WO2008087123A2 - Utilisation d'antagonistes de 5-ht6 pour empêcher une récidive d'addiction - Google Patents

Utilisation d'antagonistes de 5-ht6 pour empêcher une récidive d'addiction Download PDF

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WO2008087123A2
WO2008087123A2 PCT/EP2008/050360 EP2008050360W WO2008087123A2 WO 2008087123 A2 WO2008087123 A2 WO 2008087123A2 EP 2008050360 W EP2008050360 W EP 2008050360W WO 2008087123 A2 WO2008087123 A2 WO 2008087123A2
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group
alkyl
addiction
compound
alcohol
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PCT/EP2008/050360
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WO2008087123A3 (fr
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Natasja M.W.J. De Bruin
Arnold Van Loevezijn
Johan Wijnen
Arnoldus H.J. Herremans
Cornelis G. Kruse
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Solvay Pharmaceuticals B.V.
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Publication of WO2008087123A2 publication Critical patent/WO2008087123A2/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence

Definitions

  • 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.
  • CB r receptor antagonist SR141716A rimonabant
  • SR141716A rimonabant
  • 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
  • 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.
  • 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.
  • 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.
  • 5-HT 6 antagonists BGC-20-761 , BVT-74316, CNS-10000, C
  • 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,
  • 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- ⁇ -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- ⁇ -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,
  • 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 ).
  • - 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,
  • 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,
  • 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.
  • R 1 , R 4 , R 5 and Re represents hydrogen
  • R 2 and R 3 independently represent an alkyl(Ci -3 ) group,
  • '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.
  • 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.
  • alkyl denotes a univalent saturated, branched or straight, hydrocarbon chain. Unless otherwise stated, such chains can contain from 1 to 18 carbon atoms.
  • 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.
  • the alkyl group 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.
  • 'alkyl(Ci -4 )' means 'methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl or 2-methyl-n-propyl'.
  • the term 'alkenyl' denotes straight or branched hydrocarbon radicals having one or more carbon-carbon double bonds, such as vinyl, allyl, butenyl, etc., and for example represents (C 2-4 )alkenyl.
  • alkenyl'and 'alkynyl chains can contain from 1 to 18 carbon atoms.
  • 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
  • '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.
  • 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.
  • unsubstituted means that the specified group bears no substituents.
  • 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.
  • 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- ⁇ heterocycloalkyl' refers to heteroatom containing rings including but not limited to piperidinyl, morpholinyl, azepanyl, pyrrolidinyl, thiomorpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl;
  • amino 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.
  • sulfinyl and sulfonyl as used herein as part of another group respectively refer to an -SO- or an - SO 2 - group.
  • 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 )
  • Prodrugs are therapeutic agents, inactive per se but transformed into one or more active metabolites.
  • 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.
  • 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.
  • 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)
  • 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.
  • selective compounds of the present invention may display reactivity towards 5-HT 6 receptors without displaying substantial cross- reactivity towards other 5-HT receptors.
  • 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.
  • 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.
  • composition 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.
  • compositions 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.
  • 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.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • 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.
  • 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.
  • 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.
  • terapéuticaally effective amount 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.
  • 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).
  • treatment 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.
  • the present method includes both medical therapeutic and/or prophylactic administration, as appropriate.
  • 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.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • Animals 64 male Wistar rats, weighing 280 - 300 g at arrival (Harlan, the Netherlands) were used for testing compound 33.
  • 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.
  • PPM-100 MedAssociates, Georgia, VT
  • 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.
  • responses in the inactive hole were monitored, but without consequences.
  • 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.
  • testday 1 4 hr
  • testday 2 3 hr
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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:
  • 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.
  • 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.
  • 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.
  • 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.
  • compositions 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.
  • 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.
  • Childress, A. R., Ehrman, R., Rohsenow, D. J., Robbins, S. J. and O'Brien, C. P., "Classically conditioned factors in drug dependence" in: Lowinson, J. W., Luiz, P., Millman, R. B. and
  • Ettmayer P. et al., "Lessons learned from marketed and investigational prodrugs", J.Med.Chem., 47, 2393-2404, 2004.

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention porte sur une nouvelle utilisation de composés et de sels pharmaceutiquement acceptables de ceux-ci, qui sont des antagonistes de 5-HT6. Ces composés sont utiles pour la préparation de médicaments de prévention d'une récidive d'addiction, en particulier une récidive d'addiction à l'usage de substances toxiques (opiacés, hallucinogènes, produits pour inhalation, phencyclidine, amphétamines, cocaïne, cannabis, nicotine et alcool) ainsi qu'à certains médicaments (sédatifs, hypnotiques et anxiolytiques), et de prévention d'une rechute dans certains comportements addictifs comme le jeu.
PCT/EP2008/050360 2007-01-16 2008-01-15 Utilisation d'antagonistes de 5-ht6 pour empêcher une récidive d'addiction WO2008087123A2 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8076326B2 (en) 2009-04-30 2011-12-13 Abbott Gmbh & Co. Kg N-phenyl- (piperazinyl or homopiperazinyl)-benzenesulfonamide or benzenesulfonyl-phenl-(piperazine or homopiperazine) compounds suitable for treating disorders that respond to modulation of the serotonin 5-HT6 receptor
US8183237B2 (en) 2009-04-30 2012-05-22 Abbott Laboratories Benzenesulfonanilide compounds suitable for treating disorders that respond to modulation of the serotonin 5-HT6 receptor
US8343959B2 (en) 2009-04-30 2013-01-01 Abbott Gmbh & Co. Kg N-phenyl-(piperazinyl or homopiperazinyl)-benzenesulfonamide or benzenesulfonyl-phenyl-(piperazine or homopiperazine) compounds suitable for treating disorders that respond to modulation of the serotonin 5-HT6 receptor
US8362010B2 (en) 2009-04-30 2013-01-29 Abbott Gmbh & Co. Kg Benzenesulfonanilide compounds suitable for treating disorders that respond to modulation of the serotonin 5-HT6 receptor
US20140303372A1 (en) * 2006-09-22 2014-10-09 Abbvie Bhamas Ltd. Sulfonylpyrazole and sulfonylpyrazoline carboxamidine derivatives as 5-ht6 antagonists
JP2015522522A (ja) * 2012-03-27 2015-08-06 アルバニー メディカル カレッジ 刺激に誘発される薬物再発の阻止
WO2017134280A1 (fr) * 2016-02-05 2017-08-10 Pharnext Nouvelles thérapies combinées contre les troubles neurologiques

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003072548A1 (fr) * 2002-02-22 2003-09-04 Pharmacia & Upjohn Company Derives de pyridyl sulfone utilises comme antagonistes du recepteur 5-ht
WO2003072558A2 (fr) * 2002-02-22 2003-09-04 Pharmacia & Upjohn Company Derives d'arylsulfone
WO2003099797A1 (fr) * 2002-05-23 2003-12-04 Pharmacia & Upjohn Company Sels de bis-arylsulfones destines au traitement de troubles du systeme nerveux central
WO2004009600A1 (fr) * 2002-07-18 2004-01-29 Wyeth 1-heterocyclylalkyl-3-sulfonylazaindole ou derives d'-azaindazole utilises en tant que ligands de 5-hydroxytryptamine-6
WO2005066157A1 (fr) * 2004-01-02 2005-07-21 Suven Life Sciences 3-(pyrrolidine-3-l)indoles en tant que modulateurs du recepteur 5-ht6
WO2007147883A1 (fr) * 2006-06-23 2007-12-27 Laboratorios Del Dr. Esteve, S.A. Combinaison d'un inhibiteur de la cholinestérase et d'un composé ayant une affinité envers le récepteur 5-ht6

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003072548A1 (fr) * 2002-02-22 2003-09-04 Pharmacia & Upjohn Company Derives de pyridyl sulfone utilises comme antagonistes du recepteur 5-ht
WO2003072558A2 (fr) * 2002-02-22 2003-09-04 Pharmacia & Upjohn Company Derives d'arylsulfone
WO2003099797A1 (fr) * 2002-05-23 2003-12-04 Pharmacia & Upjohn Company Sels de bis-arylsulfones destines au traitement de troubles du systeme nerveux central
WO2004009600A1 (fr) * 2002-07-18 2004-01-29 Wyeth 1-heterocyclylalkyl-3-sulfonylazaindole ou derives d'-azaindazole utilises en tant que ligands de 5-hydroxytryptamine-6
WO2005066157A1 (fr) * 2004-01-02 2005-07-21 Suven Life Sciences 3-(pyrrolidine-3-l)indoles en tant que modulateurs du recepteur 5-ht6
WO2007147883A1 (fr) * 2006-06-23 2007-12-27 Laboratorios Del Dr. Esteve, S.A. Combinaison d'un inhibiteur de la cholinestérase et d'un composé ayant une affinité envers le récepteur 5-ht6

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MITCHELL, ELLEN S. ET AL: "BGC20-761, a novel tryptamine analog, enhances memory consolidation and reverses scopolamine-induced memory deficit in social and visuospatial memory tasks through a 5-HT6 receptor-mediated mechanism" NEUROPHARMACOLOGY , 50(4), 412-420 CODEN: NEPHBW; ISSN: 0028-3908, 2006, XP005287695 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140303372A1 (en) * 2006-09-22 2014-10-09 Abbvie Bhamas Ltd. Sulfonylpyrazole and sulfonylpyrazoline carboxamidine derivatives as 5-ht6 antagonists
US8076326B2 (en) 2009-04-30 2011-12-13 Abbott Gmbh & Co. Kg N-phenyl- (piperazinyl or homopiperazinyl)-benzenesulfonamide or benzenesulfonyl-phenl-(piperazine or homopiperazine) compounds suitable for treating disorders that respond to modulation of the serotonin 5-HT6 receptor
US8183237B2 (en) 2009-04-30 2012-05-22 Abbott Laboratories Benzenesulfonanilide compounds suitable for treating disorders that respond to modulation of the serotonin 5-HT6 receptor
US8343959B2 (en) 2009-04-30 2013-01-01 Abbott Gmbh & Co. Kg N-phenyl-(piperazinyl or homopiperazinyl)-benzenesulfonamide or benzenesulfonyl-phenyl-(piperazine or homopiperazine) compounds suitable for treating disorders that respond to modulation of the serotonin 5-HT6 receptor
US8362010B2 (en) 2009-04-30 2013-01-29 Abbott Gmbh & Co. Kg Benzenesulfonanilide compounds suitable for treating disorders that respond to modulation of the serotonin 5-HT6 receptor
JP2015522522A (ja) * 2012-03-27 2015-08-06 アルバニー メディカル カレッジ 刺激に誘発される薬物再発の阻止
WO2017134280A1 (fr) * 2016-02-05 2017-08-10 Pharnext Nouvelles thérapies combinées contre les troubles neurologiques
US10799499B2 (en) 2016-02-05 2020-10-13 Pharnext Combinatorial therapies of neurological disorders
AU2017216288B2 (en) * 2016-02-05 2022-06-02 Pharnext Novel combinatorial therapies of neurological disorders

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