KR20100022955A - (thio) -carbamoyl-cyclohexane derivatives and method for treating schizophrenia - Google Patents

Abstract

The present invention relates to use of (thio)-carbamoyl-cyclohexane derivatives, particularly trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of schizophrenia. Furthermore, the present invention relates to the treatment of schizophrenia through the administration of (thio)-carbamoyl cyclohexane derivatives, particularly trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine and pharmaceutically acceptable salts thereof.

Description

(Thio) -carbamoyl-cyclohexane derivatives and methods for treating schizophrenia {(THIO) -CARBAMOYL-CYCLOHEXANE DERIVATIVES AND METHOD FOR TREATING SCHIZOPHRENIA}

The invention relates to (thio) -carbamoyl-cyclohexane derivatives, in particular trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl]-in the manufacture of a medicament for the treatment of schizophrenia. Ethyl} -N, N-dimethylcarbamoyl-cyclohexylamine and pharmaceutically acceptable salts thereof. The invention also relates to (thio) -carbamoyl cyclohexane derivatives, in particular trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl] -N, N And to treat schizophrenia through the administration of -dimethylcarbamoyl-cyclohexylamine and its pharmaceutically acceptable salts.

Schizophrenia is a life-threatening mental disorder with an estimated incidence of approximately 1% worldwide, including 3.2 million Americans (see, for example, the National Institute of Mental Health, Schizophrenia, http // www.nimh.nih.gov / healthinformation / Schizophrenia menu.cfm 2006; Mueser and McGurk, Lancet 2004; 363: 2063-72, 2004). This disorder usually occurs during adolescence or adolescence; The main symptom is classified into three domains: positive symptoms such as illusion and delusion; Negative symptoms such as impulse and recluse alone; And cognitive symptoms such as problems related to attention and memory. These result in social and occupational dysfunction, which in turn have a significant impact on the family and the individual's position in the wider society. In addition to mental symptoms, schizophrenic patients are more at risk of medical co-occurrence than the general population.

Drug treatment with dopamine antagonists is the touchstone for managing schizophrenia during the acute as well as the residual phases. Current guidelines recommend atypical antipsychotics, including risperidone, olanzapine, gumtiapine, ziprasidone, and aripiprazole as the first treatment of schizophrenia. These drugs can be constantly characterized by dual mode of action: In addition to antagonism of the dopamine D ₂ receptor, they are also potent inhibitors in the serotonin 5-HT _2A receptor.

While improved over traditional neuroleptics, atypical antipsychotics still have drawbacks in effective management of the disease. In particular, these drugs are associated with the development of side effects (eg, extrapyramidal symptoms at high doses [EPSs], sedation, cardiovascular effects such as QTc prolongation, liver modification, effects on sexual function, weight gain, metabolic abnormalities). In addition, treatment resistance remains as high as 10% to 30% of patients with low or no response to currently available antipsychotic drugs, and only 30% of patients with partial therapeutic responses (see, eg, Lehman et. al, Am . J. Psychiatry , 161 (2 Suppl), 1-56, 2004). This results in the use of conventional clinical trials of high dosage atypical, antipsychotic multidose and other psychotic drug augmentations (see, eg, Zink et al, Eur . Psychiatry , 19: 56-58, 2004; Stahl and Grady, Curr . Med . Chem ., 11, 313-27, 2004).

According to the American Psychiatric Association guidelines for schizophrenia, 60% to 70% of patients spend one year without maintenance therapy and nearly 90% spend two years (see, eg, Lehman et al. , Am . J. Psychiatry , 161 (2 Suppl), 1-56, 2004).

Overall, there is still an unmet medical need that is important in the treatment of schizophrenia and much effort is needed to develop improved antipsychotics.

In this study, the D ₃ dopamine receptor has emerged as a possible target for antipsychotic drug treatment. This strategy is based on the brain distribution and suggested role of the D ₃ receptor and has the highest density in the ventral striatum (e.g., Gurevich and Joyce, Neuropsychopharmacology , 20, 60-80, 1999), in disease pathology. One of the core areas. Dopamine D ₃ receptors exhibit motor activity (e.g. Shafer and Levant, Psychopharmacology (Berl), 135, 1-1, 1998) and cognitive action (e.g. Ukai et al, Eur . J. Pharmacol , 324, 147-51). , 1997;... Smith et al, Pharmacol Biochem Behav, 63, appears to participate in 201-11, 1999). Selective antagonists of dyskinesia (ankylosing) regulated or eliminated in rodent models induced by D ₂ antagonists (see, eg, Millan et al, Eur . J. Pharmacol , 321, R7-9, 1997; Gyertyan et al, [ Int . J. Neuropsychopharmacol . , 5 Suppl. 1, 174, 2002) do not cause motor side effects or increase prolactin levels when treated alone (see, for example, Reavill et al, AJ Pharmacol . Exp) . . Ther, 294, 1154-65, 2000 ;.... Millan et al, J. Pharmacol Exp Ther, 293, 1063-73, 2000). This presents a significantly reduced extracorporeal liability. D ₃ antagonists are used in a variety of drugs in rodents (eg Sigala et al, Eur. J. Pharmacol, 336, 107-12, 1997; Laszy et al, Psychopharmacology (Berl), 179, 567-75, 2005) and primates. It has been found to improve the cognitive deficiency caused by this, suggesting the possibility of a promising approach to the treatment of cognitive disorders of schizophrenia. Dopamine D ₃ receptor antagonists increase the motor activity in the habitual environment (See. For example Waters et al, J. Neural transm Gen Sect, 98, 39-55, 1994; Sautel et al, J. Pharmacol Exp . Ther ., 275, 1239-46, 1995; Gyertyan and Saghy, Behav. Pharmacol , 15, 253-62, 2004). This activating effect can be found to be effective against the negative symptoms of the disease.

However, the lack of the effects of selective D ₃ antagonists in the various animal models used to assess (human) antipsychotic effects has been shown to be effective in "pure" D ₃ antagonists alone to be strong enough to justify clinical development. Suggest that you may not have. Occupancy of about 60% to 80% of the dopamine D ₂ receptor has been shown to be necessary to achieve antipsychotic effects in the clinic (see, eg, Nyberg et al, Br . J. Psychiatry. Suppl , (29), 40-4, May 1996; Seeman, Clin . Neurosci . Res ., 1, 53-60, 2001). The latter phenomenon provides the basis for the aspect that D ₂ antagonism is essential for antipsychotic action. Therefore, D ₂ addition of D ₃ antagonism to the antagonistic action is that it can provide an increased effect on the clear advantage, that no EPSs, improved cognitive potential, and negative symptoms relative to the existing antipsychotics in the treatment of schizophrenia Is considered.

US Patent Publication No. 2006/0229297 discloses (thio) -carbamoyl-cyclohexane derivatives which are D ₃ and D ₂ dopamine receptor subtype preferred ligands having the formula (I):

In the formula, R ₁ , R ₂ , X, and n are as defined herein.

Hungarian patent application No. P0700339 discloses trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N-dimethylcarbamoyl-cyclohexylamine Initiate salts. One particular compound described herein is trans-l- {4- [2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl] -cyclohexyl} -3,3-dimethyl Trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl] -N, N-dimethylcarbamoyl-cyclohexylamine hydro, also known as -urea hydrochloride Chloride, the chemical formula of which is:

These (thio) -carbamoyl-cyclohexane derivatives are orally active and very potent dopamine D ₃ / D ₂ receptor antagonists and bind much more strongly to D ₃ than the D ₂ receptor. D ₃ receptor antagonism is about one more large D ₂ times compared to receptor antagonism, which is believed to offset some of the side effects outside of the vertebral body produced by D ₂ receptor antagonists. In addition to the increased relative affinity for dopamine D ₃ relative to D ₂ , for example, trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N- Dimethylcarbamoyl-cyclohexylamine hydrochloride has low efficacy at other receptor sites such as 5-HT ₂ c, histamine H ₁ , and adrenergic receptor sites, which are more likely for side effects such as EPS and weight gain. Present the low.

Thus, there is still a need for effective therapies to treat schizophrenia symptoms and cognitive effects associated with schizophrenia without the side effects associated with traditional therapies.

Summary of the Invention

The invention relates to (thio) -carbamoyl-cyclohexane derivatives of formula (I), in particular trans-4- {2- [4- (2,3-dichlorophenyl) -piperazine-, in the manufacture of a medicament for the treatment of schizophrenia. 1-yl] -ethyl} -N, N-dimethylcarbamoyl-cyclohexylamine and pharmaceutically acceptable salts thereof. The invention also relates to (thio) -carbamoyl cyclohexane derivatives of formula (I), in particular trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} A method of treating schizophrenia through the addition of -N, N-dimethylcarbamoyl-cyclohexylamine and its pharmaceutically acceptable salts.

Detailed description of the invention

The present invention relates to (thio) -carbamoyl-cyclohexane derivatives of formula (I) and / or geometric isomers and / or stereoisomers and / or diastereomers and / or salts thereof in the manufacture of a medicament for the treatment of schizophrenia. And / or hydrates and / or solvates and / or polymorphic uses:

In the formula,

R ₁ and R ₂ are independently of each other hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aroyl, or R ₁ and R ₂ combine with adjacent nitrogen atoms to form a heterocyclic ring; X is O or S; n is 1 or 2.

In certain embodiments, if R ₁ and / or R ₂ are alkyl, these alkyl moieties may be straight or branched and contain about 1 to about 6 carbon atoms (particularly 1 to 4 carbon atoms), and in some cases, more than ₁ C 1 _-6 alkoxycarbonyl, aryl (e.g. phenyl), or (C _1-6 alkoxycarbonyl) -C _{1 -6} alkyl group, or which may be substituted by a combination thereof, a substituted or unsubstituted Ring saturated saturated hydrocarbon radical.

In an additional embodiment, R ₁ and R ₂ combine with adjacent nitrogen atoms to form a heterocyclic ring, which may be a saturated or unsaturated, optionally substituted monocyclic or bicyclic ring, O, N, or S It may further contain a heteroatom selected from. For example, the heterocyclic ring may be pyrrolidine, piperazine, piperidine or morpholine.

As an additional embodiment, if R ₁ and / or R ₂ are alkenyl, these alkenyl moieties may have 2 to 7 carbon atoms and 1 to 3 double bonds.

As an additional embodiment, if R ₁ and / or R ₂ are aryl, such aryl moieties may be, but are not limited to, such as phenyl, naphthyl, fluorononyl, or anthraquinonyl groups (such as phenyl or naphthyl) It may be selected from substituted monocyclic, bicyclic or tricyclic aryl. And the aryl moiety is one or more C _{1 -6} alkoxy, trifluoromethyl -C _{1 -6} alkoxy, C _{1 -6} alkoxycarbonyl, C _{1 -6} alkanoyl, aryl, C _{1 -6} alkylthio, halogen, cyano It may be substituted by a group or a combination thereof.

As an additional embodiment, if R ₁ and / or R ₂ are cycloalkyl, these cycloalkyl moieties may be selected from substituted monocyclic, bicyclic or tricyclic cycloalkyl groups, such as cyclohexyl or adamantyl. have.

In an additional embodiment, if R ₁ and / or R ₂ are aroyl, such aryl moieties are as defined above, such as phenyl.

Pharmaceutically acceptable salts include those obtained by reacting a main compound serving as a base with an inorganic or organic acid to form a salt, such as hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, Salts of maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carboxylic acid. Pharmaceutically acceptable salts also include the major compounds acting as acids and reacting with appropriate bases to form, for example, sodium, potassium, calcium, magnesium, ammonium, and choline salts. Those skilled in the art will appreciate that acid addition salts of the claimed compounds can be prepared by reacting the compounds with the appropriate inorganic or organic acid via a number of known methods. Alternatively, alkali and alkaline earth metal salts can be prepared by reacting a compound of the present invention with an appropriate base through a number of known methods.

Other examples of acid salts obtainable by reaction with inorganic or organic acids are: acetates, adipates, alginates, citrate, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, digluconates , Cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrobromide, hydroiodide, 2-hydroxy Ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, Propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoate T.

In one embodiment, the pharmaceutically acceptable salt is a hydrochloride salt.

Those skilled in the art will recognize that some of the compounds useful in the present invention may exist in different polymorphic forms. As is known in the art, polymorphisms are the ability of a compound to crystallize into one or more distinct crystals or "polymorphic" species. Polymorphs are polymorphic forms of compound molecules in the solid crystalline or solid state of compounds having two or more different configurations. Polymorphic forms of certain compounds are defined by the same chemical structure or composition and are distinguished in chemical structure as the crystal structure of two different chemical compounds. Use of such polymorphisms falls within the scope of the present invention.

Some of the compounds useful in the present invention may exist in different solvate forms. Solvates of the compounds of the present invention may be formed when solvent molecules are incorporated into the crystal lattice structure of the compound molecules during the crystallization process. For example, suitable solvates include hydrates such as monohydrates, dihydrates, sesquihydrates, and hemihydrates. The use of such solvates falls within the scope of the present invention.

The invention also relates to trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N-dimethyl, in particular in the manufacture of a medicament for the treatment of schizophrenia. Use of carbamoyl-cyclohexylamine and pharmaceutically acceptable salts thereof, more particularly trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N , N-dimethylcarbamoyl-cyclohexylamine hydrochloride.

In addition, the present invention provides a therapeutically effective amount of a compound of formula (I) and / or its geometric isomers and / or stereoisomers and / or diastereomers and / or salts and / or hydrates and / or solvates and / or polymorphs. A method for treating schizophrenia by administering to a patient in need thereof with an active ingredient. The present invention particularly relates to a therapeutically effective amount of trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N-dimethylcarbamoyl-cyclohexylamine or Pharmaceutically acceptable salts thereof, more particularly therapeutically effective amounts of trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N-dimethylcarba A method of treating schizophrenia by administering to patient in need thereof with moyl-cyclohexylamine hydrochloride as an active ingredient.

In certain embodiments, the active ingredient is about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg , About 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, or about 12 mg. In another embodiment, the active ingredient is administered in an amount within these dosage ranges. For example, in one embodiment, the active ingredient is administered in an amount of about 1.5 mg to about 4.5 mg. In another embodiment, the active ingredient is administered in an amount of about 6 mg to about 12 mg. In another embodiment, the active ingredient is administered in an amount of about 0.5 mg to about 12 mg.

In an exemplary embodiment, the active ingredient is in an amount of about 0.5 mg, about 1.0 mg, about 1.5 mg, about 3 mg, about 4.5 mg, about 6 mg, about 9 mg or about 12 mg, such as about 1.5 mg, It is administered in an amount of about 3 mg, about 4.5 mg, about 6 mg, about 9 mg or about 12 mg.

The desired dose may be administered in one or more daily subdose at appropriate time intervals per day, or alternatively in a single dose, such as for example morning or evening administration. For example, the daily dose may be administered in divided doses of one, two, three or four times.

The duration of treatment can be 10 years, years, months, weeks or days as long as the benefit exists.

In one embodiment, the invention provides about 0.5 mg of trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-l-yl-ethyl} -N, N-dimethylcarbamoyl- A method of treating schizophrenia by administering cyclohexylamine or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In one embodiment, the invention provides about 1.0 mg of trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N-dimethylcarbamoyl A method for treating schizophrenia by administering cyclohexylamine or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In one embodiment, the invention provides about 1.5 mg of trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N-dimethylcarbamoyl A method for treating schizophrenia by administering cyclohexylamine or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In another embodiment, the invention provides about 3 mg of trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N-dimethylcarbamoyl A method for treating schizophrenia by administering cyclohexylamine or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In another embodiment, the invention provides about 4.5 mg of trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N-dimethylcarbamoyl A method for treating schizophrenia by administering cyclohexylamine or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In another embodiment, the present invention provides about 6 mg of trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N-dimethylcarbamoyl A method for treating schizophrenia by administering cyclohexylamine or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In another embodiment, the invention provides about 9 mg of trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N-dimethylcarbamoyl A method for treating schizophrenia by administering cyclohexylamine or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In another embodiment, the present invention provides about 12 mg of trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N-dimethylcarbamoyl A method for treating schizophrenia by administering cyclohexylamine or a pharmaceutically acceptable salt thereof to a patient in need thereof.

 In an additional embodiment, the active ingredient administered is trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N-dimethylcarbamoyl -Cyclohexylamine hydrochloride.

In one embodiment, the active ingredient is administered in daily or divided doses.

In one embodiment, administration of the active ingredient provides a therapeutic effect in the treatment of cognitive symptoms of schizophrenia. In another embodiment, administration of the active ingredient provides a therapeutic effect in the treatment of positive symptoms of schizophrenia. In another embodiment, administration of the active ingredient provides a therapeutic effect in the treatment of negative symptoms of schizophrenia.

In another embodiment, the administration provides a therapeutic effect in the treatment of affective symptoms of schizophrenia, residual symptoms of schizophrenia, or schizophrenia.

The compound of formula (I) may be administered alone or as an active ingredient of a pharmaceutical composition.

A number of standard references are available describing the process of preparing various formulations suitable for administering the compounds according to the invention. Examples of possible formulations and formulations include, for example, Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current edition by Marcel Dekker, Inc. As well as in Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current edition).

Dosage modes and dosage forms relate to the therapeutic amount of the compound or composition that is desirable and effective for a given therapeutic application.

Suitable dosage forms include, but are not limited to, oral, rectal, sublingual, mucosal, nasal, ophthalmic, subcutaneous, intravenous, transdermal, spinal, intradural, intraarticular, intraarterial, subarachnoid, intrabronchial, lymph and intrauterine administration And other dosage forms for systemic delivery of the active ingredient. Formulations suitable for oral administration are preferred.

In order to prepare such pharmaceutical dosage forms, the active ingredient is intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical combination techniques. The carrier may take a variety of forms depending on the form of preparation desired for administration.

In preparing the compositions in oral dosage form, any type of pharmaceutical medium may be used. Thus, in the case of liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavors, preservatives, colorants and the like. For example in the case of powders, capsules and tablets and thin solid oral preparations, suitable carriers and additives include starch, sugars, diluents, granules, lubricants, binders, disintegrants and the like. Due to the ease of administration, tablets and capsules are the most advantageous oral dosage unit forms. If desired, tablets may be dragee or enteric coated by standard techniques.

For parenteral formulations, the carrier often contains sterile water, but includes other ingredients, such as other ingredients to aid in solubility or preservation. Injectable solutions can be prepared when appropriate stabilizers are applied.

In some cases, the active agent is encapsulated in liposomes or other encapsulating media, or the active agent is immobilized on suitable biomolecules such as proteins, lipoproteins, glycoproteins, and polysaccharides, such as by covalent linkage, chelation, or associative coordination. It may be advantageous to use active agents in "vectorized" form.

The methods of treatment of the present invention using formulations suitable for oral administration may be presented in discrete units such as capsules, cachets, tablets or lozenges containing a predetermined amount of the active ingredient in powder or granules. If desired, suspensions in aqueous liquids or non-aqueous liquids such as syrups, elixirs, emulsions or drafts can be used.

Tablets may be prepared by compression or molding, or wet granulation, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing the active compound in free flowing form, such as powders or granules, optionally mixed with a binder, disintegrant, lubricant, inert diluent, surfactant, or release agent in a suitable machine. Molded tablets consisting of a mixture of a powdered active compound and a suitable carrier can be prepared by molding in a suitable machine.

Syrups can be prepared by adding the active compound to a concentrated aqueous solution of a sugar such as sucrose and adding any auxiliary ingredient thereto. Such auxiliary components may include flavoring agents, suitable preservatives, crystallization retardants of sugars, and solubility increasing agents of other components such as polyhydroxyalcohols such as glycerol or sorbitol.

 Formulations suitable for parenteral administration typically include sterile aqueous formulations of active compounds (such as physiological saline solutions) that are isotonic with the blood of the receptor. Such formulations include suspending and thickening agents and other particulate systems designed to direct liposomes or compounds to blood components or one or more organs. The formulations may be provided in a single dose or in multidose form.

Parenteral administration may include suitable forms for systemic delivery or direct delivery to the CNS. Administration includes intravenous, intraarterial, intradural, intramuscular, subcutaneous, intramuscular, intraperitoneal (such as intraperitoneal), and the like, and may be by infusion pump (external or implantable) or by means suitable for the desired mode of administration. May be affected.

 Nasal and other mucosal spray formulations (eg, inhaled forms) can include purified aqueous solutions of the active compounds with preservatives and isotonic agents. Such formulations are preferably adjusted to pH and isotonicity to suit the nose or other mucous membranes. Alternatively, they may be in the form of finely divided solid powders suspended in a gas carrier. Such formulations may be delivered by any suitable means or method, such as by nebulizer, atomizer, survey dose inhaler, or the like.

Formulations for rectal administration may be presented in the form of suppositories with suitable carriers such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acids.

Transdermal formulations can be prepared by incorporating the active agent in a cellulose medium such as thixotropic or gelatinous carriers such as methyl cellulose or ethyl cellulose, and the resulting formulation is packaged in a transdermal device adapted for skin contact with the user's skin. .

In addition to the components described above, the formulations of the present invention may further comprise one or more accessory ingredients selected from diluents, buffers, flavors, binders, disintegrants, surfactants, thickeners, lubricants, preservatives (including antioxidants), and the like.

Formulations of the present invention may have immediate release, sustained release, delayed onset release or other release profiles known to those skilled in the art.

In one embodiment of the invention, trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N-dimethylcarbamoyl-cyclohexylamine Or a pharmaceutically acceptable salt thereof is administered to one or more additional therapeutic agents (such as antipsychotics, antidepressants) as adjuvant therapy. In another embodiment, trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N-dimethylcarbamoyl-cyclohexylamine or pharmaceutical Salts thereof may be co-administered as a combination therapy with one or more additional therapeutic agents (such as antipsychotics, antidepressants).

Antipsychotics are atypical or typical antipsychotics, preferably atypical antipsychotics. Atypical antipsychotics include, but are not limited to olanzapine, clozapine, risperidone, sertindol, gestiapine, aripiprazole, ziprasidone, and surmontil. Examples of typical antipsychotics include, but are not limited to, acepromazine, benperidol, bromazepam, bromperidol, clopromazine, cloproticen, clothiapine, cyameazine, diazepam, dixiazine, dropperidol , Flufentisol, flufenazine, flupyrylene, haloperidol, heptaminol, isopropamide iodide, levomepromazine, levosulpyride, roxapine, melferon, mesodazine, molindon, Oxypertin, Oxyprotepine, Fenfluridol, Ferrazine, Ferricazine, Perphenazine, Pimozide, Fifamferon, Pipeothiazine, Prochlorperazine, Promazine, Promethazine, Protifendil, Pyridoxine , Sulfyrides, sulfofrides, tetrabenazine, thiopropazine, thiolidazine, thiapride, thiotixene, trifluoroperazine, triflupromazine, trihexhenidyl, and zuplofenticol It includes.

Definition :

The term "pharmaceutically acceptable" means biologically or pharmaceutically acceptable for in vivo use in an animal or human, and is preferably accepted by a federal or state supervisory authority or in the United States pharmacopoeia or animal, in particular human Means listed in other commonly recognized pharmacopoeia for use.

The term "schizophrenia" is meant to include a group of psychiatric disorders characterized by disruption in thought or cognitive abilities, as well as schizophrenia (and all its subtypes; paranoia, tension, inattention, residual, undifferentiated) and other psychosis ( Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, Washington, DC (1994): American Psychiatric Association, or The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines, Geneva (1992): World Health Organization ) Such as schizophrenic and mental affective disorders, short mental disorders, and the like.

In clinical evaluation, schizophrenia is often a "negative symptom" such as fantasy (especially voice hearing), inattentive thought processes, and delusions, as well as "negative voice" such as emotional dullness, ataxia, apathy, and anesthesia. Symptoms ".

The term “negative symptom of schizophrenia” refers to the symptoms of schizophrenia that reflects a loss of action, directed thinking and creativity. Negative symptoms of schizophrenia are well known in the art and also include emotional dullness (e.g. characterized by immobile and / or unresponsive facial expressions, poor visual contact, reduced physical language), ataxia ("lack of language") Or simple, verbal and / or unresponsive), apathy (characterized by a decrease or absence of the ability to initiate and execute goal-oriented activity), numbness (loss of interest or pleasure), antisociality (social motivation) And reduced interactions), numbness, and other negative symptoms known to those skilled in the art. Negative symptoms of schizophrenia can be assessed using any method known to those skilled in the art, but include, but are not limited to, the Brief Psychiatric Rating Scale (BPRS), and the Positive and Negative Symptom Scale (PANSS). BPRS and PANSS have substandards or factors that can be used to measure negative symptoms. Other criteria can be devised to specifically interpret negative symptoms: for example, Scale for the Assessment of Negative Symptoms (SANS), Negative Symptom Assessment (NSA) and the Schedule for the Deficit Syndrome (SDS). While subcriteria of BPRS and PANSS can also be used to assess positive symptoms, methods for specifically assessing positive symptoms are also available (eg the Scale for the Assessment of Positive Symptoms).

The term “cognitive deficits associated with schizophrenia” refers to cognitive deficits in schizophrenic patients. Cognitive impairment in schizophrenia is a key feature of the disease (ie it is not the result of treatment or clinical symptoms). Cognitive deficits include, but are not limited to, emotional / arousal states, working memory, language learning and memory, memory for spatial vision, reasoning / problem solving, and social cognition. There are many neuropsychological tests used to measure cognitive deficits in schizophrenia, such as the Wisconsin Card Sorting Test (WCST).

The terms “treat” “treatment” and “treating” refer to one or more of the following:

(a) alleviating or alleviating at least one symptom of a disease, including allergic and inflammatory diseases such as, for example, asthma and COPD;

(b) alleviating or alleviating the intensity and / or duration of the disorder experienced by the patient in response to, but not limited to, certain stimuli (eg pressure, tissue damage, low temperature, etc.);

(c) stopping, delaying the onset of the onset (ie, the period prior to the clinical outbreak of the disease) and / or reducing the concern or exacerbation of the disease.

An “effective amount” is defined as an amount of active ingredient sufficient to affect the treatment of a disease when administered to a patient (eg, a mammal) to treat a disease (ie, schizophrenia), or a dopamine receptor ( Eg, the amount of active ingredient sufficient to modulate dopamine D ₂ and / or dopamine D ₃ receptor). An "effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, sensitivity, etc. of the patient to be treated.

The sample or patient to which the therapeutic compound is administered for a therapeutic regimen effective for a disease or disorder is preferably a human, but can be an animal and includes laboratory animals in connection with an experiment or screening or active experiment. Thus, those skilled in the art will appreciate that the methods, compounds and compositions of the present invention may be used in animals, in particular mammals and, without limitation, human, livestock animals such as feline or canine animals, farm animals such as but not limited to cattle, horses, goats, sheep and swine specimens, Wild animals (live in wild or animal gardens), research animals such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., for veterinary use, and birds, such as chickens, turkeys, songbirds, and the like.

 The term “about” or “appropriate” means within acceptable tolerances for a particular value as determined by one of ordinary skill in the art, and will vary in part depending on how the value is measured or determined, ie, the limits of the measurement system. For example, “about” can be within one or more than one standard deviation in the practice of the art. Alternatively, the "about" for the composition may range from ± 20%, preferably 10%, more preferably 5%. Alternatively, for biological systems or methods, the term may be within one time of the value, preferably within five times, more preferably within two times. If a particular value is described in the application and claims, the term "about" means within an acceptable error range for that particular value unless specifically defined otherwise.

The following examples are intended to illustrate the invention and should not be construed as limiting the scope of the invention in any sense, and many variations and equivalents included in the invention will become apparent to those skilled in the art upon reading the disclosure. .

Example  One

This clinical study will be conducted in a multicenter, randomized, double-blind, placebo-controlled, similar group, flexible-dose study. Approximately 375 inpatients totaled (i) the DSM-IV-TR (Diagnostic and Statistical Manual of Mental) for schizophrenia based on the SCID (Structured Clinical Interview for DSM-IV). Disorders, Fourth Edition, Text Revision) (295.30 Paranoid Type, 295.10 Disorganized Type, 295.20 Catatonic Type, or 295.90 Undifferentiated Type) Patients who currently or have met the past (ii) PANSS total score visited Patients with> 70 to <120 in 1 and Visit 2, (iii) having a score of> 4 (Medium) in Item P1 (Phantom) or P3 (Delusional Behavior) of PANSS in Visit 1 and Visit 2. Patients will be selected using criteria including, and (iv) Patients with scores of> 4 (medium) at either item P2 (cognitive confusion) or P6 (suspect / persecution) of PANSS at Visit 1 and Visit 2.

This study will take 10 weeks; Six weeks of double blind treatment and four weeks of safety follow-up. A no-drug washout period of seven days or less will optionally precede. Patients will be hospitalized during the screening phase. Patients will be hospitalized for at least 21 days after the start of the minimum randomized and double blind dosing. The evaluation schedule is shown in Table 1.

Patients who meet the eligibility criteria at Visit 1 will enter a 7 day washout period. After the washout period, patients who met the eligibility criteria were assigned any number in Visit 2 and provided a corresponding blister pack of double blind dosing for a week of double blind treatment.

All patients who meet the eligibility criteria are randomly assigned to one of three treatment groups (1: 1: 1):

(I) placebo

(II) 1.5-4.5 mg of trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N-dimethylcarbamoyl-cyclohexylamine Hydrochloride, or

(III) 6-12 mg of trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N-dimethylcarbamoyl-cyclohexylamine Hydrochloride.

1.5 mg, 3.0 mg, or 6.0 mg of trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N-dimethylcarbamoyl to the patient A similar looking capsule containing cyclohexylamine hydrochloride or placebo was fed.

All study drugs will be supplied once a week in blister packs. Each card will contain 30 capsules arranged in 10 rows and 3 transverses, which is appropriate for 7 days a week plus 3 days extra. The structure of the blister pack is provided in Table 2. All study drugs will be administered in a single daily dose at bedtime. If there is a problem of tolerance, the dose can be changed to morning; However, such alterations should allow at least 24 hours between two consecutive doses.

On days 1 and 2, all patients received one capsule from one side of the blister pack. On day 3, the dose can be increased to two capsules (one side and two side) if the response is not appropriate and there is no tolerability problem. Starting at day 5, depending on the reaction and tolerability, the dosage may be increased by 1 capsule up to 3 capsules. For patients treated randomly in Group II (1.5-4.5 mg trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N-dimethyl Carbamoyl-cyclohexylamine hydrochloride), a maximum dosage of 4.5 mg can be reached up to 5 days, whereas for patients randomly treated with Group III (6-12 mg trans-4- {2- [ 4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N-dimethylcarbamoyl-cyclohexylamine hydrochloride), the maximum dosage of 12 mg can be reached up to 9 days have. Dose escalation will be effected by one capsule increase.

Assessments conducted using established grading methods include:

PANSS (Positive and Negative Syndrome Scale) Total score (e.g. Kay et al., Schizophr. Bull., 13, 261-76, 1987)

Clinical Global Impressions-Severity (CGI-S) Overall clinical impression severity (e.g. Guy ECDEU Assessment Manual for Psychopharmacology.Rockville, Md: US Department of Health, Education, and Welfare, 218-22, Publication ADM 76-338, 1976 )

CGI-I (Clinical Global Impressions-Improvement) Improve overall clinical impressions (e.g. Guy ECDEU Assessment Manual for Psychopharmacology.Rockville, Md: US Department of Health, Education, and Welfare, 218-22, Publication ADM 76-338, 1976 )

Calgary Depression Scale for Schizophrenia (CDSS) (see, eg, Addington et al., Schizophr. Res., 19, 205-12, 1996)

Blood samples will be collected at 14, 21, 28, 35, 42, 56, and 70 days.

The above-mentioned therapeutic regimen using trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N-dimethylcarbamoyl-cyclohexylamine hydrochloride Is expected to have a significant effect in the treatment of schizophrenia compared to placebo treated controls.

The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent from the foregoing detailed description and the accompanying drawings. Such modifications fall within the scope of the appended claims. All values are approximate and provided herein.

The entire contents of all patent applications, patents, and publications cited above and below are hereby incorporated by reference.

Claims (41)

A therapeutically effective amount of a (thio) -carbamoyl-cyclohexane derivative of formula (I) and / or its geometric isomers and / or stereoisomers and / or diastereomers and / or salts and / or hydrates and / or solvates And / or administering the polymorph to a patient in need thereof.

In the formula, R ₁ and R ₂ are independently of each other hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aroyl, or R ₁ and R ₂ combine with adjacent nitrogen atoms to form a heterocyclic ring; X is O or S; n is 1 or 2. The compound of formula (I) according to claim 1, wherein the compound of formula (I) is trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N-dimethylcarba Moyl-cyclohexylamine and / or its salts and / or hydrates and / or solvates and / or polymorphs. The compound of formula (I) according to claim 1, wherein the compound of formula (I) is trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N-dimethylcarba Moyl-cyclohexylamine hydrochloride and / or its hydrates and / or solvates and / or polymorphs. The method of claim 1, wherein the therapeutically effective amount of the compound of formula (I) is about 0.1 to 12 mg. The method of claim 4, wherein the therapeutically effective amount of the compound of formula (I) is about 0.5 mg. The method of claim 4, wherein the therapeutically effective amount of the compound of formula (I) is about 1.0 mg. The method of claim 4, wherein the therapeutically effective amount of the compound of formula (I) is about 1.5 mg. The method of claim 4, wherein the therapeutically effective amount of the compound of formula (I) is about 3 mg. The method of claim 4, wherein the therapeutically effective amount of the compound of formula (I) is about 4.5 mg. The method of claim 4, wherein the therapeutically effective amount of the compound of formula (I) is about 6 mg. The method of claim 4, wherein the therapeutically effective amount of the compound of formula (I) is about 9 mg. The method of claim 4, wherein the therapeutically effective amount of the compound of formula (I) is about 12 mg. 13. The method of any one of claims 4 to 12, wherein the compound of formula (I) is administered in one, two, three or four divided daily doses. The method of claim 4, wherein the compound of formula (I) provides a therapeutic effect in the treatment of cognitive symptoms of schizophrenia. The method of claim 4, wherein the compound of formula (I) provides a therapeutic effect in the treatment of negative symptoms of schizophrenia. The method according to claim 4, wherein the compound of formula (I) provides a therapeutic effect in the treatment of positive symptoms of schizophrenia. The method of claim 4, wherein the compound of formula (I) provides a therapeutic effect in the treatment of affective and residual symptoms of schizophrenia. The method of claim 4, wherein the compound of formula (I) provides a therapeutic effect in the treatment of secondary social and occupational dysfunction of schizophrenia. The method of claim 4, wherein the compound of formula (I) provides a therapeutic effect in the treatment of schizophrenic and psychopathic disorders. The method of claim 4, wherein the compound of formula (I) is administered to one or more additional therapeutic agents as adjuvant therapy. The method of claim 4, wherein the compound of formula (I) is co-administered as a combination therapy with one or more additional therapeutic agents. A therapeutically effective amount of a (thio) -carbamoyl-cyclohexane derivative of formula (I) and / or its geometric isomers and / or stereoisomers and / or diastereomers and / or salts and / or salts in the manufacture of a medicament for the treatment of schizophrenia and / or Or use of hydrates and / or solvates and / or polymorphs:

In the formula, R ₁ and R ₂ are independently of each other hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aroyl, or R ₁ and R ₂ combine with adjacent nitrogen atoms to form a heterocyclic ring; X is O or S; n is 1 or 2. 23. The compound of claim 22, wherein the compound of formula (I) is trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N-dimethylcarba Moyl-cyclohexylamine and / or its salts and / or hydrates and / or solvates and / or polymorphs. 23. The compound of claim 22, wherein the compound of formula (I) is trans-4- {2- [4- (2,3-dichlorophenyl) -piperazin-1-yl] -ethyl} -N, N-dimethylcarba Moyl-cyclohexylamine hydrochloride and / or its hydrates and / or solvates and / or polymorphs. The use according to any one of claims 22 to 24, wherein the therapeutically effective amount of the compound of formula (I) is about 0.1 to 12 mg. The use of claim 25, wherein the therapeutically effective amount of the compound of formula (I) is about 0.5 mg. The use of claim 25, wherein the therapeutically effective amount of the compound of formula (I) is about 1.0 mg. The use of claim 25, wherein the therapeutically effective amount of the compound of formula (I) is about 1.5 mg. The use of claim 25, wherein the therapeutically effective amount of the compound of formula (I) is about 3 mg. The use according to claim 25, wherein the therapeutically effective amount of the compound of formula (I) is about 4.5 mg. The use of claim 25, wherein the therapeutically effective amount of the compound of formula (I) is about 6 mg. The use of claim 25, wherein the therapeutically effective amount of the compound of formula (I) is about 9 mg. The use according to claim 25, wherein the therapeutically effective amount of the compound of formula (I) is about 12 mg. 34. The use according to any one of claims 25 to 33, wherein the compound of formula (I) is administered in one, two, three or four divided daily doses. 35. The use of any one of claims 25 to 34, wherein the compound of formula (I) provides a therapeutic effect in the treatment of cognitive symptoms of schizophrenia. 35. The use of any one of claims 25 to 34, wherein the compound of formula (I) provides a therapeutic effect in the treatment of negative symptoms of schizophrenia. 35. The use of any one of claims 25 to 34, wherein the compound of formula (I) provides a therapeutic effect in the treatment of positive symptoms of schizophrenia. 35. The use of any one of claims 25 to 34, wherein the compound of formula (I) provides a therapeutic effect in the treatment of affective and residual symptoms of schizophrenia. 35. The use of any one of claims 25 to 34, wherein the compound of formula (I) provides a therapeutic effect in the treatment of affective and residual symptoms of schizophrenia. 35. The use of any one of claims 25 to 34, wherein the compound of formula (I) provides a therapeutic effect in the treatment of secondary social and occupational dysfunction of schizophrenia. 35. The use according to any one of claims 25 to 34, wherein the compound of formula (I) provides a therapeutic effect in the treatment of schizophrenic and psychopathological disorders.