VAN LOEVEZIJN, Arnold (IPSI DepartmentC.J. Van Houtenlaan 36, CP Weesp, NL-1381, NL)
WIJNEN, Johan (IPSI DepartmentC.J. Van Houtenlaan 36, CP Weesp, NL-1381, NL)
HERREMANS, Arnoldus H.J. (IPSI DepartmentC.J. Van Houtenlaan 36, CP Weesp, NL-1381, NL)
KRUSE, Cornelis G. (IPSI DepartmentC.J. Van Houtenlaan 36, CP Weesp, NL-1381, NL)
DE BRUIN, Natasja M.W.J. (IPSI DepartmentC.J. Van Houtenlaan 36, CP Weesp, NL-1381, NL)
VAN LOEVEZIJN, Arnold (IPSI DepartmentC.J. Van Houtenlaan 36, CP Weesp, NL-1381, NL)
WIJNEN, Johan (IPSI DepartmentC.J. Van Houtenlaan 36, CP Weesp, NL-1381, NL)
HERREMANS, Arnoldus H.J. (IPSI DepartmentC.J. Van Houtenlaan 36, CP Weesp, NL-1381, NL)
KRUSE, Cornelis G. (IPSI DepartmentC.J. Van Houtenlaan 36, CP Weesp, NL-1381, NL)
THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:
1. Use of a 5-HT 6 antagonist for the preparation of a pharmaceutical composition for preventing relapse into addiction.
2. Use as claimed in claim 1 , wherein said 5-HT 6 antagonist is selected from: BGC-20-761 , BVT-74316, CNS-10000, CNS-1 1010, CNS-25100, diF-BAMPI, E-6837, FMPD, GSK-215083, JCF-177, KR-055014, KR-055015, LY-483518, MS-245, PHA- 565272A, PRX-07034, Ro 04-6790, Ro-4368554, Ro 63-0563, Ro 65-7199, Ro 65-7674, Ro 66-0074, SAM-315, SB-21411 1 , SB-258510, SB-258585, SB-271046, SB-33171 1 ,
SB-357134, SB-399885, SB-699929, SB-737050A, SB-742457 and ST-1938, or a tautomer, stereoisomer, N-oxide, isotopically-labelled analogue, or a pharmacologically acceptable salt, hydrate or solvate of any of the foregoing.
3. Use as claimed in claim 1 , wherein said 5-HT 6 antagonist is a compound of formula (1 ):
or a tautomer, stereoisomer, N-oxide, isotopically-labelled analogue, or a pharmacologically acceptable salt, hydrate or solvate of any of the foregoing, wherein:
Ri represents hydrogen, an unsubstituted alkyl(Ci -4 ) group or an alkyl(Ci -4 ) group substituted with one or more halogen atoms,
R 2 and R 3 independently represent hydrogen, an unsubstituted alkyl(Ci -4 ) group or an alkyl(Ci -4 ) group substituted with one or more halogen atoms, or,
R 1 and R 2 , together with the C-atoms marked 'a' and 'b' form a C 5- 8-cycloalkyl ring, or R 2 and R 3 , together with the carbon atom marked 'b' form a C 3-8 -cycloalkyl ring,
the dotted line between the carbon atoms marked 'b' and 'c' represents either a single or a double bond, R 4 and R 5 independently represent hydrogen, an unsubstituted alkyl(Ci -4 ) group or an alkyl(Ci -4 ) group substituted with one or more halogen atoms, or, R 3 and R 4 , together with the C-atoms marked 'b' and 'c' form a C 3 . 8 -cycloalkyl ring, or R 4 and R 5 , together with the carbon atom marked 'c' form a C 3-8 -cycloalkyl ring,
R 6 and R 7 independently represent hydrogen, an alkyl(Ci -4 ) group, an alkyl (Ci -4 ) group substituted with one or more halogen atoms, a (Ci -3 )alkoxy group, a dialkyl(Ci -3 )amino- alkyl(Ci -3 ) group, an optionally substituted aryl group, an optionally substituted C 5-8 - cyclo-alkyl group or an optionally substituted C 5-8 -heterocycloalkyl group, or R 6 and R 7 , together with the nitrogen atom to which they are attached, form an optionally substituted C 5-8 -heterocycloalkyl group,
R 8 represents an optionally substituted aryl group, an -CR 9 =CRio-aryl group wherein R 9 and R 1 0 independently represent hydrogen or an alkyl-(Ci -3 ) group, or an -C≡C-aryl group.
4. Use as claimed in claim 3, wherein said 5-HT 6 antagonist is a compound of the general formula (1 ): wherein: R 1 , R 4 , R 5 and R 6 represents hydrogen, R 2 and R 3 independently represent an alkyl(Ci -3 ) group, or R 2 and R 3 , together with the carbon atom marked 'b' form a cyclopentyl, or cyclohexyl ring, the dotted line between the carbon atoms marked 'b' and 'c' represents a single bond, R 7 represents an alkyl(Ci -3 ) group, R 8 represents a mono- or bicyclic aryl group, substituted with one or more halogen atoms.
5. Use as claimed in claim 3, wherein said 5-HT 6 antagonist is the compound:
6. Use as claimed in any of the claims 1-5, wherein said addiction is to substances of abuse, to medicines, or to addictive behaviors.
7. Use as claimed in claim 6, wherein said substances of abuse are selected from opiates, hallucinogens, inhalants, phencyclidine, amphetamines, cocaine, cannabis, nicotine, and alcohol.
8. Use as claimed in claim 6, wherein said substance of abuse is alcohol.
9. Use as claimed in claim 6, wherein said medicines are selected from sedatives, hypnotics and anxiolytics.
10. Use as claimed in claim 6, wherein said addictive behavior is gambling. |
USE OF 5-HT 6 ANTAGONISTS TO PREVENT RELAPSE INTO ADDICTION
TECHNICAL FIELD The invention relates to a novel use of 5-HT 6 antagonists and pharmaceutically acceptable salts thereof. These compounds are useful for the preparation of medicaments for preventing relapse into addiction or addictive behaviors.
BACKGROUND ART
Caused by a combination of genetic, drug-induced and environmental factors, addiction often is considered a chronic relapsing disease. Many times it is. But — fortunately — not always. 'Addiction', physical and/or psychical dependence, can be the result of the use of a variety of substances of abuse, such as opiates, hallucinogens, cocaine, cannabis, nicotine and alcohol, often termed 'drugs'. This sometimes causes confusion with 'real' drugs: medicines. It should be realized however, that the distinction between 'drugs' and 'drugs' is vague. When used in appropriate concentrations opiates, cocaine and cannabis certainly have clear therapeutic benefits. Mutatis mutandis: when used improperly, medicines, in particular certain sedatives, hypnotics and anxiolytics, certainly can become addictive. For many people, running, shopping, gambling, smoking, and drinking, are enjoyable pastimes. Yet, in particular the latter three, they often result in an addiction.
Save for discipline, there is no established therapy that can prevent addiction. Psychotherapy, as well as a number of different medicines, to a different extend can be successful to overcome an addiction. When a once addicted person no longer is compulsively seeking for the drug, does not crave for it anymore, neither experiences its withdrawal symptoms, the addiction is over, and that person can no longer considered to be a patient. This happens, but — unfortunately — not always. Once an addict is 'clean' the story ends, at least as far as pharmacological intervention is concerned. There are no drugs clinically proven to prevent relapse.
It is generally known that even after prolonged periods of drug abstinence, vulnerability to relapse is high. Relapse can be triggered by re-exposure to the drug (De Wit, 1996), by re- exposure to drug-associated stimuli {Childress, 1992) or by exposure to stressors (Sinha, 1999). Alcohol is one of the most widely and frequently abused addictive drugs in the world. In laboratory animals it is possible to study relapse to alcohol seeking in a so-called 'reinstatement model'. In this model, similar conditions as in the human situation are able to reinstate alcohol seeking after prolonged periods of withdrawal (Liu, 2002; Le, 1998). In the reinstatement model, De Vries et al. observed that the CB r receptor antagonist SR141716A (rimonabant) is able to selectively reduce relapse behavior induced by conditioned drug cues previously associated
with cocaine, heroin, nicotine and alcohol delivery (De Vries, 2001, 2003, 2005). This indicates a possible therapeutic role for CBrantagonists in preventing relapse into addiction to substances of abuse.
5-HT 6 antagonists have been suggested to be of value in treating drug and alcohol addiction(alcoholism), and in treating withdrawal from drug abuse, specifically: alcohol, cocaine, nicotine, and benzodiazepines (GS 2,341,549, US 2003/0220325, US 2005/020575, US
2005/020596, US6187805, WO 01/017963, WO 02/041889, WO 02/051832, WO 02/051837,
WO 02/060903, WO 2002/089811, WO 2002/098857, WO 2003/013510, WO 2003/053433,
WO 2003/066632, WO 2003/072548, WO 2003/072558, WO 2003/089438, WO 2003/099797, WO 2004/009600, WO 2005/066157 and WO 2006/081332). There are no indications that 5-
HT 6 antagonists are potential therapeutics for preventing relapse into addiction.
The goal of the present invention is to develop drugs for preventing relapse into addiction, drugs that have a mechanism of action different from antagonism of cannabinoid-CBi receptors.
DISCLOSURE
Surprisingly, 5-HT 6 antagonists were found active in an animal model predictive of relapse behavior in humans: stimulus induced reinstatement of extinguished self-administration behavior in rats (Shaham, 2003). After learning to consume alcohol 12 % (v/v) in a two-bottle paradigm, rats were trained to self-administer alcohol in the operant cage. When response-rates were stable, animals were withdrawn from alcohol for three weeks. Subsequently, the effect of 5-HT 6 antagonists on relapse was tested by re-exposing the animals to alcohol-related stimuli. It was found that these compounds were able to suppress cue-induced alcohol-seeking behavior. Using a very similar test protocol, 5-HT 6 antagonists were also found to suppress cue- induced nicotine-seeking behavior. Thus 5-HT 6 antagonists are useful for the preparation of medicaments for preventing relapse into addiction, in particular relapse into addiction to substances of abuse, including opiates, hallucinogens, inhalants, phencyclidine, amphetamines, cocaine, cannabis, nicotine, and alcohol, into relapse to addiction to certain medicines, including sedatives, hypnotics and anxiolytics, and into relapse to certain addictive behaviors, including gambling.
In a preferred embodiment, the invention embraces the use of the following 5-HT 6 antagonists: BGC-20-761 , BVT-74316, CNS-10000, CNS-11010, CNS-25100, diF-BAMPI, E- 6837, FMPD, GSK-215083, JCF-177, KR-055014, KR-055015, LY-483518(=SGS-518), MS- 245, PHA-565272A, PRX-07034, Ro 04-6790, Ro-4368554, Ro 63-0563, Ro 65-7199, Ro 65- 7674, Ro 66-0074, SAM-315, SB-2141 11 , SB-258510, SB-258585, SB-271046, SB-33171 1 , SB-357134, SB-399885, SB-699929, SB-737050A, SB-742457(=GSK-742457) and ST-1938.
BGC-20-761 BVT-74316 CNS-10000
CNS-11010 CNS25100 diF-BAMPI
E-6837 FMPD GSK-215083
JCF-177 KR-055014 KR-055015
PRX-07034 MS-245 PHA-565272
N
Ro-04-6790 RO-4368554 Ro-63-0563
Ro-65-7199 Ro-65-7674 RO-66-0074
SB-214111 SB-258510 SB-258585
SB-271046 SB-331711 SB-357134
SB-399885 SB-737050A ST-1938
The invention also relates to the use of 5-HT 6 antagonists described in the following patents and patent applications: EP 0 815 861 , DE 10053794, DE 10053795, DE 10053796, DE 10053799, DE 10053813, GB 2,341 ,549, US 2003/220325, US 2003/229069, US 2004/019064, US 2005/124613, US 2005/020575, US 2005/020596,US 2006/069094, US 2006/084676, US 5,990,105, US 6,133,287, US 6,187,805, US 6,191 ,141 , US 6,194,410, US 6,943,169, WO 1998/027058, WO 1998/027081 , WO 1999/002502, WO 1999/037623, WO 1999/042465, WO 1999/047516, WO 1999/065906, WO 2000/012073, WO 2000/012623, WO 2000/034242, WO 2000/037452, WO 2000/063203, WO 2001/012629, WO 2001/017963, WO 2001/032646, WO 2001/032660, WO 2001/038316, WO 2002/008178, WO 2002/008179, WO 2002/018358, WO 2002/032863, WO 2002/036115, WO 2002/041889, WO 2002/042293, WO 2001/017963, WO 2002/041889, WO 2002/051832, WO 2002/051837, WO 2002/060871 , WO 2002/060903, WO 2002/078693, WO 2002/089811 , WO 2002/092585, WO 2002/098857, WO 2002/100822, WO 2002/100842, WO 2003/013510, WO 2003/014097, WO 2003/035061 , WO 2003/039547, WO 2003/042175, WO 2003/053433, WO 2003/066056, WO 2003/066632, WO 2003/068220, WO 2003/068732, WO 2003/068740, WO 2003/068752, WO 2003/072198, WO 2003/072548, WO 2003/072558, WO 2003/080580, WO 2003/082877, WO 2003/089438, WO 2003/099792, WO 2003/099797, WO 2003/101962, WO 2003/101990, WO 2003/104193, WO 2004/000828, WO 2004/009548, WO 2004/009600, WO 2004/014895, WO 2004/026830, WO 2004/031181 , WO 2004/035047, WO 2004/041781 , WO 2004/041792, WO 2004/048328, WO 2004/050085,
WO 2004/078176, WO 2004/080969, WO 2004/098588, WO 2005/014578, WO 2005/016891 , WO 2005/021530, WO 2005/025576, WO 2005/026177, WO 2005/037834, WO 2005/051397, WO 2005/051398, WO 2005/051399, WO 2005/058858, WO 2005/066157, WO 2005/067933, WO 2005/095346, WO 2005/105776, WO 2005/113539, WO 2006/037481 , WO 2006/037482, WO 2006/038006, WO 2006/061 126, WO 2006/062481 , WO 2006/066745, WO 2006/066746, WO 2006/066748, WO 2006/066756, WO 2006/066790, WO 2006/081332, WO 2006/091703, WO 2006/114402 and WO 2006/134150.
Other embodiments relate to the use of one or more compounds of formula (1 ):
or a tautomer, stereoisomer, N-oxide, isotopically-labelled analogue, or a pharmacologically acceptable salt, hydrate or solvate of any of the foregoing, wherein:
Ri represents hydrogen, an unsubstituted alkyl(Ci -4 ) group or an alkyl(Ci -4 ) group substituted with one or more halogen atoms,
R 2 and R 3 independently represent hydrogen, an unsubstituted alkyl(Ci -4 ) group or an alkyl(Ci -4 ) group substituted with one or more halogen atoms, or,
R 1 and R 2 , together with the carbon atoms marked 'a' and 'b' form a C 5-8 -cycloalkyl ring, or R 2 and R 3 , together with the carbon atom marked 'b' form a C 3-8 -cycloalkyl ring,
the dotted line between the carbon atoms marked 'b' and 'c' represents either a single or a double bond,
- R 4 and R 5 independently represent hydrogen, an unsubstituted alkyl(Ci -4 ) group or an alkyl(Ci -4 ) group substituted with one or more halogen atoms, or, R 3 and R 4 , together with the carbon atoms marked 'b' and 'c' form a Ca-β-cycloalkyl ring, or R 4 and R 5 , together with the carbon atom marked 'c' form a C 3 . 8 -cycloalkyl ring,
R 6 and R 7 independently represent hydrogen, an alkyl(Ci -4 ) group, an alkyl(Ci -4 ) group substituted with one or more halogen atoms, a (Ci -3 )alkoxy group, a dialkyl(Ci -3 )amino- alkyl(Ci -3 ) group, an optionally substituted aryl group, an optionally substituted C 5-8 -cyclo- alkyl group or an optionally substituted Cs-β-heterocycloalkyl group, or Re and R 7 , together with the nitrogen atom to which they are attached, form an optionally substituted C 5-8 -heterocycloalkyl group,
R 8 represents an optionally substituted aryl group, an -CR 9 =CRio-aryl group wherein R 9 and Rio independently represent hydrogen or an alkyl-(Ci -3 ) group, or an -C≡C-aryl group.
The invention relates to the use of racemates, mixtures of diastereomers as well as the individual stereoisomers of the compounds having formula (1 ). The invention also relates to the use of the E isomer, Z isomer and E/Z mixtures of compounds having formula (1 ).
Compounds of formula (1 ), their synthesis, physicochemical properties, affinity for 5-HT 6 receptors (pK-values), and functional activity as antagonists (pA 2 values) on 5-HT 6 receptors, were disclosed in PCT/EP2007/059944, filed on September 20, 2007, the disclosure of which is incorporated by reference herein.
Further embodiments relate to the use of one or more compounds of formula (1 ) or a tautomer, stereoisomer, N-oxide, isotopically-labelled analogue, or a pharmacologically acceptable salt, hydrate or solvate of any of the foregoing, wherein:
- Ri represents hydrogen or R 1 and R 2 , together with the carbon atoms marked 'a' and 'b' form a cyclohexyl ring,
R 2 and R 3 independently represent hydrogen or an alkyl(Ci -3 ) group, or R 2 and R 3 , together with the carbon atom marked 'b' form a cyclopentyl or cyclohexyl ring,
the dotted line between the carbon atoms marked 'b' and 'c' represents either a single or a double bond,
R 4 and R 5 independently represent hydrogen, an alkyl(Ci -3 ) group, or R 3 and R 4 , together with the carbon atoms marked 'b' and 'c' form a C 3-8 -cycloalkyl ring,
R 6 and R 7 independently represent hydrogen, an alkyl(d -3 ) group, an alkyl(Ci -4 ) group substituted with one or more halogen atoms, a methoxy group, a cyclohexyl group, a benzyl group or a 4-piperidinyl group,
- R 8 represents optionally substituted aryl group, an -CR 9 =CRio-aryl group wherein R 9 and Rio independently represent hydrogen or an alkyl(d -3 ) group, or an -C≡C-aryl group.
In another embodiment the invention relates to the use of compounds of formula (1 ) or a tautomer, stereoisomer, N-oxide, isotopically-labelled analogue, or a pharmacologically acceptable salt, hydrate or solvate of any of the foregoing, wherein: R 1 , R 4 , R 5 and Re represents hydrogen, R 2 and R 3 independently represent an alkyl(Ci -3 ) group, or R 2 and R 3 , together with the carbon atom marked 'b' form a cyclopentyl, or cyclohexyl ring, the dotted line between the carbon atoms marked 'b' and 'c' represents a single bond, R 7 represents an alkyl(Ci -3 ) group, R 8 represents a mono- or bicyclic aryl group, substituted with one or more halogen atoms.
Most preferred is the use of the compound with formula (1 ), disclosed as 'compound 33' in PCT/EP2007/059944, having the following structure:
Other embodiments of the invention include, but are not limited to:
methods for preventing relapse into addiction to substances of abuse, to medicines, or to addictive behaviors;
methods for preventing relapse into addiction to substances of abuse, selected from opiates, hallucinogens, inhalants, phencyclidine, amphetamines, cocaine, cannabis, nicotine, and alcohol;
methods for preventing relapse into addiction to alcohol;
methods for preventing relapse into addiction to nicotine;
methods for preventing relapse into addiction to cannabis;
methods for preventing relapse into addiction to opiates;
methods for preventing relapse into addiction to cocaine;
methods for preventing relapse into addiction to medicines selected from sedatives, hypnotics and anxiolytics.
methods for preventing relapse into addiction to gambling.
DEFINITIONS
Within the context of this description, the term '5-HT 6 receptor antagonist' refers to a compound displaying this activity — measured by unambiguous and well accepted pharmacological assays, including those described in PCT/EP2007/059944 — without displaying substantial cross-reactivity towards another receptor. In one embodiment, a compound of the present invention is at least 10 times more potent as 5-HT 6 receptor antagonist than as agonist or antagonist on any other receptor. Preferred are compounds with a 100-fold selectivity, most preferred are compounds with a selectivity of a factor 1 ,000 or higher.
General terms used in the description of compounds herein disclosed bear their usual meanings. The term alkyl as used herein denotes a univalent saturated, branched or straight, hydrocarbon chain. Unless otherwise stated, such chains can contain from 1 to 18 carbon atoms. Representative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, te/f-butyl, pentyl, isopentyl, neopentyl, te/f-pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, and the like. When qualified 'lower', the alkyl group will contain from 1 to 6 carbon atoms. The same carbon content applies to the parent term 'alkane', and to derivative terms such as 'alkoxy'. The carbon content of various hydrocarbon containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix C x
-C y
defines the number of carbon atoms present from the integer "x" to the integer "y" inclusive.
such as ethynyl, propargyl, 1-butynyl, 2-butynyl, etc., and for example represent (C 2-4 )alkynyl. Unless otherwise stated, alkenyl'and 'alkynyl chains can contain from 1 to 18 carbon atoms.
The term 'acyl' means alkyl(d -3 ) carbonyl, arylcarbonyl or aryl-alkyl(Ci -3 )carbonyl. 'Aryl' embraces monocyclic or fused bicyclic aromatic or hetero-aromatic groups, including but not limited to furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, imidazo[2,1-b][1 ,3]thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,3,5-triazinyl, phenyl, indazolyl, indolyl, indolizinyl, isoindolyl, benzo[b]furanyl, 1 ,2,3,4-tetrahydro-naphtyl, 1 ,2,3,4-tetrahydroisoquinolinyl, indanyl, indenyl, benzo[b]thienyl, 2,3-dihydro-1 ,4-benzodioxin-5- yl, benzimidazolyl, benzothiazolyl, benzo[1 ,2,5]thia-diazolyl, purinyl, quinolinyl, isoquinolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, naphthyl, pteridinyl or azulenyl. 'Halo' or 'Halogen' means chloro, fluoro, bromo or iodo; 'hetero' as in 'heteroalkyl, heteroaromatic' etc. means containing one or more N, O or S atoms, 'heteroalkyl' includes alkyl groups with heteroatoms in any position, thus including N-bound O-bound or S-bound alkyl groups.
The term "substituted" means that the specified group or moiety bears one or more substituents. Where any group may carry multiple substituents, and a variety of possible substituents is provided, the substituents are independently selected, and need not to be the same. The term "unsubstituted" means that the specified group bears no substituents. With reference to substituents, the term "independently" means that when more than one of such substituents are possible, they may be the same or different from each other. 'Optionally substituted' means that a group may or may not be further substituted by one or more groups selected from Ci -8 alkyl, Ci -8 alkenyl, Ci -8 alkynyl, aryl, fluoro, chloro, bromo, hydroxyl, Ci -8 alkyloxy, Ci -8 alkenyloxy, aryloxy, acyloxy, amino, Ci -8 alkylamino, dialkyl(Ci -8 )- amino, arylamino, thio, Ci -8 alkylthio, arylthio, cyano, oxo, nitro, acyl, amido, Ci -8 alkylamido, dialkyl(Ci -8 )amido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6-membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulphur. Optional substituents may themselves bear additional optional substituents. Preferred optional substituents include Ci -3 alkyl such as for example methyl, ethyl, and trifluoromethyl, fluoro, chloro, bromo, hydroxyl, Ci -3 alkyloxy such as for example methoxy, ethoxy and trifluoromethoxy, and amino. 'C 3-8 -cycloalkyl' means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopheptyl or cyclooctyl; 'Cs-β heterocycloalkyl' refers to heteroatom containing rings including but not limited to piperidinyl, morpholinyl, azepanyl, pyrrolidinyl, thiomorpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl;
The terms "oxy", "thio" and "carbo" as used herein as part of another group respectively refer to an oxygen atom, a sulphur atom and a carbonyl (C=O) group, serving as linker between two groups, such as for instance hydroxyl, oxyalkyl, thioalkyl, carboxyalkyl, etc. The term "amino" as used herein alone, or as part of another group, refers to a nitrogen atom
that may be either terminal, or a linker between two other groups, wherein the group may be a primary, secondary or tertiary (two hydrogen atoms bonded to the nitrogen atom, one hydrogen atom bonded to the nitrogen atom and no hydrogen atoms bonded to the nitrogen atom, respectively) amine. The terms "sulfinyl" and "sulfonyl" as used herein as part of another group respectively refer to an -SO- or an - SO 2 - group.
To provide a more concise description, the terms 'compound' or 'compounds' include tautomers, stereoisomers, N-oxides, isotopically-labelled analogues, or pharmacologically acceptable salts, hydrates or solvates, also when not explicitly mentioned.
N-oxides of the compounds mentioned above belong to the invention. Tertiary amines may or may not give rise to N-oxide metabolites. The extent to what N-oxidation takes place varies from trace amounts to a near quantitative conversion. N-oxides may be more active than their corresponding tertiary amines, or less active. Whilst N-oxides can easily be reduced to their corresponding tertiary amines by chemical means, in the human body this happens to varying degrees. Some N-oxides undergo nearly quantitative reductive conversion to the corresponding tertiary amines, in other cases conversion is a mere trace reaction, or even completely absent (Bickel, 1969).
Any compound metabolized in vivo to provide the bioactive agent (i.e., the compound of formula (1 )) is a prodrug within the scope and spirit of the application. Prodrugs are therapeutic agents, inactive per se but transformed into one or more active metabolites. Thus, in the methods of treatment of the present invention, the terms "administering" or "use in the treatment of shall encompass treating the various disorders described with the compound specifically disclosed, or with a compound that not specifically disclosed, but that converts to the specified compound in vivo after administration to the patient. Prodrugs are bioreversible derivatives of drug molecules used to overcome some barriers to the utility of the parent drug molecule. These barriers include, but are not limited to, solubility, permeability, stability, presystemic metabolism and targeting limitations {Bundgaard, 1985; King, 1994; Stella, 2004; Ettmayer, 2004; Jarvinen, 2005). Prodrugs, i.e. compounds that when administered to humans or mammals by any known route, are metabolised to compounds having formula (1 ), belong to the invention. In particular this relates to compounds with primary or secondary amino or hydroxy groups. Such compounds can be reacted with organic acids to yield compounds having formula (1 ) wherein an additional group is present that is easily removed after administration, for instance, but not limited to amidine, enamine, a Mannich base, a hydroxyl-methylene derivative, an O- (acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone.
'Solvates' are generally a crystal form that contains either stoichiometric or non- stoichiometric amounts of a solvent. Often, during the process of crystallization some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. When the solvate is water, 'hydrates' may be formed. The
compound of formula (1 ) and pharmaceutically acceptable salts thereof may exist in the form of a hydrate or a solvate, and such a hydrate and solvate are also encompassed in the present invention. Examples thereof include % hydrate, dihydrochloride dihydrate, and the like. 'Amorphous' forms are noncrystalline materials with no long range order, and generally do not give a distinctive powder X-ray diffraction pattern. Crystal forms in general have been described by Byrn (1995) and Martin (1995)
To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about". It is understood that whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value.
The terms "selective" and "selectivity" refer to compounds that display reactivity towards a particular receptor (e.g. a 5-HT 6 receptor) without displaying substantial cross- reactivity towards another receptor. Thus, for example, selective compounds of the present invention may display reactivity towards 5-HT 6 receptors without displaying substantial cross- reactivity towards other 5-HT receptors. In one embodiment, a compound of the present invention has at least about 10fold selectivity to the 5-HT 6 receptor, at least about 50fold selectivity to the 5-HT 6 receptor, at least about IOOfold selectivity to the 5-HT 6 receptor, at least about 250fold selectivity to the 5-HT 6 receptor, or at least about 500fold selectivity to the desired target.
Throughout the description and the claims of this specification the word "comprise" and variations of the word, such as "comprising" and "comprises" is not intended to exclude other additives, components, integers or steps. While it may be possible for the compounds of formula (1 ) to be administered as the raw chemical, it is preferable to present them as a 'pharmaceutical composition'. According to a further aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula (1 ), at least one pharmaceutically acceptable salt or solvate thereof, or a mixture of any of the foregoing, together with one or more pharmaceutically acceptable carriers thereof, and optionally one or more other therapeutic ingredients. The carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The term "composition" as used herein encompasses a product comprising specified ingredients in predetermined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts. In relation to pharmaceutical compositions, this term encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation or
aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. The pharmaceutical composition includes enough of the active object compound to produce the desired effect upon the progress or condition of diseases. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Dose. The affinity of the compounds of the invention for 5-HT 6 receptors was determined as described below. From the binding affinity measured for a given compound of formula (1 ), one can estimate a theoretical lowest effective dose. At a concentration of the compound equal to twice the measured K-value, nearly 100% of the 5-HT 6 receptors likely will be occupied by the compound. Converting that concentration to mg of compound per kg of patient yields a theoretical lowest effective dose, assuming ideal bioavailability. Pharmacokinetic, pharmacodynamic, and other considerations may alter the dose actually administered to a higher or lower value. The typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient, and may be determined by a physician. In general, total daily dose administration to a patient in single or individual doses, may be in amounts, for example, from 0.001 to 10 mg/kg body weight daily, and more usually from 0.01 to 1 ,000 mg per day, of total active ingredients. Such dosages will be administered to a patient in need of treatment from one to three times each day, or as often as needed for efficacy, and for periods of at least two months, more typically for at least six months, or chronically.
The term "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent to treat a condition treatable by administrating a composition of the invention. That amount is the amount sufficient to exhibit a detectable therapeutic or ameliorative response in a tissue system, animal or human. The effect may include, for example, treating the conditions listed herein. The precise effective amount for a subject will depend upon the subject's size and health, the nature and extent of the condition being treated, recommendations of the treating physician (researcher, veterinarian, medical doctor or other clinician), and the therapeutics, or combination of therapeutics, selected for administration. Thus, it is not useful to specify an exact effective amount in advance. The term "pharmaceutically acceptable salt" refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals
without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. They can be prepared in situ when finally isolating and purifying the compounds of the invention, or separately by reacting them with pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids (Berge, 1977). The 'free base' form may be regenerated by contacting the salt with a base or acid, and isolating the parent compound in the conventional matter. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention. 'Complex' refers to a complex of the compound of the invention, e.g. formula (1 ), complexed with a metal ion, where at least one metal atom is chelated or sequestered. Complexes are prepared by methods well known in the art (Dwyer, 1964).
The term "treatment" as used herein refers to any treatment of a mammalian, for example human condition or disease, and includes: (1 ) inhibiting the disease or condition, i.e., arresting its development, (2) relieving the disease or condition, i.e., causing the condition to regress, or (3) stopping the symptoms of the disease. The term 'inhibit' includes its generally accepted meaning which includes prohibiting, preventing, restraining, alleviating, ameliorating, and slowing, stopping or reversing progression, severity, or a resultant symptom. As such, the present method includes both medical therapeutic and/or prophylactic administration, as appropriate. As used herein, the term "medical therapy" intendeds to include prophylactic, diagnostic and therapeutic regimens carried out in vivo or ex vivo on humans or other mammals. 'Mammals' include animals of economic importance such as bovine, ovine, and porcine animals, especially those that produce meat, as well as domestic animals, sports animals, zoo animals, and humans, the latter being preferred. The term "subject" as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
EXAMPLES
STIMULUS INDUCED REINSTATEMENT OF EXTINGUISHED SELF-ADMINISTRATION OF ALCOHOL
Animals: 64 male Wistar rats, weighing 280 - 300 g at arrival (Harlan, the Netherlands) were used for testing compound 33. The animals were housed individually in a temperature- (T = 22 ± 2 0 C) and humidity (rel% = 60 ± 5 %) controlled room on a reversed 12h light-dark cycle (lights off at 7:00 AM) with water available ad libitum. The animals were on a diet of 18 gr chow per
animal per day. The experiment started after one week of acclimatization and lasted 12 - 14 weeks.
Drug Self-administration: All training and testing was conducted in 16 operant chambers (30.5 x 24.1 x 29.2 cm) surrounded by sound attenuating ventilated cubicles (Med Associates, Georgia, VT). The chambers were fitted with a grid floor, a red dim house light and opposite the house light an intelligence panel. In the intelligence panel there were two nose-poke holes (0 2.5 cm) located 5.5 cm above the grid floor and 16 cm separated from each other. A red dim stimulus light was located 12 cm above both nose-poke holes. Between the two nose-poke holes, a receptacle was located, in which the alcohol was delivered. High above the receptacle was a sonalert tone module. One nose-poke hole served as active- and the other as inactive hole. Pokes made in the active hole resulted in the delivery of an alcohol drop (0.19 ml; 12 %) in the receptacle. The alcohol drop was delivered by an infusion pump (PHM-100, MedAssociates, Georgia, VT) in 4.2 seconds. During alcohol delivery, the active nose-poke hole was illuminated and a tone (± 65 dB) was presented by the sonalert tone module for 2 seconds. The receptacle was illuminated for 5 seconds (discrete cues). The stimulus light switched off for 15 seconds (discriminative cue). In this 15 second time-out period, nose-poking was without consequences. During all sessions, responses in the inactive hole were monitored, but without consequences.
Acquisition & withdrawal: The animals were trained on a Fixed Ratio 1 schedule (FR1- schedule) for 10 daily sessions (every active response resulted in a reward; sessions of 60 min). Subsequently, animals were trained via an FR2-schedule up to an FR4-schedule (every 2 nd and 4 th active response respectively resulted in a reward; daily sessions of 60 min). Animals were selected for further testing if they consumed alcohol doses (in the FR4-schedule) above the in the literature described pharmacological effective dose of 0.3 g/kg/hr (Linseman, 1987). Subsequently, when response behavior on the FR4-schedule was stable, there was a 3 week period of withdrawal in the homecage.
Test for reinstatement: After the withdrawal period, each animal was tested twice for cue induced reinstatement with a week of further extinction training and wash-out in between.
Animals were randomly distributed over the different experimental groups and never received the same treatment twice. On testdays, the animals were placed in the operant cage for three or four hours (testday 1 : 4 hr; testday 2: 3 hr) in absence of alcohol and alcohol related stimuli
(discrete and discriminative cues) to extinguish response behavior. One hour before the end of this extinction session, the animal was removed from the operant cage and treated with a 5-HT 6 antagonist. After drug administration the animals was placed back into the operant chamber, where the session continued. When the last hour had passed, the cue-induced relapse test
session started (duration: 45 min). During this test, the experimental conditions were similar to the conditions during training on an FR4-schedule, with the exceptions that 1) at the beginning of the session, a 12 % alcohol drop of 0.20 ml was available (delivered in the receptacle by the experimenter at the begin of the test session) and 2) after every 4 th response, only cues were presented (no alcohol was delivered). Tests were operated and raw data was saved by the MED-PC IV program (Tatham, 1989)
Drugs: Alcohol 12% (v/v) was made from alcohol 96 % and diluted with tap water. Compound 33 was suspended in 5% Tween 80, 0.25% methylcellulose, 5% PEG 400 and H 2 O HPLC (65% of end volume). Ethanol was added and evaporated under N 2 -gas. The pH was adjusted to 5.8. In the range: 0, 3, 10, and 30 mg/kg, compound 33 was administered intraperitoneally, 15 minutes before testing. The injection volume was 2 ml/kg.
Statistical analysis: For analysis of the cue-induced reinstatement data, the total number of nose-pokes (responses) in the active and inactive hole were subjected to a one-way ANOVA, followed by a Fisher's LSD Multiple-Comparison Test, with the different doses of 5-HT 6 antagonist as between factor. Because each animal was tested twice for cue-induced reinstatement and cue-reactivity is usually lower during the second test, test day was used as a covariate.
STIMULUS INDUCED REINSTATEMENT OF EXTINGUISHED SELF-ADMINISTRATION OF NICOTINE
Animals: 32 male Wistar rats, weighing 280 - 300 g at arrival (Harlan, the Netherlands) were used for testing compound 33. The animals were housed individually in a temperature- (T = 22 ± 2 0 C) and humidity (rel% = 60 ± 5 %) controlled room on a reversed 12h light-dark cycle (lights off at 7:00 AM) with water and food available ad libitum. The experiment started after one week of acclimatization and lasted 12 - 14 weeks.
Surgery: after a week of acclimatization, intravenous silicon catheters are implanted in the right jugular vein under isoflurane anesthesia as described previously in detail (De Vries, 1999).
Drug Self-administration: All training and testing was conducted in 16 operant chambers (30.5 x 24.1 x 29.2 cm) surrounded by sound attenuating ventilated cubicles (Med Associates, Georgia, VT). The chambers were fitted with a grid floor, a red dim house light and opposite the house light an intelligence panel. In the intelligence panel there were two nose-poke holes (0 2.5 cm) located 5.5 cm above the grid floor and 16 cm separated from each other. A red dim
stimulus light was located 12 cm above both nose-poke holes. A tone module was located at the top of the center of the intelligence panel. During self-administration, animals were connected to an infusion pump (PHM-100, Med Associates, Georgia, V.T.) by a swivel to receive intravenous infusions of nicotine (40 μg/kg/inf). One nose poke hole served as active- and the other as inactive hole. Pokes made in the active hole resulted in the delivery of a nicotine infusion for 2 seconds. During this infusion, the active nose poke hole was illuminated (yellow light) and an audio stimulus was presented (tone of 2900 Hz and 65 dB for 2 seconds) (discrete cues). From the moment of nicotine delivery, the stimulus light switched off for 15 seconds (discriminative cue). In this time-out period, nosepoking was without consequences. During all sessions, responses in the inactive hole were monitored, but without consequences.
Acquisition, withdrawal and reinstatement: Behavioral training started 5 - 7 days after surgery. The animals were trained on a Fixed Ratio 1 schedule (FR1 -schedule) for 10 daily sessions (every active nose poke resulted in a nicotine infusion and associated cues; daily sessions of 60 min). Subsequently, animals were trained on an FR2-schedule for three days and then moved up to an FR3-schedule (respectively, every 2 nd and 3 rd active nose poke resulted in a reward and associated cues; daily sessions of 60 min). When response behavior was stable, animals were selected for further testing if they earned at least 5 rewards during the last three sessions of the FR3 schedule and the reward delivery was equal distributed over the session. Subsequently, responding for nicotine was extinguished. In this extinction phase (11 daily sessions of 60 min), the animals were placed in the operant chambers, but the nicotine and nicotine related stimuli (discrete and discriminative cues) were not available. Finally, the animals were tested for cue-induced reinstatement. During this test (duration of 30 minutes), the experimental conditions were similar to the conditions during training on an FR3-schedule, with the exception that no nicotine was available and the animals were not connected to the swivel. Tests for cue-induced reinstatement were conducted twice; between these two test days, there was a week of further extinction training (wash-out period). During cue-induced reinstatement, effects of 5-HT 6 antagonists were studied on output measurements.
Drugs: Nicotine for self-administration: (-) nicotine hydrogen tartrate salt (Sigma, St Louis, MO) was dissolved in sterile saline. The pH of the solution was adjusted to +/- 7.4 with diluted NaOH. Nicotine dose was expressed as free base weight. Compound 33 was suspended in 5% of end volume Tween 80. Ethanol was added and evaporated under N 2 -gas for 30 minutes. Subsequently, 5% of the end volume PEG 400, 25% of the end volume Methylcellulose 1% and 55% of the end volume H 2 O HPLC was added which resulted in a homogenous suspension with a pH of 3.76. After the pH was adjusted to 5.5, 10% of end volume H 2 O HPLC was added. In the range: 0, 3, 10, and 30 mg/kg, compound 33 was administered intraperitoneal^, 15 minutes before testing. The injection volume was 2 ml/kg.
Statistical analysis: For analysis of the cue-induced reinstatement data, the total number of nose-pokes (responses) in the active and inactive hole were subjected to a one-way ANOVA, followed by a Fisher's LSD Multiple-Comparison Test, with the different doses of 5-HT 6 antagonist as between factor. Because each animal was tested twice for cue-induced reinstatement and cue-reactivity is usually lower during the second test, test day was used as a covariate.
PHARMACOLOGICAL TESTRESULTS
Cue-induced relapse of alcohol seeking in the rat: compound 33
In the operant cage, all animals readily acquired alcohol self-administration behavior and consumed their rewards. They made a clear distinction between the active and inactive hole. Mean alcohol intake amounted to 0.50 g/kg/hr. During test day's extinction session, responding in the previously active hole extinguished in all of the animals.
A one-way ANOVA followed by a Fisher's LSD Multiple-Comparison Test revealed that during testing for cue induced alcohol seeking, the amount of active nose-pokes of animals treated with 30 mg/kg compound 33, was significantly lower than animals treated with placebo. (*p < 0.005). There was no significant difference in inactive nose-pokes between placebo and the tested dosages of compound 33.
Cue-induced relapse of alcohol seeking in the rat: SB-271046
In the operant cage, all animals readily acquired alcohol self-administration behavior and consumed their rewards. They made a clear distinction between the active and inactive hole. Mean alcohol intake amounted to 0.50 g/kg/hr. During test day's extinction session, responding in the previously active hole extinguished in all of the animals.
.HCI
SB-271046
A one-way ANOVA followed by a Fisher's LSD Multiple-Comparison Test revealed that during testing for cue induced alcohol seeking, the amount of active nose-pokes of animals treated with 10 mg/kg SB-271046, was significantly lower than animals treated with placebo ( * p < 0.05). For the dose of 20 mg/kg SB-271046 the amount of active nose-pokes was significantly lower than placebo at the level of ** p < 0.005. There was no significant difference in inactive nose-pokes between placebo and the tested dosages of SB-271046.
Cue-induced relapse of nicotine seeking in the rat.
In the operant cage, 27 out of 32 rats met the criterion for nicotine self-administration, and were selected for further testing. The selected animals readily acquired nicotine self-administration behavior, and showed a clear preference for the active nose-poke hole. During extinction sessions, responding in the previously active hole were extinguished in all of the animals.
A one-way ANOVA followed by a Fisher's LSD Multiple-Comparison Test revealed that during testing for cue induced nicotine seeking, the amount of active nose-pokes of animals treated with 30 mg/kg compound 33, was significantly lower than animals treated with placebo. (*p < 0.05). There was no significant difference in inactive nose-pokes between placebo and the tested dosages of compound 33.
PHARMACEUTICAL PREPARATIONS
For clinical use, 5-HT 6 antagonists are formulated into pharmaceutical compositions that are important and novel embodiments of the invention because they contain the compounds, more particularly specific compounds disclosed herein. Types of pharmaceutical compositions that may be used include, but are not limited to, tablets, chewable tablets, capsules (including microcapsules), solutions, parenteral solutions, ointments (creams and gels), suppositories, suspensions, and other types disclosed herein, or are apparent to a person skilled in the art from the specification and general knowledge in the art. The active ingredient for instance, may also be in the form of an inclusion complex in cyclodextrins, their ethers or their esters. The compositions are used for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or other ways to administer.
The pharmaceutical formulation contains at least one 5-HT 6 antagonist in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier. The total amount of active ingredients suitably is in the range of from about 0.1% (w/w) to about 95% (w/w) of the formulation, suitably from 0.5% to 50% (w/w) and preferably from 1 % to 25% (w/w).
5-HT 6 antagonists can be brought into forms suitable for administration by means of usual processes using auxiliary substances such as liquid or solid, powdered ingredients, such as the pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances. Frequently used auxiliary substances include magnesium carbonate, titanium dioxide, lactose, saccharose, sorbitol, mannitol and other sugars or sugar alcohols, talc, lactoprotein, gelatin, starch, amylopectin, cellulose and its derivatives, animal and vegetable oils such as fish liver oil, sunflower, groundnut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture may then be processed into granules or pressed into tablets. A tablet is prepared using the ingredients below:
Ingredient Quantity (mg/tablet)
COMPOUND No. 33 10
Cellulose, microcrystalline 200
Silicon dioxide, fumed 10
Stearic acid 10
Total 230
The components are blended and compressed to form tablets each weighing 230 mg.
The active ingredients may be separately premixed with the other non-active ingredients, before being mixed to form a formulation. The active ingredients may also be mixed with each other, before being mixed with the non-active ingredients to form a formulation.
Soft gelatin capsules may be prepared with capsules containing a mixture of the active ingredients of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules. Hard gelatin capsules may contain granules of the active ingredients. Hard gelatin capsules may also contain the active ingredients together with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin. Dosage units for rectal administration may be prepared (i) in the form of suppositories that contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule that contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatin rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
Liquid preparations may be prepared in the form of syrups, elixirs, concentrated drops or suspensions, e.g. solutions or suspensions containing the active ingredients and the remainder consisting, for example, of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain
coloring agents, flavoring agents, preservatives, saccharine and carboxymethyl cellulose or other thickening agents. Liquid preparations may also be prepared in the form of a dry powder, reconstituted with a suitable solvent prior to use. Solutions for parenteral administration may be prepared as a solution of a formulation of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and/or buffering ingredients. Solutions for parenteral administration may also be prepared as a dry preparation, reconstituted with a suitable solvent before use.
Also provided according to the present invention are formulations and 'kits of parts' comprising one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the invention, for use in medical therapy. Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals products, which notice reflects approval by the agency of manufacture, use, or sale for human or veterinary administration. The use of formulations of the present invention in the manufacture of medicaments for preventing relapse into addiction, and methods of medical treatment or comprising the administration of a therapeutically effective total amount of at least one 5-HT 6 antagonist, either as such or, in the case of prodrugs, after administration, to a patient.
By way of example and not of limitation, several pharmaceutical compositions are given, comprising preferred active compounds for systemic use or topical application. Other compounds of the invention or combinations thereof, may be used in place of (or in addition to) said compounds. The concentration of the active ingredient may be varied over a wide range as discussed herein. The amounts and types of ingredients that may be included are well known in the art.
BIBLIOGRAPHY
To the extend in which the following references are useful to one skilled in the art, or to more fully describe this invention, they are incorporated herein by reference. Neither these, nor any other documents or quotes cited herein, nor citations to any references, are admitted to be prior art documents or citations.
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