JP2010515704A - Compound exhibiting a combination of cannabinoid-CB1 antagonism and serotonin reuptake inhibition - Google Patents

Abstract

The present invention relates to a compound showing a combination of cannabinoid-CB ₁ antagonism and serotonin reuptake inhibition, a pharmaceutical composition containing these compounds, a method for producing the compounds, and a novel useful for use in the synthesis thereof. The present invention relates to a method for producing an intermediate and a method for producing a composition. The invention also relates to the use of said compounds and compositions, in particular psychosis, anxiety, depression, attention deficit, cognitive impairment, obesity, drug addiction, Parkinson's disease, Alzheimer's disease, pain disorder, neuropathic pain disorder And their use when administered to patients for the purpose of achieving therapeutic effects in sexual disorders. In particular, the present invention relates to general formula (1):
[Chemical 1]

[The symbols in the formula have the meanings shown in this specification]
It is related with the compound represented by these.
[Selection figure] None

Description

The present invention relates to the fields of pharmaceutical and organic chemistry, and provides compounds, intermediates, formulations and methods that exhibit a combination of cannabinoid-CB ₁ antagonism and serotonin reuptake inhibition.

  The reductionist '1 target-1 disease' strategy has been the mainstream of the pharmaceutical industry for decades. Numerous effective drugs have been found using this strategy. Nevertheless, the treatment of numerous illnesses remains inadequate. This discovery justifies alternative strategies for developing chemicals that simultaneously modulate multiple targets. Such agents may exhibit advantageous properties such as high clinical efficacy or lack of undesirable pharmacokinetic agent-drug interactions or undesirable pharmacokinetic and pharmacodynamic properties. The latter can lead to unpredictable diversity among individual patients. For the purpose of combining different therapeutic mechanisms, mixtures of two or more drugs are still used in clinical practice. Alternatively, multi-component drugs are used in which two or more pharmaceutically active compounds are formulated together in a single tablet or capsule for the purpose of improving patient acceptance. Another strategy utilizes pharmaceutical treatment with chemicals that have the ability to simultaneously modulate two or more biological targets. It is clear that using such a 'single substance-multitarget strategy' has the advantage that the risk of undesired drug-drug interactions is lower than when using drug mixtures or multi-component drugs. is there. Several multitargeting ligands are known. Most of them were found retrospectively or accidentally, and only a few ligands were theoretically devised.

Cannabinoid receptors are part of the endo-cannabinoid system involved in various diseases. Cannabinoid receptor, detailed information about the CB ₁ receptors modulators and their pharmacology observed the activities of recent review, has been the subject (non-patent document 5, 6, 7 , 8, 9, 10, 11, 12, 13). Possible therapeutic uses of the CB ₁ receptor modulator disclosed in this cited review include psychosis, anxiety, depression, attention deficit, memory impairment, cognitive impairment, appetite disorder, obesity, addiction, strong desire, Drug dependence, neurodegenerative disease, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette syndrome, brain imagination Pain disorders (including neuropathic pain disorders) as well as drugs to treat blood, cerebral hemorrhage, cranial cerebral trauma, spinal cord injury, neuroinflammatory disease, plaque sclerosis, viral encephalitis, demyelination related disorders, Drugs to treat septic shock, glaucoma, diabetes, cancer, vomiting, nausea, gastrointestinal disorders, gastric ulcers, diarrhea, sexual disorders, impulse control disorders and cardiovascular diseases included.

Mood disorders and anxiety disorders cause many sufferings. The introduction of selective serotonin reuptake inhibitors more than two decades ago is a major step in the development of safer antidepressants. Representative examples of selective serotonin reuptake inhibitors are fluvoxamine, fluoxetine, paroxetine, sertraline, citalopram, zimeldine, clomipramine, indalpine and indatraline. Most selective serotonin reuptake inhibitors are based on monoamines despite their striking diversity in structure, ie they contain a basic nitrogen atom (Non-Patent Document 14). Scientific papers, patents and patent applications have shown that serotonin reuptake inhibitors have the following therapeutic uses: alcoholism, Alzheimer's disease, anorexia nervosa, anxiety disorder, attention deficit hyperactivity disorder Bipolar disorder, bulimia nervosa, central nervous system disease, chemotherapy-induced vomiting, cocaine dependence, cognitive impairment, diabetic neuropathy, drug dependence, eating disorders, female sexual dysfunction, functional bowel disease, Generalized anxiety disorder, headache, inflammation, irritable bowel syndrome, male sexual dysfunction, major depressive disorder, climacteric disorder, migraine, muscle pain, neuralgia, neuropathic pain, obesity, tachycardia disorder, degenerative joint Disease, pain, panic disorder, Parkinson's disease, premature ejaculation, premenstrual syndrome, mental disorders, psychosis, rheumatoid arthritis, schizophrenia, sleep disorders and urinary incontinence.

Compounds showing a combination of cannabinoids -CB ₁ antagonism and serotonin reuptake inhibition, either cannabinoid CB ₁ antagonist or a serotonin reuptake inhibitor for reasons that morbidity of various medical conditions are often observed together Can be useful in the treatment of diseases for which is potentially effective. Thus, the compounds of the present invention include addiction, alcoholism, Alzheimer's disease, anorexia nervosa, anxiety disorder, appetite disorder, attention deficit hyperactivity disorder, bipolar disorder, bulimia nervosa, cancer, Cardiovascular disease, central nervous system disease, cerebral ischemia, cerebral hemorrhage, chemotherapy-induced vomiting, cocaine dependence, cognitive impairment, dementia, demyelination related disorder, diabetes, diabetic neuropathy, diarrhea, drug dependence, dystonia, Eating disorder, vomiting, epilepsy, female sexual dysfunction, functional bowel disease, gastrointestinal dysfunction, gastric ulcer, generalized anxiety disorder, glaucoma, headache, Huntington's disease, impulse regulation disorder, inflammation, irritable bowel syndrome, male sexual dysfunction , Major depression disorder, memory disorder, climacteric disorder, migraine, muscle spasticity, multiple sclerosis, myalgia, nausea, neuralgia, neurodegenerative disease, neuroinflammatory disease, neuropathic pain, obesity, bradycardia Disorder, osteoarthritis Pain, panic disorder, Parkinson's disease, plaque sclerosis, premature ejaculation, premenstrual syndrome, psychological disorder, psychosis, rheumatoid arthritis, septic shock, schizophrenia, sexual disorder, sleep disorder, spinal cord injury, stroke, It can be used to treat Tourette syndrome, traumatic encephalopathy, tremor, urinary incontinence and viral encephalitis.

In particular, it is important to use the compounds of the invention in the treatment of disorders that are emphasized that they can be treated using not only cannabinoid CB ₁ antagonists but also serotonin reuptake inhibitors. Attacking such obstacles simultaneously using two different mechanisms of action may have a synergistic effect. Thus, the compounds of the present invention are particularly useful for psychosis, anxiety, depression, attention deficit, cognitive impairment, obesity, drug addiction, Parkinson's disease, Alzheimer's disease, pain disorder, neuropathic pain disorder and sexual disorder. Useful in therapy.

The pharmacophore possessed by the majority of cannabinoid CB ₁ receptor antagonists has been the subject of several reviews (Non-Patent Documents 7 and 15). This is shown in Scheme 1.

Ar ₁ and Ar _{2 in} Scheme 1 represent a phenyl group optionally substituted with 1 or 2 halogen atoms, a trifluoromethyl group or a methoxy group. The 'spacer' in Scheme 1 contains a 5-membered heterocyclic group such as 4,5-dihydropyrazole, imidazole, pyrazole, thiazole, thiophene or pyrrole, or the spacer is a phenyl group or 6-membered Contains heterocyclic groups such as pyridine, pyrimidine or pyrazine. The spacer may also contain an azetidine moiety, a 1,3-benzodioxole moiety or an alkyl moiety as in MK-0364 (see below). In addition, one of the aromatic groups may be fused with the spacer or connected to the spacer through an additional ring (ie, so-called structural constraints). Several types of structural constraints have been successfully implemented in such pharmacophore models. An H-bond acceptor represents a carbonyl group, a sulfonyl group, or a nitrogen atom that may be incorporated into a heterocyclic ring structure, such as an imidazole ring. 'Lip' in Scheme 1 represents a lipophilic moiety such as piperidin-1-ylamino, pyrrolidinyl-1-amino, cycloalkylamino, phenylamino, arylamino, benzyl-amino or alkylamino.

Molecular model studies have shown that the presence of a hydrogen bond receptor is important: it is inactive by interacting with the Lys-192 amino acid residue side chain in the CB ₁ receptor It is thought to stabilize the state.

For the purpose of illustrating the pharmacophore model of CB ₁ receptors antagonists, show a number of specific examples of CB ₁ receptors below. Putative hydrogen bond acceptor atoms (carbonyl atom oxygen atom, sulfonyl oxygen atom or N atom in heteroaromatic ring) are shown in bold:

  A pharmacophore model of a serotonin reuptake inhibitor has been reported (Non-patent Document 16). This is shown in Scheme 2:

It is characterized by having a basic nitrogen atom (N), an extended lipophilic fragrance region (Ar ₁ ) and a lipophilic moiety (Lip-SRI). The basic amino function may be unsubstituted as in fluvoxamine (R ₁ and R ₂ represent hydrogen) or monosubstituted as in fluoxetine, indatraline and sertraline. Or may be disubstituted as in the case of citalopram, zimeldine and clomipramine. The basic nitrogen atom may be part of a 6-membered ring such as indalpine and paroxetine, ie R ₁ represents a hydrogen atom and R ₂ is part of the carbocyclic skeleton of the pharmacophore. Numerous 4- (3-indolyl-alkyl) piperidine derivatives [including indalpine and 4- (3-indolyl-alkyl) piperazine derivatives] have been shown to have potent serotonin reuptake inhibitory activity (non-patent literature) 17, 18).

SR141716A (Rimonabant), a selective CB ₁ receptor antagonist, has been known for over a decade. A number of other selective CB ₁ antagonists were later devised. Serotonin reuptake inhibitors have been known for over 20 years. To date, no compound showing a combination of CB ₁ receptor antagonist activity and serotonin reuptake inhibitor activity has been disclosed.

The object of the present invention was to develop a compound that exhibits a combination of CB ₁ antagonism and serotonin reuptake inhibition.

Landsman, R.M. S. Et al., Eur. J. et al. Pharmacol. 1997, 334, R1-R2 Lichtman, A.M. H. Others, Prostaglandins Leukotrienes and Essential Fatty Acids 2002, 66, 269-285 De Petrocellis, L.M. Et al., Br. J. et al. Pharmacol. 2004, 141, 765-774 Di Marzo, V.D. Et al., Nature Rev. Drug Discov. 2004, 3, 771-784 Hertzog, D.M. L. Expert Opin. Ther. Patents 2004, 14, 1435-1452 Lange, J. et al. H. M.M. And Kruse, C.I. G. , C.I. Curr. Opin. Drug Discovery Dev. 2004, 7, 498-506 Lange, J. et al. H. M.M. And Kruse, C.I. G. Drug Discov. Today 2005, 10, 693-702 Smith, R.A. A. And Fathi, Z .; IDrugs 2005, 8, 53-66 Thakur, G .; A. Et al., Mini-Rev. Med. Chem. 2005, 5, 631-640 Padgett, L.M. W. Life Sciences 2005, 77, 1767-1798 Muccioli, G.M. G. Et al., Curr. Med. Chem. 2005, 12, 1361-1394 Lambert, D.C. M.M. And Fowler, C.I. J. et al. J. et al. Med. Chem. 2005, 48, 5059-5087 Vandevoorde, S.W. And Lambert, D .; M.M. Curr. Pharm. Des. 2005, 11, 2647-68 Pacher, P.A. And Kecskemeti, V.M. Curr. Med. Chem. 2004, 11, 925-943 Reggio, P.A. H. Curr. Pharm. Des. 2003, 9, 1607-1633 Bureau, R.A. J. et al. Chem. Inf. Comput. Sci. 2002, 42, 429-436 Le Fur, G.G. And Uzan, A .; Biochem Pharmacol. 1977, 26, 497-503 Malleron, J.M. -L. J. et al. Med. Chem. 1993, 36, 1194-1202

Disclosures The activity of both molecules from which a molecule containing a basic part of a known cannabinoid-CB ₁ antagonist and a basic part of a known serotonin reuptake inhibitor, indalpine or fluvoxamine, is cannabinoid-CB ₁ antagonistic. And found to share both serotonin reuptake inhibition. The present invention relates to compounds that exhibit a combination of cannabinoid-CB ₁ antagonism and serotonin reuptake inhibition, and in particular to compounds with a pK _i value of> 6.00 in both CB ₁ receptor binding and serotonin reuptake binding.

  More particularly, the present invention provides a compound of formula (1):

[Where:
Any of the known cannabinoid-CB ₁ antagonists containing at least two phenyl rings optionally independently substituted with one or two substituents independently selected from halogen, methoxy and trifluoromethyl Wherein the basic structural element is bonded to a hydrogen bond acceptor in the cannabinoid-CB ₁ antagonist and the hydrogen bond acceptor moiety is a carbonyl group, a sulfonyl group, or a heteroaromatic ring Either a nitrogen or oxygen atom incorporated into the structure,
N represents a non-basic nitrogen atom;
T may be replaced by a nitrogen atom in which one carbon atom may optionally be substituted with a (C ₁ -C ₃ ) -alkyl or CH ₂ CF ₃ group, or may be replaced by an oxygen atom or a sulfur atom. Optionally substituted and optionally substituted with one or more substituents selected from fluoro, amino, cyano, (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy and trifluoromethyl. Represents a saturated or unsaturated carbon chain of 0-8 atoms,
R represents a hydrogen atom or a (C ₁ -C ₃ ) -alkyl group, or R together with the nitrogen atom to which it is attached and together with part of T (C ₄ -C ₇ )-forming a heterocycloalkyl or heteroaryl group,
B represents a basic structural element of any known serotonin reuptake inhibitor]
Or a tautomer, stereoisomer, N-oxide, isotope-labeled analog, or any of the pharmacologically acceptable salts, hydrates or solvates thereof.

In another embodiment, the cannabinoid-CB ₁ antagonist is 11C-JHU-75528, A-796260, ajurem acid, AM 251, AM 630, AVE-1625, CP-228771, CP-945598, EMD-68843, GRC- 10389, LY-2077855, LY-320135, NIDA-41020, O-2093, SLV319, SLV326, SR-140098, SR-144385, SR-41716A (Rimonabant), Srinabant, V-24343, WIN-54461 and WIN-56098 And said 5-HT reuptake inhibitor is 403U76, A-80426, AD-337, adinazolam, agomelatin, alaprocrate, amineptin, amitriptyline, ARAK-00 9, ARAK-0051, befeptipant, befloxatone, BGC-20-1259, bicifazine, BMS-505130, brophalomin, bupropion, buttriptyline, celiclamine, citalopram, CL: -275838, clomipramine, cloxoxamine, CX-157, dapoxetine, dapoxetine Xin, dexfenfluramine, dibenzepin, diclofensin, doslepine, DOV-21947, DOV-1026777, DOV-216303, duloxetine, DU
125530, DuP-631, EN-3215, EpiCept NP-1, ecitalopram, femoxetine, fluoxetine, (S) -fluoxetine, fluvoxamine, gepirone, IDN-5491, imipramine, indalpin, iprindole, L-7301, LI-301 , Ritoxetine, lofepramine, LU-10134-C, LU-AA21004, rubazodone, LY-214281, LY-367265, LY-3
93558, maprotiline, MCI-225, MCL-0042, McN-5562, melitracene, mianserin, milnacipran, mirtazepine, moclobemide, modafinil, nefazodone, 6-nitroquipazine, nortriptyline, NR-200s, NS-2381, NS-2389, NS-2463, NS-4194, NS-23459, omiloxetine, OPC-14523, opipramol, Org-6582, paroxetine, pramipexole, PRC-025, propizepine, quetiapine, quinupramine, ramelteon, R-fluoxetine, rizotriprotan, rozotriptan , RS-1439, SB-649915, S-9777, SD-726, selegiline, SEP-225289, SEP-2271 2, sertraline, sibutramine, (S) -sibutramine, (R) -didemethylsibutramine, SLV310, SLV314, SPD-473, tramadol, trazodone, udenafil, UK-416244, UP-23716, VANH-36, venlafaxine, One or more compounds represented by the formula (1) selected from vilazodone, VML-670, VN-2222, vorinanserin, WF-23, Wf-516, WL-1011, WL-1017, YM-922 and zimeldine I will provide a.

In a further aspect, A is a fragment (A ^1a ), (A ^1b ), (A ² ), (A ³ ) (A ⁴ ), (A ⁵ ), (A ⁶ ), (A ⁷ ) or (A ⁸ ). :

[here,
X represents a sulfonyl or carbonyl group, the “+” sign represents the point at which the fragment is attached to the moiety N in formula (1), where N represents a non-basic nitrogen atom, R ¹ , R ² and R ³ independently represent one or more hydrogen atoms, trifluoromethyl groups or halogen atoms, and R ⁴ represents hydrogen or halogen atoms or methyl, ethyl, trifluoromethyl, hydroxymethyl , Fluoromethyl, 2,2,2-trifluoroethyl, propyl, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfanyl, ethylsulfinyl, ethylsulfonyl, C _1-3 -dialkyl-aminomethyl, pyrrolidin-1-ylmethyl, Represents a piperidin-1-ylmethyl or morpholin-4-ylmethyl group and other The symbols have the meanings shown above]
One or more compounds represented by formula (1) representing one of the above are provided.

In another embodiment, the invention provides that A is a fragment (A ^1a ), (A ^1b ), (A ² ),
(A ³ ) (A ⁴ ), (A ⁵ ), (A ⁶ ), (A ⁷ ) or (A ⁸ ) representing one of the above and the NRTB sequence of formula (1) is a fragment (NTRB ¹ ), (NRTB ² ), (NTRB ³ ), (NRTB ⁴ ), (NTRB ⁵ ), (NRTB ⁶ ), (NTRB ⁷ ), (NRTB ⁸ ), (NTRB ⁹ ) or (NRTB ¹⁰ ):

[here,
R represents a hydrogen atom or a (C ₁ -C ₃ ) -alkyl group]
It is related with the compound represented by Formula (1) which is one of these.

In another embodiment, the invention provides that A is a fragment (A ^1a ) or (A ² ):

[here,
X represents a sulfonyl or carbonyl group, + represents the point where the fragment is bonded to the non-basic nitrogen atom N in formula (1), R ¹ , R ² and R ³ are independently Represents hydrogen, trifluoromethyl or halogen, and R ⁴ represents a hydrogen or halogen atom or methyl, ethyl, trifluoromethyl, hydroxymethyl, fluoromethyl, 2,2,2-trifluoroethyl, propyl, methylsulfanyl, methyl Represents a sulfinyl, methylsulfonyl, ethylsulfanyl, ethylsulfinyl, ethylsulfonyl, C _1-3 -dialkyl-aminomethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl or morpholin-4-ylmethyl group, and the other symbols are It has the meaning shown above]
It relates to a compound represented by the formula (1) representing one of

In another embodiment, the invention provides that A represents one of the fragments (A ^1a ) or (A ² ) and the NRTB sequence of formula (1) is a fragment (NTRB ¹ ), (NRTB ² ), (NTRB) ³ ), (NRTB ⁴ ), (NTRB ⁵ ), (NRTB ⁶ ), (NTRB ⁷ ), (NRTB ⁸ ), (NTRB ⁹ ), or (NRTB ¹⁰ ), represented by Formula (1) It relates to the compound to be made.

In another embodiment, the invention provides that A is a fragment (A ³ ) or (A ⁴ ):

And the NRTB sequence of formula (1) is a fragment (NTRB ¹ ), (NRTB ² ), (NTRB ³ ), (NRTB ⁴ ), (NTRB ⁵ ), (NRTB ⁶ ), (NTRB ⁷ ), (NRTB ⁸ ), (NTRB ⁹ ), or (NRTB ¹⁰ ), the compound represented by formula (1).

  In another aspect, the invention provides:

It is related with the compound represented by Formula (1) which is.

These pharmacologically acceptable salts as well as the compounds of the present invention represented by the general formula (1) show a combination of cannabinoid-CB ₁ antagonism and serotonin reuptake inhibition. They involve cannabinoid-CB ₁ receptors and serotonin reuptake sites or disorders that can be treated by modulation of such receptors, such as addiction, alcoholism, Alzheimer's disease, anorexia nervosa, Anxiety disorder, appetite disorder, attention deficit hyperactivity disorder, bipolar disorder, bulimia nervosa, cancer, cardiovascular disease, central nervous system disease, cerebral ischemia, cerebral hemorrhage, chemotherapy-induced vomiting, cocaine dependence, cognitive impairment , Dementia, demyelination-related disorders, diabetes, diabetic neuropathy, diarrhea, drug addiction, dystonia, eating disorders, vomiting, epilepsy, female sexual dysfunction, functional bowel disease, gastrointestinal disorders, gastric ulcers, generalized anxiety Disorder, glaucoma, headache, Huntington's disease, impulse control disorder, inflammation, irritable bowel syndrome, male sexual dysfunction, major depressive disorder, memory disorder, climacteric disorder, migraine, muscle spasm, many Multiple sclerosis, myalgia, nausea, neuralgia, neurodegenerative disease, neuroinflammatory disease, neuropathic pain, obesity, brutal disorder, osteoarthritis, pain, panic disorder, Parkinson's disease, plaque sclerosis Symptom, premature ejaculation, premenstrual syndrome, mental disorder, psychosis, rheumatoid arthritis, septic shock, schizophrenia, sexual disorder, sleep disorder, spinal cord injury, stroke, Tourette syndrome, traumatic brain disorder, vibration Useful in the treatment of war, urinary incontinence and viral encephalitis.

Other embodiments of the invention include, but are not limited to, the following:
For example, a pharmaceutical composition for treating a disorder or disease treatable by a combination of cannabinoid-CB ₁ antagonism and serotonin reuptake inhibition [this composition comprises a compound represented by formula (1) and a pharmaceutical Containing an acceptable carrier]];
A method of treating a disorder or disease treatable by a combination of cannabinoid-CB ₁ antagonism and serotonin reuptake inhibition [this method comprises administering a compound of formula (1) to a mammal in need of said treatment Comprising];
For example, a pharmaceutical composition for treating a disorder or disease selected from the disorders shown herein;
A method of treating a disorder or disease selected from the disorders shown herein [this method comprises administering a compound of formula (1) to a patient in need of such treatment] ;
A pharmaceutical composition for treating a disorder or disease selected from the disorders shown in the present specification [this composition comprises a compound represented by formula (1) and a pharmaceutically acceptable carrier. Consisting of];
A method of treating a disorder or disease selected from the disorders shown herein [this method comprises administering a compound of formula (1) to a patient in need of such treatment] ;
A method of antagonizing cannabinoid-CB ₁ antagonistic receptors and inhibiting serotonin reuptake [this method comprises administering to a subject in need thereof an effective amount of a compound of formula (1) Comprising].

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

  The present invention further includes one or two additional therapeutic agents for the purpose of treating one or more of the diseases presenting a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention. It also relates to combination therapy administered simultaneously or separately or as a combination preparation. Administration of one or more such other therapeutic agents can be performed before, simultaneously with, or after administering the compound of the present invention.

  The present invention also provides compounds, pharmaceutical compositions, kits and methods for treating a disorder or disease selected from the disorders set forth herein, which method requires such treatment. Administering a compound of formula (1) to a patient.

The compounds of the present invention exhibit a combination of cannabinoid-CB ₁ antagonism and serotonin reuptake inhibition. Demonstration of the (antagonistic) agonist / inhibitory activity exhibited by the compounds of the present invention is facilitated, for example, using one or more of the assays described herein or known in the art.

  The present invention also provides methods for producing the compounds of the present invention and intermediates used in the methods.

  Isolation and purification of the compounds and intermediates described herein can be performed using appropriate separation or purification procedures such as filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick layer chromatography, if necessary. It can be performed using either preparative low pressure or high pressure liquid chromatography or a combination of these procedures. Specific examples of suitable separation and isolation procedures can be taken from the preparations and examples. However, of course, other corresponding separation and isolation procedures can also be used.

The compounds of the present invention may contain one or more asymmetric centers and can thus exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. . There may be additional asymmetric centers depending on the nature of the various substituents the molecule has. Each such asymmetric center independently results in two optical isomers, all of the possible optical isomers and diastereomers as a mixture and as a highly purified or partially purified compound of the present invention. It is intended to be included within the scope. The present invention is meant to include all such isomeric forms of the compounds. Formula (1) represents the structure of such a class of compounds without exhibiting a suitable stereochemistry. Individual synthesis of such diastereomers or their chromatographic separation can be accomplished as is known in the art by appropriate modification of the methods disclosed herein. Their absolute stereochemistry measurements are made using x-ray crystallography of crystalline products or crystalline intermediates (generated with reactants containing asymmetric centers of known absolute configuration if necessary). It can be implemented. If necessary, individual enantiomers may be isolated by subjecting a racemic mixture of such compounds to separation. Such separation can be accomplished by methods well known in the art, such as combining a racemic mixture of a compound with an enantiomerically pure compound to form a diastereomeric mixture followed by individual diastereomers. Can be carried out by standard methods such as fractional crystallization or chromatography. Such coupled reactions are often enantiomerically pure acids or bases, such as (−)-di-p-toluoyl-D-tartaric acid and / or (+)-di-p-toluoyl-L-tartaric acid. It is a reaction that produces a salt using Next, the additional chiral residue of the diastereomeric derivative may be cleaved to change to a high purity enantiomer. The racemic mixture of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, and such methods are well known in the art. Alternatively, stereoselective synthesis using optically pure starting materials or reactants of known configuration can be performed using methods well known in the art to provide an enantiomer of a compound. It is also possible to get either

  Further, cis and trans isomers of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof are also within the scope of the present invention, and this is also the compound represented by the formula (1). This also applies to the tautomers of or the pharmaceutically acceptable salts thereof.

  Some of the crystalline forms exhibited by the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates (ie, hydrates) with water or solvates with common organic solvents, such solvents Japanese equivalents are also intended to be included within the scope of the present invention.

In addition, an isotope-labeled compound represented by the formula (1) or a pharmaceutically acceptable salt thereof [a compound represented by the formula (1) which is isotopically labeled so as to be detectable by PET or SPECT Is also included within the scope of the present invention, and the same applies to [ ¹³ C]-, [ ¹⁴ C]-, [ ¹⁸ F]-, [ ³ H]-, [ ¹²⁵ I]-or other isotopes This also applies to compounds of the formula (1) labeled with abundant atoms, which are suitable for use in receptor binding or metabolic studies.

  The compounds of the invention can also be used as reactants or standards in biochemical tests of neurological function, dysfunction and disease.

Defined within the context of the present description, the term 'compound indicates cannabinoid -CB ₁ antagonism' and 'cannabinoid -CB ₁ antagonist' is such without showing substantially cross-reactivity to another receptor A compound that exhibits a specific activity is performed using a well-defined pharmacological assay (including those described herein) that is well accepted to measure its activity. In one embodiment, the efficacy of the compounds of the present invention as cannabinoid-CB ₁ antagonists is at least 10-fold higher than the efficacy they exhibit as agonists or antagonists for any other receptor. A compound showing a selectivity of 100 times is preferred, and a compound showing a selectivity of 1,000 times or more is most preferred. The term 'compound exhibiting serotonin reuptake inhibitory activity' or serotonin reuptake inhibitor 'refers to a compound that exhibits such activity without substantially showing cross-reactivity to another reuptake site and measuring its activity Are performed using well-accepted clear pharmacological assays, including those described herein. In one embodiment, the potency of the compounds of the invention as serotonin reuptake inhibitors is at least 10 times higher than the potency they show as reuptake inhibitors of any other neurotransmitter. A compound showing a selectivity of 100 times is preferred, and a compound showing a selectivity of 1,000 times or more is most preferred. A compound that 'shows both cannabinoid-CB ₁ antagonism and serotonin reuptake inhibitory activity' exhibits both activities with no substantial cross-reactivity to other receptors or reuptake sites. Identifies the indicated compound and is performed using well-defined pharmacological assays (including those described herein) that are well accepted to measure its activity. In one embodiment, the efficacy of the compounds of the invention as a cannabinoid-CB ₁ antagonist and as a serotonin reuptake inhibitor is other than the efficacy they exhibit as agonists or antagonists to any other receptor. It is at least 10 times higher than the potency shown as an inhibitor of any reuptake site. A compound showing a selectivity of 100 times is preferred, and a compound showing a selectivity of 1,000 times or more is most preferred.

The general terms used in the description of the compounds disclosed herein have their ordinary meanings. The term alkyl as used herein represents a monovalent branched or straight chain saturated hydrocarbon chain. Unless otherwise specified, the number of carbon atoms contained in such chains can be from 1 to 18. Representative examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, Decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl and the like. When a 'lower' modification is applied to an alkyl group, it contains from 1 to 6 carbon atoms. The same carbon content applies to the parent term 'alkane' and derivative terms such as 'alkoxy'. The carbon content of various hydrocarbon-containing moieties is represented by a prefix indicating the minimum and maximum number of carbon atoms in the moiety, ie the prefix C _x -C _y is an integer including the number of carbon atoms present It is defined to be an integer “y” from “x”. For example, “alkyl (C _1-3 )” means methyl, ethyl, n-propyl or isopropyl, and “alkyl (C _1-4 )” is “methyl, ethyl, n-propyl, isopropyl, n- Means butyl, 2-butyl, isobutyl or 2-methyl-n-propyl and the like.

The term “acyl” means alkyl (C _1-3 ) carbonyl, arylcarbonyl or aryl-alkyl (C _1-3 ) carbonyl. 'Aryl' includes monocyclic or fused bicyclic aromatic or heteroaromatic groups including but not limited to furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, imidazolo [2,1 -B] [1,3] thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, phenyl, indazolyl, indolyl, indolizinyl, isoindolyl, benzo [b] furanyl, 1, 2,3,4-tetrahydro-naphthyl, 1,2,3,4-tetrahydroisoquinolinyl, indanyl, indenyl, benzo [b] thienyl, 2,3-dihydro-1,4-benzodioxin-5-yl , Benzimidazolyl, benzothiazolyl, benzo [1 2,5] thiadiazolyl, purinyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, Kinakisariniru, 1,8-naphthyridinyl, naphthyl, pteridinyl or azulenyl. 'Halo' or 'halogen' means chloro, fluoro, bromo or iodo, and 'hetero', as in 'heteroalkyl, heteroaromatic', etc. is N,
Means containing one or more O or S atoms. 'Heteroalkyl' includes an alkyl group having a heteroatom in any position and thus includes an N-linked, O-linked or S-linked alkyl group.

  The term “substituted” means that the specified group or moiety has one or more substituents. Where any group may have more than one substituent and exhibit a variety of possible substituents, such substituents are independently selected and they need not be the same. The term “unsubstituted” means that the specified group has no substituent. The term “independently” when referring to a substituent means that where two or more such substituents are possible, they may be the same or different from each other.

When the terms “oxy”, “thio” and “carbo” are used herein as part of another group, these each represent an oxygen atom, a sulfur atom and a carbonyl (C═ O) refers to groups such as hydroxyl, oxyalkyl, thioalkyl, carboxyalkyl, and the like. When the term “amino” is used herein alone or as part of another group, it refers to a nitrogen atom that may be present at the end or may be a linker between two other groups; And the group is primary, secondary or tertiary, each having two hydrogen atoms bonded to the nitrogen atom, one hydrogen atom bonded to the nitrogen atom, and It may be an amine in which no hydrogen atom is bonded to the nitrogen atom. When the terms “sulfinyl” and “sulfonyl” are used herein as part of another group, they refer to a —SO— or —SO ₂ — group, respectively.

  For the purpose of providing a more precise explanation and unless explicitly stated otherwise, the term 'compound' or 'two or more compounds' is used as a tautomer, stereoisomer, N-oxide, isotope-labeled analogue or pharmacology. Pharmaceutically acceptable salts, hydrates or solvates are included.

  The term “leaving group” (L) as used herein refers to a charged or uncharged atom or group that is eliminated during a substitution or substitution reaction. The term refers to groups that can be readily displaced by nucleophiles such as amines, thiols or alcohol nucleophiles. Such leaving groups are well known in the art. Examples include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halide (Br, Cl, I), triflate, mesylate, tosylate, and the like.

  N-oxides of the above-mentioned compounds also belong to the present invention. Tertiary amines may or may not give N-oxide metabolites. The degree to which N-oxidation occurs varies from trace amounts to almost quantitative conversion. N-oxides may have higher or lower activity than the corresponding tertiary amine. N-oxides can be readily reduced by chemical means in the human body to the corresponding tertiary amines, but the degree to which it occurs varies. Certain N-oxides undergo reductive transformation almost quantitatively to the corresponding tertiary amine, and in other cases the transformation may be merely a trace reaction or even no reaction at all. (Bickel, 1969).

  Any compound that undergoes metabolism in vivo to become a bioactive agent (ie, a compound represented by formula (1)) is a prodrug within the scope and spirit of this application. Prodrugs are therapeutic agents that are essentially inert but change to one or more effective metabolites. Thus, the terms “administration” and “used in treatment” in the treatment methods of the present invention refer to specifically disclosed compounds or specifically designated compounds in vivo after administration to a patient that was not specifically disclosed. It includes treating various disorders described with compounds that change. Prodrugs are in vivo reversible drug molecule derivatives that are used to overcome certain obstacles to the use of parent drug molecules. Such disorders include, but are not limited to, solubility, permeability, stability, metabolism and target limitations that occur before reaching the whole body (Bundgaard, 1985; King, 1994; Stella, 2004). Ettmayer, 2004; Jaervinen, 2005). Prodrugs, that is, compounds that undergo metabolism to become a compound of formula (1) when administered to a human or mammal by any known route belong to the present invention. In particular, this relates to compounds having primary or secondary amino or hydroxy groups. Such compounds can react with organic acids to give compounds of formula (1) in which there are additional groups that are easily removed after administration, such additional groups being, for example, Nonlimiting examples include amidine, enamine, Mannich base, hydroxyl-methylene derivatives, O- (acyloxymethylene carbamate) derivatives, carbamates, esters, amides or enaminones.

  'Crystal form' refers to various solid forms of the same compound, such as polymorphs, solvates and amorphous forms. 'Polymorphs' are crystal structures in which a compound can crystallize in various crystal packing arrangements, all of which have the same elemental composition. Polymorphism is a phenomenon that often occurs and is affected by several crystallization conditions such as temperature, degree of supersaturation, presence of impurities, solvent polarity, cooling rate, and the like. Different polymorphs generally exhibit different X-ray diffraction patterns, solid state NMR spectra, infrared or Raman spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility. Depending on the recrystallization solvent, crystallization rate, storage temperature and other factors, one major crystal form can occur. A 'solvate' is generally a crystalline form containing a solvent in a stoichiometric or non-stoichiometric amount. Certain compounds tend to form solvates by trapping solvent molecules at a fixed molar ratio in the crystalline solid state during the crystallization process. If the solvate is water, a hydrate can be formed. The compound represented by the formula (1) and pharmaceutically acceptable salts thereof may exist in the form of hydrate or solvate, and such hydrate and solvate are also included in the present invention. Is included. Examples include 1/4 hydrate, dihydrochloride dihydrate and the like. The 'amorphous' form is an amorphous material that does not exhibit long-range order and generally does not yield a well-defined powder X-ray diffraction pattern. Crystal forms are generally described in Byrn (1995) and Martin (1995).

  For the purpose of more accurate explanation, some of the quantitative expressions given herein are not modified by the term “about”. Regardless of whether the term “about” is explicitly used, all quantities given herein are meant to refer to actual values obtained and are also approximations of such obtained values [technical It is understood to mean also an approximation that is reasonably inferred on the basis of ordinary skill in the art (experimental and / or measurement conditions relating to such obtained values include an approximation of the reason).

  Throughout the description and claims of this specification, the term “comprises” and variations of this term, eg “comprising”, “comprises” And the like are not intended to exclude other additives, ingredients, integers or steps.

While it may be possible to administer the compounds of formula (1) as raw chemicals, it is preferred to provide them as a 'pharmaceutical composition'. According to a further aspect, the invention provides at least one compound of formula (1), at least one pharmaceutically acceptable salt or solvate thereof, or one mixture of any of the foregoing. Pharmaceutical compositions comprising the above pharmaceutically acceptable carriers and optionally one or more other therapeutic ingredients are provided. One or more such carriers should be 'accepted' in the sense of being compatible with the other ingredients included in the formulation and not deleterious to the recipient thereof. As used herein, the term “composition” is produced directly or indirectly by combining specified materials in specified amounts as well as products comprising the specified materials in predetermined amounts or proportions. Any product is included. With respect to pharmaceutical compositions, this term includes not only products comprising one or more active ingredients and optional carriers (including inert materials), but also any two or more of such materials together. Or complex or agglomerate, or separate one or more of such materials, or cause one or more other types of reactions or interactions of such materials. Any product directly or indirectly resulting from this is included. The preparation of a pharmaceutical composition generally involves shaping the product into the desired formulation if necessary after associating the active ingredient uniformly or closely with a liquid carrier or a fine solid carrier or both. carry out. The amount of active object compound contained in such pharmaceutical compositions is sufficient to have a favorable effect on the progression or condition of the disease. Accordingly, the pharmaceutical compositions of the present invention include any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. “Pharmaceutically acceptable” means that the carrier, diluent or excipient should be compatible with the other ingredients of the formulation and not deleterious to its recipients.

The affinity of the compounds of the present invention for the CB ₁ receptor and the 5-HT reuptake site was determined as described below. The theoretically lowest effective dose can be estimated using the binding affinity measured for a given compound of formula (1). When the concentration of the compound corresponds to twice the measured K _i -value, the compound is likely to occupy almost 100% of the CB ₁ receptor. Converting such a concentration to mg of compound per kg patient yields the theoretically lowest effective dose assuming that bioavailability is ideal. Depending on pharmacokinetics, pharmacodynamics and other considerations, the actual dose administered may be changed to a higher or lower value. The amount of the compound to be administered will depend on the relevant indication, the age, weight and sex of the patient, but the physician will be able to determine it. The dosage is preferably in the range of 0.01 mg / kg to 10 mg / kg. The typical daily dose of the active ingredient varies within a wide range and depends on various factors such as the relevant indication, route of administration, patient age, weight and sex, etc. Could be determined. The total amount administered per day to a patient at one time or in individual doses may generally be, for example, from 0.001 to 10 mg / kg body weight per day, more generally the total active ingredient amount is 0 per day. .01 to 1,000 mg may be used. Such doses are administered to a patient in need of treatment 1 to 3 times per day or as frequently as required for efficacy for at least 2 months, more typically for at least 6 months or over a long period of time.

The term “therapeutically effective amount” as used herein refers to the amount of a therapeutic agent that treats a disease treatable by administering a composition of the invention. The amount is sufficient to produce a detectable therapeutic or ameliorative response in the tissue system, animal or human. Such effects can include, for example, treatment of the diseases indicated herein. An exact effective amount for a subject is the size and health of the subject, the nature and extent of the disease to be treated, the recommendation and administration of the treating physician (researcher, veterinarian, doctor or other clinician) Will depend on the therapeutic agent or combination of therapeutic agents selected for this purpose. Thus, it is not effective to specify an exact effective amount in advance. The term “pharmaceutically acceptable salt” is suitable and reasonable to contact human and lower animal tissues within the scope of sound medical judgment without causing excessive toxicity, irritation, allergic reactions, etc. Refers to the salt corresponding to the benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. Their preparation can be performed in situ when the compounds of the invention are finally isolated and purified, or individually they are pharmaceutically acceptable non-toxic bases or acids (inorganic or organic bases and inorganics). Alternatively, it can be carried out by reacting with an organic acid (Berge, 1977). The 'free base' form can be formed by contacting the salt with a base or acid and isolating the parent compound as the usual material. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but in other respects such salts are the parent form of the compound for purposes of the present invention. Equivalent to. The “complex” refers to a complex of the present invention, for example, a compound in which the compound represented by the formula (1) forms a complex with a metal ion, in which at least one metal atom is chelated or sequestered. Yes. The preparation of the complex is carried out using methods well known in the art (Dwyer, 1964).

  As used herein, the term “treatment” refers to any treatment of a disease or condition in a mammal, such as a human, including (1) suppression of the disease or condition, ie, preventing its progression, ( 2) alleviating the disease or disorder, i.e. causing the regression of the disease, or (3) stopping the symptoms of the disease. The term 'suppression' includes a generally accepted meaning, including prophylaxis, prevention, suppression, reduction, amelioration, and progression, severity or resulting delay, cessation or reversal. Thus, the method encompasses both medical treatment and / or prophylactic administration as appropriate. The term “medical treatment” as used herein is intended to include prophylactic, diagnostic and therapeutic therapies performed in vivo or ex vivo on humans or other mammals. 'Mammal' includes economically important animals such as cattle, sheep and pigs, especially domestic animals, sports animals, zoo animals and humans, as well as animals for meat production. Is preferred. The term “subject” as used herein refers to an animal, preferably a mammal, most preferably a human, that is a control for treatment, observation or experiment.

Abbreviated BOC t-butoxycarbonyl BOP hexafluorophosphate benzotriazol-1-yl-oxytris
Suphonium CB ₁ cannabinoid receptor subtype-1
CB ₂ cannabinoid receptor subtype-2
CHO Chinese hamster ovary (cells)
CIP 2-chloro-1,3-dimethylimidazolinium DCC hexafluorophosphate DCC dicyclohexylcarbodiimide DIPEA N, N-diisopropylethylamine DMAP 4-dimethylaminopyridine DMSO dimethyl sulfoxide EDCI 1- (3-dimethylaminopropyl) -3 -Ethylcarbodiimide HBTU hexafluorophosphoric acid O-benzotriazol-1-yl-N, N, N '
, N'-tetramethyluronium HOAt N-hydroxy-7-azabenzotriazole mg milligram min minute PET positron emission tomography PyAOP hexafluorophosphate 7-azabenzotriazol-1-yl-oxyto
Lith- (pyrrolidino) -phosphonium PyBOP hexafluorophosphate benzotriazol-1-yl-oxytris (pi
Loridino) -phosphonium R _f retention coefficient (thin layer chromatography)
SPECT single photon emission computed tomography (S) SRI (selective) serotonin reuptake inhibitor TBTU tetrafluoroborate O- (benzotriazol-1-yl) -N, N
, N ′, N′-tetramethyluronium THF tetrahydrofuran

Analytical method Unless otherwise specified in the specified solvent for measurement of nuclear magnetic resonance spectra ( ¹ H NMR and ¹³ C NMR, APT), a Bruker ARX 400 ( ¹ H: 400 MHz, ¹³ C: 100 MHz) is used at 300 K or Bruker. (300 MHz). Spectral measurements were taken at Cambridge Isotop Laboratories Ltd. Performed in deuterated chloroform or DMSO-d ₆ obtained from Chemical shift (δ) is shown in ppm downfield from tetramethylsilane ( ¹ H, ¹³ C) or CCl ₃ F ( ¹⁹ F). The coupling constant J is indicated in Hz. The peak shape in the NMR spectrum is represented by the symbols' q '(quadruplex),' dq '(double quartet),' t '(triple line),' dt '(double triplet),' d '(Double line),' dd '(double double line),'s' (single line), 'br s' (wide single line) and' m '(multiple line).

  Flash chromatography / column chromatography refers to purification using indicator eluent and silica gel (Acros: 0.030-0.075 mm or Merck silica gel 60: 0.040-0.063 mm) or specifically Where indicated, refers to purification using alumina: 'Aluminumoxide Fluka for Chromatography'; pH = 9.5; 0.05-0.15 mm.

Thin layer chromatography (TLC): Merck Kieselgel 60 F ₂₅₄ plate 20x20 cm.

  Melting points were recorded using a Büchi B545 melting point apparatus.

  All reactions involving moisture sensitive compounds or conditions were performed under an anhydrous nitrogen atmosphere.

Reaction monitoring was performed using thin layer chromatography with silica coated plastic sheets (pre-coated with Merck silica gel 60 F254) with indicator eluent. Spots were visualized with ultraviolet light (254 nm) or I ₂ .

  Distillation of dichloromethane (phosphorus pentoxide and calcium hydride), tetrahydrofuran (sodium / benzophenone ketyl) and gas oil (60-80) were freshly performed before use. All other commercial chemicals were used without further purification.

General aspects of synthesis The synthesis of the basic structural elements of known cannabinoid-CB ₁ antagonists has been described in patent applications and / or scientific literature. For example, basic cannabinoid structural elements (A ^1a ) (WO010070700, Lange, 2004 ^b ), (A ^1b ) (WO03026648), (A ² ) (WO03027076, WO030040107, WO03063811, Lange, 2005 ^b ; Dyck (2004), ( ^{A 3) (EP0576357, EP1150961,} Lan, 1999; Seltzman, 1995; Dutta, 1994 and ^{Katoch-Rouse, 2003), (} A 4) (WO03007887, Plummer, 2005), (A 5) (WO0307069), (A 6 ^{) (WO03078413, Lange, 2005 b} ), (A 7) (WO2004026301, Lange, 2005 b; Dyck, 2004) and A ⁸⁾ (WO2004013120) has been well documented.

From a general point of view, the synthesis of the compound represented by the formula (1) in which R represents a hydrogen atom is represented by the compound represented by the general formula A-L in which L represents a leaving group and the general formula HRN-TB. This can be achieved by reacting the compound. It will be apparent to those skilled in the art that the nucleophilicity of the amino group present in HRN-TB must be high enough to drive the leaving group out of A-L in such a reaction. When L represents a hydroxy group that is a part of a carboxylic acid group, an activator or a coupling agent may be added for the purpose of increasing the reaction rate (Bodanzsky, 1994; Akaji, 1994; Albertico, 1997; Montalbetti, 2005).

A represents a cannabinoid structural element represented by the structure (A ^1a ) or (A ^1b ), and R ¹ , R ² and R ³ independently represent one or more hydrogen atoms, trifluoromethyl groups or halogen atoms The outline of the synthesis of the compound represented by the general formula (1) is shown in Scheme 3.

Reaction of a compound represented by the general formula (A ^1a1 ) with POCl ₃ in an inert organic solvent such as dichloromethane in the presence of DMAP ^{yields a} corresponding derivative represented by the general formula (A ^1a2 ). Can be made. The compound represented by the general formula (A ^1a2 ) can be reacted with the compound represented by the general formula HRN-TB. This reaction yields a compound of the general formula (1) in which A has the meaning as indicated hereinabove for (A ^1a ) and R, N, T and B have the meanings given above. obtain. Similarly, represented by the general formula inert organic solvent in the presence of a compound and POCl ₃ represented DMAP in ^{(A 1b1),} for example, corresponding the general formula by reacting a medium such as dichloromethane ^{(A 1b2)} Chloride derivatives can be produced. The compound represented by the general formula (A ^1b2 ) can be reacted with the compound represented by the formula HRN-TB. This reaction yields a compound of the general formula (1) in which A has the meaning indicated above for (A ^1b ) and R, N, T and B have the meanings described above. obtain.

An outline of the synthesis of the compound represented by the general formula (1) in which A represents a cannabinoid structural element represented by the structure (A ² ) is shown in Scheme 4.

R ¹ and R ^{2 in} Scheme 4 independently represent one or more hydrogen atoms, trifluoromethyl groups or halogen atoms, and R ₄ represents hydrogen or halogen atoms or methyl, ethyl, trifluoromethyl, hydroxymethyl, fluoro Methyl, 2,2,2-trifluoroethyl, propyl, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfanyl, ethylsulfinyl, ethylsulfonyl, C _1-3 -dialkyl-aminomethyl, pyrrolidin-1-ylmethyl, piperidine- 1-ylmethyl, morpholin-4-ylmethyl and the other symbols have the meanings indicated above.

By reacting the ester represented by the general formula (A ²ⁱ¹ ) and the compound represented by the general formula HRN-TB, the compound represented by the general formula (1) in which the moiety A is derived from the basic structure A ² is generated. be able to. The reaction can be catalyzed with trimethylaluminum (AlMe ₃ ) (Levin, 1982).

Alternatively, the compound represented by the general formula (A ²ⁱ¹ ) can be hydrolyzed to produce the corresponding carboxylic acid represented by the general formula (A ²ⁱ² ). By reacting the compound represented by the general formula (A ²ⁱ² ) and the compound represented by the general formula HRN-TB, the compound represented by the general formula (1) in which the moiety A is derived from the basic structure A ² is generated. be able to. This reaction is preferably activated and coupled to methods such as active esters or so-called coupling reactants such as DCC, HBTU, TBTU, HOAt, PyBOP, BOP, CIP, 2-chloro-1 chloride , 3-dimethylimidazolinium, PyAOP and the like are allowed to proceed.

Alternatively, the acid represented by the general formula (A ²ⁱ³ ) can be converted by converting the compound represented by the general formula (A ²ⁱ² ) in the presence of a chlorinating agent such as thionyl chloride or oxalyl chloride. It is also possible to produce chloride. By reacting the compound represented by the general formula (A ²ⁱ³ ) with the compound represented by the general formula HRN-TB, the compound represented by the general formula (1) in which the moiety A is derived from the basic structure A ² is generated. be able to. A base such as DIPEA may be added to the reaction mixture for the purpose of scavenging the liberated hydrochloric acid, or HRN-TB may be used in excess for this purpose.

Similarly, conversion into the basic structure represented by the general formula (A ³ ), (A ⁴ ), (A ⁵ ), (A ⁶ ), (A ⁷ ) or (A ⁸ ) as shown above is performed. By receiving, the part A is represented by the general formula (1) derived from the basic structure (A ³ ), (A ⁴ ), (A ⁵ ), (A ⁶ ), (A ⁷ ) or (A ⁸ ), respectively. Can be produced.

  The choice of the individual synthesis procedure depends on factors known to the person skilled in the art, such as the compatibility of the functional groups with the reactants used, the possibility of using protecting groups, catalysts, activators and coupling agents and the final compounds to be prepared Depends on the final structural features present in the

  Standard procedures well known in the art can be used to obtain pharmaceutically acceptable salts, such as mixing the compounds of the present invention with a suitable acid, such as an inorganic or organic acid, etc. Can be obtained at

Synthesis of intermediate Intermediate A: 4-Chloro-1- (5-fluoro-1H-indol-3-yl) -butan-1-one

4-Chloro-butyryl chloride (21 ml, 0.19 mol) was slowly added to a mixture of AlCl ₃ (25 g, 0.19 mol) in dichloromethane with magnetic stirring at 0 ° C. The resulting mixture was stirred for 30 minutes before 5-fluoro-1H-indole (25 g, 0.19 mol) was added slowly. After stirring for another 30 minutes, the resulting orange mixture was poured onto concentrated hydrochloric acid (140 ml) and ice (200 ml) resulting in a pink precipitate. The precipitate was collected by filtration to give pink 4-chloro-1- (5-fluoro-1H-indol-3-yl) -butan-1-one (29 grams, 65% yield). .
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.09 (quintet, J = 7, 2H), 3.02 (t, J = 7, 2H), 3.70 (t, J = 7, 2H), 7.07 (dt, 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 (brs, 1H).

Intermediate B: 4- [4- (5-Fluoro-1H-indol-3-yl) -4-oxobutyl] -piperazine-1-carboxylic acid t-butyl ester

A solution of 4-chloro-1- (5-fluoro-1H-indol-3-yl) -butan-1-one (10.93 g, 45.6 mmol) in acetonitrile (100 ml) was magnetically added. To this was added piperazine (20.33 gml, 236 mmol) and a small amount of potassium iodide (0.1 gram) with stirring and the resulting mixture was heated to 80 ° C. for 48 hours. The resulting solid material was removed by filtration and the residue was concentrated in vacuo to give a crude yield of 37 grams. The crude product was further purified by column chromatography (gradient: ethyl acetate / methanol / 25% aqueous ammonia = 90/5/5 to methanol) to give 17.1 grams of crude 1- (5-fluoro-1H -Indol-3-yl) -4- (piperazin-1-yl) -butan-1-one was obtained. 10.71 grams (0.389 mol) of the crude 1- (5-fluoro-1H-indol-3-yl) -4- (piperazin-1-yl) -butan-1-one in dichloromethane (500 ml) After dissolution, Boc ₂ O (25.53 g, 0.117 mol) was added. The resulting mixture was stirred at room temperature for 4 hours. The mixture was washed sequentially with 5% aqueous NaHCO ₃ and water. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. Thereafter, the column chromatography (gradient: dichloro-methane / methanol = 99/1 to dichloro-methane / methanol = 90/10 (volume / volume)) was applied to high-purity 4- [4- (5-fluoro- 1H-Indol-3-yl) -4-oxobutyl] -piperazine-1-carboxylic acid t-butyl ester (3.85 grams, 37% yield) was obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.38 (s, 9H), 1.80 (quintet, J = 7, 2H), 2.25-2.35 (m, 6H), 2 .84 (t, J = 7, 2H), 3.22-3.32 (m, 4H), 7.06 (dt, 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 (brs, 1H).

Intermediate C: 5-Fluoro-3- [4- (piperazin-1-yl) butyl] -1H-indole

4- [4- (5-Fluoro-1H-indol-3-yl) -4-oxobutyl] -piperazine-1-carboxylic acid t-butyl ester (3.85 grams, 9.88 mmol) is placed in dichloromethane. To this was added hydrochloric acid (dissolved in dioxane: 4.94 ml, 4M solution, 19.8 mmol HCl) to the resulting solution with magnetic stirring, and the resulting mixture was reacted at room temperature for 4 hours. I let you. The reaction mixture was concentrated thoroughly under vacuum to give 1- (5-fluoro-1H-indol-3-yl) -4- (piperazin-1-yl) butan-1-one (3.20) dihydrochloride. G). Several characteristic ¹ H-NMR signals exhibited by 1- (5-fluoro-1H-indol-3-yl) -4- (piperazin-1-yl) butan-1-one dihydrochloride: (400 MHz, DMSO-d ₆ ) δ 2.07 (quintet, J = 7, 2H), 3.03 (t, J = 7, 2H), 7.08 (dt, J-9 and 3, 1H), 7. 50 (dd, J-9 and 4, 1H), 7.85 (dd, J-9 and 3, 1H), 8.43 (d, J-3, 1H), 12.21 (brs, 1H) .

The obtained 1- (5-fluoro-1H-indol-3-yl) -4- (piperazin-1-yl) butan-1-one (3.20 grams) dihydrochloride was dissolved in tetrahydrofuran (50 ml). Thereafter, it was cooled to 0 ° C. A solution formed by placing LiAlH ₄ in tetrahydrofuran (60 ml; 1 M, ˜53 mmol LiAlH ₄ ) was added slowly. The mixture was then heated to 80 ° C. for 20 hours. Excess LiAlH ₄ was carefully hydrolyzed and then extracted to give 5-fluoro-3- [4- (piperazin-1-yl) butyl] -1H-indole (2.39 grams, 98% Yield). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.40-1.50 (m, 2H), 1.61 (quintet, 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).

Intermediate D: 7- (Tetrahydropyran-2-yloxy) -1- [4- (trifluoromethyl) phenyl] heptan-1-one

Magnesium (1.20 g, 0.0494 mol) was added to anhydrous THF (5 ml) followed by sequential 1,2-dibromoethane (1 ml), small crystals of iodine and 2- (6-chlorohexyl) at reflux temperature. Oxy) tetrahydro-2-pyran (10.0 grams, 0.0453 mol; dissolved in 9 ml THF) was added and the resulting mixture was brought to reflux temperature 3
Heated for 0 minutes. 4-Trifluoromethylbenzonitrile (7.0 grams, 0.0412 mol: dissolved in 8 ml toluene) was slowly added and the mixture was heated for an additional 30 minutes. The mixture was brought to room temperature and quenched with acetic acid (30 ml). The organic layer was separated and washed sequentially with water, 5% aqueous NaHCO ₃ solution, water (twice) and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. After that, high purity 7- (tetrahydropyran-2-yloxy) -1- [4- (trifluoromethyl) phenyl] is applied by column chromatography (ethyl acetate / heptane = 10/90 (volume / volume)). Heptan-1-one (10.92 grams, 74%) was obtained as an oil. R _f = 0.25 (ethyl acetate / heptane = 1/6 (volume / volume).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.39-1.88 (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

7- (Tetrahydropyran-2-yloxy) -1- [4- (trifluoromethyl) phenyl] heptan-1-one (7.70 grams, 0.0215 mol) was formed by placing in methanol (50 ml). To this was added para-toluenesulfonic acid hydrate (4.18 grams, 0.022 mol) with magnetic stirring. 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 under vacuum. NaOH (1N, 50 ml) was added and the mixture was extracted with dichloromethane (3 ×). The organic layers were combined and washed sequentially with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give crude 7-hydroxy-1- [4- (trifluoromethyl) phenyl] heptan-1-one (5.85 g, 99% yield) was obtained as a white solid. The resulting solid was treated with pyridine (29.6 ml) and then a solution of tosyl chloride (17.72 grams, 0.093 mol) in pyridine (89 ml) was added at 0 ° C. The mixture was brought to room temperature and reacted for 1 hour. The mixture was cooled to −10 ° C. and the reaction was quenched with excess water. Extraction with diethyl ether (3 ×) followed by drying with Na ₂ SO ₄ , filtration and concentration in vacuo gave the crude product which was purified by column chromatography (dichloromethane / heptane = 2 / 1 (v / v)) and purified by high purity toluene-4-sulfonic acid 7-oxo-7- [4- (trifluoromethyl) phenyl] heptyl ester (7.91 grams, 87% yield) ) ¹ H-NMR (400 MHz, CDCl ₃ ) 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).

Intermediate F: Toluene-4-sulfonic acid 7,7-dimethoxy-7- [4- (trifluoromethyl) phenyl] heptyl ester

A solution of toluene-4-sulfonic acid 7-oxo-7- [4- (trifluoromethyl) phenyl] heptyl ester (2.77 grams, 6.464 mmol) in methanol (75 ml) was magnetically treated. To this was added in succession a catalytic amount of para-toluenesulfonic acid (0.097 grams, 0.508 mmol) and an excess of trimethyl orthoformate (16 ml, 142 mmol) with stirring. The resulting mixture was heated to reflux temperature for 20 hours. The reaction mixture was allowed to reach room temperature and then sequentially saturated aqueous NaHCO ₃ and dichloromethane were added. The organic layer was separated and washed with saturated aqueous NaHCO ₃ solution. The organic layer was then dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give crude toluene-4-sulfonic acid 7,7-dimethoxy-7- [4- (trifluoromethyl) phenyl]. A heptyl ester was obtained and purified by column chromatography (alumina, ethyl acetate / heptane = 1/10 (volume / volume)) to obtain high-purity toluene-4-sulfonic acid 7,7-dimethoxy-7-. [4- (Trifluoromethyl) phenyl] heptyl ester (1.82 grams, 59% yield) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.84-0.93 (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, 3.835 mmol) magnetically to in methanol 7M NH ₃ solution (30ml) After dissolving with stirring, the mixture was stirred at room temperature for 72 hours. After removing the solvent under vacuum, the residue was dissolved again in dichloromethane and washed with saturated aqueous NaHCO ₃ solution. The organic layer was then dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to provide crude 7,7-dimethoxy-7- [4- (trifluoromethyl) phenyl] heptylamine (1.43 Gram) and was not further purified. ¹ H-NMR (400 MHz, CDCl ₃ ) 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, 3.14)
-OMe single line included), 7.56 (d, J-8, 2H), 7.60 (d, J-8, 2H).

Synthesis of Specific Compounds The specific compounds described below in the synthesis are intended to further illustrate the invention in more detail and are therefore not intended to limit the scope of the invention in any way. Other aspects 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, it is intended that the specification and examples should be considered as exemplary 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] -methylidene} -4-chloro-benzenesulfonamide (Compound 1)

Part A: 3- (4-Chlorophenyl) -N-[(4-chlorophenyl) sulfonyl] -4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide has been described (Lange, 2004 ^b ). Was obtained. 3- (4-Chloro-phenyl) -N-[(4-chloro-phenyl) sulfonyl] -4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (0.708 grams, 1.493 moles) ) In anhydrous dichloromethane (15 ml) followed by sequential addition of DMAP (0.820 grams, 6.716 mmol) and POCl ₃ (0.209 g, 2.238 mmol), resulting in the resulting mixture. Was refluxed for 5 hours. The mixture was cooled to 0 ° C. 7,7-dimethoxy-7- [4- (trifluoromethyl) phenyl] -heptylamine (1.43 grams, 4.477 mmol) and DIPEA (0.740 ml, 4.48 mmol) were added sequentially. . The mixture was then heated to reflux temperature for 30 hours. The mixture was brought to room temperature, washed with 5% aqueous NaHCO ₃ solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The obtained crude product was purified by column chromatography (alumina; gradient: heptane / ethyl acetate = 6/1 to ethyl acetate and ethyl acetate / methanol = 95/5 (volume / volume)). -Chloro-N-{[3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-1H-pyrazol-1-yl]-[7- (4-fluorophenyl) -7,7-dimethoxyheptyl Amino] methylene} benzenesulfonamide (0.200 grams, 17% yield) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) 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), NH protons are not visible.

Part B: 4-chloro-N-{[3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-1H-pyrazol-1-yl]-[7- (4-fluoro-phenyl) -7 , 7-dimethoxyheptylamino] methylene} -benzenesulfonamide (0.200 grams, 0.258 mmol) was dissolved in a 1: 1 THF / methanol mixture (30 ml) and 5 ml of 1N hydrochloric acid was added. The resulting mixture was stirred at room temperature for 20 hours. The reaction in the mixture was quenched with 5% aqueous NaHCO ₃ solution. Most of the THF and methanol were removed by evaporation under vacuum. The remaining aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The resulting crude 4-chloro-N-{[3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-1H-pyrazol-1-yl]-[7- (4-fluorophenyl) -7 No further purification of -oxo-heptylamino] methylene} benzenesulfonamide (203 mg) was performed. Some characteristic fragrance ¹ H-NMR signals: (400 MHz, CDCl ₃ ) δ 7.12 (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).

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 grams, 0.278 mmol) was dissolved in absolute ethanol (10 ml) and then sequentially O- (2-aminoethyl) hydroxylamine dihydrochloride ( 61 mg, 1.5 molar equivalents) and pyridine (0.04 ml) were added. The resulting mixture was stirred at reflux temperature for 20 hours. The mixture was brought to room temperature. After removing the solvent under vacuum, the residue was dissolved in dichloromethane and washed sequentially with aqueous KHSO ₄ solution and brine. The organic layer was then dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give N- {1- [7- (2-amino-ethoxyimino) -7- [4- (trifluoro Methyl) phenyl] heptylamino] -1- [3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-1H-pyrazol-1-yl] -methylidene} -4-chloro-benzenesulfonamide (compound 1) (0.231 grams) was obtained as a mixture of E / Z stereoisomers. Melting point: 53-58 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) 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 (brs, 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 WO03040107. It is generated by putting ethyl 2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazole-4-carboxylate (5.80 g, 0.0149 mol) in tetrahydrofuran (40 ml). To this was added a solution of LiOH (0.715 g) in water (40 ml) with magnetic stirring. The resulting mixture was heated to 70 ° C. for 16 hours. The resulting mixture was brought to room temperature and treated with concentrated hydrochloric acid (3.5 ml). Tetrahydrofuran was evaporated under vacuum and the resulting mixture was stirred overnight. The resulting precipitate 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. The acid (4.52 grams, 84% yield) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): 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).

Part B: 2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazole-4-carboxylic acid (1.48 g, 4.123 mmol) sequentially in dichloromethane (30 ml), Analogous to the synthesis of 7-amino-1- (4- (trifluoromethyl) phenyl) heptan-1-one (1.127 g, 4.123 mmol) [intermediate G (see also Teubner, 1993)] Intermediate 72 (toluene-4-sulfonic acid 7-oxo-7- [4- (trifluoromethyl) phenyl] heptyl ester) and 7M NH _{3 in} methanol at room temperature for 72 hours, 7-amino- 1- (4- (trifluoromethyl) phenyl) heptan-1-one was obtained in 62% yield], EDCI, HOAt (0.67 grams, 4.95 Mmol) and DIPEA (1.44 ml, 8.246 mmol) were dissolved, followed by magnetic stirring at room temperature for 70 hours. The reaction mixture was washed sequentially with water, 5% aqueous NaHCO ₃ and water, then dried over Na ₂ SO ₄ , 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 was obtained and was subjected to column chromatography. (Alumina; heptane / ethyl acetate = 4/1 (volume / volume)) followed by another column chromatography (silica gel; heptane / ethyl acetate = 4/1 (volume / volume)) 2- (2-Chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazole-4-carboxylic acid {7- [4- (trifluoromethyl) -phen Le] -7-oxo - heptyl} amide was obtained (1.28 g, 50% yield). ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 0.92 (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 (brd, 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).

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 grams, 1.86 mmol) was dissolved in absolute ethanol (10 ml) and then sequentially O- (2-aminoethyl) hydroxylamine dihydrochloride (0.276 mg, 1.865 mol). Pyridine (0.18 ml) was then added. The resulting mixture was stirred at reflux temperature for 20 hours. The mixture was brought to room temperature. After removing the solvent under vacuum, the residue was dissolved in dichloromethane and washed sequentially with aqueous KHSO ₄ solution and brine. The organic layer was then dried over Na ₂ SO ₄ , filtered, and concentrated under vacuum to give 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) (1.34 grams) as a mixture of E / Z stereoisomers Got as. Melting point: 90-95 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.05 (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 (brs, 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)

In analogy to the procedure described in Part B of the preparation of compound 2, 2- (2-chlorophenyl) -1- (4-chlorophenyl) -5-ethyl-1H-imidazole-4-carboxylic acid (0.880 g, 2 .44 mmol) and intermediate C (5-fluoro-3- [4- (piperazin-1-yl) butyl] -1H-indole), EDCI, HOAt and K ₂ CO ₃ (1.55 molar equivalents) at room temperature. Of [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) (704 mg, 76% yield) (1.28 grams, 50% yield). . Melting point: 91-92 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) 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} methylidene] -benzenesulfone-amide (compound 4)

Analogously to the procedure of Part A of the preparation of compound 1, 3- (4-chlorophenyl) -N-[(4-chlorophenyl) sulfonyl] -4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (0.950 grams, 2.00 mmol) was dissolved in anhydrous dichloromethane and reacted with DMAP and POCl ₃ before intermediate C (5-fluoro-3- [4- (piperazin-1-yl) butyl] -1H-indole) and DIPEA to react with 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} methylidene] -benzenesulfonamide (Compound 4) (660 mg, 45% yield) was obtained. Melting point: 98-102 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ1.56-1.66 (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 ( br s, 1H).

Formulations used in animal studies For oral (po) administration: Add desired amount (0.5-5 mg) of solid compound 1 to glass tube, add some glass beads, then swirl for 2 minutes The solids were crushed by doing. After adding 1 ml of a solution containing 1% methylcellulose and 2% (volume / volume) 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 (0.1 N). The particles remaining in the suspension were further suspended in an ultrasonic bath.

For intraperitoneal (ip) administration: Add the desired amount (0.5-15 mg) of solid compound 1 to a glass tube, add some glass beads, and then swirl for 2 minutes to stir the solid. Crushed. After adding 1 ml of a solution containing 1% methylcellulose and 5% mannitol in water, the compound was suspended by vortexing for 10 minutes. Finally, the pH was adjusted to 7.

Membrane Preparation CHO cells Compound of in vitro affinity present invention was measured affinity indicate to the cannabinoid CB ₁ receptors was transfected stably human cannabinoid CB ₁ receptors for Pharmacological Methods human cannabinoid CB ₁ receptors Can be performed using [ ³ H] CP-55,940 as a radioligand. After incubation of the newly prepared cell membrane preparation with [ ³ H] -ligand, with or without the addition of the compounds of the invention, separation of bound and free ligand is performed by filtration using a glass fiber filter. Radioactivity adhering to the filter is measured by liquid scintillation counting.

In Vitro Affinity for Serotonin Reuptake Site The measurement of the affinity of the compound for the serotonin reuptake site was performed using the receptor binding assay described (Habert, 1985).

Pharmacological Test Results Cannabinoid-CB ₁ receptor affinity data and serotonin reuptake inhibition data obtained according to the protocol shown above are shown in the table below.

The data presented above indicates that the compounds of the present invention show high affinity for both the CB ₁ receptor and the 5-HT reuptake site. While their affinity for the CB ₁ receptor is as high as that exhibited by rimonabant, for example, Compound 1 is a serotonin reuptake inhibitor that at the same time is as potent as fluoxetine. This is due to the structurally closely related potent CB ₁ antagonists disclosed in, for example, WO 03/027076 (see the structure shown above) [which is totally unacceptable as a serotonin reuptake inhibitor. It is in sharp contrast to [active]. Other CB ₁ antagonists tested have no affinity at the site of 5-HT reuptake and 5-HT reuptake inhibitors tested have no affinity for the CB ₁ receptor.

Pharmaceutical Formulations For clinical use, the compound of formula (1) was constructed into a pharmaceutical composition, which is an important and novel aspect of the present invention, This is because they contain the present compounds, and more particularly the specific compounds disclosed herein. The types of pharmaceutical compositions that can be used include, but are not limited to, tablets, chewable tablets, capsules (including microcapsules), solutions, parenteral solutions, ointments (creams and gels). ), Suppositories, suspensions and other types disclosed herein, or they will be apparent to those skilled in the art based on the present specification and general knowledge in the art. It is also possible for the active ingredient to be in the form of inclusion complexes, for example in cyclodextrins, ethers or esters thereof. Such compositions are used for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or other modes of administration. Such pharmaceutical formulations contain at least one compound of formula (1) in admixture with at least one pharmaceutically acceptable adjuvant, diluent and / or carrier. . The total amount of the active ingredient is suitably about 0.1% (w / w) to about 95% (w / w), suitably 0.5% to 50% (w / w) of the formulation, preferably Is in the range of 1% to 25% (weight / weight). In some embodiments, the amount of the active ingredient is greater than or equal to about 95% (w / w) or less than about 0.1% (w / w).

  The compounds according to the invention can be mixed with auxiliary substances such as liquid or solid powdered materials such as pharmaceutically common liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavors, colorants and / or buffers. It may be in a form suitable for administration by a usual method using a drug substance or the like. Commonly used auxiliary substances include magnesium carbonate, titanium dioxide, lactose, saccharose, sorbitol, mannitol and other sugars or sugar alcohols, talc, milk protein, gelatin, starch, amylopectin, cellulose and derivatives thereof, animal and Vegetable oils such as fish liver oil, sunflower, peanut or gum oil, polyethylene glycols and solvents such as sterile water and mono- or polyhydric alcohols such as glycerol as well as disintegrants and lubricants such as magnesium stearate, calcium stearate, Examples include sodium stearyl fumarate and polyethylene glycol wax. The mixture can then be processed into granules or compressed into tablets. Tablets are prepared using the materials shown below.

  The ingredients were mixed and then compressed to give tablets each weighing 230 mg.

  The active ingredient may be individually mixed with other non-active ingredients before mixing to produce a formulation. It is also possible to produce a formulation by mixing the active ingredients with each other and then with the non-active ingredients.

  Soft gelatin capsules can be prepared by including in the capsules a mixture of the active ingredient of the present invention, vegetable oil, fat or other suitable medium for soft gelatin capsules. Hard gelatin capsules may contain granules of the active ingredient. Hard gelatin capsules can also contain a solid powdered material such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin together with the active ingredient.

  Preparation of a dosage unit for rectal administration consists of (i) a suppository form in which the active substance is mixed with a neutral fat base; (ii) the active substance is vegetable oil, paraffin oil or rectal Rectal gelatin capsule form mixed with other medium suitable for gelatin capsules; (iii) ready-made fine enema form; or (iv) reconstitution with a suitable solvent just prior to administration It can be carried out in the form of a dry fine enema formulation.

  Liquid preparations can be prepared in the form of syrups, elixirs, concentrated drops or suspensions, such as solutions or suspensions, in which the active ingredient is placed and the remainder such as sugar or sugar alcohol and ethanol, water , A mixture of glycerol, propylene glycol and polyethylene glycol. If necessary, such liquid preparations can contain coloring agents, flavoring agents, preservatives, saccharin and carboxymethylcellulose or other thickening agents. Liquid formulations can also be prepared in the form of a dry powder that is reconstituted with a suitable solvent prior to use. A solution for parenteral administration can be prepared as a solution containing the preparation of the present invention in a pharmaceutically acceptable solvent. Such solutions can also contain stabilizing materials, preservatives and / or buffering materials. It is also possible to prepare solutions for parenteral administration as dry formulations that are reconstituted with a suitable solvent prior to use.

In accordance with the present invention, and a formulation comprising one or more containers filled with one or more of the materials included in the pharmaceutical composition of the present invention for use in medical treatment We also provide 'made kits'. Along with one or more such containers, materials, such as instructions for use or a form prescribed by a government agency that regulates the manufacture, use or sale of pharmaceuticals (this notice may be human or veterinary) May indicate that it has been approved by a government agency to manufacture, use or sell for administration purposes). Use of the formulations of the present invention in the manufacture of a medicament for treating a disease in which antagonism of CB ₁ receptor and / or inhibition of serotonin reuptake is required or desired, and antagonism of CB ₁ receptor and / or serotonin reuptake Administer at least one compound of formula (1) as is or in the case of a prodrug in a therapeutically effective total amount to a patient suffering from or susceptible to a disorder in which inhibition is required or desired A medical treatment method comprising:

  By way of example and not limitation, several pharmaceutical compositions comprising active compounds suitable for systemic use or topical application are shown. Other compounds of the invention or combinations thereof may be used in place of (and in addition to) the compounds. The concentration of the active ingredient can vary over a wide range as discussed herein. The amount and type of materials that can be included are well known in the art.

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Claims (15)

A compound showing a combination of cannabinoid-CB ₁ antagonism and serotonin reuptake inhibition. CB ₁ pK _i value at both serotonin reuptake bond in addition to the receptor binding> 6.00 an a compound of claim 1. Formula (1):
[Where:
Any of the known cannabinoid-CB ₁ antagonists containing at least two phenyl rings optionally independently substituted with one or two substituents independently selected from halogen, methoxy and trifluoromethyl Wherein the basic structural element is bonded to a hydrogen bond acceptor in the cannabinoid-CB ₁ antagonist and the hydrogen bond acceptor moiety is a carbonyl group, a sulfonyl group, or a heteroaromatic ring Either a nitrogen or oxygen atom incorporated into the structure,
N represents a non-basic nitrogen atom,
T may be replaced by a nitrogen atom in which one carbon atom is optionally substituted by a (C ₁ -C ₃ ) -alkyl or CH ₂ CF ₃ group, or may be replaced by an oxygen atom or a sulfur atom. Optionally substituted and optionally substituted with one or more substituents selected from fluoro, amino, cyano, (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy and trifluoromethyl. Represents a saturated or unsaturated carbon chain of 0-8 atoms,
R represents a hydrogen atom or a (C ₁ -C ₃ ) -alkyl group, or R together with the nitrogen atom to which it is attached and together with part of T (C ₄ -C ₇ )-forming a heterocycloalkyl or heteroaryl group,
B represents a basic structural element of any known serotonin reuptake inhibitor]
Or a tautomer, stereoisomer, N-oxide, isotope-labeled analog, or any of the pharmaceutically acceptable salts, hydrates or solvates thereof. object. A is as follows: 11C-JHU-75528, A-796260, Ajulemic acid, AM251, AM630, AVE-1625, CP-228771, CP-945598, EMD-68843, GRC-10389, LY-2077855, LY-320135, NIDA Of a cannabinoid-CB ₁ antagonist selected from -41020, O-2093, SLV319, SLV326, SR-140098, SR-144385, SR-41716A (Rimonabant), Srinabant, V-24343, WIN-54461 and WIN-56098 Represents the basic structural element and B is: 403U76, A-80426, AD-337, adinazolam, agomelatin, alaprocrate, amineptin, amitriptyline, ARAK-0029 , ARAK-0051, befetipant, befloxaton, BGC-20-1259, bicifazine, BMS-505130, brophalomin, bupropion, buttriptyline, celiclamine, citalopram, CL: -275838, clomipramine, clovoxamine, CX-157, dapoxetine Dexfenfluramine, dibenzepin, diclofensin, doslepine, DOV-21947, DOV-102676, DOV-216303, duloxetine, DU125
530, DuP-631, EN-3215, EpiCept NP-1, ecitalopram, femoxetine, fluoxetine, (S) -fluoxetine, fluvoxamine, gepirone, IDN-5491, imipramine, indalpin, iprindole, L-7301 , Ritoxetine, lofepramine, LU-10134-C, LU-AA21004, ruvazodone, LY-214281, LY-367265, LY-393558, maprotiline, MCI-225, MCL-0042, McN-5562, melitracene, mianserin, milnacipran , Mirtazepine, moclobemide, modafinil, nefazodone, 6-nitroquipazine, nortriptyline, NR-200s, NS-2381, NS-2389, NS-246 3, NS-4194, NS-23459, omiloxetine, OPC-14523, opipramol, Org-6582, paroxetine, pramipexole, PRC-025, propizepine, quetiapine, quinopramine, ramelteon, R-fluoxetine, rizatriptan, rovalzotan, rovalzotan -1439, SB-649915, S-9777, SD-726, Selegiline, SEP-225289, SEP-227162, Sertraline, Sibutramine, (S) -Sibutramine, (R) -Didemethylsibutramine, SLV310, SLV314, SPD-473 , Tramadol, trazodone, udenafil, UK-416244, UP-23716, VANH-36, venlafaxine, vilazodone, VML-670, VN 2222, bolinserin, WF-23, Wf-516, WL-1011, WL-1017, YM-922 and represented by formula (1) representing the basic structural elements of a 5-HT reuptake inhibitor selected from zimeldine The compound according to claim 3 and tautomers, stereoisomers, prodrugs and N-oxides thereof, isotope-labeled compounds represented by the formula (1), and compounds represented by the formula (1) And pharmaceutically acceptable salts, hydrates, solvates, complexes and conjugates of the tautomers, stereoisomers, prodrugs, N-oxides or isotopically labeled analogs thereof. A is a fragment (A ^1a ), (A ^1b ), (A ² ), (A ³ ) (A ⁴ ), (A ⁵ ), (A ⁶ ), (A ⁷ ) or (A ⁸ ):
[here,
X represents a sulfonyl or carbonyl group, the “+” sign represents the point at which the fragment is attached to the moiety N in formula (1), where N represents a non-basic nitrogen atom, R ¹ , R ² and R ³ independently represent one or more hydrogen atoms, trifluoromethyl groups or halogen atoms, and R ⁴ represents hydrogen or halogen atoms or methyl, ethyl, trifluoromethyl, hydroxymethyl , Fluoromethyl, 2,2,2-trifluoroethyl, propyl, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfanyl, ethylsulfinyl, ethylsulfonyl, C _1-3 -dialkyl-aminomethyl, pyrrolidin-1-ylmethyl, Represents a piperidin-1-ylmethyl or morpholin-4-ylmethyl group]
And the NRTB sequence of formula (1) is a fragment (NTRB ¹ ), (NRTB ² ), (NTRB ³ ), (NRTB ⁴ ), (NTRB ⁵ ), (NRTB ⁶ ), (NTRB ⁷ ) ), (NRTB ⁸ ), (NTRB ⁹ ) or (NRTB ¹⁰ ):
[here,
R represents a hydrogen atom or a (C ₁ -C ₃ ) -alkyl group]
The compound of Claim 3 represented by Formula (1) which is one of these. A is a fragment (A ^1a ) or (A ² ):
[here,
X represents a sulfonyl or carbonyl group, + represents the point where the fragment is bonded to the non-basic nitrogen atom N in formula (1), R ¹ , R ² and R ^{3 are} independently Represents hydrogen, trifluoromethyl or halogen, and R ⁴ represents a hydrogen or halogen atom or methyl, ethyl, trifluoromethyl, hydroxymethyl, fluoromethyl, 2,2,2-trifluoroethyl, propyl, methylsulfanyl, methyl Represents a sulfinyl, methylsulfonyl, ethylsulfanyl, ethylsulfinyl, ethylsulfonyl, C _1-3 -dialkyl-aminomethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl or morpholin-4-ylmethyl group, and the other symbols are It has the meaning of claim 5]
The compound of Claim 3 represented by Formula (1) showing one of these. A is a fragment (A ³ ) or (A ⁴ ):
4. A compound according to claim 3, which is represented by formula (1), wherein one of the formulas and the other symbols have the meanings of claim 5. following:
-N- {1- [7- (2-amino-ethoxyimino) -7- [4- (trifluoromethyl) phenyl] heptylamino] -1- [3- (4-chlorophenyl) -4-phenyl-4 , 5-dihydro-1H-pyrazol-1-yl] -methylidene} -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} methylidene] -benzenesulfonamide,
The compound of Claim 3 represented by Formula (1) selected from these.   The compound or tautomer, stereoisomer, N-oxide, isotope-labeled analog or any one of the above-described compounds represented by formula (1) which is an optically active enantiomer Pharmacologically acceptable salt, hydrate or solvate. following:
The compound of Claim 3 represented by Formula (1) selected from these.   A drug comprising the compound according to claim 1 or a pharmacologically acceptable salt, hydrate, solvate, complex or conjugate thereof.   In addition to a pharmaceutically acceptable carrier and / or at least one pharmaceutically acceptable auxiliary substance, at least one compound according to one of claims 1-10 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a salt, hydrate, solvate, complex or conjugate as an active ingredient in a pharmacologically effective amount.   The pharmaceutical composition of claim 12, further comprising at least one additional therapeutic agent. Addiction, alcoholism, Alzheimer's disease, anorexia nervosa, anxiety disorder, appetite disorder, attention deficit hyperactivity disorder, bipolar disorder, bulimia nervosa, cancer, cardiovascular disease, central nervous system disease, brain Ischemia, cerebral hemorrhage, chemotherapy-induced vomiting, cocaine dependence, cognitive impairment, dementia, demyelination related disorders, diabetes, diabetic neuropathy, diarrhea, drug dependence, dystonia, eating disorders, vomiting, epilepsy, femininity Functional disorder, functional bowel disease, gastrointestinal disorder, gastric ulcer, generalized anxiety disorder, glaucoma, headache, Huntington's disease, impulse control disorder, inflammation, irritable bowel syndrome, male sexual dysfunction, major depression disorder, memory disorder, menopause , Migraine, muscle spasm, multiple sclerosis, myalgia, nausea, neuralgia, neurodegenerative disease, neuroinflammatory disease, neuropathic pain, obesity, bullish disorder, osteoarthritis, pain, panic Obstacle, parkin Disease, plaque sclerosis, premature ejaculation, premenstrual syndrome, psychotic disorder, psychosis, rheumatoid arthritis, septic shock, schizophrenia, sexual disorder, sleep disorder, spinal cord injury, stroke, Tourette syndrome, trauma Use of a compound according to any one of claims 1-10 for the manufacture of a pharmaceutical composition for the treatment of congenital encephalopathy, tremor, urinary incontinence and viral encephalitis.   Manufacture pharmaceutical compositions to treat psychosis, anxiety, depression, attention deficit, cognitive impairment, obesity, drug addiction, Parkinson's disease, Alzheimer's disease, pain disorder, neuropathic pain disorder and sexual disorder Use according to claim 14 for.