HK1143362A - Compounds with a combination of cannabinoid-cb1 antagonism and serotonin reuptake inhibition - Google Patents

Description

having cannabinoid-CB1Compounds combining antagonism and 5-hydroxytryptamine reuptake inhibition

Technical Field

The present invention relates to the fields of pharmaceutical and organic chemistry and provides compounds having cannabinoid-CB₁Compounds, intermediates, formulations and methods which combine an antagonistic effect with an inhibitory effect on the reuptake of 5-hydroxytryptamine.

Background

The medical industry has been generally held in the way of reducing a speaker's ' one target-one disease ' for the last decades. Many successful drugs were discovered using this strategy. However, many diseases are nevertheless not treated properly. These findings illustrate another approach in which chemical entities have been developed that can modulate multiple targets simultaneously. Such drugs may have advantageous properties such as improved clinical efficacy, or lack undesirable pharmacokinetic drug-drug interactions, or lack unfavorable pharmacokinetic and pharmacodynamic properties. The latter may lead to unpredictable variability from patient to patient. In order to combine different therapeutic mechanisms, combinations of two or more drugs are still used in clinical practice. Alternatively, a multi-component drug is used, wherein two or more pharmaceutically active ingredients are formulated into a tablet or capsule to improve patient compliance. Another approach utilizes drug therapy with chemical entities that can simultaneously modulate more than one biological target. It is clear that this "single entity-multi-targeting approach" offers the advantage that it reduces the risk of unwanted drug-drug interactions compared to drug combinations or multi-component drugs. Several multi-targeting ligands are known. Most are discovered retrospectively or by chance. Only a few are obtained by rational design.

Cannabinoid receptors are part of the endo-cannabinoid system and are involved in a number of diseases. Related cannabinoid receptor, CB₁Receptor modulators and their pharmacology are well-defined and the subject of recent reviews (Landsman, 1997; Lichtman, 2002; De Petrocellis, 2004; Di Marzo, 2004; Hertzog, 2004; Lange, 2004, 2005; Smith, 2005; Thaku, et al; Tachtman, et alr, 2005; padgett, 2005; muccioli, 2005; lambert, 2005; vandavorode, 2005). CB disclosed in the cited review₁Potential therapeutic applications of receptor modulators include as medicaments for the treatment of the following diseases: psychosis, anxiety, depression, attention deficit, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, desire (apentence), drug dependence, neurodegenerative disorders, dementia, dystonia, myotonia, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, parkinson's disease, alzheimer's disease, epilepsy, huntington's disease, Tourette's syndrome, cerebral ischemia, cerebral stroke, craniocerebral trauma, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, diseases associated with demyelination, and pain disorders including neuropathic pain disorders, septic shock, glaucoma, diabetes, cancer, emesis, nausea, gastrointestinal disorders, gastric ulcers, diarrhea, sexual dysfunction, impulse control disorders, and cardiovascular disorders.

Mood disorders and anxiety disorders produce tremendous pain. Selective 5-hydroxytryptamine reuptake inhibitors introduced twenty years ago have taken a major step in the development of safer antidepressants. Representative examples of selective 5-hydroxytryptamine reuptake inhibitors are fluvoxamine, fluoxetine, paroxetine, sertraline, citalopram, zimelidine, clomipramine, indaparine and indatriline. Despite the significant structural differences between selective 5-hydroxytryptamine reuptake inhibitors, most inhibitors are based on monoamine structures: they contain basic nitrogen atoms (Pacher, 2004). The following therapeutic applications of 5-hydroxytryptamine reuptake inhibitors are given in scientific articles, patents and patent applications: alcoholism, alzheimer's disease, anorexia nervosa, anxiety disorders, attention deficit hyperactivity disorder, bipolar disorder, bulimia nervosa, central nervous system disorders, chemotherapy-induced emesis, cocaine addiction, cognitive disorders, diabetic neuropathy, drug dependence, eating disorders, female sexual dysfunction, functional bowel disorders, general anxiety disorders, headache, inflammation, irritable bowel syndrome, male sexual dysfunction, major depressive disorder, menopause, migraine, myalgia, neuralgia, neuropathic pain, obesity, obsessive compulsive disorder, osteoarthritis, pain, panic disorder, parkinson's disease, premature ejaculation, premenstrual syndrome, psychological disorders, psychosis, rheumatoid arthritis, schizophrenia, sleep disorders, and urinary incontinence.

Has 5-hydroxytryptamine reuptake inhibiting effect and cannabinoid-CB due to the joint onset of symptoms frequently occurring in different diseases₁Antagonistic combinations of compounds can be used for the treatment of diseases, among which cannabinoid CB₁Treatment with antagonists or 5-hydroxytryptamine reuptake inhibitors is potentially effective. Thus, the compounds of the present invention can be used to treat the following diseases: addiction, alcoholism, Alzheimer's disease, anorexia nervosa, anxiety disorders, appetite disorders, attention deficit hyperactivity disorder, bipolar disorder, bulimia nervosa, cancer, cardiovascular disease, central nervous system disorder, cerebral ischemia, cerebral stroke, chemotherapy-induced emesis, cocaine addiction, cognitive disorders, dementia, diseases associated with demyelination, diabetes, diabetic neuropathy, diarrhea, drug dependence, dystonia, eating disorders, emesis, epilepsy, female sexual dysfunction, functional bowel disorders, gastrointestinal disorders, gastric ulcers, generalized anxiety disorder, glaucoma, headache, Huntington's disease, impulse control disorders, inflammation, irritable bowel syndrome, male sexual dysfunction, severe depressive disorders, memory disorders, menopause, migraine, muscle spasms, multiple sclerosis, anxiety disorders, depression, anxiety disorders, depression disorders, cerebral ischemia, stroke disorders, diabetes mellitus, diabetes, Myalgia, nausea, neuralgia, neurodegenerative diseases, neuroinflammatory diseases, neuropathic pain, obesity, obsessive-compulsive disorders, osteoarthritis, pain, panic disorder, Parkinson's disease, plaque sclerosis, premature ejaculation, premenstrual syndrome, psychosexual disorders, psychosis, rheumatoid arthritis, septic shock, schizophrenia, sexual dysfunction, sleep disorders, spinal cord injury, stroke, Tourette's syndrome, traumatic brain injury, tremor, urinary incontinence and viral encephalitis.

Of particular value is the treatment by cannabinoid CB using the compounds of the invention₁Antagonists and 5-hydroxytryptamine reuptake inhibitors. Simultaneous attack of this disease by two different mechanisms of action can produce a synergistic effect. Thus, the compounds of the present invention can be used in particular for the treatment of the following diseases: psychosis, anxiety, depression, attention deficit, cognitive disorders, obesity, drug dependence, parkinson's disease, alzheimer's disease, pain disorders, neuropathic pain disorders, and sexual dysfunction.

There are several reviews on the subject matter of most cannabinoid CB₁Pharmacophores for receptor antagonists (Lange, 2005; Reggio, 2003). See scheme 1.

Scheme 1: CB (CB)₁Pharmacophores of receptor antagonists, and methods of use thereof₁One putative major interaction of receptors

In scheme 1, Ar₁And Ar₂Represents phenyl optionally substituted by one or two halogen atoms, trifluoromethyl or methoxy. In scheme 1, the 'spacer' comprises a five-membered heterocyclic group such as 4, 5-dihydropyrazole, imidazole, pyrazole, thiazole, thiophene or pyrrole, or the spacer comprises a phenyl or six-membered heterocyclic group such as pyridine, pyrimidine or pyrazine. The spacer can also contain an azetidine moiety, a 1, 3-benzodioxole moiety or an alkyl moiety, as in MK-0364 (see below). Furthermore, one aryl group can be fused to the spacer, or can be connected to the spacer via another ring: so-called conformational constraints. Several types of conformational constraints have been successfully obtained in this pharmacophore model. H-bond acceptors (H-bond acceptors) represent a carbonyl group, a sulfonyl group or a nitrogen atom, which may be incorporated into a heterocyclic structure such as an imidazole ring. In scheme 1, 'lipid (Lip)' means a lipophilic moiety such as piperidin-1-ylamino, pyrrolidinyl-1-amino, cycloalkylamino, phenylamino, arylamino, benzylamino or alkylamino。

Studies to construct molecular models indicate that the presence of hydrogen bond receptors is crucial: it is believed to be linked to CB₁The Lys-192 amino acid residue side chains of the receptor interact, thereby stabilizing its inactive state.

To illustrate CB₁Pharmacophore models of receptor antagonists, some of which are described below₁Specific examples of the receptor. The hydrogen bond acceptor atom (oxygen from carbonyl, oxygen from sulfonyl or N in the heteroaromatic ring) is assumed to be the bold moiety shown.

A pharmacophore model for 5-hydroxytryptamine reuptake inhibitors has been reported (Bureau, 2002). See scheme 2.

Scheme 2: graphical overview of SRI pharmacophores

It is characterized by having a basic nitrogen atom (N), an extended lipophilic aromatic region (Ar)₁) And lipophilic moieties (Lip-SRI). The basic amino function may be unsubstituted ((R)₁And R₂Representing hydrogen) as in fluvoxamine, or mono-substituted as in fluoxetine, indatrilin and sertraline, or di-substituted as in citalopram, zimelidine and clomipramine. The basic nitrogen atom may be part of a six-membered ring, for example as in indapadine and paroxetine: namely R₁Represents a hydrogen atom, R₂Is part of the pharmacophore carbon ring framework. Many 4- (3-indolyl-alkyl) piperidine derivatives, including indacen and 4- (3-indolyl-alkyl) piperazine derivatives, have been shown to have potential5-hydroxytryptamine reuptake inhibitor activity (Le Fur, 1977; Malleron, 1993).

We know of Selective CB₁The receptor antagonist SR141716A (rimonabant) has been available for more than a decade. Subsequently, a number of other selective CBs were invented₁A receptor antagonist. We know that 5-hydroxytryptamine reuptake inhibitors have been known for more than two decades. So far, no combination of CB has been disclosed₁A compound having a receptor antagonistic activity and a 5-hydroxytryptamine reuptake inhibiting activity.

The object of the present invention is to develop a composition having CB₁A compound having a combination of antagonism and 5-hydroxytryptamine reuptake inhibition.

BRIEF SUMMARY OF THE PRESENT DISCLOSURE

It has been found that known cannabinoid-CB is included₁Molecules having a basic moiety derived from cannabinoid-CB of antagonists and of known inhibitors of the reuptake of 5-hydroxytryptamine as indamines or fluvoxamine₁Antagonism and 5-hydroxytryptamine reuptake inhibition. The present invention relates to compounds having cannabinoid-CB₁Compounds combining antagonism and 5-hydroxytryptamine reuptake inhibition, particularly in combination with CB₁In receptor binding and binding to 5-hydroxytryptamine reuptake, pK_iCompounds with a value > 6.00.

More particularly, the present invention relates to compounds of formula (1):

a tautomer, stereoisomer, N-oxide, isotopically-labeled analog thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein:

-A represents any known cannabinoid-CB₁AntagonistsComprises at least two phenyl rings, each independently, optionally substituted with one or two substituents selected from halogen, methoxy and trifluoromethyl, said basic moiety and said cannabinoid-CB₁The hydrogen bond acceptor moiety in the antagonist is a carbonyl group, a sulfonyl group, or a nitrogen or oxygen atom bonded in a heteroaromatic ring structure,

-N represents a non-basic nitrogen atom,

-T represents a saturated or unsaturated carbon chain having 0 to 8 atoms, in which one carbon atom may be substituted by a nitrogen atom (optionally substituted by (C)₁-C₃) -alkyl or CH₂CF₃Substituted by groups), or by oxygen or sulfur atoms, wherein the chain is optionally substituted by one or more groups selected from fluorine, amino, cyano, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy or trifluoromethyl, or a pharmaceutically acceptable salt thereof,

r represents a hydrogen atom, or (C)₁-C₃) -alkyl, or R and the nitrogen atom to which R is attached, and together with part of T form (C)₄-C₇) -a heterocycloalkyl or a heteroaryl group,

-B represents the basic moiety of any known 5-hydroxytryptamine reuptake inhibitor.

Other embodiments provide one or more compounds of formula (1), wherein the cannabinoid-CB₁The antagonist is selected from:

11C-JHU-75528, A-796260, ajulemic acid, AM 251, AM 630, AVE-1625, CP-272871, CP-945598, EMD-68843, GRC-10389, LY-2077855, LY-320135, NIDA-41020, O-2093, SLV319, SLV326, SR-140098, SR-144385, SR-41716A (rimonabant), surrinan, V-24343, WIN-54461 and WIN-56098,

the 5-HT reuptake inhibitor is selected from the group consisting of:

403U76, A-80426, AD-337, aclidinum, agomelatine, alaproplate, amiheptanoic acid, amitriptyline, ARAK-0029, ARAK-0051, befilptan, befloxatone, BGC-20-1259, bicifadine, BMS-505130, bromofamine, bupropion, butiline, West chloramine, citalopram, CL: -275838, clomipramine, clovoxamine, CX-157, dapoxetine, desvenlafaxine, dexfenfluramine, diphenylazepine, diclofenac, duloxetine, DOV-21947, DOV-102677, DOV-216303, duloxetine, DU 125530, DuP-631, EN-3215, EpiCept NP-1, escitalopram, femoxetine, fluoxetine, (S) -fluoxetine, fluvoxamine, gepirone, IDN-5491, imipramine, indamine, iprindole, L-792239, LI-301, ritoxetine, lofepramine, LU-10134-C, LU-AA21004, batrox, LY-214281, LY-367265, LY-393558, maprotiline, MCI-225, MCL-0042, McN-5652, trimestrine, amphetamine, clomipramine, duloxetine, dulcamide, duloxetine, dulcamine, modafinil, nefazodone, 6-nitroquinpiperazine, nortriptyline, NR-200S, NS-2381, NS-2389, NS-2463, NS-4194, NS-23459, omixetine, OPC-14523, opipramol, Org-6582, paroxetine, pramipexole, PRC-025, propiheptipine, quetiapine, quinupramine, ramelteonine, R-fluoxetine, rizatriptan, robuzotan, rocco indole, RS-1439, SB-649915, S-9977, SD-726, selegiline, SEP-225289, SEP-227162, sertraline, sibutramine, (S) -sibutramine, (R) -dinotebuconazole, SLV310, SLV, SL314-473, tramadol, tritazone, Udenafil, UK-416244, VANH-2336, Venlafaxine, vilazodone, VML-670, VN-2222, volinanserin, WF-23, WF-516, WL-1011, WL-1017, YM-922 and zimelidine.

Other embodiments provide one or more compounds of formula (1): wherein A represents (A)^1a)、(A^1b)、(A²)、(A³)、(A⁴)、(A⁵)、(A⁶)、(A⁷) Or (A)⁸) One of the fragments:

wherein X represents a sulfonyl group or a carbonyl group, the symbol "+" represents the point at which the fragment is attached to the N moiety of formula (1) wherein N represents a non-basic nitrogen, and R¹、R²And R³Independently of one another, represents or more hydrogen, trifluoromethyl or halogen atoms, R⁴Represents a hydrogen or halogen atom, or a methyl, ethyl, trifluoromethyl, hydroxymethyl, fluoromethyl, 2, 2, 2-trifluoroethyl, propyl, methylsulfanyl (methylsulfanyl), methylsulfinyl, methylsulfonyl, ethylsulfanyl (ethylsulfanyl), ethylsulfinyl, ethylsulfonyl, C_1-3-dialkyl-aminomethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl or morpholin-4-ylmethyl, the other symbols having the meanings indicated above.

In another embodiment, the present invention relates to compounds of formula (1) wherein A represents (A)^1a)、(A^1b)、(A²)、(A³)(A⁴)、(A⁵)、(A⁶)、(A⁷) Or (A)⁸) One of the fragments, the NRTB sequence of formula (1) is (NTRB)¹)、(NRTB²)、(NTRB³)、(NRTB⁴)、(NTRB⁵)、(NRTB⁶)、(NTRB⁷)、(NRTB⁸)、(NTRB⁹) Or (NRTB)¹⁰) One of the fragments:

wherein R represents a hydrogen atom or (C)₁-C₃) -an alkyl group.

In another embodiment, the present invention relates to compounds of formula (1) wherein A represents (A)^1a) Or (A)²) One of the fragments: ):

wherein X represents a sulfonyl group or a carbonyl group, + is the point at which the fragment is attached to the nitrogen atom N which is not basic in formula (1), and R¹、R²And R³Independently of one another, represents a hydrogen, trifluoromethyl or halogen atom, R⁴Represents a hydrogen or halogen atom, or a methyl, ethyl, trifluoromethyl, hydroxymethyl, fluoromethyl, 2, 2, 2-trifluoroethyl, propyl, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfanyl, ethylsulfinyl, ethylsulfonyl, C_1-3-dialkyl-aminomethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl or morpholin-4-ylmethyl, the other symbols having the meanings indicated above.

In another embodiment, the present invention relates to compounds of formula (1) wherein A represents (A)^1a) Or (A)²) One of the fragments, the NRTB sequence of formula (1) is (NTRB)¹)、(NRTB²)、(NTRB³)、(NRTB⁴)、(NTRB⁵)、(NRTB⁶)、(NTRB⁷)、(NRTB⁸)、(NTRB⁹) Or (NRTB)¹⁰) One of the fragments.

In another embodiment, the present invention relates to compounds of formula (1) wherein A represents (A)³) Or (A)⁴) One of the fragments:

the NRTB sequence of formula (1) is (NTRB)¹)、(NRTB²)、(NTRB³)、(NRTB⁴)、(NTRB⁵)、(NRTB⁶)、(NTRB⁷)、(NRTB⁸)、(NTRB⁹) Or (NRTB)¹⁰) One of the fragments.

In another embodiment, the present invention relates to compounds of the following formula (1):

the compounds of the general formula (1) of the present invention, as well as pharmaceutically acceptable salts thereof, have cannabinoid-CB₁A combination of antagonism and 5-hydroxytryptamine reuptake inhibition. They are useful in therapy with respect to cannabinoid-CB₁Diseases in which the receptor 5-hydroxytryptamine reuptake site is involved, or diseases which can be treated by manipulation of these receptors. For example: addiction, alcoholism, Alzheimer's disease, anorexia nervosa, anxiety disorders, appetite disorders, attention deficit hyperactivity disorder, bipolar disorder, bulimia nervosa, cancer, cardiovascular disease, central nervous system disorder, cerebral ischemia, cerebral stroke, chemotherapy-induced emesis, cocaine addiction, cognitive disorders, dementia, diseases associated with demyelination, diabetes, diabetic neuropathy, diarrhea, drug dependence, dystonia, eating disorders, emesis, epilepsy, female sexual dysfunction, functional bowel disorders, gastrointestinal disorders, gastric ulcers, generalized anxiety disorder, glaucoma, headache, Huntington's disease, impulse control disorders, inflammation, irritable bowel syndrome, male sexual dysfunction, severe depressive disorders, memory disorders, menopause, migraine, muscle spasms, multiple sclerosis, anxiety disorders, depression, anxiety disorders, depression disorders, cerebral ischemia, stroke disorders, diabetes mellitus, diabetes, Myalgia, nausea, neuralgia, neurodegenerative diseases, neuroinflammatory diseases, neuropathic pain, obesity, obsessive-compulsive disorders, osteoarthritis, pain, panic disorder, Parkinson's disease, plaque sclerosis, premature ejaculation, premenstrual syndrome, psychosexual disorders, psychosis, rheumatoid arthritis, septic shock, schizophrenia, sexual dysfunction, sleep disorders, spinal cord injury, stroke, Tourette's syndrome, traumatic brain injury, tremor, urinary incontinence and viral encephalitis.

Other embodiments of the invention include, but are not limited to:

pharmaceutical compositions for use in therapy, e.g. as may be obtained by cannabinoid-CB₁A combination of antagonism and 5-hydroxytryptamine reuptake inhibition for the treatment of a disorder or disease, the composition comprising a compound of formula (1), and a pharmaceutically acceptable carrier;

methods of treating a disorder or disease, wherein the disorder or disease can be treated by cannabinoid-CB₁Antagonism and 5-hydroxytryptamine reuptake inhibition, which comprises administering to a mammal in need of such treatment a compound of formula (1)

A pharmaceutical composition for use in the treatment of a condition or disease, for example selected from those listed herein;

a method of treating a condition or disease, wherein the condition or disease is selected from the diseases listed herein, which comprises administering to a patient in need of such treatment a compound of formula (1);

a pharmaceutical composition for treating a condition or disease selected from those listed herein, the composition comprising a compound of formula (1) and a pharmaceutically acceptable carrier;

a method of treating a condition or disease selected from the diseases listed herein, which comprises administering to a patient in need of such treatment a compound of formula (1).

Antagonistic cannabinoid-CB₁A method of antagonizing an interacting receptor and inhibiting 5-hydroxytryptamine reuptake comprising administering to a subject in need thereof an effective amount of a compound of formula (1).

The invention also provides the use of a compound according to formula (1) for the manufacture of a medicament.

The invention further relates to combination therapies in which a compound of the invention or a pharmaceutical composition or formulation containing a compound of the invention is administered, either simultaneously or sequentially or as a formulation in combination with one or more other therapeutic agents, for the treatment of one or more of the listed diseases. Such additional therapeutic agent or agents may be administered prior to, concurrently with, or subsequent to the administration of the compounds of the present invention.

The invention also provides compounds, pharmaceutical compositions, kits and methods for treating a condition or disease selected from those listed herein, comprising administering to a patient in need of such treatment a compound of formula (1).

The compounds of the present invention have cannabinoid-CB₁A combination of antagonism and 5-hydroxytryptamine reuptake inhibition. The (antagonistic) agonistic/inhibitory activity properties of the compounds of the invention are readily characterized, for example, using one or more assays described herein or known in the art.

The invention also provides processes for preparing the compounds of the invention and intermediates useful in these processes.

If desired, the compounds and intermediates described herein may be isolated and purified by any suitable separation or purification step, such as filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick layer chromatography, preparative low or high pressure liquid chromatography, or a combination of such steps. Suitable separation and isolation procedures are specifically described in the preparations and examples. However, other equivalent separation or isolation steps can of course also be used.

The compounds of the invention may also contain one or more asymmetric centers, whereby racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers can exist. Other asymmetric centers may also be present depending on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, all possible optical isomers and diastereomers, in admixture or as a purified or partially purified compound, intended to be included within the scope of the present invention. The present invention is intended to encompass all such isomeric forms of these compounds. Formula (1) shows the structure of the class of compounds without preferred stereochemistry. The independent synthesis of these diastereomers or their chromatographic separations can be achieved by appropriate modification of the methodology disclosed herein, as is well known in the art. Its absolute stereochemistry may be determined by X-ray diffraction crystallography of crystalline products or crystalline intermediates, which may be derivatized, if desired, with asymmetric centers containing known absolute configurations. If desired, racemic mixtures of the compounds can be separated so that the individual enantiomers are separated. Separation can be carried out by methods known in the art, such as coupling a racemic mixture of compounds with an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often carried out using enantiomerically pure acids or bases, for example (-) -di-p-toluoyl-D-tartaric acid and/or (+) -di-p-benzoyl-L-tartaric acid, to form salts. Diastereomeric derivatives can then be converted into the pure enantiomers by cleavage of the added chiral residue. Racemic mixtures of compounds can also be separated directly by chromatography using a chiral stationary phase, a method well known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reactants of known configuration by methods well known in the art.

Cis and trans isomers of the compound of formula (1) or a pharmaceutically acceptable salt thereof are also included in the scope of the present invention, and this also applies to tautomers of the compound of formula (1) or a pharmaceutically acceptable salt thereof.

Some forms of the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some compounds may form solvates with water (i.e., hydrates) or conventional organic solvents, and such solvates are also included within the scope of the present invention.

Isotopically labeled compounds of formula (1) or pharmaceutically acceptable salts thereof, including isotopically labeled compounds of formula (1) for detection by PET or SPECT are also included in the scope of the present invention, and the same applies to¹³C]-、[¹⁴C]-、[¹⁸F]-、[³H]-、[¹²⁵I]-compounds of formula (1) labelled or labelled with other isotopically enriched atoms suitable for receptor binding or metabolic studies.

The compounds of the invention may also be used as reagents or standards in biochemical studies of nervous system functions, disorders and diseases.

Definition of

In the context of the present specification, the term' having cannabinoid-CB₁Antagonistic compounds 'and' cannabinoid-CB₁Antagonist' refers to a compound having such activity-as determined by well-defined and generally accepted pharmacological assays, including the methods described herein-without exhibiting substantial cross-reactivity to other receptors. In one embodiment, the compounds of the invention are as cannabinoid-CB₁The antagonist is at least 10 times as potent as any other receptor agonist or antagonist. Preferred are compounds having 100-fold selectivity, more preferred are compounds having a factor of selectivity of 1,000 or more. The term 'compound having 5-hydroxytryptamine reuptake inhibitor activity' or '5-hydroxytryptamine reuptake inhibitor' refers to a compound having this activity-as determined by well-defined and generally accepted pharmacological assays, including the methods described herein-without showing substantial cross-reactivity to other reuptake sites. In one embodiment, the compounds of the present invention are at least 10 times as potent as 5-hydroxytryptamine reuptake inhibitors as any other neurotransmitter reuptake inhibitor. Preferred are compounds having 100-fold selectivity, more preferred are compounds having a factor of selectivity of 1,000 or more. ' having cannabinoid-CB₁Compounds having antagonistic and 5-hydroxytryptamine reuptake inhibiting activities' refer to compounds having both activities-as determined by well-defined and generally accepted pharmacological assays, including the methods described herein-without showing substantial cross-reactivity to other receptors or reuptake sites. In one embodiment, the compounds of the invention are as cannabinoid-CB₁Antagonists and 5-hydroxytryptamine reuptake inhibitors are at least 10 times as potent as agonists or antagonists at any other receptor, or as inhibitors at any other reuptake site. Preferred are compounds having 100-fold selectivity, more preferred is 1,000 or moreA factor selective compound.

The general terms used in the description of the compounds disclosed herein have their ordinary meanings. The term alkyl, as used herein, refers to a monovalent saturated, branched or straight hydrocarbon chain. Unless otherwise indicated, such chains can contain from 1 to 18 carbon atoms. Representative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, and the like. When defined as 'lower', alkyl groups will contain from 1 to 6 carbon atoms. The same carbon content applies to the parent term 'alkane' and to derivative terms such as 'alkoxy'. The carbon content of the fraction containing the various hydrocarbons is indicated by a prefix representing the minimum and maximum number of carbon atoms in the fraction, i.e. prefix C_x-C_yThe number of carbon atoms is defined as an integer "x" to an integer "y". For example, ` alkyl (C)_1-3) 'represents methyl, ethyl, n-propyl or isopropyl,' alkyl (C)_1-4) ' means ' methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl or 2-methyl-n-propyl '.

The term 'acyl' denotes alkyl (C)_1-3) Carbonyl, arylcarbonyl or aryl-alkyl (C)_1-3) A carbonyl group. 'acyl' includes monocyclic or fused bicyclic aromatic or hetero-aromatic groups including, but not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, imidazo [2, 1-b ]][1，3]Thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1, 3, 5-triazinyl, phenyl, indazolyl, indolyl, indolizinyl, isoindolyl, benzo [ b ]]Furyl, 1, 2, 3, 4-tetrahydronaphthyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, indanyl, indenyl, benzo [ b ]]Thienyl, 2, 3-dihydro-1, 4-benzodioxine (benzodioxin) -5-yl, benzimidazolyl, benzothiazolyl, benzo [1, 2, 5 ] yl]Thia-diazolyl, purinyl, quinolyl,Isoquinolinyl, 2, 3-naphthyridine (phtalazinyl), quinazolinyl, quinoxalinyl, 1, 8-naphthyridinyl, naphthyl, pteridinyl or azulenyl. 'halo' or 'halogen' represents chlorine, fluorine, bromine or iodine; the 'hetero' in 'heteroalkyl, heteroaromatic' and the like means containing one or more N, O or S atoms. 'heteroalkyl' includes alkyl groups having a heteroatom at any position, including N-linked O-linked or S-linked alkyl groups.

The term "substituted" means that a particular group or moiety has one or more substituents. When any group can have multiple substituents, and various possible substituents are provided, the substituents can be independently selected and need not be the same. The term "unsubstituted" means that the particular group has no substituents. With reference to a substituent, the term "independently" means that when more than one such substituent is possible, they may be the same or different from each other.

As used herein, the terms "oxygen", "sulfur" and "carbonyl" as another group denote an oxygen atom, a sulfur atom and a carbonyl group (C ═ O), respectively, as a linker between the two groups, for example, a hydroxyl group, an oxyalkyl group, a sulfanyl group, a carboxyalkyl group and the like. The term "amino", alone or as part of another group, as used herein, refers to a nitrogen atom that may be terminal or a linker to two other groups, where the groups may be primary, secondary, or tertiary (two hydrogen atoms attached to the nitrogen atom, one hydrogen atom attached to the nitrogen atom and no hydrogen atom attached to the nitrogen atom) amines. The terms "sulfinyl" and "sulfonyl" as used herein as another group denote-SO-or-SO, respectively₂-a group.

To provide a more concise description, the term 'compound' or 'compounds' includes tautomers, stereoisomers, N-oxides, isotopically-labeled analogs, or pharmaceutically acceptable salts, hydrates, or solvates, also when not explicitly mentioned.

The term "leaving group" (L) as used herein shall denote a charged or uncharged atom or group capable of leaving when subjected to a substitution or substitution reaction. The term refers to groups that can be readily substituted by nucleophiles, such as amine, thiol, or alcohol nucleophiles. Such leaving groups are well known in the art. Examples include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides (Br, Cl, I), triflates, mesylates, tosylates, and the like.

N-oxides of the above-mentioned compounds also belong to the invention. The tertiary amines may or may not produce metabolites of N-oxides. The extent of N-oxidation occurring ranges from trace amounts to near quantitative conversion. N-oxides may be more or less effective than their corresponding tertiary amines. At the same time, N-oxides can be readily reduced chemically to the corresponding tertiary amines, which vary to varying degrees in the human body. Some N-oxides are reduced to the corresponding tertiary amines almost quantitatively, in other cases only a trace amount of reaction or even no reaction at all (Bickel, 1969).

Any compound that undergoes metabolism in vivo to provide a biologically active agent (i.e., the compound of formula (1)) is a prodrug within the scope and spirit of the present application. A prodrug is a therapeutic agent that is inactive by itself but is capable of being converted to one or more active metabolites. Thus, in the methods of treatment of the present invention, the terms "administration" and "therapeutic application" will encompass the treatment of various diseases described in conjunction with the following compounds: a specifically disclosed compound, or a compound that is not specifically disclosed but which converts to a specific compound in vivo upon administration to a patient. Prodrugs are bioreversible derivatives of drug molecules that are used to overcome some of the barriers encountered when using parent drug molecules. These barriers include, but are not limited to, solubility, permeability, stability, pre-systemic metabolism and targeting limitations (Bundgaard, 1985; King, 1994; Stella, 2004; Ettmayer, 2004;2005). Prodrugs, i.e. compounds which, when administered to a human or mammal by any known route, are metabolized to compounds of formula (1)The compound of (a) is a compound of the present invention. This relates in particular to compounds having primary or secondary amino or hydroxyl groups. Such compounds can be reacted with organic acids to form compounds having formula (1) wherein other groups are present that can be easily removed after administration, such as, but not limited to, amidines, enamines, mannich bases, hydroxy-methylene derivatives, O- (acyloxymethylene carbamate) derivatives, carbamates, esters, amides or enaminones.

'crystalline forms' refer to different solid forms of the same compound, such as polymorphs, solvates, and amorphous forms of the examples. 'polymorphs' are crystal structures in which a compound can be crystallized into different crystal packing arrangements (packingarrangements), all of which have the same elemental composition. Polymorphism is a frequently occurring phenomenon that is influenced by some crystallization conditions, such as temperature, supersaturation level, presence of impurities, polarity of solvent, cooling rate. Different polymorphs typically have different X-ray diffraction parameters, solid state NMR spectra, infrared or raman spectra, melting points, densities, hardness, crystal form, optical and electrical properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may all produce a predominant crystalline form. 'solvate' is a conventional crystalline form comprising a stoichiometric or non-stoichiometric amount of solvent. In general, some compounds have a tendency to trap a fixed molar ratio of solvent molecules in a crystalline solid state when prepared for crystallization, thus forming solvates. When the solvate is water, a 'hydrate' may be formed. The compounds of formula (1) and pharmaceutically acceptable salts thereof may exist in the form of hydrates or solvates. Such hydrates and solvates are also encompassed by the present invention. Examples thereof include 1/4 hydrate, dihydrochloride dihydrate and the like. The 'amorphous' form is an amorphous material that is no longer ordered and generally lacks the characteristic powder X-ray diffraction parameters. The crystal forms have been described in general in Byrn (1995) and Martin (1995).

In an effort to provide a concise description, the quantitative representation provided herein is not intended to be limiting with the term "about". It is to be understood that, whether the term "about" or not is used explicitly, each quantity given herein is intended to refer to the actual given value, as well as to the approximation of the given value that would reasonably be inferred by one of ordinary skill in the art, including approximations due to the experimental and/or measurement conditions under which the given value is measured.

Throughout the description and claims of this specification, the word "comprise", and variations of the word, such as "comprises" and "comprising", is not intended to exclude other additives, components, integers or steps.

Although the compound of formula (1) may be administered in the form of various raw chemicals, it is preferably present in the form of a 'pharmaceutical composition'. According to another aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula (1), at least one pharmaceutically acceptable salt or solvate thereof, or a mixture of any of the foregoing, and one or more pharmaceutically acceptable carriers thereof, optionally with one or more other therapeutic agents. The carrier must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The term "composition" as used herein includes a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. In referring to pharmaceutical compositions, this term includes products comprising one or more active ingredients and an optional carrier comprising inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from separation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Generally, the pharmaceutical compositions are prepared by the following method: the active ingredient is introduced uniformly and directly into a liquid carrier, or a finely divided solid carrier, or both, and then, if necessary, the product is shaped into the desired formulation. The pharmaceutical composition includes a sufficient amount of the active subject compound to produce the desired effect on the disease process or condition. Accordingly, the pharmaceutical compositions of the present invention encompass any composition prepared by admixing a compound of the present invention and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Compound of the present invention vs CB₁The affinity of the receptor and the 5-HT reuptake site was determined by the method described below. From the results used to determine the avidity of a given compound of formula (1), the theoretical minimum effective dose can be assessed. At a concentration of compound equal to the measured K_iAt a value of two times, almost 100% of CB₁The receptor will likely be occupied by the compound. By converting this concentration to mg of the desired compound per kg of patient, the theoretical lowest effective dose, presumably the ideal bioavailability, can be achieved. The actual dose administered may be increased or decreased in pharmacokinetic, pharmacodynamic and other considerations. The dosage of the compound given will depend on the relevant indication, the age, weight and sex of the patient and may be determined by a physician. The dosage will preferably be from 0.01mg/kg to 10 mg/kg. The typical daily dosage of the active ingredients will vary within wide limits and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient and may be determined by a physician. In general, the total daily dose given to a patient in a single or individual dose may be, for example, from 0.001 to 10mg/kg body weight per day, more usually from 0.01 to 1,000mg per day, based on total active ingredient. Such doses will be administered to a patient in need of such treatment one to three times daily or each time to achieve the desired effect, and may last for at least two months, more typically at least six months, or for an extended period of time.

The term "therapeutically effective amount" as used herein refers to the amount of a therapeutic agent that is capable of treating a disease by administration of a compound of the present invention. The amount is an amount sufficient to display a perceptible therapeutic or ameliorative response in a tissue system, animal or human. The effect may include, for example, treating a disease listed herein. The precise effective amount for a subject will depend upon the size and health of the subject, the nature and extent of the condition being treated, the recommendations of the treating physician (researcher, veterinarian, medical doctor or other clinician), and the selected therapy or combination of therapies to be administered. Thus, there is no need to specify an exact effective amount in advance. The term "pharmaceutically acceptable salt" refers to salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. When the compounds of the present invention are finally isolated and purified, they can be prepared in situ or by reacting them individually with pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and acids (Berge, 1977). The "free base" form can be regenerated by contacting the salt with a base or acid and isolating the parent compound in conventional manner. The parent form of the compound differs from the various salt forms in specific physical properties, such as solubility in polar solvents, but the salts are equivalent to the parent form of the compound for purposes of the present invention. 'Complex' refers to a complex of a compound of the present invention, e.g., formula (1), complexed with a metal ion, wherein at least one metal ion is chelated or sequestered. The complexes are prepared by methods known in the art (Dwyer, 1964).

The term "treatment" as used herein refers to any treatment of a mammal, such as a human condition or disease, including: (1) inhibiting the disease or disorder, i.e., preventing its development, (2) alleviating the disease or disorder, i.e., allowing the disease to recover, or (3) halting the symptoms of the disease. The term 'inhibit' includes its generally accepted meaning which includes preventing, suppressing, alleviating, ameliorating and slowing, halting or reversing progression, severity or symptoms resulting therefrom. Thus, the methods of the invention encompass medical therapeutic and/or prophylactic administration, where appropriate. The term "medical treatment" as used herein is intended to include prophylactic, diagnostic and therapeutic regimens carried out in vivo or in vitro in humans or other mammals. 'mammals' include economically valuable animals such as bovine, ovine and porcine animals, particularly animals used for meat production, as well as domestic animals, sports-related animals, zoo animals and humans, the latter being preferred. The term "subject" as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the subject of treatment, observation or experiment.

Abbreviations

BOC tert-butoxycarbonyl

BOP benzotriazol-1-yl-oxytri-phosphonium hexafluorophosphate

CB₁Cannabinoid receptor subtype-1

CB₂Cannabinoid receptor subtype-2

CHO Chinese hamster ovary (cell)

CIP 2-chloro-1, 3-dimethylimidazolinium hexafluorophosphate

DCC dicyclohexylcarbodiimide

DIPEA diisopropylethylamine

DMAP 4-dimethylaminopyridine

DMSO dimethyl sulfoxide

EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

HBTU O-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium hexafluorophosphate

HOAt N-hydroxy-7-azabenzotriazole

mg of

min for

PET positron emission tomography

PyAOP 7-azabenzotriazol-1-yloxytris (pyrrolidine) -phosphonium hexafluorophosphate

PyBOP benzotriazol-1-yloxytris (pyrrolidine) -phosphonium hexafluorophosphate

R_fStasis factor (thin-layer chromatography)

SPECT single photon emission computed tomography

(S) SRI (Selective) 5-hydroxytryptamine reuptake inhibitors

TBTU O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate

THE Tetrahydrofuran (THE)

Examples

Example 1: analytical method

Nuclear magnetic resonance spectrum (¹H NMR and¹³c NMR, APT) use of Bruker ARX400 (APT) in the indicated solvent¹H：400MHz，¹³C: 100MHz) at 300K, or Bruker (300MHz), unless otherwise noted. The spectra were taken in deuterated chloroform or DMSO-d from Cambridge Isotope laboratories Ltd₆Is measured. Chemical shifts (. delta.) are given in ppm from tetramethylsilane (A)¹H，¹³C) Or CCl₃F(¹⁹F) The low magnetic field of (a) starts. The coupling constant J is given in Hz. The peak shape of the NMR spectrum is represented by the following symbols: 'q' (quartet), 'dq' (two quartets),'t' (triplet), 'dt' (two triplets),'d' (doublet), 'dd' (two doublets),'s' (singlet), 'br s' (broad singlet), and'm' (multiplet).

Flash chromatography/column chromatography refers to purification using the indicated eluents and silica gel (Acros: 0.030-0.075mm or Merck silica gel 60: 0.040-0.063mm), or if in particular alumina: 'AlumiminoxidiFluka for Chromatography'; pH 9.5; 0.05-0.15 mm.

Thin Layer Chromatography (TLC): merck Kieselgel 60F₂₅₄The plates were 20X 20 cm.

Melting points were recorded on a B ü chi B545 melting point tester.

All reactions including humidity sensitive compounds or conditions were carried out under anhydrous nitrogen.

The reaction was monitored by using thin layer chromatography on silica gel coated plastic cloth (Merck precoated silica gel 60F254) with indicated eluent. Spots were passed through UV lamps (254nm) or I₂And (6) displaying.

Methylene chloride (phosphorus pentoxide and calcium hydride), tetrahydrofuran (sodium/benzophenone-hydroxy) and petroleum ether (60-80) were freshly distilled just prior to use. All other commercially available chemicals were used without further purification.

Example 2: general aspects of the Synthesis

Known cannabinoid-CB₁The synthesis of the basic structural parts of antagonists is described in the patent applications and/or in the scientific literature. For example, it is well documented that the basic cannabinoid moiety (A)^1a)(WO01070700，Lange，2004^b)、(A^1b)(WO03026648)、(A²)(WO03027076，WO03040107，WO03063781，Lange，2005^b；Dyck(2004)、(A³)(EP0576357，EP1150961，Lan，1999；Seltzman，1995；Dutta，1994 and Katoch-Rouse，2003)、(A⁴)(WO03007887，Plummer，2005)、(A⁵)(WO0307069)、(A⁶)(WO03078413，Lange，2005^b)、(A⁷)(WO2004026301，Lange，2005^b(ii) a Dyck, 2004) and (A)⁸)(WO2004013120)。

From a general point of view, the synthesis of compounds of formula (1), wherein R represents a hydrogen atom, can be carried out by reacting compounds of general formula A-L, wherein L represents a leaving group, with compounds of general formula HRN-TB. It will be apparent to those skilled in the art that the amino group present in HRN-TB must be sufficiently nucleophilic to allow transfer of the leaving group from A-L in this reaction. In the case where L represents a hydroxyl group, where the hydroxyl group is part of a carboxylic acid group, an activating or coupling reagent may be added to increase the rate of reaction (Bodanszky, 1994; Akaji, 1994; Albericio, 1997; Montalbetti, 2005).

The synthesis of compounds of general formula (1), wherein A represents the cannabinoid moiety (A), is shown in scheme 3^1a) Or (A)^1b) Structure (II) wherein R¹、R²And R³Independently represent one or more hydrogen atoms, trifluoromethyl groups or halogen atoms.

Scheme 3

General formula (A)^1a1) The compound can be reacted with POCl₃In the presence of DMAP in an inert organic solvent such as dichloromethane to give the corresponding general formula (A)^1a2) And (3) derivatives. This general formula (A)^1a2) The compounds can be reacted with compounds of the general formula HRN-TB. This reaction gives compounds of the general formula (1) in which A has the meaning given here above (A)^1a) Wherein R, N, T and B have the same meanings as described above. Similarly, formula (A)^1b1) The compound can react with POCl₃In the presence of DMAP in an inert organic solvent such as dichloromethane to give the corresponding general formula (A)^1b2) A chlorinated derivative. This general formula (A)^1b2) Can react with the compound with the general formula HRN-TB. This reaction gives compounds of the general formula (1) in which A has the meaning given here above (A)^1b) Wherein R, N, T and B have the same meanings as described above.

The synthesis of compounds of general formula (1), wherein A represents the cannabinoid moiety (A), is shown in scheme 4²) And (5) structure.

Scheme 4

In scheme 4, R¹And R²Independently represent one or more hydrogen, trifluoromethyl or halogen atoms, R₄Represents a hydrogen or halogen atom or a methyl, ethyl, trifluoromethyl, hydroxymethyl, fluoromethyl, 2, 2, 2-trifluoroethyl, propyl, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfanyl, ethylsulfinyl, ethylsulfonyl, C_1-3Dialkyl-aminomethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, the other symbols having the meanings given above.

General formula (A)²ⁱ¹) Can be reacted with a compound of the formula HRN-TB to give a compound of the formula (1) wherein part A is derived from the structure A². This reaction can be carried out by trimethylaluminum (AlMe)₃) Catalysis (Levin, 1982). Or is of the formula (A)²ⁱ¹) The compounds can be hydrolyzed to the corresponding general formula (A)²ⁱ²) A carboxylic acid. General formula (A)²ⁱ²) The compound can be reacted with a compound of formula HRN-TB to give a compound of formula (1) wherein moiety A is derived from structure A². The reaction is preferably carried out by an activation and coupling method, for example to form an active ester, or in the presence of a so-called coupling agent, for example DCC, HBTU, TBTU, HOAt, PyBOP, BOP, CIP, 2-chloro-1, 3-dimethyl-imidazolinium chloride, PyAOP, etc.

Or is of the formula (A)²ⁱ²) The compounds can be converted into the corresponding general formula (A) in the presence of a chlorinating agent, for example thionyl chloride or oxalyl chloride²ⁱ³) An acid chloride. General formula (A)²ⁱ³) The compound can be reacted with a compound of formula HRN-TB to give a compound of formula (1) wherein moiety A is derived from structure A². A base like DIPEA can be added to the reaction mixture to scavenge the liberated hydrochloric acid, or excess HRN-TB can be used for this purpose.

Similarly, formula (A)³)、(A⁴)、(A⁵)、(A⁶)、(A⁷) Or (A)⁸) The substructures of (A) can be converted, as given above, into compounds of the general formula (1), in which the moieties A are each derived from (A)³)、(A⁴)、(A⁵)、(A⁶)、(A⁷) Or (A)⁸)。

The choice of a particular synthetic step depends on factors known to those skilled in the art, such as the compatibility of the functional group with the reagents used, the possibility of using protecting groups, catalysts, activating and coupling agents, and the final structural characteristics present in the final prepared compound.

Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example by mixing a compound of the invention with a suitable acid, such as an inorganic or organic acid.

Example 3: synthesis of intermediates

An intermediate A: 4-chloro-1- (5-fluoro-1H-indol-3-yl) -butan-1-one

AlCl in dichloromethane with magnetic stirring at 0 deg.C₃(25g, 0.19mol) to the mixture was slowly added 4-chloro-butyryl chloride (21ml, 0.19 mol). The resulting mixture was stirred for 30 minutes and 5-fluoro-1H-indole (25g, 0.19mol) was added slowly. After stirring for a further 30 minutes, the resulting orange mixture was poured into concentrated hydrochloric acid (140ml) and ice (200ml) to give a pink precipitate. The precipitate was collected by filtration to give 4-chloro-1- (5-fluoro-1H-indol-3-yl) -butan-1-one (29 g, 65% yield) as a pink color.

¹H-NMR(400MHz，DMSO-d₆) δ 2.09 (quintuple, J ═ 7, 2H), 3.02(t, J ═ 7, 2H), 3.70(t, J ═ 7, 2H), 7.07(d t, J ═ 9 and 2, 1H), 7.49(dd, J ∼ 9 and 4, 1H), 7.85(dd, J ═ 9 and 2, 1H), 8.41(d, J ═ 3, 1H), 12.21(br s, 1H).

An intermediate B: 4- [4- (5-fluoro-1H-indol-3-yl) -4-oxobutyl ] -piperazine-1-carboxylic acid tert-butyl ester

To a solution of 4-chloro-1- (5-fluoro-1H-indol-3-yl) -butan-1-one (10.93g, 45.6mmol) in acetonitrile (100ml) under magnetic stirring was added piperazine (20.33g ml, 236mmol) and a small amount of potassium iodide (0.1gram) and the resulting mixture was heated at 80 ℃ for 48 hours. The solid formed was removed by filtration and the residue was concentrated in vacuo to give 37 g of crude yield. The crude product was further purified by column chromatography (gradient: ethyl acetate/methanol/25% ammonia 90/5/5 to methanol) to yield 17.1 g of crude 1- (5-fluoro-1H-indol-3-yl) -4- (piperazin-1-yl) -butan-1-one. 10.71 g (0.389mol) of the crude 1- (5-fluoro-1H-indol-3-yl) -4- (piperazin-1-yl) -butan-1-one were dissolved in dichloromethane (500ml) and Boc was added₂O (25.53g, 0.117 mol). The resulting mixture was stirred at room temperature for 4 hours. The mixture was washed with 5% aqueous NaHCO₃And water washing continuously. The organic layer was washed with Na₂SO₄Dried, filtered and concentrated under vacuum. Followed by column chromatography (gradient: dichloro-methane/methanol-99/1 to dichloro-methane/methanol-90/10 (v/v)) to give pure 4- [4- (5-fluoro-1H-indol-3-yl) -4-oxobutyl ] -4-carboxylic acid methyl ester]Tert-butyl (3.85 g, 37% yield) piperazine-1-carboxylate.¹H-NMR(400MHz，DMSO-d₆) δ 1.38(s, 9H), 1.80 (quintuple, J ═ 7, 2H), 2.25-2.35(m, 6H), 2.84(t, J ═ 7, 2H), 3.22-3.32(m, 4H), 7.06(d t, J ∼ 9 and 3, 1H), 7.47(dd, J ═ 9 and 5, 1H), 7.85(dd, J ═ 9 and 3, 1H), 8.38(s, 1H), 12.01(br s, 1H).

An intermediate C: 5-fluoro-3- [4- (piperazin-1-yl) butyl ] -1H-indole

To 4- [4- (5-fluoro-1H-indol-3-yl) -4-oxobutyl in dichloromethane with magnetic stirring]To a solution of tert-butyl (3.85 g, 9.88mmol) piperazine-1-carboxylate was added hydrochloric acid (dissolved in dioxane: 4.94ml, 4M solution, 19.8mmol HCl) and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated well in vacuo to give 1- (5-fluoro-1H-indol-3-yl) -4- (piperazin-1-yl) butan-1-one dihydrochloride (3.20 g). Some characteristics of 1- (5-fluoro-1H-indol-3-yl) -4- (piperazin-1-yl) butan-1-one dihydrochloride¹H-NMR Signal: (400MHz, DMSO-d)₆) δ 2.07 (quintuple, J ═ 7, 2H), 3.03(t, J ═ 7, 2H), 7.08(dt, J. about 9 and 3, 1H), 7.50(dd, J. about 9 and 4, 1H), 7.85(dd, J. about 9 and 3, 1H), 8.43(d, J. about 3, 1H), 12.21(br s, 1H).

The resulting 1- (5-fluoro-1H-indol-3-yl) -4- (piperazin-1-yl) butan-1-one dihydrochloride (3.20 g) was dissolved in tetrahydrofuran (50ml) and cooled to 0 ℃. LiAlH in tetrahydrofuran was added slowly₄Solution (60 ml; 1M, 53mmol LiAlH₄). The mixture was subsequently heated at 80 ℃ for 20 hours. Excess LiAlH₄Is carefully hydrolyzed to obtain 5-fluoro-3- [4- (piperazin-1-yl) butyl]-1H-indole (2.39 g, 98% yield).¹H-NMR(400MHz，DMSO-d₆) δ 1.40-1.50(m, 2H), 1.61 (quintuple, J ═ 7, 2H), 2.12-2.35(m, 7H), 2.60-2.70(m, 6H), 6.85-6.92(m, 1H), 7.17(d, J-2, 1H), 7.23(dd, J-9 and 2, 1H), 7.30(dd, J-9 and 4, 1H), 10.85(br s, 1H).

An intermediate D: 7- (tetrahydropyran-2-yloxy) -1- [4- (trifluoromethyl) phenyl ] heptan-1-one

Magnesium (1.20g, 0.0494mol) was added to anhydrous THF (5ml) and 1, 2-bis was added continuously at reflux temperatureBromoethane (1ml), a small amount of iodine crystals and 2- (6-chlorohexyloxy) tetrahydro-2-pyran (10.0 g, 0.0453 mol; dissolved in 9ml THF) and the resulting mixture was heated at reflux temperature for 30 minutes. 4-Trifluoromethylbenzonitrile (7.0 g, 0.0412 mol: dissolved in 8ml of toluene) was added slowly and the mixture was heated for a further 30 minutes. The mixture was allowed to reach room temperature and the reaction was quenched with acetic acid (30 ml). The organic layer was separated and water, 5% aqueous NaHC0, was added continuously₃Water (twice) and brine. The organic layer was washed with Na₂SO₄Dried, filtered and concentrated under vacuum. Subsequent column chromatography (ethyl acetate/heptane ═ 10/90(v/v)) afforded pure 7- (tetrahydropyran-2-yloxy) -1- [4- (trifluoromethyl) phenyl ] as an oil]Hept-1-one (10.92 g, 74%). R_f0.25 (ethyl acetate/heptane-1/6 (v/v).

¹H-NMR(400MHz，CDCl₃)δ1.39-1.88(m，14H)，3.00(t，J＝7，2H)，3.36-3.43(m，1H)，3.47-3.52(m，1H)，3.71-3.77(m，1H)，3.83-3.90(m，1H)，4.56-4.58(m，1H)，7.73(d，J～8，2H)，8.06(d，J～8，2H)。

Intermediate E: toluene-4-sulfonic acid 7-oxo-7- [4- (trifluoromethyl) phenyl ] heptyl ester

To 7- (tetrahydropyran-2-yloxy) -1- [4- (trifluoromethyl) phenyl group in methanol (50ml) under magnetic stirring]Heptan-1-one (7.70 g, 0.0215mol) solution was added p-toluenesulfonic acid hydrate (4.18 g, 0.022 mol). The resulting acidic mixture (pH 2, pH paper) was reacted at room temperature for 20 hours. NaOH (1N) was added until the solution was neutral (pH 7, pH paper) and the resulting mixture was concentrated in vacuo. NaOH (1N, 50ml) was added and the mixture was extracted with dichloromethane (3 ×). The combined organic layers were washed successively with water and brine. The organic layer was washed with Na₂SO₄Drying, filtering and concentrating under vacuum to give crude 7-hydroxy-1- [4- (trifluoromethyl) methyl ] hydrate as a white solid) Phenyl radical]Hept-1-one (5.85g, 99% yield). The resulting solid was treated with pyridine (29.6ml) and added to a solution of tosyl chloride (17.72 g, 0.093mol) in pyridine (89ml) at 0 ℃. The mixture was allowed to reach room temperature and reacted for 1 hour. The mixture was cooled at-10 ℃ and quenched with excess water. After extraction with diethyl ether (3X), over Na₂SO₄Drying, filtration and concentration in vacuo afforded the crude product, which was purified by column chromatography (dichloromethane/heptane ═ 2/1(v/v)) to afford pure toluene-4-sulfonic acid 7-oxo-7- [4- (trifluoromethyl) phenyl ] ester]Heptyl ester (7.91 g, 87% yield).¹H-NMR(400MHz，CDCl₃)δ1.35-1.38(m，4H)，1.57-1.73(m，4H)，2.44(s，3H)，2.97(t，J＝7，2H)，4.03(t，J＝7，2H)，7.35(d，J～8，2H)，7.73(d，J～8，2H)，7.79(d，J～8，2H)，8.04(d，J～8，2H)。

An intermediate F: toluene-4-sulfonic acid 7, 7-dimethoxy-7- [4- (trifluoromethyl) phenyl ] heptyl ester

To toluene-4-sulfonic acid 7-oxo-7- [4- (trifluoromethyl) phenyl ] in methanol (75ml) under magnetic stirring]To the heptyl ester (2.77 g, 6.464mmol) was added continuously a catalytic amount of p-toluenesulfonic acid (0.097 g, 0.508mmol) and an excess of trimethyl orthoformate (16ml, 142 mmol). The resulting mixture was heated at reflux temperature for 20 hours. After allowing the reaction mixture to reach room temperature, saturated aqueous NaHCO was added continuously₃And dichloromethane. The separated organic layer was washed with saturated aqueous NaHCO₃And (6) washing. The organic layer was then washed with Na₂SO₄Drying, filtering and concentrating under vacuum to obtain crude toluene-4-sulfonic acid 7, 7-dimethoxy-7- [4- (trifluoromethyl) phenyl]Heptyl ester, which was purified by column chromatography (alumina, ethyl acetate/heptane ═ 1/10(v/v)) to give pure toluene-4-sulfonic acid 7, 7-dimethoxy-7- [4- (trifluoromethyl) phenyl ester]Heptyl ester (1.82 g, 59% yield).¹H-NMR(400MHz，CDCl₃)δ0.84-0.93(m，2H)，1.06-1.26(m，4H)，1.51-1.57(m，2H)，1.80-1.86(m，2H)，2.44(s，3H)，3.13(s，6H)，3.94(t，J＝7，2H)，7.32(d，J～8，2H)，7.55(d，J～8，2H)，7.60(d，J～8，2H)，7.75(d，J～8，2H)。

Intermediate G: 7, 7-dimethoxy-7- [4- (trifluoromethyl) phenyl ] heptylamine

Toluene-4-sulfonic acid 7, 7-dimethoxy-7- [4- (trifluoromethyl) phenyl]Heptyl ester (1.82 g, 3.835mmol) was dissolved in 7M NH in methanol (30ml) under magnetic stirring₃The solution was stirred at room temperature for 72 hours. After removal of the solvent under vacuum, the residue was redissolved in dichloromethane and washed with saturated aqueous NaHCO₃And (6) washing. The organic layer was then washed with Na₂SO₄Drying, filtering and concentrating under vacuum to give crude 7, 7-dimethoxy-7- [4- (trifluoromethyl) phenyl]Heptylamine (1.43 g), which was not further purified.¹H-NMR(400MHz，CDCl₃) δ 0.88-0.95(m, 2H), 1.12-1.16(m, 4H), 1.33-1.38(m, 2H), 1.83-1.88(m, 2H), 2.59-2.65(m, 2H), 3.10-3.26(m, 8H, including-OMe singlet, at 3.14), 7.56(d, J-8, 2H), 7.60(d, J-8, 2H).

Example 4: synthesis of specific Compounds

The synthesis of specific compounds described below is intended to further illustrate the present application in a more detailed manner and therefore should not be considered as limiting the scope of the invention in any way. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. Thus, the specification and examples are to be regarded as illustrative only.

N- {1- [7- (2-amino-ethoxyimino) -7- [4- (trifluoromethyl) phenyl ] heptylamino ] -1- [3- (4-chlorophenyl) -4-phenyl-4, 5-dihydro-1H-pyrazol-1-yl ] -methine (methylidene) } -4-chloro-benzenesulfonamide (compound 1)

Part A: such as (Lange, 2004)^b) Obtaining 3- (4-chlorophenyl) -N- [ (4-chlorophenyl) sulfonyl group as described]-4-phenyl-4, 5-dihydro-1H-pyrazole-1-carboxamide. Reacting 3- (4-chloro-phenyl) -N- [ (4-chloro-phenyl) sulfonyl]-4-phenyl-4, 5-dihydro-1H-pyrazole-1-carboxamide (0.708 g, 1.493mol) was dissolved in anhydrous dichloromethane (15ml) and DMAP (0.820 g, 6.716mmol) and POCl were added continuously₃(0.209g, 2.238mmol) and the resulting mixture was refluxed for 5 hours. The mixture was cooled at 0 ℃. Adding 7, 7-dimethoxy-7- [4- (trifluoromethyl) phenyl group continuously]Heptylamine (1.43 g, 4.477mmol) and DIPEA (0.740ml, 4.48 mmol). The reaction was then heated at reflux temperature for 30 hours. The mixture was brought to room temperature and diluted with 5% aqueous NaHCO₃Washing with Na₂SO₄Dried, filtered and concentrated under vacuum. The crude product obtained was purified by column chromatography (alumina; gradient: heptane/ethyl acetate 6/1 to ethyl acetate/methanol 95/5(v/v)) to give pure 4-chloro-N- { [3- (4-chlorophenyl) -4-phenyl-4, 5-dihydro-1H-pyrazol-1-yl]- [7- (4-fluorophenyl) -7, 7-dimethoxyheptylamino group]Methylene } benzenesulfonamide (0.200 g, 17% yield).¹H-NMR(400MHz，CDCl₃) δ 0.91-1.01(m, 2H), 1.17-1.28(m, 4H), 1.49-1.57(m, 2H), 1.85-1.92(m, 2H), 3.15(s, 6H), 3.50-3.58(m, 2H), 4.04-4.13(m, 1H), 4.47-4.65(m, 2H), 7.10(d, J-8, 2H), 7.22-7.32(m, 5H)7.35(d, J-8, 2H), 7.48(d, J-8, 2H), 7.58(d, J-8, 2H), 7.61(d, J-8, 2H), 7.82(d, J-8, 2H), no NH proton is visible.

And part B: 4-chloro-N- { [3- (4-chlorophenyl) -4-phenyl-4, 5-dihydro-1H-pyrazol-1-yl]- [7- (4-fluoro-phenyl) -7, 7-dimethoxyheptylamino group]Methylene } -benzenesulfonamide (0.200 g, 0.258mmol) was dissolvedIn a 1: 1 mixture of THF/methanol (30ml) and 5ml of 1N hydrochloric acid were added and the resulting mixture was stirred at room temperature for 20 hours. The mixture was passed through 5% aqueous NaHCO₃And (6) quenching. Most of the THF and methanol were removed by evaporation in vacuo. The remaining aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with Na₂SO₄Dried, filtered and concentrated under vacuum. The crude 4-chloro-N- { [3- (4-chlorophenyl) -4-phenyl-4, 5-dihydro-1H-pyrazol-1-yl radical obtained]- [7- (4-fluorophenyl) -7-oxy-heptylamino group]Methylene } benzenesulfonamide (203mg) was not further purified. Some characteristic fragrance¹H-NMR Signal: (400MHz, CDCl)₃)δ7.12(d，J～8，2H)，7.22-7.33(m，5H)7.39(d，J～8，2H)，7.50(d，J～8，2H)，7.72(d，J～8，2H)，7.84(d，J～8，2H)，8.05(d，J～8，2H)。

And part C: 4-chloro-N- { [3- (4-chlorophenyl) -4-phenyl-4, 5-dihydro-1H-pyrazol-1-yl]- [7- (4-fluoro-phenyl) -7-oxo-heptylamino]Methylene } benzenesulfonamide (0.203 g, 0.278mmol) was dissolved in absolute ethanol (10ml) and O- (2-aminoethyl) hydroxylamine dihydrochloride (61mg, 1.5mol equiv.) and pyridine (0.04ml) were added continuously. The resulting mixture was stirred at reflux temperature for 20 hours. The mixture was allowed to reach room temperature. After removal of the solvent in vacuo, the residue is dissolved in dichloromethane and taken up with aqueous KHSO₄The solution and brine were washed continuously. The organic layer was then washed with Na₂SO₄Dried, filtered and concentrated in vacuo to yield N- {1- [7- (2-amino-ethoxyimino) -7- [4- (trifluoromethyl) phenyl]Heptylamino group]-1- [3- (4-chlorophenyl) -4-phenyl-4, 5-dihydro-1H-pyrazol-1-yl]-methine } -4-chloro-benzenesulfonamide (compound 1) (0.231 g), which is the melting point of the mixture of E/Z stereoisomers: 53-58 ℃.¹H-NMR(400MHz，CDCl₃) δ 1.30-1.67(m, 8H), 2.80(t, J ═ 7, 2H), 3.33-3.40(m, 2H), 3.56-3.66(m, 2H), 4.03(dd, J ═ 11 and 5, 1H), 4.43-4.55(m, 3H), 4.60-4.70(m, 2H), 7.10(d, J-8, 2H), 7.20-7.37(m, 7H)7.48(d, J-8, 2H), 7.58(d, J-8, 2H), 7.71(d, J-8, 2H), 7.82(d, J-8, 2H), 8.60(br s, 2H).

2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazole-4-carboxylic acid [7- (2-amino-ethoxyimino) -7- [4- (trifluoromethyl) phenyl ] heptyl ] amide (Compound 2)

Part A: ethyl 2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazole-4-carboxylate was obtained according to WO 03040107. To a solution of ethyl 2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazole-4-carboxylate (5.80g, 0.0149mol) in tetrahydrofuran (40ml) under magnetic stirring was added a solution of LiOH (0.715g) in water (40 ml). The resulting mixture was heated at 70 ℃ for 16 hours. The resulting mixture was allowed to reach room temperature and was then treated with concentrated hydrochloric acid (3.5 ml). The tetrahydrofuran was evaporated under vacuum and the resulting mixture was stirred overnight. The precipitate formed was collected by filtration and washed with petroleum ether (40-60) to give 2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazole-4-carboxylic acid (4.52 g, 84% yield).¹H-NMR(400MHz，CDCl₃): δ 1.09(t, J ═ 7, 3H), 2.90(q, J ═ 7, 2H), 3.70(br s, 1H), 7.12(dt, J ═ 8 and 2, 2H), 7.22-7.28(m, 1H), 7.29-7.38(m, 5H).

And part B: from intermediate E (toluene-4-sulfonic acid 7-oxo-7- [4- (trifluoromethyl) phenyl)]Heptyl ester), 7M NH used in methanol₃2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazole-4-carboxylic acid (1.48G, 4.123mmol), 7-amino-1- (4- (trifluoromethyl) phenyl) heptan-1-one (1.127G, 4.123mmol) (7-amino-1- (4- (trifluoromethyl) phenyl) heptan-1-one were obtained in 62% yield, 72H at room temperature, analogously to the synthesis of intermediate G (see also Teubner, 1993), EDCI, HOAt (0.67G, 4.95mmol) and DIPEA (1.44ml, 8.246mmol) were dissolved successively in dichloromethane (30ml) and magnetically stirred at room temperature for 70H₃The solution and water were washed successively, then over Na₂SO₄Dried, filtered and concentrated in vacuo to give crude 2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazole-4-carboxylic acid{7- [4- (trifluoromethyl) phenyl]-7-oxo-heptyl } amide, purified by column chromatography (alumina; heptane/ethyl acetate ═ 4/1(v/v)), followed by another column chromatography (silica gel; heptane/ethyl acetate ═ 4/1(v/v)) to give pure 2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazole-4-carboxylic acid {7- [4- (trifluoromethyl) -phenyl ] -imidazole-4-carboxylic acid]-7-oxo-heptyl } amide (1.28 g, 50% yield).¹H-NMR(300MHz，DMSO-d₆)：δ0.92(t，J＝7，3H)，1.28-1.68(m，8H)，2.84(q，J＝7，2H)，3.08(t，J＝7，2H)，3.23(q，J＝7，2H)，7.30-7.42(m，5H)，7.49(br d，J＝8，2H)，7.56(d，J＝8，2H)，7.89(d，J＝8，2H)，8.04(t，J＝6，1H)，8.15(d，J＝8，2H)。

And part C: 2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazole-4-carboxylic acid {7- [4- (trifluoromethyl) phenyl]-7-oxo-heptyl } amide (1.15 g, 1.86mmol) was dissolved in absolute ethanol (10ml) and O- (2-aminoethyl) hydroxylamine dihydrochloride (0.276mg, 1.865mol) and pyridine (0.18ml) were added continuously. The resulting compound was stirred at reflux temperature for 20 hours. The mixture was allowed to reach room temperature. After removal of the solvent in vacuo, the residue is dissolved in dichloromethane and taken up with aqueous KHSO₄The solution and brine were washed continuously. The organic layer was then washed with Na₂SO₄Dried, filtered and concentrated in vacuo to give 2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazole-4-carboxylic acid [7- (2-amino-ethoxyimino) -7- [4- (trifluoromethyl) phenyl ] amide]Heptyl radical]Amide (compound 2) (1.34 g), which is a mixture of E/Z stereoisomers. Melting point: 90-95 ℃.¹H-NMR(400MHz，CDCl₃)δ1.05(t，J＝7，3H)，1.34-1.62(m，8H)，2.81(br t，J＝7，2H)，2.93(q，J＝7，2H)，3.32-3.42(m，4H)，4.44-4.50(m，2H)，7.11(d，J＝8，2H)，7.21-7.34(m，5H)，7.37(d，J＝8，1H)，7.49(br s，1H)，7.59(d，J＝8，2H)，7.71(d，J＝8，2H)，8.65(br s，2H)。

[2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazol-4-yl ] {4- [4- (5-fluoro-1H-indol-3-yl) butyl ] piperazin-1-yl } methanone (Compound 3)

2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazole-4-carboxylic acid (0.880g, 2.44mmol) was reacted with intermediate C (5-fluoro-3- [4- (piperazin-1-yl) butyl) at room temperature]-1H-indole), EDCI, HOAt and K in dichloromethane (30ml)₂CO₃(1.55mol equiv.) for 70 hours, in analogy to the procedure for preparation of Compound 2, part B, to give [2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazol-4-yl]{4- [4- (5-fluoro-1H-indol-3-yl) butyl]-piperazin-1-yl } methanone (compound 3) (704mg, 76% yield) (1.28 g, 50% yield). Melting point: 91-92 ℃.¹H-NMR(400MHz，CDCl₃) δ 1.03(t, J ═ 7, 3H), 1.57-1.76(m, 4H), 2.42(t, J ═ 7, 2H), 2.48-2.58(m, 4H), 2.72(t, J ═ 7, 2H), 2.77(q, J ═ 7, 2H), 3.81(br s, 2H), 4.08(br s, 2H), 6.91(dt, J-8 and 2, 1H), 7.01(d, J ═ 2, 1H), 7.10(d, J ═ 8, 2H), 7.15-7.35(m, 8H), 8.08(br s, 1H).

4-chloro-N- { [1- [3- (4-chlorophenyl) -4-phenyl-4, 5-dihydro-1H-pyrazol-1-yl ] -1- {4- [4- (5-fluoro-1H-indol-3-yl) butyl ] piperazin-1-yl } methine ] -benzenesulfonamide (compound 4)

Coupling 3- (4-chlorophenyl) -N- [ (4-chlorophenyl) sulfonyl]-4-phenyl-4, 5-dihydro-1H-pyrazole-1-carboxamide (0.950 g, 2.00mmol) was dissolved in anhydrous dichloromethane and reacted with DMAP and POCl₃Reacted with the intermediate C (5-fluoro-3- [4- (piperazin-1-yl) butyl)]-1H-indole) and DIPEA in analogy to the procedure for the preparation of the compounds, part a, to give 4-chloro-N- { [1- [3- (4-chlorophenyl) -4-phenyl-4, 5-dihydro-1H-pyrazol-1-yl]-1- {4- [4- (5-fluoro-1H-indol-3-yl) butyl]Piperazin-1-yl } methine]Benzenesulfonamide (compound 4) (660mg, 45% yield). Melting Point：98-102℃.¹H-NMR(400MHz，CDCl₃) δ 1.56-1.66(m, 2H), 1.70-1.80(m, 2H), 2.47(t, J ═ 7, 2H), 2.57-2.70(m, 4H), 2.75(t, J ═ 7, 2H), 3.69-3.86(m, 5H), 4.42(t, J ═ 11, 1H), 4.54(dd, J ═ 11 and 5, 1H), 6.93(dt, J-8 and 2, 1H), 7.03(d, J-2, 1H), 7.10(d, J ═ 8, 2H), 7.21-7.38(m, 8H), 7.48(d, J ═ 8, 2H), 7.83(d, J ═ 8, 2H), 7.98(brs, 1H).

Example 5: preparation used in animal experiments

For oral (p.o.) administration: to the desired amount (0.5-5mg) of solid compound 1 in a glass tube was added some glass beads and the solid was crushed by vortexing for 2 minutes. After fusion by adding 1ml of solution of 1% methylcellulose and 2% (v/v) poloxamer 188(Lutrol F68) in water, the compound was suspended by vortexing for 10 minutes. The pH was adjusted to 7 with a few drops of aqueous NaOH (0.1N). The remaining particles in the suspension were further suspended with an ultrasonic bath.

For intraperitoneal (i.p.) administration: to the desired amount (0.5-15mg) of solid compound 1 in a glass tube was added some glass beads and the solid was crushed by vortexing for 2 minutes. After addition of 1ml of solution of 1% methylcellulose and 5% mannitol in water, the compound was suspended for 10 minutes by vortexing. Finally the pH was adjusted to 7.

Example 6: pharmacological methods

In vitro human cannabinoid-CB₁Affinity of receptors

The compounds of the present invention are cannabinoid CB₁Receptor affinity can be determined using membrane preparations of CHO cells in which human cannabinoid CB is involved₁Receptor and [2 ] as radioligand³H]CP-55, 940 was stably transfected together. In the term of³H]After incubation in a freshly prepared cell membrane preparation of the ligand, with or without addition of the compound of the invention, bound and free ligand are separated by filtration through a glass fibre filter. Radioactivity on the filter was determined by liquid scintillation counting.

Affinity for 5-hydroxytryptamine reuptake sites in vitro

The affinity of the compounds for the 5-hydroxytryptamine reuptake site was determined using the receptor binding assay described in Habert, 1985.

Example 7: results of pharmacological tests

The following table shows the cannabinoid-CB obtained according to the experimental design given above₁Affinity data for the receptor and data for the 5-hydroxytryptamine reuptake inhibitor.

The data given above illustrate that the compounds of the invention are directed to CB₁Both the receptor and the 5-HT reuptake site have high affinity. It is to CB₁The affinity of the receptor is as high as rimonabant, while, for example, compound 1 is simultaneously as effective as a 5-hydroxytryptamine reuptake inhibitor as fluoxetine. This therefore forms a strong contrast with, for example, the following compounds: concerning structurally similar effective CBs₁Receptor antagonists, which are disclosed in WO 03/027076 (see above structure), are completely inactive as 5-hydroxytryptamine reuptake inhibitors. Other CB under test₁Antagonists lack of affinity for 5-HT reuptake site, 5-HT reuptake inhibitors tested for CB₁The receptor has no affinity.

Example 8: pharmaceutical preparation

For clinical use, the compounds of formula (1) are formulated into pharmaceutical compositions, which are important and novel embodiments of the present invention, as they comprise the compounds disclosed herein, more particularly the specific compounds. The types of pharmaceutical compositions that can be used include, but are not limited to, tablets, chewable tablets, capsules (including microcapsules), solutions, injectable solutions, ointments (creams and gels), suppositories, suspensions, and other types disclosed herein, or will be apparent to those skilled in the art from the specification and general knowledge in the art. The active ingredient may also be in the form of an inclusion complex in a cyclodextrin, an ether thereof or an ester thereof, for example. The compositions are for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or other routes of administration. Pharmaceutical compositions comprise at least one compound of formula (1) in admixture with at least one pharmaceutically acceptable adjuvant, diluent and/or carrier. The total amount of active ingredient is suitably from about 0.1% (w/w) to about 95% (w/w), suitably from 0.5% to 50% (w/w), preferably from 1% to 25% (w/w) of the formulation. In some embodiments, the amount of active ingredient is greater than about 95% (w/w) or less than about 0.1% (w/w).

The compounds of the invention can be brought into a form suitable for administration by conventional procedures using auxiliary substances such as liquid or solid substances, powder ingredients, e.g. pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorants, colorants and/or buffer substances. Frequently used auxiliary substances include magnesium carbonate, titanium dioxide, lactose, sucrose, sorbitol, mannitol and other sugars or sugar alcohols, talc, milk protein, gelatin, starch, amylopectin, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, groundnut or sesame oil, polyethylene glycols and solvents, such as sterile water and mono-or polyhydric alcohols such as glycerol, and disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture is then processed into granules or compressed into tablets. A tablet was prepared using the following ingredients.

Component amount (mg/tablet)

Compound 110

Cellulose, microcrystalline 200

Silica, fuming 10

Stearic acid 10

Total 230

The ingredients were mixed and compressed into tablets, each weighing 230 mg.

The active ingredients may be separately pre-mixed with other inactive ingredients before being mixed to form the formulation. The active ingredients may also be mixed with each other before being mixed with the inactive ingredients to form a formulation.

Soft capsules may be prepared by including a mixture of the active ingredient of the present invention, vegetable oil, fat or other soft gelatin suitable carrier. The hard capsules may contain granules of the active ingredient. Hard capsules may also contain the active ingredient and solid powder ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.

Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active ingredient in admixture with a neutral fatty base; (ii) in the form of gelatin rectal capsules comprising the active substance in admixture with vegetable oils, paraffin oils or other suitable carriers for gelatin rectal capsules; (iii) in the form of ready-to-use micro-enema; or (iv) in the form of a dry micro-enema which is reconstituted in a suitable solvent prior to administration.

Liquid preparations may be prepared in the form of syrups, elixirs, concentrated drops or suspensions, for example solutions or suspensions, containing the active ingredient with the remainder comprising, for example, a sugar or sugar alcohol, a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. Such liquid preparations may, if desired, contain coloring agents, flavoring agents, preservatives, saccharin and carboxymethylcellulose or other thickening agents. Liquid preparations may also be prepared in the form of a dry powder which is reconstituted with a suitable solvent immediately prior to use. Solutions for parenteral administration may be prepared as solutions of the formulations of the invention in pharmaceutically acceptable solvents. These solutions may also contain stabilizing ingredients, preservatives and/or buffering ingredients. Solutions for parenteral administration may also be prepared as a dry preparation which is reconstituted with a suitable solvent prior to use.

Also provided according to the invention are formulations and 'kit of parts' comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention for use in medical therapy. Associated with such containers are written materials such as instructions for use or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human or veterinary administration. Use of the formulations of the invention in the manufacture of a medicament for the treatment of a disease where CB is required or desired₁Receptor antagonists and/or 5-hydroxytryptamine reuptake inhibition, and methods of medical treatment or methods comprising administering to a patient suffering from or susceptible to a disease, after administration, a therapeutically effective total amount of at least one compound of formula (1), wherein CB is required or desired for the disease₁Receptor antagonists and/or 5-hydroxytryptamine reuptake inhibition.

By way of example, and not by way of limitation, several pharmaceutical compositions containing preferred active compounds for systemic or topical application are given. Other compounds of the invention, or combinations thereof, may be substituted for (or supplemented by) the compounds described. The concentration of the active ingredient may vary over a wide range, as described herein. The amounts and types of ingredients that can be included are well known in the art.

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Claims (15)

1. Having cannabinoid-CB₁A compound having a combination of antagonism and 5-hydroxytryptamine reuptake inhibition.

2. A compound of claim 1 in CB₁Receptor binding and 5-hydroxytryptamine reuptake binding, pK_iAll values are > 6.00.

3. The compound of claim 1, of formula (1):

or a tautomer, stereoisomer, N-oxide, isotopically-labeled analog thereof, or a pharmacologically acceptable salt, hydrate, or solvate of any of the foregoing, wherein:

-A represents any known cannabinoid-CB₁An antagonist of the basic structural moiety comprising at least two benzene rings, each independently, optionally substituted with one or two substituents selected from halogen, methoxy and trifluoromethyl, said basic structural moiety and said cannabinoid-CB₁The hydrogen bond acceptor moiety in the antagonist is a carbonyl group, a sulfonyl group, or a nitrogen or oxygen atom bonded in a heteroaromatic ring structure,

-N represents a non-basic nitrogen atom,

-T represents a saturated or unsaturated carbon chain having 0 to 8 atoms, in which one carbon atom may be substituted by a nitrogen atom, optionally substituted by (C)₁-C₃) -alkyl or CH₂CF₃Substituted by radicals, or by oxygen or sulfur atoms, wherein the chain is optionally substituted by one or more radicals selected from fluorine, amino, cyano, (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy or trifluoromethyl, or a pharmaceutically acceptable salt thereof,

r represents a hydrogen atom, or (C)₁-C₃) -alkyl, or R and the nitrogen atom to which R is attached, and together with a part of T form (C)₄-C₇) -a heterocycloalkyl or a heteroaryl group,

-B represents the basic moiety of any known 5-hydroxytryptamine reuptake inhibitor.

4. A compound of formula (1) according to claim 3, tautomers, stereoisomers, prodrugs and N-oxides thereof, isotopically labeled compounds of the compounds of formula (1), and pharmacologically acceptable salts, hydrates, solvates, complexes and conjugates of said compounds of formula (1) and tautomers, stereoisomers, prodrugs, N-oxides or isotopically labeled analogues thereof,

wherein A represents cannabinoid-CB selected from the group consisting of₁Basic structural part of the antagonist:

11C-JHU-75528, A-796260, ajulemic acid, AM 251, AM 630, AVE-1625, CP-272871, CP-945598, EMD-68843, GRC-10389, LY-2077855, LY-320135, NI DA-41020, O-2093, SLV319, SLV326, SR-140098, SR-144385, SR-41716A (rimonabant), surrinan, V-24343, WIN-54461 and WIN-56098,

wherein B represents the basic moiety of a 5-HT reuptake inhibitor selected from the group consisting of:

403U76, A-80426, AD-337, aclidinum, agomelatine, alaproplate, amiheptanoic acid, amitriptyline, ARAK-0029, ARAK-0051, befilptan, befloxatone, BGC-20-1259, bicifadine, BMS-505130, bromofamine, bupropion, butiline, West chloramine, citalopram, CL: -275838, clomipramine, clovoxamine, CX-157, dapoxetine, desvenlafaxine, dexfenfluramine, diphenylazepine, diclofenac, duloxetine, DOV-21947, DOV-102677, DOV-216303, duloxetine, DU 125530, DuP-631, EN-3215, EpiCept NP-1, escitalopram, femoxetine, fluoxetine, (S) -fluoxetine, fluvoxamine, gepirone, IDN-5491, imipramine, indamine, iprindole, L-792239, L I-301, ritoxetine, lofepramine, LU-10134-C, LU-AA21004, badzodong, LY-214281, LY-367265, LY-393558, maprotiline, MCI-225, MCL-0042, McN-5652, meretritrinin, amphetamine, clomipramine, dox-5652, clomipramine, clomiprami, Modafinil, nefazodone, 6-nitroquinpiperazine, nortriptyline, NR-200S, NS-2381, NS-2389, NS-2463, NS-4194, NS-23459, omixetine, OPC-14523, opipramol, Org-6582, paroxetine, pramipexole, PRC-025, propiheptipine, quetiapine, quinupramine, ramelteonine, R-fluoxetine, rizatriptan, robuzotan, rocco indole, RS-1439, SB-649915, S-9977, SD-726, selegiline, SEP-225289, SEP-227162, sertraline, sibutramine, (S) -sibutramine, (R) -dinotebuconazole, SLV310, SLV, SL314-473, tramadol, metrizadone, UK-416244, UP-23, VANH-36, venlafaxine, vilazodone, VML-670, VN-2222, volinanserin, WF-23, WF-516, WL-1011, WL-1017, YM-922 and zimelidine.

5. A compound of formula (1) according to claim 3, wherein a represents (a)^1a)、(A^1b)、(A²)、(A³)、(A⁴)、(A⁵)、(A⁶)、(A⁷) Or (A)⁸) One of the fragments:

wherein X represents a sulfonyl group or a carbonyl group, the symbol "+" represents the point at which the fragment is attached to the N moiety of formula (1) (wherein N represents a non-basic nitrogen atom), and R represents¹，R²And R³Independently of one another, represents one or more hydrogen, trifluoromethyl or halogen atoms, R⁴Represents a hydrogen or halogen atom, or a methyl, ethyl, trifluoromethyl, hydroxymethyl, fluoromethyl, 2, 2, 2-trifluoroethyl, propyl, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfanyl, ethylsulfinyl, ethylsulfonyl, C_1-3-dialkyl-aminomethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl or morpholin-4-ylmethyl, and the NRTB sequence of formula (1) is (NTRB)¹)、(NRTB²)、(NTRB³)、(NRTB⁴)、(NTRB⁵)、(NRTB⁶)、(NTRB⁷)、(NRTB⁸)、(NTRB⁹) Or (NRTB)¹⁰) One of the fragments:

wherein R represents a hydrogen atom or (C)₁-C₃) -an alkyl group.

6. A compound of formula (1) according to claim 3, wherein a represents (a)^1a) Or (A)²) One of the fragments:

wherein X represents a sulfonyl group or a carbonyl group, "+" is the point at which the fragment is attached to the non-basic nitrogen atom N in formula (1), and R is¹，R²And R³Independently of one another, represents a hydrogen, trifluoromethyl or halogen atom, R⁴Represents a hydrogen or halogen atom, or a methyl, ethyl, trifluoromethyl, hydroxymethyl, fluoromethyl, 2, 2, 2-trifluoroethyl, propyl, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfanyl, ethylsulfinyl, ethylsulfonyl, C_1-3-dialkyl-aminomethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl or morpholin-4-ylmethyl, the other symbols having the meaning according to claim 5.

7. A compound of formula (1) according to claim 3, wherein a represents (a)³) Or (A)⁴) One of the fragments:

the other symbols have the same meanings as defined in claim 5.

8. A compound of formula (1) according to claim 3, selected from:

-N- {1- [7- (2-amino-ethoxyimino) -7- [4- (trifluoromethyl) phenyl ] heptylamino ] -1- [3- (4-chlorophenyl) -4-phenyl-4, 5-dihydro-1H-pyrazol-1-yl ] -methine } -4-chloro-benzenesulfonamide

-2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazole-4-carboxylic acid [7- (2-amino-ethoxyimino) -7- [4- (trifluoromethyl) phenyl ] heptyl ] amide

- [2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazol-4-yl ] {4- [4- (5-fluoro-1H-indol-3-yl) butyl ] piperazin-1-yl } methanone

-4-chloro-N- { [1- [3- (4-chlorophenyl) -4-phenyl-4, 5-dihydro-1H-pyrazol-1-yl ] -1- {4- [4- (5-fluoro-1H-indol-3-yl) butyl ] piperazin-1-yl } methine ] -benzenesulfonamide.

9. A compound of formula (1) according to any one of claims 3 to 7, which is an optically active enantiomer, or a tautomer, stereoisomer, N-oxide, isotopically-labelled analogue, or a pharmacologically acceptable salt, hydrate or solvate of any of the foregoing.

10. A compound of formula (1) according to claim 3, selected from:

11. a medicament containing a compound according to any one of claims 1 to 10, or a pharmacologically acceptable salt, hydrate, solvate, complex or conjugate thereof.

12. A pharmaceutical composition comprising: a pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable auxiliary substance, in addition to which a pharmacologically active amount of at least one compound according to any one of claims 1 to 10, or a pharmacologically acceptable salt, hydrate, solvate, complex or conjugate thereof, as active ingredient.

13. The pharmaceutical composition of claim 12, further comprising at least one additional therapeutic agent.

14. The use of a compound according to any one of claims 1 to 10 for the preparation of a pharmaceutical composition for the treatment of: addiction, alcoholism, Alzheimer's disease, anorexia nervosa, anxiety disorders, appetite disorders, attention deficit hyperactivity disorder, bipolar disorder, bulimia nervosa, cancer, cardiovascular disease, central nervous system disorder, cerebral ischemia, cerebral stroke, chemotherapy-induced emesis, cocaine addiction, cognitive disorders, dementia, diseases associated with demyelination, diabetes, diabetic neuropathy, diarrhea, drug dependence, dystonia, eating disorders, emesis, epilepsy, female sexual dysfunction, functional bowel disorders, gastrointestinal disorders, gastric ulcers, general anxiety, glaucoma, headache, Huntington's disease, impulse control disorders, inflammation, irritable bowel syndrome, male sexual dysfunction, severe depressive disorders, memory disorders, menopause, migraine, muscle spasms, multiple sclerosis, anxiety disorders, diabetes, depression, anxiety disorders, depression, anxiety disorders, anxiety disorders, dementia, demyelination, depression, Myalgia, nausea, neuralgia, neurodegenerative diseases, neuroinflammatory diseases, neuropathic pain, obesity, obsessive-compulsive disorders, osteoarthritis, pain, panic disorder, Parkinson's disease, plaque sclerosis, premature ejaculation, premenstrual syndrome, psychosexual disorders, psychosis, rheumatoid arthritis, septic shock, schizophrenia, sexual dysfunction, sleep disorders, spinal cord injury, stroke, Tourette's syndrome, traumatic brain injury, tremor, urinary incontinence and viral encephalitis.

15. The use according to claim 14 for the preparation of a pharmaceutical composition for the treatment of:

psychosis, anxiety, depression, attention deficit, cognitive disorders, obesity, drug dependence, parkinson's disease, alzheimer's disease, pain disorders, neuropathic pain disorders, and sexual dysfunction.