SA07280276B1 - Sulphur Containing Pyrazole Derivatives as Selective Cannabinoid CB1 Receptor Antagonists - Google Patents

Abstract

Sulfur Containing Pyrazole Derivatives as Selective Cannabinoid CB1 Receptor Antagonists Abstract The present invention relates to sulfur-containing pyrazole derivatives, and their S-oxidized active metabolites, as selective cannabinoid CB1 receptor antagonists comprising High selectivity for a subtype of the CB1/CB2 receptor, methods for preparing these compounds, new intermediates useful for the synthesis of the aforementioned pyrazole derivatives, pharmaceutical formulations containing one or more pyrazole derivatives as active ingredients, and the use of these pharmaceutical formulations for the treatment of psychiatric and neurological disorders disorders. These compounds have the general formula (I) where the symbols used have the meanings given in the specification.

Description

_Y—

CB; ill sulfur-containing pyrazole derivatives as selective receptor antagonists

Sulfur containing pyrazole derivatives as selective cannabinoid CB; receptor antagonists Full description BACKGROUND The present invention relates to pyrazole derivatives containing receptor sulfur; The active S-oxidized metabolites of HA as cannabinoid receptor antagonists,03 have high selectivity for a subtype of CB receptor; / CB) and methods for preparing these compounds; e and with new intermediates useful for the synthesis of the said pyrazole derivatives; and in pharmaceutical compositions containing one or more pyrazole derivatives as active ingredients; In addition to the use of these pharmaceutical formulations for the treatment of psychiatric and neurological disorders (these compounds have the general formula . disorders 0).

Cl

N—N

CHEE

RiAxy0

R, where the symbols used have the meanings indicated in the specification

Y — — pyrazole derivatives with an affinity for the CB receptor are known from several patent applications; (Including international applications Nos.: 44/175756 R. 14/673176 and for etc. 1/0, 4 and 17H/; Yeu and European Patent No. 189736786; and American Patent No. 1/0011 100); and other publications -Matthews, 1999 ¢Meschler, 2000 ¢Katoch-Rouse, 2003 ¢Francisco, 2002 ¢Lan, 1999© The CB receptor antagonists were; - namely SR141716A (now known as La lac ly 'rimonabant' ¢ Its potential therapeutic applications are the subject of numerous articles: Smith, ¢ Hertzog, 2004 ¢Lange, 2004, 2005 ¢Carai, 2005 ¢Sorbera, 2005 ¢Boyd, 2005 Adam, 2006 ¢Reggio, 2003 ¢Muccioli, 2005, 2006 ¢Padgett, 2005 ¢Thakur, 2005 ¢2005 01 Patent applications and previous articles reveal a number of selective receptor antagonists for a subtype of the CB, / CB receptor; cannabinoid (CB) receptors are part of the internal cannabinoid system that is involved in psychiatric and neurological disorders; cardiovascular; gastrointestinal; reproductive; and related to eating disorders. to cancer: Centonze, ¢Vandevoorde, 2005 ¢Lambert, 2005 ¢Di Marzo, 2004 ¢De Petrocellis, 2004 2007. 03 receptor modifiers have many potential therapeutic applications; Such as / drugs for the treatment of psychosis, anxiety, anxiety and depression; and lack of attention

deficits ¢ and memory disorders – cognitive disorders – cognitive disorders – appetite disorders – obesity – addiction – caddiction – appetite disorders – drug dependence – and neurological degeneration disorders neurodegenerative disorders « dementia; dystonia, muscle spasticity, and tremor; epilepsy and multiple sclerosis; traumatic brain injury ¢, stroke ¢, Parkinson's disease » and Alzheimer's disease; epilepsy + Huntington's disease; Tourette's syndrome ¢ cerebral ischaemia ¢ cerebral apoplexy 0 ¢ and craniocerebral trauma; stroke; spinal cord injury; Neuroinflammatory disorders ¢ Plaque sclerosis » Viral encephalitis ¢ And disorders related to demyelinisation (p-lell “related disorders” In addition to the treatment of pain disorders ¢ Including 10 neuropathic pain disorders - septic shock - glaucoma, diabetes ¢ and cancer; emesis 0 and nausea ¢ Gastrointestinal disorders, gastric ulcers, diarrhea, sexual disorders, impulse control disorders, and cardiovascular disorders.

So _ — CB receptors are predominantly located in the immune system (spleen ¢ tonsils “immune cells” as well as microglial cells; astrocytes ¢ It has also been found recently in the brainstem of the central nervous system and in the cerebellum - (Ashton, 2006 ¢ Van Sickle, 2005) (cerebellum)

Effective CB receptor modulators with low affinity for the CB receptor (ie, compounds with high selectivity for a subtype of the CB/CB receptor) are advantageous compared to cannabinoid receptor modulators. non-selective or low-selectivity where Lgl is free of the undesirable side effects of the 0132 receptor; such as: immunological side-effects; or side effects related to infections

0 0 inflammatory related side -effects on neuropathic pain perception General Description of the Invention The object of the present invention was to develop effective CB receptor antagonists that are administered by Oral is highly selective for a subtype of CB;/032 receptor.

«CH; (see below) represents a group X where (I) is given the formula pyrazole there are derivatives 1 Surprisingly; It was discovered that (CB) are known as antagonists of a receptor that leads to obtaining compounds that are not sulfur agents with a sulfur seed CH, replacing a group, but are more “wad CB, / CB, Selective CB receptor subtype, receptor antagonist when tested orally in a sulfur potency test than non-sulfur-containing analogues

- A drug mediated by the CB receptor) in the organism. Gad can consider compounds having the general formula (1) where X represents a 0-8 group or an SO group, as metabolites of compounds of formula ol) where X represents a sulfur atom . Surprisingly, it was discovered that these compounds have formula (1); where X is the 0-8 sulfoxide group (m or sulfone group) SO; ) that also has a significant affinity for the “CB;” receptor. They can be considered as active oxidative metabolites-8 for compounds having the general formula (1); Where X represents a sulfur atom. in general; It is known that the formation of active metabolites enhances the efficacy of drugs in vivo. Active metabolites having the general formula oT) where X is the 8-0 group or the SO; group are part of the present invention. Cytochrome 24500 is an endogenous enzyme (Laid) that is Gosia involved in the metabolic oxidations of alkyl sulfides to sulfoxides and their corresponding sulfone compounds (2001 (Denisov, 2005; Nnane, 2001). The present invention relates to compounds having the general formula (): 0 Cl gos | X=Y 0 R, Vo where: Yer

- ,2 represents H or “Cl or Br” - C represents “Br J” Cl X - represents a sulfur atom ¢ or a sulfoxide fraction (5-0) or fraction “(SO,) sulfone -7 represents the ethyl group of methyl ¢ -“ can have the value 10 or 7 or ?; and N-oxidess enantiomers (terminated tautomers and isotope-numbered compounds having the formula ); In addition to the pharmaceutically acceptable salts 5 hydrates » and the solutes of the aforementioned compounds that have formula (I) 5 and the tautomers; or N-oxides or their isotope-numbered isotopes. a

0 All of the sulfoxide compounds included in this invention have a center of asymmetry. The invention relates to racemates ¢ and mixtures of diastereomers. The invention Lad relates to the © isomer, the 2 isomer and 2 / 28 mixtures of compounds of formula (). The invention relates particularly to compounds having the general formula (I) where Ry and 8 represent Cl and 7 represents methyl dc gana; And it shall have the meanings described above; and “represents 1 or 7.

ve additionally; The invention relates specifically to compounds represented by the formulas:

why - 0 0 Cl Ci ] + ? ~ )+ 7 2 S—CH, for S—CH, cl sans Cl Cl Cl due to active activity of the ,013 receptor antagonist or reverse cofactor; The compounds according to the invention are suitable for use in the treatment of mental disorders; Such as: psychosis, anxiety, anxiety, depression, attention deficits, memory disorders, cognitive disorders, and appetite disorders; obesity; als obesity, obesity among dl juniors, anal obesity from taking drugs, caddiction, appetite disorders, and drug dependence; neurological disorders; such as: neurodegenerative disorders; dementia »; dystonia  0, muscle spasticity  tremor  epilepsy  multiple sclerosis  traumatic brain injury  stroke  and Parkinson’s disease Parkinson's disease + Alzheimer's disease; epilepsy + Huntington's disease, Tourette's syndrome ¢ and cerebral ischaemia; and cerebral apoplexy Vo; craniocerebral trauma; stroke and spinal cord injury; neuroinflammatory disorders; Plaque sclerosis, viral encephalitis, and disorders related to demyelinisation.

And -

related disorders « In addition to the treatment of disorders resulting from pain, pain disorders ¢ included

neuropathic pain disorders; Other diseases included

cannabinoid neurotransmission; including treatment for septic shock; and blue water

nausea; nausea, emesis, and vomiting, “diabetes”; sugar, cancer, glaucoma, gastrointestinal disorders, asthma, respiratory diseases, and gastrointestinal disorders ©

gastric ulcers; Diarrhea, diarrhea, and sexual disorders

Disorders and impulse control disorders ¢ and disorders

Cardiovascular.

The cannabinoid receptor modulating activity of the compounds of the invention makes them particularly useful in the treatment of obesity; Obesity in young people and obesity

7_ resulting from ingestion of ila-0 drugs when used in combination with 0-lipase enzyme inhibitors

Specific examples of compounds that can be used are preparations consisting of

Synthetic lipase and lipase inhibitors Orlistat is an enzyme inhibitor (Je) but it is not limited (did

isolated from microorganisms; such as: lipstatin (from Streptomyces m ebelactone By (from aburaviensis 50©0107065); and synthetic derivatives of these compounds;

plus extracts from a plant known to have lipase inhibitory activity; for example

JU extracts from Alpinia officinarum or compounds isolated from such extracts as:

,. (A. officinarum (from 3-methylethergalangin

The invention Cad includes:

Yevs

- 1 and.

pharmaceutical composition for the treatment of; For example » a disorder or condition treatable by a disability

cannabinoid CB receptors; the formulation includes a compound of formula (I) or a salt

Pharmaceutical Acceptable Ala and Pharmaceutical Acceptable Carrier ¢

A way to treat a disorder or AE Alls to treat by blocking the Cl para-receptors Cannabinoid CB; © The method includes administration of a compound of formula (I) or a pharmaceutically acceptable salt

(Ala) to a mammal in need of this treatment;

a pharmaceutical composition for the treatment of; For example (JB) a disorder or condition selected from the group that makes up

of the disorders listed in this application;

A method of treating a disorder or condition selected from the group consisting of the disorders listed in this order; The method includes administering a compound of formula (1) or a pharmaceutically acceptable salt thereof. To

a mammal in need of this treatment;

a pharmaceutical formulation to treat the disorders listed in this application; The composition includes a compound for him

Formula (1) or a pharmaceutically acceptable salt (cain) and a pharmaceutically acceptable carrier;

a method for treating the disorders listed in this application; The method comprises administration of a compound of formula 1_(0) or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.

A method of blocking the cannabinoid receptor involves administering an effective amount of a compound of it

formula (1) to an object in dala to;

The invention, Caf, provides for the use of a compound or salt of formula (1) for the manufacture of a drug.

Yes

— \ \ _— The invention further relates to a combination therapy where a compound of the invention or a pharmaceutically acceptable salt thereof is administered; or a pharmaceutical composition or preparation containing the compound of the invention; Concomitantly, sequentially, or as a combination preparation with another therapeutic agent or agents for the treatment of one or more of the conditions listed. This other therapeutic Jal gall may be given before; or with; or 0 respectively to give the compounds of the invention. The invention Cad provides 6 compounds and pharmaceutical compositions; medical kits; methods for treating the disorders listed in this application; Methods include administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof; to a patient who is in dala for this treatment. The compounds of the invention have anti-cannabinoid (CB; - cannabinoid) activity The antagonistic activities of the compounds of the invention are demonstrated, for example, using one or more of the experiments described in this application or known in this field. The invention provides Bh Und for the preparation of compounds The invention and the intermediate compounds used in those methods The dads of the compounds of the invention can be deposited on one or more non-homologous centers 0 and then can be racemates, mixtures of racemates and single enantiomers. Depending on the nature of the various substituent groups, the molecule can include additional delocals Each of the delocals independently produces two optical isomers All optical isomers belong to either R

- 11

mixtures or as pure or partially purified compounds - belong to this invention. The present invention includes all isomeric forms of these compounds. Formula (1) shows the composition of the class of compounds without the preferred stereochemistry. The independent synthesis of these diastereomers, or chromatographic separations of ely as they are known in the art, can be carried out by

M0 Appropriate modification of the curriculum disclosed in this application. The absolute stereochemistry of these compounds can be determined by X-ray crystallography of the crystalline products or intermediates; which, if required, are derived using a reactant containing a declination center of known absolute conformation. Mixtures of racemates of single enantiomersdga compounds can be separated by methods well known in the art; Such as: pairing method

0 racemic mixture of compounds with a conformationally pure compound to form a dichotomous mixture; followed by separation of individual diastereomers by standard methods; For example: partial crystallization or chromatographic separation. The conjugation process often consists of forming salts with an isotropicly pure acid or base. For example, Jaw; (-)-di-p-toluoyl-D-tartaric acid and | or (+)-di-p- .toluoyl-L-tartaric acid

Vo laf can separate the racemic mixture of compounds in the form of dle by means of chromatographic separation methods using 4G chiral phases known methods in this field. By the method is AT isomers of a compound can be obtained by selective stereosynthesis using optically pure starting materials or reactants of known terminal conformation well known in the art.

Yes

Y — \ — Cis and trans isomers of the compound of formula (I) or a pharmaceutically acceptable die salt also belong to the invention; This Lad applies to the tautomers of compounds of formula (1); or a pharmaceutically acceptable salt thereof. Some crystalline forms of the compounds may exist as polymorphic forms: they are intended to be included in the invention with these forms. Moreover; Some compounds may form solutes with water (ie, hydrates); or known organic solvents. These solutes are also within the scope of the invention. cell includes the compound of formula (I) or pharmaceutically acceptable salts thereof; Isotope-numbered - including compounds of formula (1) isotopically numbered so that they can be detected by PET or SPECT - are within the scope of the invention. The same applies to compounds of formula (1) Aa yall 0 using SPC) -[©"']; or PHI or (BF) or -[1”"'] or other isotope-rich atoms; appropriate for future binding or for metabolomics studies. Definitions of Chemical and Other Terms The term “alkyl” refers to straight or branched saturated hydrocarbon radicals. ~(C13)' Alkyl " means 'methyl, ethyl, n-propyl or isopropyl, and 'alkyl(C,.4)' means 'methyl, ethyl, n-propyl, Vo isopropyl, n-butyl, 2-butyl, isobutyl or 2-methyl-n-propyl; the term "aryl" includes heterocyclic aromatic groups or fused or monocyclic aromatic groups including but not limited to: Yer

- 14 — 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[1,2,5]thia-0 diazolyl, purinyl, quinolinyl, isoquinolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl , naphthyl, pteridinyl or azulenyl. or 0; "heterogeneous" means bromo fluoro or chloro to "halogen" or "halo" indicates heterogeneous; or heterogeneous aromatic; or so on" contain one ALKYL as in

ALKYL heterocyclic 'alkyl groups' or 8. The term includes 0 JN or more than 0 or more N bonded alkyl bonded N atoms having heteroatoms in any position; including groups and "carbo" as used herein is "thio" 'oxy' with 0 or related to 8. The terms refer - respectively - to an oxygen atom and a sulfur atom os AT order as part of the oxy group or hydroxyl acts as a linker between two groups; such as “carbonyl (C=0) and a sulfur group as “amino” or so on. Indicating “carboxyalkyl, alkyl thio, or alkyl 0 may be terminal nitrogen used in this order alone or as part of another group to a primary or secondary AMINE atom or a linker between two other groups, where the group may be one with a hydrogen atom and one ¢ nitrogen atom attached to a hydrogen atom or triple (two atoms are bonded, respectively.) The terms 'nitrogen' denote a hydrogen atom and no 'nitrogen' atoms are bonded as used herein as part of another group on sulfonyl' 5' sulfinyl' 0 respectively; to group -50- or group -,50-.

10 - - As used in this application; Unless otherwise indicated; The term ic gens means “leaving” a charged or uncharged atom or group that leaves during a substitution reaction. Appropriate examples include, but are not limited to “tosylate s” mesylate s “ClgBr” and the like. N-oxide of the aforementioned compounds to the invention Tertiary amines may or may not lead to the appearance of N-oxide metabolites The extent to which Gay N-oxidation occurs varies from trace amounts to Amounts close to stated amounts.N-oxides can be more or less potent than their corresponding tertiary amines.While N-oxides can easily reduce their 0 counterpart tertiary amines by By chemical means, it occurs in the human body to different degrees.Some 0108-11 undergo an approximate quantitative reduction transformation to turn into the corresponding tertiary amines, in other cases it is only a simple reaction, or even the absence of a reaction (Bickel, 1969) Gla. To provide a more succinct description, some of the quantitative expressions shown in this application are inconsistent with ve the term 'about'. It is understood that whether or not the term "about" is expressly used, each quantity shown in this order refers to the actual value specified; It also indicates the approximate proportion of this specific value that Gy is derived for normal skill in the domain; Ley in that approximate ratio resulting from experimental and/or standard conditions for this specified value. Over the course of this application and its protections; Jad over, 'included', and 'included' © are not intended to exclude add-ons, components, integers, or other steps. Answer

- 11 -

ing Any compound that has been metabolized in an organism to provide the biologically active (Jalal) gl) A compound of formula (0) is a "prodrug" that falls within the scope of application. Pharmaceutical drugs are Ade agents that are inactive at all sites but are converted to one or more active metabolites. and on dia it is in the treatment methods of the present invention; The term 0 “administration” includes the treatment of the various disorders described using the specifically disclosed compound; or by using a compound that aie is not detected on the face of the canard but is transformed into a specific compound in the organism after administration to the patient. Prodrugs are biologically reversible derivatives of drug molecules used to overcome some of the barriers to benefit from the parent drug molecule. These barriers include; But it is not limited to solubility; 0 and transmittance; constancy; Primary Comprehensive Metabolic System and Target Limitations (Jarvinen, 2005 ¢<Ettmayer, 2004 ¢Stella, 2004 ¢King, 1994 ¢Bundgaard, 1 985) belong to compounds which, when administered to humans by any of the known routes, are metabolized. to compounds having the formula (0 - to the invention. Specifically; this relates to compounds with amino or dud) hydroxy groups or subgroups. These compounds can react with 1 organic acids to obtain compounds that have formula (I), where there is an additional group that facilitates its removal after administration, for example but not limited to amidine, i.e. enamine – J base Mannich or

Hydroxyl-methylene derivative + or derived from :

0 enaminone or amide or ol 810106 0 «O-(acyloxymethylene carbamate)

The term 'combination', as used herein, includes a product that includes specified ingredients 3 in predetermined amounts or proportions 0 as well as any product that produces, either directly or indirectly,

17 - From mixing specific ingredients in specific quantities. With regard to pharmaceutical formulations; Jody This term includes a compound that includes one or more active ingredients and an optional Alda that includes inactive ingredients; In addition to any product that results - directly or indirectly - from the assembly, complexity or agglomeration of any two or more components; or from the separation of one or more components; or 0 of other types of reactions that take place in one or more of the components. and in general; Pharmaceutical compositions are prepared by systematically and cohesively combining the active ingredient with a liquid carrier, or a finely divided solid carrier, or both, and then, if necessary, forming the product into the form of the required preparation. The pharmaceutical formulation includes a sufficient amount of the active compound to produce the desired effect when Alls Diseases progresses. Accordingly; The pharmaceutical compositions covered by the present invention include A composition which is prepared by mixing a compound covered by the present invention and a pharmaceutically acceptable carrier. in the context of this application; The term “combination preparation” includes “two correct combinations” which means the compounds of the invention and other drugs physically combined in a single preparation such as a tablet or fluid (in) and the term “parts of medicinal combinations”; it includes the fifth compounds 1 of the invention and an enzyme inhibitor lipase in separate dosage forms; with “Instructions for Use”; optionally with other methods to facilitate compliance with the administration of the compounds that make up the drug; eg by labeling or graphics. With the correct combinations, drug therapy is simultaneous. The contents of the Medicinal Kit Parts may be given Either simultaneously or at different intervals

- \A- The administration of treatment either simultaneously or sequentially depends on the properties of the other drugs used; And so on, as well as la DU, represented in the initiation and length of effect; levels and stage; and the individual characteristics of the patient. cm al “Pharmacologically acceptable” means that the carrier, diluent, or excipient must be compatible with other components of the formulation; and not be harmful to recipients. As defined below. It is a cannabinoid The affinity of the compounds of the invention for cannabinoid receptors has been determined The lowest effective dose can be estimated (oI) The measured binding affinity for a specific compound of the measured formula; the compound could theoretically occupy K at a concentration of the compound equal to twice the value of By shifting said concentration to approximately 0.03, -cannabinoid from cannabinoid receptors.

JY is the unit of milligrams of compound per kilogram of patient weight; The dose is 0 effective theoretically; This is assuming optimal bioavailability. Pharmacokinetic, co-pharmacokinetic, and other considerations may alter the dose actually administered to a higher or lower value. The effective administered dose of mg/kg is from 100 mg/kg to 1-00 mg/kg; Preferably from 0001 mg/kg to 10 of the patient's body weight. No The term 'therapeutic effective amount', as used herein, refers to an amount of a therapeutic agent intended to treat or prevent a treatable condition By administering the composition of the invention, the amount is the amount sufficient to produce a detectable therapeutic, prophylactic, or improving response in the tissue system of either humans or animals. The effect may include, for example, treatment or prevention of the conditions mentioned in This order The exact amount effective for the case depends on the size of the © over

the object and its health; the nature and severity of the disease subject to the hall and the recommendations of the treating physician (whether researcher, veterinary doctor, human or other treating physician); medical treatments; or a combination of selected therapies for administration. and then; There is no point in determining an exact effective amount 0 The term "pharmaceutically acceptable salt" refers to such salts; that fall within the scope of valid medical opinion; suitable for use with human and lower animal tissues without excessive toxicity; irritation and allergic response; Etc. and proportional Lad relates to an acceptable rate of interest / risk. Pharmaceutical acceptable salts are well known in this field. and may be prepared on site at 0 separation and final purification of the compounds of the invention; or separately by reacting with non-toxic, pharmaceutically acceptable bases or acids; Including organic or inorganic bases and organic or inorganic acids. The term "treatment" indicates; as used in this application; to any treatment of a mammalian organism; favors a human condition or disease; It includes: (i) 06 preventing the disease or condition from occurring in an organism that is susceptible to the disease but has not yet been diagnosed as having already been infected; or (vii) inhibiting the disease or condition—that is, halting its progression; or (i) mitigating the disease or The condition; i.e. making the condition recede; or (;) stopping the symptoms of the disease. As it is in front of m in this for 1 _ ' L Ll 3 1 zoe! 1). 0. Ly # 1 Protective; i. Yeh; And therapeutic that is carried out in the body of the organism or outside, whether on humans or other mammals. Flee

mso Y — denotes the term "object" as used in this application; to an animal; Preferably Gan LIS, preferably human; He was the target of the treatment. or note. or experiment. Examples Example: (1) Analytical methods: 0’ H NMR spectra were recorded on a 01 MHz Bruker or Yeo MHz medium using CDCl3 as a solvent with 080011511206 as an internal standard. NMR 36! on a 001 (Bruker MHz) medium using CDCl as a solvent Chemical displacements are given in ppm (scale 5) in the field of tetramethylsilane Coupling constants (( ) are expressed in Hz Flash chromatography was performed using 0 01 silica gel (from 140 to 117 Merck cae) and column chromatography using 0 1 silica gel (from 0.07 to 0.001). mm; (Merck Melting Points were recorded on a Melting Point Recorder 3-545 Biichi. Example 7): General Aspects of the Synthesis Process The synthesis of compounds of formula (I) is illustrated in the diagram (% 1 The synthesis of intermediates of formula (I) similarly precedes published procedures: Katoch-Rouse 2003 ¢Francisco, 2002 ¢Lan, 1999. A brominated group can be introduced on carboxylic acid (Formula 63). general ol) where Ry and 82 Lgl have the meanings mentioned above; To obtain the corresponding 4-bromo (II) derivative using a brominated group “introducer” such as: bromine in an inert organic solvent such as: dichloromethane . This (Says) is a derivative handle

yy - - (TTT) bromine, where Rog Ry have the meanings mentioned above; using a strong base such as: n-butyllitium in an inert anhydrous organic solvent such as: tetrahydrofuran; Thus, interaction with 77 thousand electrons derived from sulfur Cua sulfur 7 represents a methyl group or an ethyl group to obtain a compound with the general formula (IV) where Ry, Y18, and 7 have 0 meanings mentioned before ; Ry is an atom of X 5 hydrogen representing a sulfur atom The conversion of this compound of general formula (IV) to the corresponding ester of general formula (V) where Roy Ry and 7 shall have the meanings mentioned above; It represents a group: 06 linear alkyl methyl) “that is, n-propyl sf” ethyl ( and 7 Jad is a sulfur atom. This ester can be oxidized (63) of the general formula (V) Using 1 molar equivalent of an oxidizing reactant, such as meta-chloroperbenzoic acid 0 to obtain the corresponding sulfingl isotope, otherwise a reaction of a compound of general formula (V) with two or more From molars AS of meta- chloroperbenzoic acid to the conversion of the sulfinyl moiety to the corresponding sulfonyl moiety the ester of general formula (V) can be analyzed - where Ry, 12 and 7 have the meanings mentioned before and represent the sulfoxide part or the sulfone part - with water; preferably under acidic conditions; 1 to obtain the corresponding carboxylic acid (71). The resulting compound having the general formula (VI) can be made ) with amine in the presence of sale as an activating or conjugating reactant to obtain a compound of the general formula (0; where Ros Ry nor and “ have the meanings mentioned before and * represents the (S=0) sulfoxide part or the sulfone fraction (and 50). By the egal method a compound of general formula (IV) wherein Rpg Ry and 7 have the meanings given by Xp representing a sulfur atom 00 ¢ can be paired with an amine In the presence of an activating or reducing reactant to obtain a compound of the general formula (0; Where Ros Ry and 7 have the meanings given by Xp representing an atom of sulfur

sulfur in an alternative way; An ester derivative of formula (V) can be carried out in a so-called Weinreb reaction to convert to an amide with an amine to yield a compound of the general formula ol) where R; e and 7 are has the meanings given by Xs representing a sulfur atom » or sulfoxide moiety » (S=0) or (SO) sulfone moiety The Weinreb reactions of conversion to amide can be enhanced by © The use of trimethylaluminum AI(CH3)3 (Levin) 1982, activation and coupling methods for amine compounds to convert them into carboxylic acids are well documented (1994 ¢ Bodanszky, (Montalbetti, 2005 ¢ Albericio, 1997 ¢ Akaji, 1994. Scheme (17) a 8 8 , 0 . 0 on 0 Ne oH " N= OH ' N= J | 1" bhikhi " F =—— a #8 ja Pay - p l 2 - p P PR H ( 4 l dq an 2 11 ol 5 9 5 21 oH i N—N = , rl 9% until coordinator 7: ar i — Lg ryl P, d P. 0 a sulfiny orsulforyl moiety aa X mt moiety for (Wh) wherein X & a sulfinyl or sulfonyl moiety 7 3 Ll Ba 0 reactants and reaction conditions: 0) ¢CH,Cl, «Br (b) ¢YSSY (z) ¢THF en-Buli (4) amine derivative; coupling substrate; dichloromethane; Room temperature; (e) (R3-OH) acid catalyst or 1 (9) ¢thionylchoride equivalent of “CH,Cl,” m-CPBA, room temperature; (g) Y or more equivalents of 00188 - «CH Cly room temperature; (h)amine; (i) and ()l;

- yy - An alternative synthesis process for compounds of formula (1) is illustrated in Scheme (29). A bromoacetophenone derivative of general formula (VII) where Ry has the meaning given above can be reacted with a compound of The general formula is 1188-57 to obtain the derivative: 1-aryl-2-(alkylsulfanyl)ethanone (VIII) in an organic solvent “Jala” as: methanol). © It is possible to react this derivative 1-aryl-2-(alkylsulfanyl)ethanone (VII) where Ry has the aforementioned meaning with an oxalic ester derivative of the general formula (IX) in the presence of a base like : arylhydrazine (X) followed by reaction with cold in an anhydrous organic solvent sodium alkanoate having the general formula ester having the aforementioned meaning to yield Ry or a salt thereof; Where alkyl C13 Jodi group R35 and 7 have the meanings mentioned before; (Ros Ry where (V) this can be analyzed. sulfur represents a sulfur atom X 5 ) n-propyl or « ethyl or » methyl) linear 0 with water under alkaline conditions - for example - using (V) of the general formula ester or the corresponding (IV) salt of the general formula carboxylic acid to obtain lithium hydroxide carboxylic This (lithium, sodium or potassium : Jia) can be paired with its alkali and 7 is Ras Ry where - (IV) is the salt of its alkali of the general formula of acid In the presence of an amine substance with - sulfur. It has the meanings mentioned above; It does not represent a 1 sulfur atom to obtain dimethylformamide as an activator or coupler reactant in an inert organic solvent. For example: and “have the meanings mentioned before and Ys Ros 18, where oI) is a compound of the general formula

Ros Ry where ol) This compound of the general formula can be oxidized. sulfur represents a sulfur atom in molar equivalence 1 with sulfur and and “have the meanings mentioned before and 16 represents a sulfur atom: the sulfinyl analogues to obtain a meta-chloroperbenzoic acid isotope of 0

(I) A compound reaction with the general formula cs AT (group 0-5) can result. By way of X) meta- with two or more molar equivalents of - sulfur representing a sulfur atom X Cus corresponding to sulfonyl to part (I) in sulfinyl to convert part of chloroperbenzoic acid (2 ] ] | 0 0 04, ORa 0 0

Cl

Br , base N= OR, N-N 0 0 1 Le R. ae Pg _y 1 l a 5 Js “sum (1X) a ! X=Y2Cl "©

R. Rs free 5 ' R R. oD vin , 4 (wherein X represents 5 a cl 1 a I

N= “OR, N= Re at N 2 1

C5 Bugs and Ney — Fo RZ a : Ze ' 00 ci

R t i (Dwherein X represents § (2) ¢YSSY ©) ¢THF «n-Buli (b) ¢CH,Cl, «Br, (1) Reactants and reaction conditions: * 0 «R3 -OH; Room temperature; (e) dichloromethane; coupler reactant; amine derivative room temperature; “CHCl,” “m-CPBA” equivalent of 1(f)¢thionylchoride acid catalyst or one or more equivalents of 0158© 011:012 ; Room temperature; (h) an aqueous base; Y (g) t(t0)h; Adin 1 is based on factors known to those with experience in this field, such as: the compatibility of functional groups with the used reactants; And the possibility of using

Yer

— M Y — protective groups; catalysts; activating and coupler reactants; And the features of the basic structure present in the final compound that is prepared. Pharmacologically acceptable salts can be obtained using standard procedures well known in the field eg; By mixing the compound of the present invention with an acid “ala eg © inorganic acid hydrochloric acid (Jie”) or with an organic acid 85 can be obtained using standard procedures known in the art, eg JB by crystallization Or evaporation from an organic solvent containing water (not anhydrous) Example (3): Synthesis of certain compounds (1) 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-1 H- pyrazole-3-carboxylic acid 0 and then obtaining . M) from: methyl 5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-1H-pyrazole-3-carboxylate through 1 ester hydrolysis under methanol basic conditions ); KOH (aqueous). -Bromo-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1 H-pyrazole-3-carboxylic acid to a solution that was stirred with a magnetic tool consisting of:

0 ) 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-1 H-pyrazole-3-carboxylic acid body 58 mmol) in dichloromethane (+£4 ml); 011 “Ja ©.1Y bromine mmol) was added slowly and the resulting mixture was reacted for 11 hours at room temperature. Diethyl ether (£44 mL) and more of the saturated aqueous solution and 1,101,100 were added, respectively. ° the organic layer has been separated; and washed Ob ye with saturated aqueous NaHCO; then washed with saline solution; dried on MSOs, filtered and concentrated to obtain: 4-bromo-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1 H-pyrazole-3 -carboxylic acid V4.VY) g ; AY output 7). Melting point: from 177 °C to 774 °C. 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3 -carboxylic acid \ to a solution that was stirred with a magnetic tool composed of : 4-bromo-5 -(4-chlorophenyl)-1-(2,4-dichlorophenyl)- 1 H-pyrazole-3-carboxylic acid © 1111 aa ) mmol) in anhydrous tetrahydrofuran Yo. ) (THF mL); (Yo.Ve) n-butyllithium added ml; A solution of 011 M YOY mM (Uso) and the resulting solution, V0, was stirred for 1 32 minutes in an Np atmosphere at a temperature of YA = C. A solution of (CHsS)y 11 was added a) 9 mmol) in anhydrous THF (Se 1) using a syringe; then the resulting solution was stirred at YA = C overnight. The reaction mixture was quenched with more water and the resulting solution was extracted using diethyl ether The diethyl ether layer was washed with water, dried at 0.24850, filtered and concentrated to obtain:

Y 7 — _ 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3 -carboxylic acid crude which was further purified using a chromatogram Flash (separation liquid: 0 = methanol / dichloromethane | © (vol/vol)) followed by purification by 0 separation by flash chromatography (separation liquid: ethanol / dichloromethane = 40 © (vol/vol)) to yield On : 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1 H-pyrazole-3-carboxylic acid ; (7.5 g) which was converted directly to the reaction step next. 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-N-(piperidin-1-yl)-1 H- 01 pyrazole-3-carboxamide 0 Cl als ri) Cl NN s—ch, Cl compound 1 to a magnetically stirred solution of: 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methylsulfanyl-1 H-pyrazole-3-carboxylic acid.

Vo

4 c 1117 mmol) in 001 (dichloromethane ml); Added : 11 aa 7 ) 7-aza-1-hydroxybenzotriazole (HOAt) mmol); and (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI)) ) ).¥ g; 061 mM 1-aminopiperidine s (Je 1 g; 11 mmol) respectively. after flipping 1 sad © hour; The resulting mixture was successively jue with water (xT), dried at 1250, and filtered; and concentrate it to obtain a raw solid. This crude solid was further purified by chromatograph separating YA 77 = heptane / EtOAc « silica gel (vol/vol)) and pulverizing with n-heptane/methanol to yield: 5-(4). Compound (1(1)-2.00 g; 01 7 output). Melting point: from 177.4 to 174.5 C. (m, 2H), 1.72-1.81 (m, 4H), 2.40 (s, 3H), 1.41-1.49 E" H-NMR (CDCls, 400 MHz) (m, 4H), 7.15 (br) d, J = 8 Hz, 2H), 7.28-7.35 (m, 4H), 7.42 (br d, ] =2 Hz, 2.83-2.95 1H), 7.94 (br s, 1H).*C-NMR ( CDCl;, 100 MHz) § 20.03, 23.32, 25.29, 57.02, 113.66, Vo 4, 127.99, 126.20, 158.62, 147.30.

compound (Y) 1-(4-Chlorophenyl)-2-(methylsulfanyl)ethanone to a magnetically stirred solution of A) bromo-4-chloro-acetophenone .11 g YY mmol ) in Yeo ) methanol ml); YY (px ©. Y ¥) NaSCH; mmol) 0 was added for an exothermic reaction. then react the resulting mixture for ¥ an hour at ia room temperature; his focus; suspended in (Je V0 +) dichloromethane and washed with water; dried on <MgSOy and filtered; And its concentration to obtain: 1-(4-chlorophenyl)-2-(methylsulfanyl)ethanone (8.1 g). (s, 3H), 3.72 ) 2H), 7.44 (br d, ] = 8 Hz, 2H), 2.13 E" H-NMR (CDCls, 400 MHz) (br d, J = 8 Hz, 2H) \ 7.92 Ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3- carboxylate Y) Sodium metal dissolved g; AY (mmol) in Av) ethanol (ml). The resulting solution was added to a magnetically stirred solution of (can) diethyl oxalate (1 mmol) and d(A) 1-(4) -chlorophenyl)-2-(methylsulfanyl)ethanone 56 mmol) The resulting mixture was reacted for 0 h at room temperature, then poured into 001 aqueous hydrochloric acid (ml; 1 N) The resulting mixture was extracted twice with methyl-tert-butyl ether (Ja 001) (MTBE), dried over MSOs, filtered, and concentrated. The resulting residue was dissolved in acetic acid 001 ml; 2,4-dichlorophenylhydrazine and

b m A ) HCl g Ee m ag (Js) Heat the resulting mixture at Te mm for ? hours. The reaction mixture is allowed to come to room temperature; its concentration is approximately *0 ml; and pour it into (Ja Yoo ) slo followed by extraction with MTBE (¥ volumes of Yoo ml). The combined organic layers were washed with 78 NaHCO;3 aqueous; dried on MSOs©, filtered and concentrated. Further purification with a silica gel column chromatography) lysed separator: 01 / 90 = heptane/ethylacetate (vol/v)) yielded: ethyl 5-(4-chlorophenyl)-1-(2,4 -dichlorophenyl)-4-methylsulfanyl-1 H-pyrazole-3- carboxylate) £.9 g; With an output of Rs. (% YY about ¢.+ ) 01 [ 40 = heptane/ethylacetate (vol 0 vol)). (t, J = 7 Hz, 3H), 2.32 (s, 3H), 4.46 (q, J = 7, 2H), 1.44 E (CDCls, 300 MHz) 11-111 (m, 7H) 7.10-7.45. Lithium 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3- carboxylate 1 to a solution stirred with a magnetic tool composed of: ethyl 5- (4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1 H-pyrazole-3-carboxylate

Y \ — — ) .9 pounds; 11 mmol) in V+ + (tetrahydrofuran ml); (+.£Y) LIOH.H0 g added; 11 mmol) and the resulting mixture was reacted for 10 hours at a temperature of 6°C, then concentrated in vacuo. Then use: lithium 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3- carboxylate ° in the next step. 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-N-(pyrrolidin-1-yl)-1H- pyrazole-3-carboxamide (compound ))1 ( 0 Cl of lS N= S—CH, b cl compound 2 \ to a magnetically stirred solution of: lithium 5-(4-chlorophenyl)-1-(2 ,4-dichlorophenyl)-4-methylsulfanyi- 1 H-pyrazole-3- carboxylate (110 g; ? mmol max) in YO) dimethylformamide ml); Added: a

1 FEN Y.Yo ) O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate g +.&) +) l-aminopyrrolidine hydrochloride 5 «(Je 011) triethylamine 5 mmol ) m; 00 hours were allowed at temperature VA mmol), respectively. After stirring for a period of time, it was concentrated in the medium of an incubator. The ad yall of the resulting mixture was crushed by reaching a temperature; the remaining silica gel) with water and then purified by flash chromatography (0: vol) to obtain /axa) Ao / Yo = heptane / EtOAc: sequential 5-(4-chlorophenyl)-1- (2,4-dichlorophenyl)-4-methyl-sulfanyl-N-(pyrrolidin-1-yl)-1 H- pyrazole-3-carboxamide .) 7 5 4 product can +. YA) (Y) compound H-NMR (CDCl3, 400 MHz) 1.88-1.96 (m, 4H), 2.39 (s, 3H), 3.02-3.08 (m, 4H), 7.15 yo . (brd, J = 8 Hz, 2H), 7.29-7.33 (m, 4H), 7.42 (br s, 1H), 7.98 (br s, 1H) 5-(4-Chlorophenyl)-1-(2,4- dichlorophenyl)-4-methylsulfanyl-N-(azepan-1-yl)-1 H- pyrazole-3-carboxamide ((¥) (compound 0 Cl HI 7 s—CH, d3

Cl component "

Yevn

Compound () was prepared similarly as described for compound (?) Lad above from: lithium 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3 - carboxylate, azepan-1-ylamine

.707 by DMF AEN «TBTU "H-NMR (CDCl;, 400 MHz) § 1.64-1.68 (m, 4H), 1.72-1.79 (m, 4H), 2.38 (s, 3H), 3.18- © 3.22 (m, 4H), 7.15 (br d, J = 8 Hz, 2H), 7.29-7.33 (m, 4H), 7.42 (br t, J ~ 2 Hz, 1H), 8.43 (brs, 1H). -NMR (CDCl;, 100 MHz) .65, 136.36, 147.26, 147.31, 158.87 -5( 4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfonyl-N-(piperidin-1-yl)-1H-p' pyrazole-3-carboxamide (4) (compound) : to a magnetically stirred solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-N-(piperidin-1-yl)-1H-pyrazole-3- carboxamide Vo mM 5 Ye g aqueous solution (Y.Y) m-CPBA mM); 0141 gm added; +. V1) and then pour it into “ad yall” for an hour at a temperature of 11 mol). Then conduct a reaction for the resulting mixture for a period of 1 ml). YO) dichloromethane (ml) has been separated. The resulting mixture was extracted using Yo) Yer water

Separation by column chromatography (methanol / dichloromethane ¢ silica gel) = 90 / © (vol / volume)) resulted in obtaining: 5-(4-chlorophenyl)- 1-(2,4-dichlorophenyl)-4-methylsulfonyl-N-(piperidin-1-yl)-1 H-pyrazole-3-carboxamide HT YA) mg; Jo) compound (¢(( (m, 6H), 2.47-2.63 (m, 2H), 3.31 (s, 3H), 3.55-1.70-2.10 E” H-NMR (CDCls, 400 MHz) ) (m, 1H), 3.82-3.90 (m, 1H), 7.12 (br d, J = 8 Hz, 2H), 7.31-7.36 (m, 4H), 7.42 (d, 1 3.62 1H) , 10.80 (br s, 1H). 2,4-dichlorophenyl)-4-methylsulfinyl-N-(piperidin-1-yl)-1 H- 01 pyrazole-3-carboxamide (compound )°(( 0 Cl N —_ L B harmful / Cl N SCH, 7 0 cl compound 5

Doss - to a solution stirred with a magnetic applicator consisting of: 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-N-(piperidin-1-yl)-1H- pyrazole- 3-carboxamide 0 no 0.41 cpa mmol); m-chloro-perbenzoic acid (m-CPBA) (+©.+ 0 g 1 Ve mmol aqueous solution) was added. The resulting mixture, Yo sad, was reacted for an hour at room temperature; Then it was dua in water (YO) ml). The resulting mixture was extracted using (Je YO) dichloromethane. The organic layer was separated, dried over MgSO, filtered, and concentrated. Separation was performed by a silica gel column chromatography; methanol / dichloromethane = 59 © (vol/vol)) to obtain: 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-sulfinyl-N-(piperidin-1-) yl)-1H-1 pyrazole-3-carboxamide cpaVO) with (£7) (compound (0)” H-NMR (CDCls, 400 MHz) § 1.41-1.49 (m, 2H), 1.72-1.81 (m, 4H), 2.84-2.96 (m, 4H), (s, 3H), 7.15 (br d, J = 8 Hz, 2H), 7.27-7.32 (m, 4H), 7.43 ( br s, 1H), 8.70 (brs, 3.11 m ,128.03 ,124.67 ,122.91 ,56.97 ,41.84 ,25.22 ,23.28 AH 1H).BC-NMR (CDCl, 100 MHz) 157.60 ,144.85 ,144.62 , 136.98 , 130.41 , 130.41 , 130.63 , 133.01 , 133.01 , 133.01 , 133.01 , 136.51 , 130.63 , 130.41 , 128.66 Example 4: Pharmacological methods Affinity in vitro for cannabinoid CB receptors; The affinity of the compounds of the invention for cannabinoid CB receptors can be determined; © ull Using membrane preparations from WDA Chinese hamster ovary (CHO) in which the cannabinoid receptor CB was stably infected with PHICP-55,940 as compound

Cope with Radiant Bion. After incubation of the cell membrane preparation prepared Jad with or without the addition of the compounds of the invention; [PH] bonded compound was separated by filtration on glass fiber filters. All of the bond and the ligand were measured on the filter by scintillation counting using liquid. The cannabinoid receptor (CHO) using ovarian cell membrane preparations as PHICP-55,940 ligand was consistently infected with (54d) cannabinoid CB, radioactive. After incubation of the freshly prepared cell membrane preparation with the compound with or without the addition of the compounds of the invention; Separation of the ligand [PH] 0 and the free ligand compound was carried out by filtration on glass fiber filters. The radioactivity on the filter was measured by scintillation using a liquid. In vitro cannabinoid CB; ill The antithesis of a quasi-future

CB; In vitro using the cannabinoid receptor CB antagonist to the cannabinoid-like receptor ani (Sa) in culture medium from human CHO cloned in ovarian (0110) cells. 1 Jae cells were cultured from 701 fetal serum using Js (DMEM) Dulbecco's Modified Eagle aly without fetal calf serum; “heat-activated DMEM”. Medium was rinsed, replaced with /75, and overnight incubated in a [*H]-arachidonic acid cell culture oven. contains m; water-saturated atmosphere). acid include 0

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lod) the medium was rinsed and the cells washed three times with .01* mL of DMEM containing 70.7 bovine serum albumin (BSA) stimulation of the CB receptor; by : 2-2 1718 led to PLA is activated, followed by the release of [H]-arachidonic acid into the medium. There was an antagonism of 55,212-2 WIN concentration-dependently induced release by CB receptor antagonist Agents 0; hypotension induced by CP-55,940 in rats Anesthetized normal blood pressure male rats (of YYO to Yoo g; The “Horst” Harlan (Netherlands) using At) pentobarbital mg/kg transperitoneally). Cal pressure was measured with a pipette inserted into the left carotid artery with a 0 bial transducer. (Spectramed B.V., Bilthoven, The Netherlands) Spectramed DTX-plus 0 Nihon Kohden Carrier Amplifier ddan Type: “AP-621G; Nihon Kohden B.V., Amsterdam, The Netherlands, and then recording the blood pressure signal on a personal computer (Compaq Deskpro 386s) with Po-Ne data acquisition software (Po-Ne-Mah Inc., Storrs, USA). -Mah The heart rate was inferred from the pulse 1 pressure signal. All compounds were administered orally as a microsuspension in 7 methylcellulose ½ min before the induced sedation sensation occurred 01 min before the administration of receptor cofactor CP-55,940,63. The volume of the syringe was 01 ml/kg. after hemodynamic stabilization; then give adjuvant CP-55,940 ) + 1 mg/kg; intravenously) to the CB receptor; and then stabilize the hypotensive effect.

A — — Example (2): Results of pharmacological tests Affinity data for CB para-receptors, cannabinoid CB, are shown; ull (mean results for at least three independent variables; performed according to the protocols described above) of the recombination product and compounds (1) to (*) are shown in the following table. These °data show the effect on a thousand CB receptors, and D03; CBin receptor selectivity ratios as well as their activity in the organism after oral administration which is achieved by means of structural modification which are the bases of the present invention; A CBin receptors for compounds (4) 5 (0) are also explained. oxidative stress- 5. CB1/ |WCB; |68: |(average) blood pressure CB,

Compound X | no | KioM | KM | n | ratio | EDsp (mg/

pas oral) the product of the return union | 012 | 11 | ny YoA.

Yo 1 that the genetic

Saqan | [eo [ve [ORS] »| At Sian ‎[x JOBSO] JA | PN 07 | Label [wT [ORS] Yer

Dom - Table: (1) A CB receptor) 5 CB and activity in the organism in a rat model resulting from a CB receptor specific to the product of genetic recombination and compounds from (1) to (©) of this invention and A CB receptor for (;) and (*) oxidized compounds - 5 ; and 00 - unspecified Example (+): Pharmaceutical preparations:

oo for clinical use; The compounds of formula (1) are formulated into pharmaceutical formulations which are new and important embodiments of the invention since they contain the compounds; Especially the specific vehicles described in this application. Among the types of pharmaceutical formulations that can be used, for example, are not limited to; al BY and chewable tablets; capsules (including mini capsules); solutions; and solutions that are given through the digestive system; and ointments

0 (creams and gels); suppositories; Commentaries and other types are described in this application or are clear to those with experience in this field from this application or general information in this field. The formulations are used for oral ¢, intravenous, subcutaneous ¢ or tracheal administration; or through the bronchial + or through the nose ¢ intranasal ¢ or through the lung 0 pulmonary or through the skin transdermal ; or by

10 buccal or rectal rectal + or other than through the digestive system; or by using other methods of administration. A pharmaceutical preparation contains at least one compound of Formula (1) in a mixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier. It is appropriate that the total amount of active ingredients range from about 7000 (w/w) to about 795 (w/w) of the preparation and it is appropriate for it to range between 70.8 and 780 (w/w).

© wt); Preferably between 71 and 775 (w/w).

benefit

The compounds covered by the invention can be formed into forms suitable for administration by conventional processes using adjuvants as liquid, solid or powder components; Such as: liquid or solid fillers, liquid or solid fillers, and/or solvents; and/or emulsifiers and/or lubricants ¢ and | or flavorings ©; And / or coloring materials and / or materials regulating pH 711. Commonly used auxiliaries are: titanium dioxide “magnesium carbonate ¢” and “lactose” and “saccharose” and “sorbitol”; and 8101 «other sugar alcohols or sugar alcohols» TALC s; milk protein; gelatin; and starch, amylopectin « cellulose s and its derivatives; vegetable and animal oils; Jie; fish liver oil; or (0)onal sunflower oil or peanut oil; or sesame oil; and 1e”in polyethylene, solvents such as sterile water, mono- or poly-alcohols, glycerol Jia hydroxyl; As well as loosening and lubricating agents such as: magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture can be processed into granules or compressed into tablets. Active ingredients may be mixed with other inactive ingredients separately in advance; This is before Gee mixes it to form the lotion. like that; Active ingredients can be mixed with each other; before mixing it with inactive ingredients to form a lotion. Aad softgel capsules can be prepared using capsules containing a mixture of the © active ingredients of the invention; or vegetable oil; or fat; or other suitable carrier for softgel capsules

LAL) hard gelatin capsules may contain granules of active ingredients. Hard gelatin capsules may also contain the active ingredients together with a solid ingredient in powder form such as lactose, saccharose, sorbitol, mannitol, potato starch, or cornstarch; or starch pectin or cellulose derivatives; or gelatin. Dosage units 0 for rectal administration may be prepared as (1) as a suppository containing the active ingredient mixed with a neutral lipid base; or (Y) as a softgel capsule for rectal use containing the active ingredient in a mixture with oil vegetable, paraffin, or other suitable carrier for these capsules; or (TF) as a ready-to-use microenema; or (;) as

A dry microenema preparation that is reconstituted in a suitable solvent immediately prior to administration. 0 Liquid formulations may be prepared as syrups; or elixirs or concentrated points; or suspensions - such as solutions or suspensions containing the active ingredients and the remainder consisting, for example, of sugars or sugar alcohols and a mixture of ethanol; water 5 glycerol; polyethylene glycol 5 » propylene glycol . as you like; These liquid preparations may contain coloring agents. or flavoring agents” or “preservatives” i.e. carboxymethyl cellulose s saccharine ¢ or other flavoring agents. Liquid preparations can also be prepared in the form of a dry powder; It can be reconstituted with a suitable solvent before use. Solutions for non-gastrointestinal administration may be prepared as a solution of the formula of the invention in a pharmaceutically acceptable solvent. Also, these solutions may contain stabilizing ingredients and/or preservatives; and/or pH regulator components. Solutions for administration can also be prepared without the device

digestive in the form of a dry preparation; It can be reconstituted with a suitable solvent before use.

M. There are also preparations according to the present invention and “parts of therapeutic combinations” comprising one or more containers filled with one or more components of the pharmaceutical composition covered by the invention; For use in medical treatment. Associated with these container(s) are various written materials such as instructions for use; or a notice in the form provided by a government agency regulating the manufacture, use, or sale of pharmaceutical products” and such notice reflects the agency’s approval of the manufacture; use, or sale for human or veterinary administration. The preparations covered by the present invention can also be used in the manufacture of drugs used in the treatment of a condition in which resistance to 5, cannabinoid receptors is desired; and methods of medical treatment comprising the administration of a total therapeutically effective amount of at least one compound of the formula (:); to a patient suffering from m or ys susceptible to; A condition in which resistance to cannabinoid ull receptors is desired. CB;

Yer

Claims (1)

Broad Claims 1 -1 Compounds having the general formula (): 0 Cl GH 1 rhs" R, Y 0 7 R, 7 where: "Br J " Cl § HJR - 6 © - according to “Br § “Cl X - 1 represents a sulphur ¢ atom or sulfoxide fraction (0-m) or sulfone fraction not” (S0Oy ) Y - A represents the ethyl sl methyl group « 4 - © » can have value 0, 7 or 7 0 and the enantiomers are tautomers ; ¢ and 11-0<1088_terminator and isotopic numbered compounds that Ld 1 of formula oI) in addition to the pharmaceutically acceptable salts 5 hydrates; and the solutes of 10 of the said compounds having formula (I) and the tautomers ¢ or N-oxides yy or 1 ?- Compounds according to claim No. (1) having the general formula (1) where Ros Ry - represents “Cl and 7 represents a methyl group; and “ represents 1 or ; and 2 shall have the meanings Y indicated pursuant to Claim No. (1). — $ $ —_ =F) The Gig compounds of claim No. (1) represented by the following formulas: 0 0 Cl Cl =r v= S—CH, Cl N 7 S—CH, 7 His Cl Cl 1 ;- a pharmaceutical composition comprising, in addition to one pharmaceutically acceptable carrier and/or one acceptable JY adjuvant (Giana), a therapeutically effective amount of one compound Je Y Least Gay of Claim (1); or a salt thereof as an Active Ingredient. +- A method for preparing a pharmaceutical composition according to Claim No. (?) or No. (*); characterized by Y in that the compound (Gs of claim No. (1) is formed in a form suitable for administration. -Y 1 Compound according to claim No. ( \ ) for use as a drug. 1 +- Compounds having the general formula (IV) Yer C — 0 Cl Y N — OR, / Ri NA xy (IV) R, Ros Ry Cum Y and 7 have the meanings given under claim (1); Ras is ¢ a lithium ¢ hydrogen atom "ie sodium" or potassium ; It does not represent a sulfur ©¢ atom, (S=0) sulfoxide part, or (SO) sulfone part, and these 1 compounds are useful in the synthesis of compounds of the general formula (1) 1-4 compounds having the formula General (V) 0 Cl N= OR, / N Ry 5 ( > xy Y ) 0 R, © where , 18, y and 7 have the mentioned meanings according to For claim No. (1); Rs ¢ represents a methyl group », “ethyl or propyl” These compounds are useful in the synthesis of 6 compounds having the general formula (1) - 1-01 Use a compound according to Protection Element No. (1) to prepare a pharmaceutical formula for the treatment of psychosis, anxiety, depression, attention deficits 3, memory disorders and perception disorders cognitive disorders ¢ ¢ and appetite disorders; Obesity — Tala 8 Obesity in young adults and Obesity Resulting from Drug Dependence 1; addiction, caddiction and appetite disorders, and drug dependence; neurodegenerative disorders A » dementia; dystonia ¢ q, muscle spasticity, tremor s, epilepsy | 0 and multiple sclerosis “traumatic brain injury 1”; stroke ¢ Parkinson's disease » Alzheimer's disease ¢ epilepsy ¢ Huntington's disease 0 embolus stenosis Tourette's syndrome ; localized cerebral insufficiency \R cerebral ischaemia; and sclerosis “plaque sclerosis” and viral encephalitis 08; demyelinisation related disorders | 4; in addition to the treatment of pain disorders Ye – including neuropathic pain disorders pain disorders YO and other diseases involving cannabinoid neurotransmission including YY including septic shock ¢, glaucoma and cancer YY; sugar diabetes; emesis vomiting; Nausea, asthma, respiratory diseases, gastrointestinal disorders, and gastric ulcers; diarrhea &diarrhea; and sexual disorders | 1 ¢ and cardiovascular disorders. Yes 11-1 Use of a compound according to Claim No. (1) to prepare a pharmaceutical composition for the treatment of obesity, especially obesity in young people and obesity resulting from drug dependence. 1? VY) is characterized by the aforementioned lipase enzyme being an orlistat or jipstatin —VE 1 process for the preparation of lily compounds of claim No. (1); where the Y reaction of the derivative (VII) takes place ) 1-aryl-2-alkylsulfanyl-ethanone (S—Y 0 ?) (Vly R, where Y 5 Ry shall have the meanings mentioned in accordance with Claim No. (1) in the form E-sequence with an oxalic ester derivative 4 of the general form (IX) Os, ORs "or 1 0 3 Yeyn V where Ry is a linear alkyl group Cp; 0” methyl) or n-propyl J”ethyl ( in A in the presence of a base, eg (NaOR;) sodium alkanoate in a solvent inert anhydrous organic; 1 as: methanol, lectin, or propanol, followed by reaction with the derivative “(X) arylhydrazine Ye a NH, 0 b” N H 11 ester to yield (1) For claim No. Gis, where 8 has the aforementioned meaning VY (V) has the general form VY 0 al: N= OR, / Ry NA S—Y Vv) y¢ R , M Ys «Rpg «Ry Cus 1 shall have the mentioned meanings according to Claim No. (Xs $) 1 ,. sulfur is an atom of sulfur yy Yer