EP1966138A2

EP1966138A2 - Substituted tricyclic piperidone derivatives

Info

Publication number: EP1966138A2
Application number: EP06846988A
Authority: EP
Inventors: Stefan Schunk; Stefan OBERBÖRSCH; Hagen-Heinrich Hennies; Martin Maier; Anton Khartulyari
Original assignee: Gruenenthal GmbH
Current assignee: Gruenenthal GmbH
Priority date: 2005-12-22
Filing date: 2006-12-19
Publication date: 2008-09-10
Also published as: DE102005061426A1; WO2007079929A3; WO2007079929A2; US20080312268A1; JP2009520719A

Abstract

The invention relates to substituted tricyclic piperidone derivatives of formula (I), methods for production thereof, medicaments comprising said compounds and the use of substituted tricyclic piperidone derivatives for the production of medicaments having analgetic effect.

Description

Patent application of Grünenthal GmbH, D-52078 Aachen (own sign GRA 3317)

Substituted tricyclic piperidone derivatives

The present invention relates to substituted tricyclic piperidone derivatives, processes for their preparation, medicaments containing these compounds and the use of substituted tricyclic piperidone derivatives for the preparation of medicaments.

The treatment of chronic and non-chronic pain is of great importance in medicine. There is a worldwide need for effective pain therapies. The urgent need for a patient-oriented and goal-oriented treatment of chronic and non-chronic pain states, which is to be understood as the successful and satisfactory treatment of pain for the patient, is documented in the large number of scientific papers in the field of applied analgesics or basic research to the Nociception lately have appeared.

Classic opioids such as morphine are effective in the treatment of severe to severe pain. Their use is, however, by the known side effects z. As respiratory depression, vomiting, sedation, constipation and tolerance development limited. In addition, they are less effective in the case of neuropathic or incidental pain, in particular tumor patients.

WO 9951602 discloses bridged keto-substituted cyclohexane rings which affect the nicotinic acetylcholine receptor. However, these compounds carry neither a carboxylic acid ester nor a phenyl ring is fused. An object underlying the invention was to provide novel analgesic substances which are suitable for the treatment of pain - especially chronic and neuropathic pain.

The invention therefore relates to substituted tricyclic piperidone derivatives derivatives of the general formula I ₁

The invention relates to substituted tricyclic piperidone derivatives of the general formula I.

wherein

R ^{1 is} methyl, ethyl or phenyl;

X _{1 is} NR ² and X _{2 is} CH ₂ or X _{2 is} NR ² and X _{1 is} CH ₂ ;

R ^{2 is} C _1-8 -alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted, optionally with a heteroatom as chain member; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted Ci-β-alkyl group, optionally, with a heteroatom as a chain member, attached aryl, C _3-8 -cycloalkyl or Heteroaryl, in each case unsubstituted or monosubstituted or polysubstituted; (C = O) R ⁴ , (C = O) NR ⁵ R ⁶ , (C = S) NR ⁵ R ⁶ , SO ₂ R ⁷ or (C = O) OR ⁸ ;

R ^{3 is} H ₁ F, Cl, Br, OH, OCH ₃ , SCH ₃ , NO ₂ , CN; d. _8- alkyl or Cs-β-cycloalkyl, each saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted by F, Cl ₁ OH, OCH ₃ , SCH ₃ , NO ₂ , CN, CF ₃ , methyl or ethyl;

R ^4, R ⁷ and R ⁸ is Ci _-8 alkyl or C _3-8 cycloalkyl, respectively saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted, optionally having a hetero atom N, O, S as a chain member ; Aryl, or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C _1-8 -alkyl group, optionally with one heteroatom N, O, S as chain member, attached aryl or C _3-8 -cycloalkyl or heteroaryl, in each case unsubstituted or simple or substituted several times; stand;

R ⁵ and R ^{6 are} independently H; Ci _-8 alkyl or C _3-8 cycloalkyl, respectively saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted, optionally having a hetero atom N, O, S as a chain member; Aryl, or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted Ci _-8 alkyl group, optionally in each case unsubstituted with a hetero atom N, O, S as a chain member, bound aryl or C _3-8 -cycloalkyl or heteroaryl or mono- or substituted several times; where R ⁵ and R ^{6 may} not be H at the same time;

or the radicals R ⁵ and R ⁶ together form a five-, six- or seven-membered ring which may be saturated or unsaturated, but not aromatic, which optionally contains one further heteroatom from the group S, O or NR ⁹ and with benzyl or may be substituted Ci- ₅ alkyl, wherein R ^{9 is} Ci _-5- alkyl, branched or unbranched; Phenyl or benzyl, unsubstituted or mono- or polysubstituted by F, Cl ₁ OH ₁ OCH ₃ , SCH ₃ , NO ₂ , CN, CF ₃ , methyl or ethyl.

in the form of the Razemats; the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers, or a single enantiomer or diastereomer; the bases and / or salts of physiologically acceptable acids.

The expressions "Ci. ₃ alkyl "," Ci _-5 alkyl "and" Ci _-8 alkyl "include for the purposes of this invention acyclic saturated or unsaturated hydrocarbon radicals which have branched or straight chained and unsubstituted or may be mono- or polysubstituted, having 1 to 3 carbon atoms and 1 to 5 C atoms or 1 to 8 carbon atoms, ie, C _-3 -Alkanyle, C _2-3 alkenyls and _C2-3 alkynyls or Ci _-5 -Alkanyle, C _{2 -5} alkenyls and _C2-5 alkynyls or Ci _-8 -Alkanyle, _C2-8 alkenyls and _C2-8 alkynyls. in this case, alkenyls have at least one C-C double bond and alkynyls at least one C-C triple bond. Advantageously, alkyl is selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl , n-hexyl, 2-hexyl, ethylenyl (vinyl), ethynyl, propenyl (-CH ₂ CH = CH ₂ , -CH = CH-CH ₃ , -C (= CH ₂ ) -CH ₃ ), propynyl (-CH -C≡CH, -C≡C-CH ₃ ), butenyl, butynyl, pentenyl, pentynyl, hexenyl, hexynyl, heptyl, heptenyl, heptynyl,

Octyl, octenyl and octynyl includes. Especially vorteihaft are methyl, ethyl, n-propyl, n-butyl, sec-butyl, iso-butyl. Very particularly advantageous is methyl.

When two substituents of an N atom "together form a five-, six- or seven-membered ring which may be saturated or unsaturated but not aromatic, optionally containing one further heteroatom from the group S, O or N" this means within the meaning of this invention, that the two substituents form a ring which comprises the N-atom Advantageous are rings from the group

Pyrrolidine, piperidine, azepane, piperazine, diazepane, imidazolidine, morpholine, thiomorpholine, oxazepan, thiazepane, oxazole or thiazolidine. Particularly preferred are piperidine, piperazine, morpholine and thiomorpholine.

The term "aryl" in the context of this invention means aromatic hydrocarbons, including phenyls and naphthyls. The aryl radicals can also be with be condensed further saturated, (partially) unsaturated or aromatic ring systems. Each aryl radical may be unsubstituted or monosubstituted or polysubstituted, wherein the aryl substituents may be the same or different and may be in any desired and possible position of the aryl. Advantageously, aryl is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, which may each be unsubstituted or mono- or polysubstituted. Particularly advantageous is the phenyl radical.

The term "heteroaryl" represents a 5-, 6- or 7-membered cyclic aromatic radical containing at least 1, optionally, also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms are the same or different and the heterocycle is unsubstituted or in the case of substitution on the heterocycle, the substituents may be the same or different and may be in any and possible position of the heteroaryl The heterocycle may also be part of a bicyclic or polycyclic system Preferred heteroatoms are nitrogen It is preferred that the heteroaryl moiety is selected from the group consisting of pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, thienyl (thiophenyl), benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzodioxolanyl, benzodioxanyl, phthalazinyl , Pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazoyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazol l, purinyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl or oxadiazolyl, wherein the binding to the compounds of the general structure I can take place via any and possible ring member of the heteroaryl radical. Particularly preferred are pyridyl, furyl, thienyl and indolyl.

The term "aryl or heteroaryl bonded via C _1-3 -alkyl" means for the purposes of the present invention that C i. ₃ alkyl and aryl or heteroaryl have the meanings defined above and the aryl or heteroaryl radical is bonded via a Ci_ ₃ - alkyl group to the compound of general structure I. Benzyl is particularly advantageous for the purposes of this invention.

In the context of "alkyl" or a "five-, six- or seven-membered ring, which may be saturated or unsaturated, but not aromatic" is understood by the term "substituted" in the context of this invention, the substitution of a hydrogen radical by F, Cl, Br ₁ I, -CN, NH ₂ , NH-Cm alkyl, NH-C _1-6 alkyl-OH, Ci _-6 -alkyl , N (Ci _-6 alkyl) _2, N (C _1-6 alkyl-OH) _2l _NO2, SH, SC _1-6 alkyl, S-benzyl, OC _1-6 alkyl, OH, OC _{1 -6-} alkyl-OH, = O, O-benzyl, C (= O) C _1-6 -alkyl, CO ₂ H ₁ CO ₂ -C _1-6 -alkyl or benzyl, where among multiply substituted radicals such radicals to which are substituted either on different or on the same atoms several times, for example two or three times, for example, three times on the same carbon atom as in the case of CF3 or -CH ₂ CF ₃ or at different locations as in the case of -CH (OH) - CH = CH-CHCl ₂ . Multiple substitution can be with the same or different substituents. Particularly preferred for the purposes of the present invention, "mono- or polysubstituted" in connection with alkyl or a saturated or unsaturated ring which may not be aromatic, means benzyl or methyl.

In the context of this invention, "aryl" and "heteroaryl" are understood as meaning "mono- or polysubstituted" the substitution of one or more, for example two, three or four times, substitution of one or more hydrogen atoms of the ring system by F, Cl , Br, I ₁ CN, NH _2, NH-C _1-6 alkyl, NH- Ci _-6 alkyl-OH, N (C _1-6 alkyl) _2, N (C _1-6 - alkyl-OH) _{2 |} NO _2, SH, SC _1-6 alkyl, OH, OC _1-6 alkyl, _{O-Ci-6-alkyl-OH,} C (= O) C _1-6 alkyl, CO ₂ H, CO ₂ -Ci _-6- alkyl, CF ₃ , Ci- ₆ -alkyl, on one or optionally, different atoms (where a substituent may optionally be substituted in turn.) The multiple substitution takes place with the same or different substituents "and" heteroaryl "are preferred substituents -F, - Cl, -CF ₃ , -O-CH ₃ , methyl, ethyl, n-propyl, nitro, terf.-butyl, and -CN. Particularly preferred is methyl.

For the purposes of the present invention, the term salt formed with a physiologically acceptable acid means salts of the respective active ingredient with inorganic or organic acids which are physiologically compatible, in particular when used in humans and / or mammals. Particularly preferred is the hydrochloride. Examples of physiologically tolerated acids are: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydro1λ ⁶ - benzo [cisothiazol-3-one (saccharic acid), monomethyl sebacic acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, α-lipoic acid , Acetylglycine, hippuric acid, phosphoric acid and / or aspartic acid. Particularly preferred is the hydrochloric acid.

Preferred are substituted tricyclic piperidone derivatives of the general formula wherein X _{1 is} NR ² and X _{2 is} CH ₂ .

Further preferred tricyclic piperidone derivatives are of the general formula I, wherein R ² is saturated Ci _-5 alkyl, or unsaturated, branched or unbranched; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C-ι- ₃ alkyl group, bound aryl, C _{_3-8} -cycloalkyl or heteroaryl, in each case unsubstituted or mono- or poly-substituted.

Particularly preferred tricyclic piperidone derivatives are of the general formula I, wherein R ² represents Ci _-5 alkyl, branched or unbranched, unsubstituted and saturated; a Ci _-3 alkyl group bonded phenyl, naphthyl, pyridyl, furyl, thienyl and indolyl, each unsubstituted or mono- or polysubstituted with -F, -Cl, - CF _3, -0-CH _3, methyl, ethyl , n-propyl, nitro, tert-butyl, and -CN;

in particular methyl or benzyl.

Preference is furthermore given to tricyclic piperidone derivatives of the general formula I in which R ^{2 is} (C =O) R ⁴ , (C =O) NR ⁵ R ⁶ , (C =S) NR ⁵ R ⁶ , SO ₂ R ⁷ or (C = O) OR ⁸ stands.

And tricyclic piperidone derivatives are preferred of the general formula I, wherein R ^4, R ⁷ and R ⁸ represents Ci _-5 alkyl or C _3-8 cycloalkyl, branched or unbranched; Aryl, or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; a Ci _-3 alkyl group-bound aryl, C _3-8 -cycloalkyl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; stand; Particular preference is given to tricyclic piperidone derivatives of the general formula I in which R ⁴ , R ⁷ and R ^{8 are} methyl, ethyl, n-propyl. iso-propyl, n-butyl or te / t-butyl; Phenyl, naphthyl, thienyl, furyl or pyridyl, each singly or multiply substituted with F, Cl, CF ₃ , NO ₂ , CH ₃ , OH, SH, OCH ₃ or SCH ₃ or unsubstituted; a Ci _-3 alkyl group bonded phenyl, naphthyl, thienyl, furyl or pyridyl, respectively unsubstituted or singly or multiply substituted with F, Cl, CF _3, NO _2, CH _3, OH, SH, OCH ₃ or SCH ₃ ; stand

in particular methyl, ethyl, phenyl or tosyl.

Preference is also given to tricyclic piperidone derivatives of the general formula I ₁ in which R ⁵ and R ⁶ independently of one another are H; Cis-alkyl or C _3-8 -cycloalkyl, branched or unbranched; Aryl, or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; a Ci _-3 alkyl group-bound aryl or _C3-S - cycloalkyl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; stand;

or the radicals R ⁵ and R ⁶ together form piperidine, piperazine, morpholine or thiomorpholine.

Particular preference is given to tricyclic piperidone derivatives of the general formula I in which R ⁵ and R ⁶ independently of one another are H; Methyl, ethyl, π-propyl. / so-propyl, π-butyl or tert-butyl; Phenyl, naphthyl, thienyl, furyl or pyridyl, each singly or multiply substituted with F, Cl, CF ₃ , NO ₂ , CH ₃ , OH, SH, OCH ₃ or SCH ₃ or unsubstituted; via a C-ι _-3 alkyl group bonded phenyl, naphthyl, thienyl, furyl or pyridyl, respectively unsubstituted or singly or multiply substituted with F, Cl, CF _3, NO _2, CH _3, OH, SH, OCH _3, or SCH ₃ ; stand;

in particular H or phenyl. Preference is furthermore given to tricyclic piperidone derivatives of the general formula I in which R ^{3 is} H ₁ F, Cl, OH ₁ OCH ₃ , SCH ₃ , NO ₂ , CN, CF ₃ , methyl, ethyl or benzyl,

in particular for H, CN, OCH ₃ or methyl.

Very particular preference is given to substituted tricyclic piperidone derivatives from the group

Ethyl N -benzyl-11-0X0-1, 3,4,6-tetrahydro-1,5-methano-3-benzazocine-5 (2H) -carboxylate

Ethyl N -benzyl-10-methyl-11-0X0-1, 3,4,6-tetrahydro-1, 5-methano-3-benzazocine-5 (2H) -carboxylate

Ethyl N -benzyl-8-methoxy-11-0X0-1, 3,4,6-tetrahydro-1, 5-methano-3-benzazocine-5 (2H) -carboxylate

Ethyl N-methyl-11-0X0-1, 3,4,6-tetrahydro-1,5-methano-3-benzazocine-5 (2H) -carboxylate hydrochloride

Ethyl N-10-dimethyl-11-oxo-1,3,4,6-tetrahydro-1,5-methano-3-benzazocin-5 (2H) -carboxylate, diethyl-11-oxo-1, 3,4, 6-tetrahydro-1, 5-methano-3-benzazocine-3,5 (2H) -dicarboxylate

Ethyl N- (anilinocarbonyl) -11-0X0-1, 3,4,6-tetrahydro-1,5-methano-3-benzazocine-5 (2H) -carboxylate

Ethyl N-tosyl-11-oxo-1,3,4,6-tetrahydro-1,5-methano-3-benzazocin-5 (2H) -carboxylate ethyl 2-benzyl-11-0X0-1, 3,4 , 6-tetrahydro-1, 5-methane-2-benzazocin-5 (2H) -carboxylate ethyl N-benzyl-9-cyano-11-oxo-1,3,4,6-tetrahydro-1,5-methano-1-one 3-benzazocin-5 (2 / - /) - carboxylate

Another object of the invention is a process for preparing a tricyclic piperidone derivative of the invention. Tricyclic piperidone derivatives of general formula I in which X ^{1 is} NR ² and X ^{2 is} CH ₂ can be prepared according to the following synthesis scheme:

or

in which

R ^{2a is} Ci _-8- alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted, optionally with a heteroatom as a chain member; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted Ci-β-alkyl group, optionally, with a heteroatom as a chain member, attached aryl, C ₃ - ₈ -cycloalkyl or heteroaryl, each unsubstituted or mono- or polysubstituted .

and

R ^{2b is} C = O) R ⁴ , (C = O) NR ⁵ R ⁶ , (C = S) NR ⁵ R ⁶ , SO ₂ R ⁷ or (C = O) OR ⁸ .

In this case, piperidone derivatives of the general formula A are added with the addition of a base, for example diisopropylethylamine, triethylamine, pyridine, diethylamine, diisopropylamine, butyl lithium, lithium diisopropylamide, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate in an organic solvent, for example acetone, dichloromethane, THF, diethyl ether Benzene, toluene reacted with diethyl carbonate. The products of general formula B are in an organic solvent, for example acetone, acetonitrile, benzene, toluene, methanol, ethanol, dichloromethane, diethyl ether, tetrahydrofuran with the addition of a base, for example K ₃ PO ₄ , K ₂ CO ₃ , Na ₂ CO ₃ , NaOH, KOH, KOtBu, diisopropylethylamine, triethylamine, pyridine, diethylamine, diisopropylamine with the corresponding benzyl bromide at a temperature of 0-100 ° C to give compounds of general formula C. The compounds of general formula C are in an organic solvent, for example acetone, benzene, toluene, acetonitrile, dichloromethane, diethyl ether, tetrahydrofuran with the addition of a base, for example K ₃ PO ₄ , K ₂ CO ₃ , Na ₂ CO ₃ , NaOH , KOH,

Diisopropylethylamine, triethylamine, pyridine, diethylamine, diisopropylamine with a catalyst such as Pd (dba) ₂₎ PdCl ₂ , Pd (OAc) ₂ and a corresponding ligand, for example, t-Bu ₃ P, Ph ₃ P at a temperature of 40-130 ⁰ C reacted under inert gas to compounds of general formula Ia. The compounds of the general formula Ia are dissolved in a compound of the general formula CIC (O) OR ⁸ , for example benzyloxycarbonyl chloride, optionally dissolved in acetone, acetonitrile, benzene, dichloromethane, diethyl ether, toluene or tetrahydrofuran, and at a temperature from 0 to 10O ⁰ C converted to compounds of general formula Ib. The products of general formula Ib are dissolved in an organic solvent, for example acetone, acetonitrile,

Benzene, toluene, methanol, ethanol, dichloromethane, diethyl ether, tetrahydrofuran with trimethylsilyl iodide at a temperature of -20 to 100 ⁰ C implemented. After working up in an organic solvent, for example acetone, benzene, toluene, acetonitrile, dichloromethane, diethyl ether, tetrahydrofuran with the addition of a base, for example K ₃ PO ₄ , K ₂ CO ₃ , Na ₂ CO ₃ , NaOH, KOH, diisopropylethylamine, triethylamine , Pyridine, diethylamine, diisopropylamine, butyllithium, lithium diisopropylamide, sodium hydride, potassium hydride with the corresponding electrophile, for example acid chlorides, acid anhydrides, sulfonyl chlorides, isocyanates or isothiocyanates at a temperature of - 20 ⁰ C-100 I ⁰ C to compounds of general formula Ic reacted.

Tricyclic piperidone derivatives of general formula I in which X ^{1 is} CH ₂ and X ² NR ² may be prepared according to the following synthesis scheme:

Base, Pd (dba) _2, P ₃ JBU

Compounds of general formula H are in an organic solvent, for example acetone, acetonitrile, benzene, toluene, methanol, ethanol, dichloromethane, diethyl ether, tetrahydrofuran with the addition of a base, for example K ₃ PO ₄ , K ₂ CO ₃ , Na ₂ CO ₃ , NaOH, KOtBu, KOH, diisopropylethylamine, triethylamine, pyridine, diethylamine, diisopropylamine with the corresponding benzyl bromide at a temperature of 0-10O ⁰ C to compounds of general formula J implemented. The compounds of general formula J are in an organic solvent, for example acetone, benzene, toluene, acetonitrile, dichloromethane, diethyl ether, tetrahydrofuran with the addition of a base, for example K ₃ PO ₄ , K ₂ CO ₃ , Na ₂ CO ₃ , NaOH , KOH, diisopropylethylamine, triethylamine, pyridine, diethylamine, diisopropylamine with a Katralysator as the addition of Pd (dba) ₂ , PdCl ₂ , Pd (OAc) ₂ and a corresponding ligand, for example, t-Bu ₃ P, Ph ₃ P at a temperature of 40-130 ⁰ C reacted under inert gas to compounds of general formula Id. The compounds of general formula Id are in benzyloxycarbonyl chloride, optionally dissolved in acetone, acetonitrile, benzene, dichloromethane, diethyl ether, toluene or tetrahydrofuran, dissolved and reacted at a temperature of 0 to 100 ⁰ C to compounds of general formula Ie. The products of general formula Ie are in an organic solvent, for example acetone, acetonitrile, benzene, toluene, methanol, ethanol, dichloromethane, diethyl ether, tetrahydrofuran with Trimethylsilyliodide reacted at a temperature of -20 to 100 ⁰ C. After working up in an organic solvent, for example acetone, benzene, toluene, acetonitrile, dichloromethane, diethyl ether, tetrahydrofuran with the addition of a base, for example K ₃ PO ₄ , K ₂ CO ₃ , Na ₂ CO ₃ , NaOH, KOH, diisopropylethylamine, triethylamine , Pyridine, diethylamine, diisopropylamine, butyllithium, lithium diisopropylamide, sodium hydride, potassium hydride with the corresponding electrophile example, acid chlorides, acid anhydrides, sulfonyl chlorides, isocyanates, isothiocyanates at a temperature of -2O ⁰ C-100 ° C to compounds of general formula If implemented.

For the preparation of the required benzyl bromides are in principle the methods known to those skilled in the preparation of benzyl bromides into consideration. For example, the benzyl bromides are prepared from the corresponding alcohols, esters or aldehydes by reduction and subsequent bromination. Friedel-Crafts or metallation strategies can be used to prepare the aldehydes.

It has been found that the substances according to the invention inhibit serotonin and norepinephrine reuptake. Noradrenaline and serotonin reuptake inhibitors have antidepressant and anxiolytic effects, but are also useful in the treatment of pain (Analgesics - from Chemistry and Pharmacology to Clinical Application, Wiley 2002, pp. 265-284).

The substances according to the invention are suitable as pharmaceutical active ingredients in medicaments. Another object of the invention are therefore medicaments containing at least one inventive substituted tricyclic piperidone derivative, and optionally suitable additives and / or adjuvants and / or optionally other active ingredients.

The medicaments according to the invention contain, in addition to at least one substituted tricyclic piperidone derivative according to the invention, optionally suitable additives and / or adjuvants, as well as carrier materials, fillers, solvents, diluents, dyes and / or binders and can be used as liquid dosage forms in the form of injection solutions, drops or juices, as semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules, patches or aerosols. The choice of excipients etc. as well as the amounts to be used depend on whether the drug is oral, peroral, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal or topical, for example on the skin, mucous membranes or in the eyes, to be applied. For oral administration, preparations in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable, for parenteral, topical and inhalative administration solutions, suspensions, readily reconstitutable dry preparations and sprays. Inventive tricyclic piperidone derivatives in a depot, in dissolved form or in a plaster, optionally with the addition of skin penetration promoting agents, are suitable percutaneous administration preparations. Orally or percutaneously applicable preparation forms can release the tricyclic piperidone derivatives according to the invention with a delay. In principle, other active compounds known to the person skilled in the art may be added to the medicaments according to the invention.

The amount of drug to be administered to the patient varies depending on the weight of the patient, the mode of administration, the indication and the severity of the disease. Usually, 0.005 to 20 mg / kg, preferably 0.05 to 5 mg / kg of at least one tricyclic piperidone derivative according to the invention are administered.

The pharmaceutical composition may contain a tricyclic piperidone derivative according to the invention as a pure diastereomer and / or enantiomer, as a racemate or as a non-equimolar or equimolar mixture of the diastereomers and / or enantiomers.

Another object of the invention is the use of a tricyclic piperidone derivative of the invention for the manufacture of a medicament for Treatment of pain, especially acute, neuropathic or chronic pain.

Another object of the invention is the use of a tricyclic piperidone derivative of the invention for the manufacture of a medicament for the treatment of depression and / or anxiolysis.

The substituted tricyclic piperidone derivatives of the general formula I are also suitable for the treatment of urinary incontinence, diarrhea, pruritus, alcohol and drug abuse, drug dependence and listlessness.

The invention therefore also relates to the use of a substituted tricyclic piperidone derivative of general formula I for the manufacture of a medicament for the treatment of urinary incontinence, diarrhea, pruritus, alcohol and drug abuse, drug dependence and listlessness.

Examples

General working instructions (AAV 1 - AAV 4):

AAV 1 Synthesis of bromobenzyl-substituted oxopiperidine derivatives

To a suspension of the corresponding piperidinecarboxylate (B or H; 1 eq.) And dry K ₂ CO ₃ (3.9 eq.) In dry acetone was added the appropriate benzylbromide (1.2 eq.) Dissolved in dry tetrahydrofuran under a nitrogen atmosphere. The reaction mixture was heated at reflux for 6 h. Subsequently, the inorganic salts were filtered off and washed with acetone. Finally, the combined organic phases were concentrated and purified by column chromatography. The desired bromobenzyl-substituted oxopiperidine derivatives C and J were thus obtained.

AAV 2 Synthesis of benzazocine carboxylates

The corresponding bromobenzyl-substituted oxopiperidine derivative e or J (1 eq.), K ₃ PO ₄ (2 eq.) And Pd (dba) ₂ (2 mol%) was charged to a dry argon-flooded Schlenk flask. This mixture was under argon atmosphere with toluene and / -Bu ₃ P (4 mol%) and stirred in an oil bath at 110 ⁰ C for 12 hours. The reaction mixture was then cooled to room temperature, diluted with diethyl ether, filtered through Celite and concentrated in vacuo. The crude product was purified by column chromatography and the desired Benzazocincarboxylate Ia and Id thus obtained.

AAV 3 Synthesis of Cbz protected benzazocinecarboxylates

The corresponding benzyl-protected Benzazocincarboxylate D and J (1 eq.) Was dissolved in benzyloxycarbonyl chloride and heated to 80 ⁰ C until complete conversion. Finally, the solvent was removed by vacuum distillation. The crude product was purified by column chromatography and the desired Cbz protected Benzazocincarboxylaten Ib and Ie thus obtained.

AAV 4 Cleavage of the Cbz group A solution of the corresponding Cbz protected Benzazocincarboxylates Ib or Ie (1 eq.) In acetonitrile was heated in a water bath and treated dropwise with trimethylsilyl iodide (8.1 eq.). After the reaction mixture stirred for 1 hour at room temperature, the reaction mixture was concentrated under vacuum. The resulting residue was added with water and washed with dichloromethane. Concentration of the aqueous phase resulted in the desired products.

AAV 5 Synthesis of bromobenzyl-substituted oxopiperidine derivatives

To a suspension of sodium hydride (1.05 eq.) In toluene is added the corresponding piperidine carboxylate (B or H; 1 eq.). The reaction mixture was heated at 80 ^° C. for 1 h. Subsequently, the corresponding bromobenzyldimethylanilinium salt was added and the reaction mixture was heated to reflux for 6 hours. After cooling, the reaction mixture was poured carefully onto water, the organic Pase separated, washed with sat. NaCl solution. Washed, dried with sodium sulfate. Finally, the combined organic phases were concentrated and purified by column chromatography. The desired bromobenzyl-substituted oxopiperidine derivatives C and J were thus obtained. AAV 6 Synthesis of Λ / -carbamato-benzazocinecarboxylates

A solution of the salt obtained according to AAV 4 (1 eq.) In acetonitrile was treated with triethylamine (1.6 eq.) And stirred for 1 hour at room temperature. Subsequently, the corresponding isocyanate (1.6 eq.) Was added and the reaction mixture was stirred for 24 hours at room temperature. Finally, the solvent was removed under vacuum. The crude product was purified by column chromatography and the desired Λ / -Carbamato- benzazocincarboxylate Ic and If so obtained.

AAV 7 Synthesis of Λ / -sulfonylated benzazocinecarboxylates

A solution of the salt obtained according to AAV 4 (1 eq.) In acetonitrile was treated with triethylamine (1.6 eq.) And stirred for 1 hour at room temperature. Subsequently, the corresponding sulfonyl chloride (1.6 eq.) Was added and the reaction mixture was stirred for 24 hours at room temperature. Finally, the solvent was removed under vacuum. The crude product was purified by column chromatography and the desired Λ / -sulfonylated Benzazocincarboxylate Ic and If so obtained.

Ethyl 3- (2-bromobenzyl) -N-benzyl-4-oxopiperidine-3-carboxylate (1):

After AAV 1, ethyl 1-benzyl-4-oxopiperidine-3-carboxylate (3.93 g, 15 mmol) dissolved in 25 ml acetone was reacted with 2-bromo-benzylbromide (4.5 g, 18.0 mmol) dissolved in 25 ml THF. The desired product, after purification by column chromatography (silica gel, Et ₂ O / EtOAc, 20: 1), was a light yellow oil. Yield: 4.72 g (73%)

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.43 (d, J = 8.0 Hz, 1 H, aromatic), 7.25-7.07 (m, 7H ₁ aromatic), 7.00-6.94 (m, 1 H (aromatic) ), 4.10-3.95 (m, 2H), 3.57 (d, J = 13.3 Hz, 2H), 3.51 (dd, J = 11.6 Hz, J = 2.9 Hz, 1 H), 3.43 (d, J = 5.9 Hz, 1 H), 3.39 (d, J = 7.1 Hz, 1 H), 3.10 (d, J = 14.5 Hz, 1H), 2.97-2.89 (m, 1H), 2.86-2.76 (m, 1H), 2.37 -2.30 (m, 1 H), 2.26 (d, J = 11.6 Hz, 1 H), 2:25 to 2:17 (m, 1 H) ₁ 1:03 (t, J = 7.1 Hz, CH _3); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 205.25 (carbonyl), 170.72 (carbethoxy); 137.7, 136.3, 132.7, 132.1, 128.8, 128.2, 128.2, 127.2, 127.0, 125.9 (aromatic), 62.2, 61.8, 61.4, 61.0, 52.6, 40.5, 35.8, 13.8; HRMS (ESI): calcd for C ₂₂ H ₂₄ BrNO ₃ [M + H] ^+: 430.10123, found 430.10129.

Ethyl 3- (2-bromo-3-methylbenzyl) -N-benzyl-4-oxopiperidine-3-carboxylate (2): After AAV 1, ethyl-i-benzyl-M-oxopiperidine-S-carboxylate (1.31 g, 5.0 mmol ) was reacted with 2-bromo-1- (bromomethyl) -3-methylbenzene (1.32 g, 5.0 mmol). The desired product, after purification by column chromatography (silica gel, Et ₂ O / EtOAc, 20: 1), was in the form of colorless crystals. Yield: 1.2 g (54%). Melting point: 60-61 ⁰ C. ¹ H NMR (400 MHz, CDCI _3): δ = 7:26 to 7:25 (m, 5H), 7.05-6.93 (m, 2H) ₁ 4.12-3.97 (m, 2H), 3.60 ( d, J = 13.1 Hz, 1 H) ₁ 3.52 (dd, J = 11.5, 3.0 Hz, 1 H), 3.49 (d, J = 14.4 Hz, 1 H), 3.43 (d, J = 13.1 Hz, 1 H ) ₁ 3.16 (d, J = 14.4 Hz, 1H), 2.98-2.91 (m, 1H), 2.87-2.78 (m, 1H), 2.38-2.32 (m, 4H), 2.30 (d, J = 11.6 Hz, 1H), 2.27-2.20 (m, 1H), 1.05 (t, J = 7.1 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 205.3, 170.8, 138.5, 137.8, 136.7, 129.4, 129.2, 128.9, 128.7, 128.2, 127.2, 126.3, 62.2, 61.8, 61.46, 61.1, 52.65, 40.5, 36.5 , 24.5, 13.8; HRMS (ESI): calculated for C ₂₃ H ₂₆ BrNO ₃ [M + H] ⁺ : 444.11688, found 444.11739.

Ethyl 3- (2-bromo-5-methoxybenzyl) -N-benzyl-4-oxopiperidine-3-carboxylate (3): After AAV 1, ethyl i-benzyl-M-oxopiperidine-S-carboxylate (2.61 g, 10.0 mmol ) was reacted with 1-bromo-2- (bromomethyl) -4-methoxybenzene (2.95 g, 11.0 mmol). The desired product was obtained after purification by column chromatography (silica gel, Et ₂ O / EtOAc, 20: 1) as a yellow oil. Yield: 2.4 g (52%).

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.34 (d, J = 8.9 Hz, 1H), 7.27-7.18 (m, 5H), 6.74 (d, J = 3.0 Hz, 1H), 6.59 ( dd, J = 8.9, 3.0 Hz, 1H), 4.15-4.00 (m, 2H), 3.69 (s, 3H) ₁ 3.63- 3.54 (m, 2H), 3.47 (d, J = 13.3 Hz, 1H) , 3.37 (d, J = 14.4 Hz, 1H), 3.10 (d, J = 14.4 Hz, 1H), 3.00-2.93 (m, 1H), 2.89-2.80 (m, 1H), 2.50-2.33 (m, 1H), 2.30-2.21 (m, 2H), 1.09 (t, J = 7.1Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 205.3, 170.8, 158.5, 137.7, 137.2, 133.1, 128.9, 128.2, 127.2, 117.5, 116.4, 114.3, 62.3, 61.8, 61.4, 60.9, 55.4, 52.6, 40.5 , 36.0 13.8; HRMS (ESI): calculated ₂₃ H ₂₄ BrNO ₄ [M + H] ⁺ C: 460.11180, found 460.11252. Ethyl 3- (2-bromobenzyl) -N-methyl-4-oxopiperidine-3-carboxylate (4):

After AAV 5, NaH (235 mg, 5.85 mmol, 60% in mineral oil) and ethyl 1-methyl-4-oxopiperidine-3-carboxylate (1.07 g, 5.8 mmol) with o-bromo-benzyldimethylanilinium bromide (2.06 g, 5.55 mmol). The desired product was obtained by column chromatography (silica gel, petroleum ether / EtOAc, 1: 1) as a slightly yellow oil. Yield: 550 mg (28%).

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.50 (d, J = 7.9 Hz, 1H), 7.21-7.16 (m, 2H), 7.09-7.02 (m, 1H), 4.17-4.07 (m , 2H), 3.46 (d, J = 14.4 Hz, 1 H), 3.43 (dd, J = 11.6, 2.8 Hz, 1 H), 3.17 (d, J = 14.4 Hz, 1 H), 3.05-2.96 (m , 1H), 2.94-2.84 (m, 1H), 2.97-2.89 (m, 1H), 2.45-2.39 (m, 1H), 2.33-2.24 (m, 4H), 2.20 (d, J = 11.6 Hz, 1H), 2.25-2.17 (m, 1H), 1.04 (t, J = 7.1 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 204.9, 170.3, 136.1, 132.9, 132.2, 128.4, 127.1, 125.9, 62.9, 61.6, 61.6, 55.8, 45.6, 406, 36.0, 17.8; HRMS (ESI): calculated for Ci ₆ H ₂₀ BrNO ₃ [M + H] ⁺ : 354.06993, found 354.07013.

Ethyl 3- (2-bromo-3-methylbenzyl) -N-methyl-4-oxopiperidine-3-carboxylate (5):

After AAV 5, ethyl i-methyl-oxopiperidine-S-carboxylate (1.07 g, 5.8 mmol) was reacted with o-bromo-m-methylbenzyldimethylanilinium bromide 2.22 g (5.7 mmol). The desired product was obtained by column chromatography (silica gel, petroleum ether / Et ₂ O, 1: 1) as a slightly yellow oil. Yield: 410 mg (25%).

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.10-7.05 (m, 2H), 7.00-6.96 (m, 1H), 4.19-4.06 (m, 2H), 3.53 (d, J = 14.4 Hz, 1 H), 3.43 (dd, J = 11.6, 2.8 Hz, 1 H), 3.22 (d, J = 14.4 Hz, 1 H), 3.04-2.96 (m, 1 H), 2.94-2.84 (m, 1 H ), 2.45-2.39 (m, 1H), 2.40 (s, 3H), 2.32-2.25 (m, 1H), 2.30 (S, 3H), 1.15 (t, J = 7.1 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 204.9, 170.4, 138.6, 136.5, 129.5, 129.3, 128.6, 126.4, 62.9, 61.6, 61.5, 55.8, 45.6, 40.6, 36.7, 24.6, 13.8; HRMS (ESI): calculated for C ₁₇ H ₂₂ BrNO ₃ [M + H] ⁺ : 368.08558, found 368.08568.

Ethyl N-benzyl-11-oxo-1,3,4,6-tetrahydro-1,5-methano-3-benzazocin-5 (2H) -carboxylate (6): After AAV 2, ethyl 1-benzyl-3- (2-bromobenzyl) -4-oxopiperidine-3-carboxylate (1) (430 mg, 1 mmol) with K ₃ PO ₄ (425 mg, 2 mmol), Pd ( dba) ₂ (11.5 mg, 2 mol%) and JBu ₃ P (1 ml of 0.04 N in toluene, 4 mol%). implemented. The desired product was obtained after purification by column chromatography (silica gel, petroleum ether / Et ₂ O, 9: 1) as a yellow solid. Yield: 230 mg (65%). mp 117-119 ⁰ C.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.31-7.13 (m, 6H, aromatic), 6.95-6.87 (m, 3H, aromatic), 4.25 (q, J = 14.2, 7.1 Hz, CH ₂ (carbethoxy )), 4.00 (d, J = 17.2 Hz, 1 H), 3.61-3.51 (m, 2H), 3.43 (d, J = 17.2 Hz, 1 H), 3.45-3.42 (m, 1 H), 3.18 ( dd, J = 11.2, 2.8 Hz, 1 H), 3.12 (d, J = 11.2 Hz, 1 H), 3.01 (ddd, J = 10.6, 2.8, 2.8 Hz, 1 H), 2.75 (dd, J = 10.6 , 2.4 Hz, 1 H), 1.30 (t, J = 7.1 Hz, CH ₃ ); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 207.4 (carbonyl), 170.2 (carbethoxy), 138.2, 137.3, 136.3, 128.2, 128.1, 127.5, 127.1, 127.0, 126.2, 126.2 (aromatic), 63.5, 61.9, 61.5, 60.2, 59.1, 52.7, 41.0, 14.1; HRMS (ESI): calcd for C ₂₂ H ₂₃ NO ₃ [M + H] ^+: 350.17507, found 350.17524; methanol adduct (hemiacetal) calculated for C ₂₃ H ₂₇ NO ₄ [M + CH ₃ OH + H] ^+: 382.20128 found 382.20076.

Ethyl N-benzyl-M-methyl-oxo-I-S-β-tetrahydro-1-S-methano-S-benzazocine-5 (2H) -carboxylate (7):

Ethyl 3- (2-bromo-3-methylbenzyl) -N-benzyl-4-oxopiperidine-3-carboxylate (2) 455 mg (1.02 mmol) was converted to AAV 2. The desired product was after column chromatography (silica gel, petroleum ether / EtOAc, 20: 1) as a colorless oil. Yield: 95 mg (30%).

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.26-7.17 (m, 5H), 7.05-6.99 (m, 1H), 6.94-6.88 (m, 2H), 4.04 (q, J = 14.2, 7.1 Hz, 2H), 3.51 (d, J = 13.4 Hz, 1H), 3.36 (d, J = 13.4 Hz, 1H), 3.07 (s, 2H), 2.70 (d, J = 11.6 Hz, 1H) , 2.55-2.47 (m, 1H), 2.41 (s, 3H), 2.37-

2.27 (m, 1H), 2.25-2.18 (m, 1H), 2.14-2.05 (m, 1H), 1.11 (t, J = 7.1 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 205.3, 176.5, 138.8, 134.3, 129.7, 128.9, 128.6, 128.2, 128.2, 127.7, 126.9, 122.6, 62.2, 60.9, 57.8, 49.7, 40.5, 37.1, 35.0 , 18.5, 13.9; HRMS (ESI): calculated ₂₃ H ₂₅ NO ₃ [M + H] ⁺ C: 364.19072, found 364.19171.

Ethyl N-benzyl-8-methoxy-11-oxo-1,3,4,6-tetrahydro-1, 5-methano-3-benzazocine-5 (2H) -carboxylate (8): Ethyl 3- (2-bromo-5-methoxybenzyl) -N-benzyl-4-oxopiperidine-3-carboxylate (3) 577 mg (1.25 mmol) was converted to AAV 2. The desired product was present after purification by column chromatography (silica gel, petroleum ether / EtOAc, 20: 1) in the form of yellow crystals. Yield: 144 mg (40%). mp 84-85 ⁰ C. ¹ H NMR (400 MHz ₁ CDCI _3): δ = 7:19 to 7:15 (m, 3H), 6.97-6.93 (m, 2H), 6.86-6.82 (m, 1 H), 6.75- 6.72 (m, 2H), 4.27-4.20 (m, 2H), 3.97 (d, J = 17.4 Hz, 1H), 3.84-3.82 (s, 3H), 3.56 (s, 2H), 3.42-3.35 (m , 2H), 3.15 (dd, J = 11.2, 2.8 Hz, 1 H), 3.08 (d, J = 11.2, 1H), 2.98 (ddd, J = 10.6, 2.8, 1 H), 2.72 (dd, J = 10.6, 2.5 Hz, 1 H), 1.29 (t, J = 7.1 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 207.5, 170.3, 158.8, 138.2, 137.4, 129.6, 128.5, 128.2, 128.1, 127.1, 112.3, 111.4, 63.4, 62.0, 61.5, 60.3, 58.8, 55.4, 52.0 , 41.1, 14.1; HRMS (ESI): calcd (Or C ₂₃ H ₂₅ NO ₄ [M + H] ⁺ : 380.18563, found 380.18573; methanol adduct (hemiacetal) calcd for C ₂₄ H ₂₉ NO ₅ [M + CH ₃ OH + H] ⁺ : 412.21185, found 412.21114.

Ethyl N-methyl-11-oxo-1,3,4,6-tetrahydro-1,5-methano-3-benzazocin-5 (2H) -carboxylate hydrochloride (9):

After AAV 2, 1-methyl-3- (2-bromobenzyl) -4-oxopiperidine-3-carboxylate (4) (745 mg, 2.16 mmol) with K ₃ PO ₄ (1.3 g, 6.1 mmol), Pd (dba) ₂ (25 mg, 2 mol.%) And ffiu ₃ P (2 ml of a 0.04N solution in toluene, 4 mol%) was reacted and heated for 72 h at 120 ⁰ C in an oil bath. The desired product was present after acidic aqueous workup as a yellow solid. Yield: 192 mg (25%).

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.25-7.12 (m, 3H), 6.91 (d, J = 7.5 Hz, 1H), 4.27 (q, J = 14.3, 7.1 Hz), 4.02 (i.e. , J = 17.3 Hz, 1 H), 3.52 (d, J = 17.3 Hz, 1 H), 3.39 (t, J = 2.5 Hz, 1 H), 3.15 (dd, J = 11.3, 2.8, 1 H), 3.04-2.96 (m, 2H), 2.67 (dd, J = 10.7, 2.8, 1H), 2.25 (s, 3H), 1.31 (t, J = I Λ Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 207.5, 170.29, 137.3, 135.8, 127.5, 127.2, 126.6, 126.3, 66.6, 64.7, 61.6, 58.6, 52.5, 45.0, 41.0, 14.1; HRMS (ESI): calcd for Ci ₆ H ₁₉ NO ₃ [M + H] ⁺ : 274.14377, found 274.14323; methanol adduct (hemiacetal) calcd for Ci ₇ H ₂₃ NO ₄ [M + CH ₃ OH + H] ⁺ : 306.16998, found 306.16986.

Ethyl N-10-dimethyl-11-oxo-1,3,4,6-tetrahydro-1,5-methano-3-benzazocin-5 (2H) -carboxylate (10): Ethyl 3- (2-bromo-3-methylbenzyl) -N-methyl-4-oxopiperidine-3-carboxylate (5) 147 mg (0.40 mmol) was converted to AAV 2 while stirring for 72 h at 120 ^° C. in an oil bath The desired product was obtained after purification by column chromatography (silica gel, petroleum ether / EtOAc, 20: 1) in the form of crystals. Yield: 27 mg (25%).

¹ H NMR (400 MHz ₁ CDCl ₃ ): δ = 7.13-7.09 (m, 1H), 7.03-6.98 (m, 2H), 4.30-4.24 (m, 2H) ₁ 4.01 (d, J = 17.3 Hz, 1 H), 3.60 (t, J = 2.5 Hz, 1 H), 3.49 (d, J = 17.3 Hz, 1 H), 3.19 (dd, J = 11.3, 2.8 Hz, 1 H), 3.04-2.96 (m , 1 H) ₁ 2.63 (dd, J = 10.8, 3.0 Hz, 1 H), 2.27 (s, 3H), 2.30 (s, 3H), 1.31 (t, J = IA Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 208.1, 170.4, 135.7, 135.3, 134.7, 128.0, 126.8, 124.6, 66.3, 62.4, 61.6, 58.5, 48.7, 45.1, 41.0, 18.5, 14.1.

Diethyl-11-oxo-1,3,4,6-tetrahydro-1, 5-methano-3-benzazocine-3,5 (2H) -dicarboxylate (11): ethyl-N-benzyl-11-OXO-1, 3,4,6-tetrahydro-1, 5-methano-3-benzazocin-5 (2H) - (225 mg, 0.64 mmol) carboxylate (6) was dissolved in ethoxycarbonyl chloride (5 ml) and for 3 days at 60 ⁰ C heated. The excess of ethoxycarbonyl chloride was removed by vacuum distillation. The desired product, after purification by column chromatography (silica gel, petroleum ether / EtOAc, 5: 1), was in the form of a colorless oil. Yield: 135 mg (64%). Implementation: approx. 75%

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.23-7.14 (m, 2H), 7.13-7.00 (m, 2H) ₁ 4.79 (dd, J = 13.6, 3.3 Hz, 0.6H), 4.60-4.37 ( m, 0.5H), 4.32-4.22 (m, 2.6H), 4.05-3.87 (m, 1.6H), 3.77-3.51 (m, 4H), 3.47-3.30 (m, 1.3H), 1.31 (t, J = 7.2 Hz, 3H), 1.13 (t, J = 7.2 Hz, 1H), 0.77 (t, J = 7.2 Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 205.3, 169.3, 155.8, 134.8, 134.4, 128.2, 127.7, 127.3, 126.8, 61.8, 61.6, 59.7, 53.9, 53.2, 52.5, 39.0, 14.1. According to the NMR spectra (11) is a mixture of rotamers (-2: 1); HRMS (ESI): calculated ₁₈ H ₂ INO ₅ [M + H] ⁺ C: 332.14925, found 332.14910.

3-Benzyl-5-ethyl-11-oxo-1,3,4,6-tetrahydro-1,5-methano-3-benzazocine-3,5 (2H) -dicarboxylate (12):

Ethyl N-benzyl-11-OXO-1,3,4,6,6-tetrahydro-1,5-methano-3-benzazocin-5 (2H) -carboxylate (6) (1.0 g, 2.8 mmol) became AAV 3 implemented. The wished After purification by column chromatography (silica gel, petroleum ether / EtOAc, 95: 5), the product was in the form of a colorless oil. Yield: 780 mg (70%).

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.36-7-03 (m, 7H), 7.02-6.85 (m, 2H), 4.98-4.72 (m, 2H) ₁ 4.62-4.39 (m, 1.5H ) ₁ 4.32-4.22 (m, 2.5H), 4.03-3.90 (m, 1H), 3.77-3.63 (m, 1H), 3.59-3.52 (m, 1.5H), 3.46-3.28 (m, 1.5H ), 1.35-1.27 (m, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 205.2, 169.3, 169.2, 155.6, 154.9, 136.0, 135.8, 134.8, 134.6, 134.3, 133.5, 128.5, 128.4, 128.4, 128.3, 128.2, 127.9, 127.8, 127.6 , 127.4, 127.2, 126.9, 126.8, 67.6, 67.5, 61.9, 59.6, 59.1, 54.1, 53.9, 53.2, 52.4, 52.4, 39.2, 39.0, 14.1. (12), according to NMR, is a mixture of rotamers (~ 2: 1); HRMS (ESI): calculated ₂₃ H ₂₃ NO ₅ [M + H] ⁺ C: 394.16490, found 394.16512.

Ethyl 11-oxo-1,3,4,6-tetrahydro-1,5-methano-3-benzazocin-5 (2H) -carboxylate hydroiodide hydrate (13):

3-Benzyl-5-ethyl-11-OXO-1,3,4,6,6-tetrahydro-1, 5-methano-3-benzazocine-3,5 (2H) -dicarboxylate (12) (350 mg, 0.9 mmol) was converted to AAV 4. The desired product was obtained in the form of yellow crystals. Yield: 180 mg (50%) (x HI, x H ₂ O). (x HI, x H ₂ O). mp 170-172 ⁰ C

¹ H NMR (400 MHz, CDCl ₃ ): δ = 9.30-9.10 (broad, 1H), 7.50-7.30 (broad, 1H) ₁ 7.30-7.17 (m, 4H), 4.25-4.13 (m, 2H) ₁ 3.64 (d, J = 17.7 Hz, 1H), 3.53-3.44 (m, 1H), 3.43-3.31 (m, 2H), 3.17-3.09 (m, 2H) ₁ 3.06 (d, J = 17.7 Hz , 1 H), 1.25 (t, J = 7.1 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 171.0, 134.7, 134.3, 129.1, 127.9, 127.0, 126.3, 91.5, 61.4, 48.5, 48.3, 47.0, 44.2, 35.7, 13.9; HRMS (ESI): calcd for C ₁₅ H ₁₈ NO ₃ [M] ^+: 260.12812, found 260.12857; Methanol Aduct (hemiacetal) calculated ₁₆ H ₂₂ NO ₄ [M + CH ₃ OH] ⁺ C: 292.15433, found 292.15432.

Ethyl N- (anilinocarbonyl) -11-OXO-1,3,4,6-tetrahydro-1, 5-methano-3-benzazocine-5 (2H) -carboxylate (14):

Ethyl 11-OXO-1,3,4,6,6-tetrahydro-1,5-methano-3-benzazocin-5 (2H) -carboxylate Hydroiodide hydrate (13) (45 mg, 0.11 mmol) was obtained after AAV 6 Phenylisocyanate (20 .mu.l, 0.18 mmol) reacted. The desired product was obtained in the form of light yellow crystals. Yield: 35 mg (84%). mp 199-203 ⁰ C ¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.24-7.18 (m, 2H), 7.14-7.06 (m, 4H), 6.93-6.88 (m, 1H), 6.72 (d, J = 7.8 Hz, 2H), 5.40-5.34 (broad, 1H) ₁ 4.86 (dd, J = 13.6, 3.5 Hz, 1H), 4.29-4.21 (m, 2H), 3.98-3.87 (m, 2H), 3.66-3.59 ( m, 3H), 3.49 (d, J = 17.9 Hz, 1 H), 1.27 (t, J = 7.1 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 204.6, 169.2, 155.1, 138.1, 135.1, 134.9, 128.6, 128.5, 128.1, 127.4, 127.3, 123.4, 120.5, 62.0, 59.8, 54.6, 53.5, 52.4, 39.0 , 14.1; HRMS (ESI): calculated for C ₂₂ H ₂₂ N ₂ O ₄ [M + H] ^+: 379.16523, found 379.16559; [M + Na] ⁺ : 401.14718, found 401.14749.

Ethyl N-tosyl-11-oxo-1,3,4,6-tetrahydro-1,5-methano-3-benzazocin-5 (2H) -carboxylate (15):

Ethyl 11-oxo-1, 3,4,6-tetrahydro-1,5-methano-3-benzazocin-5 (2H) -carboxylate Hydroiodide hydrate (13) (48 mg, 0.12 mmol) was obtained according to AAV 7 Toluenesulfonyl chloride (35 mg, 0.18 mmol). The desired product was after column chromatography purification (silica gel, petroleum ether / EtOAc, 3: 1) in the form of a yellowish oil. Yield: 42 mg (80%).

¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.46 (d, J = 8.3 Hz, 2H), 7.26-7.16 (m, 4H), 7.11 (d, J = 7.6 Hz, 1H) ₁ 6.98 (i.e. , J = 7.6 Hz, 1 H), 4.27 (dd, J = 14.2, 7.1 Hz, 2H), 4.13 (dd, J = 12.1, 3.3 Hz, 1 H), 4.03 (d, J = 17.5 Hz, 1 H ), 3.96-3.90 (m, 1H), 3.52-3.49 (m, 1H), 3.46 (d, J = 17.6Hz, 1H), 3.40 (d, J = 12.1Hz, 1H), 3.12 ( dd, J = 11.4, 2.3Hz, 1H), 2.40 (s, 3H), 1.29 (t, J = 7.1Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 205.2, 169.0, 143.9, 134.8, 134.7, 134.2, 129.8, 128.0, 127.9, 127.2, 127.2, 127.1, 62.1, 58.1, 55.9, 54.9, 51.3, 34.0, 21.5 , 14.1; HRMS (ESI): calculated for C ₂₂ H ₂₃ NO ₅ S [M + H] ^+: 414.13697, found 414.13655; [IvHNa] ⁺ : 436.11738, found 436.11738.

Ethyl 2-benzyl-11-oxo-1, 3,4,6-tetrahydro-1, 5-methane-2-benzazocin-5 (2H) -carboxylate (16)

Process for the preparation of L from K is described in the literature: (M. Scalone, P. Waldmeier, Org. Process Res. Dev. 2003, 7, 418)

Preparation of Ethyl 1-benzyl-4- (2-bromobenzyl) -3-oxopiperidone-4-carboxylate (Yes): A mixture of potassium te / t-butylate (7.5 g, 65.0 mmol) and absolute THF (150 mL). was stirred at RT for 0.5 h. After cooling to ⁰ ° C., Λ / -benzyl-3-oxo-4-piperidinecarboxylate hydrochloride (L) (10.0 g, 33.6 mmol) was added, keeping the temperature below 5 ° C. After warming to RT and stirring for 1 h, the reaction mixture was recooled to 0 ^C and a solution of 2-bromobenzylbromide (8.8 g, 35.2 mmol) in absolute THF (40.0 mL) was added dropwise. After warming to RT, the reaction mixture was stirred for 4 h at RT. Aqueous saturated NH ₄ Cl solution (100 ml) was then added at 0 ^° C., the organic phase was separated and the aqueous phase was extracted with ethyl acetate (2 × 100 ml). The combined organic phases were dried over Na ₂ SO ₄ and filtered. The solvent was removed in vacuo and the residue purified by column chromatography (petroleum ether / ethyl acetate, 10: 1, R _f = 0.2). The product was obtained with a yield of 50% (7.4 g) (50%). ¹ H NMR (400 MHz, CDCl ₃ ): D = 7.57 (d, J = 8.1 Hz, 1H, ar.), 7.37-7.22 (m, 7H, ar.), 7.15-7.08 (m, 1H, ar.), 4.25 ^ .15 (m, 2H, CO ₂ CH ₂ CH ₃ ), 3.57 (s, 2H, PhCH ₂ NR ₂ ), 3.51 (d, J = 14.1 Hz, 1 H ₁ 2-H) ₁ 3.31 (d, J = 14.1 Hz, 1H, 2-H), 3.24 (d, J = 15.9 Hz, 1H, ArCH ₂ ), 3.12 (d, J = 15.9 Hz, 1H, ArCH ₂ ), 2.80 -2.70 (m, 1H, CH ₂ CH ₂ ), 2.65-2.55 (m, 2H, CH ₂ CH ₂ ), 1.87-1.77 (m, 1H, CH ₂ CH ₂ ), 1.22 (t, J = 7.1 Hz, 3H, CO ₂ CH ₂ CH ₃ ); ¹³ C NMR (100 MHz, CDCl ₃ ): D = 203.9 (C = O), 169.8 (CO ₂ Et), 137.1 (quat. Ar.), 136.2 (quat. Ar.), 132.9, 132.3, 128.8, 128.3 , 128.2, 127.3, 127.0 (9C tertiary ar), 125.9 (quat. ar.), 62.2 (C-4, quat.), 61.5, 61.4, 58.7, 48.7, 37.4, 30.0 (6C, sec), 13.9 (CO ₂ CH ₂ CH ₃ ).

Ethyl 2-benzyl-1-oxo-1,3,4,6-tetrahydro-1,5-methane-2-benzazocin-5 (2W) -carboxylate (16): Under an inert gas atmosphere, 1-benzyl-3- ( 2-bromobenzyl) -4-oxopiperidine-3-carboxylate (J) (430 mg, 1 mmol) in 5 mL absolute toluene, K ₃ PO ₄ (425 mg, 2 mmol) and Pd (dba) ₂ (34.5 mg, 6 mol%), the fBu ₃ P (3 ml of 0.04 N in toluene, 12 mol%). The reaction mixture was stirred vigorously at 110 ^° C. for 48 h. The reaction mixture was then cooled to RT and filtered through Celite. The solvent was removed and the residue was removed by means of

Column chromatography (petroleum ether / ethyl acetate, 5: 1, R _f = 0.5). The product Id was obtained in 35% yield (125 mg) ¹ H NMR (400 MHz, CDCl ₃ ): D = 7.38-7.30 (m, 5H, ar.), 7.28-7.21 (m, 3H, ar. ), 6.98 (d, J = 7.6 Hz, 1 H, ar.), 4.29 (dd, J = 14.4, 7.1 Hz, 2H, CO ₂ CH ₂ CH ₃ ), 4.08 (s, 1 H, 1-H) , 4.07 (d, J = 17.6 Hz, 1 H, 6-H) ₁ 3.69 (d, J = 13.4 Hz, 1 H, PhCH ₂ NR ₂ ), 3.42 (d, J = 13.4 Hz, 1 H, PhCH ₂ NR ₂ ), 3.27 (d, J = 17.6 Hz, 1 H, 6-H), 2.87 (dddd, J = 13.2, 5.5, 1.8 Hz, 1 H. 3-H), 2.61 (ddd, J = 12.5, 5.5, 1.8, 1H, 4-H), 2.49 (ddd, J = 12.8, 3.1, 1H, 4-H), 1.98 (ddd, J = 13.4, 3.0, 1.8Hz, 1H3-H) , 1.33 (t, J = 7.1 Hz, 3H, CO ₂ CH ₂ CH ₃ ); ¹³ C NMR (100 MHz, CDCl ₃ ): D = 205.0 (C = O), 171.2 (CO ₂ Et), 137.8 (quat. Ar.), 136.4 (quat. Ar.), 130.4 (tert. , 129.9 (quat. Ar.), 128.7, 128.6, 128.5, 127.3, 127.1, 126.2 (8C tert. Ar.), 67.9 (C-1, tert.), 61.7 (CO ₂ CH ₂ CH ₃ ), 57.7 ( PhCH ₂ NR ₂ ), 57.1 (C-5, quat.), 42.8 (C-4, seα), 40.2 (C-6, sec), 37.3 (C-2, sec), 14.2 (CO ₂ CH ₂ CH ₃ ); IR (film): nu (tilde) = 2974, 2831, 1732, 1450, 1227, 737 cm ^"1; HRMS (ESI): calcd for C ₂₂ H ₂₄ NO ₃ [M + H] ^+: 350.1751, found 350.1749.

Ethyl N -benzyl-9-cyano-11-oxo-1,3,4,6-tetrahydro-1, 5-methano-3-benzazocine-5 (2W) -ca-rboxylate (17)

Ethyl 3- (2-bromo-4-cyano-benzyl) -N-benzyl-4-oxopiperidine-3-carboxylate To a suspension of K ₂ CO ₃ (0.911 g, 6.6 mmol) and ethyl 1-benzyl-4-oxopiperidine-3 -carboxylate (0.436 g, 1.65 mmol) in absolute THF (5 mL) was added under inert gas atmosphere a solution of 2-bromo-4-cyanobenzylbromide (0.50 g, 1.8 mmol) in absolute THF (5 mL). The reaction mixture was refluxed for 17 h, then filtered and the filter cake was washed with THF (3 x 5 mL). The solvent was removed in vacuo and the residue purified by column chromatography (petroleum ether / ethyl acetate, 5: 1, R _f = 0.2). Yield: 0.563 g (72%), ¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.73 (s, 1 H, ar.), 7.41 (d, J = 8.1 Hz, 1 H, ar.), 7.31 (d, J = 8.1Hz, 1H, ar.), 7.27-7.18 (m, 5H, N-benzyl ar.), 4.10-4.03 (m, 2H, CO ₂ CH ₂ CH ₃ ), 3.56 (d, J = 13.2 Hz, 1H, PhCH ₂ NR ₂ ), 3.51-3.45 (m, 3H, PhCH ₂ NR ₂ , 2-H and ArCH ₂ ), 3.11 (d, J = 14.5 Hz, 1 H, ArCH ₂ ) , 3.02-2.98 (m, 1H, 5-H), 2.94-2.85 (m, 1H, 5-H), 2.38 (d, J = 14.5Hz, 1H, 6-H), 2.29-2.26 ( m, 2H, 2H and 6H), 1.07 (t, J = 7.1, 3H, CO ₂ CH ₂ CH ₃ ). ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 205.2 (C = O), 170.7 (CO ₂ Et), 142.9, 137.9 (2C quat. Ar.), 136.2, 133.0, 130.8, 129.2, 128.7, 127.8 ( 6C tertiary aryl), 126.6 (quat. Ar.), 117.6 (CN), 112.4 (quat. Ar.), 62.4, 62.1, 62.03, 61.50, 53.3, 40.8, 36.4 (7C sec), 14.2 (CO ₂ CH ₂ CH ₃ ).

Ethyl N -benzyl-9-cyano-11-oxo-1,3,4,6-tetrahydro-1, 5-methano-3-benzazocine-5 (2H) -carboxylate (17)

Under inert gas atmosphere, ethyl 3- (2-bromo-4-cyanobenzyl) -N-benzyl-4-oxopiperidine-3-carboxylate (0.306 g, 0.64 mmol), absolute toluene (5 ml), K ₃ PO _{4 was added}

(0.400 g, 1.88 mmol), and Pd ₂ (dba) ₃ CHCl ₃ (13 mg, 2 mol%) of the fBu ₃ P (0.7 mL of 0.04 N in toluene, 4 mol%). The reaction mixture was stirred vigorously at 100 ^° C. for 15 h. The reaction mixture was then cooled to RT, filtered through Celite and washed with toluene (3 × 5 ml). The solvent was added Vacuum removed and the residue purified by column chromatography (petroleum ether / ethyl acetate, 5: 1, R _f = 0.2). The product was obtained in a yield of 22% (0.055 g).

Melting point 158-160 ⁰ C. ¹ H NMR (400 MHz, CDCI _3): δ = 7.78 (. D, J = 7.9 Hz, 1 H, ar), 7:53 (d, J = 7.9 Hz, 1 H ₁ ar. 7.46-7.39 (m, 5H, ar.), 7.10-7.08 (m, 2H, ar.), 4.47 (dd, J = 14.4, 7.1Hz, 2H, CO ₂ CH ₂ CH ₃ ), 4.26 (i.e. , J = 18.5 Hz, 1H, 1-H), 3.83 (d, J = 13.5 Hz, 1H, 6-H), 3.77 (d, J = 13.5 Hz, 1H, 6-H), 3.70 ( s, 2H ₁ PhCH ₂ NR ₂ ), 3.44 (dd, J = 11.5, 1.5 Hz ₁ 1 H ₁ 4-H), 3.38 (d, J = 11.5 Hz, 1 H, 4-H), 3.20 (ddd, J = 10.9, 2.3Hz, 1H 2-H), 3.03 (dd, J = 9.2, 2.0Hz, 1H, 2-H), 1.51 (t, J = 7.1Hz ₁ 3H, CO ₂ CH ₂ CH ₃ ). ¹³ C NMR (100 MHz, CDCl 3): δ = 203.9 (C = O), 168.0 (CO ₂ Et), 140.6 (quat. Ar.), 129.7, 129.4, 127.0 (3C tertiary), 126.8, 125.9 (2C quat. Ar.), 117.2 (CN), 108.8 (tert. Ar.), 61.8, 60.5, 60.0, 58.9 (4C sec), 57.4 (C-5 quat.), 50.6 (C-1 tert.). , 39.6 (C-6 sec.) 12.71 (CO ₂ CH ₂ CH ₃ ).

The structures of the example compounds are summarized in the following table

Connection No. Structure Name

Ethyl-N-benzyl-11-oxo-1, 3 _l 4,6-tetrahydro-1, 5- methano-3-benzazocin- 5 (2H) -carboxylate

Ethyl N-benzyl-10-methyl-11-oxo-1, 3,4,6-tetrahydro-1, 5-methano-3-benzazocine-5 (2H) -carboxylate

Ethyl N-benzyl-8-methoxy-1 1 -oxo-1, 3,4,6-tetrahydro-

8 1, 5-methano-3-benzazocine-5 (2H) -carboxylate

Ethyl-N-methyl-11-oxo-

1, 3,4,6-tetrahydro-1, 5-methano-3-benzazocine

carboxylate 5 (2H) hydrochloride

Studies on the effectiveness of the compounds of the invention Measurement of serotonin reuptake

To perform these in vitro studies, synaptosomes from rat brain areas are freshly isolated. In each case a so-called. ^ "Fraction is used, which is prepared according to the instructions of Gray and Whittaker (EG Gray and VP Whittaker (1962) J. Anat., 76, 79-88) .These become available for the 5HT uptake vesicular particles isolated from the medulla + pons region of male rat brains.

A detailed description of the method can be found in the literature (M. Ch. Frink, H.-H. Hennies, W. Englberger, M. Haurand and B. Wilffert (1996) Arzneim.-Forsch./Drug Res. 46 (III), 11, 1029-1036).

Measurement of norepinephrine reuptake

To perform these in vitro studies, synaptosomes from rat brain areas are freshly isolated. In each case a so-called. ^ "Fraction is used which is prepared according to the instructions of Gray and Whittaker (EG Gray and VP Whittaker (1962) J. Anat., 76, 79-88.) For the NA uptake these become vesicular Particles isolated from the hypothalamus of male rat brains.

A detailed description of the method can be found in the literature (M.Ch. Frink, H.-H. Hennies, W. Englberger, M. Haurand and B. Wilffert (1996) Arzneim.-Forsch./Drug Res. 46 (IM), 11, 1029-1036).

As an example, inhibition of serotonin and noradrenaline reuptake was determined for compound 9:

Claims

Claims:

1. Substituted tricyclic piperidone derivatives of the general formula I.

wherein

R, 1 ^{1 represents} methyl, ethyl or phenyl

X _{1 is} NR ² and X _{2 is} CH ₂ or X _{2 is} NR ² and X _{1 is} CH ₂

R is C _1-8 -alkyl, saturated or unsaturated, branched or unbranched, monosubstituted or polysubstituted or unsubstituted, optionally with a heteroatom as chain member; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C _1-8 -alkyl group, optionally, with a heteroatom as chain member, attached aryl, C _3-8 -cycloalkyl or heteroaryl, in each case unsubstituted or monosubstituted or polysubstituted; (C = O) R ⁴ , (C = O) NR ⁵ R ⁶ , (C = S) NR ⁵ R ⁶ , SO ₂ R ⁷ or (C = O) OR ⁸ ;

R ^{3 is} H, F, Cl, Br, OH, OCH ₃ , SCH ₃ , NO ₂ , CN; C _1-8 -alkyl or C _3-8 -cycloalkyl, in each case saturated or unsaturated, branched or unbranched, monosubstituted or polysubstituted or unsubstituted; Phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted with F ₁ Cl, OH, OCH ₃ , SCH ₃ , NO ₂ , CN, CF ₃ , methyl or ethyl;

R ⁴ , R ⁷ and R ^{8 are} Ci-β-alkyl or C _3-8 -cycloalkyl, each saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted, optionally, with a heteroatom N, O ₁ S as a chain member ; Aryl, or

Heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C _1-6 -alkyl group, optionally with one heteroatom N, O, S as chain member, bonded aryl or C _3-8 -cycloalkyl or heteroaryl, in each case unsubstituted or mono- or substituted several times; stand;

R ⁵ and R ^{6 are} independently H; d-β-alkyl or C _3- a -cycloalkyl, in each case saturated or unsaturated, branched or unbranched, monosubstituted or polysubstituted or unsubstituted, if appropriate, with a heteroatom N, O, S as chain member; Aryl, or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted Ci _-8 alkyl group, optionally in each case unsubstituted with a hetero atom N, O, S as a chain member, bound aryl or C _3-8 -cycloalkyl or heteroaryl or mono- or substituted several times; where R ⁵ and R ^{6 may} not be H at the same time;

or the radicals R ⁵ and R ⁶ together form a five-, six- or seven-membered ring which may be saturated or unsaturated, but not aromatic, which optionally contains one further heteroatom from the group S, O or NR ⁹ and with benzyl or Ci.s-alkyl may be substituted,

wherein R ^{9 is} Ci _-5- alkyl, branched or unbranched; Phenyl or benzyl, unsubstituted or mono- or polysubstituted by F, Cl, OH, OCH ₃ , SCH ₃ , NO ₂ , CN, CF ₃ , methyl or ethyl. in the form of the Razemats; the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers, or a single enantiomer or diastereomer; the bases and / or salts of physiologically acceptable acids.

2. Substituted piperidone tricyclic derivatives according to claim 1, wherein Xi is NR ² and X _{2 is} CH ₂ .

3. Substituted tricyclic piperidone derivatives according to claim 1, wherein R ^{2 is} C _1-5 -alkyl, branched or unbranched, unsubstituted and saturated; via a C-ι _-3 alkyl group bonded phenyl, naphthyl, pyridyl, furyl, thienyl and indolyl, each unsubstituted or mono- or polysubstituted with -F, -Cl, -CF _3, -0-CH _3, methyl, Ethyl, n-propyl, nitro, te / f.-butyl, and -CN.

4. Substituted tricyclic piperidone derivatives according to claim 2, wherein R ^{2 is} methyl or benzyl.

5. Substituted tricyclic piperidone derivatives according to one of claims 1 or 2, wherein R ^{2 is} (C =O) R ⁴ , (C =O) NR ⁵ R ⁶ , (C =S) NR ⁵ R ⁶ , SO ₂ R ⁷ or (C = O) OR ⁸ .

6. Substituted tricyclic piperidone derivatives according to claim 1, wherein R ⁴ , R ⁷ and R ^{8 are} methyl, ethyl, n-propyl. iso-propyl, n-butyl or te / t-butyl; Phenyl, naphthyl, thienyl, furyl or pyridyl, each singly or multiply substituted with F, Cl, CF ₃ , NO ₂ , CH ₃ , OH, SH, OCH ₃ or SCH ₃ or unsubstituted; a Ci _-3 alkyl group bonded phenyl, naphthyl, thienyl, furyl or pyridyl, respectively unsubstituted or singly or multiply substituted with F, Cl, CF _3, NO _2, CH _3, OH, SH, OCH ₃ or SCH ₃ ; stand.

7. A substituted tricyclic piperidone derivative according to claim 6, wherein R ⁴ , R ⁷ and R ^{8 is} methyl, ethyl, phenyl or tosyl.

8. Substituted piperidone tricyclic derivatives according to claim 1, wherein R ⁵ and R ⁶ are each independently H; Cis-alkyl or C _3-8 -cycloalkyl, branched or unbranched; Aryl, or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; over a Ci. Aryl or C _3-8 -cycloalkyl or heteroaryl bonded to the _3- alkyl group, each unsubstituted or monosubstituted or polysubstituted; stand; or the radicals R ⁵ and R ⁶ together form piperidine, piperazine, morpholine or thiomorpholine.

9. Substituted piperidone tricyclic derivatives according to claim 8, wherein R ⁵ and R ^{6 are} independently H; Methyl, ethyl, π-propyl. / so-propyl, n-butyl or tert-butyl; Phenyl, naphthyl, thienyl, furyl or pyridyl, each singly or multiply substituted with F, Cl, CF ₃ , NO ₂ , CH ₃ , OH, SH, OCH ₃ or SCH ₃ or unsubstituted; a Ci _-3 alkyl group bonded phenyl, naphthyl, thienyl, furyl or pyridyl, respectively unsubstituted or singly or multiply substituted with F, Cl, CF _3, NO _2, CH _3, OH, SH, OCH ₃ or SCH ₃ ; stand.

10. Substituted tricyclic piperidone derivatives according to claim 9, wherein R ⁵ and R ^{6 are} independently H or phenyl.

11. A substituted piperidone tricyclic derivative according to claim 1, wherein R ^{3 is} H, F ₁ Cl, OH, OCH ₃ , SCH ₃ , NO ₂ , CN, CF ₃ , methyl, ethyl or benzyl.

12. Substituted tricyclic piperidone derivatives according to claim 11, wherein R ^{3 is} H, CN, OCH ₃ or methyl.

13. Substituted tricyclic piperidone derivatives according to claim 1 from the group

Ethyl N -benzyl-8-methoxy-11-0X0-1, 3,4,6-tetrahydro-1, 5-methano-3-benzazocine-5 (2H) -carboxylate Ethyl N-methyl-11-0X0-1, 3,4,6-tetrahydro-1,5-methano-3-benzazocine-5 (2H) -carboxylate hydrochloride

Ethyl-N-10-dimethyl-11-0X0-1, 3 _l 4,6-tetrahydro-1, 5-methano-3-benzazocin-5 (2H) - carboxylate

Diethyl-11-0X0-1, 3,4,6-tetrahydro-1,5-methano-3-benzazocine-3,5 (2H) -dicarboxylate

Ethyl N- (anilinocarbonyl) -11-oxo-1, 3,4,6-tetrahydro-1, 5-methano-3-benzazocine-5 (2H) -carboxylate

Ethyl N-tosyl-11-0X0-1, 3,4,6-tetrahydro-i, 5-methano-3-benzazocin-5 (2H) -carboxylate Ethyl 2-benzyl-11-0X0-1, 3,4 , 6-tetrahydro-1, 5-methane-2-benzazocine-5 (2H) -carboxylate

Ethyl N -benzyl-9-cyano-11-0X0-1, 3,4,6-tetrahydro-1,5-methano-3-benzazocin-5 (2 / - /) - carboxylate

14. A process for the preparation of a substituted tricyclic piperidone derivative according to claim 1, wherein compounds of general formula B in an organic solvent with the addition of a base, with a benzyl bromide at a temperature of 0-10O ⁰ C to compounds of general formula C. become,

the compounds of general formula C in an organic solvent, with the addition of a base with a Katralysator such as Pd (dba) 2, PdC ^, Pd (0Ac) ₂ and a corresponding ligand, for example, t-Bu ₃ P, PhaP in a Temperature of 40-130 ⁰ C under inert gas to give compounds of general formula Ia according to the invention,

if appropriate, the compounds of general formula Ia in a compound of general formula CIC (O) OR ⁸ , for example benzyloxycarbonyl, optionally with the addition of a suitable solvent, dissolved and reacted at temperatures of 0 to 100 ⁰ C to give compounds of general formula Ib .

_R 2a

C - ^RΪ

Ia

ib

and optionally the products of general formula Ib are reacted in an organic solvent with trimethylsilyl iodide at a temperature of -20 to 100 ⁰ C and then in an organic solvent with addition of a base with the appropriate electrophile, for example acid chlorides, acid anhydrides, sulfonyl chlorides, isocyanates or isothiocyanates is reacted ⁰ C to novel compounds of the general formula Ic at a temperature of -20 ⁰ C-IOO, R ^2b Ic

in which

R ^{2a is} C _1-8 -alkyl, saturated or unsaturated, branched or unbranched, monosubstituted or polysubstituted or unsubstituted, optionally with a heteroatom as chain member; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted Ci. _8- alkyl group, optionally, with a heteroatom as chain member, bound aryl, C _3-8 -cycloalkyl or heteroaryl, in each case unsubstituted or monosubstituted or polysubstituted,

and

15. A process for the preparation of a substituted tricyclic piperidone derivative according to claim 1, wherein

Compounds of general formula H are reacted in an organic solvent with the addition of a base, with a benzyl bromide at a temperature of 0-10O ⁰ C to compounds of general formula I,

the compounds of general formula I in an organic solvent, adding a base with a Katralysator such as Pd (dba) ₂ , PdCl ₂ , Pd (OAc) ₂ and a corresponding ligand, for example, t-Bu ₃ P, Ph ₃ P. be reacted under inert gas at a temperature of 40-130 ⁰ C to give compounds of general formula Id according to the invention,

if appropriate, the compounds of the general formula Id are dissolved in a compound of the general formula CIC (O) OR ⁸ , for example benzyloxycarbonyl chloride, if appropriate with addition of a suitable solvent, and reacted at a temperature of 0 to 100 ° C. to give compounds of general formula Ie according to the invention .

and optionally the products of general formula Ie are reacted in an organic solvent with trimethylsilyl iodide at a temperature of -20 to 100 ⁰ C and then in an organic solvent with addition of a base with the appropriate electrophile, for example acid chlorides, acid anhydrides, sulfonyl chlorides, isocyanates or isothiocyanates is reacted ⁰ C to novel compounds of the general formula If at a temperature of -20 ⁰ C-IOO,

R ⁸

in which

R ^{2a is} Ci _-8- alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted, optionally with a heteroatom as a chain member; via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted Ci ₈ alkyl group, optionally having a heteroatom as chain member, bound aryl, C _{_3-8} cycloalkyl or heteroaryl, respectively unsubstituted or singly or multiply substituted, .

and

16. A pharmaceutical composition containing at least one substituted tricyclic piperidone derivative according to claim 1, optionally in the form of the racemate; of the

Enantiomers, diastereomers, mixtures of the enantiomers or diastereomers or a single enantiomer or diastereomer; the bases and / or salts physiologically acceptable acids, and optionally containing suitable additives and / or adjuvants and / or optionally other active ingredients.

17. Use of a substituted tricyclic piperidone derivative according to claim 1, optionally in the form of the racemate; the enantiomers,

Diastereomers, mixtures of the enantiomers or diastereomers or a single enantiomer or diastereomer; the bases and / or salts of physiologically acceptable acids, for the manufacture of a medicament for the treatment of pain, in particular of acute, neuropathic or chronic pain.

18. Use of a substituted tricyclic piperidone derivative according to claim 1, optionally in the form of the racemate; the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers, or a single enantiomer or diastereomer; the bases and / or salts of physiologically acceptable acids, for the manufacture of a medicament for the treatment of

Depression, urinary incontinence, diarrhea, pruritus, alcohol and drug abuse, drug dependence, listlessness and / or anxiolysis.