SA05250465B1 - 1,3,5-trisubstituted 4,5-dihydro-1H-pyrazole derivatives having CB1- antagonists activity - Google Patents

Abstract

The present invention relates to 1,3,5-trisubstituted 4,5-dihydro-1H-pyrazole derivatives as CB1 antagonists, to methods for the preparation of these compounds and to novel intermediates useful for the synthesis of said pyrazole derivatives. The invention also relates to the use of a compound disclosed herein for the manufacture of a medicament giving a beneficial effect. The compounds have the general formula (I), wherein the symbols have the meanings given in the specification.

Description

Y —_ _— derivatives of 0— dihydro-111-pyrazole substituted at the three digit positions oy and "; e and have antiactivity — CB, 1,3,5-trisubstituted 4, 5-dihydro-1H-pyrazole derivatives having CB;- antagonists activity FULL DESCRIPTION BACKGROUND The present invention relates to 4,5-dihydro-1H-pyrazole derivatives having a substitution at ADB positions 0 and 5 © as antagonists to “CBI” and methods for preparing these compounds and new intermediates useful in the synthesis of the said pyrazole derivatives. The invention also relates to the use of a compound disclosed herein for the manufacture of a drug that gives a beneficial effect. Here the beneficial effect is revealed or is evident For the expert person in this field of full description as well as the general knowledge of this field. The invention also relates to the use of the compound of the invention to manufacture a drug for the treatment or prevention of a disease or As. More specifically; the invention relates to a new use for the treatment of a disease or condition that is disclosed Aie herein or would be apparent to a person expert in this field from the description or general knowledge of the field.In the embodiments of the invention certain compounds disclosed herein are used to synthesize a drug useful in the treatment of disorders involving cannabinoid-like receptors; Or that can be treated by manual treatment of these receptors. and in | International Application No. $1 Derivatives of: N-Aryl-4,5-dihydro- 1H-pyrazole-3-carboxamide are described as insecticides; But not as antagonists of 1 for the future of al and . 3,4-Diaryl-4,5-dihydropyrazole-1-carboxamidine derivatives are known as yyy.

_ 9"b as antagonists of the CBI receptor (see International Applications Nos. VV and 36771444; 741 and 07774/). With “ld,” the 4,5-dihydropyrazole derivatives described in this invention It has a significantly different system of substitutions at positions 1a, 5, and 5 and as a result must be prepared by a completely different method of synthesis. Present in the new 4,5-dihydro-1H-pyrazole derivatives substituted in the new 1, 0 and 0 positions of formula (1); and its conjugates and their salts: X N— / N - b wa (1) 0 where it has: Ry Ry - independently represent phenyl « or thienyl » or pyridyl groups that may have 1, 7 or ¥ substituent groups oF which can be the same or different; branched or linear alkyl Cp; or alkoxy; or phenyl “¢ or hydroxy ¢ or chloro” or bromo; or fluoro ¢ or m00 or trifluoromethyl Vo ¢ or trifluoromethylthio ¢ or trifluvoromethoxy or

— $ _ methylsulfonyl “or carboxyl”¢ or trifluoromethylsulfonyl ¢ or cyano ¢ or carbamoyl “¢ or sulfamoyl and acetyl ¢ or representing R; and/or naphtyl R ; “¢ - * represents one of the subsets (i) or (ii) R 0 AL 4 Ry SN Ro 0 N I]”> R, As R, ci y © 0 where it has: — s represents a hydrogen atom or a branched or linear © alkyl group; - b is alkyl Cr dc sane ar ven - dc ia alkyl = Ci, - cycloalkyl or linear; or the alkoxy group Cis ¢ rmin — alkyl - Ci, - cycloalkyl branched or linear; or a group of sands of cycloalkyl mi + any range of bicycloalkyl ¢ 01 or 0dm© tricycloalkyl branched or linear; These groups may contain one or more heteroatoms from group (0<(SN) and these groups may have a substitution of a hydroxy ¢ group or 1 — methyl groups or an ethyl group or 1 - “fluoro atoms” or representing some phenyl group “or phenethyl J” benzyl J “phenoxy or phenylpropyl ; having an optional substitution on its Vo of its phenyl ring by 1 - ¥ substituent sets of oY where for y is yy

Ajen - the aforementioned meaning; or Ry is a pyridyl or thienyl group ; Or represents ic gana Ry m 1182 where it has: Rs and with two formations with the nitrogen atom attached to it a heterocyclic group; saturated or unsaturated; Monocyclic or bicyclic: to 10 m atoms per ring; This heterocyclic group contains one or two heterocyclic atoms from the group (0; 5) and this heterocyclic group can have a substitution of a linear R-branched group between the alkyl «hydroxy of «phenyl» or trifluoromethyl or a fluoro atom “or Ry 5 Ry forming with its attached nitrogen atom a non-homocyclic group 1; saturated or unsaturated; Monocyclic or bicyclic: to 10 atoms per ring; This heterocyclic group contains one or two heterogeneous atoms from the group (0; 8) and this heterocyclic group can have a substitution of a branched or linear group of alkyl “that is, phenyl” that is, “amino” hydroxy « or trifluoromethyl or fluoro atoms ysl atom « Ry - Vo representing a benzyl group « or thienyl « phenyl ; or to pyridyl; 5 038 Groups may have a substitution on their aromatic ring of 1 or FF or ; replace groups 7 where 7 has the meaning given above; which may be the same or different; of a linear J-branched alkyl C5 Caio of « alkenyl Css of cycloalkyl ; or bicycloalkyl Cs. “or mono tricycloalkyl” or Cs cycloalkenyl 7 or b stands for 0 naphtyl or Ry stands for amino group ” or 87 stands for

-

“dialkylamino C;.3 group” or “monoalkylamino group” or group

monocyclic, bicyclic or heterocyclic saturated or unsaturated with it of;

to 10 cyclic atoms; This heterocyclic group contains an atom or

Two nitrogen atoms may contain this heterocyclic group

> on one heterocyclic atom of group (0 5) and this heterocyclic group can have a substitution of an alkyl group C13 “or” phenyl or

0 hydroxy or trifluoromethyl branched or linear or fluoro atoms;

- M8 represents a hydrogen atom or a branched or linear b-alkyl group;

id Ry 0 - hydrogen atom or branched or linear alkyl Cs group;

of 01 min cycloalkyl or bi alkyl is heterogeneous and may ui these groups with the keto group; Or with a group of 0 trifluoromethyl or a fluoro atoms or

Ry stands for amino ¢ or hydroxy group OR phenoxy ¢ or benzyloxy group ¢ or Ry stands for

alkoxy Cry branched or linear group; which may be replaced by a hydroxy group; or with a trifluoromethyl group or a chloro fluoro atoms “or and representing a phenyl Vo” or benzyl group; or pyridyl ¢ or thienyl ¢ or methyl pyridyl or phenyl ethyl where aromatic rings may be substituted by 1 or 1 or ¥ substituent groups of 7;

where Y has the meaning given above; or Ry representing an NRyoR group, provided that Rg represents a hydrogen atom or a methyl group and where Rio and Ry are the same or different and are represented by an alkyl or 7 between trifluoroalkyl Or form Rios Ryo - with the two bonded nitrogen atoms

1

in it - a heterogeneous annular cleft saturated or unsaturated with it from; to 8 cyclic atoms and contains this

The heterocyclic slit contains one or more atoms of group (0; ON 5) and can substitute

This heterocyclic moiety is saturated or unsaturated with the “alkyl Cp” group

Ros Ry - with its nitrogen atom attached to it - forms a monocyclic or dicyclic heterocyclic ila moiety; saturated or unsaturated with it from; to 01 dala atoms

This heterocyclic moiety contains one or two atoms from group (0; (SN) or

keto group or -SO group; -; This moiety can be replaced by a group: © alkyl ¢

or hydroxy “¢ or phenyl” or methylamino “¢ or dimethylamino” or azetidinyl ¢ or

,. hexahydro-1H-azepinyl or piperidinyl or ¢ pyrrolidinyl

4,5-dihydro-1H- of the Cs moiety at position 2 ie) at least one chirality and a center 0 exist; and mixtures of racemates of JS tracers. The invention relates (I) to compounds of the formula (pyrazole) different from stereoisomers and diastereomers of asmqn and ©9000 27 and 1E mixtures. The invention also relates to each of (I) Compounds with formula (I) are compounds with formula 27

1 Prodrugs are therapeutic agents that are inactive by themselves but are converted to one or more active metabolites. Prodrugs are biologically reversible derivatives of drug molecules used to overcome certain contraindications to the original drug molecule. This sal includes; But it is not limited to solubility; permeability; constancy; Pre-exhaustive metabolites and target selections:

Y.

A —_ _ Medical Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed.: F.

D. King, p. 215; J.

Stella, “Prodrugs as Therapeutics”, Expert Opin.

Ther.

Patents, 14(3), p.

Ettmayer et al., “Lessons learned from marketed and investigational prodrugs 2004, 277-280”, J.Med.Chem., 47, 2393-2404, 2004. Any compounds which, when administered to humans by a known method, are metabolized to compounds of formula (oT) belonging to the invention. In particular, these relate to compounds with a primary or secondary amino or hydroxy group. These compounds can react with organic acids to produce compounds of formula Cua(I) that have an additive group and that are easily removed after administration; For example; But it is not limited to enamine § « amidine ; ye or Mannich base ¢ or : hydroxyl-methylene derivative, an O-(acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone. The invention relates particularly to compounds having the formula (0): X N y / R,—N is (0) vo where it has: yyy

- ,8 and 82 independently represent phenyl ; This phenyl group can be replaced by 1, 7, or ¥ 7 substitution groups; which may be the same or different; of the linear J subgroup bar alkyl or alkoxy » or phenyl or hydroxy « ¢ or chloro » or bromo ; or fluoro ¢ or 1000 or trifluoromethyl ¢ or trifluoromethoxy 0 ¢ trifluoromethylthio ° ¢ or methylsulfonyl “or carboxyl” or trifluoromethylsulfonyl “or cyano ¢ or carbamoyl” or acetyl 3 sulfamoyl « or stands for B and / R naphtyl R » i.e. thienyl » i.e. pyridyl . - * represents one of the subsets (1) or H(i) R 0 and a) 8 AL Rs N N 0 / "L R > N—S—R, 4 ka (i) iy © 0 where it has: - and 8 represents a hydrogen atom « -mg represents a branched or linear alkyl Cis Ac gana or an alkoxy Cis ic gana ¢ or a branched cycloalkyl group or linear; these groups may have a substitution of a hydroxy ¢ group, 1- µ-methyl groups, an ethyl ¢ group, or -1 Vo fluoro atoms” or represent Ry 0 phenoxy group i.e. 0 thienyl 4 “pyridyl or Ry represents the NRsRs group where it has yyy

- 1,0 to which they are attached to a non-nitrogen atom ring group forming with the nitrogen atom Res Rs homologous 01 atoms; saturated or unsaturated; Monocyclic or bicyclic: to the loop. This heterocyclic group contains one or two heterocyclic atoms from group (0; 27 5); or to which they are attached to a non-nitrogen atom ring group and form with the nitrogen atom Rs ° 01 homologous atoms; saturated or unsaturated; Monocyclic or bicyclic: to by loop This heterocyclic group contains one or two heterocyclic atoms of, and this heterocyclic group can have a substitution (SN 0) of the group “fluoro atoms ssl” or a trifluoromethyl atom or “hydroxy” « methyl with this group on its phenyl ring, and the ¢ phenyl group can be replaced representing the 8 - 01 group, where 7 has the meaning of the aromatic oY with the number 1; or?; or 9 or; Branched alkyl Cig substituent groups representing the Ry shown above; which may be the same or different; or JAG group or BA 1. bicycloalkyl form of ¢ cycloalkyl form of or sin

Cig ic sans a “dialkylamino” or “b” amino group or “monocyclic, bicyclic or heterocyclic” monoalkylamino Vo cyclic atoms; This ring group contains 10 saturated or unsaturated from ; To these 0100860 heterocyclic atoms may contain one or two nitrogen atoms (S < 0) of the heterocyclic group on one heterocyclic atom of the group

Cis and in this heterocyclic group can be replaced by an F group

phenyl J “alkyl” or hydroxy “or trifluoromethyl branched or linear or fluoro atoms “ Rg - represents a hydrogen atom or a branched or linear © alkyl group; - and 8 represents a hydrogen atom or a branched or linear alkyl Cig group; ° or mo-cycloalkyl + and these groups may be replaced by a trifluoromethyl group » or a fluoro atom 1 fluoro atoms or Ry representing a hydroxy ¢ amino group » or phenoxy i.e. <0 number or Ry The group represents: © branched or linear alkoxy; Or Ro is a phenyl group where the aromatic ring may be substituted by the number 1, 7, or ? oY substitution groups where 7 has the meaning given above; or Ro 01 representing the NR group oR; provided that Rg represents a hydrogen atom or a methyl group and where Rig and Ry; are the same or different and represent an alkyl Cia or between trifluoroalkyl or Rigs Ry forms - with a nitrogen atom attached to it - a heterocyclic moiety saturated or unsaturated with it; to 8 cyclic atoms and this heterocyclic moiety contains one or two atoms of group (0; 8 5) or RosRgVo - with its attached nitrogen atom - forming a monocyclic or dicyclic heterocyclic; saturated or unsaturated with it from; to 10 cyclic atoms; This heterocyclic moiety contains one or more atoms of group (0; (SN) keto group or -SO; - group.

- 11 -

It has also been found that compounds of the general formula (1) in which the meaning of Ry is phenyl;

Any compounds described in International Application No. 8805647; They are effective as .CB receptor antagonists

Due to the potent antagonistic activity of the CB receptor, the compounds according to the invention are suitable for use

In the treatment of psychiatric disorders such as psychosis and anxiety

canxiety and depression; Attention deficits ¢ and memory disorders

memory disorders, cognitive disorders, and appetite disorders

Appetite disorders ¢ and obesity Obesity ¢ Especially obesity Obesity among boys and obesity

Obesity caused by cdrugs, addiction ¢ and impulse control disorders

impulse control disorders 0; appetite; Drug dependence and disorders

Neurological disorders such as neurodegenerative disorders » dementia

0 and dystonia; muscle spasm and tremor; and epilepsy

0 epilepsy, multiple sclerosis, and traumatic brain injury

traumatic brain injury ¢ stroke; Parkinson's disease ¢ disease

Huntington's disease; Huntington's disease; epilepsy; and epilepsy Alzheimer's disease vo

Tourette's syndrome; and cerebral ischaemia

cerebral stroke (bleeding); craniocerebral traumatic apoplexy; and spinal cord injury

« demyelinisation related disorders viral encephalitis

In addition to the treatment of pain disorders; Including pain disorders

treatment of pain disorders 00 neuropathic pain disorders » and disorders

8 for others involving cannabinoid neurotransmission al ¢

DSG-Lay includes treatment of septic shock ¢, glaucoma ¢ and cancer; Diabetes mellitus «emesis vomiting» and nausea nausea; Asthma & respiratory diseases; gastrointestinal disorders; gastric ulcers; diarrhea, and cardiovascular disorders; Articular sclerosis, catherosclerosis, liver cirrhosis, and sexual disorders. The IL receptor modulating activity of the compounds of the invention makes them particularly useful in the treatment of obesity; obesity in boys; drug-induced obesity; When used in combination with lipase inhibitors! such as lipstatin (from Streptomyces toxytricini) and 8 ebelactone (from Streptomyces aburaviensis) and synthetic derivatives of these compounds, as well as extracts from plants known to have lipase inhibitory activity, for example extracts of Alpinia officinarum or compounds isolated from these vo extracts 3-methylethergalangin Jie (from A. officinarum). General aspects of synthesis: Synthesis of compounds of formula (1) wherein X represents the subgroup ( i) is mentioned in Scheme No. 1. Intermediate compounds of the general formula (VII) can be obtained according to known methods; laf for example: International Application No. AAJ eT and the references mentioned therein.

— $ \ — Intermediate compounds of the formula (Vv) can be obtained according to known methods; and for example:

<Shawali et al., J.

Heterocyclic Chem. 2003, 40 (2), 207 and the references cited therein. The conversion of compounds of formula (I) to compounds of diazonium chloride diazotation of formula (IIT) by treatment with NaNO, under acidic conditions (HCI) can be given

With (Im) e the alkyl 2-chloro-3-oxobutanoate derivative, such as ethyl 2-chloro-3-oxobutanoate (IV) can give a 2-chloro(hydrazono)acetate derivative of general formula (V). Reaction of (V) with an alkene derivative of formula (VI) can give a 1,5-disubstituted-4,5-dihydro-1H- pyrazole-3-carboxylate. (vm) substituted in positions No. 05 with the general formula 0 to give (Me;AL) trimethylaluminum 117b8e8; It is preferable to have an amine with (VII) and with 8 that have the same meaning given Rs, and (i) is the subgroup X, where it is represented by (I) in the above formula on page ?. For more information on amide group insertion reactions reinforcing esters, see: trimethylaluminum AL(CHs); .J 1. Levin, E.

Turos, S.

M.

Weinreb, Synth Commun. (1982), 12, 989-993. \o

_ 1 m — 0 mile NaNO,/HCI (IV) km' Ri Cl

R—NH, from R—Nj+Cl- Calt = NN

CO,Et 0 (i) v) (V1) 0 0 n— © soc, N= OH N=

R—N ~—— RA = Re

R, R, Re (IX) (Vin (Vin)

RyR,NH, RyR,NH

AN Labbaqi | coupling reagent MeAl

AN

N=

R,—N

R, 0) wherein X represents subgroup (i) 1. Plot the carboxylic acid number with water to (VII) as an alternative method; A compound of general formula can be analyzed

RsRNH amine the resulting analogue with (VIII) carboxylic acid analogue. And it is possible to interact (VIN) and B with the same Ry and be (i) in which it represents the subgroup (oT) to give a compound with the formula “active” or ester “Jie formation” meaning given above on page 7 ; By activation and coupling methods: Jia ¢ in the presence of what is called a coupling agent

DCC, HBTU, BOP, CIP (2-chloro-1,3-dimethylimidazolinium hexafluorophos-phate),

PyAOP (7-azabenzotriazol-1-yloxytris(pyrrolidino) phos-phonium hexa- fluorophosphate) carboxylic acids to amines and the like. For more information on activation and pairing methods: Refer to °

M. Bodanszky and A. Bodanszky: The Practice of Peptide Synthesis, Springer-Verlag, {¢t New York, 1994; ISBN: 0-387-57505-7; K. Akaji et al., Tetrahedron Lett. (1994), 35, 3315-3318) b. .F. Albericio et al., Tetrahedron Lett. (1997), 38, 4853-4856) (z thionyl chloride) with a halogenating agent such as (VIII) carboxylic acid Jeli Alay can be 0 amine with the corresponding (IX) compound. The compound (IX) can be reacted ) carbonyl chloride to give (SOCI,)

Ros Ry and oi) is the subgroup X to give the compound of formula (1); where it stands for R;RNH ?.dada have the same meanings given above in Rss R; And subgroup 0 is mentioned, X, and the synthesis of compounds with formula (1), where it represents

XY in Scheme No. \o corresponds to (X) carboxamidine to derivative (VI) and the compound of general formula can be converted and 01b011; followed by treatment with a water base. (Me3Al) trimethylaluminum Example using: carboxamidine to ester and for more information on this transformation of the

1 - - Lett. 2002, 43, 419 (Gielen et al.) Compounds of the general formula (X) where γ is ri and y have the meanings given above on p1 are new compounds. A compound of general formula (x) can be reacted with sulfonyl chloride R7SO,Cl in the presence of N-diisopropylethylamine Jie (DIPEA) to give a compound of formula oI) where X represents the subgroup (if ) and “Ros Ry” have the meanings given above on page 7; Rog Rg represents a hydrogen atom. The intermediate with general formula 1875071012 can be prepared from the corresponding compound 2750201 or by synthetic protocols (see, for example, McManus et al, J. (Med.

Chem. 1965, 8, 766 Carbonyl chloride of the general formula (IX) can be reacted with a compound of the general formula R7SONH, in the presence of a base such as NaH to give a compound of the general formula Cus (XT) 0 with which Ros Ry is formed And B-8 have the meanings given above on pages 1 and F, and compounds of the general formula (XT), whereby 18 is Rpg, and 57 have the meanings given above on page 1, and they are new compounds. The compound of formula (XT) can be reacted with a halogenating agent; For example, a chlorinating agent such as PCs and the like to give a compound with the formula (XT) where it represents 2 atoms of chloro or bromo. Compounds with the general formula Cua (XI) being RosRi and 87 having the 1 meanings given above on page 1 are new compounds. The compounds (XID) can be reacted with an amine of the general formula 311 and 8M8 to give a compound of the general formula No. (1); where X represents subset (ii) and Ry and B are Ros Rss have the meanings given above on pages 1 to 0.

A — \ _ NA, = X N= 0 / luminous / N= a MA, NHA R—art R 8 R 0 i, Jud 151370110015 9 (M1) 02331 27017, wherein R R HBSS NH 1 X 0 O hdogardi 2 ORME NA mt 3 ) 01 An 8 Ab R R R 5 od) 0 00 and 0 vherdin Xrepresarts subgroup (i) schematic number (Y) The choice of a particular synthesis method depends on factors such as compatibility of functional groups with the reagents used; possibility of using protecting groups; catalysts; activation and coupling agents and intrinsic structural features. contained in the final compound to be prepared.According to these procedures the following compounds can be prepared.Their purpose is to explain the invention in more detail, and therefore they are not considered as limiting the scope of the invention in any way.

- and 1 - Pharmaceutical Preparations: The compounds of the invention can be made into forms suitable for administration by usual processes using additional materials such as a solid or liquid carrier. The pharmaceutical compositions of the invention may be administered via the stomach; or by mouth; or by non-gastrointestinal route (by intramuscular or intravenous injection); or rectally; or locally (outwardly). They can be given in the form of solutions; or powders; or tablets; or Le capsules (including microcapsules); or ointments (creams or gels) or suppositories. The appropriate excipients for these formulations are liquid and solid fillers and extenders; solvents; emulsifiers; lubricants; flavorings; pharmaceutically available coloring and/or buffering agents. Frequently used additional substances that may be mentioned are: magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars. and tale, lactoprotein, gelatin, starch, cellulose and its derivatives; animal and vegetable oils, cod liver oil; or sun ale oil, or chervil oil, or sesame oil; 5 polyethylene glycol and Jia ¢ solvents sterile water; 5 mono- or polyhydric alcohols such as glycerol. Ve and the compounds of the present invention are generally given as AV ana combinations which are important and new embodiments of the invention due to the presence of the compounds; More specifically, the specific compounds that are CoS reported here. The types of pharmaceutical formulations that may be used include, but are not limited to, tablets and chewable tablets; capsules; solutions; non-gastrointestinal solutions; suppositories; pendants; And other types that are disclosed here or that are clear to a person who is an expert in this field © from the description and general information in this field. in invention models; Package or crew is offered

A. A medicinal product comprising one or more containers filled with one or more substances of the pharmaceutical composition of the invention. Various written materials may be attached to this container(s) Jie Instructions for use; a notice in the form of a recipe by the government agency regulating the manufacture; the use or volume of drug products; This note reflects the agency's approval of the manufacturing; or 0 usage; or size for human or veterinary administration.

Pharmacological methods:

Affinity for cannabinoid-like receptors - CB; in vitro:

The affinity of the compounds of the invention for OB receptors can be determined; oll And using membrane preparations from Chinese rabbit ovary (CHO) cells in which the infection was stably transduced with a cannabinoid-like receptor (CB).

01 human in association with [‘H]CP-55,940 as a radioactive ligand. and after incubation of the freshly prepared cell membrane preparation with the bonding compound [PH] with or without the addition of the compounds of the invention; Separation of the bound and free bonded compound was performed by filtration over glass fiber filters. Radioactivity on the filter was measured by fluorescence counting of the liquid. Antagonism of the β-receptor (CB) in the laboratory:

1 Antagonism of the CB receptor can be determined in vitro with human CB receptor cultured in Chinese rat ovary cells (0110). CHO cells were grown in Dulbecco's Modified Eagle culture medium (DMEM); Supplementing with 701% of heat-inactivated fetal dae serum. The medium was aspirated and replaced with DMEM without calf germ serum; but with [PH] radioligand contained and incubated overnight in a cell culture oven (70 CO, / 7485 air; saga VY is saturated

01 in the phospholipids of the membrane. And on [‘H] radioligand with water). During this period, the test medium containing DMEM was incorporated, the medium was respirated, and the cells were washed three times with .+0 ml to WIN 55,212-2 by CB; Bovine serum albumin (BSA) receptor booster 7 was brought into the medium. This release by [PH] radioligand is followed by release of PLA, activation of CB; It is a concentrate reliably antagonized by WIN55212-2 receptor antagonists © in vivo: ©, -il) receptor antagonism cognate in CP-55, 940 antagonism rating: 0 in vivo by deficiency test The pressure it produces (Sa

Harlan, Horst, The 001 g to YY0 (from pall rat. Normal female rats were anaesthetized mg/kg intraperitoneally). blood pressure was measured; for A+) pentobarbital. And that) Netherlands

Spectramed inserted into the left carotid artery; By means of a pressure transducer, Scannula, by way of 0, and after enlarging it with a magnifier. (Bilthoven, The Netherlands «Spectramed B.V.] DTX-plus

Amsterdam, The 1 Nihon Kohden B.V.¢ AP-621G (type Nihon Kohden Carrier “(Compaq Deskpro 386s) 25 PC blood pressure signal recording (Netherlands) and Storrs, USA (Po-Ne-Mah) By 20-40-2485 data recognition software (inc.) Elicited heart rate from the pulsed pressure signal. All compounds were administered via 10 min 0 min prior to anesthesia i.e. Yo before 1 methylcellulose Oral as a precise suspension in kg., and after equilibrium [da 01, which is 00-55,940. The injection volume was CB; administration of a receptor adjuvant to a receptor, 03 (+ mg / kg intravenously) and CP-55,940 was The hemodynamic was given to help create the effect but the pressure.

Y Y _— _ Wagner, J.

A.; Jarai, Z.; Batkai, S.; Kunos, G.

Hemodynamic effects of cannabinoids: coronary and cerebral vasodilation mediated by cannabinoid CB; receptors.Eur.J.

Pharmacol. 2001, 423, 203-10. Pharmacologically acceptable salts can be obtained using standard procedures well known in the field; For example, by mixing the compound of the present invention with a suitable acid »; For example, an inorganic acid, hydrochloric acid Jie; or with an organic acid. Dosage: The affinity of the compounds of the invention for cannabinoid receptors was determined as described above. and from the measured binding affinity for a given compound by formula (1); One can theoretically estimate the lowest effective dose. and at 0 the concentration of the compound is twice the measured value of 0.16; Up to 7000 cannabinoid receptors are likely to be occupied by the compound. Converting this concentration to mg of compound per kg of patient weight, J yields a theoretical effective dose assuming typical bioavailability. Other considerations may change Jie pharmacokinetics; pharmacodynamics; And other than the dose that is already given to a higher or lower value. The appropriately administered dose ranges from 5010 to 0001 mg/kg; It is preferred from 101 to 100 mg / kg of the patient's body weight.

Examples: Example No. (1): Synthesis of specific compounds: compounds from 1 to 4: 0 Part A: to a solution that was stirred from cal a (19.248 dchloroaniline 00177 mol) in lg + mL) and (Js ¥+) R= hydrochloric acid clay was added to a solution of NaNO ; ) 1 g; 1 mol) in water (1 (Ja) and the resulting solution was stirred for an hour at between zero and a, followed by the addition of (Je You) ethanol and “Je Y1.1) ethyl 2-chloro- 3-oxobutanoate (NY mol) to a cold mixture of 118086 YY) grams; 179 mol). After stirring the resulting mixture 0a for one hour, the precipitate formed was collected by filtration; and washed it with ethanol and dried it under vacuum to give YY.44) ethyl 2-chlorof(4-chlorophenyl)hydrazono]acetate grams; 7 _ output). The melting point is from 17.5 to 044.6 C. “H-NMR (200 MHz, CDCL): J 1.40 (t, J = 7 Hz, 3H), 4.39 (q, J = 7 Hz, 2H), 7.16 (br d, J = 8 Hz, 2H ), 7.30 (br d, J = 8 Hz, 2H), 8.31 (br s, 1H). acetate YY 40 g; AA ++ mol) 0011 styrene ml YE mol in benzene (Ja V £4) added 17 47 Jo VET triethylamine mol) and the resulting solution was heated at the reflux temperature for one hour.The resulting solution was cooled to room temperature

The precipitate formed was removed by filtration and washed with ©01006. The filtrate was concentrated under vacuum and purified by flash chromatography (silica gel, dichloromethane) to give: ethyl1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylate) 7. /? cal ya 4 product) in the form of syrup which slowly solidifies upon settling. H-NMR (200 MHz, CDCL): 7 1.38 (t, J = 7 Hz, 3H), 3.06 (dd, J = 18 and 7 Hz, 1H), 5 (dd, J = 18 and 13 Hz, 1H), 4.33 (q, J = 7 Hz, 2H), 5.38 (dd, J = 13 and 7 Hz, 1H), 3.73 (br d, J = 8 Hz, 2H), 7.08-7.40 ( m, 7H). 01 Ay" mol) in Saad (Ja Yoo ) methanol adding water (NaOH (Ja \o concentrate ) 0 ml) and the resulting solution was heated to the reflux temperature for 2 hours. The methanol was removed Partially by evaporation and the residue was dissolved in a water-ethyl acetate mixture. Ice was alternately added; Washing the resulting residue diethyl ether (Je 0011) 1 and diisopropyl ether on cai ill to give: yi. ) 1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H )-pyrazole-3-carboxylic acid gm; 797/8 yield.) Melting point: from 11717 to 179 C.

— mg Y — Part D: to a suspension stirred from: 0 5( 1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylic acid g; mmol) in anhydrous acetonitrile (£4) (Jo) to which N-diisopropylethylamine 11 “Ja (.4Y) (DIPEA) was successively added); f: O-benzotriazol-1-yl-N, N, N', N'-tetramethyluronium hexafluorophos-phate (HBTU) ° can ..(5.5 mmol) 5 «Ja v.08 ( 1- aminopiperidine 0.0 mmol) and the resulting mixture was reacted at room temperature for 11 hours under an atmosphere of 1:a1. The mixture was concentrated and added to a mixture of ethyl acetate and NaHCO; 0 aqueous, and the ethyl acetate layer was collected, dried over 24850, filtered, and concentrated under vacuum. The resulting residue was recrystallized 0 from acetonitrile to give: N-(piperidin-1-yl)-1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3 - carboxamide (compound 1); 01 E) grams 7976 product). Melting point: 189 to VAY (() / H—N 7 N= LO N cl compound 1 yyy

Y A — _— In a similar way, the compounds of formula (1) listed below were prepared: compounds 7; Fs and: compound ?: N-(Piperidin-1-yl)-5-(4- chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-(1H)- pyrazole-3-carboxamide ° Melting point: 185 to VAY m (( / H) —N cl 0 N== LO N 0 compound 2 cl Compound ?: N-(Piperidin-1-yl)-1-(2,4-dichlorophenyl )-5-phenyl-4,5-dihydro-(1H)-pyrazole-3- carboxamide 01 Melting point: 11 to 176 C. Yi

/ H—N cl 0 N=—= N cl compound 3 compound 4: N-Cyclohexyl)-1-(2,4-dichlorophenyl)-5-phenyl-4 ,5-dihydro-(1H)-pyrazole-3-carboxamide© Melting point: 101 to 17.5 °C. H—N cl 0 N=— N ci compound 4 compound 0 part a: A stirred suspension of 111101 can Y.TA (0 +++ mol) cooled in (J- YO) toluene to safram in an atmosphere of Ny and cay was added to a solution of Me;AL in toluene (Yo) Vo ml of molar Y solution) and left the mixture to reach a temperature room temperature. A solution of: ethyl 1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylate was slowly added.

) 14 g; 01 mmol) in (Jo YO) toluene and the reaction mixture was stirred at Av C for 1 hour. After cooling to Safram, methanol was slowly added and the precipitate formed was removed by filtration. The filtrate was concentrated and the residue dissolved in Jada of methanol 5 dichloromethane. The precipitate formed was removed by filtration. The leachate was concentrated and the remaining residue of dichloromethane 0 was crystallized to give: 0 v) 1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamidine (gm 7 product) . [J 3.08 (dd, 1218 and 7 Hz, 1H), 3.82 (dd, J = 18 and :01150-0 "H-NMR (200 MHz, Hz, 1H), 5.84 (dd, J) = 13 and 7 Hz, 1H), 7.15-7.46 (m, 9H), 8.85 (br s, 2H), 9.00 (br 13 s, 2H). 4-dichlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamidine HCl “H-NMR (200 MHz, DMSO-ds with addition of some trifluoroacetic acid): [J 3.32 ( dd, J and 7 Hz, 1H), 3.82 (dd, J = 18 and 13 Hz, 1H), 6.08 (dd, ] = 13 and 7 Hz, 1H), 18 = (m, 6H), 7.42 (d, J = 2 Hz, 1H), 7.52 (d, J] = 8 Hz, 1H), 8.95 (br s, 2H), 9.05 \o 7.13-7.31 (brs, 2H). Part B : to a solution stirred from : yyy

}.AY) 1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamidine. HCI g; © mmol) in +.qV) 4-fluorophenylsulfonyl chloride s g; © mmol) mmol) and 15 da YD) triethylamine was added (Je 01) 2 no acetonitrile h. After concentrating under vacuum, the resulting mixture was sucked out by VT by stirring at room temperature for a period and dried over ethyl acetate and water. The ethyl acetate layer was collected, the residue was dissolved in a mixture of 0, filtered and concentrated under vacuum. The resulting residue was recrystallized from MgSO, to give methyl-t-butyl ether

N-[(4-fluorophenyl)sulfonyl]-1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3- carboxamidine

A YY to 100 grams; 784 output). Melting point: from (.YY) 0

F

0=5=0 "\

NH,

N=—7

N

Cl compound 5: + In a similar way the compound was prepared

1. Compound +: N-[(4-fluorophenyl)sulfonyl]-1-(2,4-dichlorophenyl)-5-phenyl-4,5-dihydro-(1H)- pyrazole-3-carboxamidine Melting point: from 117 to 169.6 C. z 0=5=0 NH 0 cl 2 N== 7 N cl compound 6 o compounds from JY part A: to a solution stirred from: Vou ) 1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylic acid g; 0 mmol) in (Je ¥ +) toluene “Ja Y.4) (SOCL) thionyl chloride 0 Yo mmol) was added and the resulting mixture was heated at a Av for 1 hour. After fully concentrating under vacuum, the residue was dissolved in anhydrous acetonitrile (04) (Je) to give solution A. and into a stirred solution of 01 <p)a (0.57 mmol) 4-chlorophenylsulfonamide in o+) acetonitrile (Ja NaOH concentrate) ¥ Yo (a .mmol) added . To the resulting mixture solution A was slowly added. The resulting mixture was stirred at room temperature for 17 hours. And it sucks

Y \ —_ — add Hydrochloric acid (+0 ml of 1 N) slay (00 ml). The precipitate was collected by filtration; and wash it with water; Dissolving it in dichloromethane ¢, drying it over MgSO, filtering it, and concentrating it under vacuum. The remaining ethanol residue was recrystallized to give: N-[(4-chlorophenyl)sulfonyl]-1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3- carboxamide (°la £.Y0) 2974 _ yield). Melting point: from YY to 779 C. In a similar way, N-[(4-chlorophenyl)sulfonyl]-1-(2,4-dichlorophenyl)-5-phenyl-4,5-dihydro-(1H)- pyrazole-3-carboxamide was prepared. 0 (Melting point: 178 to S(a YAY N- {[4-(trifluoromethyl)phenyl]sulfonyl}-1-(2,4-dichlorophenyl)-5-phenyl-4,5- dihydro-(1H)-pyrazole-3-carboxamide (Melting point: 175 to 11777 um) Part B: Heated stirred mixture of: D-N-[(4-chlorophenyl) sulfonyl]-1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3- carboxamide

— b _ (7.77 g; © mmol); benzene chloro (Js— lle 0.0 aa 1.10) PCls )+© (Jo) for 90 minutes at 1636 a. After the mixture was cooled to room temperature, the residue was dissolved in dichloromethane and can + was added. ¥E) methylamine.

HC] © 04 mmol (DIPEA) ml 0 mmol) in succession. The resulting mixture was stirred for 16 hours at 0 rt; and washed it twice with water; dried over MgSO, filtered, and concentrated under vacuum. The remaining Lola was further purified by silica gel flash chromatography; acetone / dichloromethane = 1/49 (vol/v); followed by crystallization of diisopropyl ether to give: N-[(4-chlorophenyl)sulfonyl]-N'-methyl-1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)- pyrazole-3-carboxamidine 01 cal ya .77 (715 yield). Melting point: from 184 to 4540 °C (diethyl « silica gel) Ry ether = 4 ..). ci and whah NG / N H N= 7 N cl compound 7 In a similar way the compounds of formula (I) listed below were prepared:

— vy — 8: N-[(4-Chlorophenyl)sulfonyl]-N'-methyl-1-(2,4-dichlorophenyl)-5-phenyl-4,5-dihydro- (1H)- pyrazole-3-carboxamidine. (+. = diethyl ether « silica gel) Ry. to 7006 C 118 Melting point: from cl 0=8=0

N

\ 7 cl N

N==

N cl compound 8°14S yall

N- {[(4-Trifluoromethyl)phenyl]sulfonyl }-N’-methyl-1-(2,4-dichlorophenyl)-5-phenyl- 4,5-dihydro-(1H)-pyrazole-3-carboxamidine.

A(+-© = diethyl ether © silica gel) to 104 m. sold 157 Fusion: from dbs

CF, 0=5=0

N

\ 7 0 N

N=

N cl compound 9 a Yi

_— P7 — the two compounds, Ye and AR, part A into a solution and then stirred from; Yoo ) 1 -(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylic acid g; 0 mmol) in (Je ¥ +) toluene “Ja Y.1) (SOCL,) thionyl chloride 60 0 mmol) was added and the resulting mixture was heated at a A for 1 h . After full concentration under vacuum, the residue was dissolved in anhydrous acetonitrile (04) (Jo) to give solution B. and into an ice-cooled stirred solution of ¥.YA) piperidine-1-sulfonamide g; 01 mmol) in anhydrous .006 (04) (Ja) NaH (7760_dispersant; 14 g; 01 mmol) was added and the resulting mixture was stirred at room temperature for 1 hour. To the suspension The resulting solution was slowly added to solution B. The resulting mixture was stirred at room temperature for 11 hours and then concentrated under vacuum. Hydrochloric acid (1 N) dichloromethane s was added to the residue. The dichloromethane layer was collected, washed with water, dried over 04850, filtered, and concentrated under vacuum. The remaining ethanol residue was recrystallized to give: N-[(piperidin-1-yl)sulfonyl]-1-(4-chlorophenyl) -5-phenyl-4,5-dihydro-(1H)-pyrazole-3- \o carboxamide (ml 787 cal ja 7.74) Melting point: from 79.5 to 70.6 C. In a similar manner it was Preparation: yyy

— vo —

N-[(morpholin-4-yl)sulfonyl]-1-(2,4-dichlorophenyl)-5-phenyl-4,5-dihydro-(1H)- pyrazole-3-carboxamide Melting point: 171 to 1179 AD. Part B: A stirred mixture of: N-[(piperidin-1-yl)sulfonyl]-1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3- ° carboxamide (Y.YY) grams; © ms aa 01 0) PClss “(Je 0.0 mM benzene chloro (Js— ) +© (Ja) for 0 min at 060 C. After cooling the mixture to room temperature, followed by concentration under vacuum; The residue was dissolved in dichloromethane and methylamine HCl 1.74 (0 g © mmol) 5 0174 (DIPEA ml; Ale 0 1 mol) was added successively. The resulting mixture was stirred for 1 hour at dd yall temperature, washed twice with water, dried over MgSO, filtered and concentrated under vacuum.The resulting residue was further purified by silica gel (dichloromethane) followed by crystallization from diisopropyl ether to give: N -[(piperidin-1-yl)sulfonyl]-N'-methyl-1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)- pyrazole-3-carboxamidine Vo 0107 (grams 749 output). Melting point: from VE) to 44 diethyl “silica gel) Ry .p 0.7 = ether yyy

— y 45 — B 0=5=0 N \ /

N

H

N = 7

N cl compound 10 In a similar way, compounds of formula (1) listed below were prepared:

NY Compound N-[(Morpholin-4-yl)sulfonyl]-N'-methyl-1-(2,4-dichlorophenyl)-5-phenyl-4,5-dihydro- (1H)-pyrazole- 3-carboxamidine. ° = acetone / dichloromethane « silica gel) Ry a Yio to 111 Melting point: from

A No = (p> (vol/ 1/8 9 0=$=0

NG

0N

N—

N

Cl compound 11 Example No. (7): Formulas used in animal studies:

— vv —

For oral administration (.0.m): to the required amount (from 105 to ¾ mg) of the compound?

steel in a glass tube; Some glass pellets were added and the solid was ground

Spin for two minutes. And after adding 1 ml of a solution of methylcellulose 71 in water and IY

(volume/volume) of 188 ¢ (Lutrol F68) Poloxamer The compound was suspended by vortex for 10 minutes. The pH was adjusted to 1 with a few drops of 0.1 (le NaOH standard) 0 and the particles were suspended.

remaining in suspension using an ultrasonic bath.

To give Jala peritoneum (0.0): to the required amount (© to © mg) of the compound?

steel in a glass tube; Some glass pellets were added and the solid was ground

Spin for two minutes. and after adding 1 mL of a solution of 71 methylcellulose and 78 0 mannitol in water; The boat was suspended by vortex for 10 minutes. Finally the pH was set to 7.

Example No. (©): Results of Pharmacological Tests:

Cannabinoid receptor affinity data and in vitro functionalization obtained according to

The protocols given above are shown in the table below.

Table A, pharmacological data: human cannabinoid-like receptor - 09, in vitro antibody, compound number 1, inhibition at “01 molar” of compound 01

Claims (1)

Claims 1 1 - Compounds having the general formula (1): X 3 / R,—N Y R, (0 1) where they have: Rs Ry ¢ represent metals in the form Independent phenyl «¢ or thienyl ¢ or pyridyl groups may 0 can have a substitution of 1 or 7 or ? oF replacement groups which 1 can be the same or different; of the branched or linear group alkyl cis or alkoxy l' or phenyl “¢ or hydroxy” or bromo 0 “chloro” or 10010 or iodo “or trifluoromethyl A¢ or trifluoromethylthio ¢ or trifluoromethoxy ¢ or methylsulfonyl 1 “or carboxyl” or cyano 0 ¢ trifluoromethylsulfonyl ¢ or carbamoyl Ye “¢ or acetyl 5 sulfamoyl “¢ or representing R; and/ or naphtyl Rj « 11 represents one of the subsets (1) or (il) R 0 AL 7 Ry "Nn 7 Rs 0 N R Ae / > N— S—R, \Y 4 ka iy © 0 yy where it has: Rs V4 representing a hydrogen atom or a branched:© alkyl group or linear Yo; Jaci Ry 4 alkyl Cig group R alkyl - Ci — cycloalkyl - Cag branched or Yin = .4 - VY is linear; or alkoxy Cig dc sana + or mc - dc ye alkyl — Ci; — cycloalkyl YA or linear; or alkoxy Cys Ac sana ¢ or cycloalkyl Cs.” or 14+bicycloalkyl cities or 0m branched tricycloalkyl or (phd) and these groups can contain one or more heteroatoms of group 7 (0<) SN and 71 in these groups can have a substitution of a hydroxy ¢ group or 1 - ¥ methyl YY groups “ or ethyl ic sana or -1 ¥ fluoro atoms ; or Ry stands for a phenoxy group YY “any benzyl”, phenethyl or phenylpropyl ¢ has an optionally substituent Y ¢ on its phenyl ring with 1 - ¥ 57 substituent groups; where it has Yo is the Y of the aforementioned meaning; or Ry represents a pyridyl or thienyl group “or R, v1 represents a Cus NRsRg group with: Res Rs TV forming with an atom The nitrogen atom attached to it is a YA heterocyclic group; saturated or unsaturated; monocyclic or dicyclic having from 0 to 4 atoms per ring; this heterocyclic group contains one or more non-ve atoms A homolog of group )0 < (N 5) and this heterocyclic group 91 can have a substitution of a branched or linear group of ¢alkyl Cis or phenyl » or hydroxy 797 » or trifluoromethyl or an atom fluoro atoms ¢ or Rs vy and b form with the attached nitrogen atom de gana heterocyclic ve; saturated or unsaturated; Monocyclic or bicyclic: to 0 vo atoms in the ring; This heterocyclic group contains one or two v1 heterocyclic atoms from group (S (NO) and this heterocyclic group vv can have a substitution of a branched or linear group of alkyl Cia “or” phenyl hydroxy 4 ¢ amino TA “or trifluoromethyl § fluoro atoms sys atom “Ry v4” represents a benzyl group “or phenyl ¢ or pyridyl “thienyl” and these £ Groups can have a substitution on its aromatic ring of 1, 7, or 1 Jor ; 7 replacement sets; where YI is the above meaning; which 3 can be the same or different; or with a branched or linear alkyl Cig representation; R alkenyl Cag or cycloalkyl “or notation bicycloalkyl” or tricycloalkyl mon “or cycloalkenyl £¢ or Ry stands for naphtyl” or Ry has an amino group ¢ or Ja Ry “dialkylamino Cgie sana {o or a monoalkylamino ¢ group or £0 monocyclic, dicyclic, or heterocyclic group thereof is saturated or unsaturated of ; 37 to 10 cyclic atoms; This heterocyclic group contains an atom, EA, two nitrogen atoms, and this heterocyclic group £4 may contain one heterocyclic atom from group (0<8) and can be in this - heterocyclic group replaced with an alkyl group “or phenyl or hydroxy 511” or a branched or linear trifluoromethyl group or a fluoro atoms “Rg oY representing a hydrogen atom or a branched alkyl Cis group or linear oy; Re of is a hydrogen atom, an alkyl Cig subgroup, or a linear eo; or cycloalkyl Cag or alkyl Coup is heterocyclic and can have in these groups a substitution of a keto + group or a trifluoromethyl group “or a fluoro atoms ov” or a Ry representing an amino group “or hydroxy « or phenoxy » or benzyloxy oA » or Ro is a branched or linear alkoxy Cg group; which may substitute 04 with a hydroxy group “or a trifluoromethyl group with a fluoro atom Te + or Ry representing a phenyl group” or “benzyl” or “pyridyl ¢ or thienyl” or methyl pyridyl 11 or Cua ethyl phenyl aromatic rings may be replaced by the number 1 or ? TY or * oY substitution combinations where 7 has the above meaning; or yy > It represents a group, 118,8, provided that Rg represents a hydrogen atom, a hydrogen atom, or 1 methyl group, and where Rijs Rip are similar or different, and they represent Cia alkyl 10 between trifluoroalkyl or form Rigg Rpg - with a nitrogen atom laid atom TN in it - a heterocyclic moiety saturated or unsaturated with ; into 8 TY cyclic atoms and this heterocyclic moiety contains an atom or two of TA atoms group (0 (SN) and this heterocyclic moiety can be saturated or 14 unsaturated replaced by an alkyl group Ci or L Rg and together with the nitrogen atom attached to it form a heterocyclic WY moiety monocyclic or dicyclic; saturated or unsaturated with from to 01 VY atoms; this cyclic moiety contains The heterocyclic has a VY atom or two of the (0) S ON group, a keto group, or a -,50- group; the V¢ can have a hydroxy J ¢ alkyl group substituted in this moiety » or phenyl « or methylamino yo « dimethylamino » or azetidingl or pyrrolidinyl + or piperidinyl yA or hexahydro-1H-azepinyl and salts thereof. 1 " — compounds having the general formula (I) N— 0 - Y R, (0) t where by: Ry 3 Ry ¢ independently represent phenyl « and this phenyl group can be replaced by the number 1° or ? or ¥ oY substituent groups which can be the same or different” from the 1 branched group or linear bro alkyl or hydroxy s ¢ phenyl J “ alkoxy ¢ 7 , chloro ” or bromo ; or fluoro “or 050” or trifluoromethyl ¢ or trifluoromethylthio A ¢ or trifluoromethoxy ¢ or methylsulfonyl “or carboxyl” q or trifluoromethylsulfonyl ¢ or cyano ¢ or carbamoyl “or acetyl 3 sulfamoyl 01” or stands for R, and/or pyridyl ¢ thienyl § » naphtyl R, . X 11 represents one of the subsets (i) or (ii) VY 0 mai" mal OR, Asi R, ka (i) ii © 1" where it has: 1b represents a hydrogen atom “Ry Vo” is a branched or linear alkyl Cig group; or “alkoxy Cig” group or > a branched or linear cycloalkoxy group; it can be in these groups vy substituted with a hydroxy ¢ group or 1 - ¥ methyl groups ; or an ethyl group ; or \A — © fluoro atoms + or represent thienyl 5 « pyridyl J ¢ phenoxy ic sane Ry ¢ 4 or Ry represents the NRsRg group where it has .2 M8 and M form with the nitrogen atom attached to it a heterocyclic yy group; saturated or unsaturated; monocyclic or dicyclic with of ; to - ss — 0 YY atoms in the ring; This heterocyclic group contains one or two YY heterocyclic atoms from group (NO) 58); or Y¢ D15 5 Ry forms with its bonded nitrogen atom a Yo heterocyclic group; saturated or unsaturated; Monocyclic or bicyclic: to 11 0 atoms per ring; This heterocyclic group contains one or two Yv heterocyclic atoms from group (NO) 5) and this heterocyclic group YA can have a substitution of a trifluoromethyl group 4 «hydroxy J methyl or Yq 43 5 fluoro atoms « : 79 mg represents the phenyl group ¢ and this phenyl group on its aromatic ring © can be replaced by the number 1, -, oF, or ; 7 replacement sets; where 7 has the meaning YY shown above; which may be the same or different; Ry of m alkyl vy is branched or linear; of cycloalkyl range “i.e. bicycloalkyl Cs.qg ¢ or Ry representing naphtyl Ye + or b representing amino group” or R; representing “dialkylamino Ci. ic sane “Yo” or “monoalkylamino group C3” or a monocyclic, dicyclic or WY heterocyclic group is saturated or unsaturated thereof; to 10 cyclic atoms; This heterocyclic group vy contains one or two nitrogen atoms YA and this heterocyclic group may contain one heterocyclic atom of 4 group (0<) S and it can be in this cyclic group heterocyclic substitution of 2 by a B-alkyl group “ie 0-hydroxy” phenyl or trifluoromethyl branched or linear 1 or fluoro atoms; Ry A is a hydrogen atom or an alkyl Crs branched or linear £y group; yy -fo- Ry 23 represents a hydrogen atom or an alkyl Crs branched group or a M Ahad or a cycloalkyl min ; These groups may be replaced by a 0 trifluoromethyl group £1 or a fluoro atoms + or 8 representing an amino group “or an L-hydroxy group” meaning 0 phenoxy meaning 0 benzyloxy or 18 representing an M-alkoxy group 8 > branched or linear; Or Ry is a phenyl group where the aromatic ring may be substituted by 1 £4 or ? or ¥ oF substitution sets where y has the meaning given above; or Ry 8 represents group 1101, provided that Rg represents a hydrogen atom or 51 methyl group, and where 0 and ::8 are similar or different and represent Cry of alkyl oY between trifluoroalkyl or form Rigs Ryp = with the nitrogen atom Oise atom oY in it - a heterocyclic slit saturated or unsaturated with it; to + of cyclic atoms and this heterocyclic moiety contains one or more atoms from group oo (0< 27 5) or 85 M Ros - with the nitrogen atom attached to it - forms a heterocyclic monocyclic or dicyclic ov; saturated or unsaturated with it from; to 01 0A cyclic atoms; This heterocyclic moiety contains one or two xX atoms of group (0; (SN), keto group, or -R,50- group, and salts thereof. 1 ¥ - Pharmaceutical compositions including; In addition to a pharmaceutically acceptable carrier and/or at least one additional acceptable Y (Liana) contains a pharmaceutically effective amount of one compound and at least one of the protective ingredient compounds) ¥¢ or a salt terminated as the active substance. _— $4 — 1 ¢ - Compounds having the general formula ¢(X) and conjugated compounds and salts thereof: NH, NH N= R, (X) v where by Ry shall have the meanings given in claim No. (¢ od ag) Compounds useful in the synthesis of compounds of the general formula (1) 1 © - compounds of the general formula (XT) b 0-6- 0 NH Y 0 N= / R,—N R, (X1) Y wherein Ris Rs Ry has the meanings given in claim no. od a4 1 ¢ Compounds useful in the synthesis of compounds of general formula (1) (XT) Compounds having the general formula - 1 1 R; Oo= 5 =0 27 1 N— / R,—N R; (X11) where it has 1 and has the meanings given in the claim No. RyRy where it is and these compounds are useful in the synthesis of compounds of the general formula Br representing 7 atoms of © or ¢ (1) ° salt Of it; OY or Claim 1 Compound use as Claim No. - 1 for use in treatment. Y Y or Claim 1 Compound use as Claim No. A - 1 Cl) To prepare a pharmaceutical formulation for the treatment of disorders including Y ¢ anxiety, anxiety, psychosis such as cannabinoid neurotransmission 3, memory disorders, attention deficits, lack of concentration, depression, and cognitive disorders Disorders of knowledge “memory disorders” in obesity, especially obesity and obesity, ¢ appetite disorders 1 that occur due to drugs; Addiction” and obesity control disorders for boys and obesity P4 - A in impulse control disorders; appetite; drug dependence 9 and neurological disorders Jie neurodegenerative disorders 01; dementia ¢ and dystonia 8 ; muscle spasm 11 ¢ tremor tremor and epilepsy l; multiple sclerosis 11; traumatic brain injury; Stroke, Parkinson's disease, Alzheimer's epilepsy g pall 5 disease, Huntington's disease, Vo Tourette's syndrome, and cerebral anemia cerebral ischaemia “yi” and “cerebral hemorrhage”; Stroke Traumatic cranial stroke Dial La and spinal cord injury Viral encephalitis And inflammatory disorders (andl demyelinisation related disorders YA) In addition to the treatment of pain disorders All La » treatment of pain disorders includes pain disorders treatment of pain 01 65 neuropathic pain disorders; and other disorders 71 involving cannabinoid neurotransmission al; including YY including treatment of septic shock ¢ and glaucoma « 7 cancer, diabetes mellitus, emesis, nausea, asthma, respiratory disorders, respiratory diseases, gastrointestinal disorders, and ulcers. Infectious gastric ulcers « 7 and diarrhea diarrhoea ¢ and cardiovascular disorders Cardiovascular «lal and joint sclerosis atherosclerosis ¢ and liver cirrhosis «and disorders YA sexual disorders. PP cannabinoid ca) neurotransmitter similar to JEN method for the treatment of disorders including 4 1 - depression + anxiety; and anxiety psychosis like psychosis CB; neurotransmission memory; memory disorders, attention deficits, lack of concentration, depression 7, appetite disorders, cognitive disorders, and knowledge disorders; addiction, impulse control disorders, obesity, appetite disorders, drug dependence, and neurological disorders such as impulse control disorders 1, muscle spasm and muscle spasm, dystonia; dementia for multiple dementia; multiple sclerosis, epilepsy, tremor, tremor, stroke, traumatic brain injury, sclerosis q; epilepsy, Alzheimer's disease; Alzheimer's disease, Parkinson's disease, Tourette's, Tourette's disease, Huntington's disease, epilepsy (bleeding), stroke, stroke, cerebral ischaemia, and cerebral ischemia (VY syndrome) Traumatic craniocerebral palsy; In addition to treating brain stroke disorders; stroke Y; nerve pathogen; Other disorders that treat pain disorders like La ¢ cannabinoid neurotransmission JEN include yo “nausea” and emesis; vomiting cancer; cancer, glaucoma and respiratory diseases; respiratory disorders asthma gl VV gastric ulcers gastrointestinal disorders YA cardiovascular disorders cardiovascular disorders s diarrhoea 14 and disorders s liver cirrhosis; And atherosclerosis, and joint sclerosis Ye. sexual disorders (Y) (I) Characterized by the use of a compound of formula YY Les X N=— / R,—N YY R, (1) Y¢ where Ry Ry Yo stand for independently phenyl or thienyl or 71 which are groups of b that can have a substitution by 1 or 1 or ? oY substitution groups which can be the same or different from the subset or linear: © alkyl or alkoxy YA, phenyl, hydroxy, chloro, bromo, fluoro, 1000 0 0 trifluoromethyl v4, trifluoromethylthio, or trifluoromethoxy or methylsulfonyl 0 “or carboxyl “¢ or trifluoromethylsulfonyl ¢ or cyano ¢ 0 carbamoyl vy ” or acetyl 3 sulfamoyl “¢ or representing R; and/or naphtyl R; « X vy represents one of the subsets (i) or (n): 0 /Rs Roe o if N I .~ \ R, ry all oued Rs for iy © ) 0 yg where it has: vo, 8 Jud hydrogen atom or 0:2 branched alkyl group or linear py; Ry py is alkyl Cig 4c seme R alkyl - Ci — cycloalkyl - Cas branched or YA linear; or alkoxy group Cig ¢ or min — cycloalkyl — yin — branched alkyl vq or linear; Or alkoxy cig ic sana » 3 of cycloalkyl » + any range of bicycloalkyl 1e - 6 or they are dc jie tricycloalkyl or linear; These groups (Sa) can contain Baal 1 or more heteroatoms from group (0; (S ON) and £Y in these groups can be substituted by a hydroxy group; or 1 - ¥ methyl groups ” or 1 ethyl group or 1 - ¥ fluoro atoms ; or Ry represents a phenoxy group ” or 1 β or phenethyl or phenylpropyl ¢ has an optional substitution on a ring phenyl to has the number 1 - ?57 substituent groups, wherein 7 has the aforementioned meaning 7; or Ry represents a pyridyl or thienyl ¢ group or Ry represents a Cus group NRsR £v having: Re 9 Rs ¢A forming with its bonded nitrogen atom £9 heterocyclic group; saturated or unsaturated; monocyclic or dicyclic having from 0 to 84 atoms per ring This heterocyclic group contains one or two (© heterocyclic) atoms of group (0) (N 8) and this heterocyclic group oY can have a substitution of a branched or linear group of alkyl Cry » that is “phenyl or hydroxy oY” or trifluoromethyl or “fluoro atoms” or “Rs of” form with the attached nitrogen atom a 00 heterocyclic group; saturated or unsaturated; Monocyclic or bicyclic: to 0 8 atoms per ring; This heterocyclic group contains one or two heterocyclic OV atoms from group (0; (SN) and this heterocyclic group 0A can have Jagd with a branched or linear group of calkyl Cry or 0 dim ; or hydroxy 04 « or trifluoromethyl or fluoro atoms « Ry 1. It represents the pyridyl group « thienyl § » phenyl § ¢ benzyl and these TY groups can have a substitution on their aromatic ring by 1 or ?; or 8 or + ; oF substitution combinations where 7 has the indicated meaning dled which can be yyy to - 47 be the same or different; or Ry is a branched or linear alkyl m; or mon alkenyl 0” + i.e. sl ¢ cycloalkyl cap range bicycloalkyl ¢ 5 and m tricycloalkyl “or + min cycloalkenyl or Ry representing naphtyl” or Ry representing a group amino; or R; to 10 cyclic atoms; This heterocyclic group contains 18 or two nitrogen atoms, and this heterocyclic Ala group may contain one heterocyclic atom from group (0; (S) and it can be in VY) of this group Heterocyclic substitution of a bar© alkyl group » or phenyl » or hydroxy YY » or trifluoromethyl branched or linear or fluoro atoms M0 for Rg representing a hydrogen atom or group . ..© a branched alkyl or linear VE Ry vo represents a hydrogen atom or a branched alkyl group ©. These \A% groups replace with a keto group ; or with a trifluoromethyl group » or a fluoro atoms YA ; or with an Rg representing a phenoxy group “ hydroxy ¢ amino » , benzyloxy v4 ¢ , or . Ry represents a branched or linear © alkoxy group; which may substitute Ae with a hydroxy group » or trifluoromethyl dc gana or a fluoro atoms ¢ AY or Ry representing a thienyl group § » pyridyl J ¢ benzyl § ¢ phenyl “ie pyridyl Gus ethyl phenyl J methyl 6” aromatic rings may be replaced by 1 or ? or 0 AY substitution sets oY where 7 has the meaning shown above; Or Ry At represents a group::118.05, provided that Rg represents a hydrogen atom or Ao a methyl group, and where Rips Rip are similar or different and represent Cra oy — - alkyl AT er trifluoroalkyl trifluoroalkyl or form Rig Ryp = with the nitrogen atom AY “dah_ associated with it - a heterocyclic moiety saturated or unsaturated with it of ; to 8 AA cyclic atoms and this heterocyclic moiety contains one or two atoms of 4 . Group (0) SN This saturated or 4 unsaturated heterocyclic moiety can be replaced by a Cp group and Lah; or Rg 49 and with — together with the nitrogen atom attached to it — form a monomeric heterocyclic 97 cyclic or dicyclic; saturated or unsaturated edo to 01 cd 3 AY cyclic; this heterocyclic moiety contains one or more atoms of the 4- (0<) S (N) group or keto group or group - =S0; and qo can replace this moiety with an alkyl group Crp; or hydroxy » or phenyl » or methylamino » or ¢azetidingl 4 + dimethylamino 5 or pyrrolidinyl Or piperidinyl or hexahydro-1H-azepinyl Vv and salts thereof. juvenile sal obesity and drug-induced obesity. In particular, obesity, childhood obesity, and drug-related obesity; Characterized ; - That the aforementioned pharmaceutical composition contains Lad, at least one lipase inhibitor. _ 4m VY 1 - Use as stated in claim No. VY. It is distinguished that the aforementioned lipase inhibitor! is orlistat or lipstatin.