DE102006015733A1 - Use of buprenorphine compounds to treat emotionally unstable personality disorder, alcohol dependence or multiple substance dependence - Google Patents

Abstract

Buprenorphine compounds (I) are used to treat emotionally unstable personality disorder, alcohol dependence or multiple substance dependence. Buprenorphine compounds of formula (I) or their salts, esters, ethers, tautomers or hydrates are used to treat emotionally unstable personality disorder, alcohol dependence or multiple substance dependence. X : O, NH, 1-6C alkylimino or S; R 1>-R 4>H, 1-12C alkyl, 2-12C alkenyl, 2-12C alkynyl or (CH 2) nR, all optionally substituted with halo, OH, NO 2, NH 2, mono- or di(1-6C alkyl)amino, guanidino or 1-6C alkoxy and optionally with a CH 2 group replaced by C(O); R : 3-8C (hetero)cycloalkyl, 3-8C (hetero)cycloalkenyl or 6-14C (hetero)aryl; and n : 0-6. An independent claim is also included for a composition comprising (I) and a kappa opioid receptor antagonist. [Image] ACTIVITY : Tranquilizer; Antialcoholic; Antiaddictive. No biological data given. MECHANISM OF ACTION : None given.

Description

The The invention relates to the use of buprenorphine and buprenorphine derivatives for the treatment of emotionally unstable personality disorder, alcohol dependence and / or multiple substance dependence or for making a drug that is used to treat emotional unstable personality disorder, alcohol dependence and / or multiple substance dependence suitable is.

It are a series of personality disorders People who, if left untreated, become too serious Consequences for lead the person concerned can. examples for Personality disorders, which in some cases have serious consequences for the person concerned can, are, for example, the emotionally unstable personality disorder (also known as borderline syndrome), but also personality disorders, resulting in a substance abuse and a resulting substance dependence or even a multiple substance dependence (polytoxikomania) can knock down. Under emotionally unstable personality disorder understands you have a personality disorder clear tendency, impulses without consideration of consequences to act out, combined with unpredictable and moody mood. There is a tendency for emotional outbursts and an inability to to control impulsive behavior.

• • Entwicklung einer Toleranz, das bedeutet, der Betroffene muss immer mehr von einer Substanz einnehmen, um die gleiche Wirkung zu erzielen. Die Dosis wird immer mehr gesteigert.
• • Wird das Suchtmittel abgesetzt, zeigen sich körperliche Entzugserscheinungen. Diese Entzugserscheinungen sind je nach Substanz unterschiedlich und werden medizinisch auch als Entzugssyndrom bezeichnet.

Dependence is generally defined as: "various forms of reliance on particular substances or behaviors". The range goes from simple habits to dependency with considerable destruction potential. As "different forms" the physical (physical) dependence and mental (mental) dependency are differentiated. The criteria of physical dependence are counted:

• • Development of a tolerance, which means that the person affected must take more and more of a substance in order to achieve the same effect. The dose is increasing more and more.
• • If the addictive substance is discontinued, physical withdrawal symptoms appear. These withdrawal symptoms vary depending on the substance and are also referred to medically as withdrawal syndrome.

substances are taken to avoid withdrawal symptoms or to alleviate, relieve.

• • Heftiges und gelegentlich unbezwingbares, sehr starkes Verlangen, eine Substanz zu konsumieren mit dem Ziel, positive Empfindungen herbeizuführen oder unangenehme Empfindungen zu vermeiden.

In mental dependency, other characteristics are emphasized. These include:

• • Violent and sometimes unconquerable, very strong desire to consume a substance with the aim of inducing positive sensations or avoiding unpleasant sensations.

Affected have over the beginning and end of consumption as well as the amount of substance use only a diminished control.

One example for a substance dependence is, for example, alcohol dependence or cocaine addiction. Of a multiple substance dependence one speaks, if at the same time a dependence of two or more Substances consists, for example, alcohol and cocaine and optionally further.

The The present invention is concerned with the treatment of the above Personality disorders, this means the treatment of emotionally unstable personality disorder, the Alcohol dependence and / or multiple substance dependence. For the treatment of emotionally unstable personality disorder (Borderline Syndrome) are already developed a variety of therapeutic procedures but mostly with only moderate success. Also for treatment of alcohol dependence there are some approaches for example, treatment with acamprosate or naltrexone (see e.g. The Merck Index, 13th edition, 2001, p. 5 and 1141). buprenorphine is known as a painkiller (see The Merck Index, 13th Edition, 2001, p. 252).

task The present invention is thus alternative and, where appropriate improved treatment methods of emotionally unstable personality disorder, alcohol dependence and / or multiple substance dependence to disposal to deliver.

worin
X unabhängig voneinander O, NH, N-C_1-6-Alkyl oder S ist,
R¹, R², R³ und R⁴ jeweils unabhängig voneinander H, lineares oder verzweigtes C_1-12-Alkyl, lineares oder verzweigtes C_1-12-Alkenyl, lineares oder verzweigtes C_2-12-Alkinyl, -(CH₂)_n-C_3-8-Cycloalkyl, -(CH₂)_n-C_3-8-Cycloalkenyl, -(CH₂)_n-C_3-8-Heterocycloalkyl, -(CH₂)_n-C_3-8-Heterocycloalkenyl, -(CH₂)_n-C_6-14-Aryl oder -(CH₂)_n-C_6-14-Heteroaryl sind, wobei alle Reste unsubstituiert oder mit Halogen, -OH, -NO₂, -NH₂, -NHC_1-6-Alkyl, -N(C_1-6-Alkyl)₂, -NH(C=NH)NH₂ oder -O-C_1-6-Alkyl substituiert sein können und eine Methylengruppe der obigen Reste durch -(C=O)- ersetzt sein kann, und
n jeweils unabhängig voneinander 0, 1, 2, 3, 4, 5 oder 6 ist,
oder pharmazeutisch annehmbarer Salze, Ester, Ether, Tautomere und/oder Hydrate davon.The object is achieved by a compound of general formula I,

wherein
X is independently of one another O, NH, NC _1-6- alkyl or S,
R ¹ , R ² , R ³ and R ^{4 are} each independently H, linear or branched C _1-12 alkyl, linear or branched C _1-12 alkenyl, linear or branched C _2-12 alkynyl, - (CH ₂ ) _n -C _3-8 -cycloalkyl, - (CH ₂ ) _n -C _3-8 -cycloalkenyl, - (CH ₂ ) _n -C _3-8 -heterocycloalkyl, - (CH ₂ ) _n -C _3-8 - Heterocycloalkenyl, - (CH ₂ ) _n -C _6-14 -aryl or - (CH ₂ ) _n -C _6-14 -heteroaryl, where all radicals are unsubstituted or substituted by halogen, -OH, -NO ₂ , -NH ₂ , -NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂ , -NH (C = NH) NH ₂ or -OC _1-6 alkyl, and a methylene group of the above radicals may be substituted by - (C = O) - can be replaced, and
each n is independently 0, 1, 2, 3, 4, 5 or 6,
or pharmaceutically acceptable salts, esters, ethers, tautomers and / or hydrates thereof.

Preference is given to compounds of the general formula I in which X is O,
R ^{1 is} H or linear C _1-6 -alkyl,
R ^{2 is} - (CH ₂ ) _n -C _3-4 -cycloalkyl with n = 1 or 2,
R ^{3 is} H or linear C _1-6 alkyl, and
R ^{4 is} branched C _5-8 alkyl, optionally substituted by -OH, or pharmaceutically acceptable salts, esters, ethers, tautomers and / or hydrates thereof.

oder pharmazeutisch annehmbare Salze, Ester, Ether und/oder Hydrate davon.It is particularly preferred if the compound of general formula I has the following structure:

or pharmaceutically acceptable salts, esters, ethers and / or hydrates thereof.

The Compounds of general formula I, or their pharmaceutically acceptable salts, esters, ethers, tautomers and / or hydrates to treat emotionally unstable personality disorder, alcohol dependence and / or multiple substance dependence or for the manufacture of a drug for the treatment of emotional unstable personality disorder, alcohol dependence and / or multiple substance dependence. Optionally, pharmaceutically acceptable carriers are also Auxiliaries and additives added.

Pharmaceutically acceptable salts are preferably selected from chloride, bromide, iodide, sulfate, Phosphate, tartrate, acetate, mucin. The hydrates are preferably selected from mono-, di-, tri-, tetra- and pentahydrate. As esters, preference is given to using carboxylic acid esters with C _1-6 -alkyl, acyl, benzyl, benzoate and the like.

pharmaceutical acceptable carriers and auxiliaries and additives are, for example, a solid, a liquid or a gas. examples for solid carriers include lactose, china earth, sucrose, talc, gelatin, Agar, pectin, acacia, magnesium stearate and stearic acid. Examples for liquid carriers Sugar syrup, peanut oil, olive oil and water. examples for gaseous carrier include carbon dioxide and nitrogen. Examples of auxiliary and additives are diluents, Buffers, granulating agents, lubricants, disintegrants, binders, surfactants Agents, thickeners and dyes and pigments, preservatives (including Antioxidants), flavors and flavorings.

The Compounds of general formula I, or their pharmaceutically acceptable salts, esters, ethers and / or hydrates are preferred used in an amount of 1 mg to 1000 mg, more preferably from 10 mg to 600 mg and especially from 50 mg to 500 mg, respectively per dosage form, corresponding to 0.01 mg to 13 mg, especially preferably 0.1 mg to 8 mg and in particular 0.6 mg to 7 mg per kilogram Body weight. Administration may take the form of powder, tablets, solution, suppository or patch, each with delayed or without delay Release done. Other forms of administration, including oral, intravenous, buccal, transdermal, subcutaneous, rectal, inhalative or sublingual Allow administration, are conceivable.

worin
X unabhängig voneinander O, NH, N-C_1-6-Alkyl oder S ist,
R¹, R², R³ und R⁴ jeweils unabhängig voneinander N, lineares oder verzweigtes C_1-12-Alkyl, lineares oder verzweigtes C_2-12-Alkenyl, lineares oder verzweigtes C_2-12-Alkinyl, -(CH₂)_n-C_3-8-Cycloalkyl, -(CH₂)_n-C_3-8-Cycloalkenyl, -(CH₂)_n-C_3-8-Heterocycloalkyl, -(CH₂)_n-C_3-8-Heterocycloalkenyl, -(CH₂)_n-C_6-14-Aryl oder -(CH₂)_n-C_6-14-Heteroaryl sind, wobei alle Reste unsubstituiert oder mit Halogen, -OH, -NO₂, -NH2, -NHC_1-6-Alkyl, -N(C_1-6-Alkyl)₂, -NH(C=NH)NH₂, oder -O-C_1-6-Alkyl substituiert sein können und eine Methylengruppe der obigen Reste durch -(C=O)- ersetzt sein kann, und
n jeweils unabhängig voneinander 0, 1, 2, 3, 4, 5 oder 6 ist,
oder pharmazeutisch annehmbare Salze, Ester, Ether, Tautomere und/oder Hydrate davon,
und ein oder mehrere kappa-Opioidrezeptor-Antagonisten oder pharmazeutisch annehmbarer Salze, Ester, Ether, Tautomere und/oder Hydrate davon, zur Behandlung von emotional instabiler Persönlichkeitsstörung oder zur Herstellung eines Medikaments zur Behandlung von emotional instabiler Persönlichkeitsstörung verwendet werden.In a further embodiment of the invention, a compound of the general formula I

wherein
X is independently of one another O, NH, NC _1-6- alkyl or S,
R ¹ , R ² , R ³ and R ^{4 are} each independently N, linear or branched C _1-12 alkyl, linear or branched C _2-12 alkenyl, linear or branched C _2-12 alkynyl, - (CH ₂ ) _n -C _3-8 -cycloalkyl, - (CH ₂ ) _n -C _3-8 -cycloalkenyl, - (CH ₂ ) _n -C _3-8 -heterocycloalkyl, - (CH ₂ ) _n -C _3-8 - Heterocycloalkenyl, - (CH ₂ ) _n -C _6-14 -aryl or - (CH ₂ ) _n -C _6-14 -heteroaryl, where all radicals are unsubstituted or substituted by halogen, -OH, -NO ₂ , -NH ₂ , - NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂ , -NH (C = NH) NH ₂ , or -OC _1-6 alkyl, and a methylene group of the above radicals may be substituted by - (C = O) - can be replaced, and
each n is independently 0, 1, 2, 3, 4, 5 or 6,
or pharmaceutically acceptable salts, esters, ethers, tautomers and / or hydrates thereof,
and one or more kappa opioid receptor antagonists or pharmaceutically acceptable salts, esters, ethers, tautomers and / or hydrates thereof, for the treatment of emotionally unstable personality disorder or for the manufacture of a medicament for the treatment of emotionally unstable personality disorder.

Again, preferred are compounds wherein X is O,
R ^{1 is} H or linear C _1-6 -alkyl,
R ^{2 is} - (CH ₂ ) _n -C _3-4 -cycloalkyl with n = 1 or 2,
R ^{3 is} H or linear C _1-6 alkyl, and
R ^{4 is} branched C _5-8 alkyl, optionally substituted by -OH, or pharmaceutically acceptable salts, esters, ethers, tautomers and / or hydrates thereof.

oder pharmazeutisch annehmbare Salze, Ester, Ether und/oder Hydrate davon.Again, it is particularly preferred if the compound of general formula I has the following structure:

or pharmaceutically acceptable salts, esters, ethers and / or hydrates thereof.

When kappa opioid receptor antagonists may be compounds or their pharmaceutically acceptable salts, esters, ethers, tautomers and / or Hydrate can be used, as described for example by D. Metcalf and A. Coop in The AAPS Journal 2005; 7 (3) Art. 71 (October 27, 2005) Pages 704 to 722 are described.

The Opioid receptor system includes 3 types of heterogeneous, G protein coupled opioid receptors. The μ, δ and κ (kappa) receptors, each one This receptor has selective agonists and antagonists. Antagonists (blockers) have a high affinity for the receptor if missing or low intrinsic activity (effect). The reaction mechanism The antagonist at the receptor can be found in the competitive and non-competitive Divide antagonism. Competitive means having a surplus an agonist of the antagonist may be completely from Repressed receptor can be. In noncompetitive antagonism, this displacement reaction is not or only partially possible, for example, by irreversible binding of the antagonist or by a reaction of the antagonist with another site of the Receptor as the binding site of the agonist.

worin die Reste R, R¹ und X jeweils gleich oder verschieden sein können und wobei Y -(CHR¹)_m mit m = 0,1 oder 2 ist, R¹ und X wie bei Formel I definiert sind und R Halogen, -OH, -NO₂, -NH₂, -NHC_1-6-Alkyl, -N(C_1-6-Alkyl)₂, -NH(C=NH)NH₂ oder -O-C_1-6-Alkyl sowie R¹ der allgemeinen Formel I ist,
oder pharmazeutisch annehmbare Salze, Ester, Ether, Tautomere und/oder Hydrate davon.Preferred are kappa opioid receptor antagonists of the general formula II

wherein the radicals R, R ¹ and X may each be the same or different and wherein Y is - (CHR ¹ ) _m with m = 0.1 or 2, R ¹ and X are as defined for formula I and R is halogen, -OH , -NO ₂ , -NH ₂ , -NHC _1-6 -alkyl, -N (C _1-6 -alkyl) ₂ , -NH (C = NH) NH ₂ or -OC _1-6 -alkyl and R ¹ of general formula I,
or pharmaceutically acceptable salts, esters, ethers, tautomers and / or hydrates thereof.

To the selective kappa opioid receptor antagonists included in the general formula II fall, count e.g. Binaltorphimin (BNI) and Norbinaltorphimin (norBNl) as well as derivatives and isomers thereof, for example, furan or pyran analogs.

worin die Reste R, R¹ und X jeweils gleich oder verschieden sein können und wobei
Y -(CHR¹)_m mit m = 0, 1 oder 2 ist,
R¹ und X wie bei Formel I definiert sind und R Halogen, -OH, -NO₂, -NH₂, -NHC_1-6-Alkyl, -N(C_1-6-Alkyl)₂, -NH(C=NH)NH₂ oder -O-C_1-6-Alkyl sowie R¹ der allgemeinen Formel I ist, der Ring A einen 5-14-gliedrigen, aliphatischen, heteroaliphatischen, aromatischen oder heteroaromatischen, mono- oder bicyclischen Ring (vorzugsweise 6-gliedrigen monocyclischen aromatischen oder heteroaromatischen Ring) darstellt, der gegebenenfalls mit Z substituiert sein kann,
wobei Z Halogen, lineares oder verzweigtes C_1-12-Alkyl, lineares oder verzweigtes C_2-12-Alkenyl, lineares oder verzweigtes C_2-12-Alkinyl, -(CH₂)_n-C_3-8-Cycloalkyl, -(CH₂)_n-C_3-8-Cycloalkenyl, -(CH₂)_n-C_3-8-Heterocycloalkyl, -(CH₂)_n-C₃-₈-Heterocycloalkenyl, -(CH₂)_n-C_6-14-Aryl, -(CH₂)_n-C_6-14-Heteroaryl, -(CH₂)_n-NH₂, -(CH₂)_n-NH(C=NH)-C_1-8-Alkyl, -(CH₂)_n-NH(C=NH)-NH₂,
-(CH₂)_n-NH(C=NH)NH(C=NH)NH₂, -(CH₂)_n-NH(C=N-CN)NH₂, -(CH₂)_n-C=O-C_1-8-Alkyl, -(CH₂)_n-C=O-C_1-6-Alkyl-NH-C=O-C_1-6-Alkyl-NH₂, -(CH₂)_n-NH(C=S)NH₂, -(CH₂)_n-NH(C=NH)S-C_1-6-Alkyl, -(CH₂)_n-(C=NH)NH₂, -(CH₂)_n-NH(C=NH)NH-C_{1- 6}-Alkyl, -(CH₂)_n-C=O-NH-C_1-8-Alkyl, -(CH₂)_n-C=O-NH-Aryl, -(CH₂)_n-C=O-NH-C_{1- 6}-Alkylaryl sind, wobei alle Reste unsubstituiert oder mit Halogen, -NO₂, -OH, -NH₂, -NHC_1-6-Alkyl, -N(C_1-6-Alkyl)₂, -NH(C=NH)NH₂ oder -O-C_1-6-Alkyl substituiert sein können, ein oder mehrere Wasserstoffatome durch C_1-6-Alkyl, Aryl oder C_1-6-Alkylaryl ersetzt sein können, und eine Methylengruppe der obigen Reste durch -(C=O)- ersetzt sein kann, und
n jeweils unabhängig voneinander 0, 1, 2, 3, 4, 5 oder 6 ist,
oder pharmazeutisch annehmbare Salze, Ester, Ether, Tautomere und/oder Hydrate davon.Further preferred are kappa opioid receptor antagonists of the general formula III

wherein the radicals R, R ¹ and X may each be the same or different and wherein
Y is - (CHR ¹ ) _m with m = 0, 1 or 2,
R ¹ and X are as defined for formula I and R is halogen, -OH, -NO ₂ , -NH ₂ , -NHC _1-6 -alkyl, -N (C _1-6 -alkyl) ₂ , -NH (C = NH) NH ₂ or -OC _1-6 -alkyl and R ^{1 of} the general formula I, the ring A is a 5-14-membered, aliphatic, heteroaliphatic, aromatic or heteroaromatic, mono- or bicyclic ring (preferably 6-membered monocyclic aromatic or heteroaromatic ring), which may be optionally substituted with Z,
wherein Z is halogen, linear or branched C _1-12 -alkyl, linear or branched C _2-12 -alkenyl, linear or branched C _2-12 -alkynyl, - (CH ₂ ) _n -C _3-8 -cycloalkyl, - ( CH ₂ ) _n -C _3-8 -cycloalkenyl, - (CH ₂ ) _n -C _3-8 -heterocycloalkyl, - (CH ₂ ) _n -C ₃ - ₈ -heterocycloalkenyl, - (CH ₂ ) _n -C _{6 14} -aryl, - (CH ₂ ) _n -C _6-14 -heteroaryl, - (CH ₂ ) _n -NH ₂ , - (CH ₂ ) _n -NH (C = NH) -C _1-8- alkyl, (CH ₂ ) _n -NH (C = NH) -NH ₂ ,
- (CH ₂ ) _n -NH (C = NH) NH (C = NH) NH ₂ , - (CH ₂ ) _n -NH (C = N-CN) NH ₂ , - (CH ₂ ) _n -C = OC _1-8 alkyl, - (CH ₂ ) _n -C = OC _1-6 alkyl NH-C = OC _1-6 alkyl NH ₂ , - (CH ₂ ) _n -NH (C = S) NH ₂ , - (CH ₂ ) _n - NH (C = NH) SC _1-6 alkyl, - (CH ₂ ) _n - (C = NH) NH ₂ , - (CH ₂ ) _n -NH (C = NH) NH-C _{1- 6} alkyl, - (CH _{2) n} -C = O-NH-C _1-8 alkyl, - (CH _{2) n} -C = O-NH-aryl, - (CH _{2) n} -C = O-NH-C _{1- 6} -alkyl are, where all radicals being unsubstituted or substituted by halogen, -NO _2, -OH, -NH _2, -NHC _1-6 alkyl, -N (C _1-6 - Alkyl) ₂ , -NH (C = NH) NH ₂ or -OC _1-6 -alkyl, one or more hydrogen atoms may be replaced by C _1-6 -alkyl, aryl or C _1-6 -alkylaryl, and a methylene group of the above radicals may be replaced by - (C = O) -, and
each n is independently 0, 1, 2, 3, 4, 5 or 6,
or pharmaceutically acceptable salts, esters, ethers, tautomers and / or hydrates thereof.

To the kappa opioid receptor antagonists under the general formula III fall e.g. Indolmorphinans and Amidines, for example Guanidinnaltrindol (GNTI) as well as derivatives and isomers thereof.

worin R¹ die unter der allgemeinen Formel I definierte Bedeutung hat (vorzugsweise H und C_1-3-Alkyl),
R⁵ und R⁶ H, -OH, -SH, NH oder -N-C_1-6-Alkyl ist,
und R⁵ und R⁶ gegebenenfalls zusammen einen carbocyclischen oder heterocyclischen Ring mit 5-7 Gliedern, insbesondere 6 Gliedern, bilden können,
R¹ H, -OH oder -O-C_1-6-Alkyl, insbesondere -OH, ist
oder pharmazeutisch annehmbare Salze, Ester, Ether, Tautomere und/oder Hydrate davon.Further preferred are kappa opioid receptor antagonists of the general formula IV;

in which R ^{1 has} the meaning defined under general formula I (preferably H and C _1-3 -alkyl),
R ⁵ and R ^{6 is} H, -OH, -SH, NH or -NC _1-6 -alkyl,
and R ⁵ and R ^{6 may} optionally together form a carbocyclic or heterocyclic ring having 5-7 members, in particular 6 members,
R ^{1 is} H, -OH or -OC _1-6 -alkyl, especially -OH
or pharmaceutically acceptable salts, esters, ethers, tautomers and / or hydrates thereof.

Links, which fall under the general formula IV are among others so-called non-epoxymorphinans, e.g. JDTic, a trans- (3R, 4R) -dimethyl-4- (3-hydroxyphenyl) -piperidine and derivatives and isomers thereof.

bei denen R die oben in Formel V dargestellten Reste sein können und bei denen gegebenenfalls ein oder mehrere Wasserstoffatome ersetzt sein können durch lineares oder verzweigtes C_1-12-Alkyl, lineares oder verzweigtes C_2-12-Alkenyl, lineares oder verzweigtes C_2-12-Alkinyl, -(CH₂)_n-C_3-8-Cycloalkyl, -(CH₂)_n -C_3-8-Cycloalkenyl, -(CH₂)_n-C_3-8-Heterocycloalkyl, -(CH₂)_n-C_3-8-Heterocycloalkenyl, -(CH₂)_n-C_6-14-Aryl oder -(CH₂)_n-C_6-14-Heteroaryl, wobei alle Reste unsubstituiert oder mit Halogen, -OH, -NO₂, -NH₂, -NHC_1-6-Alkyl, -N(C_1-6-Alkyl)₂, -NH(C=NH)NH₂ oder -O-C_1-6-Alkyl substituiert sein können und eine Methylengruppe der obigen Reste durch -(C=O)- ersetzt sein kann, und
n jeweils unabhängig voneinander 0, 1, 2, 3, 4, 5 oder 6 ist,
oder pharmazeutisch annehmbare Salze, Ester, Ether, Tautomere und/oder Hydrate davon.Further preferred kappa opioid receptor antagonists are compounds of general structural formula V

in which R may be the radicals shown above in formula V and in which optionally one or more hydrogen atoms may be replaced by linear or branched C _1-12 -alkyl, linear or branched C _2-12 -alkenyl, linear or branched C _{2- 12-} alkynyl, - (CH ₂ ) _n -C _3-8 -cycloalkyl, - (CH ₂ ) _n -C _3-8 -cycloalkenyl, - (CH ₂ ) _n -C _3-8 -heterocycloalkyl, - (CH ₂ ) _n -C _3-8 -heterocycloalkenyl, - (CH ₂ ) _n -C _6-14 -aryl or - (CH ₂ ) _n -C _6-14 -heteroaryl, where all radicals are unsubstituted or substituted by halogen, -OH, - NO ₂ , -NH ₂ , -NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂ , -NH (C = NH) NH ₂ or -OC _1-6 alkyl, and a methylene group the above radicals may be replaced by - (C = O) -, and
each n is independently 0, 1, 2, 3, 4, 5 or 6,
or pharmaceutically acceptable salts, esters, ethers, tautomers and / or hydrates thereof.

worin die Reste R⁸ gleich oder verschieden sein können und H, lineares oder verzweigtes C_1-12-Alkyl (vorzugsweise C_1-3-Alkyl), lineares oder verzweigtes C_{2- 12}-Alkenyl, lineares oder verzweigtes C_2-12-Alkinyl, -(CH₂)_n-C_3-8-Cycloalkyl, -(CH₂)_n-C_3-8-Cycloalkenyl, -(CH₂)_n-C_3-8-Heterocycloalkyl, -(CH₂)_n-C_3-8-Heterocycloalkenyl, -(CH₂)_n-C_6-14-Aryl, -(CH₂)_n-C_6-14-Heteroaryl oder ein Cinnamat sind, wobei alle Reste unsubstituiert oder mit Halogen, -OH, -NO₂, -NH₂, -NHC_1-6-Alkyl, -N(C_1-6-Alkyl)₂, -NH(C=NH)NH₂, oder -O-C_1-6-Alkyl substituiert sein können und eine Methylengruppe der obigen Reste durch -(C=O)- ersetzt sein kann, und
n 0, 1, 2, 3, 4, 5 oder 6 ist,
und die Reste R⁸ gegebenenfalls einen carbocyclischen oder heterocyclischen aliphatischen oder aromatischen Ring bilden,
oder pharmazeutisch annehmbare Salze, Ester, Ether, Tautomere und/oder Hydrate davon.Further preferred are kappa opioid receptor antagonists of the general formula VI

wherein the radicals R ⁸ may be the same or different and are H, linear or branched C _1-12 alkyl (preferably C _1-3 alkyl), linear or branched C _{2- 12} alkenyl, linear or branched C _2-12 - Alkynyl, - (CH ₂ ) _n -C _3-8 -cycloalkyl, - (CH ₂ ) _n -C _3-8 -cycloalkenyl, - (CH ₂ ) _n -C _3-8 -heterocycloalkyl, - (CH ₂ ) _n C _3-8 -heterocycloalkenyl, - (CH ₂ ) _n -C _6-14 -aryl, - (CH ₂ ) _n -C _6-14 -heteroaryl or a cinnamate, all radicals being unsubstituted or substituted by halogen, -OH , -NO ₂ , -NH ₂ , -NHC _1-6 -alkyl, -N (C _1-6 -alkyl) ₂ , -NH (C = NH) NH ₂ , or -OC _1-6 -alkyl may be substituted and a methylene group of the above radicals may be replaced by - (C = O) -, and
n is 0, 1, 2, 3, 4, 5 or 6,
and the radicals R ⁸ optionally form a carbocyclic or heterocyclic aliphatic or aromatic ring,
or pharmaceutically acceptable salts, esters, ethers, tautomers and / or hydrates thereof.

bei denen gegebenenfalls ein oder mehrere Wasserstoffatome ersetzt sein können durch lineares oder verzweigtes C_1-12-Alkyl (vorzugsweise C_1-3-Alkyl), lineares oder verzweigtes C_2-12-Alkenyl, lineares oder verzweigtes C_2-12-Alkinyl, -(CH₂)_n-C_3-8-Cycloalkyl, -(CH₂)_n-C_3-8-Cycloalkenyl, -(CH₂)_n-C_3-8-Heterocycloalkyl, -(CH₂)_n-C_3-8-Heterocycloalkenyl, -(CH₂)_n-C_6-14-Aryl, -(CH₂)_n-C_6-14-Heteroaryl oder ein Cinnamat sind, wobei alle Reste unsubstituiert oder mit Halogen, -OH, -NO₂, -NH₂, -NHC_1-6-Alkyl, -N(C_1-6-Alkyl)₂, -NH(C=NH)NH₂, oder -O-C_1-6-Alkyl substituiert sein können und eine Methylengruppe der obigen Reste durch -(C=O)- ersetzt sein kann, und
n 0, 1, 2, 3, 4, 5, 6 ist, und
wobei 0 wahlweise durch S, NH oder N-C_1-6-Alkyl ersetzt sein kann, oder pharmazeutisch annehmbare Salze, Ester, Ether, Tautomere und/oder Hydrate davon.Other preferred kappa opioid receptor antagonists in this invention are competitive kappa opioid receptor antagonists, eg, the prior art compounds Mr2266, WIN44,441 (quadazocine) or triethylene glycol naltrexamine (TENA) of the formulas below,

in which optionally one or more hydrogen atoms may be replaced by linear or branched C _1-12 -alkyl (preferably C _1-3 -alkyl), linear or branched C _2-12 -alkenyl, linear or branched C _2-12 -alkynyl, - (CH ₂ ) _n -C _3-8 -cycloalkyl, - (CH ₂ ) _n -C _3-8 -cycloalkenyl, - (CH ₂ ) _n -C _3-8 -heterocycloalkyl, - (CH ₂ ) _n -C _3-8 -heterocycloalkenyl, - (CH ₂ ) _n -C _6-14 -aryl, - (CH ₂ ) _n -C _6-14 -heteroaryl or a cinnamate, all radicals being unsubstituted or with halogen, -OH, - NO ₂ , -NH ₂ , -NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂ , -NH (C = NH) NH ₂ , or -OC _1-6 alkyl may be substituted and one Methylene group of the above radicals by - (C = O) - may be replaced, and
n is 0, 1, 2, 3, 4, 5, 6, and
wherein O may optionally be replaced by S, NH or NC _1-6 alkyl, or pharmaceutically acceptable salts, esters, ethers, tautomers and / or hydrates thereof.

Of the kappa opioid receptor antagonist is preferred in an amount of 0.1 mg to 1000 mg, more preferably from 1 mg to 750 mg and in particular from 5 mg to 250 mg, in each case per dosage form, corresponding to 0.001 mg to 13 mg, more preferably 0.01 mg to 10 mg and especially 0.06 mg to 3 mg per kilogram of body weight. The compound of the formula I is used in an amount as already stated above administered, the administration being administered simultaneously, can be consecutive or separate. That means the two Active ingredients can together, directly one after another, or staggered in time (e.g., at a distance from 5 to 60 minutes) to a patient. The administration can, as already mentioned in the form of powder, tablets, solution, suppository or Pave each with delayed or without delay Release done.

Also other dosage forms for oral, intravenous, buccal, transdermal, subcutaneous, rectal, inhalative or sublingual administration are conceivable.

Further the subject of the invention is a medicament for the treatment of emotionally unstable personality disorder and that is a compound of general formula I and a kappa opioid receptor antagonist and optionally pharmaceutically acceptable carriers and excipients and additives contains.

The Preparation of the compounds of the general formulas I to VI takes place according to methods known in the art. For production of Compounds of the general formula I and buprenorphine may be found on The Merck Index, 13.

pad, 2001, p. 252 and references cited therein. Derivatives of buprenorphine can also prepared from buprenorphine by conventional methods become. For the preparation of the compounds of the general formulas II to VI should be referred in particular to "The AAPS Journal 2005; 7 (3) Art. 71 (October 27, 2005) pages 704 to 722 "and the references cited therein directed.

The Production of drugs in the form of powder, tablets, solution, suppositories or Plaster, each with delayed or without delay Release is carried out by methods known in the art, for example, by mixing the components, optionally adding the carrier as well as auxiliaries and additives, and further mixing, if necessary Loosen or Dispersing the components or pressing the components to a tablet.

EXAMPLES

Example 1:

Preparation of a film-coated tablet containing pharmaceutically active ingredients by type and amount:
200 mg buprenorphine is mixed with the excipients lactose monohydrate, polyacrylate dispersion 30%, methacrylic acid ethacrylate copolymer (1: 1), ammonium methacrylate copolymer type B, hypromellose 4000, magnesium stearate, macrogol 6000, talc, hypromellose S, titanium dioxide, iron oxide red E 172 mixed and pressed into a prolonged-release tablet.

Example 2:

Preparation of a film-coated tablet containing pharmaceutically active ingredients by type and amount:
200 mg buprenorphine and 100 mg binaltorphimine (BNI) are mixed with the excipients lactose monohydrate, polyacrylate dispersion 30%, methacrylic acid ethacrylate copolymer (1: 1), ammonium methacrylate copolymer type B, hypromellose 4000, magnesium stearate, macrogol 6000, talc, hypromellose S , Titanium oxide, iron oxide red E 172 mixed and pressed into a film-prolonged-release tablet.

Medical application examples:

In in medical application examples 1 to 3 is buprenorphine alone or in conjunction with a kappa opiod receptor antagonist in patients with the diagnosis of multiple substance dependence as a possibility the reduction of the consumption of the multiple substances, especially the Reduction of alcohol due to an alcoholic reaction and the substitution in opiate dependence, to reduce consumption of multiple substances and reduction the accompanying social, somatic and psychiatric Consequences used.

In in medical application examples 4 and 5 is buprenorphine alone or in conjunction with a kappa opiod receptor antagonist in patients diagnosed with emotionally unstable personality disorder as possibility the treatment of personality disorder and the reduction of the associated social, somatic and used psychiatric consequences.

1. Medical application example:

buprenorphine is used as a tablet with an active ingredient content of 12 mg in sublingual Application form to a patient diagnosed with long-term alcohol dependence in the sense of an alcoholic reaction of alcohol consumption to Reduction of alcohol consumption and the reduction of the associated social, somatic and psychiatric consequences.

2. Medical application example:

buprenorphine is called mucoadhäsives Sachet with a buprenorphine content of 12 mg during treatment of longtime alcohol addiction administered to a patient.

3. Medical application example:

buprenorphine is given in a dosage of 12 mg and norbinaltorphimine in one Dosage of 10 mg per kg body weight (750 mg per tablet) as a corresponding kappa antagonist in one Sublingual tablet to a patient diagnosed with multiple substance dependence (Alcohol and opiate addiction) administered.

4. Medical application example:

Buprenorphine is a mucoadhesive sachet with a drug content of 12 mg a patient administered with the diagnosis of emotionally unstable personality disorder.

5. Medical application example:

buprenorphine is called mucoadhäsives Sachet with a potency of 12 mg and norbinaltorphimine at a dose of 10 mg per kg of body weight (750 mg per tablet) as a corresponding kappa opiod receptor antagonist to a patient administered with the diagnosis of emotionally unstable personality disorder.

Claims (11)

Use of a compound of general formula I.

in which X independently of one another is O, NH, NC _1-6- alkyl or S, R ¹ , R ² , R ³ and R ^{4 are} each independently H, linear or branched C _1-12 -alkyl, linear or branched C _{2- 12} alkenyl, linear or branched C _2-12 alkynyl, - (CH ₂ ) _n -C _3-8 cycloalkyl, - (CH ₂ ) _n -C _3-8 cycloalkenyl, - (CH ₂ ) _n -C _3-8 -heterocycloalkyl, - (CH ₂ ) _n -C _3-8 -heterocycloalkenyl, - (CH ₂ ) _n -C _6-14 -aryl or - (CH ₂ ) _n -C _6-14 -heteroaryl, wherein all radicals unsubstituted or with halogen, -OH, -NO ₂ , -NH ₂ , -NHC _1-6- alkyl, -N (C _1-6 -alkyl) ₂ , -NH (C = NH) NH ₂ , or - OC _1-6 alkyl may be substituted and a methylene group of the above radicals may be replaced by - (C = O), and n is each independently 0, 1, 2, 3, 4, 5 or 6, or pharmaceutically acceptable salts , Esters, ethers, tautomers and / or hydrates thereof, for the treatment of emotionally unstable personality disorder, alcohol dependence and / or multiple substance dependence or for production a drug for the treatment of emotionally unstable personality disorder, alcohol dependence and / or multiple substance dependence. Use according to claim 1, wherein X is O, R ^{1 is} H or linear C _1-6 -alkyl, R ^{2 is} - (CH ₂ ) _n -C _3-4 -cycloalkyl with n = 1 or 2, R ^{3 is} H or linear C _1-6 alkyl, and R ^{4 is} branched C _5-8 alkyl optionally substituted by -OH. Use according to claim 1 or 2, wherein the compound of the general formula I has the following structure:

or pharmaceutically acceptable salts, esters, ethers and / or hydrates thereof. Use according to claim 1 to 3 for the production a drug in the form of powder, tablets, solution, suppository or Plaster, each with delayed or without delay Release. Use of a compound of general formula I,

in which X independently of one another is O, NH, NC _1-6- alkyl or S, R ¹ , R ² , R ³ and R ^{4 are} each independently H, linear or branched C _1-12 -alkyl, linear or branched C _{2- 12} alkenyl, linear or branched C _2-12 alkynyl, - (CH ₂ ) _n -C _3-8 cycloalkyl, - (CH ₂ ) _n -C _3-8 cycloalkenyl, - (CH ₂ ) _n -C _3-8 -heterocycloalkyl, - (CH ₂ ) _n -C _3-8 -heterocycloalkenyl, - (CH ₂ ) _n -C _6-14 -aryl or - (CH ₂ ) _n -C _6-14 -heteroaryl, wherein all radicals are unsubstituted or substituted by halogen, -OH, -NO ₂ , -NH ₂ , -NHC _1-6 -alkyl, -N (C _1-6 -alkyl) ₂ , -NH (C = NH) NH ₂ or -OC _1-6 alkyl may be substituted and a methylene group of the above radicals may be replaced by - (C = O) - and n is each independently 0, 1, 2, 3, 4, 5 or 6, or pharmaceutically acceptable salts , Esters, ethers, tautomers and / or hydrates thereof, and one or more kappa opioid receptor antagonists or pharmaceutically acceptable salts, esters, ethers, tautomers and / or hydrates thereof, e.g. For the treatment of emotionally unstable personality disorder or for the manufacture of a drug for the treatment of emotionally unstable personality disorder. Use according to claim 5 wherein X is O, R ^{1 is} H or linear C _1-6 alkyl, R ^{2 is} - (CH ₂ ) _n C _3-4 cycloalkyl with n = 1 or 2, R ^{3 is} H or linear C _1-6 alkyl, and R ^{4 is} branched C _5-8 alkyl optionally substituted by -OH. Use according to claim 5 or 6, wherein the compound of general formula I has the following structure tur has:

or pharmaceutically acceptable salts, esters, ethers and / or hydrates thereof. Use according to one of claims 5 to 7 for the preparation a drug for simultaneous, consecutive or separate administration in the form of powder, tablets, solution, suppository or patch, each with delayed or without delay Release. Composition containing a compound of the general Formula I as defined in claim 5 and one or more kappa-opioid receptor antagonist. The composition of claim 9 further containing a pharmaceutically acceptable carrier and / or excipient. Process for the preparation of a composition according to claim 9 or 10 by mixing a compound of the general Formula I as defined in claim 5 and one or more kappa-opioid receptor antagonist and optionally a pharmaceutically acceptable carrier and / or Help material.