HK1140474A - Metabolites of (thio) carbamoyl-cyclohexane derivatives - Google Patents

Description

Metabolites of (thio) carbamoyl-cyclohexane derivatives

Technical Field

The present invention relates to metabolites of (thio) -carbamoyl cyclohexane derivatives, and in particular to trans-4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -N, N-dimethylcarbamoyl-cyclohexylamine and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the same and their use in the treatment and/or prevention of disorders requiring modulation of dopamine receptors.

Background

U.S. patent publication No. US2006/0229297 discloses (thio) -carbamoyl-cyclohexane derivatives which are D₃And D₂Preferred ligands of dopamine receptor subtypes have the formula (I):

wherein R is₁，R₂And X and n are as defined herein.

One specific compound disclosed in hungarian patent application P0700339 is trans-4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -N, N-dimethylcarbamoyl-cyclohexylamine hydrochloride, also known as trans-1- {4- [2- [4- (2, 3-dichlorophenyl-piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride, of the formula shown below:

trans-4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl]-ethyl } -N, N-dimethylcarbamoyl-cyclohexylamine hydrochloride is orally active and is a very effective dopamine D₃/D₂Receptor antagonists, with D₂The receptors are particularly highly potent compared with D₃Receptor binding. D₃Antagonistic ratio of receptor D₂Receptor antagonism is about one order of magnitude higher, and D is believed to be₃Receptor antagonism will counteract D₂Receptor antagonism has resulted in some extrapyramidal side effects. Trans-4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl]Another unique feature of-ethyl } -N, N-dimethylcarbamoyl-cyclohexylamine hydrochloride is that it functions as a "dopamine system stabilizer" in vivo. In this respect, it has a preferential dopaminergic effect on the limbic zone, and, depending on the functional state of the particular dopaminergic system, it regulates presynaptic D for biosynthesis (and release)₂The receptors show (dual) agonistic and antagonistic activity.

These compounds are useful for dopamine D₃The receptor has a high or very high affinity for dopamine D₂The receptor has a moderate to high affinity, and the combination is such that it is directed to D₃Affinity comparison of (D)₂The affinity of (A) is 5-200 times higher. In addition, these compounds have much higher selectivity than other receptors, such as the α -1 receptor. Doublets (i.e. D) combined in the above specified proportions₃And D₂) Antagonism of receptor function is particularly important as it allows modulation of D to be shown simultaneously₃And D₂The beneficial effects of the receptors do not suffer from the known disadvantages of acting individually on each receptor.

Except for dopamine D₃And D₂In addition to the relative increased affinity of trans-4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl]-Ethyl } -N, N-dimethylcarbamoyl-cyclohexylamine hydrochloride for other acceptor sitesSuch as 5-HT_2cHistamine H₁And a less potent adrenergic receptor site, suggesting that side effects such as extrapyramidal symptoms (EPS) and weight gain are less likely to occur.

These compounds are useful in the treatment and/or prevention of pathological conditions which require modulation of dopamine receptors.

Disclosure of Invention

The present invention relates to metabolites of (thio) -carbamoyl cyclohexane derivatives, in particular trans-4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -N, N-dimethylcarbamoyl-cyclohexylamine and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the same and their use in the treatment and/or prevention of disorders requiring modulation of dopamine receptors.

Detailed Description

The present invention relates to isolated and/or purified and/or synthetic metabolites of compounds of formula (I):

wherein

R₁And R₂Each independently is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aroyl, or R₁And R₂Together with the adjacent nitrogen atom form a heterocyclic ring;

x is O or S;

n is 1 or 2;

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates and/or polymorphs thereof.

In some embodiments, the present invention relates to compounds of formula (II) and/or (III):

wherein

R₁And R₂Each independently is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, or aroyl, or R₁And R₂Independently form a heterocyclic ring with the adjacent nitrogen atom;

x is O or S;

n is 1 or 2;

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates and/or polymorphs thereof.

In one embodiment, the compound of formula (II) and/or (III) is in purified form. In another embodiment, the compounds of formula (II) and/or (III) are present in substantially pure form. In another embodiment, the compounds of formula (II) and/or (III) are isolated and/or synthesized.

In one embodiment, the compound of formula (II) is represented by formula (IIa):

wherein R is₁，R₂X and n are as defined above for formula (II).

In some embodiments, when R₁And/or R₂When representing an alkyl group, the alkyl moiety is a substituted or unsubstituted saturated hydrocarbon group, which may be straight or branched chain, and which contains from about 1 to about 6 carbon atoms (particularly preferably 1 to 4 carbon atoms),and optionally with one or more C_1-6Alkoxycarbonyl, aryl (e.g. phenyl) or (C)_1-6Alkoxycarbonyl) -C_1-6Alkyl groups or combinations thereof.

In other embodiments, R₁And R₂Together with the adjacent nitrogen atom, form a heterocyclic ring, which may be saturated or unsaturated, optionally substituted, monocyclic or bicyclic, which may contain an additional heteroatom selected from O, N or S. For example, the heterocycle may be pyrrolidine, piperazine, pyridine or morpholine.

In other embodiments, when R₁And/or R₂When representing an alkenyl group, the alkenyl moiety may have 2 to 7 carbon atoms and 1 to 3 double bonds.

In other embodiments, when R₁And/or R₂When aryl is represented, the aryl moiety may be selected from optionally substituted mono-, di-or tricyclic aryl groups such as, but not limited to, phenyl, naphthyl, fluorononyl, or anthraquinone (e.g., phenyl or naphthyl). The aryl moiety may be substituted by one or more C_1-6Alkoxy, trifluoro-C_1-6Alkoxy radical, C_1-6Alkoxycarbonyl, C_1-6Alkanoyl, aryl, C_1-6Alkylthio, halogen, cyano, or combinations thereof.

In other embodiments, when R₁And/or R₂When represents cycloalkyl, the cycloalkyl moiety may be selected from optionally substituted mono-, di-or tricyclic cycloalkyl groups, such as cyclohexyl or adamantyl.

In other embodiments, when R₁And/or R₂When an aroyl group is represented, the aryl moiety is as defined above, for example, phenyl.

In some embodiments, the present invention relates to compounds of formula (II) and/or (III), wherein

R₁And R₂Each independently of the others being hydrogen, optionally substituted by one or more C_1-6Alkoxycarbonyl, aryl or (C)_1-6Alkoxycarbonyl) -C_1-6Alkyl substituted straight or branched C_1-6Alkyl, C having 1-3 double bonds_2-7Alkenyl, optionally substituted by one or more C_1-6Alkoxy, trifluoro-C_1-6Alkoxy radical, C_1-6Alkoxycarbonyl, C_1-6Alkanoyl, aryl, C_1-6Alkylthio, halogen or cyano-substituted mono-, di-or tricyclic aryl, optionally substituted mono-, di-or tricyclic cycloalkyl, aroyl, or R₁And/or R₂Together with the adjacent nitrogen atom, form a heterocyclic ring, which may be saturated or unsaturated, optionally substituted monocyclic or bicyclic, which may contain an additional heteroatom selected from O, N or S;

x is O or S;

n is 1 or 2.

In other embodiments, the invention relates to compounds of formula (II) and/or (III), wherein

R₁And R₂Each independently of the others being hydrogen, optionally substituted by one or more C_1-6Alkoxycarbonyl, phenyl or (C)_1-6Alkoxycarbonyl) -C_1-6Alkyl substituted straight or branched C_1-6Alkyl, C having 1 double bond_2-7Alkenyl, optionally substituted by one or more C_1-6Alkoxy, trifluoro-C_1-6Alkoxy radical, C_1-6Alkoxycarbonyl, C_1-6Alkanoyl, aryl, C_1-6Phenyl or naphthyl substituted by alkylthio, halogen or cyano, cyclohexyl, adamantyl, benzoyl, or R₁And/or R₂Together with the adjacent nitrogen atom form a heterocyclic ring which may be saturated, optionally substituted by C_1-6An alkyl or hydroxy substituted monocyclic ring which may contain an additional heteroatom selected from O or N;

x is O or S; and

n is 1 or 2.

In a further embodiment, the invention relates to compounds of the formulae (II) and/or (III), in which

R₁And R₂Each independently is hydrogenOptionally is coated with C_1-6Alkoxycarbonyl-or phenyl-substituted straight-chain or branched C_1-6Alkyl, allyl, optionally substituted by one or more C_1-6Alkoxy, cyano or C_1-6Alkanoyl substituted phenyl, cyclohexyl, or R₁And/or R₂Together with the adjacent nitrogen atom forming an optionally substituted C_1-6An alkyl or hydroxy substituted pyrrolidine, piperazine, piperidine or morpholine ring;

x is O or S; and

n is 1.

In other embodiments, R₁And R₂Each independently selected from hydrogen or alkyl (e.g., methyl).

In other embodiments, the invention relates to compounds of formula (II) and/or (III), wherein R₁And R₂Each independently hydrogen or methyl (e.g., R)₁And R₂Are all hydrogen, R₁And R₂One of which is hydrogen and the other is methyl, R₁And R₂Both methyl).

In another embodiment, the present invention relates to metabolites of trans-4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -N, N-dimethylcarbamoyl-cyclohexylamine, and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates and/or polymorphs thereof.

In some embodiments, the metabolite may be a glucuronide, an oxidized compound, a monohydroxylated compound, or a sulfate conjugate.

In one embodiment, the metabolite of trans-4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -N, N-dimethylcarbamoyl-cyclohexylamine is present in substantially pure form.

In another embodiment, the metabolite of trans-4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -N, N-dimethylcarbamoyl-cyclohexylamine is isolated.

In another embodiment, the metabolite of trans-4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -N, N-dimethylcarbamoyl-cyclohexylamine is in purified form.

In another embodiment, the metabolite of trans-4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -N, N-dimethylcarbamoyl-cyclohexylamine is synthetic.

In another embodiment, the metabolite of the invention is selected from:

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates and/or polymorphs thereof.

Pharmaceutically acceptable salts

Pharmaceutically acceptable salts include those formed by the reaction of the principal compound, which functions as a base, with inorganic or organic acids such as hydrochloric, sulfuric, phosphoric, methanesulfonic, camphorsulfonic, oxalic, maleic, succinic, citric, formic, hydrobromic, benzoic, tartaric, fumaric, salicylic, mandelic, and carbonic acids. Pharmaceutically acceptable salts also include, for example, the sodium, potassium, calcium, magnesium, ammonium, and choline salts formed by reacting the principal compound, which functions as an acid, with an appropriate base. One skilled in the art will recognize that acid addition salts of the claimed compounds can be prepared by reacting the claimed compounds with the appropriate inorganic or organic acid by any of a number of known methods. Alternatively, alkali metal salts and alkaline earth metal salts may be prepared by reacting a compound of the present invention with an appropriate base via a number of known methods.

The following are other examples of salts that may be obtained by reaction with inorganic or organic acids: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, digluconate, cyclopentylpropionate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, methanesulfonate, and undecanoate.

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

One of ordinary skill in the art will also recognize that some of the compounds used in the present invention may exist in different crystalline forms. As is known in the art, polymorphism is the ability of a compound to crystallize into more than one different crystalline or "polymorphic" species. Polymorphs are solid crystalline phases of a compound having at least two different arrangements or polymorphic forms of the compound molecule in the solid state. Polymorphic forms of any given compound may be defined by the same chemical formula or composition, the chemical structures of two different compounds being different due to their different crystal structures. It is within the scope of the present invention to use these polymorphs.

One of ordinary skill in the art will also recognize that some of the compounds used in the present invention may exist in different solvate forms. Solvates of the compounds of the invention also form when solvent molecules are incorporated into the crystal lattice structure of the compound molecules during crystallization. For example, suitable solvates include hydrates, such as the monohydrate, dihydrate, sesquihydrate, and hemihydrate. It is within the scope of the invention to use these solvates.

One of ordinary skill in the art will also recognize that the compounds of formula (II) and/or (III) may exist as cis and trans isomers with respect to the configuration of the cyclohexane ring. These isomers and mixtures thereof are also within the scope of the present invention. The compounds of the invention are preferably in the trans configuration.

When certain compounds of formula (II) and/or (III) comprise C_2-7When alkenyl, these compounds may exist in the cis and/or trans isomer forms. These compounds are also within the scope of the present invention, which includes all such isomers and mixtures thereof.

Certain compounds of formula (II) and/or (III) may also exist in stereoisomeric and diastereomeric forms. Such compounds and mixtures thereof are also within the scope of the present invention.

Since the present invention also relates to salts of compounds of formula (II) and/or (III) with acids, in particular with pharmaceutically acceptable acids, the meaning of compounds of formula (II) and/or (III) independently refers to the free base or salt, when not indicated separately.

One of ordinary skill in the art will recognize that the compounds of formula (II) and/or (III) may exist in different tautomeric and geometric isomeric forms. All such compounds, including cis-isomers, trans-isomers, diastereomeric mixtures, racemic mixtures, non-racemic mixtures of enantiomers, substantially pure and pure enantiomers, are within the scope of the invention. The substantially pure enantiomer comprises not more than 5% w/w of the corresponding opposite enantiomer, preferably not more than 2%, most preferably not more than 1%.

Optical isomers may be obtained by resolution of the racemic mixture according to conventional procedures, for example, by formation of diastereomeric salts using optically active acids or bases, or by formation of covalent diastereomers. Examples of suitable acids are tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. Mixtures of diastereomers may be separated into their diastereomeric monomers according to their physical and/or chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. The optically active base or acid is then released from the separated diastereomeric salt. A different method of separating optical isomers involves the use of chiral chromatography (e.g., a chiral HPLC column), with or without conventional induction, with optimal selection to maximize separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Diacel, e.g., chiralel OD and chiralel OJ, among others, all of which can be routinely selected. Enzyme isolation with or without conventional induction may also be used. Optically active compounds of formula (II) and/or (III) can be obtained by using optically active starting materials under reaction conditions which do not lead to racemization in chiral synthesis processes.

Furthermore, those skilled in the art will appreciate that the compounds of the present invention may be used in different isotopically enriched forms, e.g., enriched in²H、³H、¹¹C、¹³C and/or¹⁴C. In a particular embodiment, the compounds of the invention are deuterated. Deuterated forms thereof can be prepared by the methods described in U.S. Pat. nos. 5,846,514 and 6,334,997. As described in U.S. patent nos. 5,846,514 and 6,334,997, deuteration can improve the efficacy of the drug and prolong the duration of activity.

Deuterium substituted compounds can be synthesized using various methods, for example as described in the following articles: dean, Dennis c.; receptor Advances In the Synthesis Applications of radio bound Compounds for Drug discovery Development [ In: curr, pharm. 6(10) ] (2000), 110pp. CAN 133: 68895AN 2000: 473538 CAPLUS; kabaka, georgew.; varma, rajerer s, the synthesis of a radio spherical composite organic intermediates tetrahedron (1989), 45(21), 6601-21, CODEN: TETRAB ISSN: 0040-4020.CAN 112: 20527 AN 1990: 20527 CAPLUS; and Evans, E.Anthony.Synthesis of radioLabeledcompounds, J.Radioanal.chem. (1981), 64(1-2), 9-32. CODEN: JRACBN ISSN: 0022-4081, CAN 95: 76229AN 1981: 476229 caps.

The invention also relates to useful forms of the compounds described herein, if applicable, such as the free base forms of all compounds of the invention, as well as pharmaceutically acceptable salt or prodrug forms which can be prepared successfully.

Composition comprising a metal oxide and a metal oxide

The invention also includes pharmaceutical compositions of the metabolites of the invention, comprising, for example, one or more pharmaceutically acceptable carriers.

Various standard references may be used which describe the preparation of various formulations suitable for administration of the compounds of the present invention. For example, in Handbook of Pharmaceutical excipients, American Pharmaceutical Association (latest edition); pharmaceutical Dosage Forms: examples of possible agents and preparations are included in the latest edition of Tablets (edited by Lieberman, Lachman and Schwartz), published by Marcel Dekker, Inc., and Remington's Pharmaceutical Sciences (edited by Arthur Osol), 1553-.

Administration of the compounds of formula (II) and/or (III) of the invention may be accomplished according to the needs of the patient, for example, oral, nasal, parenteral (subcutaneous, intravenous, intramuscular, intrasternal and by infusion), by inhalation, rectal, vaginal, topical and by ocular administration.

The compounds of formula (II) and/or (III) of the present invention may be administered using a variety of solid oral dosage forms, including tablets, soft gelatin capsules, caplets, granules, lozenges, and bulk powders. The polymorphs and solvates of the present invention can be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (e.g., sucrose, mannitol, lactose, starch) and excipients known in the art including, but not limited to, suspending agents, solubilizers, buffers, binders, disintegrants, preservatives, colorants, flavoring agents, lubricants, and the like. Time release capsules, tablets and gels are also advantageous for administration of the compounds of the invention.

Various liquid oral dosage forms may also be used to administer the compounds of formula (II) and/or (III), including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Such dosage forms may also contain suitable inert diluents (e.g., water) as are known in the art and suitable excipients (e.g., preservatives, wetting agents, sweeteners, flavoring agents, and agents for emulsifying and/or suspending the compounds of the present invention) as are known in the art. The polymorphs and solvates of the present invention may be injected in the form of isotonic sterile solutions, for example, intravenously. Other formulations are also possible.

Suppositories for rectal administration of the compounds of formula (II) and/or (III) of the invention can be prepared by mixing the compounds with suitable excipients such as cocoa butter, salicylates and polyethylene glycols. Formulations for vaginal administration may be presented as pessaries, suppositories, creams, gels, pastes, foams or sprays containing, in addition to the active ingredient, suitable carriers known in the art.

For topical administration, the pharmaceutical composition may be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays and drops suitable for application to the skin, eye, ear or nose. Topical administration may also include transdermal administration by means of, for example, a transdermal patch.

Aerosols suitable for administration by inhalation may also be prepared. For example, for the treatment of diseases of the respiratory tract, the compounds of the invention may be administered by inhalation in the form of a powder (e.g., micronized) or in the form of a nebulized solution or suspension. The aerosol may be placed in a pressurized acceptable propellant.

The invention also provides the use of a compound of the invention for the preparation of a medicament for the treatment of a condition requiring modulation of dopamine receptors, in particular dopamine D₃And/or D₂The use in medicine for the treatment of a disorder of a receptor.

The invention also provides methods for treating a need for modulation of dopamine receptors, particularly dopamine D₃And/or D₂A method of treating a disease of a receptor. In other embodiments, the invention provides for the use of the inventionModulation of dopamine D in need of treatment with one or more compounds₃And/or D₂A method of treating a disease of a receptor.

Dysfunction of the dopaminergic neurotransmitter system is associated with the pathology of a number of neuropsychiatric and neurodegenerative diseases, such as schizophrenia, drug abuse and parkinson's disease, respectively. The dopamine acts by belonging to D₁-(D₁，D₅) Or D₂-(D₂，D₃，D₄) At least 5 different dopamine receptors of the receptor family. D₃Receptors have been shown to have a characteristic distribution in the brain dopaminergic system. That is, it was found to be high density in certain edge structures such as the nucleus accumbens and islands of Karaja (Calleja). Thus, D₃Preferential targeting of receptors may be a promising approach for more selective modulation of dopaminergic function and thus provides a successful treatment in several abnormalities such as schizophrenia, mood or cognitive disorders and addiction (see, e.g., Sokoloff, p. et al: Nature, 1990, 347, 146; Schwartz, J.C, et al: clin. neuropharmacol.1993, 16, 295; Levant, b. pharmacol.rev.1997, 49, 231), addiction (see, e.g., pila, c. et al: Nature1999, 400, 371) and parkinson's disease (see, e.g., Levant, b. et al: CNS Drugs1999, 12, 391) or pain (see, e.g., Levant, b. et al: neurosci.lett.2001, 303, 9).

Dopamine D₂Receptors are widely distributed in the brain and are known to be involved in numerous physiological functions and pathological conditions. D₂Antagonists are widely used, for example, as antipsychotics. However, D is also known₂The large antagonism of the receptor leads to undesirable side effects such as extrapyramidal motor symptoms, psychomotor sedation or cognitive impairment. These side effects severely restrict D₂Therapeutic use of antagonist compounds. (Wong A.H.C. et al: neurosci.Biobehav.Rev.2003, 27, 269)

In another aspect, the invention provides a method for treating a patient in need of preferential modulation of dopamine D₃And/or D₂A method of a disorder of a subject, such as psychosis (e.g., schizophrenia, schizoaffective disorder), schizophrenia with accompanying cognitive impairment, mild to moderate cognitive deficits, dementia, psychotic conditions associated with dementia, psychotic depression, mania, paranoid psychotic disorders and delusional disorders, obsessive compulsive disorder, movement disorders (e.g., parkinson's disease), neuroleptic-induced parkinsonism, tardive dyskinesia, eating disorders (e.g., bulimia nervosa), attention deficit hyperactivity disorder, depression, anxiety, sexual dysfunction, sleep disorders, emesis, aggression, autism, and drug abuse, comprising administering to a patient in need thereof an effective amount of a compound and/or composition of the invention.

Of the invention having D₃Preferred is D₃/D₂Preferred uses of the antagonists are in the treatment of schizophrenia, schizoaffective disorder, schizophrenia with concomitant cognitive impairment, mild to moderate cognitive deficits, dementia, psychotic conditions associated with dementia, psychotic depression, mania, paranoid and delusional disorders, obsessive compulsive disorder, movement disorders (e.g. parkinson's disease), neuroleptic-induced parkinsonism, depression, anxiety, substance abuse (e.g. cocaine, alcohol, nicotine abuse).

The specific combination of the actions of the two receptors mentioned above allows the simultaneous display of D₃Antagonism (e.g. cognitive enhancing effects, inhibition of extrapyramidal motor symptoms, inhibition of drug abuse) and D₂Antagonism (e.g. antipsychotic effect). Furthermore, this same combination surprisingly eliminates D₂Adverse features of antagonism (e.g. extrapyramidal symptoms, psychomotor sedation, cognitive impairment).

The term "substantially pure" refers to a compound having a purity of greater than, for example, about 90% by weight, such as greater than about 91% by weight, greater than about 92% by weight, greater than about 93% by weight, greater than about 94% by weight, greater than about 95% by weight, greater than about 96% by weight, greater than about 97% by weight, greater than about 97.5% by weight, greater than about 98% by weight, greater than about 99% by weight, greater than about 99.5% by weight, or greater than about 99.9% by weight. One of ordinary skill in the art can readily identify methods by which the purity of a particular compound can be determined.

The term "treating" refers to alleviating, delaying, reducing, reversing, ameliorating, or preventing at least one symptom of a disease in a patient. The term "treating" may also refer to preventing, delaying the onset of (i.e., prior to clinical manifestation of) a disease and/or reducing the risk of developing or worsening a disease.

By "effective amount" is meant an amount of a compound of the invention sufficient to effect treatment of a disease, or an amount of a compound sufficient to modulate a dopamine receptor (particularly dopamine D), when administered to a patient (e.g., a mammal) to treat the disease₂And/or dopamine D₃Receptor) to achieve the object of the invention. The "effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the patient to be treated.

The individual or patient to whom a therapeutic compound is administered as an effective treatment regimen for a disease or disorder is preferably a human, but can be any animal, including laboratory animals in clinical trials, screens, or activity experiments. Thus, one of ordinary skill in the art will readily appreciate that the methods, compounds, and compositions of the present invention are particularly suitable for administration to any animal, particularly mammals, including, but not limited to, humans, domestic animals such as felines or canines, farm animals (such as, but not limited to, cows, horses, goats, sheep, and pigs), wild animals (whether outdoors or in zoos), research animals (such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, and the like), birds (such as chickens, turkeys, song birds, and the like), i.e., for veterinary use.

In some embodiments, the compounds of the present invention are administered as monotherapies. In other embodiments, the compounds of the invention are administered as part of a combination therapy. For example, the compounds of the invention are used in combination with other drugs or treatments for treating/preventing/inhibiting or ameliorating the diseases or conditions for which the compounds of the invention are useful.

These other drugs may be administered by their usual routes and amounts, either simultaneously or sequentially with the compounds of the present invention. When the compound of the present invention is used simultaneously with one or more other drugs, a pharmaceutical unit dosage form may be used which contains the other drugs mentioned above in addition to the compound of the present invention. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients in addition to the compounds of the present invention.

The compounds of the invention are usually administered (in adult patients) on a daily regimen, e.g. the compounds of the invention are administered in an oral dose of 1mg to 500mg, e.g. 10mg to 400mg, especially 10mg to 250mg, or in an intravenous, subcutaneous or intramuscular dose of 0.1mg to 100mg, e.g. 0.1mg to 50mg, especially 1 to 25 mg. The compounds of the invention may be administered from 1 to 4 times daily. The compounds of the invention may suitably be administered for continuous treatment for a period of time, for example one week or more.

Treating a patient suffering from a condition requiring treatment for, for example, schizophrenia or acute mania, as well as other conditions noted above, comprising administering a therapeutically effective amount of a compound of formulae (II) and (III) formulated in accordance with, for example and without limitation, the compositions and dosage forms described herein,

based on their HPLC and MS characteristics, the compounds of the invention obtained by the synthetic method appear to be identical to the compounds found in biological samples.

The following examples are merely illustrative of the present invention and should not be considered as limiting the scope of the invention in any respect, since many modifications and equivalents will become apparent to those skilled in the art to which the invention pertains upon reading this disclosure.

Examples

The metabolites of the invention are synthesized according to the following methods:

example 1.

Trans-1- {4- [2- [4- (2, 3-dichlorophenyl) -1-oxo-piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea (compound D)

0.8g (1.6mmol) of trans-1- {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl]-ethyl radical]-cyclohexyl } -3, 3-dimethyl-urea was dissolved in dichloromethane (60 ml). A solution of 0.54g (2.4mmol) of 3-chloroperbenzoic acid in dichloromethane (10ml) was added dropwise thereto, and the reaction mixture was stirred at room temperature for 24 hours. The reaction was checked by TLC. With saturated NaHCO₃Solution the solution was washed 2 times, the organic layer was dried and evaporated in vacuo. Flash chromatography gave 0.45g (63.3%) of the title compound, m.p. 175-178 ℃.

Example 2.

Trans-1- {4- [2- [4- (2, 3-dichloro-4-hydroxy-phenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea (compound C)

0.92g (2mmol) trans-4- {2- [4- (2, 3-dichloro-4-methoxy-phenyl) -piperazin-1-yl]The dihydrochloride of-ethyl } -cyclohexylamine was suspended in dichloromethane (60ml), triethylamine (1.26ml, 9mmol) was added, followed by 0.21ml (2.3mmol) of N, N-dimethylcarbamoyl chloride. The reaction mixture was stirred at room temperature for 48 hours. The solution was washed with water (2 × 10ml), dried and evaporated in vacuo. Purification by flash chromatography gave 0.66g of trans-1- {4- [2- [4- (2, 3-dichloro-4-methoxy-phenyl) -piperazin-1-yl]-ethyl radical]Cyclohexyl } -3, 3-dimethyl-urea, melting point 196-. This product was dissolved in dichloromethane (60ml) and then washed6.4ml (6.4mmol) of boron tribromide solution (1M CH) were added dropwise at 5 deg.C₂Cl₂Solution), and the mixture was stirred at room temperature for 24 hours. The reaction was checked by TLC. 4ml of methanol are added, followed by 25ml of saturated NaHCO₃And (3) solution. After separation, the organic layer was dried and evaporated in vacuo. Purification by flash chromatography gave 0.4g of the title compound, m.p. 278-.

Example 3.

Trans-1- {4- [2- [4- (2, 3-dichloro-4-hydroxy-phenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3-methyl-urea (compound B)

1.38g (3mmol) trans-4- {2- [4- (2, 3-dichloro-4-methoxy-phenyl) -piperazin-1-yl]The dihydrochloride of-ethyl } -cyclohexylamine was suspended in dry dichloromethane (100ml), triethylamine (1.72ml, 12.4mmol) was added and 0.34g (1.14mmol) of triphosgene dissolved in dichloromethane was added dropwise. After stirring at room temperature for 1 hour, methylamine (33% ethanol solution) was added and stirring was continued for 20 hours. The mixture was evaporated. 20ml of water are added, the precipitate is filtered off, washed with water and dried. The product was recrystallized from methanol to give trans-1- {4- [2- [4- (2, 3-dichloro-4-methoxy-phenyl) -piperazin-1-yl]-ethyl radical]-cyclohexyl } -3-methyl-urea (0.86g, 65%) with a melting point above 250 ℃. This product was dissolved in methylene chloride (60ml), and then 10ml (10mmol) of a boron tribromide solution (1M CH) was added dropwise at 5 ℃₂Cl₂Solution), and the mixture was stirred at room temperature for 24 hours. The reaction was checked by TLC. 4ml of methanol were added and the mixture was evaporated. 35ml of saturated NaHCO were added₃And (3) solution. The precipitate was filtered, washed with water and dried, and recrystallized from methanol to give 0.34g of the title compound, m.p. 237-241 ℃.

Example 4.

Trans-1- {4- [2- [4- (2, 3-dichloro-4-hydroxy-phenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -urea (Compound A)

1.38g (3mmol) trans-4- {2- [4- (2, 3-dichloro-4-methoxy-phenyl) -piperazin-1-yl]The dihydrochloride of-ethyl } -cyclohexylamine was suspended in dry dichloromethane (100ml), triethylamine (1.72ml, 12.4mmol) was added and 0.34g (1.14mmol) of triphosgene dissolved in dichloromethane was added dropwise. After stirring at room temperature for 1 hour, ammonia (20% methanol solution) was added and stirring was continued for 20 hours. The mixture was evaporated. 20ml of water are added, the precipitate is filtered off, washed with water and dried. The product was recrystallized from methanol to yield 0.86g of trans-1- {4- [2- [4- (2, 3-dichloro-4-methoxy-phenyl) -piperazin-1-yl]-ethyl radical]-cyclohexyl } -urea having a melting point higher than 250 ℃. This product was dissolved in methylene chloride (60ml), and then 10ml (10mmol) of a boron tribromide solution (1M CH) was added dropwise at 5 ℃₂Cl₂Solution), and the mixture was stirred at room temperature for 24 hours. The reaction was checked by TLC. 4ml of methanol were added and the mixture was evaporated. 35ml of saturated NaHCO were added₃And (3) solution. The precipitate was filtered, washed with water and dried, and recrystallized from methanol to give 0.37g of the title compound, m.p. 195-198 ℃.

Biological assay method

Receptor binding assays

1.D ₃ Receptor binding

The term "was used according to the supplier's instructions (Packard Bioscience, BioSignal packardlnc. Cat. No.6110139, Technical Data Sheet)³H]Spiroperone (0.85nM) as ligand, non-specific binding determined with haloperidol (10. mu.M), recombinant D in rat₃The receptor (expressed in Sf9 cells) was subjected to a binding assay.

2.D ₂ Receptor binding

The use of [2 ] is described in Creese et al (European Journal of Pharmacology, 60, 55-66, 1979)³H]Spiperone (0.6nM) as ligand, D on rat brain striatal membrane specimens₂A receptor binding assay. Nonspecific binding was determined in the presence of 1 μ M (+) -butalamol.

3.Alpha-1 receptor binding

According to the method described by Greengars and Bremmer (European Journal of Pharmacology 55: 323-³H]-prazosin (prasin) (0.5nM) as ligand, and α -1 receptor binding assay studies were performed on rat cerebral cortical membrane specimens. Nonspecific binding was determined in the presence of 10. mu.M phentolamine.

D of selected metabolites of the invention₃、D₂And alpha-1 receptor binding data are listed in table 1 below.

TABLE 1

Compound (I)	rD3 Ki(nM)	rD2 Ki(nM)	αKi(nM)
				Compound A	0.26	8.4	＞＞1000
Compound B	0.24	2.49	＞＞1000
				Compound C	0.37	80.5	＞＞1000
Compound D	＞＞10	＞＞100	＞＞1000

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 to those skilled in the art from the foregoing description and the accompanying drawings. Such modifications are also intended to fall within the scope of the appended claims. Further, it is to be understood that all numerical values are approximate (approximate) and are for purposes of illustration.

All applications, patents, and publications cited above and below are hereby incorporated by reference in their entirety.

Claims (26)

1. An isolated metabolite of a compound of formula (I):

wherein

R₁And R₂Each independently is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aroyl, or R₁And R₂Together with the adjacent nitrogen atom form a heterocyclic ring;

x is O or S;

n is 1 or 2;

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates and/or polymorphs thereof.

2. An isolated and/or synthesized metabolite of a compound of formula (I) according to claim 1, wherein the compound of formula (I) is

And/or salts and/or hydrates and/or solvates and/or polymorphs thereof.

3. An isolated and/or synthesized compound of formula (II):

wherein

R₁And R₂Each independently is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aroyl, or R₁And R₂Together with the adjacent nitrogen atom form a heterocyclic ring;

x is O or S;

n is 1 or 2;

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates and/or polymorphs thereof.

4. An isolated and/or synthesized compound of formula (III):

wherein

R₁And R₂Each independently of the others is hydrogen,Alkyl, alkenyl, aryl, cycloalkyl, aroyl, or R₁And R₂Together with the adjacent nitrogen atom form a heterocyclic ring;

x is O or S;

n is 1 or 2;

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates and/or polymorphs thereof.

5. The compound of claim 3, wherein formula (II) is represented by formula (IIa),

wherein R is₁、R₂X and n are as defined above for formula (II).

6. The compound of claim 3, wherein

R₁And R₂Each independently of the others being hydrogen, optionally substituted by one or more C_1-6Alkoxycarbonyl, aryl or (C)_1-6Alkoxycarbonyl) -C_1-6Alkyl substituted straight or branched C_1-6Alkyl, C having 1-3 double bonds_2-7Alkenyl, optionally substituted by one or more C_1-6Alkoxy, trifluoro C_1-6Alkoxy radical, C_1-6Alkoxycarbonyl, C_1-6Alkanoyl, aryl, C_1-6Alkylthio, halogen or cyano-substituted mono-, di-or tricyclic aryl, optionally substituted mono-, di-or tricyclic cycloalkyl, aroyl, or R₁And/or R₂Together with the adjacent nitrogen atom, form a heterocyclic ring, which may be saturated or unsaturated, optionally substituted monocyclic or bicyclic, which may contain an additional heteroatom selected from O, N or S;

x is oxygen;

n is 1.

7. The compound of claim 3, wherein

R₁And R₂Each independently of the others being hydrogen, optionally substituted by one or more C_1-6Alkoxycarbonyl, phenyl or (C)_1-6Alkoxycarbonyl) -C_1-6Alkyl substituted straight or branched C_1-6Alkyl, C having 1 double bond_2-7Alkenyl, optionally substituted by one or more C_1-6Alkoxy, trifluoro-C_1-6Alkoxy radical, C_1-6Alkoxycarbonyl, C_1-6Alkanoyl, aryl, C_1-6Phenyl or naphthyl substituted by alkylthio, halogen or cyano, cyclohexyl, adamantyl, benzoyl, or R₁And/or R₂Together with the adjacent nitrogen atom form a heterocyclic ring, which may be saturated, optionally substituted by C_1-6An alkyl or hydroxy substituted monocyclic ring which may contain an additional heteroatom selected from O or N;

x is oxygen;

n is 1.

8. The compound of claim 3, wherein

R₁And R₂Each independently of the others is hydrogen, optionally substituted by C_1-6Alkoxycarbonyl-or phenyl-substituted straight-chain or branched C_1-6Alkyl, allyl, optionally substituted by one or more C_1-6Alkoxy, cyano or C_1-6Alkanoyl substituted phenyl, cyclohexyl, or R₁And/or R₂Together with the adjacent nitrogen atom forming an optionally substituted C_1-6An alkyl or hydroxy substituted pyrrolidine, piperazine, piperidine or morpholine ring;

x is oxygen;

n is 1.

9. The compound of claim 3, wherein

R₁And R₂Each independently is hydrogen or alkyl; x is oxygen; n is 1.

10. The compound of claim 4, wherein

R₁And R₂Each independently of the others being hydrogen, optionally substituted by one or more C_1-6Alkoxycarbonyl, aryl or (C)_1-6Alkoxycarbonyl) -C_1-6Alkyl substituted straight or branched C_1-6Alkyl, C having 1-3 double bonds_2-7Alkenyl, optionally substituted by one or more C_1-6Alkoxy, trifluoro C_1-6Alkoxy radical, C_1-6Alkoxycarbonyl, C_1-6Alkanoyl, aryl, C_1-6Alkylthio, halogen or cyano-substituted mono-, di-or tricyclic aryl, optionally substituted mono-, di-or tricyclic cycloalkyl, aroyl, or R₁And/or R₂Together with the adjacent nitrogen atom, form a heterocyclic ring, which may be saturated or unsaturated, optionally substituted monocyclic or bicyclic, which may contain an additional heteroatom selected from O, N or S;

x is oxygen;

n is 1.

11. The compound of claim 4, wherein

R₁And R₂Each independently of the others being hydrogen, optionally substituted by one or more C_1-6Alkoxycarbonyl, phenyl or (C)_1-6Alkoxycarbonyl) -C_1-6Alkyl substituted straight or branched C_1-6Alkyl, C having 1 double bond_2-7Alkenyl, optionally substituted by one or more C_1-6Alkoxy, trifluoro-C_1-6Alkoxy radical, C_1-6Alkoxycarbonyl, C_1-6Alkanoyl, aryl, C_1-6Phenyl or naphthyl substituted by alkylthio, halogen or cyano, cyclohexyl, adamantyl, benzoyl, or R₁And R₂Together with the adjacent nitrogen atom form a heterocyclic ring, which may be saturated, optionally substituted by C_1-6An alkyl or hydroxy substituted monocyclic ring which may contain an additional heteroatom selected from O or N;

x is oxygen;

n is 1.

12. The compound of claim 4, wherein

R₁And R₂Each independently of the others is hydrogen, optionally substituted by C_1-6Alkoxycarbonyl-or phenyl-substituted straight-chain or branched C_1-6Alkyl, allyl, optionally substituted by one or more C_1-6Alkoxy, cyano or C_1-6Alkanoyl substituted phenyl, cyclohexyl, or R₁And/or R₂Together with the adjacent nitrogen atom forming an optionally substituted C_1-6An alkyl or hydroxy substituted pyrrolidine, piperazine, piperidine or morpholine ring;

x is oxygen;

n is 1.

13. The compound of claim 4, wherein

R₁And R₂Each independently is hydrogen or alkyl; x is oxygen; and n is 1.

14. A compound according to any one of claims 3 to 4 selected from

And/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates and/or polymorphs thereof.

15. A pharmaceutical composition comprising:

isolated metabolites of compounds of formula (I)

Wherein

R₁And R₂Each independently is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aroyl, or R₁And R₂Together with the adjacent nitrogen atom form a heterocyclic ring;

x is O or S;

n is 1 or 2;

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates and/or polymorphs thereof,

and

one or more pharmaceutically acceptable carriers.

16. A pharmaceutical composition comprising:

a compound of formula (II)

Wherein

R₁And R₂Each independently is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, or aroyl, or R₁And R₂Together with the adjacent nitrogen atom form a heterocyclic ring;

x is O or S;

n is 1 or 2;

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates and/or polymorphs thereof, and

one or more pharmaceutically acceptable carriers.

17. A pharmaceutical composition comprising:

a compound of formula (III)

Wherein

R₁And R₂Each independently is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, or aroyl, or R₁And R₂Together with the adjacent nitrogen atom form a heterocyclic ring;

x is O or S;

n is 1 or 2;

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates and/or polymorphs thereof, and

one or more pharmaceutically acceptable carriers.

18. A pharmaceutical composition comprising a compound of claim 14 and one or more pharmaceutically acceptable carriers.

19. A method for the treatment and/or prevention of a disorder requiring modulation of dopamine receptors, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1-2.

20. A method for the treatment and/or prevention of a disorder requiring modulation of dopamine receptors, comprising administering to a patient in need thereof a therapeutically effective amount of a metabolite according to any of claims 3 to 14.

21. A method of treatment and/or prevention according to any of claims 19 to 20, wherein the dopamine receptor is dopamine D₃Receptor and/or dopamine D₂A receptor.

22. A method of treating and/or preventing a disorder requiring modulation of dopamine receptors comprising administering to a patient in need thereof a therapeutically effective amount of a composition according to any one of claims 15 to 18.

23. The method of treatment and/or prevention according to claim 22, wherein the dopamine receptor is dopamine D₃Receptor and/or dopamine D₂A receptor.

24. Use of a metabolite according to any of claims 1-2 for the manufacture of a medicament for the treatment and/or prevention of a condition requiring modulation of dopamine receptors.

25. The use of a compound according to any one of claims 3 to 14 for the preparation of medicaments for the treatment and/or prevention of diseases which require modulation of dopamine receptors.

26. The use of any one of claims 24 to 25, wherein the dopamine receptor is dopamine D₃Receptor and/or dopamine D₂A receptor.