Patent Application
20060241099
The present invention relates to the use of compounds from the class of 2-thia-dibenzo[e,h]azulenes as well as of their pharmacologically acceptable salts and solvates for the manufacture of a pharmaceutical formulation for the treatment and prevention of diseases, damages and disorders of the central nervous system (CNS) caused by disorders of the neurochemical equilibrium of biogenic amines or other neurotransmitters.
Irregularities in the steady state of biogenic amines (serotonin, norepinephrine, dopamine) and of other neurotransmitters and their receptors that are part of the central neurotransmitter system in the central nervous system (“CNS”) may be the cause of various mental diseases, damages and disorders (e.g. depression, schizophrenia, manic behavior and similar). Pathological changes in the CNS caused by disorders of neurotransmitter concentration may occur due to an unbalanced (too big or too small) synthesis, irregularities in storing, releasing, metabolizing and/or reabsorptioni of biogenic amines and/or certain neurotransmitters.
The results of investigations directed to the understanding of pathogenesis of mental disorders have shown that a disorder in the serotonin equilibrium plays an important role in various diseases. The monoamine-deficiency hypothesis was one of the first explanations, wherein the symptoms of depression were connected to a reduction in the neurotransmission of monoamines, especially serotonin (5-HT) and noradrenaline, which was also confirmed by neurochemical tests as well as by a successful treatment of the patients with substances increasing monoaminergic neurotransmission (Expert Opin. Investig. Drugs 2003, 12, 531-543). In addition to the serotonergic and noradrenergic systems, a very important role in CNS function disorders is also played by the dopaminergic system. The understanding of the exact role and of the interactions of these neurotransmitter systems is made rather difficult by the great number of receptor subtypes and their pharmacological complexity. Thus, it has been observed that e.g. dopaminergic neurotransmission is regulated by 5-HT2A receptors (L. G. Spampinato, J. Neurochem. 2000, 74, 693-701) and hence 5-HT2A receptors may also be the target receptors in treating diseases and disorders, in whose pathology an important role is played by a disorder of the function of the dopaminergic system (psychoses and various addictions).
Glutamate receptors play a vital role in the mediation of excitatory synaptic transmission as one of the major excitatory neurotransmitters in the CNS. It is widely accepted that σ1 receptor ligands can modulate neurotransmission mediated by central neurotransmitter systems, including glutamatergic/NMDA (F. P. Monnet, G. Debonnel, J.-L. Junien, C. de Montigny, Eur. J. Pharmacol., 1990, 179, 441-445). Many pharmacological and physiological actions have been attributed to σ1 receptor. These include the regulation of IP3 receptors and calcium signaling at the endoplasmic reticulum, mobilization of cytoskeletal adaptor proteins, modulation of nerve growth factor-induced neurite sprouting, modulation of neurotransmitter release and neuronal firing, modulation of potassium channels as a regulatory subunit, alteration of psychostimulant-induced gene expression, and blockade of spreading depression. Behaviorally, σ1 receptor is involved in learning and memory, psychostimulant-induced sensitization, cocaine-induced conditioned place preference, schizophrenia and pain perception. Thus, it is hypothesized that σ1 receptor, at least in part, is an intracellular amplifier creating a supersensitized state for signal transduction in the biological system.
For treatment of pathological CNS disorders and particularly in the therapy of mental disorders a significant role as the most frequently applied medicines is given to substances that, according to their structure, are polycyclic compounds (benzodiazepines, tricyclic and tetracyclic antidepressants, monoamino oxidase (MAO) inhibitors, selective inhibitors of serotonin reabsorption etc.).
A new area in pharmacotherapy was opened by introducing the novel tetracyclic antidepressant mianserin (Claghom, J.; Lesem, M. D. Prog. Drug Res. 1996, 46, 243-262; Sperling, W.; Demling, J. Drugs Today 1997, 33, 95-102). Numerous tetracyclic derivatives showing pharmacological action in the treatment of the disorders of the neurochemical equilibrium in CNS are disclosed in the literature. WO 99/19317, WO 97/38991 and U.S. Pat. No. 6,511,976 describe the manufacture of tetracyclic derivatives containing a tetrahydrofuran ring and the use thereof as substances having antipsychotic, cardiovascular and gastrokinetic actions. U.S. Pat. No. 4,145,434 discloses the manufacture of dibenzo(cyclohepta-, oxepino-, thiepino-)pyrrolidine and dibenzopyrrolidinoazepine derivatives as well as the use thereof as substances having a potential CNS action. The manufacture and an antidepressive action of some 1,2-diazadibenzoazepines are disclosed in EP 0063525. The manufacture and a potential anxiolytic action of some tetracyclic isooxazolidine derivatives are disclosed as well (Drugs Fut. 2002, 27, Suppl. A: C41; Drugs Fut. 2002, 27, Suppl. A: P182, WO 96/14320, WO 96/14321). The introduction of a piperidine ring into a tetracyclic structure containing an oxepine ring resulted in the formation of the molecule Org-4428 showing an antidepressive action (Sperling, W.; Demling, J. Drugs Today 1997, 33, 95-102). The molecule Org-5222 contains a pyrrolidine ring fused to an oxepine nucleus and is described as a potential anxiolytic and antipsychotic (Sperling, W.; Demling, J. Drugs Today 1997, 33, 95-102).
However, art known medicines used in therapy of pathological CNS disorders and particularly in the therapy of mental disorders are associated with a wide range of adverse effects. There is thus a need for a safe and effective treatment of diseases and disorders of the CNS.
In our earlier International publication WO 03/084962, herein incorporated by reference in its entirety as amended with letter of 15.04.2004, we disclose compounds of 2-thia-dibenzo[e,h]azulene class, their pharmaceutically acceptable salts and solvates, processes and intermediates for preparation thereof as well as their antiinflammatory effects, especially to the inhibition of tumor necrosis factor-α (TNF-α) production and the inhibition of interleukin-1 (IL-1) production along with their analgetic action.
We have now surprisingly found that compounds from the class of 2-thia-dibenzo[e,h]azulenes as described in the aforementioned specification are effective in the treatment of diseases and disorders of the CNS. The present compounds differ structurally from the art-known tetracyclic compounds acting upon the CNS by an unsaturated tetracyclic structure since they contain a thiophene ring as the fourth ring, whereas art-known tetracyclic compounds acting upon the CNS (WO 99/19317, WO 97/38991; Sperling, W.; Demling, J. Drugs Today 1997, 33, 95-102) contain at least one saturated ring in their structure, and are further distinguished by valuable pharmacological and physicochemical properties.
According to our knowledge, the use of 2-thia-dibenzo[e,h]azulenes and of their pharmaceutically acceptable salts and solvates disclosed in our earlier International publication WO 03/084962 for the manufacture of a pharmaceutical formulation for the treatment and prevention of diseases, damages and disorders of the central nervous system caused by disorders of neurochemical steady state has hitherto been neither disclosed nor suggested.
The present invention relates to a pharmaceutical composition comprising a compound of formula I
or a pharmaceutically acceptable salt or solvate thereof,
wherein
The present invention further relates to methods of treating a disease, disorder or damage of the central nervous system caused by a disruption in the neurochemical equilibrium of a neurotransmitter in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier or solvent.
The term “halo”, “hal” or “halogen” relates to a halogen atom which may be fluorine, chlorine, bromine or iodine (most preferably chlorine or bromine).
The term “alkyl” relates to alkyl groups with the meaning of alkanes wherefrom radicals are derived, which radicals may be straight, branched or cyclic or a combination of straight and cyclic ones and branched and cyclic ones. The preferred straight or branched alkyls are e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. The preferred cyclic alkyls are e.g. cyclopentyl or cyclohexyl.
The term “haloalkyl” relates to alkyl groups which must be substituted with at least one halogen atom. The most frequent haloalkyls are e.g. chloromethyl, dichloromethyl, trifluoromethyl or 1,2-dichloropropyl.
The term “alkenyl” relates to alkenyl groups having the meaning of hydrocarbon radicals, which may be straight, branched or cyclic or are a combination of straight and cyclic ones or branched and cyclic ones, but having at least one carbon-carbon double bond. The most frequent alkenyls are ethenyl, propenyl, butenyl or cyclohexenyl.
The term “alkynyl” relates to alkynyl groups having the meaning of hydrocarbon radicals, which are straight or branched and contain at least one and at most two carbon-carbon triple bonds. The most frequent alkynyls are e.g. ethynyl, propynyl or butynyl.
The term “alkoxy” relates to straight or branched chains of alkoxy group. Examples of such groups are methoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or methylprop-2-oxy.
The term “aryl” relates to groups having the meaning of an aromatic ring, e.g. phenyl, as well as to fused aromatic rings. Aryl contains one ring with at least 6 carbon atoms or two rings with a total of 10 carbon atoms and with alternating double (resonant) bonds between carbon atoms. The most frequently used aryls are e.g. phenyl or naphthyl. In general, aryl groups may be linked to the rest of the molecule by any available carbon atom via a direct bond or via a C1-C4 alkylene group such as methylene or ethylene.
The term “heteroaryl” relates to groups having the meaning of aromatic and partially aromatic groups of a monocyclic or bicyclic ring with 4 to 12 carbon atoms, at least one of them being a hetero atom such as O, S or N, and the available nitrogen atom or carbon atom is the binding site of the group to the rest of the molecule either via a direct bond or via a C1-C4 alkylene group defined earlier. Examples of this type are thiophenyl, pyrrolyl, imidazolyl, pyridinyl, oxazolyl, thiazolyl, pyrazolyl, tetrazolyl, pirimidinyl, pyrazinyl, quinolinyl or triazinyl.
The term “heterocycle” relates to five-member or six-member, fully saturated or partly unsaturated heterocyclic groups containing at least one hetero atom such as O, S or N, and the available nitrogen atom or carbon atom is the binding site of the group to the rest of the molecule either via a direct bond or via a C1-C4 alkylene group defined earlier. The most frequent examples are morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, pirazinyl or imidazolyl.
The term “alkanoyl” group relates to straight chains of acyl group such as formyl, acetyl or propanoyl.
The term “aroyl” group relates to aromatic acyl groups such as benzoyl.
The term “optionally substituted alkyl” relates to alkyl groups which may be optionally additionally substituted with one, two, three or more substituents. Such substituents may be halogen atom (preferably fluorine or chlorine), hydroxy, C1-C4 alkoxy (preferably methoxy or ethoxy), thiol, C1-C4 alkylthio (preferably methylthio or ethylthio), amino, N—(C1-C4) alkylamino (preferably N-methylamino or N-ethylamino), N,N-di(C1-C4-alkyl)-amino (preferably dimethylamino or diethylamino), sulfonyl, C1-C4 alkylsulfonyl (preferably methylsulfonyl or ethylsulfonyl), sulfinyl, C1-C4 alkylsulfinyl (preferably methylsulfinyl).
The term “optionally substituted alkenyl” relates to alkenyl groups optionally additionally substituted with one, two or three halogen atoms. Such substituents may be e.g. 2-chloroethenyl, 1,2-dichloroethenyl or 2-bromo-propene-1-yl.
The term “optionally substituted aryl, heteroaryl or heterocycle” relates to aryl, heteroaryl or heterocyclic groups which may be optionally additionally substituted with one or two substituents. The substituents may be halogen (preferably chlorine or fluorine), C1-C4 alkyl (preferably methyl, ethyl or isopropyl), cyano, nitro, hydroxy, C1-C4 alkoxy (preferably methoxy or ethoxy), thiol, C1-C4 alkylthio (preferably methylthio or ethylthio), amino, N—(C1-C4) alkylamino (preferably N-methylamino or N-ethylamino), N,N-di(C1-C4-alkyl)-amino (preferably N,N-dimethylamino or N,N-diethylamino), sulfonyl, C1-C4 alkylsulfonyl (preferably methylsulfonyl or ethylsulfonyl), sulfinyl, C1-C4 alkylsulfinyl (preferably methylsulfinyl).
When X has the meaning of NRa, Ra relates to hydrogen or group selected from the alkyl (preferably methyl or ethyl), alkanoyl (preferably acetyl), alkoxycarbonyl (preferably methoxycarbonyl or tert-butoxycarbonyl), arylmethoxycarbonyl (preferably benzyloxycarbonyl), aroyl (preferably benzoyl), arylalkyl (preferably benzyl), alkylsilyl (preferably trimethylsilyl) or alkylsilylalkoxyalkyl (preferably trimethylsilylethoxymethyl).
When R3 and R4 together with N have the meaning of heteroaryl or heterocycle, this means that such heteroaryl or heterocycle has at least one carbon atom replaced by a nitrogen atom through which the groups are linked to the rest of the molecule. Examples of such groups are morpholine-4-yl, piperidine-1-yl, pyrrolidine-1-yl, imidazole-1-yl or piperazine-1-yl.
Depending upon the nature of particular substituents, the compounds of the formula I may have geometric isomers and one or more chiral centres so that there can exist enantiomers or diastereoisomers. The present invention also relates to such isomers and mixtures thereof, including racemates.
The present invention also relates to all possible tautomeric forms of particular compounds of the formula I.
Whenever used hereinafter, the term “compounds of formula I” or “compounds of the present invention” is meant to also include the pharmaceutically acceptable addition salts and solvates.
In one embodiment of the present invention preferred compounds of formula I are those wherein X represents CH2, O, S, or NRa, wherein Ra is hydrogen or substituent selected from the group consisting of C1-C3-alkyl (preferably methyl, ethyl, propyl or isopropyl), C1-C3-alkanoyl (acetyl), C6-C10-aroyl (preferably benzoyl) and C7-C10-arylalkyl (preferably benzyl).
In another embodiment of the present invention preferred compounds of formula I are those wherein Y and Z independently from each other mean one or more identical or different substituents linked to any available carbon atom selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C1-C4-alkyl (preferably methyl, ethyl, propyl or isopropyl), trifluoromethyl, halo-C1-C4-alkyl, hydroxy, C1-C4-alkoxy (preferably methoxy), trifluoromethoxy, C1-C4-alkanoyl (preferably acetyl), amino, amino-C1-C4-alkyl, C1-C4-alkylamino, N—(C1-C4-alkyl)amino (preferably N-methyl or N-ethyl), N,N-di(C1-C4-alkyl)amino (preferably dimethylamino or diethylamino), thiol, C1-C4-alkylthio (preferably methylthio), cyano and nitro.
In yet another embodiment of the present invention preferred compounds of formula I are those wherein R1 has the meaning of hydrogen, halogen, C1-C7-alkyl optionally substituted with one, two, three or more substituents selected from the group consisting of halogen atom (preferably fluorine or chlorine), hydroxy, C1-C4 alkoxy (preferably methoxy), thiol, C1-C4 alkylthio (preferably methylthio), amino, N—(C1-C4) alkylamino (preferably N-methyl or N-ethyl) and N,N-di(C1-C4-alkyl)-amino (preferably dimethylamino or diethylamino); C2-C7 alkenyl optionally substituted with one, two, three or more halogen atoms; C2-C7 alkinyl, monocyclic or bicyclic aryl group having from 6 to 10 carbon atoms and altering double bond and said group can be optionally substituted with one or two substituents selected from the group consisting of fluoro, chloro, C1-C4 alkyl (preferably methyl, ethyl, propyl or isopropyl), cyano, nitro, hydroxy, C1-C4 alkoxy (preferably methoxy), thiol, C1-C4 alkylthio (preferably methylthio), amino, N—(C1-C4) alkylamino (preferably N-methyl or N-ethyl), N,N-di(C1-C4-alkyl)-amino (preferably dimethylamino or diethylamino) and can be linked to the rest of the molecule by any available carbon atom via direct bond or via C1-C4 alkylene group; monocyclic or bicyclic heteroaryl having the meaning of aromatic and partially aromatic groups of a monocyclic or bicyclic ring with 4 to 12 carbon atoms and at least one of them being heteroatom selected from the group consisting of O, S and N wherein available carbon or nitrogen represent the binding site of the group to the rest of the molecule either via direct bond or via C1-C4 alkylene group and where said heteroaryl can be optionally substituted with fluoro, chloro, C1-C4 alkyl (preferably methyl, ethyl, propyl or isopropyl), cyano, nitro, hydroxy, C1-C4 alkoxy (preferably methoxy), thiol, C1-C4 alkylthio (preferably methylthio), amino, N—(C1-C4) alkylamino (preferably N-methyl or N-ethyl), N,N-di(C1-C4-alkyl)-amino (preferably dimethylamino or diethylamino); five-member or six-member fully saturated or partly unsaturated heterocycle group containing at least one hetero atom selected from the group consisting of O, S and N wherein carbon or nitrogen represent the binding site of the group to the rest of the molecule either via direct bond or via C1-C4 alkylene group and where said heterocycle can be optionally substituted with fluoro, chloro, C1-C4 alkyl (preferably methyl, ethyl, propyl or isopropyl), cyano, nitro, hydroxy, C1-C4 alkoxy (preferably methoxy), thiol, C1-C4 alkylthio (preferably methylthio), amino, N—(C1-C4) alkylamino (preferably N-methyl or N-ethyl), N,N-di(C1-C4-alkyl)-amino (preferably dimethylamino or diethylamino); hydroxy, C1-C7 alkoxy (preferably methoxy), thiol, C1-C7 alkylthio (preferably methylthio), amino, N—(C1-C7 alkyl)amino (preferably N-methyl or N-ethyl), N,N-di-(C1-C7 alkyl)amino (preferably dimethylamino or diethylamino), C1-C7 alkanoyl (preferably acetyl), aroyl (preferably benzoyl), C1-C7 alkanoyloxy, an C1-C7 alkyloxycarbonyl or aryloxycarbonyl, carbamoyl, N—(C1-C7-alkyl)carbamoyl, N,N-di(C1-C7-alkyl)carbamoyl, cyano, cyano-C1-C7 alkyl, nitro,
In yet another embodiment of the present invention the specifically preferred compounds of formula I are:
Generally, the compounds of 2-thia-dibenzo[e,h]azulene class, their pharmaceutically acceptable salts and solvates represented by the formula I can be prepared by the processes set forth in our earlier International publication WO 03/084962, herein incorporated by reference in its entirety as amended with letter of 15.04.2004.
The compounds of the present invention are especially effective in treating those diseases and disorders where the neurochemical equilibrium of biogenic amines such as serotonin, norepinephrine and dopamine was disturbed and which may be caused by unbalanced (too big or too small) synthesis, irregularities in storing, releasing, metabolizing and/or reabsorption of a certain neurotransmitter.
It has been found that the compounds of the present invention exhibit a significant affinity for binding and have a high degree of selectivity to serotonin receptors, especially to 5-HT2A and 5-HT2C, as well as for σ1 receptor.
In one embodiment of the present invention the compounds of formula I, or salts, or solvates thereof show binding affinity to 5-HT2A and 5-HT2C serotonin receptors in the concentration expressed as an IC50 value less than 1 μM and having a Ki value less than 1 μM.
In another embodiment of the present invention the compounds of formula I, or salts, or solvates thereof show binding affinity to 5-HT2A serotonin receptor in the concentration expressed as an IC50 value less than about 200 nM and having a Ki value less than about 100 nM.
In yet another embodiment of the present invention the compounds of formula I, or salts, or solvates thereof show binding affinity to 5-HT2C serotonin receptor in the concentration expressed as an IC50 value less than about 200 nM and having a Ki value less than about 100 nM.
It has been found that the compounds of the present invention exhibit a significant binding affinity to σ1 receptor.
In one embodiment of the present invention the compounds of formula I, or salts, or solvates thereof show binding affinity to σ1 receptor in the concentration expressed as an IC50 value less than 1 μM and having a Ki value less than 1 μM.
In another embodiment of the present invention the compounds of formula I, or salts, or solvates thereof show binding affinity to σ1 receptor in the concentration expressed as an IC50 value less than about 200 nM and having a Ki value less than about 100 nM.
Since serotonin receptors are crucial in pathophysiology of a series of CNS disorders (directly or indirectly by participating in the activation of some other neurotransmitter e.g. dopamine and/or receptor), the compounds of the present invention may be used for the manufacture of pharmaceutical formulations for the treatment and prevention of diseases, damages and disorders, wherein biogenic amines and their receptors play an important role.
In view of the above explained favourable biological properties of the compounds of the present invention administration of a therapeutically effective amount of a compound of formula I provides an effective method of treatment of CNS diseases and disorders associated with fewer side effects due to their improved selectivity towards σ1 receptor and 5-HT2A and 5-HT2C serotonin receptors.
Pharmaceutical Compositions
In general, the compounds of the present invention may be used for the manufacture of pharmaceutical formulations that are used as antidepressants, anxiolytics, antipsychotics or as drugs for treating migraine.
Further, the compounds of the present invention may be used for the manufacture of pharmaceutical formulations for the treatment and prevention of diseases and disorders, which are the result of disorders of neurochemical equilibrium in the central nervous system such as e.g. depression and modest depression, anxiety, bipolar disorders, sleeping disorders, sexual disorders, psychoses, borderline psychoses, schizophrenia, migraine, personality disorders and obsessive-compulsive disorders, social phobias or panic attacks, organic mental disorders in children, aggression, memory disorders and personality disorders in elderly people, addiction, obesity, bulimia and similar disorders, snoring, premenstrual troubles.
Likewise, these compounds of the present invention may be used for the manufacture of pharmaceutical formulations for the treatment and/or prevention of CNS damage caused by trauma, brain stroke, neurodegenerative diseases, cardiovascular disorders such as high blood pressure, thrombosis, infarct and similar diseases as well as in gastrointestinal disorders.
The effective dose of the active substance of the present invention and of a pharmaceutically acceptable salt or solvate thereof depends on the efficacy of the compound of the general formula I, on the nature and the severity of the disease and the disorder of the CNS as well as on the body weight of the patient treated and may be from 0.001-10 mg/kg body weight. In any case a unit dose for an adult of an average weight of 70 kg is understood to be 0.07-1000 mg of the compound of the general formula I or of a pharmaceutically acceptable salt or solvate thereof. A unit dose may be administered once or several times daily, e.g. 2, 3 or 4 times daily, most frequently 1 to 3 times daily.
The present invention more specifically relates to an effective dose of the compounds which bind to serotonin, sigma, adrenergic, dopamine or muscarinic receptors and/or act as inhibitors of reabsorption of one or more biogenic amines (serotonin, dopamine, norepinephrine).
The term “salts” can include acid addition salts or addition salts of free bases. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include but are not limited to salts derived from nontoxic inorganic acids such as nitric, phosphoric, sulfuric, or hydrobromic, hydroiodic, hydrofluoric, phosphorous, as well as salts derived from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyl alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and acetic, maleic, succinic, or citric acids. Non-limiting examples of such salts include napadisylate, besylate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S. M. et al. “Pharmaceutical Salts,” J. of Pharma. Sci., 1977; 66:1).
The acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.
The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid.
Preferred pharmaceutically acceptable salts according to the invention relate to salts of hydrobromic, hydrochloric, perchloric, sulfuric, maleic, fumaric, tartaric, citronic, benzoic, mandelic, methanesulfonic, benzenesulfonic, oxalic, p-toluenesulfonic, 2-naphthalenesulfonic, phosphoric acids.
Pharmaceutically acceptable solvates formed by the compounds represented by formula I or their salts relate to hydrates, ethanolates and similar (most frequently hydrates).
The phrase “pharmaceutically acceptable”, as used in connection with compositions of the invention, refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., human). Preferably, as used herein, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeias for use in mammals, and more particularly in humans.
Further, the present invention relates to a pharmaceutical formulation containing an effective non-toxic dose of the compounds of the present invention as well as pharmaceutically acceptable carriers or solvents.
The term “carrier” applied to pharmaceutical compositions of the invention refers to a diluent, excipient, or vehicle with which an active compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. However, since memantine is highly soluble, aqueous solutions are preferred. Suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin, 18th Edition. Particularly preferred for the present invention are carriers suitable for immediate-release, i.e., release of most or all of the active ingredient over a short period of time, such as 60 minutes or less, and make rapid absorption of the drug possible.
A “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the present application includes both one and more than one such excipient.
The pharmaceutical formulations are obtained by blending a therapeutically active amount of a compound of formula I as the active ingredient with a pharmaceutically acceptable carrier, which may have different forms depending on the desired administration route. These pharmaceutical formulations especially relate to oral, sublingual, rectal, percutaneous or parenteral administration route.
Pharmaceutical formulations may be manufactured using conventional pharmaceutical auxiliaries and manufacture routes. Forms for oral administration may be syrups, capsules, tablets and similar forms, where usual solid carriers are inert substances such as lactose, starch, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, mannitol and similar, and usual liquid oral auxiliaries include ethanol, glycerol, water and similar. All auxiliaries may be optionally blended with disintegrants, diluents, granulating agents, wetting agents, binders and similar by using conventional methods. Parenteral forms may be manufactured by using water or some other sterile carrier. When for the manufacture of oral formulations some of the common liquid carriers e.g. water, glycol, oils, alcohols and similar are used, the formulation may be in the form of syrup, emulsion, soft gelatine capsules or sterile injectable liquids e.g. ampoules, or of non-aqueous liquid suspensions. When for the manufacture of oral formulations a solid carrier such as starch, sugar, kaolin, wetting agents, binders, disintegrants and similar is used, the formulation may be in the form of a powder, capsule, tablet, hard gelatine capsules or granules that may be administered in capsules, and the amount of the solid carrier may vary (most frequently from 1 mg to 1 g). Due to their easy use, tablets and capsules are the most convenient oral formulations wherein a solid carrier is used. For parenteral formulations the carrier is mostly sterile water, though other ingredients may be contained therein as well in order to improve solubility. For the manufacture of injectable solutions, sodium chloride solution, glucose solution or a mixture thereof is used. Injectable solutions may also contain a component for a delayed release of the active component. Convenient oils that may be used for this purpose are e.g. arachic oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long-chain fatty acids or a mixture of some of said oils. Injectable suspensions may be manufactured in such a way that a suitable liquid carrier used is blended with a suspending agent. In formulations convenient for percutaneous administration, as a carrier there is understood a substance improving the penetration of the active substance and/or a suitable wetting agent, which may be combined with a suitable additive of any provenience, which additives do not cause harmful effects on skin.
Said additives may facilitate the skin administration and/or may be used in the manufacture of the desired formulations, which may be applied in various ways e.g. transdermally, spot-on, or in the form of an ointment.
To improve the solubility and/or stability of the present compounds, in pharmacological formulations there may be used α-, β- or γ-cyclodextrins or derivatives thereof, especially hydroxyalkyl substituted cyclodextrins i.e. 2-hydroxypropyl-β-cyclodextrin. Cosolvents such as e.g. alcohols may also improve the solubility and/or stability of the present compounds in various pharmaceutical formulations.
“Treating” or “treatment” of a state, disorder or condition includes:
The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.
A “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
Dosages and administration regimen can be adjusted depending on the age, sex, physical condition as well as the benefit acchieved by applying the compounds of the present invention and the side effects in the patient or the mammalian subject to be treated and the judgement of the physician, as is appreciated by those skilled in the art.
The term host or subject in need thereof as used herein refers to a mammal preferably a human.
Biological Assays
The effect of the compounds of the present invention on the neurochemical steady state was determined by in vitro investigations such as a radionuclide-marked radioligand binding assay for 5-HT2A (Bonhaus D. W. Br. J. Pharmacol. 1995, 115:622; Saucier C. J. Neurochem. 1997, 68:1998) and 5-HT2C receptors (Wolf W. A. J. Neurochem. 1997, 69:1449), in vitro binding assay for al receptor (Thomson W. and Donn R. Arthritis Res. 2002, 4: 302-306) and by in vivo investigations in a tail suspension test (Vogel H. G. and Vogel W. H. Drug Discovery and Evaluation Pharmacological Assays, Springer 1997, 304), in amphethamine-induced hyperlocomotion in mice (Millan M. J. et al, 1998 J Pharmacol. Exp. Ther. 287: 167-186) in a forced swim test in mice (Porsolt R. D. et al. Arch. Int. Pharmacodyn. 1977, 229:327-336), in meta-chlorophenyl piperazine (m-CPP) test on rats (Drug Dev. Res. 1989, 18:119-144) and in apomorphine, tryptamine, norepinephrine (ATN) test in rats (Arch. Int. Pharmacodyn. 1977, 227:238-253).
In Vitro Method for Determining Binding Affinity to 5-HT2A and 5-HT2C Receptors
A small concentration of a radioligand having a great affinity for binding to a receptor was incubated with a tissue sample enriched with a certain receptor (1-5 mg of tissue) in a buffered medium (0.2-5 μL). Recombinant human HT2A and HT2C receptors were expressed in CHO-K1 or COS-7 cells and were also used for competitive binding. During incubation the radioligand bound to the receptor. When a binding balance was achieved, the receptors to which the radioligand was bound were separated from those to which said ligand was not bound, and the radioactivity of the receptor/radioligand complex was measured. The interaction of the tested compounds with receptors was tested in competitive binding experiments. Various concentrations of tested compounds were added to the incubation mixture containing a prepared tissue enriched with corresponding receptors and the radioligand. The radioligand binding was inhibited by the test compounds proportionally to the affinity of a certain compound for the receptor and to the concentration of the compound.
The radioligand used for the determination of binding to 5-HT2A receptor was [3H]-ketanserin and the tissue used was human cortex or recombinant 5-HT2A receptor expressed in CHO-K1 cells.
The radioligand used for the determination of binding to 5-HT2C receptor was [3H]-mesulergine and the tissue used was choroid plexus or recombinant 5-HT2C receptor expressed in CHO-K1 cells.
Compounds showing IC50 and Ki values lower than 1 μM, were considered to be active. Compounds: [3-(2,8-dithia-dibenzo[e,h]azulen-1-ylmethoxy)-propyl]-dimethyl-amine, [2-(2,8-dithia-dibenzo[e,h]azulen-1-ylmethoxy)-ethyl]-dimethyl-amine, dimethyl-[3-(8-oxa-2-thia-dibenzo[e,h]azulen-1-ylmethoxy)-propyl]-amine, dimethyl-[2-(8-oxa-2-thia-dibenzo[e,h]azulen-1-ylmethoxy)-ethyl]-amine, [2-(5-chloro-8-oxa-2-thia-dibenzo[e,h]azulen-1-ylmethoxy)-ethyl]-dimethyl-amine, 3-(1-chloro-8-oxa-2-thia-dibenzo[e,h]azulen-1-ylmethoxy)-propylamine and 3-(8-oxa-2-thia-dibenzo[e,h]azulen-1-ylmethoxy)-propylamine showed binding affinity to 5-HT2A and 5-HT2C serotonin receptors expressed as IC50 value less than 200 nM and Ki value less than 100 nM.
It is anticipated that similar results will be observed for other compounds of the invention.
In Vitro Method for Determining Binding Affinity to σ1 Receptor
Jurkat cell were grown in medium, RPMI supplemented with 10% fetal bovine serum, 100 U/ml penicillin and 100 μg/ml streptomycin, collected and their suspension homogenized. After centrifugation, the membrane fraction was separated, resuspended in phosphate buffer (pH=7.5) and stored in small aliquots in liquid nitrogen until use. Binding of different radiolabeled ligands to Jurkat cell membranes was measured as described previously (Ramamoorthy et al., 1995). To characterize the σ binding sites in the Jurkat cell line, [3H]haloperidol was first used as the ligand. Haloperidol is a high affinity ligand to both type 1 and type 2 σ-receptors. The binding assays were done using Jurkat cell membranes in the presence of [3H]haloperidol (100 nM) alone to determine the total binding, and in the presence of [3H]haloperidol (10 nM) and unlabeled haloperidol (10 μM) to determine the nonspecific binding. Membranes were incubated with ligands in phosphate buffer for 3 hours at room temperature. After the filter had been washed, radioactivity associated with the filter was determined by liquid scintillation spectrometry.
Compounds showing IC50 and Ki values lower than 1 μM, were considered to be active. Compounds: [3-(2,8-dithia-dibenzo[e,h]azulen-1-ylmethoxy)-propyl]-dimethyl-amine, [2-(2,8-dithia-dibenzo[e,h]azulen-1-ylmethoxy)-ethyl]-dimethyl-amine, dimethyl-[2-(8-oxa-2-thia-dibenzo[e,h]azulen-1-ylmethoxy)-ethyl]-amine and [2-(5-chloro-8-oxa-2-thia-dibenzo[e,h]azulen-1-ylmethoxy)-ethyl]-dimethyl-amine showed binding affinity to σ1 receptor expressed as IC50 value less than 200 nM and Ki value less than 100 nM.
It is anticipated that similar results will be observed for other compounds of the invention.
Forced Swim Test in Mice
Male CD1 mice of a weight of 20-25 g were used for the experiment. Groups of 10 animals were treated with the test compounds, imipramine (positive control) or the vehicle (negative control) per os by gavage 30 min prior to testing to determine efficacy. On the day of the experiment the animals were placed into a glass cylinder (height 18.2 cm, diameter 13.3 cm) filled with water warmed to 22° C. to the height of 10 cm. The immobility defined as the end of the struggling of the animal and the beginning of floating, wherein the movements were reduced to those indispensable for the animal to keep its head over the water surface, started to be recorded after two minutes and then it was monitored during 4 minutes.
The percentage of animals showing a passive behaviour was calculated and compared with a control group treated with a vehicle. The compounds that in a dose of 10 mg/kg reduced the immobility of animals for 30% and more over the control group were considered to be active.
Compound [3-(2,8-dithia-dibenzo[e,h]azulen-1-ylmethoxy)-propyl]-dimethyl-amine at the test doses of 0,1 mg/kg and 0,01 mg/kg showed reduction of immobility in a range of 30 to 40%.
It is anticipated that similar results will be observed for other compounds of the invention.
Tail Suspension Test in Mice
Male Balb/cJ mice of the weight of 20-25 g were used for the experiment. Groups of 9 animals were treated with the test compounds, imipramine (positive control) or the vehicle (negative control) by intraperitoneal injection, subcutaneous injection or per oral by gavage 30 min prior to testing to measure potential antidepressant activity. Mice were suspended from their tails at a height of about 90 cm and were observed for 5 minutes. The mice hanging fully motionless for 1 minute during the observation period were defined as depressive. In animals treated with a substance having an antidepressive action the period of immobility was shortened.
The percentage of animals showing a passive behaviour was calculated and compared with a control group treated with a vehicle. Significance of results was analysed using Fischer's exact test. The compounds that in a dose of 10 mg/kg reduced the immobility of animals for 40% and more over a control group were considered to be active. Compounds: [3-(2,8-dithia-dibenzo[e,h]azulen-1-ylmethoxy)-propyl]-dimethyl-amine, [2-(2,8-dithia-dibenzo[e,h]azulen-1-ylmethoxy)-ethyl]-dimethyl-amine, dimethyl-[3-(8-oxa-2-thia-dibenzo[e,h]azulen-1-ylmethoxy)-propyl]-amine and dimethyl-[2-(8-oxa-2-thia-dibenzo[e,h]azulen-1-ylmethoxy)-ethyl]-amine at the test doses of 1 mg/kg, 0,1 mg/kg and 0,01 mg/kg showed 40-100% reduction of immobility.
It is anticipated that similar results will be observed for other compounds of the invention.
Amphetamine-Induced Hyperlocomotion in Mice
Male Swiss OFA mice of a weight 30-35 g were treated with either vehicle (saline) or test compounds 30 minutes prior to hyperlocomotion induction. Dexamphetamine sulphate was administered intraperitoneally at 2 mg/kg. Thirty minutes later, animals were placed in a wooden box 80×80 cm2 in a room with low light intensity (100 lux) for locomotor activity recording. Locomotor activity was determined during a 30 min period using a video image analyzer. Total duration of movement, occurence of movement and total distance travelled were measured. Haloperidol was tested at the dose of 0,25 mg/kg (prepared in 0.5% methylcellulose) and served as reference substance.
Compounds were considered as active if in a dose of 10 mg/kg reduced amphetamine-induced hyperlocomotion in experimental animals for 30% and more when compared to vehicle treated control group.
Compound [2-(2,8-dithia-dibenzo[e,h]azulen-1-ylmethoxy)-ethyl]-dimethyl-ammonium citrate prepared in saline and given per os at the test doses of 1 mg/kg and 0,1 mg/kg showed 40-60% inhibition of amphetamine-induced hyperlocomotion in mice.
It is anticipated that similar results will be observed for other compounds of the invention.
Meta-Chlorophenyl Piperazine (M-CPP) Test on Rats
The tested substance was administered to rats per os 1 hour before the test and m-CPP in a dose of 1 mg/kg was administered intravenously 15 minutes before the test. At the beginning of the experiment the treated animals were subjected to an open field test (Drug Dev. Res. 1989, 18, 119-144): the apparatus consisted of an open box having the dimensions 80×65×35 cm3, which in one wall had an opening with a diameter of 10 cm, by which it was connected to a non-illuminated compartment having the dimensions 25×21×21 cm3, and the opening was illuminated by a light source (IR source or Kleverlux®; 12 V/20 W) from the distance of 66 cm; one hour after administering the tested substance, the animals were placed in the dark (non-illuminated) compartment so that their heads were turned away from the illuminated exit and the passing of the animals from the dark compartment to the bright one was measured for 10 minutes.
As an active dose of the substance there was defined a dose at which the effect induced by m-CPP was reduced for 40% and more.
Apomorphine, Tryptamine, Norepinephrine (ATN) Test in Rats
At the beginning of the experiment (t=0) the animals were injected intravenously by 1.25 mg/kg of apomorphine, then by 40 mg/kg of tryptamine (t=60 minutes) and by 1.25 mg/kg of norepinephrine (t=90 minutes).
There were watched a state of exceptional agitation and normal behaviour during 60 minutes (apomorphine test), then bilateral clonic convulsions of back paws and a general tremor of the body in tryptamine test (observation period 5 minutes) and lethality during 120 minutes after the injection in norepinephrine test.
The percentage of animals showing a passive behaviour was calculated and compared with a control group treated with a carrier.
The compounds, which in a dose of 10 mg/kg reduced the period of duration of observed effects (mobility) for 40% over a control group were considered to be active in in vivo testings.
Some of the present compounds tested in the above assays showed an action in at least two of said tests, though these results represent only an illustration of the biological action of the compounds and do not limit the present invention in any way.
| Number | Date | Country | Kind |
|---|---|---|---|
| P20030885A | Nov 2003 | HR | national |
This application is a continuation of PCT International Patent Application No. PCT/HR2004/000042, filed Nov. 3, 2004, which claims priority of Croatian Patent Application No. P20030885A, filed Nov. 3, 2003.
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/HR04/00042 | Nov 2004 | US |
| Child | 11381163 | May 2006 | US |
