SA08280759B1 - Compounds of Cannabinoid-CB1 Antagonists and Structural Components of the Serotonin Reuptake Inhibitors Indalpine or Fluvoxamine - Google Patents

Abstract

Abstract This invention relates to compounds characterized by the combination of being cannabinoid-CB1 antagonism agents and inhibitors of serotonin reuptake, pharmaceutical compositions containing these compounds, methods for preparing the said compounds, methods for preparing new intermediates useful in their synthesis, and methods for preparing compositions, as the invention relates Using these compounds and combinations, specifically administering them to patients to produce a therapeutic effect for the treatment of psychosis, anxiety, depression, attention deficits, cognitive disorders, obesity, drug dependence, Parkinson's disease, Alzheimer's disease, pain disorders, and About neuropathic pain, and sexual disorders.

Description

— © Compounds of cannabinoid-CB1 antagonists and structural components of the serotonin reuptake inhibitors indalpine or fluvoxamine Full description HANES RELIES relates This invention is in the fields of pharmaceutical and organic chemistry; It provides compounds that are a combination of cannabinoid-CB1 antagonism, serotonin re-uptake inhibitors, cintermediates, and formulations of ? and knock. © The simple approach of "one goal - one disease" has dominated the pharmaceutical industry for decades. By using this strategy; Many successful drugs have been discovered. However, despite that; There are still many diseases that have not been adequately treated. These discoveries justify resorting to the Aly method, where chemical entities have been developed that simultaneously modify several targets. These drugs may exhibit jie sade properties, increased cclinical efficacy, decreased undesirable drug interactions led to drug-to-drug interactions, or unfavorable pharmacokinetic and pharmacodynamic properties. The latter can lead to unexpected difference between individual patients. In order to combine the different therapeutic mechanisms; To date, combinations of two or more drugs are used in clinical application. Multicomponent drugs are used in which 2 or more pharmaceutically active compounds are combined in one tablet or one capsule in order to improve patient response. There is another way

A dallas pharmacopoeia uses a chemical entity capable of modifying more than one biological target at the same time. Clearly, this 'one-many-targets' approach offers the advantage of reducing the risk of unwanted drug-to-drug interactions compared to drug combinations or multicomponent drugs. There are many associative compounds with multiple © targets; known. aly Most of them were discovered based on known information in the past or by chance: only a few were designed on the basis of thought, research and study. Cannabinoid receptors are part of the ull ans cendo-cannabinoid system that contributes to many diseases. Detailed information about cannabinoid-like receptors; CB, receptor modulators and their pharmacological activities; 0 Topics for recent research: Landsman, 1997; Lichtman, 2002; De Petrocellis, 2004; Di Marzo, 2004; Hertzog, Lange, 2004, 2005; Smith, 2005; Thakur, 2005; Padgett, 2005; Muccioli. Lambert, 2005; Vandevoorde, 2005). Potential therapeutic applications of CB receptor modulators that have been disclosed in the above-mentioned research include; Medication to treat psychosis, anxiety, depression, cattention deficits, memory disorders, cognitive disorders, sppetite disorders, addiction and anorexia cappetence, dependence on drugs, “drug dependence,” neurodegenerative disorders, “dementia,” “dementia,” “ye” dysfunction caused by tension, “cdystonia,” and spasticity muscle spasticity 0115616

and ile; 60(0+), epilepsy, multiple sclerosis (brain injury Ala), stroke, 2:10500:5 disease; Alzheimer's disease, epilepsy, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischaemia, strokes, cerebral apoplexy, bruises, Lal ccraniocerebral trauma 4532 EVER, spinal cord injury, cord injury For schizophrenia, inflammatory disorders, neurological encephalitis, eneuroinflammatory disorders, eplaque sclerosis clad sll, viral encephalitis, cviral encephalitis, and demyelinisation related disorders, as well as for the treatment of 1 pain disorders, including pain disorders. Disorders 1 for pain resulting from neuropathic pain, septic shock 0, glaucoma, diabetes, cancer, vomiting, cemesis, nausea, and gastrointestinal disorders gastrointestinal disorders, stomach ulcers, gastric ulcers, diarrhea, sexual disorders, impulse control disorders (sal), cardiovascular disorders -disorders 1, mood disorders, mood disorders, Anxiety disorders cause severe suffering, enormous suffering, and the introduction of selective serotonin reuptake die inhibitors for more than two decades has been considered an important step in finding safer antidepressants. antidepressants and illustrative examples of selective reuptake inhibitors Serotonin absorption is: fluvoxamine, fluoxetine, paroxetine, sertraline, citalopram, zimeldine, clomipramine, indalpine and indatraline.

Yes

This - despite the remarkable structural diversity, most selective inhibitors of serotonin reuptake inhibitors are based on a mono-amine and contain 3) basic nitrogen (Pacher, 2004) indicating Scientific research, patents, and patent applications indicate the following therapeutic uses for serotonin reuptake inhibitors ©: for the treatment of alcoholism, Alzheimer's disease, canorexia nervosa, anxiety disorder, and hyperactivity disorder. Associated with cognitive deficit, attention deficit, bipolar disorder, cbulimia nervosa, central nervous system disease, emesis resulting from chemotherapy, and addiction. Cocaine addiction, Pes cognitive disorder, resulting from diabetes, drug dependence, eating disorder, female sexual dysfunction, and functional bowel disorder. generalized anxiety disorder, headache, cinflammation, irritable bowel esyndrome 100, male sexual dysfunction 0216, emajor depressive disorder, discontinuation menopause migraine neuralgia neuropathic pain neuropathic pain obesity obesity obsessive compulsive disorder osteoarthritis costeoarthritis and pain 0” and panic and terror disorder 8016 AD “disorder 00 and disease 2101050075 and premature ejaculation (sperm) ejaculation 0160180076 and premenstrual syndrome and psychological disorder “psychosexual disorder” Yi ¢.

A, psychosis 75 AD, rheumatoid arthritis, schizophrenia, sleep disorder, and enuresis -urinary incontinence. compounds that combine antagonism, 0800810010-08 and soley© uptake inhibitors; They may be useful in the treatment of conditions in which either a cannabinoid receptor antagonist CB; or a hie-0 reabsorption antagonist is likely to be effective. Thus, the compounds of the invention can be used to treat caddiction, alcoholism, ars calcoholism (Alzheimer's), canorexia nervosa, anxiety disorder, appetite disorders, and hyperactivity disorder. 0 Accompanying cognitive deficits Cattention deficits, bipolar disorder, cbulimia nervosa, cancer, cardiovascular disorders, central nervous system disease, and local hypoemia cerebral ischaemia in “gall,” strokes, “cerebral apoplexy,” emesis vomiting resulting from “chemotherapy,” cocaine addiction, “cognitive disorder,” and dementia. And disorders related to myelination (cdemyelinisation related disorders), diabetes (diabetes), neuropathy (neuropathy) resulting from diabetes (diarrhoea, JlewYls, diabetes, drug dependence, weakness or disorder) dystonia, eating disorder, vomiting, cemesis, epilepsy, female sexual dysfunction, functional bowel disorder, gastrointestinal disorders, ulcers, aed ) and generalized anxiety disorder

A generalized anxiety disorder, glaucoma, headache, 5p disease, inflammation resulting from impulse control disorders, es stomach syndrome, bowel syndrome 711801, and male sexual dysfunction male sexual dysfunction major depressive disorder© memory disorders menopause migraine spasticity 0101501 emultiple sclerosis myasthenia gravis 02607818:2, nausea 080568, neuralgia, disorders resulting from “neurodegenerative disorders”, disorders resulting from old neuroinflammatory disorders, pain resulting from 0 neuropathic pain, obesity, obsessive disorder Obsessive compulsive disorder, costeoarthritis, pain, panic disorder, Parkinson's disease, plaque sclerosis, premature ejaculation, and premenstrual syndrome Premenstrual syndrome, psychosexual disorder for 2N0105*0: Rom, psychosis, rheumatoid arthritis, septic shock, schizophrenia, and csexual disorders sleep disorder, spinal cord injury and stroke; Pain Tourette's syndrome, traumatic brain injury, ctremor, urinary incontinence, and viral encephalitis Yo. Of particular interest is the use of the compounds of the invention for the treatment of Disorders previously reported to be treatable with cannabinoid CB, antagonists 8h

M - as well as by using dale inhibitors of serotonin reuptake. _ Jie's resistance to these disorders simultaneously via two different OE mechanisms can have synergistic effects. Thus, the compounds of the invention are particularly useful for the treatment of psychosis, anxiety, depression, attention deficits, and cognitive disorders. © Obesity, cobesity, drug dependence, disease? Zhu, Synagogue, Alzheimer's disease, pain disorders ¢ pain disorders, pain disorders resulting from neuropathic neuropathic pain, and sexual disorders. The pharmacophore carrier of most of the 15 receptor antagonists has been a cannabinoid CB; the subject of multiple research: (Lange, 2005; Reggio, 2003) 0 and Scheme No. 1 illustrates this. Asp366- Lys{192 Ar, — Spacer—— H-bond acceptor — Lip Ar, 7 Scheme: 1 Carrier of the pharmacological property of the receptor antagonist (OB) and one of its well-known major interactions with the receptor CB; 1 in the diagram (ed) M and Ar have phenyl groups where an optionally substituted with one or two chalogen atoms, ctrifluoromethyl groups, or .methoxy groups and contains a 'spacer group' contains a heterocyclic group with © atoms such as: 4,5-dihydropyrazole, imidazole, pyrazole, thiazole, thiophene or pyrrole or containing

And the spacer group contains a phenyl group or a heterocyclic group with 6 atoms, such as: WS pyridine, pyrimidines or pyrazine. The spacer group can contain a cazetidine moiety, a 1,3-benzodioxole moiety, or a MK moiety. -0364 Jie alkyl (see below). In addition to this, one of the aromatic groups can fuse with the spacer group; Or © can be attached to the spacer group by means of an additional loop: the so-called steric formation constraint. Many types of microcompositional constraints have been used successfully in this pharmacokinetic model. The H-bond acceptor expresses a “carbonyl group, a sulfonyl group, or a nitrogen atom- that may be included in the structure of a heterocyclic Jie heterocyclic imidazole ring and in a scheme (¢ that crosses” Lip" on the lipophilic Jie lipophilic moiety: piperidin-1-ylamino, pyrrolidinyl-1 -amino, cycloalkylamino, phenylamino, arylamino, Ve benzylamino or atkylamino. Molecular presentation studies indicate that the presence of a hydrogen bond receptor It is crucial: it is believed to interact with the side chain of the Lys-192 amino acid residue of the CB receptor; this stabilizes it in its inactive state.

0 and to illustrate the dels model for the pharmacological property of the receptor antagonist, 08; A number of real-world examples of receptor antagonists (CB) are shown below. The putative hydrogen bond receptor atom (a carbonyl OXygen atom, a sulfonyl OXygen atom, or a 14 atom) is shown. in a heteroaromatic ring in the antagonists of the receptor «CB, in bold line

- 11o - 1 \ cl Br 0 0

CN

Cogs beat Gg, TI

Ny oe NN ot <) Lr NNN

OL N NL cl aH 0 al i cl a H 0

Rimonabant SR 147778 CP-272,871 NIDA-41020 cl 0 0 0, mmm m0 by manual | Yalla la la i 02 a “sound which one is a” and a to a

NESS 0327 0-1248 0 cl cl CF, No nN TL C

AO te Lo mm0 CX © ao Fg H JO HO) al ® cl i)

F - 1 0 cl o ar 1

I) Sat Seo Bm N 2 “Na Thap- 0.0 80 L Cl =N 0 OD X= CH cl cl " 0 8 y 0 8 0 N CLO Li N hy CF , O ) oO - 4 3 We take FTC CRO M cl J 9 cl © Amg A 1 8 MS L Ne CF oui

QL doe ik A Tah 0 4 _ ogre COTY os

SE z ol cl cl 0 cl (Bureau, 2002) and then a model for the carrier of the pharmacological property of reabsorption inhibitors was registered and a diagram showing this:

Ar,

A whoop RI 'N

Lip-SRI~~

R2 a

Scheme?: Schematic of an SRI pharmacological carrier characterized by the presence of a basic nitrogen atom ( ), an extended lipophilic (Ary) aromatic region, and a Call fragment of the lipids (581-M11). The basic amino function (Ry) cannot be replaced and Ry expresses (hydrogen 0) as in pigeon «0070» or it can have a single substitution as in <indatraline s «fluoxetine «sertraline Or a double substitution as in clomipramine 5 “zimeldine 5” citalopram and the basic nitrogen atom can be part of a ring with 6 atoms as in 'paroxetine y indalpine' i.e. 1 expresses 83 hydrogen and Ry It is a part of the carbocyclic framework of the pharmacological carrier.01 It has been shown that a lot of lo «4-(3-indolyl-alkyl)piperidine lide in including indalpine and its derivatives: 4-(3-indolyl-alkyl)piperazine has potent reuptake inhibitory activity (Le Fur, 1977; Malleron, 1993). The selective CB, receptor antagonist (rimonabant) SR141716A has been known for more than A full decade. Many other V0-selective antagonists for the CB receptor were devised after that. There are many reuptake inhibitors known for two decades, too. No compounds characterized by the combination of being CB receptor antagonists have yet been detected; | and inhibitors of serotonin re-uptake. The objective of the present invention was to develop compounds characterized by the combination of being antagonists of the CB receptor and inhibitors of serotonin re-uptake.

General description of the invention: Molecules containing constituent parts of known cannabinoid-CB, antagonists and constituent parts of known reuptake inhibitors have been discovered; Indalpine or fluvoxamine share activity with both molecules from which they are derived: 0 anti-cannabinoid OB effect; inhibition of Sale) uptake. This invention relates to compounds that combine being with an anti-receptor effect 03, and inhibition (sale) ley serotonin reuptake. Specifically, this invention relates to compounds having the formula (1): 0 (1) A N or an isoform “tautomer” or an “N-oxide sl ¢stereoisomer” or “lie isotopically-labelled analogue 0” or a pharmaceutically acceptable salt of any of the above; where A led expresses one of the Wail fragments: SA") Sad

8 R2

QQ CF QO b b fi N / / bE R4

N.N.N

N

0 SS AN 2 + and 08

N 2 3G 1 0 (Ata) (AP) (A?)

Q ("QL QL B N

N

N x ) M S A F © M 27 02 + + No. (A%) (AS)

Qo QE” QL” b N= 0” Yo

J. 0” + Re 9m (A7) (AB); and the symbol "+" expresses the point that binds the carbonyl or the sulfonyl expresses the X group where; non-basic) in formula (1); and nitrogen denotes an N atom at which the fragment has slit 11 (where one or more ' or hydrogen groups then each separately denotes an sR?R atom or ¢ halogen or hydrogen groups denotes R* and ¢ halogen or ¢ trifluoromethyl atoms © methyl, ethyl, trifluoromethyl, hydroxymethyl, fluoromethyl, 2,2,2-trifluoroethyl, propyl, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfanyl, ethylsulfinyl,

_ 3 ¢ —_ ethylsulfonyl, C;. A Led Another embodiment of the invention relates to compounds with formula (1), where

NRTB and the sequence (A% or (AT) or 4%) or (AY) Sah or (a) or (th) or dane or 01723 or (NRTB?) or (NTRB') fragment sequences saa) are (1) with the adjective: (NRTB'% (NTRB?) (NRTBY) or (NRTB®) AR (NTRB®) Sterilized AR 0-0 NH

N

Well Ba Haa N | SSI, Rey

H _ H (NRTB') CFs (NRTB?) (NRTB?)

R0

N 4 a N 2 : CL PN 0 F button for | "p

Cl Cl (NRTB4) 0 c 0 (NRTBS) (NRTBS) o—/ _R

N R

N

CF, : Lr

F L 1 oN 0 H M (NRTB?) (NRTBY) CN

Rr NEA - star!

NT > 7 2No 0 © (NRTB?) {(NRTB")

Vo — — m3 R Cas for a hydrogen atom or an alkyl group C3 .Another embodiment of the invention relates to compounds of formula (1) in which A expresses one of (A?) 4 fragments (A '?) Qe Qe N 1 > HN 1 3 RS 0 + (A12) (A?) X elas © denotes a sulfonyl or carbonyl group and the "+" denotes the point at which Lig has the N Cus fragment (N 3410 fragment representing a non-basic nitrogen atom) of the formula R% Rr!9 ¢ ( 3 ) and ad R3 each separately from a hydrogen atom One or more 6 or groups “trifluoromethyl” or “chalogen” atoms and RY expressing “hydrogen” or “chalogen” or group: methyl, ethyl, trifluoromethyl, hydroxymethyl, fluoromethyl, 2,2,2-trifluoroethyl, propyl, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfanyl, ethylsulfinyl, ethylsulfonyl, Ye

C,s-dialkyl-aminomethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl or morpholin-4-ylmethyl group. The other symbols carry the meanings mentioned above. Another embodiment of the invention relates to compounds of formula (1) Cua in which A stands for the sa) fragments (AY) Sl then) ve rf ca JN Yala 8! Mb a + WEY 0 + pe of the invention is for compounds with formula (1) where it is: AT and form 7 2 / / relates to

Ney 7 Noy New oo

As? "no 0 A Is, ls oN N 1 J Ass: HNN 1 J HN ON TL

J | z z 4 z and compounds of formula (1); As well as medicinally acceptable salts, it combines being effective and inhibiting re-absorption. They are useful in treating cannabinoid-CB; cannabis antagonism andl cAlzheimer's anorexia alcoholism alcoholism caddiction addiction appetite appetite disorders anxiety disorder canorexia nervosa cognitive deficit neuroticism hyperactivity disorder bulimia nervosa bipolar disorder bipolar deficits cardiovascular disorders cancer cerebral ischaemia ccentral nervous system disease central nervous system resulting from chemotherapy emesis (dlls cerebral apoplexy in the brain; strokes “cognitive disorder” and cognitive disorder “cocaine addiction” and cocaine addiction “chemotherapy”

117 - - dementia, demyelinisation related disorders, diabetes, neuropathy caused by diabetes, and diarrhea 0:20:088; dependence on drugs + weakness or disorder of strength” and disorder resulting from eating “eating disorder, vomiting cemesis, epilepsy 116 m 8.7 ©”; female sexual dysfunction, functional bowel disorder, gastrointestinal disorders, and stomach ulcers; generalized anxiety disorder (Glaucoma 20608); Headache, Huntington's disease, inflammation caused by impulse control disorders, ze stomach circulatory bowel syndrome, Ve male sexual dysfunction, and disorder major depressive disorder, memory disorders, cmemory, menopause, migraine, cmuscle spasticity, multiple sclerosis 5, neuralgia, nausea, cnausea, and pain Neuropathy 0860100811166 pain Neuropathic pain disorders Neuropathic pain 6 Obesity Obsessive compulsive disorder Costeoarthritis ail Pain Panic disorder, Parkinson's disease, plaque esclerosis, Aedes premature ejaculation, premenstrual syndrome, psychosexual disorder, and psychosis. 0 “5m”_, rheumatoid arthritis, septic shock, schizophrenia, sexual disorders and sleep disorders

“sleep disorder, spinal cord injury, and stroke; Tourette’s syndrome, traumatic brain injury, dtremor, urinary incontinence, and viral encephalitis. Other embodiments of the invention include; For example, but not limited to: © pharmaceutical formula for treatment; (JE) is a disorder or condition that can be treated by combining the antagonism of cannabinoids (2008510010-05) with serotonin Cus reuptake inhibition. The formulation includes a compound of formula (1); and a carrier carrier A method for treating a disorder or condition that can be treated by combining the antagonistic effect of a cannabinoid-0,08 with inhibition of serotonin reuptake where the method involves giving (AS) a breast mammal in need of such treatment a compound for it FORMULA ) 1; A pharmaceutical formulation to treat; for example “a disorder or condition selected from the combination of disorders listed in this application; a method to treat a disorder or condition selected from the combination of disorders listed in 0 this cll) wherein the method includes administering to a patient in need of such treatment a compound of formula (1); a pharmaceutical composition for the treatment” of a disorder or condition chosen from the group of disorders mentioned in this application; wherein the composition includes a compound of formula 1 ( ¢ and dlls are acceptable fishing online

B8 1 _ A method of treating a disorder or condition selected from the combination of disorders mentioned in this application; Where the method involves administering »+ to a patient in need of Judd This treatment is a compound of formula (1); a method to induce an antagonistic effect on the cannabinoid-CB, antagonism receptor and inhibition of serotonin reuptake 101511108 which involves giving an organism The invention also provides for the use of a compound according to formula (1) in the manufacture of a drug. The invention also relates to combination therapies where a compound of the invention, or a pharmaceutical composition or formula comprising one of the compounds of the invention, is administered simultaneously, sequentially, or As a combined preparation 0 with other therapeutic agent(s) to treat one or more of the conditions foreseen.Jie may administer such other therapeutic agent(s) before, concomitantly with, or after the administration of the compounds of the invention. The invention also provides (Se and diana combinations and dade combinations and methods for the treatment of a disorder or Alla chosen from the set of disorders mentioned in this application; VO where the method includes administering to a patient in need of such treatment a compound It has formula (1). The compounds of the invention combine their antagonistic effect (CB; - cull and l) and inhibition of (sole) serotonin reuptake. The (ant)agonizing/inhibiting effects can be clarified. the compounds of the invention; Easily; For example; Using one or more of the experiments described in this application or known in the art. ARE

The invention, Lad, also provides methods for preparing the compounds of the invention and the intermediates used in those methods. The compounds and intermediates described in this application can be isolated and authenticated, if desired; using any appropriate separation or purification procedure; For example: such as filtration, cextraction, crystallization, ccrystallization, column chromatography, thin-layer chromatography, and thick-layer chromatography; Preparative low liquid, high-pressure, or a combination of these procedures. Specific explanations of appropriate separation and isolation procedures can be obtained from preparations and examples. However; Other equivalent separation or isolation procedures can of course be used. Compounds of the present invention may contain one or more non-Shes and thus may appear as racemates, racemic mixtures, single enantiomers, or mixtures of enantiomers 12816:600(6). 16 : and independent homodimers Additional Bla centers can exist ly depending on the nature of the different Ve substituent groups on the molecule Each such heterocyclic center will independently produce optical isomers and it is planned to include all possible optical isomers and stereoisomers in the form of mixtures that are in the form of partially purified or pure compounds are within the scope of this invention. It is understood that the present invention accommodates all such isomeric forms of these compounds. Formula (1) shows the structure of a class Of compounds without stereochemistry pg 17 00©+: Independent synthesis of these enantiomers can be achieved or carried out

1 - By its separation processes as known in the field by appropriate modification of the methods disclosed in this application. Its absolute stereochemistry can be determined by crystallography by means of x-rays of crystalline products or crystalline intermediates that are derived” when necessary; Using a chemical CRS© containing a delocalization center determined using a known om-centric Ub method. And at (cde) the racemic mixtures of the compounds can be separated so that Je is the independent conformers. Separation can be performed by methods well known in the art; Jie conjugation of a mixture (en) of compounds with a conformationally pure compound in order to form a mixture of isomers; This is then followed by the separation of independent dimers by standard methods + such as fractional crystallization 0 or LAM 70020818. The coupling reaction is mostly the formation of salts using a pure (pure) acid or base morphologically; For example: (-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid, after which the diasteromeric derivatives can be converted into pure isomers. pure enantiomers by cleaving the added chiral building unit cleavage of added chiral residue 0. It is also possible to separate the racemic mixture of the compounds directly using chromatography methods using chiral stationary phases and these methods Well known in the field. Instead; Any enantiomer of a compound can be obtained by stereoselective synthesis using optically pure starting materials or known configuration centrifugal reagents by methods well known in the field.

Also, the trans 5 cis isomers of the compound of formula (1) or a pharmaceutically acceptable salt edie fall within the scope of the invention; this also applies to the tautomers of compounds of formula (1) or a pharmaceutically acceptable salt Some of the competing crystalline forms of compounds can exist in polymorphic forms © and therefore it is intended to be included in the present invention. Moreover, some compounds can form solubles in the presence of water (i.e. hydrate) using organic solvents common organic solvents; it is also intended to include Jie these solvates within the scope of this invention. An isotopically-labeled compound of formula (1) or its pharmaceutically acceptable salts 0 includes compounds Of formula (1) isotopically-labeled in order to be detected and monitored using 087 or SPECT and it also falls within the scope of the invention; the same applies to compounds of formula (1) marked by: PH ] [0] [HC] 0 [30] or other atoms rich in radioactive isotopes; suitable for use in receptor binding studies or metabolism studies Ve. Lad compounds of the invention can also be used as chemical reagents Or as standard compounds when conducting a biochemical study of neurological function, dysfunction and neurological disease. Definitions:

-YY - Within the context of this description; expression indicates:

'Compound with antagonism (800810010-013' and 'antagonist 800810010-05') to compounds with such activity - as measured using clear and well-accepted pharmacological trials; Including those experiences that are described in

© This order - without showing Als reaction to a big one towards another future. In one example; One of the compounds of the present invention is at least 10 times more effective as an anti-cannabinoid agent -

CB; is not a cofactor or antagonist acting on any other receptor. Which vehicles are preferred

It has a selectivity of 100 times the best; Compounds with a selectivity factor of 0001 or

more. My expression indicates 'compound with hie reuptake activity' or reuptake inhibitor

serotonin Ve to compounds with such activity, as measured using clear and well-accepted pharmacological trials, including those described herein, without

They show highly cross-reactivity towards another reabsorption site. In one example; One of the compounds of the present invention is at least 10 times more effective as an inhibitor of serotonin reuptake than

Being an inhibitor of re-uptake of another neurotransmitter. Compounds with a selectivity of 001 are preferred

NO weakness; the best; Compounds with a selectivity factor of 0001 or greater. The expression of a pnd compound between having an antagonism-like effect «ull ,800810010-0©8» and a serotonin re-uptake inhibitory effect indicates compounds that have both effects - as measured using clear and well-accepted trials from Pharmacologically, including those trials that have been described

0 in this order—without showing significant cross-reactivity toward receptors or reintroduction sites

other absorption. In one embodiment, one of the compounds of the present invention is at least times more potent as a CB antagonist and as a reuptake inhibitor than 5©010010; About being an agonist or an antagonist that acts on any “al” receptor or being an inhibitor of the sale site) another absorption 0 and preferably compounds with selectivity of (Cana 001 © and the best » Compounds with a selectivity factor of 0001 or more.The generic expressions used to describe the compounds disclosed in this application have the familiar meanings wherein the term alkyl as used in this application refers to a branched hydrocarbon chain branched or straight saturated saturated .univalent and unless otherwise specified these chains can contain 1 to YA 50 carbon 0 and illustrations Jid alkyl groups These include:

methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, reri-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl. 1 will contain the alkyl group Slower' and the like. and when categorized as 'zero' and on expressions Calkane' to + carbon atoms. The same carbon content applies to the parent expression 5 and the carbon content of the various moieties containing the alkoxy! Jie derivative is denoted by a prefix expressing The least number and the largest number of carbon atoms in the crack; that is, the prefix hydrocarbon x is present and starts from the number “©” to the number “l” including carbon -ren specifies the number of prefix atoms

no. For example JG the alkyl (Cra) stands for: AE

- Yo — methyl, ethyl, n-propyl or isopropyl, and 'alkyl(C,4)' means 'methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl or 2-methyl-n- propyl'. .aryl-alkyl(C,_3)carbonyl or arylcarbony! (B6) Carbonyl polyols refer to “acyl” and the expression hetero- or hetero-aromatic groups refers to “aryl” aromatic groups and includes an expression that includes, for example, bicyclic or bicyclic conjunctiva monocyclic aromatic © : furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, imidazo[2,1-b][1,3]thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5- triazinyl, phenyl, indazolyl, indolyl, indolizinyl, isoindolyl, benzo[b]furanyl, 1,2,3,4-tetrahydro-naphtyl, 1,2,3,4-tetrahydroisoquinolinyl, indanyl, indenyl, benzo[b]thienyl, 2,3-dihydro-1,4-benzodioxin-5-yl, benzimidazolyl, benzothiazolyl, benzo[l,2,5]thia-diazolyl, purinyl, quinolinyl, isoquinolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, I,8- naphthyridinyl, naphthyl, pteridinyl or azulenyl. The expression “non dng chloro, fluoro, bromo or iodo” refers to a “halogen” or “halo” and the expression heteroalkyl aromatic in the “heteroalkyl LS ' hetero homogeneous VO. or 0 or 5 one or more N etc.; until the group that contains a “heteroaromatic” atom that has heteroaromatic alkyl atoms contains “heteroalkyl” groups and includes “the heteroaromatic alkyl”

at any position; It therefore includes alkyl groups associated with 17, ©, or 5. The term “substituted” indicates that the particular group or moiety bearing Yo carries one or more substituent groups. And when any group can carry several groups

#10

replacing; A variety of possible Jain combinations are provided; It is selected groups

replace independently; And there is no need for them to be the same, and the expression “has no substitution” indicates

"unsubstituted" indicates that the given collection does not hold any substitution groups. Referring to

replacement groups” the JSG expression independently indicates that when © is possible to supply more than one replacement group; They may be similar or different from each other

some.

The expressions 'oxy', 'thio' and 'carbo' when used in this application as part of a group

other, respectively, to a coxygen atom, a sulfur atom, and a carbonyl group (p = 0);

acting as a linker between two “scarboxyalkyl” thio alkyl coxy alkyl ¢hydroxyl Jie groups etc.; Ve for example. The term 'amino' as used herein alone denotes; or as part of a group

egal to a nitrogen atom that is either a cterminal or a linker between two other groups.

where the group can be a primary amine, a secondary amine, or

tertiary (two hydrogen atoms are attached to a “nitrogen” atom, one hydrogen atom is attached to an atom of

“nitrogen (there are no hydrogen atoms attached to an enitrogen atom, respectively). The terms 0 denote “interstitial” and “sulfonyl” as used in this application eS from another group, respectively

to the set -80- or SO, -.

For a more succinct description, the terms "composite" or "AS" include anatomical images

tautomers and stereoisomers and 9p21-0<10; And isotopes marked with radioactive isotopes

“isotopically-labelled analogues, salts, hydrates, or solvates that are pharmaceutically acceptable 0 Lad if not expressly stated so.

— “LS is used in this application; de peas' leaving (L) "leaving group" will refer to a charged or uncharged atom or group that can leave during a substitution or displacement reaction and the expression refers to groups that can Easily displaced by Calli de sane Jie inucleophile The sf group “amine amantae” or “alcohol” composes © of the nucleus. These leaving groups are well known in the field. Examples of them include, but are not limited to: N -hydroxysuccinimide, N-hydroxybenzotriazole, halides (Br, CI, I), triflates, mesylates, tosylates and the like. amines may or may not increase N-oxide metabolites and the extent to which oxidation occurs at the N site varies from very small amounts to near transmutation.Noxides can be more active than tertiary amines The analogues are E or they may be less active.While the N-oxides can easily be reduced to their corresponding tertiary amines by chemical means 0, this occurs in the human body to varying degrees. Some N-oxides undergo an almost quantitative reductive transformation to give the corresponding tertiary amines. In other cases; Transformation is only a small interaction; or until it is completely absent (Bickel 1969), and any compound metabolized in vivo is considered to give the biologically active factor (i.e., the compound of formula (1)) a primary drug that enters the scope of its scope and content Application A Yo prodrug is a therapeutic debe; it is ineffective on its own but converts to one or more products

- 078 the Jal thus; In the therapeutics of the invention active metabolites the expressions 'give' and 'use in the treatment of..' will include the treatment of the various disorders described with the use of a compound that is specifically disclosed; or with a compound that is not disclosed. The drugs 510:67©:51:016_of the bioreversal derivatives of ALE are derivatives of the prodrugs© used to overcome Some of the barriers to using the parent drug molecule 0008 molecules include, but are not limited to parent drug molecule presystemic solubility, pre-systemic metabolism, stability, permeability, and solubility limitations. desired targeting emetabolism and drugs. Formula (1) is included in the scope of the invention. .secondary or secondary, in which there is an additional group that can be easily removed after (1) to give compounds of formula 05 or “Mannich base or Mannich enamine giving way; for example but not limited to” carbamate or «(acyloxymethylene carbamate) - 0 or <hydroxyl-methylene derivative <hydroxyl-methylene derivative .enaminone or camide or !6916 or different of the same solid forms refers to the crystal form the term 'crystalline', the images csolvates and the solutes cpolymorphs of the compound; For example; Polymorphic Pictures Ye

Amorphous forms and 'polymorphic forms' Ble report crystal structures 5 in which a compound can crystallize with different bonding arrangements between the crystals; all of which have the same compound composition. The ble shapes are a phenomenon Jy that results from polycrystalline conditions Jie crystallization temperature, supersaturation © presence of impurities 5, solvent polarity, cooling rate Different polymorphs usually have different ray diffraction patterns NMR spectra different solid state 0; different infrared spectra or raman spectra; emelting points, “density” and hardness: 5; and “crystal shape” different optical, coptical and electrical properties, chemical stability, solubility 0. The crecrystallization solvent, crystallization rate 0m, storage temperature + and other factors can cause a single crystal form to prevail. and Solutes (oa solvates) are generally a crystalline form containing either stoichiometric amounts or dissimilar amounts of a solvent. Je During the crystallization process, some compounds have the ability to sequester a fixed molar ratio of solvent molecules in Ye crystalline solid state, and this leads to the formation of a solute p901781. When the solubility is cele, a hydrate can be formed and the compound of formula (1) and its pharmaceutically acceptable salts may exist in the form of a hydrate or a soluble; such a hydrate or a solubility also falls within the scope of the present invention. Examples include dihydrochloride dihydrate s chydrate 1/4, etc. Non-AA forms are amorphous materials of non-long range order; generally, they do not give a streaked pattern of X-ray diffraction. pattern in the powder.The crystalline images have been described as dele by Byrn (1995) and Martin (1995).

the

In order to provide a more concise description, some of the quantitative expressions presented in this application are not suitable

To express it with the expression "about". It must be understood when the expression 'about' is used explicitly

Or not, any quantity that is given in this request is intended to refer to an actual value given

© also the approximate indication of this given value which can be reasonably deduced by a person of ordinary skill in the art; Le includes approximations due to experimental conditions

and/or standard for this given value.

Throughout the full description and special protections oder the document, the word “jad” and its synonyms are included

“Jedd Jie and includes” are not intended to exclude additional materials, components, or figures

steps; other.

0 While it may be possible to give compounds of formula (1) in the form of a raw chemical compound, it is preferable to present them in the form of a 'pharmaceutical composition'. at least one compound of formula (1); or at least one pharmaceutically acceptable salt or solvate thereof; or a mixture of any of the foregoing; together with one or more pharmaceutically acceptable carriers” and optionally with one or more of the components therapeutic

Other Ve. The sid must be such that it is compatible with the other components of the formulation and does not harm those who receive it. The expression 'combination' as used herein includes a product that contains specified components in predetermined amounts or in predetermined proportions as well as any A product produced, directly or indirectly, from the combination of specified ingredients in specified quantities.

effective ye; and an optional carrier containing ingredients

- S as well as any product produced; directly or indirectly; from merging; or complex configuration; or combines any two or more components; or from dissociation of one or more components; or from other types of interactions between one or more components. In general; Pharmaceutical compositions are prepared by uniformly and precisely combining the active ingredient with a liquid carrier or sale© solid carrier ground into finely divided or lag particles and thereafter; when necessary; Shaping the product to take the desired shape of the formula. The pharmaceutical composition includes a sufficient quantity of the active compound of the subject of the invention in order to produce the desired effect on the development or condition of diseases. According to died, the pharmaceutical compositions of the present invention include any composition made by mixing a compound of the present invention and a pharmaceutically acceptable carrier. 0 “Pharmacologically acceptable” means that the carrier or diluent of the excipient must be compatible with the other components of the formulation and not harm the recipient. ail The affinity of the compounds of the invention is determined to bind to CB receptors) and to 5 - 7 reuptake sites as described below. From the measured binding affinity for a given compound of formula (1), one can estimate the theoretically lowest effective dose. at a concentration of the compound VO equal to twice the measured value of Kj; Approximately 700 receptors,©, will be bound by the compound. By converting these concentrations to mg of the compound per kg of patient, one can obtain the lowest theoretical effective dose; And the emphasis on the availability of ideal vitality. pharmacokinetic properties can lead to; pharmacodynamic properties; Other considerations include changing the dose already administered, either by increasing or decreasing it. The typical daily dose of active ingredients varies over a wide range70 and will depend on a variety of factors Jie the related symptoms; route of administration; and immersion, weight and gender (male/female) cpanel and may be determined by a medical professional. In general; The dose, Yi.

s

Total given daily to a patient in single or independent doses; it may be in quantities ranging; For example, from 1010 to 100 mg/kg body weight per day; The usual is more than 0.00 to 0001 mg per day”; of the total active ingredients. Jie will administer these doses to a patient in need of treatment one to three times a day; or as required to reach © to the required activity; for periods of at least two months; And more typically for six

months at least; or continuously. The term “therapeutically effective amount” as used herein refers to an amount of a therapeutic agent for the treatment of a condition that can be treated by administration of a formulation of the invention. That amount is sufficient to produce a therapeutic or protective response in a tissue organ ctissue system Ve, animal” or human. Allll can include, for example, the treatment of the conditions mentioned in this application. The exact effective amount given to an organism will depend on the organism’s size and state of health, and the nature and extent of the condition being treated; and on the instructions advised by the attending physician (investigator), veterinarian +, human physician1, or any clinician (LAT) and the treatments or combination of therapies chosen for administration. Precisely effective The term “pharmaceutically acceptable salt” refers to those salts which, within the range of sound medical judgment, are suitable for use in and contact with tissues of humans and lower animals without causing unnecessary toxicity dds Irritation, allergic response, and the like eel, and balance the benefit / risk ratio in a reasonable degree. Pharmacologically acceptable salts are well known in the art. and may be prepared in situ when the compounds of the invention are finally isolated and purified; or separately when they are reacted with acceptable non-toxic acids and bases

Sars _ pharmacologically bases include inorganic or organic corganic bases and inorganic or organic acids (1977 (Berge), and the “free base” form can be generated by contacting a salt with a base or acid”; And isolate the parent compound in the traditional way.The parent form of the compound differs from the different forms of the salt in some specific physical properties: a © solubility in polar solvents, but in one way or another the salts are equivalent to the parent form parent form of the compound for the purposes of the present invention. The term “died complex” refers to a complex of the compound of the invention; Jie formula (1); wherein a complex thereof is formed with a metal ion ametal jon in which the chelation linkage takes place chelated or isolate one metal atom on ANY and the complexes are prepared by methods well known in the field (1964) (Dwyer, 0) and the expression “ede! as used in this application refers to any treatment of a mammalian organism; For example, (Jl) a disease or condition affecting man” and includes: (1) inhibition of the disease or condition, i.e. stopping its progression, (7) mitigation of the disease or condition, i.e. making the condition recede; or (©) stop the symptoms of the disease. The term ‘inhibit’ includes its generally accepted meaning which includes eliminating; preventing; restricting; mitigating; mitigating; slowing; stopping or reversing the progress or step of an outcome. In this case; The present method includes curative and/or prophylactic medical administration, as needed.As used herein, the term “medical treatment” is intended to include preventive, diagnostic, and therapeutic procedures performed in vivo or ex vivo on humans or mammals The term OWE mammals includes “mammals” on animals of economic importance “Jie” animals of the bovine family, “ovine” sheep and “porcine” pigs, especially those that produce meat, as well as domestic animals and animals used in sports; animals in zoos; and humans; where

Creamy people prefer. The subject (AST) as used herein denotes an animal that prefers a mammal; most preferably a human subject to treatment, observation, or experiments. Abbreviations tert.-butoxycarbonyl BOC benzotriazol-I-yl-oxytris-phosphonium hexafluorophosphate BOP 8 cannabinoid receptor 1 - subtype CB, CB; subtype Y — cannabinoid receptor Chinese hamster ovary (cells) CHO 2-chloro -1,3-dimethylimidazolinium hexafluorophosphate CIP dicyclohexylcarbodiimide DCC 00 diisopropylethylamine DIPEA 4-dimethylaminopyridin DMAP dimethylsulfoxide DMSO 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDCI

O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate HBTU 10 N-hydroxy-7-azabenzotriazole HOAt

dos me milligram (milligrams) min minute(s) PET tomography emission tomography positron hexafluorophosphate 7-azabenzotriazol-1-yloxytris(pyrrolidino)-phosphonium PyAOP benzotriazol -1-yloxytris(pyrrolidino)-phosphonium hexafluorophosphate PyBOP©Rf chromatography retention factor layered (488) SPECT emission tomography single photon SRI(S) (selective) serotonin reuptake inhibitor O-(Benzotriazol-1-y1)-N,N,N',N'-tetramethyluronium tetrafluoroborate TBTU 0 tetrahydrofuran THF Description Detailed Example No. 1: analytical methods Nuclear magnetic resonance spectra (NMR) and Bc (APT; NMR Ve) were determined in the indicated solvent using 400 :'H) Bruker ARX £0 MHz©'': 001 MHz) at GK Tee unless otherwise indicated. Spectra were determined in chloroform or cdeuterated chloromethane obtained from

(8) chemical shifts and chemical shifts were given. 80106:086 isotope laboratories ltd

in ppm in situ of (°F) tetramethylsilane (‘H, °C) or (‘H, °C) or.

J coupling constants in hertz. The peak shapes are indicated in the NMR spectra

In the symbols “and” (quad:908:16)” and “dq” (double quartet “t” (triplet © and AEN) “dt” double triplet and "l" (doublet) and "dd" (second doublet)

doublet, 's' (single), 'bs' (broad singlet), 0' (multiple)

-(multiple

Flash chromatography refers to the technique using a sequential filter

Indicated 5 silica gel (either Woh tb to 0 mm flakes Te Merck silica gel sl 0 to 17 mm qb or 1) specifically stated; aluminumoxide fluka': alumina

chromatography pH = 5.0 sqm - 18 mm.

Merck silica gel dishes: thin layer chromatography and thin layer chromatography

,. cm Ye 1) Kieselgel 60 yot

And the melting points P16100: It was recorded on a melting point measuring device Apparatus 05 of the type 3545 - Biichi

All reactions involving moisture sensitive compounds or

Sensitive conditions in a less than -nitrogen atmosphere

The reactions were monitored using thin layer chromatography (TLC) on wafers

‎sale using (Merck precoated silica gel 60 F254) silica coated with plastic conditions

The indicated sequential filter. The spots were seen by ultraviolet (UV (Yo£) light (nm) or D1). The ¢ (calciumhydride 5 phosphorous pentoxide) dichloromethane (benzophenone ketyl [sodium) tetrahydrofuran and light petroleum (A°°) were distilled immediately prior to their use. All other available chemicals were used on Commercial level without any additional purification Example No. ?: General aspects of the synthesis “general aspects of syntheses” The synthesis of the basic structural elements of a known “cannabinoid -0©8 antagonist Ye” is described in patent applications and/or Scientific literature, for example (JE), the following basic structural elements of the cannabinoid “dll” have been documented in previous references as follows: (WO01070700, Lange, 20047, (A'®) (W003026648), (A ?) (WO03027076, (vaccine) W003040107, WO03063781, Lange, 20055: Dyck (2004), (A) (EP0576357, EP1150961, Lan, 1999; Seltzman, 1995; Dutta, 1994 and Katoch-Rouse, 20 03 ), (AY (W003007887, Plummer, 2005), (A') (W00307069), (A®) (WO03078413, Lange, (A") (W02004026301, Lange, 2005"; Dyck, 2004) 5 (A®) (WO2004013120) 0 , 2005°

In general; The synthesis of compounds of formula 1 in which +[ expresses a hydrogen atom can be carried out by the reaction of a compound of formula m-a; Where L expresses a leaving group 6 with a compound of the general formula 13 - HRN 6 It will become clear to those skilled in the field that the amino group present in HRN - TB must be nucleophilic enough for © to replace the leaving group of ALA such a reaction. In the case where the 1, Jia lls hydroxy group is part of the carboxylic acid group, activation or coupling agents can be added in order to enhance the reaction rate. (Bodanszky, 1994; Akaji, 1994; Albericio, 1997; Montalbetti, 2005). Synthesis of compounds having the general formula (1); where A is the structural element (AT) STAT) 0 and where GR 82 and RP each separately express one or more of the chydrogen atoms trifluoromethyl groups or chalogen atoms shown in the reaction scheme No.: 3B7 2 QO" Q 1 HRN-T-B ; ken: N aa DMAP 1 8" m NL NT and 0 NT A 8 8 9 0" Tr R3 haq N NF R3 oy 0 = (Ata1) (A1a2) ( 1 ) R? 81 R! R2 R! R? $) C3 HRN-T-B : & bin PO 3) rm DMAP -— N N 1 1 1 A °N N 9 T NTN Hyrhaa s _S. 0 rn 0° a ) oS IN) =k (A? 2 0 } raftem Vol chart)

Os

A compound of formula (A) can react with (A000) in the presence of 0//0 in an inert organic solvent

(AT?) for a corresponding derivative of the formula dichloromethane Jie inert organic solvent

This compound of formula (A) can react with a compound of general formula HRN- TB

From this interaction it is possible to obtain a compound of formula (1), where it bears the meaning, as previously mentioned, © above for (9 lm); and (By “Tse Nig eR) carry the meanings previously mentioned above.

A compound of formula (A) reacts with wa000 in the presence of DMAP in an inert organic ude Jie

dichloromethane to obtain a chloride derivative that has the formula (d#m) and where it can react

This compound of formula ae (A') is an ad compound of formula TB -l182. (Kars from

This reaction yields a compound of formula (1); where A carries the aforementioned meaning with respect to 0 (“M”) and Bs “Tse NR” carries the aforementioned meanings.

Synthesis of compounds of formula (1), where A is the element of structure

,. 4 is illustrated in the interaction diagram No. (A?)

— and 3 lm 0 n" 8- N HRN-T 1 7 N ; Vg N__~ RY NA (AlMe,) OE 0” 8 “0 R (AZ) TAMM wherein A is derived from (1) basic hydrolysis OH-NO R? 8 R? R? 7 mn 0 "5 © mm N 58 NA R / coupling reagent 2 m li 'N-TB' 0 OH R -0 (A%2) (1) wherein A is derived from A? SOC, or oxalyl chloride for R! R? R2 (> .1g HRN-TB N >( rN = 1 4g L/mg No N-TB 0”Cl R 07 ¢ diagram in reaction diagram 4a and RE express Each separately from one or more of the <hydrogen atoms, or trifluoromethyl groups, or chalogen atoms, and expresses an atom: or halogen atom or methyl, ethyl, trifluoromethyl, hydroxymethyl, fluoromethyl, 8610 of the 2,2,2-trifluoroethyl, propyl, methylsulfanyl, methyl-su Ifinyl, methylsulfonyl, Ye.

1 — ctylsulfanyl, ethylsulfinyl, ethylsulfonyl, C,s-dialkyl-aminomethyl, pyrrolidin-1- ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl. The other symbols have the same meanings as above. An ester of formula (A?) can react with a compound of general formula HRN- TB to yield © compound /-38-1 of formula (1); where the m-part of the substructure (() is derived A? This reaction can be catalyzed by AlMe; trimethylaluminum (Levin, 1982) and alternatively a compound of formula (A?) can be hydrolyzed to obtain the corresponding carboxylic acid of formula (22m). A compound of formula (827) can react with a compound of formula HRN- TB to obtain a compound of formula (1) where part A is derived from substructure WA? substructure 0 and it is preferable that this interaction continue through activation methods activating and coupling Jie Jie coupling an active ester formation” or in the presence of what is called a coupling reagent eg CIP “BOP (PyBOP (HOAt” TBTU “HBTU” DCC 2) -chloro-1,3-dimethyl-imidazolinium chloride and the like, as evidenced by a compound with the formula (A*?) that can be converted in the presence of a chlorinating agent such as thionyl chloride 05 or coxalyl chloride to the corresponding acid chloride of formula (A) and a compound of formula (829) can react with a compound of formula HRN- TB to yield a compound of formula (1); whereby part A is derived of the oA sub-structure and a DIPEA Jie base may be added to the reaction mixture in order to scavenge the hydrochloric (mes) released or more 18 HRN- can be used for this purpose.

- 9 A and by mass » substructures of the general form (A) f(A") (A?) (NA) e (AT) or (A%) as shown above; can be converted to compounds of formula (1); where part A is derived from the substructures (A) (A) (3e)” A) (47); or (A) respectively. The choice of specific synthesis procedures depends on factors known to those skilled in the art, such as the compatibility of functional groups with the reagents used ¢ and the possibility of using protective groups, catalysts, activating reagents and conjugations Sel present in the ultimate structural features and coupling compound to be prepared. Pharmacologically acceptable salts may be obtained using standard procedures well known in the art; for example, by preparing a compound of the present invention using a suitable acid.” Jie an organic acid or aes inorganic .inorganic Example No. ?: Synthesis of intermediates Syntheses of intermediates Intermediate compound A: 4-chloro-1-(5-fluoro-1H -indol-3-yl)-butan-1-one 0 H © 5 Intermediate A

N

0 to a magnetically stirred mixture is (Y0) AICI; g; dichloromethane 8 (Jse 4) slay was added (YY) 4-chloro-butyryl chloride filling 4 mol) at zero. The resulting mixture was stirred for Te min and slowly added:

o) 5-fluoro-1H-indole * c.1105 mol). After stirring for an additional 0 minutes, the orange mixture formed was poured onto (Je 0 Sse hydrochloric mes) and ice (Je Yoo) to obtain a pink precipitate. The precipitate was collected by filtration to obtain: d- chloro-1-(5-fluoro-1H-indol-3-yl)-butan-1-one has a pink color (cpa YA) 8 7 product). 2H), 3.02 (t, J = 7, 2H), 3.70 (t, J ,7 = L (quintet, 2.09 AH 1111-1141 (400 MHz, DMSO-dg) 2H), 7.07 (dt, 1 ~ 9 and 2, 1H), 7.49 (dd, J ~ 9 and 4, 1H), 7.85 (dd, J ~ 9 and 2, ,7 - 1H), 8.41 (d, J ~ 3 , 1H), 12.21 (brs, 1H). Intermediate compound B: 4-[4-(5-fluoro-1H-indol-3-yl)-4-oxobutyl]-piperazine-1-carboxylic acid tert-butyl ester x ON 0 intermediate 8 0 pulp “9 F od N H 3 0 to a magnetically stirred solution of: (VAY) 4-chloro-1 -(5-fluoro-1H-indol-3-yl)-butan-1-one 0.71 mmol g) in (Je 001(acetonitrile) 0177 (0177 piperazine g; 77 mmol) and a small amount were added of potassium iodide (+.gm) and the resulting mixture was heated at 80°C for 48 hours. al) The Yo solid material formed by filtration was filtered and the rest was concentrated in vacuo to obtain YY g from the yield of yield pla 00008. This Bye ore was further purified by column chromatography.

_ ¢ $ _ ( methanol J} e/e/%. = aqueous ammonia'© / methanol/ ethylacetate (inclusion: oe g YY. for a 100 g solvation of dy. 1-(S) -fluoro-1H-indol-3-yl)-4-(piperazin-1-yl)-butan-1-one : mol) of this ore (0 TAS) (Je Osa)dichloromethane 1-(5-fluoro- 1H-indol-3-yl)-4-(piperazin-1-yl)-butan-1-one 8 mol). The resulting mixture was stirred for; hours at 011117 g; (Y0.0F) BocyO and water added. SheNaHCO was dried; 7 © Mixture proceeded using Jue at room temperature. The organic matter was obtained using 50 d, filtered and concentrated in an incubator medium. Then, dichloro-dichloro was purified to 1/14 = dichloro-methane/methanol (graded: chromatography by column: (vol/vol)) to obtain 0/0 = methane/methanol 0 4 [4-(5-fluoro-1H-indol-3-yl)-4-oxobutyl]-piperazine- 1-carboxylic acid tert-butyl ester yield. 7 YY g YAO) "H-NMR (400) MHz, DMSO-ds) 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, 1117 7.85 (dd, J ~ 9 and 3, 1H), 8.38 (s, 1H), 12.01 (brs, 1H).5-fluoro-3-[4-(piperazin-1-yl)butyl]-1H-indole intermediate compound C:

— $0 — _H b le’ intermediate C

N

into a solution that was magnetically stirred from: 4-[4-(5-fluoro-1H-indol-3-yl)-4-oxobutyl]-piperazine- 1 -carboxylic acid tert-butyl ester (T.A0C) g 5.868 (Use (lo) in edichloromethane hydrochloric acid was added (dissolved in: dioxane ¢ 4 .4 mL 6 solution ¢ 1 q . A 6 Ysa mmol (HCI) and the resulting mixture reacted at room temperature for hours, and the reaction mixture was well concentrated in an incubator medium to obtain: 1.0 g) 1-(5-fluoro-1H-indol-3-yl)-4-(piperazin- 1-yl)butan-1-one dihydrochloride Some of the distinctive 'H- NMR' signals are: 1-(3-fluoro-1H-indol-3-yl)-4-(piperazin-1-yl)butan- 1-one dihydrochloride (400 MHz, DMSO-ds) 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 ) J ~ 3, 1H), 12.21 (brs, 1H). The obtained 1-(5-fluoro-1H-indol-3-yl)-4-(piperazin-1-yl)butan-1-one dihydrochloride was dissolved and cooled to 0 °C. A solution of (Je©1 (tetrahydrofuran g) in T.V:) was slowly added to 0 and thereafter (Molar LIAIH” about #7 mmol 1 ml; 1+) tetrahydrofuran in LiAIH, from F

The mixture was heated at 80 °C for 70 hours. The excess amount of 1m/a was analyzed with water and after 5-fluoro-3-[4-(piperazin-1-yl)butyl]-1H-indole (9 7.7 g 4 yield). H-NMR (400 MHz, DMSO-d) 6 1.40-1.50 (m, 2H), 1.61 (quintet, J = 7, 2H), 2.12-2.35 (m, 9H), 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 compound D: 7-(tetrahydropyran-2-yloxy)-1-[4-(trifluoromethyl)phenyl]heptan-1-one CF, Na Intermediate 0 0 1 to 0 0 89% an 0101 (magnesium mol) was added to anhydrous THF (© mL) and at dap the reflux heat sequentially added “(Ja 1) 1, 2-dibromoethane and a small crystal of iodine and EOF can 0p) 2-(6-chlorohexyloxy)tetrahydro-2-pyran +0 mol; dissolved in 4 mL of THF The resulting mixture was heated at the reflux temperature for 0 min. 1. (4-Trifluoromethylbenzonitrile) was slowly added in the amount of 0.0 411 mol: dissolved in A ml (toluene). The mixture was heated for Te an additional min. The mixture was allowed to come to day room temperature and quenched with acetic acid (ml). The organic ball was separated by an organic layer separated and successively washed with NaHCO; 7 © «clear watery; water (twice) and brine. The organic matter was dried with NapSOy, filtered, and concentrated in vacuo.

After that, it was documented by heptane / ethylacetate ( chromatography ses 50/01 = (volume / volume)) to obtain: Am-1 mm denominator [p] for Sa’tam (a-ta’a 0111101017)-4]-1- 120-2L100L0L:61)-7 ..pure (0.57) g (AVE in oil form. 1/1 = heptane / ethylacetate) 0.176 = Ry (vol/vol). ( m, 14H), 3.00 (t, J = 7, 2H), 3.36-3.43 (m, 1H), 1.39-1.88 6 (bl000 -NMR (400 MHz, (m, 1H), 3.71-3.77 (m, 1H), 3.83-3.90 (m, 1H), 4.56-4.58 (m, 1H), 7.73 (d, J ~ 3.47-3.52 2H), 8.06 (d, J ~ 8, 2H). 8, intermediate compound E: toluene-4-sulfonic acid 7-oxo-7-[4-(trifluoromethyl)phenyl]heptyl ester F F 0 F intermediate E 1 0- = 0 ye 0 to a solution that was magnetically stirred from: 1( 7-(tetrahydropyran-2-yloxy)-1-[4-(trifluoromethyl) phenyl]heptan-1-one gm?; mol) in methanol (© ml) para-toluenesulfonic acid hydrate was added 4.1 A (0.077 mol vol). The resulting acidic mixture (pH) about 7 T (pH paper yo reacted at room temperature for 10 hours. NaOH (1p) was added until the solution neutralized pH) about qt (pH paper) The resulting mixture was concentrated in vacuo. NaOH (1p;50 (Je) was added and the mixture was extracted with dichloromethane (¥ times). The combined organic layers were 0m

M - combined organic layers were washed sequentially with ele and saline at 5:00. The organic matter was dried using NazSO4, filtered, and concentrated in fe medium to obtain - (:03?7-0 1-[4-(trifluoromethyl)phenylheptan-1-one crude 0.A0) g » 59 7 product) in the form of a white solid. This obtained solid was treated with pyridine (¥4.1 © ml) and a solution of 1 aa/.the Y) tosyl chloride 0087 mol) in Ad (pyridine ml) at 0 °C was added. The mixture was left to reach room temperature and the reaction took an hour. The mixture was cooled at Nem C and quenched with additional water. It was extracted using diethyl ether (© times); This was followed by drying using NapSOp, filtration and concentration in an incubator medium to obtain zl. Cus crude product was purified using column chromatography ) 1/1 = heptane [dichloromethane 0 (vol/v)) to obtain tester 7-ox0-7-[4-(trifluoromethyl)phenyl]heptyl ester pure ) 1.1 g; b output). H-NMR (400 MHz, CDCl3) § 1.35-1.38 (m, 4H), 1.57-1.73 (m, 4H), 2.44 (s, 3H), 2.97 (tJ =17, 2H), 4.03 ( t, J = 7, 2H), 7.35 (d, T ~ 8, 2H), 7.73 (d, J ~ 8, 2H), 7.79 (4 J ~ 8, 2H), 8.04 (d, J ~ 8 , 2H). 9 0 to a solution previously stirred magnetically from: a

1 YY) toluene-4-sulfonic acid 7-oxo-7-[4-(trifluoromethyl) phenyllheptyl ester g; 654 mM (dse in (Jo YO) methanol) to sequentially added a catalytic amount of 1.04 wax 4 V) para-toluenesulfonic acid (dee) and an additional amount of V1)trimethylorthoformate mL VEY is 0 mmol). The resulting mixture was heated at reflux temperature ©01 sad hr. After the reaction mixture was left to reach room temperature; Sequentially, saturated aqueous NaHCO and dichloromethane were added to the organic layer, which was isolated using saturated aqueous NaHCO. foie To get ore: Jus 7,7-dimethoxy-7-[4-(trifluoromethyl)phenyl]hepty! Ve ester was purified using column 0 /1 = heptane / ethylacetate «chromatography alumina (vol/v)) to yield: pure 7,7-dimethoxy-7-[4-(trifluoromethyl)phenyl]heptyl ester (aa V.AY) 08 7 output). (m, 2H), 1.06-1.26 (m, 4H), 1.51-1.57 (m, 0.84-0.93 E" H-NMR (400 MHz, CDCls) 2H), 1.80-1.86 (m, 2H ), 2.44 (s, 3H), 3.13 (s, 6H), 3.94 (1, J = 7, 2H), 7.32 (d.

J ~ 8, 2H), J ~ 8, 2H), 7.60 (d, 1 ~ 8, 2H), 7.75 (d, J ~ 8, 2H). -dimethoxy-7-[4-(trifluoromethyl)phenyl]heptylamine F F F Intermediate G H,N 0 0 1

Arg. VAY ) toluene-4-sulfonic acid 7,7-dimethoxy-7-[4-(trifluoromethyl)phenyllheptyl ester g FAYE mmol) was dissolved in a solution previously magnetically stirred from 1 1 M (methanol NH; 7 mL) and stirred at room temperature for VY hours. After removing the solvent in the medium of je the remainder was dissolved a few times in dichloromethane and washed with NaHCO; (Sle saturated aqueous) and then the organic matter was purified and dried with Na-B50; filtered and concentrated In crude media: 0.47 ( 7,7-dimethoxy-7-[4-(trifluoromethyl)phenyl]heptylamine g) which has not been further purified. MHz, CDCl3) & 0.88-0.95 (m , 2H), 1.12-1.16 (m, 4H), 1.33-1.38 (m, 2H), 400( liters (m, 2H), 2.59-2.65 (m, 2H), 3.10-3.26 (m, 8H, including -OMe singlet at 1.83-1.88 (d, J ~ 8, 2H), 7.60 (d, J ~ 8, 2H). 3.14, 7.56 Example 4: Syntheses of specific compounds The specific compounds whose synthesis is described below are intended to provide a further explanation of the invention in more _0_ detail and therefore are not intended in any way to limit the scope of the invention. Further embodiments of the invention will become clear to those skilled in the art after perusal of the full description and of the application practicability of the invention disclosed in this application.It is therefore considered that the complete description and examples are for illustrative purposes only.

oy - — N-{1-[7-(2-am ino-ethoxyimino)-7-{4-(trifluoromethyl)phenyl] heptylamino]-1-[3-(4-chlorophenyl)-4 -phenyl-4,5-dihydro-1 H-pyrazol-1-yl]-methylidene}-4-chloro- benzenesulfonamide (compound) 1 Cl J Ney oo Compound 1 ON PN No a5 TL cl CF, 5 Part 4 Then obtaining: 3-(4-Chlorophenyl)-N-[(4-chlorophenyhsulfony!]-4-phenyl-4,5-dihydro - 1H-pyrazole-1- carboxamide. As described in 0. (° ost Lange) dissolved: 3-(4\Ghloro-phenyl)-N-[(4-chloro-phenyl) )sulfonyl]-4-phenyl-4,5-dihydro- 1H-pyrazole- 1-carboxamid A) not g 0.257 mol) in anhydrous dichloromethane (© 1 ml) 0 (DMAP g; 1.7217 mmol) and M00 (1 aa 0 0 7.778 mmol) were added sequentially and the resulting mixture was reversed for 0 h. The mixture was cooled at zero. Sequentially added:

— oy — millimoles) £. EVV col.; 4 ) 7,7-Dimethoxy-7-[4-(trifluoromethyl)phenyl]-heptylamine fill 4.44 mmol).VES) and give 01 hours. The mixture was left to reach Te after which the mixture was heated at reflux temperature for 10 minutes, filtered (aqueous NapSOy), dried with NaHCO; 75 at room temperature, washed with a column, and then obtained by column. $s for a product | m a | aan and its concentration in a media divided by ° and decanted © to ethylacetate to 1/1 = ethylacetate [heptane gradient: ¢alumina] chromatography: (volume / volume) ) to obtain 5/1© = methanol [ethylacetate 4-chloro-N-{[3-(4-chloropheny!)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl]-[7 -(4- fluorophenyl)-7,7-dimethoxyheptylamino] methylene} benzenesul fonamide (product).7 17 cane Xoo) Document 0 "H-NMR (400 MHz, CDCl3) § 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), invisible NH proton.

Yo : Part B: 4-Chloro-N-{[3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl]-[ 7-(4-) dissolved fluoro-phenyl)-7,7-dimethoxyheptylamino] methylene} -benzenesulfonamide

Agm (07-: TOA con + mM) (Use) in a 1:11 mixture of (Je T+) methanol/THF. © ml of hydrochloric acid of concentration 1p was added and the resulting mixture was stirred at room temperature for 1 h.The mixture was quenched with ©7 NaHCO;aqueous.Most of the methanol THF was removed by evaporation in incubator medium.The remaining aqueous layer was extracted twice using JI;ethylacetate©.Drying the layers The combined organic slasinls combined organic layers (NapSO4), filtration and concentration in vacuo. The obtained crude: 4-chloro-N-{[3-(4-chlorophenyl)-4-phenyl-4,5-dihydro -1H-pyrazol-1-y1]-[ 7-(4-fluorophenyl)-7-oxo-heptylamino] methylene} benzenesulfonamide Yo F)mg) was not further purified.Some NMR=TH signals Characteristic aromaticity: CDCl) 8 7.12 (d, J ~ 8, 2H), 7.22-7.33 (m, 5H) 7.39 (d, J ~ 8, 2H), 7.50 (d, J ,11112 400) 2H ), 7.72 (d, J ~ 8, 2H), 7.84 (d, J ~ 8, 2H), 8.05 (d, J ~ 8, 2H). ,8 ~ Part C: Dissolved: 4-Chloro- N-{[3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl]-[ 7-(4-fluoro- phenyl)-7-oxo-heptylamino] methylene} benzenesulfonamide 11 (ax + Yo 9 a 0.mmol) in pure ethanol (Ye ml) to which: TV) O-(2-aminoethyl)hydroxylamine dihydrochloride was added sequentially mg 018 mol eq) 5 pyridine 4 mL). The resulting mixture was stirred at the reflux temperature for 10 hours. And leave the mixture

— $m to at room temperature. After removing the solvent in vacuo, the remainder was dissolved in dichloromethane and washed sequentially with 1611504 aqueous solution and .brine brine, and then dried the organic matter using “NaySOq4”, filtered and concentrated in Ede medium. To get: N-{#-[7-(2-amino-ethoxyimino)-7-[4-(trifluoromethyl)phenyl]heptylamine]-1-[3-(4-chlorophenyl)-4-phenyl- 4,5-dihydro-1H-pyrazol-1-yl]-methylidene} -4-chloro- benzenesulfonamide (YY compound) (1 + g) as a mixture of stereoisomers K/Z Melting point : OA=OY m. H-NMR (400 MHz, CDCl) 6 1.30-1.67 (m, 8H), 2.80 (t, J = 7, 2H), 3.33-3.40 (m, 2H), (m, 2H), 4.03 (dd, J = 11 and 5, 1H), 4.43-4.55 (m, 3H), 4.60-4.70 (m, 2H), 3.5613.66 (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 ~ 7.10 2H), 7.82 (d, J ~ 8, 2H), 8.60 ( br s, 2H). -7-[4-(trifluoromethyl)phenyl] heptyljamide ‎Yo (compound ¥)

oo — - Cli NH, N I a H 0 Compound 2 aam 0 0 part i then obtain: ethyl 2-(2-chlorophenyl)-1-(4-chlorophenyl )-5-ethyl-1h-imidazole-4-carboxylate. According to International Application No. 460159 .070 to a solution previously magnetically stirred © from:

ethyl 2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazole-4-carboxylate

(p> +-Y1 2) LIOH A solution of (Ja £ +) tetrahydrofuran was added at (se 0.0149 g)

in water (0£0 ml). The resulting mixture was heated at 70°C for 11 hours. And leave the resulting mixture

To reach room temperature and then it was treated with 0:5 (Se hydrochloric acid 0 ml). All the tetrahydrofuran was incubated and the resulting mixture was stirred overnight. And done

The precipitate formed by filtration was collected and washed with petroleum ether (10-50) to obtain:

£.0Y) 2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazole-4-carboxylic acid

g + LAS = 01

B_ 4 0 — “H-NMR (400 MHz, CDCls): 82 1.09 (t, J = 7, 3H), 2.90 (q, J = 7, 2H), 3.70 (brs, 1H), (dt , J = 8 and 2, 2H), 7.22-7.28 (m, 1H), 7.29-7.38 (m, 5H). 7.12 Part B Then obtain: 1. A) 2-(2-Chloropheny!)- 1-(4-chlorophenyl)-5-ethyl-1H-imidazole-4-carboxylic acid © CO 5.177 mM (dss VV YY) T-amino-1-(4-(trifluoromethyl)phenylheptan-1-one gm 0177 mmol) (7-amino-1-(4-(trifluoromethyl)phenyl)heptan-1-one by product 1" 7 from intermediate compound E: (toluene-4-sulfonic acid 7-oxo) -7-[4-(trifluoromethyl) phenyljheptyl ester) using 07 M of 1111 in VY methanol hr at room temperature, in an isotropic manner for the synthesis of intermediate Vo-g (see also: © “Tane7” 1997 800 HOAL (+1 g; 59 mmol) and “DIPEA 4 (Je 014 8.743 mmol) in 01 (dichloromethane ml) and were stirred with a magnetic stirrer at room temperature for 1 hour. Jada then washed the reaction sequentially with cele NaHCO; Jo is aqueous and water, and then dried using “Na, SOq4” and filtered and concentrated in vacuo to obtain: acid (7-[4-p1b<mtayem-102016-4d111-11-engta-5-) No. 4 (4-2)-1-(nx-dam21811010)-2 (trifluoromethyl)phenyl]-7-oxo-heptyl} amide.

Vv — g where 458% was done using 1 column Jt = ethylacetate / heptane talumina) chromatography (volume/volume) and then another column chromatography ethylacetate | heptane ¢silica gel) = 2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazole-4-carboxylic acid {7-[4-(trifRioromethyl)-phenyl] -7-oxo-heptyl} amide (pure V.YA) g" 0 © 7 product). H-NMR (300 MHz, DMSO-d): 57 0.92 (t, J = 7, 3H), 1.28-1.68 (m, 8H), 2.84 (q, J = 2H), 3.08 (t, J = 7, 2H), 3.23 (q, J = 7, 2H), 7.30-7.42 (m, 5H), 7.49 (br d, ] = 8, 2H), ,7 (d, J = 8 2H ), 7.89 (d, J = 8, 2H), 8.04 (t, J = 6, 1H), 8.15 (d, J = 8, 2H). 7.56 Ve part = dissolved: 2-(2 -chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazole-4-carboxylic acid {7-[4- (trifluoromethyl)phenyl]-7-oxo-heptyl} amide. VAT ( aa (1.00 mmol) in pure ethanol (Jo 01) to which: O-(2-aminoethyDhydroxylamine dihydrochloride ) 1 mg 10.0 mol) and pyridine (YA) YO were added sequentially 0 ml).The resulting mixture was stirred at reflux temperature for 50 hours.The mixture was left to reach at room temperature.After removing the solvent in incubator medium, the remainder was dissolved in dichloromethane and washed successively with 161150 MiO solution and brine salt

— OA — ge Then, the organic matter 5 was dried using Bo Kimmel, filtered, and concentrated in a medium. To obtain 2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazole-4-carboxylic acid [7-)2-amino-ethoxyimino)-7-[4-(trifluoromethyl) )phenyl] heptyl]-amide : for J melting point 0 E/Z (compound 7 ( ) 6 g) as a mixture of stereoisomers © "H-NMR (400 MHz, CDCl3) 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, SH), 7.37 (d, J = 8, 1H), 7.49 (brs, 1H), 7.59 (d, J = 8, 2H), 7.71 (d, J = 8, 2H), 8.65 (brs, 2H).[2-(2-Chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazole-4- yl] {4-[4-(5-fluoro-1H- indol-3-yl)butyl]piperazin-1-yi} methanone (7 (Cl = \ Cl N {ON Compound 3) bit “0 NH : acid + .AA +) 2-(2-Chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazole-4-carboxylic acid 85 : c g + A. mmol) reaction with the intermediate compound

_ 9 M “(5-fluoro-3-[4-(piperazin-1-yl)butyl]-1H-indole) Luke HOAt tr 1 .05( K>CO; mo eq ( in 1) dichloromethane ? (Jo) at room temperature for 1 hour in a manner similar to that described by Sid to prepare compound ¥” part B to obtain: [2-(2-chlorophenyl)-1-(4-chlorophenyl )-5-ethyl-1H-imidazole-4-yl] {4-[4-(5-fluoro-1H- indd1-3-y)butyl]-piperazin-1-yl}methanone smelting point). Fusion (7 0 con V.YA)) yielding 7 VT (mg Vo 4) (V (compound “H-NMR (400 MHz, CDCl3) 8 1.03 ) 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 (brs, 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]-benzenesulfon-amide (compound £(

Cl

J

N~

No, 0 Compound 4 R 0 of HN F Alaa Ye

3-(4-Chlorophenyl)-N-[(4-chlorophenyl)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1- carboxamide «PPOCL; t DMAP and the reaction of mm Sle no dichloromethane mmol) at 0.01 cpa .0

This was followed by reaction with intermediate compound C: DIPEA 5(5-fluoro-3-[4-(piperazin-1-yl)butyl]-1H-indole)© in a manner similar to that used to prepare compound 1 mol. i to obtain : 4-chloro-N-{[1-[3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl]-1-{4-[ 4-(5-fluoro-1H-indol-3-yDbutyl]piperazin-1-yl} methylidene]-benzenesulfonamide. (compound 4)tana)45/product). 'melting point (m, 2H), 1.70-1.80 (m, 2H), 2.47 (t, J = 7, 2H), 1.56-1.66 E" H-NMR (400 MHz, CDCl3) (m, 4H), 2.75 (t, J = 7, 2H), 3.69-3.86 (m, SH), 4.42 (t,] = 11, 1H), 4.54 (dd, J 2.57-2.70 and 5, 1H), 6.93 (dt, ] ~ 8 and 2, 1H), 7.03 (d, J ~ 2, 1H), 7.10 (d, J = 8, 2H), 7.21-11 = (m, 8H ), 7.48 (d, J = 8, 2H), 7.83 (d, J = 8, 2H), 7.98 (brs, 1H). 0 for oral administration (.8.0): to desired amount -05 (©mg) of compound 1 in a glass tube; a few glass beads were added and the solid ground by vortexing for Y min. After adding 1 mL of a solution of 71 methylcellulose in water and 77 (vol/v) ¢(Lutrol F68) YAA poloxamer, compound A was suspended

by vortexing for 10 minutes. The 11M was adjusted to 7 by adding a few drops of aqueous NaOH (p04) and the remaining particles were suspended in the suspension also using an ultrasonic bath for intraperitoneal (i.p.) administration. To the desired 0 quantity (15 melo) of solid compound 1 in a tube (aly) a few glass beads were added and the solid was ground by vortex rotation for 2 minutes. and after adding 1 mL of a solution of mannitolZ© 5 methylcellulose 71 in water; The compound was suspended by vortex rotation for 10 minutes. In the end, the 11th figure was set to . EXAMPLE 6: Pharmacological methods 0 In vitro binding susceptibility to human cannabinoid-CB receptors was determined using membrane preparations from CHO cells stably transfected with the human cannabinoid-CB receptor; and PHICP-55,940 as a radioactive ligand. and after incubation of a freshly prepared preparation of cell membranes with the bonding compound [PH] with or without the addition of the compounds of the invention; Separation of the free ligand and ligand compound was carried out by filtration over glass fiber filters. The radioactivity on the filter was measured by counting the affinity in the laboratory towards the serotonin reuptake sites. The affinity of the compounds towards the serotonin reabsorption sites was determined using the receptor binding experiment described by (Habert, 1985).

Example No. 1: Results of pharmacological tests. Data for binding to the CB receptor; and sales data for serotonin uptake were shown according to the protocols mentioned above; in the following table. eee | en | LE connect S-HT euptak cannabis — CB; Cow eee seer ssc

Y —_ 3 — HN 0 5 N N_ 1 1 F H | N N Z N 3 H The results clearly indicate that the compounds of the invention have a high binding affinity towards cannabinoid receptors (-:3© and sale sites) of HT uptake - 5. And its associability is quite effective crimonabant Jie instead; For example (Ji) compound 1© is at the same time a potent inhibitor of fluoxetine Jie serotonin reuptake and this strongly contrasts with; For example; Active OB antagonist) very close to it in structure disclosed in the international application ov/evvevt (see clad above) which has no efficacy as an inhibitor of serotonin reuptake and there are other antagonists tested that have no affinity for binding at 5-HT reuptake sites; and inhibitors of 5-HT reuptake have no affinity for binding to the |0 receptor Cannabinoids ~.CB, ~ cannabinoid receptors Example No. tA Pharmaceutical preparations for clinical use 6 Compounds of formula (1) are dyed into pharmaceutical formulations that represent important and new embodiments of the invention because they contain the compounds; more specifically, the specific compounds that Disclosed in this application The types of pharmaceutical compositions that may be used include, but are not limited to, tablets; chewable tablets and capsules (including microcapsules); solutions; solutions for injection; and ointments (creams and types

majority); suppositories; pendants; and other species disclosed in this application; Or that is considered known by any skilled person in the field from the full description of the invention or from general information in the field. The active ingredient (eg JU) may also be in the form of a complex that may be included in cyclodextrins, 5 or their esters and the formulations are used for oral administration; by intravenous injection; and by subcutaneous injection; tracheal; tracheal; intranasal; translung; transdermal; intravaginal; rectal; for non-intestinal Gob; or any other route of administration. The pharmaceutical formulation contains at least one compound of the formula (i) in a mixture with an adjuvant and/or diluent; and/or a carrier; at least one pharmaceutically acceptable. It is appropriate that the total amount of active ingredients be in the range from about 72009 00 (w/w) to About 795 (w/w) of the formula; 720.8 to 756 (w/w) is appropriate; 71 to AYO (w/w) is preferred. (Ay some embodiments; the amount of active ingredient is greater than about 7988 (w/w) or less than about 0-1 7 (w/ws) and the compounds of the invention can be prepared in suitable form [celled] by ordinary methods using auxiliaries such as liquid, solid or powdered components such as liquid or solid Vo fill materials; extension agents; solvents; emulsifiers; lubricants; flavoring agents; coloring agents and/or binders; usual pharmacy. Adjuvants using DES include: magnesium carbonate, lactose ¢ titanium dioxide ¢, saccharose ¢ and sorbitol; cmannitol and other sugars; sugar alcohols sl other, talc ¢, milk protein, gelatin 0 ¢, starch, amylopectin, cellulose and its derivatives; Animal and vegetable oils Jie liver oil A

- M -

Whale; or Cu) sunflower, or Cay, pistachio, or sesame oil; in polyethylene glycol ¢

and solvents quot; sterile water” glycerol Jie mono- or polyhydric alcohols; “lly with sodium stearyl, 1 calcium stearate, and 1 magnesium stearate disintegrating and lubricating agents such as

fumarate » and polyethylene glycol waxes, after which the mixture can be processed and manufactured on smooth

© granules or compressed in tablet form. A tablet can be prepared using the following ingredients:

Ingredient Amount (mg/per tablet)

Ye 1 is compound no

Yeo microcrystalline calysldl microcrystalline ¢ Cellulose

Ye smoked ¢ Silicon dioxide

| Yo stearicacid 0 0

YY. total

The ingredients are mixed and pressed to form all, each weighing 7,700 mg.

Active ingredients may be pre-mixed separately with other inactive ingredients; before

Mix them together to form a formula. The active ingredients can also be mixed with each other; before mixing it

,. With the inactive ingredients to make up Yo

Soft gelatin capsules can be prepared using capsules containing a mixture of active ingredients

of the invention; and vegetable oil.” or spread; or other suitable carrier for soft gelatin capsules.

Hard gelatin capsules may contain granules of the active ingredients. As can

- 1+ - The hard gelatin capsules contain the active ingredients together with the powdered solid ingredients saccharoses ¢ lactose Jie ¢, emannitols » sorbitol, potato starch », all starch, mannitol ¢ and cellulose derivatives or -gelatin Dosage units suitable for rectal administration can be prepared (i) in the form of suppositories containing the active substance © mixed with a natural lipid base; (?) in the form of rectal gelatin capsules containing the active ingredient mixed with vegetable oil; or zetrafen; or other suitable carrier for rectal softgel capsules; (©) as a pre-formulated micro enema; or (£) as a dry micro enema formulation that is reformulated in a suitable solvent immediately prior to administration. 0 Liquid formulations may be prepared In the form of syrups, elixirs, concentrated drops, or suspensions; Jie solutions or suspensions containing the active ingredients and the remainder consisting, for example, of sugar or sugar alcohols and a mixture of “clay and glycerol ¢” and propylene glycol “and polyethylene glycol” and if desired these ALN preparations may contain “coloring agents” or flavoring agents; or preservatives saccharine SL carboxymethyl cellulose 0 ¢ or other bulking agents. Load can prepare liquid formulations as a dry powder that is reformulated with a suitable solvent prior to use. Solutions suitable for parenteral administration may be prepared as a solution of one of the formulations of the invention in a pharmaceutically acceptable solvent. These solutions may contain stabilizing ingredients; and/or preservatives” and/or components of Adie. Solutions suitable for parenteral administration may also be prepared in the form of Cals Yo, to be reformulated with a suitable solvent prior to use.

TV

Filled JST Also according to the invention formulas and “part groups” comprising one container or components of a pharmaceutical composition of the invention are also presented; For use in medical treatment. JST with one or written information such as instructions for use may be attached to these container(s); or note the manufacture, use, or sale of platy products as advised by a government agency carrying out ally pharmaceutical purposes; This note reflects the agency's approval and approval of the manufacture and use © administration to humans or animals. The formulations of the invention are used in the manufacture of drugs for the treatment of a desired condition (or serotonin reuptake) and/or inhibition of CB; in which the receptor antagonistic effect and medical treatment modalities or methods involving the administration of a therapeutically effective total amount of cad are desirable at least one compound of Formula (1); either as first in the case of prodrugs after administration and/or CB) a patient suffering from; or is at risk of developing a condition in which an antagonistic effect on the 0 receptors is desired or desired. serotonin reuptake inhibition, to name a few; Many pharmaceutical formulations have been given; They include the preferred active ingredients for systemic or topical use. The other compounds of the invention, or combinations thereof, may be used instead of (or in addition to) said compounds. The concentration of the active ingredient can vary in a wide range as discussed in this application. the quantities and types of ingredients that may be included in the formulations; Well known in the field

ARE

Claims (1)

1A — — Protectants 1-1 Compound of formula :(1) R Y 7 or tautomer ¢ or stereoisomer ¢ or N-oxide “ or isotope numbered radioactively terminated or pharmaceutically acceptable salt of any of the foregoing, where: H is one of the fragments (SAY SA) SAY SA (SAY) SAD) SA (Th) Ar (Ah R? 81 QO) QO QE N 7 l b ss l of yo 0 N l o + Bah that) 1 8 number (AY) (5) TQ er kr - 2 "Q" N = " A 8 a R¢ sd N m of oF + 0 + 0 + (A3) (A%) (AS) R? 32 & R2 RK, bE R ?QO 2 N 07 0 b Nel S Ny 4 R® + “0 0 X + (AS) (AT) (A®) 0 where Ble X represents a group sulfonyl or carbonyl and the "+" symbol Jie the point at which the yy bonds to the Nall fragment (where N is a non-basic nitrogen atom) in formula (1); and ++ a and 82 And 83, each expressing separately one or more hydrogen atoms or groups of acids Any compound” or hydrogen and 7 expresses a chalogen atom or an atom “trifluoromethyl 1 Ls "3 : AC gaa yo methyl, ethyl, trifluoromethyl, hydroxymethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1 propyl, methylsulfanyl , methylsulfinyl, methylsulfonyl, ethylsulfanyl, 7 ethylsulfinyl, ethylsulfonyl, C,;-dialkyl-aminomethyl, pyrrolidin-1-ylmethyl, VA piperidin-1-ylmethyl or morpholin-4-ylmethyl 119 or (NRTB?) or ( NTRB') is one of the fragments (1) of the form NRTB and the sequence +, qt ar si dimmed si (NRTB®) er (NTRB®) | (NRTBY ? Sf (NTRB%) YY 0-0 NH N Nb NT Ln L, SO, pay vy H H (NRTBY) CF; (NRTB?) (NRTB?) R R \ 1 H Neg N., cl. Cl Ci ve o (NRTB?) (NRTBS) (NRTBS) has R N _R N CF, iS} 5 F L 90 R 01783 (NRTB7) SN R Roa LON i 1 TOL © ( NRTB?) (NRTB) A YY where R stands for 3,3 hydrogen or (C1.Cs) nucleus group. H(A) or (A) Waal is one of A where 11 is a compound according to Claim No. -* 1 R1 R?2G 1G Qom eon R4 Easy to N SCT ns 0 + + No. (Ata) ¥ where X represents the sulfonyl group i.e. carbonyl and the “+” symbol represents the point at which it bonds; Fragment of slit 8 (where JAAN is a non-basic nitrogen atom) in formula (1); each 0© of 18, 82, and separately represents a chydrogen atom or trifluoromethyl groups, i.e., a chalogen. And RY stands for a hydrogen atom or chalogen or group: methyl, ethyl, trifluoromethyl, hydroxymethyl, fluoromethyl, 2,2,2-trifluoroethyl, 7 propyl, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfanyl, A ethylsulfinyl, ethylsulfonyl, C, ;-dialkyl-aminomethyl, pyrrolidin-1-ylmethyl, 1 piperidin-1-ylmethyl or morpholin-4-ylmethyl Ve 1. The other symbols bear the meanings mentioned in Claim No. 11 1 *- A compound according to claim No. 1 has the formula (1) in which A has one of the fragments (TH) or (AY) except Cl Cl Qe cl rN ¥ 7 Ney oo ba +p bga + (A3) CL, (A%); The other symbols bear the same meanings previously mentioned in Claim No. 1. (2-amino-ethoxyimino)-7-[4-(trifluoromethyl)phenyl] heptylamino]-1- 7 [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 0 [7 -(2-amino-ethoxyimino)-7-[4-(trifluoromethyl)phenyl] heptyllamide 1 ‎[2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazole-4- y1] {4-[4-(5- 7 fluoro-1H-indol-3-yl)butyl]piperazin-1-yl} methanone A 4-chloro-N-{[1-[3-( 4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl}-1- q ‎{4-[4-(5-fluoro-1H-indol-3-yl)butyl| piperazin-1-yl} methylidene]- Y. benzenesulfonamide 1 1 0— compound according to either claim 1 — 4; or tautomer » or stereoisomer 7 » or Neoxide ¢ or an ole isotope of the radioisotope; or a pharmaceutically acceptable salt » of any of (Ba) wherein said COA is an optically-active enantiomer ¢ VY - — 1 + - Compound of claim number 0 is chosen from: Ci Cl / / N l N l 0..0 0..0 VL 5), ci cl of N v HN = N v CF © F 3 H,N J 1 * - A drug that contains a compound according to any of the elements of protection (= 7) or a pharmaceutically acceptable salt thereof. A 1 - a pharmaceutical composition containing; plus a pharmaceutically acceptable carrier; and or ¥ at least one pharmaceutically acceptable adjuvant; contains a pharmacologically effective amount of at least one compound »according to any of claims 1 - 1 or a pharmaceutically acceptable salt thereof; as an active ¢ ingredient. 11- The pharmaceutical composition according to claim No. oh where it also includes at least one additional therapeutic agent. 01 1 - Using a compound according to any of the protection elements (T=) to prepare a pharmaceutical composition 0 Treatment of addiction, alcoholism, salcoholism, Alzheimer's disease, anorexia nervosa, and anxiety disorder anxiety disorder and disorders Yes VY - ~— £ cappetite disorders, hyperactivity disorder associated with cattention deficits, bipolar disorder, cbulimia nervosa, cancer, and cardiovascular disorders 1 central nervous system disease A and cerebral ischaemia; strokes, cerebral apoplexy 4, emesis vomiting resulting from chemotherapy, cocaine addiction, cognitive disorder, dementia 11, and demyelinisation related disorders. Diabetes 0 Diabetes and Neuropathy “0 Diabetes” and Diarrhea 01201088; drug dependence, dystonia, and eating disorder 04; vomiting, cemesis, epilepsy (wum! zam); female sexual dysfunction (cdysfunction 0), functional bowel disorder, gastrointestinal disorders, gastric ulcers; anxiety disorder 117 General cgeneralized anxiety disorder, glaucoma, YA headache, Huntingtons disease, inflammation causing 14 impulse control disorders, Bowel syndrome 07118016, and male sexual dysfunction. sexual dysfunction Ye p. And myasthenia gravis, neuralgia, nausea, “nausea, neuralgia;” disorders resulting from neurodegenerative disorders “Yo” disorders resulting from neuroinflammatory disorders “and pain resulting from disease + neurological neuropathic pain, obesity, obsessive-compulsive disorder ccompulsive disorder 1, costeoarthritis, pain, YA panic disorder, panic disorder, Parkinson's disease, plaque sclerosis VA, premature ejaculation, premenstrual syndrome ~~ premenstrual csyndrome 0 and cpsychosexual disorder psychosis 1 rheumatoid arthritis septic shock VY schizophrenia csexual disorders sleep disorder “disorder YY, spinal cord injury, stroke; lal <Tourette's syndrome (ctraumatic brain injury ils), ctremor 8, and enuresis curinary incontinence and viral encephalitis .encephalitis 1-11 1 Use according to claim No. 01 to prepare a pharmaceutical composition for the treatment of psychosis 1, anxiety, depression, attention deficits * and cognitive disorders obesity, cobesity, drug dependence ¢, Parkinson's disease, Alzheimer's disease, pain disorders © and pain disorders resulting from neuropathic cpain 1 And sexual disorders