Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
  • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
  • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/08—Bridged systems

Definitions

• the invention relates to the use of a monoamine neurotransmitter re-uptake inhibitor comprising a 2,3-disubstituted tropane moiety, or a tautomer, a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof for the manufacture of a medicament for the sustained reduction of body weight.
• the International patent applications WO 93/09814 and WO 97/30997 disclose tropane derivatives, which are monoamine neurotransmitter re-uptake inhibitor. Moreover, the International patent applications WO 97/30997 suggests that such tropane derivatives may also be used to treat obesitas. However, there is no indication that a sustained reduction of the body weight could be achieved with the aid of such compounds.
• the objective of the invention is to make it easier for the patient to reduce their body weight without suffering from the Yo-Yo effect and thus reduce the health risks associated with overweight.
• monoamine neurotransmitter re-uptake inhibitors comprising a 2,3-disubstituted tropane moiety can be used for the sustained reduction of body weight.
• the present invention relates to the use of a monoamine neurotransmitter re- uptake inhibitor comprising a 2,3-disubstituted tropane moiety, or a tautomer, a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof for the manufacture of a medicament for the sustained reduction of body weight.
• Figure 1 shows the absolute change in weight [kg] induced in patients by different doses of a monoamine neurotransmitter re-uptake inhibitor 28 days after the beginning of the treatment.
• Figure 2 shows the absolute change in weight [kg] induced in patients by different doses of a monoamine neurotransmitter re-uptake inhibitor 56 / 70 days after the begin of the treatment.
• Figure 3 shows the relative change in weight [%] induced in patients by different doses of a monoamine neurotransmitter re-uptake inhibitor 28 days after the beginning of the treatment.
• Figure 4 shows the relative change in weight [%] induced in patients by different doses of a monoamine neurotransmitter re-uptake inhibitor 56 / 70 days after the beginning of the treatment.
• the monoamine neurotransmitter re-uptake inhibitor comprising a 2,3- disubstituted tropane moiety are those which are disclosed by International patent applications WO 93/09814 and WO 97/30997.
• R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl or 2-hydroxyethyl
• R 3 is CH 2 -X-R', wherein X is O, S, or NR"; wherein R" is hydrogen or alkyl
• R' is alkyl, alkenyl,alkynyl, cycloalkyl,cycloalkylalkyl, or-CO-alkyl
• heteroaryl which may be substituted one or more times with alkyl, cycloalkyl, or cycloalkylalkyl
• phenyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3 , CN, alkoxy, alkyl, alkenyl,alkynyl, amino, nitro, and heteroaryl; phenylphenyl; pyridyl
• R 11 is alkyl, cycloalkyl, or cycloalkylalkyl; phenyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3 , CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl ; phenylphenyl ; pyridyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3 , CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl ; o thienyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3 , CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl ; or benzyl; n is 0 or 1; and R 12
• R 3 is l,2,4-oxadiazol-3-yl which may by substituted in the 5 position with alkyl, cycloalkyl, or cycloalkylalkyl; phenyl which may be substituted one or more times with substituents selected from the group consisting ofhalogen, CF 3 , CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; phenylphenyl; or benzyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3 , CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; or l,2,4-oxadiazol-5-yl which may by substituted in the 3 position with alkyl, cycloalkyl, or cycloalkylalkyl; phenyl which may be substituted in the 5 position with alkyl, cycl
• R 3 is .CH 2 -X-R', wherein X is O, S, or NR"; wherein R" is hydrogen or alkyl ;
• R' is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, or-CO-alkyl.
• R 4 is phenyl, which is substituted once or twice with substituents selected from the group consisting of halogen, CF 3 , CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl.
• R 4 is phenyl substituted once or twice with chlorine.
• the tropane derivative having dopamine reuptake inhibitor activity is a (1 R, 2R, 3S) -2, 3-disubstituted tropane derivative of formula I.
• the tropane derivative having dopamine reuptake inhibitory activity is a compound of general formula I wherein R is hydrogen, methyl, ethyl or propyl.
• the tropane derivative having dopamine reuptake inhibitory activity is a compound of general formula I whereinR is 3,4-dichlorophenyl.
• those monoamine neurotransmitter re-uptake inhibitor comprising a 2,3- disubstituted tropane moiety are compounds of formula (II) wherein
• R represents a hydrogen atom or a C 1-6 alkyl group, preferably a hydrogen atom, a methyl or an ethyl group;
• R 5 each independently represents a halogen atom or a CF 3 or cyano group, preferably a fluorine, chlorine or bromine atom;
• R represents a hydrogen atom or a C 1-6 alkyl or C 3-6 -cycloalkyl-C 1-3 -alkyl group, preferably a methyl, ethyl or n-propyl group; and m is 0 or an integer from 1 to 3, preferably 1 or 2; or a tautomer, a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof (1).
• C 1-6 alkyl includes methyl and ethyl groups, and straight- chained and branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl.
• ex ⁇ ression C 3-6 cycloalkyl
• the ex ⁇ ression C 3-6 cycloalkyl” as used herein includes cyclic propyl, butyl, pentyl and hexyl groups such as cyclopropyl and cyclohexyl.
• halogen as used herein includes fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred.
• physiologically functional derivative includes derivatives obtained from the compound of formula (I) under physiological conditions, these are for example N-oxides, which are formed under oxidative conditions.
• pharmaceutically acceptable acid addition salt includes those salts which are selected from among the acid addition salts formed with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid, the salts obtained from hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and acetic acid being particularly preferred.
• the salts of citric acid are of particular significance.
• the tropane derivative having dopamine reuptake inhibitor activity is a compound of the general formula (I) selected from:
• the monoamine neurotransmitter re-uptake inhibitor comprising a 2,3-disubstituted tropane moiety to prepare a pharmaceutical composition for the reduction of body-weight in cases of slight or heavy overweight.
• the above mentioned monoamine neurotransmitter re-uptake inhibitor comprising a 2,3-disubstituted tropane moiety to prepare a pharmaceutical composition for the sustained reduction of body weight in healthy persons, as well as in patients with other diseases, as Pakinson's disease, or in major depressive disorders, or in attention deficit, hyperactivity disorder (ADHD) or in type 2 diabetes patients
• the patients are male or female adults or elderly people of any race, in particular aged 45 to 95, most preferred aged 60 to 80.
• the above mentioned monoamine neurotransmitter reuptake inhibitors comprising a 2,3-disubstituted tropane moiety to prepare a pharmaceutical composition for continuous administration for the sustained reduction of body weight. It is furthermore preferred to use the above mentioned monoamine neurotransmitter reuptake inhibitor comprising a 2,3-disubstituted tropane moiety to prepare a pharmaceutical composition for transdermal administration for the sustained reduction body weight.
• the monoamine neurotransmitter re-uptake inhibitors of formulae IA and IB which are preferably used within the scope of the present invention may optionally be used in the form of their pharmacologically acceptable acid addition salts, and optionally in the form of the hydrates and solvates.
• the monoamine neurotransmitter re-uptake inhibitor of formulae IA and IB which may be used according to the invention are preferably used in the form of the pharmaceutically acceptable acid addition salt thereof and optionally in the form of the hydrates and solvates.
• the pharmaceutically acceptable acid addition salts of the dopamine monoamine neurotransmitter re-uptake inhibitor of formula I are meant, according to the invention, those salts which are selected from among the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid, the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and acetic acid being particularly preferred.
• the salts of citric acid are of particular significance.
• citrate is of particular importance.
• transdermal administration it is preferable to use the base of formula I.
• the monoamine neurotransmitter re-uptake inhibitor comprising a 2,3-disubstituted tropane moiety, preferably the compounds of formula I, most preferably of formula IA and IB, which may be used according to the invention may optionally be used in conjunction with other active substances.
• Preferred combination partners are compounds selected from the categories of the Di-, D 2 -, D 3 - or D - agonists, anorectics, lipase inhibitors and sympathomimetics or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof (2), selected from among group consisting of adrogolide, A- 86929, Rotigotine, NeurVex, nolomirole, pramipexole, talipexol, CHF 1512, (-)- stepholidine, DAR-201, diacrin/Genzyme, bromocriptine, bupropion, LEK-8829, BAM- 1110, AIT-203, terguride, aripiprazole, OPC-4392, GMC-1111, PD-148903, apomorphine HC1, PD-89211, PD-158771, cabergoline, sumanirole, PNU-14277E, POL-255, dihydrexidine, GBR-12783
• the dosage of said monoamine neurotransmitter re-uptake inhibitor comprising a 2,3- disubstituted tropane moiety according to the invention is naturally highly dependent on the severity of the symptoms to be treated on the one hand and the choice of active substance on the other hand.
• some possible dosages especially for the compounds of formula IA and IB which are particularly preferred according to the invention will now be given.
• This may be used in dosages of about 0.05 to 10 mg, preferably about 0.1 to 2.0 mg, in particular about 0.125 to 1.0 mg daily or 0.1 to 5 mg once weekly.
• These dosages are based on the compound of formula IA in the form of its free base.
• the above mentioned dosages correspond to about 0.08 to 16 mg, preferably 0.16 to 2.38 mg, in particular about 0.20 to 1.58 of the compound of formula IA citrate per day.
• One possible dosing method which is described solely as an illustrative example, is described hereinafter (based on the compound of formula IA in the form of its free base): with or without individual dosage titration at weekly intervals depending on the activity and tolerance levels.
• the r onoamine neurotransmitter re-uptake inhibitors comprising a 2,3-disubstituted tropane moiety may be administered for the purposes according to the invention by oral, transdermal, intrathecal, inhalative, nasal or parenteral route, preferably by transdermal or parenteral route, most preferably by transdermal route.
• Suitable preparations include, for example, tablets, particularly slow release tablets, capsules, suppositories, solutions, syrups, emulsions, dispersible powders, implants or plasters, most preferably micronal plasters.
• transdermal preparation which may be used according to the invention reference is hereby made.
• Tablets may be obtained, for example, by mixing the active substance or substances with known excipients, e.g. inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as maize starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc, and/or agents for obtaining delayed release such as carboxymethylcellulose, cellulose acetate phthalate, or polyvinylacetate.
• excipients e.g. inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as maize starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc, and/or agents for obtaining delayed release such as carboxymethylcellulose, cellulose acetate phthalate, or polyvinylacetate.
• excipients e.g. iner
• COMPOUND IA 0.3 mg sodium chloride 0.8 mg benzalkonium chloride 0.01 mg water for injections ad 100 ml
• the studies were randomized, double-blind, placebo-controlled per ascending dose group.
• the studies were designed to assess the safety, tolerability, phamacokinetics (PK) and preliminary efficacy of multiple ascending doses of COMPOUND IA in patients with possible Alzheimer's Disease (AD).
• Two studies were performed consecutively with 0.125/0.25 and 0.5/1.0 mg of COMPOUND IA daily every morning to assess the safety and preliminary efficacy of multiple given for 28 days in those patients.
• a second study was initiated in elderly volunteers in order to investigate the safety and PK of a median dose of 0.75 mg of COMPOUND IA daily in the morning than were used in the first two studies.
• an at least double loading dose was administrated for up to 6 days.
• Safety assessments included adverse event profile, physical examination, vital sign measurements (weight, temperature, heart rate, blood pressure [BP] [supine and standing]), clinical laboratory assessments and others. All safety analyses were conducted on the safety population, defined as all patients who received at least 1 dose of study medication. Descriptive statistics were provided among other things for vital signs and clinical laboratory assessments.
• Descriptive statistics including number of observations, arithmetic mean, standard deviation, minimum, maximum, arithmetic coefficient of variation, geometric mean (gmean), and geometric coefficient of variation (gCV), were provided for plasma concentrations and pharmacokinetic parameters (only maintenance dose group of 1 mg of COMPOUND IA).

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• 2005
  • 2005-01-11 WO PCT/EP2005/000165 patent/WO2005070427A1/en not_active Ceased
  • 2005-01-11 EP EP05700803A patent/EP1727547A1/en not_active Withdrawn
  • 2005-01-11 NZ NZ547919A patent/NZ547919A/en not_active IP Right Cessation
  • 2005-01-11 CA CA002553649A patent/CA2553649A1/en not_active Abandoned
  • 2005-01-11 JP JP2006549961A patent/JP2007519646A/ja active Pending
  • 2005-01-11 AU AU2005205880A patent/AU2005205880B2/en not_active Ceased
  • 2005-01-21 US US11/039,991 patent/US20050203124A1/en not_active Abandoned

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