sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate, and primarily potassium carbonate come into consideration. As organic bases, organic amines come into consideration, especially preferably diisopropylethylamine, triethylamine, cyclic amines such as DBU or pyridine. After the addition of benzyl chloride is complete, it is stirred for another 1 to 6, preferably 2 to 4 hours at an elevated temperature, preferably at approx. 50-120°C, especially favorable at approx. 100°C, but at most at the boiling temperature of the solvent in question. Processing is done in the usual way. Purification of the product is done, depending on the tendency of compound 6 to crystallize, by crystallization or chromatography.

Compounds 7 are prepared from compounds 6 by conversion with suitable formylation reagents. For this purpose, compounds 6 are dissolved in a suitable organic solvent, preferably in an anhydrous organic solvent, preferably in an ether solvent selected from the group consisting of diethyl ether, tetrahydrofuran and dioxane, preferably in diethyl ether, and at a lower temperature, preferably at a temperature below - 20°C, especially advantageously at a temperature between -50°C and -78°C are mixed with butyllithium, preferably dissolved in n-hexane. After approx. 0.5 to 2 hours of stirring in the above-mentioned temperature range, add a formylation reagent, preferably dimethylformamide, and stir for another 0.5 to 2 hours, if necessary at a slightly elevated temperature, preferably at -30°C to 0°C, especially preferably at approx. -10°C. Processing is done in the usual way. Purification of the product is done, depending on the tendency of compound 1 to crystallize, by crystallization or chromatography.

Reduction of compounds 7 leads to methyl compounds 8. For this purpose, compounds 7 are dissolved in a suitable organic solvent, preferably in an anhydrous organic solvent, preferably in an ether solvent selected from the group consisting of diethyl ether, tetrahydrofuran and dioxane, preferably in tetrahydrofuran and are mixed with a suitable reducing agent, preferably with a metal hydride salt, especially preferably with NaBH 4 or NaCNBH 3 , preferably NaCNBH 3 . The addition of boron trifluoride, or BF3-etherate, is also required. After the addition of the reducing agent, it is stirred for another 1 to 6 hours, preferably 2 to 4 hours at a constant temperature, preferably at room temperature. After the addition of a protic solvent, especially preferably a lower alcohol selected from the group consisting of methanol, ethanol or isopropanol, especially preferably methanol, and hydrolysis with aqueous acid, preferably with aqueous hydrochloric acid, it is stirred for another 0.5 to 4 hours, if necessary at elevated temperature, preferably at a temperature above 50°C, especially preferably under solvent reflux. Processing is done in the usual way. Purification of the product is done, depending on the tendency of compound 8 to crystallize, by crystallization or chromatography.

Cleavage of the methoxy group in compounds 8 leads to hydroxy compounds 9 and takes place under the action of stronger acids, such as HJ and HBr, especially preferably concentrated HBr at an elevated temperature, preferably at a temperature above 50°C, especially preferably under reflux. When using, for example, HBr, no solvent is required. The reaction is complete after approx. 1 to 6, preferably 2 to 4 hours. Processing is done in the usual way. Purification of the product is done, depending on the tendency of compound 9 to crystallize, by crystallization or chromatography. Cleavage of the methoxy group in 8 to give hydroxy compounds 9 can also be carried out using BBr3 analogously to the procedure described for the conversion of compounds 17 to hydroxy compounds 18.

Compounds 10 can be obtained by hydrogenolytic separation of the benzyl group from compounds 9. This reduction is primarily carried out by catalytic hydrogenation, preferably on palladium catalysts or on Raney nickel, especially preferably on palladium catalysts in alcoholic solvents, preferably in methanol, at room temperature. Processing is done in the usual way. Purification of the product is done, depending on the tendency of the compound to crystallize, by crystallization or chromatography.

The preparation of compounds of general formula 2 takes place starting from compounds of general formula 10 analogously to the synthesis procedure described in WO99/14199.

The introduction of the p-fluorine substitution is carried out in the manner shown in scheme 3. For this purpose, the compound of formula 6 is dissolved in a suitable organic solvent, preferably in an anhydrous organic solvent, preferably in an ether solvent selected from the group consisting of diethyl ether, tetrahydrofuran and dioxane, preferably in diethyl ether, and at a lower temperature, preferably at a temperature below -20°C, especially advantageously at a temperature between -50°C and -78°C, mixed with butyllithium preferably dissolved in n-hexane. After approx. After 0.5 to 2 hours of stirring in the aforementioned temperature range, a suitable fluorinating agent, preferably N-fluorobenzenesulfonimide dissolved in the aforementioned solvent, is slowly added and stirred for another 0.5 to 2 hours at constant temperature. Processing is done in the usual way. Purification of the product is done, depending on the tendency of the compound to crystallize, by crystallization or chromatography.

[image]

Scheme 3:

Conversion of compounds 11 to hydroxy compounds 12 proceeds as described for the conversion of compounds 8 to compounds 9. Conversion of compounds 12 to debenzylated compounds 13 proceeds as described for the conversion of compounds 9 to compounds 10.

The preparation of compounds of general formula 2 takes place starting from compounds of general formula 13 analogously to the synthesis procedure described in WO99/14199.

The introduction of the p-CF3 substitution takes place by the synthesis procedure shown in scheme 4.

In the first step, for this purpose, the compound of formula 4 is converted into the iodide of formula 14. This conversion takes place analogously to the procedure described for the conversion of compound 4 into compound 5 using NJS (N-iodo-succinimide).

N-protected compounds 15 can be obtained from compounds 14, in which PG represents an amino protecting group. As protective groups, the usual protective groups for the amino functional group come into consideration. Examples include benzyl, benzyloxycarbonyl and tert-butyloxycarbonyl, the latter being preferred. To introduce the tert-butyloxycarbonyl group, proceed as follows. The conversion is preferably carried out in an organic solvent, preferably in a solvent selected from the group consisting of dichloromethane, dimethylformamide and dimethylacetamide, particularly preferably in dichloromethane. For this purpose, compounds 14 are dissolved in a solvent and in the presence of a base at a temperature of -50°C to 10°C, preferably at -20°C to 0°C and mixed with an inorganic base. As inorganic bases, alkaline or alkaline earth hydroxides of lithium, sodium, potassium, calcium, such as sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, and primarily potassium hydroxide, as needed in an aqueous solvent, come into consideration. Then di-t-butyldicarbonate is added, if necessary dissolved in one of the aforementioned organic solvents. After the addition is complete, let it continue to mix for another 0.5 to 6, preferably 1 to 3 hours, if necessary at a higher temperature, preferably at room temperature. Processing is done in the usual way. Purification of the product is done, depending on the tendency of compound 15 to crystallize, by crystallization or chromatography.

[image]

Scheme 4:

For the preparation of trifluoromethyl compounds 16, the starting point is compounds 15. For this purpose, compound 15 is dissolved in a suitable organic solvent, preferably in a polar organic solvent selected from dimethylacetamide, dimethylsulfoxide or dimethylformamide, especially preferably in dimethylformamide, and mixed with methyl ester of fluorosulfonyl-difluoroacetene acids and CuJ, preferably anhydrous CuJ. Then the reaction mixture is heated to a temperature in the range of 50-90°C, especially preferably to 70°C. It is mixed at a constant temperature for 1 to 4 days, preferably approx. 2 days. Depending on the course of the reaction, more fluorosulfonyl-difluoroacetic acid methyl ester and CuJ can be added as needed. Processing is done in the usual way. Purification of the product is done, depending on the tendency of compound 16 to crystallize, by crystallization or chromatography.

Removal of the amino protecting group starting from compounds 16 leads to compounds 17. Procedures for removing the used protecting group are known from the state of the art. At this point, only possible versions of the process for removing the tert-butyloxycarbonyl protecting group can be mentioned as examples. This is done by reacting compound 16 with trifluoroacetic acid in a suitable organic solvent, preferably dichloromethane, at room temperature for 1 to 3 hours. Processing is done in the usual way. Purification of the product is done, depending on the tendency of compound 17 to crystallize, by crystallization or chromatography.

Starting from compounds 17, removal of the methoxy group leads to compounds 18 and is carried out by conversion with a solution of BBr3 in the presence of trifluoroacetic acid in a suitable organic solvent, preferably in dichloromethane at a lower temperature, preferably at a temperature below -50°C, especially preferably between -75° C and -60°C. After the addition of the reactants, at the aforementioned temperature, the reaction mixture is stirred at a temperature in the range of -20°C to 20°C, preferably at approx. 0°C and the reaction is complete in 4 to 12 hours. Processing is done in the usual way. Purification of the product is done, depending on the tendency of compound 18 to crystallize, by crystallization or chromatography.

As an alternative to the previously described procedure, the removal of the methoxy group in compound 17, thereby obtaining the hydroxy compound 18, can also be carried out using a strong acid. For this purpose, suitable embodiments relating to the conversion of compounds 8 to hydroxy compounds 9 can be mentioned.

The preparation of compounds of general formula 2 takes place starting from compounds of general formula 18 analogously to the synthesis procedure described in WO99/14199.

The introduction of the p-phenyl substitution takes place by the procedure shown in scheme 5.

[image]

Scheme 5:

Starting from compounds 6, compounds 19 can be obtained by conversion with suitably substituted borates and then transmetalation with palladium(O) compounds. As borates, phenylboronic acids substituted with the residue R are used. For this conversion, compound 6 is dissolved in a suitable organic solvent, preferably in an anhydrous organic solvent that does not contain oxygen, preferably in an ethereal solvent selected from the group consisting of diethyl ether, tetrahydrofuran and dioxane, preferably in dioxane, and mixed sequentially with the above boric acid derivative, potassium phosphate and a suitable palladium(O) catalyst. As Pd(0) catalysts according to the invention, tris(dibenzylidene-acetone)-dipalladium, palladium(II) acetate or, for example, tetra-kistriphenylphosphine-palladium, preferably tris-(di-benzylidene-acetone)-palladium(0) come into consideration. . The addition of phosphine or phosphite is also required. Suitable phosphine ligands include, for example, ligands selected from the group consisting of DPPF, BINAP, p-tol-BINAP, PPh2-CHMe-P(tBu)2, phosphine-substituted ferrocene, triphenylphosphine or trimethyl phosphite, and trimethyl phosphite is preferably used . After the addition of all reaction components, it is stirred for 0.5 to 2 hours at an elevated temperature, preferably at a temperature above 50°C, especially preferably under reflux of the solvent. Processing is done in the usual way. Purification of the product is done, depending on the tendency of compound 19 to crystallize, by crystallization or chromatography.

The conversion of compounds 19 into hydroxy compounds 20 is carried out as described for the conversion of compounds 8 into compounds 10 (via compounds 9).

Preparation of compounds of general formula 2 takes place starting from compounds of general formula 20 analogously to the synthesis route described in WO99/14199.

Halogen-substituted derivatives can be obtained, for example, by reacting compounds 1 according to the invention in which X represents NH2 and R3 is hydrogen, with NJS, NBS or NCS (scheme 6). As a rule, this results in a mixture of para-, ortho- and para-/ortho-disubstituted compounds, which can be separated by chromatography.

[image]

[image]

Scheme 6:

The preparation of compounds of general formula 2 in which R3 represents hydrogen, takes place starting from compounds of general formula 4 analogously to the synthesis procedure described in WO99/14199. For the preparation of compounds 2, in which R3 represents hydrogen, the starting point is compounds of formula 21 (scheme 7). These can be obtained from compounds 4. Compounds 21 are described in WO99/14199.

Scheme 7:

[image]

Scheme 7:

The following examples serve to explain the invention in more detail, but it is not limited to the compounds and processes described as examples.

I. Synthesis of intermediates 4 to 20:

Combinations of formulas

[image]

are known, for example, from W099/14199.

Compounds of formula 5:

(2R,6S)-7-Bromo-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methane-3-benzazocine hydrochloride, 5a:

24.7 g (0.1 mol) (2R,6S)-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methane-3- benzazocine (4a) is dissolved in 220 ml of acetic acid and 22 ml of trifluoroacetic acid, cooled to 10°C and mixed with 19.6 g of NBS (N-bromosuccinimide) in portions. It is stirred for 3 h at 10°C, the solvent is removed in vacuo and the residue is mixed with an ice-cold ammonia solution. It is then extracted twice with 200 ml of ethyl acetate, the combined organic phases are dried and the solvent is removed under vacuum. The residue was dissolved in acetone and the hydrochloride precipitated with ethereal HCl. Yield: 32.6 g (91%), mp: 203°C.

Compounds of formula 6:

(2R,6S)-3-benzyl-7-bromo-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methane-S-benzazocine 6a :

32.6 g (91 mmol) (2R,6S)-7-bromo-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methane- 3-benz-azocine hydrochloride 5a is dissolved in 160 ml of dimethylacetamide, mixed with 28 g of K2CO3 and 18.9 g of benzyl chloride and stirred for 3 h at 100°C. The solvent was then removed in vacuo, the residue was mixed with water and extracted twice with 200 ml of ethyl acetate. The combined organic phase is dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel.

The corresponding fractions are concentrated in vacuo. Yield: 24.5 g (73%); oil.

Compounds of formula 7

(2R,6S)-3-benzyl-7-formyl-10-methoxy-1,2,3,4,5,6-hexa-hydro-6,11,11-trimethyl-2,6-methane-S- benzazocine 7a:

24.5 g (59 mmol) (2R,6S)-3-benzyl-7-bromo-10-methoxy-1,2,3,4,5,6-hexahydro-5,6,11,11-trimethyl- 2,6-methane-3-benzazocine 6a was dissolved in 250 ml abs. of ether, cooled to -70°C and 40.7 ml of BuLi (1.6 M in hexane) were added dropwise. Then it is allowed to stir for 1 hour at -60°C, 10 ml of DMF is added dropwise and allowed to slowly warm to -10°C for 1 hour. The reaction mixture is transferred to 500 ml of water and extracted twice with 300 ml of ether each. The combined organic phase is dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel. The corresponding fractions are concentrated in vacuo. Yield: 18.3 g (85%), oil.

Compounds of formula 8:

(2R, 6S) -3-benzyl-7-methyl-10-methoxy-1, 2, 3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methane-3-benzazocine 8a :

8 g (22 mmol) (2R,6S)-3-benzyl-7-formyl-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6- methano-3-benz-azocine 7a is dissolved in 80 ml of THF, mixed with 4 g of NaCNBH3 and 20 ml of BF3-etherate and stirred for 3 h at room temperature. Then carefully add 100 ml of methanol, add 100 ml of 2 N HCl and boil for 1 h under reflux. The solvent is removed in vacuo, the residue is mixed with ammonia and extracted twice with 100 ml of ethyl acetate. The combined organic phase is dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel. The corresponding fractions are concentrated in vacuo.

Yield: 5.5 g (72%); oil.

Compounds of formula 9:

(2R, 6S)-3-benzyl-7-methyl-10-hydroxy-1,2,3,4,5,6-hexa-hydro-6,11,11-trimethyl-2,6-methane-3- benzazocine 9a:

5.3 g (15 mmol) (2R,6S)-3-benzyl-7-methyl-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2, 6-methane-3-benz-azocine 8a is dissolved in 54 ml conc. HBr and boiled for 2 h under reflux. The reaction mixture is concentrated in vacuo, the residue is mixed with ice and conc. with ammonia and extracted twice with 50 ml of acetic ester each. The combined organic phase was dried and the solvent was removed in vacuo. The residue is dissolved in acetone and the hydrochloride precipitated with ethereal HCl. Yield: 3.7 g (66%).

Compounds of formula 10:

(2R, 6S)-3-benzyl-7-methyl-10-hydroxy-1,2,3,4,5,6-hexa-hydro-6,11,11-trimethyl-2,6-methane-3- benzazocine 10a:

3.6 g (10 mmol) (2R,6S)-3-benzyl-10-hydroxy-7-methyl-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2, 6-methane-3-benzazocine 9a. is hydrogenated for 4 h on 0.4 g of PdC in 60 ml of methanol under 5 bar. It is then filtered and the solvent is removed under vacuum. Yield 2.6 g (92%); oil.

Compounds of formula 11:

(2R,6S)-3-benzyl-7-fluoro-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methane-3-benzazocine 11a :

8 g (20 mmol) (2R,6S)-3-benzyl-7-bromo-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6- methane-3-benz-azocine 6a is dissolved in 100 ml of ether, cooled to -65°C and 15 ml of BuLi (1.6 M in hexane) is added dropwise under nitrogen. After 1 h, add 8 g of N-fluorobenzenesulfonimide in 100 ml of THF and stir for 1 h at -60°C. It is then warmed to room temperature, the insoluble ingredients are sucked off and the solvent is removed under vacuum. The residue is taken up in 100 ml of water, mixed with 10 ml of conc. of ammonia and extracted twice with 150 ml of ether each. The combined organic phase is dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel. The corresponding fractions are concentrated in vacuo. Yield: 3.4 g (48%); oil.

Compounds of formula 12

(2R,6S)-3-benzyl-7-fluoro-10-hydroxy-1, 2,3, 4,5,6-hexa-hydro-6,11,11-trimethyl-2,6-methane-3- benzazocine 12a:

It is produced analogously to the preparation of compound _9 starting from compound 11; oil.

Compounds of formula 13:

(2R,6S)-7-fluoro-10-hydroxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methane-3-benzazocine 13a;

It was produced analogously to the preparation of compound JU)-starting from compound 12; oil.

Compounds of formula 14

(2R,6S)-7-iodo-10-hydroxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methane-3-benzazocine 14a:

32.5 g (0.13 mol) (2R,6S)-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methane-3- benzazocine 4a is dissolved in 330 ml of acetic acid and 110 ml of trifluoroacetic acid, cooled to 5°C and mixed with 32.9 g of NJS in portions. It is stirred for 3 h at 10°C, the solvent is removed in vacuo and the residue is mixed with an ice-cold ammonia solution. It is then extracted twice with 200 ml of acetic ester each, the combined organic phase is dried and the solvent is removed under vacuum. The residue is dissolved in ethyl acetate and the hydrochloride precipitated with ethereal HCl. Yield: 31.7 g (59%), melting point: 231°C.

Compounds of formula 15

(2R,6S)-3-t-butyloxycarbonyl-7-iodo-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methane-3- benzazocine 15a;

31.6 g (78 mmol) (2R,6S)-7-iodo-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methane- 3-benz-azocine hydrochloride 14a is suspended in 350 ml of dichloromethane, cooled to -5°C, mixed with 9 g of KOH in 18 ml of water and 17.7 g of di-t-butyldicarbonate in 50 ml is added dropwise dichloromethane. It is then allowed to slowly come to room temperature, stirred for 2 hours at room temperature and mixed with 200 ml of water. The organic phase is separated, dried and the solvent is removed under vacuum. Yield: 36.7 g (100%) of viscous oil.

Compounds of formula 16

(2R,6S)-3-t-butyloxycarbonyl-7-trifluoromethyl-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methane-3- benz-azocine 16a:

15.8 g (34 mmol) (2R,6S)-3-t-butyloxycarbonyl-7-iodo-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl- 2,6-methane-3-benzazocine 15a is dissolved in 120 ml of DMF, 10 g of fluorosulfonyl-difluoroacetic acid methyl ester and 2.3 g of CuJ are added and heated to 70°C. After 24 h, a further 3 g of methyl ester of fluorosulfonyl-difluoroacetic acid and 0.7 g of CuJ are added and it is stirred once more for 18 h at 70°C. The reaction mixture is cooled, mixed with 500 ml of ether and the insoluble ingredients are filtered off with suction. The filtrate is washed twice with dil. ammonia solution and water. The organic phase is dried and the solvent is removed in vacuo. Yield 13.6 g (98%); orange resin.

Compounds of formula 17:

(2R,6S)-7-trifluoromethyl-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methane-3-benzazocine 17a:

13.6 g (33 mmol) (2R,6S)-3-t-butyloxycarbonyl-7-trifluoromethyl-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl- 2,6-methane-3-benzazocine 16a is dissolved in 250 ml of dichloromethane, 25 ml of trifluoroacetic acid is added dropwise and stirred for 2 h at room temperature. Then the reaction mixture is transferred to ice water and ammonia solution is added, the organic phase is separated, dried and the solvent is removed under vacuum. Yield: 10.7 g (100%) orange resin.

Compounds of formula 18:

(2R,6SV)-7-trifluoromethyl-10-hydroxy-1,2,3,4,5,6-hexa-hydro-6,11,11-trimethyl-2,6-methane-3-benzazocine 18a:

1.0 g (3.2 mmol) (2R,6S)-7-trifluoromethyl-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6- methane-3-benz-azocine 17a is dissolved in 10 ml of dichloromethane, cooled to -65°C and 7 ml of BBr3 solution (1M in dichloromethane) is added dropwise. Then let it warm up to 0°C and stir for 8 hours at that temperature. With ice cooling, it was mixed with 10 ml of MeOH and the solvent was removed in vacuo. Yield: 1.2 g (100%), brown resin.

Compounds of formula 19:

(2R,6S)-3-benzyl-7-(4-methyl)phenyl-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methane -3-benzazocine 19a:

4.1 g (10 mmol) (2R,6S)-3-benzyl-7-bromo-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2, 6-Methane-3-benz-azocine 6a was dissolved under N2 in 100 ml of degassed dioxane, mixed with 12.6 g of K2PO4, 2.9 g of 4-methylphenylboronic acid, 0.92 g of tris(dibenzylideneacetone)-palladium( 0) and 0.25 g of trimethylphosphite and boiled for 1 h under reflux. Then it is allowed to cool, the salts are sucked off and the solvent is removed under vacuum. The residue is chromatographed on silica gel. The corresponding fractions are concentrated in vacuo. Yield: 3.8 g (89%); oil.

Compounds of formula 20

(2R,6S)-10-hydroxy-7-(4-methyl)phenyl-1,2,3,4,5,6-hexa-hydro-6,11,11-trimethyl-2,6-methane-3 -benzazocine hydrobromide 20a:

It was produced starting from 19a analogous to the preparation of compound 10a; m.p.: >250°C.

Compounds of formula 21

(2R,6S)-10-hydroxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methane-3-benzazocine hydrobromide 21a:

It was produced starting from 4a analogous to the preparation of compound 9a.

(2R,6S,11R)-10-hydroxy-1,2,3,4,5,6-hexahydro-6,11-dimethyl-2,6-methane-3-35 benzazocine hydrobromide 21b:

It was produced starting from 4b analogously to the preparation of compound 9a.

(2R,6S, US)-10-hydroxy-1,2,3,4,5,6-hexahydro-6,11-dimethyl-2,6-methane-3-benzazocine hydrobromide 21c:

It was produced starting from 4c analogous to the preparation of compound 9a.

(2R,6S)-10-hydroxy-1,2,3,4,5,6-hexahydro-6-methyl-2,6-methane-3-benzazocine hydrochloride 21d:

It was produced starting from 4d analogous to the preparation of compound 9c.

II. Synthesis of compounds of formula 2

(2R,6S,2"S)-10-hydroxy-3-[2-(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6 -methane-3-benz-

azocine dihydrochloride 2a:

1.6 g (6.9 mmol) (2R,6S)-10-hydroxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methane-3- benzazocine hydrobromide 21a is suspended in 30 ml of dichloromethane and mixed with 6 ml of N-methylmorpholine. After 30 minutes, it is cooled to -5°C and a solution of 2.3 g (11.6 mmol) of (-)-S-2-benzyloxy-propionic acid chloride in 20 ml of dichloromethane is slowly added dropwise. Let it mix for another 30 minutes at -5°C, mix with 40 ml of 2 N hydrochloric acid and separate the organic phase. The organic phase is dried over MgSO4, the solvent is removed in vacuo and the residue is taken up in 80 ml of THF. 1.0 g (26 mmol) of LiAlH4 is added to this solution, and the temperature rises to 35°C. It is left to react for another 30 minutes, mixed with 0.8 ml of water and 0.4 ml of 5 N sodium hydroxide solution and separated from the inorganic precipitate. The precipitate was washed with 1.00 ml of THF and the combined organic phases were concentrated in vacuo. The residue is taken up in 200 ml of ether, dried over MgSO4 and the hydrochloride is precipitated with ethereal hydrochloric acid. The crystals are separated and washed with acetone. Yield: 2.1 g (73%), mp: 254°C, [α]D25 = (-)20.7° (C=1 in methanol).

By using appropriate carboxylic acids, the following compounds were obtained:

(2R,6S,2S')-10-hydroxy-3-[2-(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11 -trimethyl-2,6-methane-3-benzazocine-dihydrochloride 2b

It was produced starting from 21a analogous to the preparation of compound 2a.

(2R,6S,11R,2S')-10-hydroxy-3-[2-(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11 ,11-trimethyl-2,6-methane-3-benzazocine dihydrochloride 2c

It was produced starting from 21b analogous to the preparation of compound 2a.

(2R,6S,US,2S')-10-hydroxy-3-[2-(benzyloxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-2,6 -methane-3-benzazocine-dihydrochloride 2d

It was produced starting from 21c analogous to the preparation of compound 2a.

(2R,6S,2S')-10-hydroxy-3-[2-(benzyloxy)-propyl]-1,2,3,4,5,6-hexahydro-6-methyl-2,6-methane-3 -benzazocine-dihydrochloride 2e

It was produced starting from 21d analogous to the preparation of compound 2a.

(2R,6S)-10-hydroxy-3-[2-2,6-difluorophenyl-methoxy)-ethyl-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2, 6-methane-3-benzazocine-dihydrochloride 2f

It was produced starting from 21a analogous to the preparation of compound 2a.

(2R,6S,25')-10-hydroxy-3-[2-(2,6-difluorophenyl-methoxy)-isopentyl-1,2,3,4,5,6-hexahydro-6,11,11- trimethyl-2,6-methane-3-benzazocine-dihydrochloride 2g

It was produced starting from 21a analogous to the preparation of compound 2a.

(2R,6S)-10-hydroxy-3-[2-(benzyloxy)ethyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methane-3 -benzazocine-dihydrochioride 2h

It was produced starting from 21a analogous to the preparation of compound 2a.

(2R,6S)-10-hydroxy-3-[2-(2-fluorophenyl-methoxy)-ethyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2, 6-methane-3-benzazocine dihydrochloride 2i

It was produced starting from 21a analogous to the preparation of compound 2a.

(2R,6S)-10-hydroxy-3-[2-(2,4-difluorophenyl-methoxy)-ethyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl- 2,6-methane-3-benzazocine dihydrochloride 2j

It was produced starting from 21a analogous to the preparation of compound 2a.

(2R,6S)-10-hydroxy-3-[2-(2,6-dimethylphenyl-methoxy)-ethyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl- 2,6-methane-3-benzazocine dihydrochloride 2k

It was produced starting from 21a analogous to the preparation of compound 2a.

(2R,6S,2S')-10-hydroxy-3-[2-(benzyloxy)-butyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6 -methane-3-

benzazocine dihydrochloride 2m

It was produced starting from 21a analogous to the preparation of compound 2a.

(2R,65,2S')-10-hydroxy-3-[2-(2,6-difluorophenyl-methoxy)-butyl]-1,2,3,4,5,6-hexahydro-6,11,11 -trimethyl-2,6-methane-3-benzazocine-dihydrochloride 2m

It was produced starting from 21a analogous to the preparation of compound 2a.

(2R,6S,2S')-10-hydroxy-3-[2-(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6-methyl-2 ,6-methane-3-benzazocine-dihydrochloride 2n

It was produced starting from 21d analogous to the preparation of compound 2a.

(2R,6S,2"R,5"S)-10-hydroxy-3-[5"-phenyl-tetrahydrofuran-2-yl)methyl]-1,2,3,4,5,6-hexahydro-6 ,11,11-trimethyl-2,6-methane-3-benzazocine-dihydrochloride 20

It was produced starting from 21a analogous to the preparation of compound 2a.

(2R,6S,2"S,5"S)-10-hydroxy-3-[5"-phenyl-tetrahydrofuran-2-yl)methyl-1,2,3,4,5,6-hexahydro-6, 11,11-trimethyl-2,6-methane-3-benzazocine-dihydrochloride 2p

It was produced starting from 21a analogous to the preparation of compound 2a.

(2R,6S)-10-hydroxy-3-[3-(2,6-difluorophenyloxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2, 6-methane-3-benzazocine-dihydrochloride 2q

It was produced starting from 21a analogous to the preparation of the compound

(2R,6S)-10-hydroxy-3-[4-(2,6-difluorophenyl)-butyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2, 6-methane-3-benzazocine-dihydrochloride 2r

It was produced starting from 21a analogous to the preparation of compound 2a.

(2R,6S,2S')-10-hydroxy-7-methyl-3-[2-(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6 ,11,11-trimethyl-2,6-methane-3-benzazocine-dihydrochloride 2s

It was produced starting from 10a analogously to the preparation of compound 2a.

(2R,6S,2S')-10-hydroxy-7-methyl-3-[2-(benzyloxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl -2,6-methane-3-benz-azocine-dihydrochloride 2t

It was produced starting from 10a analogous to the preparation of compound 2a.

(2R,6S,2"S,5"S)-10-hydroxy-7-methyl-3-[5"-phenyl-tetrahydro-furan-2"-yl)methyl]-1,2,3,4, 5,6-hexahydro-6,11,11-trimethyl-2,6-methane-3-benzazocine-dihydrochloride 2u

It was produced starting from 10a analogous to the preparation of compound 2a.

(2R,6S,2S')-10-hydroxy-7-fluoro-3-[2-(benzyloxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl -2,6-methane-3-benz-azocine dihydrochloride 2v

It was produced starting from 13a analogous to the preparation of compound 2a.

(2R,6S,2S')-10-hydroxy-7-trifluoromethyl-3-[2-(benzyloxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl -2,6-methane-3-benzazocine-dihydrochloride 2w

It was produced starting from 18a analogous to the preparation of compound 2a.

(2R,6S,2S')-10-hydroxy-7-(4-methylphenyl)-3-[2-(2,6-difluoro-phenyl-methoxy)propyl]-1,2,3,4,5, 6-hexahydro-6,11,11-trimethyl-2,6-methane-3-benzazocine-dihydrochloride 2x

It was produced starting from 20a analogous to the preparation of compound 2a.

(2R,6S)-10-hydroxy-7-methyl-3-[2-(2,6-difluorophenyl-methoxy)-ethyl]-1,2,3,4,5,6-hexahydro-6,11, 11-trimethyl-2,6-methane-3-benzazocine dihydrochloride 2y

It was produced starting from 10a analogous to the preparation of compound 2a.

III. Synthesis of compounds of formula 1 according to the invention

Example 1

(2R,6S,2S')-10-amino-3[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl -2,6-methane-3-benz-

azocine dihydrochloride

[image]

13.5 g (0.03 mol) (2R,6S,2"S)-3-[2-(2,6-difluoro-phenyl-methoxy)-propyl]-1,2,3,4,5, 6-Hexahydro-6,11,11-trimethyl-2,6-methane-3-benzazocin-10-ol 2d was dissolved in 135 ml of dichloromethane, mixed with 30 ml of triethylamine and knife-tip 4-dimethylaminopyridine and cooled to -10° C. Then 6.8 ml of trifluoromethanesulfonic acid anhydride are added dropwise and mixed at -10° C and for another 2 h at room temperature. The reaction mixture is placed on ice, mixed with 50 ml of ammonia, the organic phase is separated and washed once with 50 ml of water. The organic phase is dried, the solvent is removed in vacuo, the residue is taken up in 350 ml of toluene and mixed with 21.6 g of CsCO3 and 10.8 g of benzophenoneimine. Then nitrogen is passed through the suspension for 30 minutes , is mixed with 1.2 g of BINAR and O, 6 g of tris(dibenzylideneacetone)-dipalladium and heated for 6 h under reflux. When cooled, it is washed with 200 ml of water, the organic phase is dried and the solvent is removed in vacuum.

The residue was taken up in ethanol and the hydrochloride was precipitated with ethereal HCl. Yield: 13.7 g (88%), mp: 266°C, [α]D20=(-) 37.0° (c = 1 in MeOH).

Further, the following compounds were obtained, among others:

Example 2

(2R,6S,2"S)-10-amino-3-[2-(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6 -methane-3-benzazocine-dihydrochloride

[image]

It was produced starting from compound 2a analogously to example 1; melting point: 257°C. [α]D2°= (-)29.3° (c = 1 in MeOH).

Example 3

(2R,6S,11,R,2"S)-10-amino-3-[2-(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro- 6,11-dimethyl-2,6-methane-3-benzazocine dihydrochloride

[image]

It was produced starting from compound 2c analogously to example 1; tal. : 232°C, [α]D 2 O = (-) 4.1° (c = 1 in MeOH).

Example 4

(2R,6S,11S,2"S)-10-amino-3-[2-(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6, 11-dimethyl-2,6-methane-3-benzazocine dihydrochloride

[image]

It was produced starting from compound 2d analogously to example 1; tal. : 267 °C, [α]D2° = (-) 2.4° (c = 1 in MeOH).

Example 5

(2R,6S,2"S)-10-amino-3-[2-(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6-methyl- 2,6-methane-3-benzazocine dihydrochloride

[image]

It was produced starting from compound 2n analogously to example 1; mp: 187°C, [α]D 2 O = 19.7° ( c =1 in MeOH).

Example 6

(2R,6S,2S')-10-amino-3-[2-(2,6-difluorophenyl-methoxy)-butyl]-1,2,3,4,5,6-hexahydro-6,11,11 -trimethyl-2,6-methane-3-benzazocine-dihydrochloride

[image]

It was produced starting from compound 2m analogously to example 1; melting point: 200°C.

Example 7

(2R,6S,2S')-10-amino-3-[2-(2,6-difluorophenyl-methoxy)-isopentyl]-1,2,3,4,5,6-hexahydro-6,11,11 -trimethyl-2,6-methane-3-benzazocine-dihydrochloride

[image]

It was produced starting from compound 2a analogously to example 1; mp: 274°C, [α]D2°= (-) 21.8° (c = 1 in MeOH).

Example 8

(2R,6S)-10-amino-3-[2-(2,6-difluorophenyl-methoxy)-ethyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl- 2,6-methane-3-

benzazocine dihydrochloride

[image]

It was produced starting from compound 2_f analogously to example 1; mp: 270°C, [α]D2° = (-) 77.4° (c = 1 in MeOH).

Example 9

(2R,6S,2S')-10-amino-3-[2-(benzyloxy)-butyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6 -methane-3-benzazocine-dihydrochloride

[image]

It was produced starting from compound 21 analogously to example 1; m.p.: >190 °C (dec.).

Example 10

(2R,6S)-10-amino-3-[2-(benzyloxy)-ethyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methane- 3-benzazocine dihydrochloride

[image]

It was produced starting from compound 2h analogously to example 1; melting point: 220°C.

Example 11

(2R,6S)-10-amino-3-[2-(2-fluorophenyl-methoxyethyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methane -3-benz-

azocine-aihydrochloride

[image]

It was produced starting from compound 2i analogously to example 1; melting point: 220°C.

Example 12

(2R,6S)-10-amino-3-[3-(2,6-difluorophenyloxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2, 6-methane-3-benz-

azocine-dihydrochlo rid

[image]

It was produced starting from compound 2q analogously to example 1; melting point: 250°C.

Example 13

(2R, 6S)-10-amino-3-[4-(2,6-difluorophenyl)-butyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2, 6-methane-3-benz-

azocine dihydrochloride

[image]

It was produced starting from compound 2r analogously to example 1; melting point: 250°C.

Example 14

(2R, 6S)-10-amino-3-[2-(2,4-difluorophenyl-methoxy)ethyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2 ,6-methane-3-benz-

azocine dihydrochloride

[image]

It was produced starting from compound 2j analogously to example 1; melting point: 220°C.

Example 15

(2R,6S)-10-amino-3-[2-(2,6-dimethylphenyl-methoxy)-ethyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl- 2,6-methane-3-benz-

azocine dihydrochloride

[image]

It was produced starting from compound 2_k analogously to example 1; melting point: 245°C.

Example 16

(2R,6S,2"S,5"S]-10-amino-3-[5"-phenyl-tetrahydrofuran-2"-yl)-methyl]-1,2,3,4,5,6-hexahydro -6,11,11-trimethyl-2,6-methane-3-benzazocine dihydrochloride

[image]

It was produced starting from compound 2p analogously to example 1; mp: 253°C, [α]D2O = (-) 135.4° (c = 1 in MeOH).

Example 17

(2R,6S,2"R,5"S)-10-amino-3-[5"-phenyl-tetrahydrofuran-2"-yl)-methyl]-1,2,3,4,5,6-hexahydro -6,11,11-trimethyl-2,6-

methano-3-benzazocine dihydrochloride

[image]

It was produced starting from compound 2o analogously to example 1; melting point: 255°C.

Example 18

(2R,6S,2"S)-10-acetamino-3-[2-(2,6-benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl -2,6-methane-3-benz-

azocine hydrochloride:

[image]

K 1.1 g (2.4 mmol) (2R,6S,2"S)-10-amino-3-[2-(benzyl-oxy)propyl]-1,2,3,4,5,6- of hexahydro-6,11,11-trimethyl-2,6-methane-3-benzazocine-dihydrochloride (example 2) and 5 ml of triethylamine in 50 ml of dichloromethane, add 2 ml of acetic anhydride and mix for 0.5 h at room temperature Then it is concentrated in vacuo, mixed with 100 ml of ether and washed twice with 50 ml of water each. The organic phase is dried, the solvent is removed in vacuo, the residue is taken up in ether and the hydrochloride is precipitated with ethereal HCl. Use: 0.8 g (73%), mp: >100 °C, [α]D2°= (-) 56.5° (c =1 in MeOH).

Example 19

(2R,6S,2"S)-10-acetamino-3-[2-(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11, 11-trimethyl-2,6-methane-3-benzazocine hydrochloride

[image]

It was produced starting from example 1 analogously to example 18; mp: 125°C, [α]D20 = (-)58.7° (c - 1 in MeOH).

Example 20

(2R,6S,2"S)-10-formylamino-3-[2-(2,6-difluorophenyl-methoxy)-propyl]-1-1,2,3,4,5,6-hexahydro-6, 11,11-trimethyl-2,6-methane-3-benzazocine hydrochloride

[image]

0.5 g (1.2 mmol) (2R,6S,2"S)-10-amino-3-[2-(2,6-di-fluorophenyl-methoxy)-propyl]-1,2,3, 4,5,6-hexahydro-6,11,11-trimethyl-2,6-methane-3-benzazocine (example 1) is mixed with 10 ml of 97% formic acid and boiled for 1 h under reflux. concentrated in vacuo, the residue is mixed with ice and 50 ml of ammonia and extracted twice with 50 ml of ethyl acetate. The combined organic phases are washed with 30 ml of water, dried and the solvent is removed in vacuo. The residue is taken up in ether and hydrochloride is precipitated with ethereal HCl.Yield: 0.3 g (52%), m.p.: amorphous, [α]D20= (-) 41.6° (c = 1 in MeOH).

Example 21

(2R,6S,2"S)-10-methylamino-3-[2-(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11, 11-trimethyl-2,6-methane-3-benzazocine dihydrochloride

[image]

1.0 g (2.4 mmol) (2R,6S,2"S)-10-amino-3-[2-(2,6-di-fluorophenyl-methoxy)-propyl]-1,2,3, 4,5,6-hexahydro-6,11,11-trimethyl-2,6-methane-3-benzazocine (Example 1) is dissolved in 10 ml of ethyl acetate and mixed with 1 ml of triethylamine and 1 ml of trifluoroacetic anhydride. It is washed twice with 10 ml of water for 10 minutes, the organic phase is dried and the solvent is removed in vacuo. The residue is taken up in 10 ml of dimethylacetamide and mixed with 0.5 g of NaH. After 15 minutes, 1 ml of methyl iodide is added and mixed for 1 h at 50° C. Then the solvent was removed in vacuo, the residue was mixed with 20 ml of methanol and 2 ml of 20% NaOH and stirred for 30 minutes at 60° C. The solution was concentrated again in vacuo, the residue was mixed with 50 ml of water and extracted twice with 100 ml of ether each. The combined organic phases were dried, the solvent was removed in vacuo and the residue was chromatographed on silica gel. The appropriate fractions were combined and the hydrochloride precipitated with ethereal HCl. Yield: 0.4 g (35%), m.p.: 243°C, [α]D2° = (-) 20.5° (c = 1 in MeOH).

Example 22

(2R,6S,2"S)-10-dimethylamino-3-[2-(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11, 11-trimethyl-2,6-methane-3-benzazocine dihydrochloride

[image]

To a solution of 0.6 ml of 37% formalin and 1.2 ml of 3N H2SO4 cooled to -10°C, a suspension of 0.4 g (1 mmol) (2R,6S,2"S)-10 was added in portions. -amino-3-[2-(2,6-difluoro-phenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-tri-methyl-2,6 -methane-3-benzazocine (Example 1) and 0.3 g of NaBH 4 in 7 ml of THF.After the addition is complete, it is allowed to react for another 10 minutes, mixed with ammonia and extracted twice with 20 ml of ethyl acetate. The organic phase is dried, the solvent is removed in vacuo, the residue is taken up in ether and the hydrochloride is precipitated with ethereal HCl. Yield: 0.5 g (97%), melting point: 125°C, [α]D20= (-) 20.0° (c = 1 in MeOH).

Example 23

(2R,6S,2"S)-10-ethylamino-3-[2-(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11, 11-trimethyl-2,6-methane-3-benzazocine dihydrochloride

[image]

1.1 g (2.4 mmol) (2R,6S,2"S)-10-acetamino-3-[2-(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4, 5,6-hexahydro-6,11,11-trimethyl-2,6-methane-3-benzazocine (example 1) is dissolved in 30 ml of THF, mixed with 0.5 g of NaBH4 and 1.5 ml of BF3 -etherate and heated under reflux for 6 h. Allow to cool, add 30 ml of MeOH and 60 ml of 2 N HCl and heat under reflux for another 30 minutes. Then the solvent is removed in vacuo, the residue is mixed with conc. ammonia and extracted is twice with 30 ml of ethyl acetate. The combined organic phases are washed once with 20 ml of water, dried and the solvent is removed in vacuo. The residue is taken up in acetone and the hydrochloride is precipitated with ethereal HCl. Yield: 0.95 g (89 %), mp: 242°C, [α]D20 = (-) 24.8° (c = 1 in MeOH).

Example 24

(2R,6S,2"S)-10-fluoro-3-[2-(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11, 11-trimethyl-2,6-methane-3-benzazocine hydrochloride

[image]

1.5 g (3.6 mmol) (2R,6S,2"S)-10-amino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5 ,6-hexahydro-6,11,11-trimethyl-2,6-methane-3-benzazocine (example 1) is placed in 30 ml of dioxane, mixed with 3 g of NOBF4 in 30 ml of dioxane and stirred for 1 h at 90 °C. The solvent is then removed in vacuo, the residue is mixed with 50 ml of ethyl acetate and washed once with 30 ml of dilute ammonia and once with 30 ml of water. The combined organic phases are dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel. The appropriate fractions were combined and the hydrochloride precipitated with ethereal HCl. Yield: 0.5 g (33%), m.p.: 190°C, [a]D2° = (-) 27.3° (c = 1 in MeOH).

Example 25

(2R,6S,2"S)-10-amino-7-methyl-3-[2-(2,6-difluorophenyl-methoxy)-propyl]-2,3,4,5,6-hexahydro-6, 11,11-trimethyl-2,6-methane-3-benzazocine dihydrochloride

[image]

It was produced starting from 2s analogously to example 1; melting point: 236°C.

Example 26

(2R,6S,2"S)-10-amino-7-methyl-3-[2-(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl -2,6-methane-3-benzazocine-dihydrochloride

[image]

It was produced starting from 2t analogously to example 1; mp: 227°C, [α]D20 = (-)31.8° (c = 1 in MeOH).

Example 27

(2R,6S,2"S)-10-formylamino-7-methyl-3-[2-(benzyloxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11- trimethyl-2,6-methane-3-benzazocine dihydrochloride

[image]

It was produced starting from example 26 analogously to example 20; melting point: 141°C.

Example 28

(2R,6S,2"S)-10-formylamino-7-methyl-3-[2-(2,6-difluorophenyl-methoxy)propyl]-1,2,3,4,5,6-hexahydro-6 ,11,11-trimethyl-2,6-methane-3-benzazocine-dihydrochloride

[image]

It was produced starting from example 28 analogously to example 20; mp: >105°C°C (dec.), [α]D2° = (-)42.2° (c = 1 in MeOH).

Example 29

(2R,6S,2"S)-10-methylamino-7-methyl-3-[2-(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl -2,6-methane-3-

benzazocine dihydrochloride

[image]

It was produced starting from example 26 analogously to example 21; m.p.: >100°C (exp.).

Example 30

(2R,6S,2"S)-10-methylamino-7-methyl-3-[2-(2,6-difluorophenyl-methoxy)propyl]-1,2,3,4,5,6-hexahydro-6 ,11,11-trimethyl-2,6-methane-3-benzazocine-dihydrobromide

[image]

It was produced starting from example 25 analogously to example 21; mp: 221°C (dec.), [α]D2O = (-) 29.4° (c = 1 in MeOH).

Example 31

(2R,63,2"S)-10-amino-8-methyl-3-[2-(benzyloxylpropyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2 ,6-methane-3-benz-

azocine dihydrochloride

[image]

It is produced analogously to example 1; melting point: 250°C.

Example 32

(2R,6S,2"S)-10-amino-7-chloro-3-[2-(benzyloxy)propyl]-,2,3,4,5,6-hexahydro-6,11,11-trimethyl- 2,6-methane-3-benz-

azocine dihydrochloride

[image]

4.5 g (10 mmol) (2R,6S,2"S)-10-amino-3-[2-(benzyl-oxy)propyl]-1,2,3,4,5,6-hexahydro-6 . it is stirred for 4 h at room temperature. The solvent is then removed in vacuo, the residue is taken up in 100 ml of aqueous ammonia solution and extracted twice with 50 ml of ethyl acetate each. The combined organic phases are dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel. Appropriate fractions were combined and the hydrochloride precipitated with ethereal HCl. Yield: 1.3 g (27%); mp: 222°C, [α]D20 = (-)17.4° (c = 1 in MeOH).

Example 33

(2R,6S,2"S)-10-amino-7,9-dichloro-3-[2-(benzyloxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11, 11-trimethyl-2,6-methane-3-benz-azocine dihydrochloride

[image]

It was produced together with example 32. After chromatographic separation, the following was obtained: Yield: 0.6 g (12%); tal. : 197°C, [α]D 2 O = 11.0° (c = 1 in MeOH).

Example 34

(2R,6S,2"S)-10-amino-7-chloro-3-[2-(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro- 6,11,11-trimethyl-2,6-methane-3-benzazocine dihydrochloride

[image]

It was produced starting from example 1 analogously to example 32; melting point: 247°C.

Example 35

(2R,6S,2"S)-10-amino-7-bromo-3-[2-(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl -2,6-methane-3-benz-

azocine dihydrochloride

[image]

It was produced starting from example 2 analogously to example 32 with the use of NBS. Melting point: 215°C, [α]D20 = (-)17.3° (c = 1 in MeOH).

Example 36

(2R,6S,2"S)-10-amino-7,9-dibromo-3-[2-(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11 -trimethyl-2,6-methane-3-benzazocine dihydrochloride

[image]

It was produced together with example 35 analogously to example 33; mp: 177°C, [α]D 2 O = 11.5° (c = 1 in MeOH).

Example 37

(2R,6S,2"S)-10-amino-7-bromo-3-[2-(2,6-difluorophenylmethoxy)-propyl]-1,2,3,4,5,6-hexahydro-6, 11,11-trimethyl-2,6-methane-3-benzazocine dihydrochloride

[image]

It was produced starting from example 1 analogously to example 32 with the use of NBS. Tal. : 233°C, [α]D 20 = (-)20.5° (c = 1 in MeOH).

Example 38

(2R,6S,2"S)-10-amino-7,9-dibromo-3-[2-(2,6-difluorophenyl-methoxy)propyl]-1,2,3,4,5,6-hexahydro -6,11,11-trimethyl-2,6-methane-3-benzazocine dihydrochloride

[image]

It was produced together with example 37 analogously to example 36; mp: 236°C, [α]D 2 O =5.9° (c = 1 in MeOH).

Example 39

(2R,6S,2"S)-10-amino-9-bromo-3-[2-(2,6-difluorophenylmethoxy)-propyl]-1,2,3,4,5,6-hexahydro-6, 11,11-trimethyl-2,6-methane-3-benzazocine dihydrochloride

[image]

It was produced together with example 37 analogously to example 32; mp: 252°C, [α]D2O = (-)14.6° (c = 1 in MeOH).

Example 40

(2R,6S,2"S)-10-amino-7-fluoro-3-[2-(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl -2,6-methane-3-benz-

azocine dihydrochloride

[image]

It is produced starting from 2v analogously to example 1; melting point: 150°C.

Example 41

(2R,6S,2"S,5"S)-10-amino-7-methyl-3-[5"-phenyl-tetrahydro-furan-2"-yl)methyl]-1,2,3,4, 5,6-hexahydro-6,11,11-trimethyl-2,6-methane-3-benzazocine dihydrochloride

[image]

It was produced starting from 2 in analogy to example 1; melting point: 250°C.

Example 42

(2R,6S,2"S,5"S)-10-methylamino-7-methyl-3-[5"-phenyl-tetra-hydrofuran-2"-ylmethyl]-1,2,3,4,5, 6-hexahydro-6,11,11-trimethyl-2,6-methane-3-benzazocine dihydrochloride

[image]

It was produced starting from example 41 analogously to example 21; melting point: 250°C.

Example 43

(2R,6S,2"S,5"S)-10-formylamino-7-methyl-3-[5"-phenyl-tetra-hydrofuran-2"-yl)methyl]-1,2,3,4, 5,6-hexahydro-6,11,11-trimethyl-2,6-methane-3-benzazocine dihydrochloride

It was produced starting from example 41 analogously to example 20; melting point: 250°C.

Example 44

(2R,6S,2"S)-10-amino-7-trifluoromethyl-3-[2-(benzyloxy)-propyl]-1,2,3,4,5,6-hexahydro-6-methyl-2, 6-methane-3-benz-azocine dihydrochloride

[image]

It was produced starting from 2w analogously to example 1; melting point: 165°C.

Example 45

(2R,6S,2"S)-10-amino-7-(4-methylphenyl)-3-[2-(2,6-difluoro-phenyl-methoxy)propyl]-1,2,3,4,5 ,6-hexahydro-6-methyl-2,6-methane-3-benzazocine dihydrochloride

[image]

It was produced starting from 2x analogously to example 1; mp: 219°C, [α]D20 = (-)19.5° (c = 1 in MeOH).

The compounds of the invention can be administered orally, transdermally, nasally, by inhalation or parenterally. In addition, the compounds according to the invention are present as an active ingredient in the usual forms for administration, for example in preparations which mainly consist of an inert pharmaceutical carrier and an effective dose of the active substance, such as for example tablets, dragees, capsules, wafers, powder, solutions, suspensions, emulsions, syrups, suppositories, transdermal systems, etc. The effective dose of the compounds according to the invention for oral administration is between l and 1000, preferably between l and 500, especially preferably between 5-300 mg/dose, for intravenous, subcutaneous or intramuscular administration is between 0.001 and 50, preferably between 0.1 and 10 mg/dose. Solutions according to the invention containing 0.01 to 1.0, preferably 0.1 to 0.5% of the active substance are suitable for inhalation. For inhalation application, the use of powder is preferred. The compounds according to the invention can also be used as infusion solutions, preferably in a physiological sodium chloride solution or a salt solution for nutrition.

The compounds according to the invention can be given alone or in combination with other active substances according to the invention, if necessary also in combination with further pharmacologically active substances. Suitable forms for application are, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersion powders. Suitable tablets can be obtained, for example, by mixing one or more active substances with known excipients, for example with inert diluents such as calcium carbonate, calcium phosphate or milk sugar, dissolving agents such as corn starch or alginic acid, binders such as starch or gelatin, glidants such as magnesium stearate or talc, and/or depot effect agents such as carboxymethylcellulose, cellulose acetate phthalate, or polyvinyl acetate. Tablets can also consist of several layers.

Suitable dragees can be produced by coating cores produced analogously to tablets with coatings commonly used for coating dragees, for example with collidon or with shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depot effect or to reduce incompatibility, the core can also consist of multiple layers. Also, in order to achieve a depot effect, the coating of the dragee can consist of several layers, whereby the excipients mentioned above for tablets can be used.

Juices of active substances according to the invention, or combinations of active substances, can additionally contain sweeteners such as saccharin, cyclamate, glycerin or sugar, as well as agents for improving taste, for example, aromatic substances such as vanillin or orange extract. In addition, they may also contain auxiliaries for the preparation of suspensions or thickening agents, such as sodium carboxymethylcellulose, leavening agents, for example condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoate.

Injection solutions are produced in the usual way, eg with the addition of preservatives such as p-hydroxybenzoate, or stabilizers, such as alkaline salts of ethylenediamine-tetraacetic acid, and are filled into injection vials or ampoules.

Capsules containing one or more active substances or a combination of active substances can be produced, for example, by mixing the active substance with inert carriers such as milk sugar or sorbitol, and encapsulating it in gelatin capsules.

Suitable suppositories can be produced, for example, by mixing with carriers intended for this purpose, such as neutral fats or polyethylene glycol or its derivatives.

The therapeutically effective daily dose for an adult is between 1 and 1000 mg, preferably 10 - 500 mg.

The following examples illustrate the proposed invention but do not, however, limit its scope.

Examples of pharmaceutical formulations

A) Tablets

1 tablet contains

active substance 300 mg

milk sugar 240 mg

corn starch 340 mg

polyvinylpinrolidone 45 mg

magnesium stearate 15 mg

940 mg

Finely ground active substance, milk sugar and part of corn starch are mixed together. The mixture is sieved, and then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated and dried. The granulate, the rest of the corn starch and the magnesium stearate are sieved and mixed together. The mixture is pressed into tablets of the appropriate shape and size.

B) Tablets

1 tablet contains

active substance 80 mg

corn starch 190 mg

milk sugar 55 mg

microcrystalline cellulose 35 mg

polyvinylpinrolidone 15 mg

sodium carboxymethyl starch 23 mg

magnesium stearate 2 mg

400 mg

The finely ground active substance, part of the corn starch, milk sugar, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved, and then sifted with the rest of the corn starch and water into a granulate, which is dried and sieved. Sodium carboxymethyl starch and magnesium stearate are added to this, mixed and the mixture is pressed into tablets of the appropriate size.

C) Dragees

1 dragee contains

active substance 5 mg

corn starch 41.5 mg

milk sugar 30 mg

polyvinylpyrrolidone 3 mg

magnesium stearate 0.5 mg

80 mg

The active substance, corn starch, milk sugar and polyvinylpyrrolidone are mixed well and moistened with water. The wet mass is pushed through a sieve with a mesh size of 1 mm, dried at approx. 45°C and then the granulate is pressed through the same sieve. Then, magnesium stearate is mixed in and rounded dragee cores with a diameter of 6 mm are pressed on a tableting machine. The dragee cores produced in this way are coated in a known way with a layer consisting mainly of sugar and talc. Finished dragees are polished with wax.

D) Capsules

1 capsule contains

active substance 150 mg

corn starch 268.5 mg

magnesium stearate 1.5 mg

420 mg

The active substance and corn starch are mixed and moistened with water. The wet mass is sieved and dried. The dry granulate is sieved and mixed with magnesium stearate. The finished mixture is filled into hard gelatin capsules of size 1.

E) Solution for ampoules

active substance 50 mg

sodium chloride 50 mg

water for inj. 5 ml

The active substance is dissolved in water at its own pH value or, if necessary, at pH 5.5 to 6.5 and mixed with sodium chloride as an isotonant, the resulting solution is filtered without pyrogens and the filtrate is filled into ampoules under aseptic conditions. Then it is sterilized and sealed. Ampoules contain 5 mg, 25 mg and 50 mg of active substance.

F) Suppositories

active substance 50 mg

Adeps solidus 1650 mg

1700 mg

The hard fat melted. The ground active substance is homogeneously dispersed at 40°C. Cool to 38°C and pour into slightly cooled suppository molds.

Claims (13)

1. Compounds of general formula 1, [image] indicated by that R1 and R2, the same or different, represent hydrogen, C1-C6-alkyl, C1-C6-alkyloxy, OH, F, Cl or Br; R3 and R3', the same or different, represent hydrogen, F, Cl, Br, methyl, ethyl, OH, CF3, methoxy or phenyl, which, if necessary, can be substituted with a radical selected from the group consisting of F, Cl, Br, methyl, ethyl , OH, CF3 and methoxy; R4, R5 and R6, the same or different, represent hydrogen, methyl or ethyl, X is NH2, NH-(C1-C6-alkyl), N(C1-C6-alkyl)2, where two C1-C6-alkyl groups can be the same or different, NH-COH, NH-CO (C1-C6 -alkyl) or F; A is -(CH2)3-, -CH2-CH2-O-, -CH2-O-CH2-, -(CH2)4-, -CH(C1-C6-alkyl)-O-CH2-, - (CH2)2-O-CH2-, -(CH2)3-O-, -(CH2)5-, -CH2-O-(CH2)3-, -(CH2)2-O-(CH2)2-, - (CH2) 3-O-CH2-, -(CH2)4-O-, -CH2-O-CH2-CH2-O-, [image] as appropriate in the form of their racemates, their enantiomers, their diastereomers and their mixtures, as and as needed their pharmacologically unmistakable acid addition salts. 2. Compounds of general formula 1 according to claim 1, characterized in that R1 and R2, the same or different, represent hydrogen, methyl, ethyl, methyloxy, ethyloxy, OH, F, Cl or Br; R3 and R3', the same or different, represent hydrogen, F, Cl, Br, methyl, ethyl, OH, methoxy or phenyl, which is substituted with a radical selected from the group consisting of F, Cl, Br, and preferably methyl; R4, R5 and R6, the same or different, represent hydrogen or methyl; X is NH2, NH-(methyl), N(methyl)2, NH-(ethyl), N(ethyl)2, NH-COH, NH-COMe or F; A is -CH2-CH2-O-, -CH2-O-CH2-, -CH (methyl) -OCH2-, -CH(ethyl)-O-CH2-, -CH(iso-propyl)-O-CH2-, -(CH2)2-O-CH2-, -(CH2)3-O-, -CH2-O-(CH2)3-, -(CH2)2-O-(CH2)2-, - (CH2) 3-O-CH2-, -(CH2)4-O-, -CH2-O-CH2-CH2-O-, [image] if necessary in the form of their racemates, their enantiomers, their diastereomers and their mixtures, as well as if necessary their pharmacologically unambiguous acid addition salts. 3. Compounds of general formula 1 according to claim 1 or 2, characterized in that R1 and R2, the same or different, represent hydrogen or F; R3 and R3', the same or different, represent hydrogen, F, Cl, Br, CF3 or methyl; R4, R5 and R6, the same or different, represent hydrogen or methyl; X is NH 2 , NH-(methyl), N(methyl) 2 , NH-COH, NH-COMe or F; A is -CH (methyl)-O-CH2-, -CH2-O-CH2- or as appropriate in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and as appropriate their pharmacologically unambiguous acid addition salts. 4. Compounds of the general formula 1 according to claim 1, 2 or 3, characterized in that R1 and R2, the same or different, represent hydrogen or F; R3 and R3', the same or different, represent hydrogen, F, Cl, Br, CF3 or methyl; R4, R5 and R6, the same or different, represent hydrogen or methyl; X is NH 2 , NH-(methyl) or NH-COH; [image] A is -CH (methyl) -O-CH2-, -CH2-O-CH2- or as appropriate in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and as appropriate their pharmacologically unambiguous acid addition salts. 5. Compounds of the general formula 1 according to claim 1, 2 or 3, characterized in that R1 and R2, the same or different, represent hydrogen or F; R3 and R3' are hydrogen; [image] R4, R5 and R6, the same or different, represent hydrogen or methyl; X is F; A is -CH(methyl)-O-CH2-, if necessary in the form of their racemates, their enantiomers, their diastereomers and their mixtures, as well as if necessary their pharmacologically unambiguous acid addition salts. 6. Pharmaceutical preparation, characterized in that it contains the compounds of formula 1 according to any claim 1 to 5 in addition to the usual auxiliary materials and carriers. 7. Use of the compound of formula 1 according to any one of claims 1 to 5, characterized in that it is used as a medicine. 8. Use of a compound of formula 1 according to any one of claims 1 to 5 for the manufacture of a medicament for the prevention or treatment of diseases or disorders in which inhibition of voltage-gated sodium channels may be therapeutically useful. 9. Use of the compound of formula 1 according to any one of claims 1 to 5, characterized in that it is used for the production of a drug for the suppression or treatment of arrhythmias, spasms, cardiac and cerebral ischemia, pain and neurodegenerative diseases. 10. Use of the compound of formula 1 according to any one of claims 1 to 5, characterized in that it is used for the production of a drug for the prevention or treatment of epilepsy, hypoglycemia, hypoxia, anoxia, brain trauma, brain edema, stroke, perinatal asphyxia, degeneration cerebellum, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotonia, heart attack, heart rhythm disorder, angina pectoris, chronic pain, neuropathic pain or for local anesthesia. 11. Process for the production of compounds of general formula 1 [image] in which the radicals R1, R2, R3, R3', R4, R5, R6 and A can have the meanings given in claims 1-5 and X is NH2, indicated that the compounds of the general formula 3 [image] in which the radicals R1, R2, R3, R3', R4, R5, R6 and A can have the meanings given in claims 1-5, react in an aromatic solvent with a palladium catalyst with a nitrogen source. 12. Intermediate compounds of general formula 3 [image] characterized by the fact that the radicals R1, R2, R3, R3', R4, R5, R6 and A can have the meanings specified in claims 1-5. 13. Process for the production of compounds of general formula 1 [image] in which the radicals R1, R2, R3, R3', R4, R5, R6 and A can have the meanings given in claims 1-5, characterized by the fact that the compounds of the general formula 1 in which X represents NH2 a) react in a polar organic solvent with a base and appropriate alkylating agents, thereby obtaining compounds of the general formula 1, in which X represents NH-(C1-C6-alkyl) or N (C1-C6-alkyl)2, or b) with cooling, in the presence of acids, they react with aldehydes or ketones, and the Schiffschen bases or iminium salts thus obtained are then reduced with metal hydrides to compounds of the general formula 1, in which X represents NH-(d-C6-alkyl) or N ( 1 -C 6 -alkyl) 2 , or c) react with an acid chloride or anhydride in the presence of a base, resulting in compounds of the general formula 1, where X represents NHCO(C1-C6-alkyl), or d) if necessary, compounds of formula 1 obtained in step c), in which X represents NHCO(C1-C6-alkyl), are then reduced with metal hydrides with Lewis acid as a catalyst to compounds of general formula 1, in which X represents NH- ( C1-C6-alkyl) or N(C1-C6-alkyl)2, or e) at elevated temperature by reaction with formic acid, they are converted into compounds of the general formula 1, in which X represents NHCOH, or f) by diazotizing and then boiling with BF4- they are converted into compounds of the formula JL in which X represents F.