MXPA06008113A - Pharmaceutical composition comprising a monoamine neurotransmitter re-uptake inhibitor and an n-methyl-d-aspartate (nmda) receptors antagonist - Google Patents

Abstract

The invention relates to a pharmaceutical composition comprising 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 (1), and at least one antagonist of N-methyl-D-aspartate (NMDA) receptors or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof (2), and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients.

Description

PHARMACEUTICAL COMPOSITION COMPRISING A REBURSING INHIBITOR OF NEUROTRANSM SOR MONOAMINE AND AN ANTAGONIST OF N-METI-D-ASPARTATE RECEPTORS (NMDA) FIELD OF THE INVENTION The present invention relates to a combination of a reuptake inhibitor of monoamine neurotransmitter and an antagonist, and the use of the combination in the treatment of neurodegenerative conditions such as dementia of the Alzheimer's type, cerebrovascular disease and depression. BACKGROUND OF THE INVENTION Alzheimer-type dementia is an insufficiently understood neurodegenerative condition that mainly affects elderly people but also young people who are mainly genetically predisposed to it. A postulated treatment method comprises the administration of NMDA receptor antagonists. International patent application WO 97/30997 discloses tropane derivatives, which are inhibitors of re-uptake of the monoamine neurotransmitter. Similar compounds of the International patent application are known WO 93/09814. However, there are no indications for combining these compounds with NMDA receptor antagonists. Ref. 173482 The present invention provides a new and . surprisingly effective combination of an 'NMDA receptor antagonist and separately, consecutive or simultaneous administration of any of the reuptake inhibitors of the monoamine neurotransmitter. Surprisingly the combination provides i) lower doses that are used as expected for the single drugs, and ii) a reduction or minimization of the adverse event profile of each single drug which increases the overall tolerability and compliance of both substances and decreases some effects adverse sides when the profile of each substance is totally different due to the different mechanism of action. BRIEF DESCRIPTION OF THE INVENTION Accordingly, the invention relates to a pharmaceutical composition comprising a monoamine neurotransmitter reuptake inhibitor comprising a 2,3,3-disubstituted tropane portion, or a tautomer, a pharmaceutically acceptable salt, solvate, or derivative physiologically functional thereof (1), and at least one NMDA receptor antagonist or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof (2), and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients . The present invention provides a greater than expected improvement in the condition of subjects suffering from a neurodegenerative disorder with an associated cognitive deficit, such as Alzheimer's dementia, Lewis body dementia, fronto-temporal dementia, or a deficit. cognitive which may arise from a normal process such as aging similar to cerebrovascular dementia, dementia from multiple infarcts and lighter forms such as memory impairment associated with age (AMD) or mild cognitive deficit (DCL) or an abnormal process such as injury, which could be expected from the administration of the active ingredients alone. In addition, the combination allows a lower full dose of each of the active ingredients to be administered thereby reducing side effects and decreasing any reduction in the effectiveness of each of the active ingredients overtime. A kit of parts comprising at least two separate unit dosage forms (A) and (B) is also provided: (A) one of which comprises a composition of a : reuptake inhibitor of monoamine neurotransmitter comprising a 2,3-disubstituted tropane portion, or a tautomer, a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof (1), and optionally a pharmaceutically acceptable carrier; (B) one of which comprises a composition containing one or more NMDA receptor antagonists or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof (2), and optionally a pharmaceutically acceptable carrier, for simultaneous, consecutive or separate administration. Also provided is the use of a combination of a monoamine neurotransmitter re-uptake inhibitor comprising a 2,3,3-disubstituted tropane portion, or a tautomer, a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof (1) , and at least one NMDA receptor antagonist or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof (2) in a combined form, either separately or separately or consecutively, wherein the consecutive administration is close in time or remote in time, for the manufacture of a medication for the prevention or treatment of a disease or disorder, which is responsive to the inhibition of re-uptake of the monoamine neurotransmitter and / or NMDA inhibition. A method is also described. for prevention or treatment of a disease or disorder, the disease or disorder is responsive to inhibition of re-uptake of the monoamine neurotransmitter, the method comprising administering effective amounts of a monoamine neurotransmitter reuptake inhibitor comprising a portion of tropane 2 , 3-disubstituted, or a tautomer, a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof (1) and at least one - NMDA receptor antagonist or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof (2) to a patient in need thereof in a combined form, either separately or separately and consecutively where the consecutive administration is close in time or Remote in time. DETAILED DESCRIPTION OF THE INVENTION As a rule, the monoamine neurotransmitter re-uptake inhibitor comprising a 2,3,3-disubstituted tropane portion are compounds of the general formula (I), or a pharmaceutically acceptable addition salt thereof or the N-oxide thereof, wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl or 2-hydroxyethyl; R3 is CH2-X-R ', wherein X is 0, S, or NR "; wherein R "is hydrogen or alkyl; and R 'is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, or -CO-alkyl; heteroaryl which can be substituted one or more times with alkyl, cycloalkyl or cycloalkylalkyl; phenyl which can be substituted one or more times with substituents selected from the group consisting of halogen, CF3, 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, CF3, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; thienyl which can be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; or benzyl which can be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; or (CH) nC? 2Ru, COR11, or CH2R12, wherein R11 is alkyl, cycloalkyl, or cycloalkylalkyl; phenyl which can be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; phenylphenyl; pyridyl which can be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; or thienyl which can be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; or benzyl; n is O or 1; and R12 is O-phenyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; or 0-CO-phenyl which can be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; or CH = NOR '; where R 'is or hydrogen; or alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl or aryl; all of which can be substituted with -COOH; -COO-alkyl; -COO-cycloalkyl; or phenyl which can be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkenyl, alkynyl, amino, and nitro; is phenyl, 3,4-methylenedioxyphenyl, benzyl, naphthyl, or heteroaryl, all of which may be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl. In a special embodiment of the compound of the general formula I, R3 is 1", 2, -oxadiazol-3-yl which can be substituted at the 5-position with alkyl, cycloalkyl, or cycloalkylalkyl, phenyl which can be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; phenylphenyl; or benzyl which can be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; or 1, 2, 4-oxadiazol-4-yl which can be substituted at the 3-position with alkyl, cycloalkyl, or cycloalkylalkyl; phenyl which can be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; phenylphenyl; benzyl which can be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; pyridyl which can be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; or thienyl which can be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl. In a further special embodiment of the compound of the general formula (I), R3 is CH2-X-R ', wherein X is O, S, or NR "; wherein R "is hydrogen or alkyl; and R 'is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, or -CO-alkyl. In a still further embodiment of the compound of the general formula (I), -R3 is CH = NOR '; wherein R 'is hydrogen; alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, or aryl; all of which can be substituted with -COOH; COO-alkyl; -COO-cycloalkyl; or phenyl which can be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkenyl, alkynyl, amino, and nitro. In a further special embodiment of the compound of the general formula (I), R4 is phenyl, which can be substituted once or twice with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl.

In a more special embodiment, R 4 is phenyl substituted once or twice with. chlorine. In a further special embodiment, the tropane derivative having dopamine re-absorption inhibiting activity is a tropane derivative (IR, 2R, 3S) -2, 3-disubstituted of the formula I. In a still further embodiment, the tropane derivative having dopamine re-uptake inhibiting activity is a compound of the general formula I wherein R3 is -CH2-X-R ', wherein X is O or S, and R 'is methyl, ethyl, propyl, or cyclopropylmethyl; -CH = NOR '; wherein R 'is hydrogen or alkyl, or 1, 2, 4-oxadiazol-5-yl which can be substituted at the 3-position with alkyl. In a still further embodiment, the tropane derivative having dopamine reuptake inhibitory activity is a compound of the general formula I wherein R is hydrogen, methyl, ethyl or propyl. In a still further embodiment, the tropane derivative having dopamine re-uptake inhibiting activity is a compound of the general formula I wherein R 4 is 3,4-dichlorophenyl. Preferably those monoamine neurotransmitter reabsorption inhibitors comprising a 2,3,3-disubstituted tropane portion are compounds of the formula (II) wherein R represents a hydrogen atom or an alkyl group of C? -β, preferably a hydrogen atom , a methyl or ethyl group; R5 each independently represents a halogen atom or a CF3 or cyano group, preferably a fluorine, chlorine or bromine atom; R 'represents a hydrogen atom or a C? _6 alkyl or C3-6 cycloalkyl-C? _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). As used herein, the term "C? _6p alkyl includes methyl and ethyl groups, and straight and branched chain propyl, butyl, pentyl and hexyl groups.The particular alkyl groups are methyl, ethyl, n-propyl, isopropyl. and "t-butyl" The term "C3-6 cycloalkyl" as used herein includes cyclic propyl, butyl, pentyl and hexyl groups such as cyclopropyl and cyclohexyl The term "halogen" as used herein includes fluoro , chlorine, bromine and iodine, of which fluoro and chloro are preferred The term "physiologically functional derivative" as used herein includes derivatives obtained from the compound of the formula (I) under physiological conditions, these are for example N- oxides, which are formed under oxidative conditions The term "pharmaceutically acceptable addition salt" as used herein includes those salts which are selected from the acid addition salts formed with acid. or hydrochloric, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid, the salts obtained from hydrochloric acid, hydrobromic acid, sulfuric acid, acid phosphoric and acetic acid are particularly preferred. The citric acid salts are of particular significance. In a special embodiment, the tropane derivative having dopamine reuptake inhibitory activity is a compound of the general formula (I) selected from: (IR, 2R, 3S) -2- (3-Cyclopropyl-2, , 4-oxadiazol-5-yl) -3- (4-fluorophenyl) tropane; (IR, 2R, 3S) -2- (3-Phenyl-1,2, -oxadiazol-5-yl) -3- (4-fluorophenyl) tropane; (IR, 2R, 3S) -2- (3-Phenyl-1,2,4-oxadiazol-5-yl) -3- (4-methylphenyl)-tropane; (IR, 2R, 3S) -2- (3-Benyl-1,2,4-oxadiazol-5-yl) -3- (4-fluorophenyl) tropane; (IR, 2R, 3S) -2- (3- (4-Phenyl-phenyl) -1,2,4-oxadiazol-5-yl) -3- (4-fluorophenyl) tropane; (1R, 2R, 3S) -2- (3-Phenyl-1, 2,4-oxadiazol-5-yl) -3- (2-naphthyl) tropane; (IR, 2R, 3S) -3- (3,4-Dichlorophenyl) tropan-2-aldoxime; (1 R, 2R, 3S) -3- (3,4-Dichlorophenyl) -tropan-2-0-methyl-aldoxime; (IR, 2R, 3S) -3- (3,4-Dichlorophenyl) tropan-2-0-benzyl-aldoxime; (IR, 2R, 3S) -3- (3,4-Dichlorophenyl) tropan-2-0-ethoxycarbonylmethyl-aldoxime; - (IR, 2R, 3S) -3- (3,4-Dichlorophenyl) tropan-2-0-methoxycarbonylmethyl-aldoxime; (IR, 2R, 3S) -3- (3,4-Dichlorophenyl) tropan-2-O- (1-ethoxycarbonyl-1,1-dimethyl-methyl) -aldoxime; (IR, 2R, 3S) -3- (3,4-Dichlorophenyl) tropan-2-0-carboxymethyl-2-aldoxime; (IR, 2R, 3S) -N-Normethyl-3- (3,4-dichlorophenyl) tropan-2-0-methyl-aldoxime; (IR, 2R, 3S) -N-Normethyl-3- (3,4-dichlorophenyl) tropan-2-0-benzyl-oxime; (1R, 2R, 3S) -3- (4-Methylphenyl) tropan-2-O-methyl-aldoxime; (IR, 2R, 3S) -3- (3,4-Dichlorophenyl) tropan-2-0- (1,1-dimethylethyl) -aldoxime; (IR, 2R, 3S) -3- (4-Chlorophenyl) tropan-2-0-aldoxime; .. Hydrochloride of (IR, 2R, 3S) -3- (4-chlorophenyl) tropan-2-0-methylaldoxime; (IR, 2R, 3S) -3- (4-Chlorophenyl) tropan-2-0-methoxycarbonylmethyl-1-oxime; (1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropan-2-0- (2-propynyl) -aldoxime; (1R, 2R, 3S) -3- (3,4-Dichlorophenyl) tropan-2-0- (2-methylpropyl) -aldoxime; (IR, 2R, 3S) -3- (3,4-Dichlorophenyl) tropan-2-O-cyclopropylmethyl-aldoxime; (IR, 2R, 3S) -3- (3,4-Dichlorophenyl) tropan-2-O-ethyl-aldoxime; (IR, 2R, 3S) -2-Methoxymethyl-3- (3,4-dichlorophenyl) -tropane; (IR, 2R, 3S) -2-Isopropoxymethyl-3- (3,4-dichlorophenyl) -tropane; (IR, 2R, 3S) -2-Ethoxymethyl-3- (3,4-dichlorophenyl) -tropane; (IR, 2R, 3 S) -2-Ethoxymethyl-3- (3,4-dichlorophenyl) -nortropane; (IR, 2R, 3S) -2-Cyclopropylmethyloxymethyl-3- (3,4-dichlorophenyl) -tropane; (IR, 2R, 3S) -2-Methoxymethyl-3- (4-chlorophenyl) -tropane; (IR, 2R, 3S) -N-Normethyl-2-methoxymethyl-3- (4-chlorophenyl) -tropane; (IR, 2R, 3S) -2-Ethoxymethyl-3- (4-chlorophenyl) -tropane; (IR, 2R, 3S) -N-Normethyl-2-methoxyethyl-3- (3,4-dichlorophenyl) -tropane; (1 R, 2R, 3S) -N-Normethyl-2-ethoxymethyl-3- (3,4-dichlorophenyl)-tropane; (IR, 2R, 3S) -N-Normethyl-2-ethoxymethyl-3- (4-cblorophenyl) -tropane; (IR, 2R, 3S) -N-Normethyl-2-cyclopropylmethyloxymethyl-3- (4-chlorophenyl) -tropane; (IR, 2R, 3S) -2-Cyclopropylmethyloxymethyl-3- (4-chlorophenyl)-tropane; (IR, 2R, 3S) -2-Ethylthiomethyl-3- (3,4-dichlorophenyl) -tropane; (IR, 2R, 3S) -2-Hydroxymethyl-3- (4-fluorophenyl) tropane; (IR, 2R, 3S) -2-Hydroxymethyl-3- (3, -dichlorophenyl) tropane; (IR, 2R, 3S) -N-Normethyl-N- (tert-butoxycarbonyl) -2-hydroxymethyl-3- (3,4-dichlorophenyl) tropane; (IR, 2R, 3S) -2-Hydroxymethyl-3- (4-chlorophenyl) tropane; (IR, 2R, 3S) -2- (3- (2-Furanyl) -1,2,4-oxadiazol-5-yl) -3- (3,4-dichlorophenyl) -tropane; (IR, 2R, 3S) -2- (3- (3-Pyridyl) -1,2,4-oxadiazol-5-yl) -3- (3,4-dichlorophenyl) -tropane; (IR, 2R, 3S) -N-Normethyl-N-allyl-2- (3- (4-pyridyl) -1,2,4-oxadiazol-5-yl) -3- (3,4-dichlorophenyl) - tropane; (IR, 2R, 3S) -N-Normethyl-N-ethyl-2- (3- (4-pyridyl) -1,2,4-oxadiazol-5-yl) -3- (3, -dichlorophenyl) -tropane; (IR, 2R, 3S) -N-Normethyl-N- (2-hydroxyethyl) -2- (3- (4-pyridyl) -1,2,4-oxadiazol-5-yl) -3- (3, 4 -dichlorophenyl) -tropane; (IR, 2R, 3S) -N-Normethyl-2- (3- (4-pyridyl) -1,2,4-oxadiazol-5-yl) -3- (3,4-dichlorophenyl) -tropane; (IR, 2R, 3S) -N-Normethyl-N-allyl-2- (3- (3-pyridyl) -1, 2, 4'-oxadiazol-5-yl) -3- (3,4-dichlorophenyl) -tropano; (IR, 2R, 3S) -N-Normethyl-N-allyl-2- (3- (2-pyridyl) -1, 2, -oxadiazol-5-yl) -3- (3, -dichlorophenyl) -tropane; (IR, 2R, 3S) -2- (3- (2-Thienyl) -1,2,4-oxadiazol-5-yl) -3- (4-chlorophenyl) -tropane; (1 R, 2R, 3S) -2- (3- (2-thienyl) -l, 2,4-oxadiazol-5-yl) -3- (3,4-dichlorophenyl) -tropane; (IR, 2R, 3S) -2- (3-4-Pyridyl) -1,2,4-oxadiazol-5-yl) -3- (3, 4-dichlorophenyl) -tropane; (IR, 2R, 3S) -2- (3- (2-Pyridyl) -1,2,4-oxadiazol-5-yl) -3- (3,4-dichlorophenyl) -tropane; (IR, 2R, 3S) -2- (3- (4-Pyridyl) -1,2,4-oxadiazol-5-yl) -3- (4-chlorophenyl) -tropane; (1 R, 2R, 3S) -2- (3- (3-Pyridyl) -l, 2,4-oxadiazol-5-yl) -3- (4-chlorophenyl) -tropane; (IR, 2R, 3S) -2- (3-2-Pyridyl) -1,2,4-oxadiazol-5-yl) -3- (4-chlorophenyl) -tropane; (IR, 2R, 3S) -2- (3-Phenyl-1,2,4-oxadiazol-5-yl) -3- (4-fluorophenyl) -tropane; (1 R, 2R, 3S) -2- (3-Phenyl-1,2,4-oxadiazol-5-yl) -3- (4-methylphenyl) tropane; (IR, 2R, 3S) -2- (3-Benzylthi, 2,4-oxadiazol-5-yl) -3- (4-fluorophenyl) -tropane; (IR, 2R, 3S) -2- (3- (4-Phenylphenyl) -1,2,4-oxadiazol-5-yl) -3- (4-fluorophenyl) -tropane; (IR, 2R, 3S) -2- (3-Phenyl-1,2,4-oxadiazol-5-yl) -3- (2-naphthyl)-tropane; (IR, 2R, 3S) -2- (4-Chlorophenoxymethyl) -3- (4-fluorophenyl) -tropane; (IR, 2R, 3S) -2- (4-Chlorophenoxymethyl) -3- (4-fluorophenyl) -tropane; (IR, 2R, 3S) -2- (4-Chlorophenoxy-methyl) -3- (3,4-dichlorophenyl)-tropane; (IR, 2R, 3S) -2- (4-Chlorophenoxymethyl) -3- (4-methylphenyl) -tropane; (1R, 2R, 3S) -2- (4-Benzoyloxy-methyl) -3- (4-fluorophenyl) -tropane; (IR, 2R, 3S) -2-Carbomethoxy-3- (2-naphthyl) -tropane; (IR, 2R, 3S) -2-Carbomethoxy-3- (3,4-dichlorophenyl) -tropane; (IR, 2R, 3S) -2-Carbomethoxy-3-benzyl-tropane; '(IR, 2R, 3S) -2-Carbomethoxy-3- (4-chlorophenyl) -tropane; (1R, 2R, 3S) -2-Carbomethoxy-3- (4-methylphenyl) -tropane; (IR, 2R, 3S) -2-Carbomethoxy-3- (1-naphthyl) -tropane; (1R, 2R, 3S) -2-Carbomethoxy-3- (4-phenylphenyl) -tropane; (IR, 2R, 3S) -2-Carbomethoxy-3- (4-t-butyl-phenyl) -tropane; (1R, 2R, 3S) -2- (4-Fluoro-benzoyl) -3- (4-fluorophenyl) -tropane; or a pharmaceutically acceptable addition salt thereof. More preferred is the compound of the formula (IA) a pharmaceutically acceptable salt thereof, in particular the citrate thereof.

NMDA receptor antagonists which may be used include any which are known to the skilled person and those which will become available in the future. Examples are aptiganel, budipine, eliprodil, felbamate, gaciclidine, remacemide, lanicemin, memantine, midafotel, remancemide, selfotel and sinnabidol. More preferred is a combination of the compound of the formula (IA) with memantine, which is 3,5-dimethyl-l-adamantanamine of the formula, in particular in the form of its hydrochloride or sulfate. The pharmaceutical compositions of the present invention are suitable for oral, intravenous, intravascular, intraperitoneal, subcutaneous, intramuscular, inhalative, topical, patch or suppository administration. The pharmaceutical compositions of the present invention are preferably in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, liquid or aerosol sprays, drops, ampoules, transdermal patches, self-regulating devices. injectors or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or - for administration by inhalation or insufflation. To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, for example conventional tablet-forming ingredients such as corn starch, cellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, lactose, sucrose, sorbitol, talc, silicon dioxide. polyethylene glycol, stearic acid, magnesium stearate and dicalcium phosphate or gums or surfactants such as sorbitan monooleate, polyethylene glycol, and other pharmaceutical diluents, for example water, to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these pre-formulation compositions as homogeneous, it is understood that the active ingredient is also dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. . This solid pre-formulation composition is then subdivided into unit dosage forms of the type described above containing from 0.05 to 10,000 mg, in particular 0.1 to approximately 500 mg, most preferably 0.1 to 250 mg of each active ingredient of the present invention. Typical unit dosage forms - contain from 0.1 to 100 mg, for example 0.1, 0.5, 1, 2, 5, 10, 25, 50 or 100 mg, of each activated ingredient. The tablets or pills of the new composition can be coated or otherwise compounded to provide a dosage form that provides the long-acting advantage. For example, the tablet or pill may comprise an internal dosage component and an external dosage component, the latter being in the form of a cover over the first. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and allows the internal component to pass intact in the duodenum or is delayed release. A variety of materials can be used for such enteric layers or coatings, such materials include a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. Similarly, pouches and pills are included. Tablets, powders, capsules, pills, pouches and pills can be used as solid forms suitable for oral administration. The liquid forms in which the new compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, oil of coconut or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidone or gelatin. To prepare suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, first melts and the active component is dispersed homogeneously therein, as by agitation. The molten homogeneous mixture is then poured into convenient dimensioned molds, allowed to cool, and thereby solidifies. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient, carriers as are known in the art to be appropriate. Administration to the respiratory tract can also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurized container with a suitable propellant such as a chlorofluorocarbon (CFC) or fluorohydrocarbon (HFC) eg dichlorodifluoromethane, trichlorofluoromethane, - dichlorotetrafluoroethane, 1,1,1,1-tetrafluoroethane (HFC-134 (a)), or 1, 1, 1, 2, 3, 3, 3-heptafluoropropane, carbon dioxide, or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin and / or a co-solvent such as ethanol. The dose of drug can be controlled by the provision of a metering valve. Alternatively, the active ingredients can be provided in the form of a dry powder, for example a powder mixture of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone.

(PVP). Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition can be presented in unit dosage form for example in capsules or cartridges of, for example, gelatin, or ampoule containers of which the powder can be administered by means of an inhaler. In formulations proposed for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size can be obtained by means known in the art, for example by micronization. For the treatment of a neurodegenerative condition, a suitable dosage level is about 0.01 to 250 mg / kg per day, preferably about 0.01 to 100 mg / kg per day, and especially about 0.01 to 5 mg / kg of body weight per day of each active ingredient. The compounds can be administered in a regime of 1 to 4 times per day. In some cases, however, dosing outside these limits can be used. More preferably, the composition of the invention will be used for the treatment or prevention of one or more of the following neurodegenerative conditions: pseudo-dementia, dementia, including Alzheimer's type dementia, Alzheimer's disease, presenile dementia, senile dementia, dementia by Body of Lewy, Down syndrome, temporal fronto dementia, HIV-related dementia, Pick's disease, cerebrovascular dementia, dementia due to multiple infarctions, memory deficit, attention deficit, cognitive deficit, memory dysfunction, mild cognitive deficit (MCI), memory impairment associated with age (DMAE), cognitive deficit associated with aging, cognitive deficit related to age and multiple system atrophy.

Preferably, the weight ratio of (1) to (2) ranges from 50: 1 to 1: 300, in particular from 1: 1 to 1: 200, more preferably from 1: 2 to 1: 100. More preferred are the following daily dose variations: • 0.5-20 mg, preferably 1.0-10 mg of memantine and 0.01-2.0 mg of the compound of the formula (IA); The following examples are used "to illustrate some formulations according to the invention, and are proposed only as possible methods described by way of example, without restricting the invention to its content.

Example 1 Composition of (IA) / memantine hydrochloride tablet coated with film 0.5 mg / 5mg Core Coating Example 3 Composition of (IA) / Memantine bilayer tablets of 0.25 mg / 4mg Bilayer tablet Constituents mg / tablet * does not appear in the final product Total weight of bilayer tablet 260,000 The advantageous effect of the combination of the present invention can be shown, for example, by comparing the combined dosage of the combination with dosages of the same amount of each of the ingredients active separately in subjects using the Mini-Mental State Examination (MSME) as described in Folstein and Folstein J. Psychiat. Res., 1975, 12, 189-198 or a variant thereof as discussed in Tombaugh and Mclntyre, JAGS, 1992, 40, 922-935. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is "that which is clear from the present description of the invention.

Claims (14)

CLAIMS Having described the invention as above, the contents of the following claims are claimed as property:

1. Pharmaceutical composition, characterized in that it comprises a monoamine neurotransmitter re-uptake inhibitor comprising a 2,3-disubstituted tropane portion, or a tautomer, a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof (1), and minus one N-methyl-D-aspartate (NMDA) receptor antagonist or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof (2), and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients.

2. Pharmaceutical composition according to claim 1, characterized in that the monoamine neurotransmitter reabsorption inhibitor comprising a 2,3,3-disubstituted tropane portion is a compound of the formula or a pharmaceutically acceptable addition salt thereof or the N-oxide thereof, wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl or 2-hydroxyethyl; R3 is CH2-X-R ', where -X. is 0, S, or NR "; wherein R "is hydrogen or alkyl; and R 'is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, or -CO-alkyl; heteroaryl which can be substituted one or more times with alkyl, cycloalkyl or cycloalkylalkyl; phenyl which can be substituted one. or more times with substituents selected from the group consisting of halogen, CF3 / CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; phenylphenyl; pyridyl which can be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; thienyl which can be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; or benzyl which can be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; or (CH2) nC02R11, COR11, or CH2R12, wherein R11 is alkyl, cycloalkyl, or cycloalkylalkyl; phenyl which can be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; phenylphenyl; pyridyl which can be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; thienyl which can be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; or benzyl; n is 0 or 1; and R12 is O-phenyl which may be substituted one or more times with substituents selected from the group consisting of "halogen, CF3, CN," alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; or 0-CO-phenyl which can be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl;. or CH = N0R '; where R 'is or hydrogen; or alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl or aryl; all of which can be substituted with -COOH; -COO-alkyl; -COO- cycloalkyl; or phenyl which can be substituted one or more times with substituents selected from the group consisting of halogen, CF3, CN, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkenyl, alkynyl, amino, and nitro; R 4 is 3,4-methylenedioxyphenyl or phenyl, benzyl, naphthyl, or heteroaryl, all of which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3, CN, alkoxy, cycloalkoxy, -alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl.

3. Pharmaceutical composition according to claim 1 or 2, characterized in that the monoamine neurotransmitter re-uptake inhibitor comprising a 2,3-disubstituted tropane portion is a compound of the formula (II) wherein R represents a hydrogen atom or an alkyl group of C? _6; R5 represents a halogen atom or a CF3 or cyano group; R 'represents a hydrogen atom or an alkyl group of C? _6 or C3_6-cycloalkyl-C? _3 alkyl; and m is 0 or an integer from 1 to 3; or a tautomer, a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof (1).

4. Pharmaceutical composition according to any of claims 1 to 3, characterized in that it consists essentially of the compound of the formula (IA) (1) and at least one NMDA receptor antagonist selected from the group consisting of aptiganel, "budipine, eliprodil, felbamate, gaciclidine, remacemide, lanicemin, memantine, midafotel, remancemide, selfotel and sinnabidol (2), and a carrier or excipient Pharmaceutically acceptable

5. Pharmaceutical formulation according to any of claims 1 to 4, characterized in that it is suitable for oral, intravascular, intraperitoneal, subcutaneous, intramuscular or topical administration

6. Pharmaceutical formulation according to any of claims 1 to 5 , characterized in that the weight ratio of (1) to (2) ranges from 50: 1 to 1: 300, preferably from 8: 1 'to 1:80 ..

7. Pharmaceutical formulation according to any of claims 1 to 6. , characterized in that a single application dose contains 1 to 10,000 milligrams, preferably 10 to 2,000 mg of the combined active ingredients (1) and (2). according to any one of claims 1 to 7, characterized in that. the pharmaceutically acceptable carrier or excipient is a carbohydrate. 9. Method for the prevention or treatment of a disease or disorder, the disease or disorder is sensitive to the inhibition of re-uptake of the monoamine neurotransmitter, the method characterized in that it comprises "the administration of effective amounts of a re-uptake inhibitor. of a monoamine neurotransmitter comprising a 2,3,3-disubstituted tropane portion, or a tautomer, a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof (1) and at least one NMDA receptor antagonist or a pharmaceutically acceptable salt, solvate , or physiologically functional derivative thereof (2) to a patient in need thereof in a combined form, either separately or separately and consecutively where the consecutive administration is close in time or remote in time. claim 9, characterized in that the disease or disorder is selected from the group consisting of pseu do-dementia, dementia, including dementia of the Alzheimer's type, Alzheimer's disease, presenile dementia, senile dementia, Lewy body dementia, Down syndrome, temporal fronto dementia, HIV-related dementia, Pick's disease, cerebrovascular dementia, dementia. by multiple infarctions, memory deficit, attention deficit, cognitive deficit, memory dysfunction, mild cognitive deficit (MCI), memory impairment associated with age (AMD), cognitive deficit associated with aging, cognitive deficit related to age and multiple system atrophy. Method according to claim 10, characterized in that the disease or disorder is dementia of the Alzheimer's type. 12. Use of a monoamine neurotransmitter reuptake inhibitor comprising a 2,3,3-disubstituted tropane portion, -or a tautomer, a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof (1) and less an NMDA receptor antagonist or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof (2) in a combined form, either separately or separately and consecutively, wherein the consecutive administration is close to time or remote from time, for the manufacture of a medication for the prevention or treatment of a disease or a disorder, which is sensitive to the inhibition of re-uptake of the neurotransmitter monoamine. 13. Use of. according to claim 12 for the manufacture of a medication for the prevention or treatment of a disease or disorder, which is selected from the group consisting of pseudo-dementia, dementia, including Alzheimer's type dementia, Alzheimer's disease, presenile dementia, senile dementia, Lewy body dementia, Down syndrome, temporal fronto dementia, HIV-related dementia, Pick's disease, cerebrovascular dementia, dementia due to multiple infarctions, memory deficit, attention deficit, cognitive deficit, memory dysfunction, deficit cognitive - mild (MCI), memory impairment associated with age (DMAE), cognitive deficit associated with aging, cognitive deficit related to age and multiple system atrophy. 14. pharmaceutical kit, characterized in that it comprises at least two separate unit dosage forms (A) and (B): (A) one of which comprises a monoamine neurotransmitter re-uptake inhibitor composition comprising a tropane portion 2,3-disubstituted, or a tautomer, a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof (1), and optionally a pharmaceutically acceptable carrier.; (B) one of which comprises a composition containing one or more NMDA receptor antagonists or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof (2), and optionally a pharmaceutically acceptable carrier.